History of Pharma PHD

BRITISHPHARMACEUTICALINDUSTRY, SYNTHETICDRUGMANUFACTUREANDTHE CLINICALTESTINGOFNOVELDRUGS 18951939.
AthesissubmittedtotheUniversityofManchesterfor thedegreeofDoctorofPhilosophyintheFacultyof LifeSciences,2005.
KeithJohnWilliams CentrefortheHistoryofScience,Technologyand Medicine.
Listofcontents,abbreviationsanddeclarations
LISTOFCONTENTS TABLEOFABBREVIATIONS ABSTRACT DECLARATIONANDCOPYRIGHTSTATEMENT ACKNOWLEDGEMENTS CHAPTERONE:GeneralIntroduction,AimsandScopeofthisThesis. 1.1 1.2 1.3 1.4 BackgroundtotheThesis. GeneralIntroductionandHistoriography. ClinicalTestingofNovelDrugs. SourcesandThesisOutline. 12 14 26 34 8 9 10 11
CHAPTERTWO:TheOriginsofthePharmaceuticalIndustry. 2.1 TheGrowthofthePharmaceuticalIndustryintheNineteenth Century. 2.2 2.3 2.4 EvolutionfromSmallPharmacyFirmsinAmerica. GermanyandtheSyntheticModelfromthe1860s. Ehrlich:Collaboration,StructureactivityTests,Biological Standardisation,andClinicalTrials. 2.5 TheScopeofChemicalResearchinGermanPharmaceutical Firms. 2.6 FailureofBritainandOtherCountriestoDevelopSynthetic Drugs. 2.7 2.7.1 2.7.2 FactorsInhibitingtheDevelopmentofBritishFirms. Introduction. TheLackofPracticallyTrainedBritishChemistsandChemical Engineers. 67 69 63 60 43 48 55 40
Listofcontents,abbreviationsanddeclarations 2.7.3 2.7.4 2.8 PatentProtection. AlcoholSuppliesandDuty. TheExtentofRelianceonGermanyforPharmaceuticalsand EspeciallySynthetics. 2.9 ConcludingRemarks. 78 73 74 75
CHAPTERTHREE:BurroughsWellcome:BritishOriginsof CollaborativeResearch. 3.1 3.2 3.3 Introduction. TheEstablishmentofBurroughsWellcome(1880). ChemicalLaboratoriesforResearchandChemicalWorksfor Manufacturing. 3.4 3.5 TheWellcomePhysiologicalResearchLaboratoriesupto1901. InteractionsBetweentheBurroughsWellcomeLaboratoriesand Worksafter1901. 3.6 Conclusions:TheImpactoftheLaboratories. 130 109 114 79 81 99
CHAPTERFOUR:WarandtheEstablishmentofaBritishSynthetic DrugIndustry. 4.1 4.2 Introduction:TheRelianceonGermanDrugsandChemicals. GovernmentResponsestotheConditionsofWarandDrug Shortages. 4.3 WhichDrugswereRequiredandCouldtheybeManufacturedin Britain? 4.4 4.5 CallsforFurtherGovernmentIntervention. BritishProductionofSalvarsanMedicalResearchCommittee (MRC)TestingofQuality. 4.6 4.7 TheMRCandtheFirstSalvarsanCommittee. TechnologyTransferfromBurroughsWellcometoBootsand May&Baker. 4.8 ProductionofFurtherSyntheticDrugsandAlkaloidsinBritain. 175 163 167 150 157 144 137 141
Listofcontents,abbreviationsanddeclarations 4.9 TheTrainingofChemistsandtheCoordinationofthe PharmaceuticalIndustry. 4.9.1 EstablishmentoftheAssociationofBritishChemical Manufacturers(ABCM). 4.9.2 TheDepartmentofScientificandIndustrialResearchandthe TrainingofChemists. 4.10 4.11 TheMRCProposeClinicalTesting. TheSecondSalvarsanCommittee. 189 194 190 179 179
4.12
Conclusions.
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CHAPTERFIVE:PostWarProblems,PatriotismandProtectionism: IndustryledCampaignsandtheRiseofFrancisCarr. 5.1 5.2 Introduction. PostWarCampaignsfortheProtectionofthePharmaceutical Industry. 5.3 5.4 5.5 5.5.1 5.5.2 5.5.3 5.5.4 5.5.5 5.5.6 5.6 TheABCMMissiontoGermanManufacturingSites. TheSankeyJudgementanditsConsequences. BritishPharmaceuticalFirmsPostWar. May&Baker. Boots. Howards. Glaxo. Allen&Hanburys. BritishDrugHouses. ProtectingtheBritishPublic:TheMRCandtheNational InstituteofMedicalResearch(NIMR) Biological StandardisationandGovernmentLegislationofDrugs. 5.7 ChemicalWorkersinBritain:FrancisCarrandChemical 245 210 213 219 220 221 223 223 225 227 229 207 208
Listofcontents,abbreviationsanddeclarations Engineering. 5.8 5.9 PostWarGermanyandOtherForeignCompetition. Conclusions. 249 254
CHAPTERSIX:TheCampaignforClinicalTrials. 6.1 6.2 6.3 Introduction. TheMRCandClinicalResearchCentres. TheABCMApproachtotheMRCforaClinicalTestingScheme in1922. 6.4 6.5 6.6 Insulin:anMRCPreoccupationandaProductionChallenge. FrancisCarrandhisGrowingInfluence. MRCExtendedRoleinClinicalTrials:IndividualMRC Subcommittees. 6.7 LobbyingforClinicalTrials:TheABCMandtheChemotherapy Committee. 6.8 CollaborationwiththeDSIR Establishmentofthe ChemotherapyCommittee. 6.9 FurtherMRCTrials:Synthalin,PneumococcalSerumandLiver Therapy. 6.10 TheThirdCampaignoftheABCMforClinicalTrials,1927 1931. 6.11 6.11 FormationoftheTherapeuticTrialsCommitteein1931. Conclusions. 308 310 304 300 297 295 277 286 291 258 259 271
CHAPTERSEVEN:BurroughsWellcomeStrategyintheInterwar Period. 7.1 7.2 7.3 7.4 Introduction. StaffChangesandFacilities. TheScientificandTechnicalCommittee. BurroughsWellcomeandVitamins:IndecisionandDecisions. 312 312 316 327
Listofcontents,abbreviationsanddeclarations 7.5 7.6 7.7 ClinicalTrialsArrangedbyBurroughsWellcome. TropicalDiseaseaCaseStudyfromLaboratorytoClinic. Conclusions. 332 334 343
CHAPTEREIGHT:TheTherapeuticTrialsCommitteeoftheMRC. 8.1 8.2 8.3 8.4 Introduction. TheTherapeuticTrialsCommittee19311939. Clinical TrialsEstablishedbytheTherapeuticTrialsCommittee. CollaborationinOrganotherapyandVitaminsLeadsto IncreasedCapacity. 8.4.1 8.4.2 8.4.3 8.4.4 8.4.5 8.5 8.6 Oestrin. SuprarenalCorticalExtract(Cortin). ProgestationalAgents. PerniciousAnaemia. Vitamins. Prontosil:aNewEraofChemotherapy. ClinicalTrialsofOtherAntisyphiliticsIncreasedSynthetic Activity. 8.7 NovelCompoundsPutForwardforTestingbyBritishFirms 19311939. 8.7.1 8.7.2 8.7.3 8.7.4 8.7.5 8.7.6 8.7.7 BootsPureDrugCompany. May&Baker. BurroughsWellcome. Glaxo. BritishDrugHouses. Allen&Hanburys. ImperialChemicalIndustriesandOtherBritishFirms. 379 382 385 394 397 399 400 379 358 362 364 366 367 368 377 345 350 355 356
Listofcontents,abbreviationsanddeclarations 8.7.8 8.8 ForeignFirms. MRCStudiesofAntisera:LargeCooperativeTrialsand Statistics. 8.9 ConclusionsRegardingtheTherapeuticTrialsCommittee. 412 421 403 408
CHAPTERNINE Conclusions. BIBLIOGRAPHY
440 484.
Listofcontents,abbreviationsanddeclarations ABBREVIATIONS A&H ABCM AGFA BASF BDH BIPM BMA BP CIBA DSIR FRS ICRF ICI IG(Farben) LSHTM M&B MRC Allen&Hanburys AssociationofBritishChemicalManufacturers AktiengesellschaftfrAnilinfabrikation,(Berlin) BadischeAnilinundSodaFabrik BritishDrugHouses BritishInstituteofPreventativeMedicine(laterListerInstitute) BritishMedicalAssociation BritishPharmacopoeia GesellschaftfrChemischeIndustrieBasel DepartmentofScientificandIndustrialResearch FellowoftheRoyalSociety ImperialCancerResearchFund ImperialChemicalIndustries Interessengemeinschaft(orcommunityofinterests) LondonSchoolofHygieneandTropicalMedicine MayandBaker MedicalResearchCommittee19131920 MedicalResearchCouncil 1920onwards NHI NIMR PRO RAMC SCI STC UCH WBSR WCRL WPRL NationalHealthInsurance NationalInstituteforMedicalResearch PublicRecordOffice RoyalArmyMedicalCorps. SocietyoftheChemicalIndustry ScientificandTechnicalCommittee UniversityCollegeHospital WellcomeBureauforScientificResearch WellcomeChemicalResearchLaboratory WellcomePhysiologicalResearchLaboratory
ABSTRACT BritishPharmaceuticalIndustry,SyntheticDrugManufactureandthe ClinicalTestingofNovelDrugs18951939.

ThisthesisaddresseshowandwhenBritishpharmaceuticalfirmsfirst manufacturedsyntheticdrugs,andhowtheypersuadeddoctorstotestnoveltherapiesin clinicaltrials.EdwardianBritainwasreliantonGermanyforsyntheticdrugs,sohowdid BritishfirmsmeetthischallengeintheFirstWorldWar,andhowwasthisnewformof theBritishpharmaceuticalindustrynurturedintheinterwarperiod? Previousstudieshavecoveredtheindustrysoriginsinpharmacyrootsand dyestuffs,andthegrowthoftheAmericanindustry,butwithoutanoverallsynthesis. ThereareseveralgoodcompanyhistoriesforBritain,andRobsonandQuirkecompared pharmaceuticalsinFranceandBritain,whilstTanseyexaminedphysiologicalresearchat BurroughsWellcomebutlittlehasappearedonchemicalresearchandsynthetic manufacture.IwillemphasisetheworkofFrancisCarrwhodevelopedsyntheticdrugsat BurroughsWellcome,BootsandBritishDrugHouses.Asfortesting,theliteraturecovers earlystatisticsandtheclinicaltrialsofmajorbiologicaldrugssuchasinsulinbutthese didnotoriginatewithindustry.Withsyntheticandothernoveldrugs,asIshow,firms founditdifficulttoarrangeclinicaltrialsandtheyturnedtotheMRCforassistance.I examinethesenegotiationsandtrialsinsomedetail. Chapter1reviewsthehistoriographyofthepharmaceuticalindustryandthe clinicaltestingofdrugs.Chapter2examinesthevariedoriginsoftheindustry,contrasting ethicalandpatentmedicines,andcomparingBritainwithGermanyandAmerica.Chapter 3showshowBurroughsWellcomecombinednoveldrugsinsophisticateddosageforms, adoptingnewsalesstrategiesandestablishinglaboratoriestostandardisedrugs.Their experienceinsmallscalesynthesisfrom1896enabledthemtoprepareGermandrugs whenpatentswereabrogatedintheFirstWorldWar(chapter4).TheMRCandother firmspoachedBurroughsWellcomeresearchers,andtheMRCtookstandardisationasa centraltheme,soestablishinganinternationalreputation.Chapter5addressesthepost warcampaignsfortariffprotection,andtheextensionofMRCdrugevaluationsasBritish firmsstrovetoremaincompetitive.Novelvitaminandhormonaldrugsallowedthemto expandtheirmanufacturingcapacitywhilegainingfurtherexperienceofdrugsynthesis. Chapter6describeshowBritishfirmscampaignedforclinicaltestingofdrugsfrom1922 1930andexplainswhyaTherapeuticTrialsCommittee(TTC)wasestablishedin1931. Chapter7examinesthestrategyofBurroughsWellcomepostwar,byanalysingthe strategicdebateswithintheirScientificandTechnicalCommittee.Chapter8examinesthe TTC,howtheyfavouredBritishdrugs,andhowstudiescomplementedtheirownresearch interestsitprovidesinsightintotheresearchstrategiesofBritish(andforeign)firms,plus anassessmentoftheTTCasseenbytheMRCandbycompanies.Chapter9offersgeneral conclusionsandcontraststhepositionofBritishmanufacturersattheoutbreakofthe SecondWorldWarwiththeirpositionattheoutbreakoftheGreatWarinAugust1914. Someopportunitiesforfurtherworkarethenidentified.
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DECLARATION
Noportionoftheworkreferredtointhisthesishasbeensubmittedinsupportofan applicationforanotherdegreeorqualificationofthisoranyotherUniversityorother Instituteoflearning.
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Copyrightinthetextofthethesis/dissertationrestswiththeauthor.Copies(byany process)eitherinfull,orofextracts,maybemadeonlyinaccordancewithinstructions givenbytheAuthorandlodgedintheJohnRylandsUniversityLibraryofManchester. DetailsmaybeobtainedfromtheLibrarian.Thispagemustformpartofanysuchcopies made.Furthercopies(byany process)ofcopiesmadeinaccordancewithsuch instructionsmaynotbemadewithoutthepermission(inwriting)oftheAuthor.
Theownershipofanyintellectualpropertyrightswhichmaybedescribedinthis thesis/dissertationisvestedintheUniversityofManchester,subjecttoanyprior agreementtothecontrary,andmaynotbemadeavailableforusebythirdpartieswithout thepermissionoftheUniversity,whichwillprescribethetermsandconditionsofany sucharrangement.
Furtherinformationontheconditionsunderwhichdisclosuresandexploitationmaytake placeisavailablefromtheHeadoftheCentrefortheHistoryofScience,Technologyand Medicine.
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ACKNOWLEDGMENTS
OvertheseveralyearsithastakentowritethisthesisIhavemanyindividualstothank. FirstlyIwouldliketothankmyoriginalandfinalsupervisorJohnPickstoneatthe ManchesterWellcomeUnitfortheHistoryofMedicinewhohassolidlysupportedme. Severalotherslookedaftermeatvarioustimes.InparticularIwishtoextendthanksto SteveSturdy,whomovedtoEdinburghpartwaythroughandbeforehimGeoffrey Tweedalewhogavemeinitialguidance.AtvariouscongressesandmeetingsIhave receivedencouragementfromJudySlinn,andDesireCoxMaximov. Morerecently VivianneQuirkecommentedonsomeofmyearlydraftchapters.Ioweagreatdealto JohnDavies,whowasthearchivistattheWellcomeInstitute,inLondonandtoMrs. MaryNicholas,attheMRC.Archives,beforetheirmovetothePRO. ThanksalsotoJulieSheppard,archivistandherassistantLesleyHallatthe ContemporaryarchivecentreandarchivistsattheRoyalSocietyandtheImperialInstitute andJ.M.LevertonintheresearchlibraryatBootsPharmaceuticalsandtoMrs.Barbara RobertswhokindlyforwardedtwobooksatonetimeownedbyThomasHenryof BurroughsWellcome. IalsoreceivedsupportfromthelibrariansattheRoyalSocietyandatAstraZeneca, thoughwhenIstarteditwasImperialChemicalIndustriesLtd.ThanksalsotoMichael PayneandJanetteMackinatTheBritishLibrary,BostonSpa,Wetherbyforhelpingto trackdownsomerelatedtheses.Finallyspecialthankstomyparentswhohavesupported methroughthisprolongedexperienceandtoLorraine,Jane,ClaireandNeilespecially.
ChapterOne:GeneralIntroduction.TheAimsandScopeofthisThesis
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CHAPTERONE:GeneralIntroduction,AimsandScopeofthisThesis.
1.1BackgroundtotheThesis. Thecentralquestionsofthisthesisare: HowdidBritishpharmaceuticalcompaniesfirstpreparenovelsyntheticdrugs,andhow didtheygetdoctorstotesttheseandtheirothernoveldrugsinclinicaltrials? Thequestionarosebecausethemodernpharmaceuticalindustryisbasedlargelyon novelsyntheticdrugs.DuringtheFirstWorldWartheimportanceofaBritish pharmaceuticalindustrybecamerecognisedandBritishfirmsswitchedfrompreparing drugsattherequestofphysicians,toofferingcompletelynovelagentsthatweretobe testedforthefirsttimeinman.ManyofthesehadpreviouslycomefromGermany.Notall weresynthetic,buttheywereuniqueintheirpotency.Thewiderquestionsthatemerged concernhowBritaincompetedwithGermanyintheinterwarperiod,andhowBritishfirms definedtheirstrategiesofdrugdevelopment,todecidewhethertocommittoproducing syntheticdrugsasopposedtoplantandanimalextracts,inorganicdrugsandantisera,and whatinternalandexternalfactorswereconsideredinmakingthesedecisions?Wasit necessaryforBritishfirmstofollowaGermanmodelorindeedanAmericanmodelofdrug research? Thethesisisthereforebroaderinscopethanoriginallyplannedanddemonstrates howcloseinterrelationshipswereforgedinBritainbetweenindustry,academia, governmentandmedicalresearch,particularlyfortheperiod19141939.Itevaluates significantstructuralchangeswithintheframeworkoftheBritishPharmaceuticalindustry, fromsmallfamilyownedfirmsoperatingindependently,tolargerbusinessesthat recognisedtheirinterdependenceandthevaluesofcollaborationandnegotiationthrough a representativetradebody. WhentheFirstWorldWarwasdeclared,BritainwasdependentonGermanyfor
1 syntheticdrugs,aswellasmanyalkaloidsandchemicalintermediates. HowdidBritish
pharmaceuticalfirmssynthesisecomplexessentialdrugswithinweeksoftheoutbreakof
W.Ormandy,BritainandGermanyinRelationtotheChemicalTradeinW.M. Gardner,TheBritishCoalTarIndustry,ItsOrigin,DevelopmentandDecline(London: Williams&Norgate,1915):335350.
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war?Whatweretheprecedentsonwhichtheybuilt?Havingpreparedthesedrugsona manufacturingscaleintheabsenceofGermancompetitionundertheemergency conditionsofwar,howdidBritishfirmscompetewithGermanypostwar? IexaminehowtheBritishcompaniesusedtherecognitionoftheirachievementsin theGreatWartonegotiateabetterdealintheinterwarperiod,whentheywereoffered variousformsofprotectioninadditiontotariffs,includingnewmethodsfortestingthe purityandstandardisationofdrugs,andthenasystemofclinicaltrialswhichseemedto favourthetestingofBritishdrugs.ItisimportanttorecognisethatBritishfirmsthemselves requestedtheseoperationalframeworksandtheywerenotimposed. TheultimatemeasureofthesuccessofBritishfirmsshouldnotrelatesimplytothe successofindividualproducts.Thistypeofappraisalhaspreviouslyledtotheconclusion thatBritishfirmsachievedlittleofconsequenceintermsofnovel discoveries.Rather,I prefertocomparehowindependentofGermany,Britainhadbecomebytheoutbreakofthe SecondWorldWar.IntakingthisapproachIidentifyaseriesoffactorsthatcontributedto thissuccess,includingthelargescalemanufactureofnoveltherapiesotherthansynthetics, andinparticularorganotherapies(hormones)andvitamins.Thecommonthemewasthat continuedinvestmentwasimportantandawiderangeofproductscontributedtoan increaseinmanufacturingcapacity.Thisthen bringsrecognitionoftheimportanceof largescalemanufactureandchemicalengineering.Athemethroughoutthewholethesisis theprominentroleofindividualsoriginatingfromBurroughsWellcomeandIgive particularprominencetoFrancisHowardCarr.FollowinghistrainingattheImperial InstituteandPharmaceuticalSociety,Carrwasresponsibleforthedailyrunningofthe ChemicalWorksreportingtoHooperA.D.JowettatBurroughsWellcomefor16years, andthenestablishedsyntheticdrugmanufactureatbothBootsandBritishDrugHouses. HealsoplayedaprominentroleintheestablishmentoftheAssociationofBritishChemical Manufacturersandtheircampaignsforprotectionandclinicaltrials,andfollowinghis successinlargescaleproduction ofinsulin,hetooktheinfluentialroleofPresidentofthe SocietyoftheChemicalIndustryandcampaignedforbettereducationofchemists,further protectionoftheBritishindustry,syntheticdrugmanufactureandagainforthe establishmentofclinicaltrials.Inasensehebecomesthecentralheroofthethesis,and yethiscareerhaspreviouslyreceivedlimitedattention.
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InthelatterchaptersIexamineaseriesoffactorsthatinfluencedhowBritishfirms gottheirnewdrugstested.Firstlythey collaboratedwiththeMRCandthePharmaceutical Societytodemonstratethatbiologicalcompoundswerestandardised,andthenthey negotiatedameansofclinicaltesting.Akeypointaboutthesechaptersisthattheyconsider thedrugsthatBritishindustrywasproducingandnotsuccessfulimporteddrugssuchas insulin.TheMRCbuiltupanetworkofresearchcentresthatbecametheircentresfor clinicaltrials,buttheycontrolledaccesstothephysicians,somuchsothatwhenBritish firmsdiddevelopimportantnovelcompounds,theybegantoemploytheirownphysicians inthe1930stomanagetheprocessofestablishingclinicaltrials.Acombinationoffactors thereforeledtothesuccessoftheBritishfirmsprotectionfromGermany,synthetic chemistswithmanufacturingexpertise,theestablishmentoflaboratories,theintroduction ofnovelorganotherapiesandvitaminsandphysiologysupport,andtheassociatedincreased manufacturingcapacity.Importantly,collaborationswerealsoestablishedwithuniversity chemistsandwiththeMRC,whichthenallowedtherapiddevelopmentofnovelvariantsof sulphonamidesfrom1936.TheBritishpharmaceuticalindustrywasakeypartnerindriving thisforward. 1.2GeneralIntroductionandHistoriography. AlthoughthereareseveralgeneralaccountsofAmericanandBritishpharmaceutical firms,therehasnotyetbeenageneralsynthesisofhowthemodernBritishpharmaceutical
2 industrydeveloped,andoftheexternalfactorsinvolved. Therehavebeenaccountsof
individualcompanieswithlongpedigreesinpharmacy,butnonefocusingonchemistryand
3 largescaledrugsynthesis. Thehistoriographyofdrugshasfocusedalmostexclusivelyon
J.T.Mahoney,TheMerchantsofLife:anAccountoftheAmericanPharmaceutical Industry (NewYork:Harper,1959)S.Miall,HistoryoftheBritishChemicalIndustry (London:ErnestBenn,1931)F.N.L.Poynter,TheEvolutionofPharmacy (London: Pitman,1965)C.J.Thomas,ThePharmaceuticalIndustryinDuncanBurn(ed.),The StructureofBritishIndustry volume2(Cambridge:CambridgeUniversityPress,1958): 33175.

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E.M.Tansey,Pills,ProfitsandPropriety:theEarlyPharmaceuticalIndustryin BritainMedicalHistory 25.3(1994):15157JonathanLiebenau,TheRiseoftheBritish PharmaceuticalIndustryBritishMedicalJournal (3October1990):72428 Goldonthe Green:50YearsofGlaxoatGreenford(London:Glaxo,1985)D.ChapmanHustonand E.C.Cripps,ThroughaCityArchway,theStoryofAllen&Hanburys17151954 (London:JohnMurray,1954)S.Chapman,JesseBootofBootstheChemist (London: Hodder&Stoughton,1974)BootsPureDrugCo.Ltd.(Nottingham:Boots,1938)R.P.
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majornaturaldrugssuchasinsulinandpenicillin,ratherthandrugsinventedbythe pharmaceuticalindustry.ThesehistoriesthereforegivenoinsightintohowBritish
4 companiesdevelopedproductsoftheirownresearch,orthestrategiestheyfollowed.
Thisintroductionoutlinesthepreviousworkdoneinthisfieldandidentifiessomeof thegaps.Chapter2developsthedetailsofhowthepharmaceuticalindustryevolved,sothe frameworkisdescribedonlybrieflyhere.Acommonthemeisthathistorianshavetriedto categorisetheBritishindustryassuccessfulornotbymeasuringhowitcomparedwith Germanyintermsofsyntheticdrugs,orwithAmericaintermsofexternalcollaborations, oftensimplifyingacomplexissuebythechoiceofunrepresentativecasestudies.Economic historianshavedescribedhowthegeneralgrowthof thepharmaceuticalindustrywas

5 achievedbydiscoveringnewdrugs,withoutgivinganinsightintohowthiswasachieved.
Insomecases,theymeasuredsuccessbysimplycountingthenumberofpatentsfiledor salesfigures,whichmaybeverymisleading,especiallyifthefirmhadinterestsotherthan justpharmaceuticals,asmanydid,oriftherewereaseriesofsimilarproducts,someof

6 whichnevermadeittomarket. Companypoliciesonpatentingcertainlyvariedgreatly.
T.DavenportHines,J.Slinn,Glaxo,AHistoryto1962 (Cambridge:Cambridge UniversityPress,1992)GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen &HanburysandtheBritishPharmaceuticalIndustry (London:JohnMurray,1990)Judy Slinn,AHistoryofMay&Baker18341984(Cambridge:Hobsons,1984).

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GladysHobby,Penicillin:MeetingtheChallenge(NewHaven:YaleUniversityPress, 1985)H.F.Dowling,FightingInfection:ConquestsoftheTwentiethCentury (Cambridge, Mass:HarvardUniversityPress,1977)R.Hare,TheBirthofPenicillin,andtheDisarming ofMicrobes (London:GeorgeAllen&Unwin,1978)R.Hare,NewLightontheHistory ofPenicillinMedicalHistory 26(1982)1.

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W.DuncanReekie,M.H.Weber,Profits,PoliticsandDrugs(London:MacMillan, 1975)MichaelH.Cooper,PricesandProfitsinthePharmaceuticalIndustry (Oxford: PergamonPress,1966)W.DuncanReekie,TheEconomicsofthePharmaceuticalIndustry (London:MacMillanPress,1975)BjornLundgren(ed.),PharmaceuticalEconomics (Stockholm:TheSwedishInstituteofHealthEconomics,1984)D.Schwartzman, InnovationinthePharmaceuticalIndustry (Baltimore:JohnsHopkins,1977)Sainsbury Report:CommitteeofEnquiryintotheRelationshipofthePharmaceuticalIndustrywith theN.H.S.19657(London:HMSO,Cmnd.3410,1967).
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J.Kemp,PharmaceuticalPatents:InBritain,India,Italy,JapanandtheUSinG. TeelingSmith(ed.),InnovationandtheBalanceofPayments:theExperienceinthe PharmaceuticalIndustry (London:OfficeofHealthEconomics,1967):23J.Liebenau,
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Thepoliticsandmarketingofdrugshavedominatedmorerecentinvestigations.The
7 OfficeofHealthEconomics hassupportedtheindustry,whilemanyauthorshavebeen 8 9 criticalofdrugsafety, pricing ,promotion,animaltesting,ormorerecently,policiesin 10 developingandmarketingdrugsfortheThirdWorld, oftenfrompreconceived
11 positions.
Haber,inhisotherwiseexhaustivediscussionofthechemicalindustriesin1971 concluded:Thereisnotenoughmaterialonthegrowthofproprietarymedicinesand, duringtheearlypartofthepresent(twentieth)century,ofthepharmaceuticalindustry.He wenton:Althoughitwouldencountergreatobstacles,astudyoftheearlyyearsofthe pharmaceuticalindustryintheprincipalcountrieswouldmakearewardingcontributionto

12 moderneconomichistory. InhisearliervolumeHaberhadstated:
Economichistorianshavefrequentlydescribedthedevelopmentof technologyinindustriesinwhichchangewassimpleandhaveneglectedthe
PatentsandtheChemicalIndustry:ToolsofBusinessStrategyinJ.Liebenau(ed.),The ChallengeofNewTechnology:InnovationinBritishBusiness(Aldershot:Gower,1988).
7
G.TeelingSmith,ThePharmaceuticalIndustryandSociety:AStudyoftheChanging EnvironmentandEconomicsoftheInternationalIndustry (London:OfficeofHealth Economics,1972).

8 9
A.Chetley,ProblemDrugs(London:AtlanticHighlands,N.J.ZedBooks,1995).
L.Marsa,PrescriptionforProfits:HowthePharmaceuticalIndustryBankrolledthe UnholyMarriagebetweenScienceandBusiness(NewYork:Scribner,1997).
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G.Gereffi,ThePharmaceuticalIndustryandDependencyintheThirdWorld (Princeton:PrincetonUniversityPress,1983)T.Heller,PoorHealth,RichProfits: MultinationalDrugCompaniesandtheThirdWorld(Nottingham:SpokesmanBooks, 1977)M.Silverman,M.Lydecker,P.R.Lee,BadMedicine:thePrescriptionDrug IndustryintheThirdWorld(Stanford:StanfordUniversityPress,1992).

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RichardHarris,TheRealVoice(NewYork:MacMillan,1964)C.Medawar, FailingsofthePharmaceuticalIndustryPharmaceuticalMedicine2(1987):259263 MiltonSilverman,PhilipR.Lee,Pills,ProfitsandPolitics(Berkeley:Universityof CaliforniaPress,1974)JamesS.Turner,TheChemicalFeast(NewYork:Grossman, 1970)BrianS.Inglis,Drugs,DoctorsandDisease(London:AndreDeutsch,1965)M. Silverman,TheDruggingoftheAmericas(Berkeley:UniversityofCaliforniaPress,1976) WyndhamDavies,ThePharmaceuticalIndustry:aMedical,EconomicandPoliticalSurvey oftheWorldwidePharmaceuticalIndustry (Oxford:PergamonPress,1967).

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L.F.Haber,TheChemicalIndustry19001930:InternationalGrowthand TechnologicalChange(Oxford:ClarendonPress,1971):7.
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morecomplexbutequallyimportantdevelopmentofchemical 13 manufacture. Thisquotecapturessomeofthereasonswhythepharmaceuticalindustryhasreceivedlittle attention,asthefactorsinvolvedarecomplexandmultifactorial,thesourcesarescattered, andgainingaccesstopharmaceuticalcompanyrecordsisproblematic,eveniftheyexist. Althoughsomeprogresshasbeenmadeinunderstandingthedevelopmentofthe pharmaceuticalindustry,Quirkewrotein2000that:historiesofthemajornational pharmaceuticalindustriesarerelativelyrare,especiallyincomparisonwiththechemical industry.Itisasectorthatisdifficulttoapprehend(sic)asawholebecauseofits

14 complexityduepartlytoitsvarietyoforigins.
Forthepurposeofthisintroduction,Ireferprimarilytothedozenmainauthorsthat haveprovidedmostofthebackground:manyothercontributionswillbereferredtointhe mainbodyofthetext.TheseareSwann,ParascandolaandLiebenaufortheAmerican industry,andLiebenau,RobsonandQuirkeforBritain,(andthelattertwoforFrance).For clinicaltrials,althoughLiebenausetoutsomeofthegroundwork,recentthesesbyDesire CoxMaksimovandHelenValierhavedevelopedthistheme,withsomereferencetoHarry MarksforAmerica,whileforcompanyhistoriesthemostexhaustivemodernhistoric accountshavebeenbyTweedale,DavenportHinesandSlinnregardingAllen&Hanburys, GlaxoandMay&Baker.ForBurroughsWellcometherehavebeennumerous contributions,themostimportantformebeingthatofTansey,whoexplainedthe backgroundtothedevelopmentofthePhysiologicalLaboratoriesandthelicensingofthe laboratory,allowingmetofocusprimarilyonthechemicaldevelopmentswithinthe
15 laboratoriesinwhichnewdrugswerecreatedtoreplacenaturalextracts. Otherhistories 16 havefocusedonHenryWellcomehimself.
13 14
L.F.Haber,(1958):ix.
VivianeQuirke,ExperimentsinCollaboration:TheChangingRelationshipBetween ScientistsandPharmaceuticalCompaniesinBritainandinFrance,19351965(University ofLondon:PhDthesis,1999).

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E.M.Tansey,TheWellcomePhysiologicalResearchLaboratories18941904:the HomeOffice,PharmaceuticalFirmsandResearchExperimentsMedicalHistory 33 (1989):141.

16
HelenTurner,HenryWellcome,theMan,hisCollectionandhisLegacy (London: Heinemann,1980).
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Nineteenthcenturypharmaceuticalmanufacturingexistedintwomainformsinallof themajorcountries.Ethicaldrugfirmsmanufacturedsciencebaseddrugsforphysicians, withemphasisonactiveprinciples,anddifferentiatedtheirproductsfromotherfirmsbased onthenoveltyoftheirtabletsorpills,theirstrength,thelevelofimpurities,theirbenefits andtolerance,andlaterpharmacologicalexperimentsandclinicalexperience. Patent medicineswereadvertiseddirectlytopatients,withfancifulnamesandextravagantclaims. Formanyyearsthetwosystemscoexistedbutthemedicalprofessionbecameincreasingly criticaloftheunsubstantiatedclaimsofpatentmedicines.TheBritishMedical AssociationsSecretremedycampaignsin190709highlightedtheunreliabilityofpatent medicines,andconcernsaboutadulteratedmedicinesinAmericaledtolegislativecontrols
17 onsecretremediesandonadvertisingofdrugs. LegislationinBritaincurbedonlythe
worstexcessesassociatedwithextravagantclaimstheheavyuseofalcohol,narcoticsor tonicsor,attheotherextreme,thefailuretoincorporateanyknownbeneficial substances. Anewformoflargescalepharmaceutical manufactureevolvedinGermanyinthe lasttwodecadesofthenineteenthcentury,basedonchemicalsynthesisfrombyproducts ofthedyestuffsindustry.Syntheticdrugsweredevelopedwithassistancefromexternal pharmacologists.Afurtherdevelopmentaround1891wasdiphtheriaantitoxinandGerman firmswerewellplacedtotakeadvantageofthisthroughtheirclosecollaborationwiththe universities.BytheendofthecenturymostGermanfirmshaddevelopedlaboratoriesfor assayingrawmaterials,forcheckingthepurityofsynthesisedproducts,butalsofor productresearch,andtestingtherelationshipofchemicalstructuretophysiological function. MuchoftheresearchonGermanfirmsfocusesontheevolutionofchemical
18 manufacturefromdyesandstatesupport. IntheEnglishliterature,anexcellentinsight
intothecollaborationofindustrywithPaulEhrlichandotheracademicscientistsisgivenin
17
J.B.Blake(ed.),SafeguardingthePublic:HistoricalAspectsofMedicinalDrug Control (Baltimore:JohnsHopkinsUniversityPress,1970):112122,144157.

18
T.Lenoir,RevolutionfromAbove:TheRoleoftheStateinCreatingtheGerman ResearchSystem,18101910TheAmericanEconomicReview(May1998):2227.
18
19
19 Bumlersaccount,towhichIreferextensivelyinChapter2. Beergivesanexcellent 20 accountof thedevelopmentoflaboratoriesinGermanfirms, whileFox,Haberand 21 Readerprovidebackgroundondyestuffsdevelopments.
ForAmerica,historianshaveconcentratedontheethicalmanufacturersthat characterisedtheirproductsscientifically,andontherelationshipbetweenindustryand academia.Liebenaucoveredtheperiodupto1914,showingthatAmericanfirmsflourished duringandaftertheAmericanCivilWarandwerenotedfortheirdevelopmentofnovel dosageforms,particularlytablets.HeshowedthatAmericanfirmsadoptedtheGerman laboratorymodellater,andalsoprepareddiphtheriaantitoxinin1895.Heshowedthat ParkeDavisemployedachemisttomeasureandstandardiseactiveprincipleswithinergot, andbothLillyandSearleemployedlaboratorystaffinthe1880s.SmithKline&French hadananalyticallaboratoryfrom1893andperformedassaysasearlyas1884.However, Liebenauassumesthattheselaboratoryworkerseventuallygotinvolvedin(unspecified)
22 productdevelopment. Howscientifictheselaboratorieswereisopentodebateas
SwannreportedthatEdwardKendallleftthelaboratoryatParkeDavisin1910becauseof
23 thelackofascholarlyatmosphereandbecausehewastreatedlikeafactoryworker.
Swannarguedthatthefoundationsfortheriseofindustrialpharmaceuticalresearchinthe interwarperiodwereprogressinnaturalsciences,aninstitutionalframework,which
19 20
E.Bumler,PaulEhrlich,ScientistforLife (NewYork:Holmes&Meier,1984).
J.J.Beer,TheOriginsoftheGermanChemicalIndustry (Urbana:Universityof IllinoisPress,1959)J.J.Beer,CoalTarDyeManufactureandtheOriginsoftheModern IndustrialResearchLaboratoryIsis49(1958)123131.

21
M.R.Fox,DyemakersofGreatBritain18561976:aHistoryofChemists, Companies,ProductsandChanges(Manchester:I.C.I.plc,1987)W.J.Reader,Imperial ChemicalIndustriesLtd.AHistory:TheForerunners18701926volume1(London: OxfordUniversityPress,1970)L.F.Haber,(1958)and(1971).

22
JonathanLiebenau,MedicalScienceandMedicalIndustry:TheFormationofthe AmericanPharmaceuticalIndustry (Basingstoke:MacMillan,1987):5,125Jonathan Liebenau,"MarketingHighTechnology:EducatingPhysicianstouseInnovative MedicinesinR.P.T.DavenportHines(ed.),History,BagmenandMarkets:Studiesin theHistoryofMarketingandBritishIndustry (Aldershot:Gower,1986):82101,183236.

23
JohnP.Swann,AcademicScientistsandthePharmaceuticalIndustry:Cooperative ResearchinTwentiethCenturyAmerica(Baltimore:JohnHopkinsPress,1988):34.
19
20
facilitateditsapplication,andthewillingnessofindustrialiststorecognisetheimportanceof scienceandofscientiststoworkwithindustrialfirms.
24 25 LikeLiebenau ,Swann concludedthatinBritainupto1920,researchdeveloped
fromassaysandlaboratorycontrols,assumingagainthatthoseperformingassaysin laboratorieslaterbeganperformingresearchfornewproducts.NeitherSwannnor Liebenaugaveanyevidenceforthis.Oneimmediateconclusionisthatamorecarefully wordeddefinitionisrequiredofwhatconstitutesresearchandtheremustbeaclear recognitionthatlaboratoriescomeindifferentforms.Alaboratoryworker,skilledin performingassaysdoesnotnecessarilyhavetheskillstosynthesiseanddevelopnewdrugs. Nordosmallstudiesinlaboratoriesequatetodevelopingasuccessfulmanufacturing procedureandtransferringthistechnologytothemanufacturingworks.

26 ParascandolaexaminedpharmaceuticaldevelopmentsinAmerica, withparticular 27 emphasisonpharmacologyandtheevolvingroleofstructureactivitystudies andshowed
theimportanceofcollaborationswithexternalpharmacologistsandpharmacistsin WisconsinandPhiladelphia.28
24
JonathanLiebenau,ScientificAmbitions:thePharmaceuticalIndustry,19001920 PharmacyinHistory 27.1(1985):311J.Liebenau,TheRiseoftheBritish PharmaceuticalIndustryBritishMedicalJournal (3October1990):72428.

25
JohnP.Swann,AcademicScientistsandthePharmaceuticalIndustry:Cooperative ResearchinTwentiethCenturyAmerica(Baltimore:JohnHopkinsPress,1988):34.
26
J.Parascandola,ThePharmaceuticalSciencesinAmerica,18521902J.Am.Pharm. Assoc.40.6(2000):73335J.Parascandola,DrugTherapyinColonialandRevolutionary AmericaAm.J.Hosp.Pharm.5.12(1976):6977.

27
J.Parascandola,IndustrialResearchComesofAge:theAmericanPharmaceutical Industry19201940PharmacyinHistory 27.1(1985):1221J.Parascandola,Structure ActivityRelationshipstheEarlyMiragePharm.Hist.13(1971):310:J.Parascandola, TheControversyoverStructureActivityRelationshipsintheEarlyTwentiethCentury Pharm.Hist.16(1974):5463.

28
J.Parascandola,TheFoundingoftheUniversityofWisconsinSchoolofPharmacy Pharm.Hist.38.2(1996):5161J.Parascandola,J.Swann,DevelopingPharmacologyin AmericanSchoolsofPharmacyPharm.Hist.25.3(1983):95115J.Parascandola,John J.AbelandtheEarlyDevelopmentofPharmacologyattheJohnsHopkinsUniversityBull. Hist.Med.56.4(1982):51227.
20
21
29 ForEngland,Tansey gavethebackgroundtothedevelopmentoflaboratoriesat
BurroughsWellcomeandtheproblemsofovercomingtheantivivisectionistmovementin Britain.EvenaftertheformationoflaboratoriesinBritain,andespeciallyafterthe DangerousDrugsActof1923,whenpharmacistshadtobeincharge,QuirkesawBritish andFrenchlaboratories,asdemandpulledratherthanresearchpushed,andthis

30 conclusioniseasytounderstand.However,asTweedalepointedout ,firmssuchasAllen
&HanburysdidnotseethemselvescompetingdirectlywithGermanfirms,evenafterthey
31 developedlaboratoriesandthisisapointthatIwilldevelop.Quirke emphasisedthe
importanceofmajormergerstoformImperialChemicalIndustries(ICI)andRhne Poulencin1926and1938respectively,thoughIfoundithardtofollowherargumentthat ICIdevelopedpharmaceuticalsin1926andthesefirmsbecametrendsetters.InfactICI onlydedicatedastaffofseventoexploratorymedicinalchemistryfrom1936afterthe discoveryofsulphonamides,andalthoughtheyexpandedtheireffortsduringandafterthe

32 SecondWorldWar,theydidnotformapharmaceuticaldivisionuntil1954.
SwannrecognisedthatsomeAmericanfirmsbecameimportantpoolsofscientists, collaboratingwithpharmacologistsinuniversitiesandmedicalschoolsintheinterwar
33 period. TheexamplesgivenincludedEliLilly,Merck,ParkeDavis,AbbottandE.R.
Squibb,allofwhichevolvedtobemajorU.S.pharmaceuticalmanufacturers.Swann identifiedthreemaintypesofexternalcollaborator:thegeneralist,thespecialistandthe projectspecificconsultant,andtheywereprimarilypharmacologistsandchemists.Froma
29

30
GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen&Hanburysand theBritishPharmaceuticalIndustry (London:JohnMurray,1990).

31
VivianeQuirke,ExperimentsinCollaboration:TheChangingRelationshipBetween ScientistsandPharmaceuticalCompaniesinBritainandinFrance,19351965(University ofLondon:PhDthesis,1999).

32
FrankL.Rose,OriginandRiseoftheSyntheticDrugsinF.N.L.Poynter(ed.), ChemistryintheServiceofMedicine(London:Pitman,1963):179197.IntheRose accountitsays1954andthemainsiteatAlderleyParkdidnotopenuntil1957.

33
JohnP.Swann,(1988):34,3334,45,51,6583Richardsperformedresearchwith HenryDaleattheNationalInstituteofMedicalResearchinLondon:C.F.Schmidt,A.N. RichardsBiographicalMemoirsofFellowsoftheRoyalSociety 13(1967):32742.
21
22
companyperspectivethebestknownarethecollaborationsofEliLillywithToronto UniversityregardinginsulinandthecollaborationofHarvardUniversitywithseveralfirms withlivertherapyforperniciousanaemia.Swannaddressedsomeofthedifficultiesof collaborativeworkincludingproprietaryinterests,sharinginformationwithoutsiders, publicationsandpatenting,butconcludedthatthiswasaparticularsuccessforthe Americanindustry. VivianeQuirkedrewparallelsbetweenthesystemsthatevolvedinFranceand Englandupto1965.ShesuggestedthatHenryDaleattheNationalInstituteofMedical ResearchandErnstFourneauatthePasteurInstituteexhibitedmanyparallelsbothcoming fromacademicbackgrounds,workinginthepharmaceuticalindustry,thenreturningto academia,butinvestingheavilyincollaborativeresearch.Shearguedthatcollaborative workdevelopedwidelyinFranceintheinterwarperioddespitealackofsupport,whereas
34 itdevelopedinBritainasaresultofgovernmentsupportandlargelythroughDale.
RobsondescribedtheBritishdrugindustryascomprisingfourdistincttypesoffirm
35 attheendofthenineteenthcentury :
1.
Traditionaltradersthatimportedrawmaterials,purifiedandprocessed them suchfirmsincludedMorsons,Whiffens,May&Baker,Allen& HanburysandHowards.
2.
Marketingfirmsconcentratingontheretailtrade,exemplifiedbyBoots, TaylorsandtheLondonDrugCompany.
3.
EdinburghbasedalkaloidmanufacturerssuchasMacFarlans,T.H.Smith andDuncanFlockhardt.
4.
MoreresearchorientedfirmsincludingBurroughsWellcomeandEvans Sons,Lescher&Webb.
Thetraditionalfirmshavereceivedlittleattention,exceptinindividualcompany historiesbyTweedaleandChapmanHuston(Allen&Hanburys),Slinn(May&Baker)
34 35
VivianeQuirke,(UniversityofLondon:PhDthesis,1999).
M.Robson,TheBritishPharmaceuticalIndustryandtheFirstWorldWarinJ. Liebenau(ed.),TheChallengeofNewTechnology:InnovationinBritishBusinessSince 1850 (Aldershot:Gower,1988):82105.
22
23
andDavenportHinesandSlinn(Glaxo)andalthoughadefinitivehistoryofBurroughs Wellcomeisawaited,mostattentionhasfocussedonphysiologicalstandardisationby
36 TanseyasBurroughsWellcomeproducedvaccinesandantitoxinsfrom 1895.
RegardingBritishfirmsintheperiodto1940,Liebenauconcludedthat:successful astheywereinmaintainingtheirsmallbusinessesandaturnoverofbasicproducts,and givenfewincentivestogrow,BritishfirmssuchasHowards,Evans,Morsons,Bells, evenAllen&Hanburys,didrelativelylittletoextendtheirmarkets.Hedidnotrefer,asI do,tothosefirmsthatdidgrowmostsignificantly,namelyBurroughsWellcome,May&

37 Baker,BootsandBritishDrugHouses. Inhisthesis,Michael Robsoncomparedthe
economicsoftheBritishpharmaceuticalindustrywithFranceandSwitzerlandbutagain
38 withlittleemphasisonthedevelopmentandtestingofdrugs. Heexpandedpreviouswork
tocomparethenumberofpatentsandpublicationsfromindustry.However,hisindepth analysisshowsthatfirmsmayhavedifferedgreatlyintheirpolicy,evenfromproductto product. Thesurprisingfindingthereforeisthatthereisasignificantpartofthehistoryofthe Britishpharmaceuticalindustrythathasnotbeenexamined.Havingreferredtotherhetoric ofbackwardnessanddeclineininterwarBritainandFrance,Quirkenotesthestronger BritishpharmaceuticalindustrythatemergedfromtheSecondWorldWarandarguesthat thiswasaresultofcollaborationwithintheTherapeuticResearchCommittee,involving severalfirms,andthevictoryofpenicillin.Oncemorethisconclusionarisesfromthe focusonmajordevelopments(inthiscasepenicillin)andanacceptancethatlittlewas achievedintheinterwarperiod.Andyetthereisaremarkablecontrastbetweentheposition oftheBritishindustryin1938,preparingtomakedrugsthatmightberequiredforwar, comparedtothestarkrealisationattheoutbreakoftheFirstWorldWarthatBritainrelied soheavilyonGermany,notonlyfordrugsbutforthechemicalintermediatesrequiredto
36
D.ChapmanHustonandE.C.Cripps,(1954)R.P.T.DavenportHinesandJ. Slinn,(1992)GeoffreyTweedale,(1990)JudySlinn(1984)E.M.Tansey,(1989):141.
37 38
M.Robson,(1988):94.
M.Robson,ThePharmaceuticalIndustryinBritainandFrance19191939(Dept.of EconomicHistory,LondonSchoolofEconomics:PhD.thesis,June1988)J.Sigvard, DrugIndustryinFrance:SomeHistoricalPointsBull.Acad.Natl.Med. 166(June 1982):82934.
23
24
makethem.ExaminingtheFirstWarinisolationisinsufficientasitwasanartificial situationwithdisruptionoftradeandtheabsenceofacompetitivethreatfromGermany. Oneofthemainchallengeswastoproducedrugsonalargescaleandcosteffectivelyto competewithGermany afterthewar. Syntheticdrugsarethemainstayofthemodernpharmaceuticalindustry,butthe molecularmanipulationthatgaverisetonewdrugsbeganinGermanyattheendofthe nineteenthcentury,andGermanyheldamonopolyinsyntheticdrugspriortotheFirst WorldWar,withdrugssuchasSalvarsan,NovocaineandAspirin.Asaresulttherehas beenadearthofinterestinthisaspectofthedevelopmentofthepharmaceuticalindustry outsidetheGermaniccountriesandanassumptionthatAmericaandBritaineventually followedtheGermanmodel.Iwilldiscusshowthiswasnotalwaysthecase,atleastuntil after1939. SwannmadeonlypassingreferencetothefactthatEliLillyestablishedaresearch teamonsyntheticdrugsin1912,involvingupto20researchershedidnotexplainwhere theycamefromorwhethertheydidevolvefromassaywork.HedescribedhowAbbott firstdevelopedsyntheticdrugs,butasaresultofexternalcollaboration,andthenby employingapostdoctoralstudentin1918.BeyerdescribedhowDilantin(phenytoin)was firstsynthesisedatParkeDavisin1911,buthedidnotdescribetheinitialevaluation only pointingoutthatitshypnoticeffectswereonlyfoundaspartofaroutinescreenin1926 anditsbenefitsinepilepsywerenotdescribeduntil10yearslater:hestatedthatParke
39 DavisdidnotformallyestablishaChemistrydepartmentuntilthe1920s.
IntheGreatWar,America,likeBritainwasdeniedGermandrugs,initiallyasaresult ofnavalblockade.The1916versionofNewandNonOfficialRemedieslisted228of 592drugsascomingfromGermany.AftertheUSAdeclaredwarinApril1917,some GermanpatentswereabrogatedandAmerica,likeBritain,hadaTradingwiththeEnemy Act,andyetSwannsuggestedthat:U.S.pharmaceuticalfirmssoonfilledthedemandfor these(synthetic)drugs.However,elsewhereinhisbookSwanndemonstratedthatitwas onlyafterthewarinmostAmericanfirmsthatinternalresearchfacilitieswereestablished, initiallyappointingexternalscientists,notablyatAbbott(1918),Lilly(1919),ParkeDavis

39
KarlH.Beyer,Discovery,DevelopmentandDeliveryofNewDrugs(NewYork:S.P. MedicalandScientificBooks,1978):43.
24
25
(1920),andMerck(1930),althoughUpjohnandSquibbappointedtheirfirstresearch scientistsin1913and1915respectively.ItremainsunclearhowAmericanpharmaceutical firmsfirstestablishedsyntheticdrugsynthesisandnothinghasbeenwrittenon manufacturingcapacity.Certainlyseveralfirmscontinuedtodependonexternal collaborationsfordiscoveriesandthisseemstobeastrongfeatureoftheAmerican

40 industry.
LiebenauaddressedtheproductionofSalvarsanbytheDermatologicalResearch LaboratoriesinChapter8ofhisbookMedicalScienceandMedicalIndustry.Robson brieflyaddressedtheproblemsofwartimedrugshortages:ItwastheFirstWorldWarthat disturbedthestatusquoandmarkedtheturningpointforthestandingofsciencewithinthe pharmaceuticalindustry.However,heconcludedthattherewerenoimmediate shortagesasaresultofthedislocationoftrade,withoutgoingintodetailabouthowthe

41 essentialdrugsweredefined,manufacturedortested. Thiscontrastswithmyfindingthat
BritainwasheavilyreliantonGermany forsyntheticdrugsandcertainalkaloids. BothRobsonandQuirketoadegreerefertosomeofthestaffmobilitybetweenthe MRCandindustry,withRobsonmakingabriefreferencetoFrancisCarrandhisdeparture fromBurroughsWellcome.However,Carrsrolewasperhapsnotfullyunderstoodby QuirkewhobrieflydescribedhimasbeingtakenonbyBDHtoproduceinsulin,whereasit washisestablishmentofthemanufacturingcapacityofBDHintheperiod192022that madetheinsulindevelopmentthesuccessthatitwas.SimilarlyIdidnotfollowQuirkes argumentthatafocusonantiserapreventedtheearlierexploitationofpenicillinin Britain.ShearguedthatFlemingwasobsessedwithdemonstratingthatpenicillincouldbe usedasaselectiveinhibitorofbacterialgrowthandspecificallyamethodtoisolate Haemophilusinfluenzae,andthatthistiedinwiththeinfluenceofAlmrothWrightin promotingvaccines,includingoneforinfluenza. AmoreobviousexplanationisthatneitherFleming,northemanyothersthat investigatedpenicillininthenext14yearscouldenvisageamethodoflargescale productionandthisseparatesaninterestinglaboratoryphenomenonfromapracticaldrug.
40
41
JohnP.Swann,(1988):356. M.Robson,(1988):82105.
25
26
Iteventuallytookamassiveinternationalefforttodeveloppenicillinandthiswasonly stimulatedbythewartimeneedsandfollowingthesuccessofthesulphonamides.Nonew drugisusefulunlessitcanbemanufacturedreliablyandpartofthechallengeforBritainin thisinterwarperiodwastoencouragethetrainingofchemicalengineersandmanufacturing chemiststomakethispossible. However,detailsasideQuirkeprovidesavaluablecomparisonofBritainandFrance, inwhichshecontraststhecentralcoordinatingrolesofthePasteurInstituteandtheMRC forwhichsheidentifiedtheimportantroleofDaleinbreakingdownthebarriersbetween industryandacademia,thoughasIwillshowbarriersstillexistedtogettingclinicaltrials performed. 1.3ClinicalTestingofNovelDrugs. Stilllessattentionhasbeengiventotheoriginsofclinicaltrialsofnewdrugsfrom industry.Someauthorshavechartedancienttrialsorthedevelopmentofmeasurement
42 inmedicine. Thehistoriographysuggeststhatnumericalmethodsofassessmentin
medicinespreadfrom ParisatthestartofthenineteenthcenturyandTroehlerexamined
43 thisinathesis,whichfocussedonthetechniquesandthescopeofdatacollected. His
thesisisanexcellentinitialsourceforanunderstandingofthedevelopmentofthenumerical accountinmedicine,offeringaseriesofindividualexamplesofwellrecordedproperly recordedobservations,startingwithJamesLindandcollectionsofstatisticsintheNavy onscurvyin1763,ratherthanaclearpathofinfluences.Heshowsthatthereweremany earlyexamplesoflargewellcontrolledstudies,andyetthemethodswereintermittently adopted.JohnFerriar,aManchesterphysician,wrotein1792thatthetendencyso

42
J.P.Bull,TheHistoricalDevelopmentofClinicalTherapeuticTrialsJournalof ChronicDiseases10(1959):218248H.J.C.J.L'Etang,HistoricalAspectsofDrug EvaluationinE.L.Harris,J.D.Fitzgerald(eds.),PrinciplesandPracticeofClinical Trials.(Edinburgh:ChurchillLivingstone,1970)JanP.Vandenbroucke,AShortNote ontheHistoryoftheRandomisedControlledTrialJournalofChronicDiseases40(1987): 985987A.M.Lilienfeld,CeterisParibus:theEvolutionoftheClinicalTrialsBulletin oftheHistoryofMedicine56(1982):118U.Troehler,QuantificationinBritish MedicineandSurgery,17501830withSpecialReferencetoitsIntroductioninto Therapeutics(UniversityofLondon:PhDthesis,1978).

43
ErwinAckerknecht,MedicineattheParisHospital17941848(Baltimore:Johns th Hopkins,1967)J.P.Vandenbrouke,ClinicalInvestigationinthe20 Century:the AscendancyofNumericalReasoningTheLancet(October1998)Sii:1216.
26
27
fashionableatpresentofpublishingsinglecases,appearsnotwellcalculatedtoenlargeour knowledgeeitherofthenatureorcureofdiseases.Troehlerdemonstratedthatthe numericalmethodwasoftenadoptedtodefendnewapproachestosurgery,orintestinga newmethodoftreatment,withseveralexamplesfromearlydebatesonvaccination,buthis mainthesiscoveredtheperiod17501830,soitdoesnotaddresshowthepharmaceutical industrygotitsdrugstested. RecognisingthatthenineteenthcenturyBritishpharmaceuticalindustry manufactureddrugsrequiredbythemedicalprofession,thatwereacceptedwithout challenge,anewsituationaroseintheinterwarperiodwhentheethicalpharmaceutical industryinBritainproducednoveldrugsandhadtopersuadedoctorstoevaluateandthen utilisethem.Agreyarea existedbetweensomeofthenoveldrugsandpatentmedicines thatwereheavilypromoted.Howwouldcompaniesgettheirnewdrugsevaluatedand whichwerethedrugsthatdoctorsneeded?Swanndescribedhowthelongstandingconflict betweenlaboratoryworkersandclinicianswasgraduallyovercomebyclinicianresearchers, biochemists,andphysiologistsreturningtoAmericafromperiodsoftraininginGermany, andestablishingUniversityChairsofClinicalResearch,basedonthemodeloutlinedin AbrahamFlexners1910reportIwilldescribeparallelstothesystemdevelopedbythe
44 MRCinBritain. HarryMarksexaminedtheestablishmentofcooperativeclinicaltrialsin
America,emphasisingthatotherformsoftherapeutictrialspredatedrandomised
45 controlledtrials. Heexaminedhowtherapeuticdecisionsweremadeandemphasisedthe
roleoftheAmericanMedicalAssociationsCouncilonPharmacyandTherapeuticsandof academicresearchcentreswithintheNationalResearchCouncilsDivisionofMedical Science.Hecautionedagainsttakingapurelymethodologicalapproach,astherewasmore tochangingviewsontherapeuticsthanthedesignoftheexperiments.Cliniciansdeferredto moreknowledgeableexpertsandpartoftherationaleforcollaborativetrialswastoengage
44
AbrahamFlexner,MedicalEducationintheUnitedStatesandCanada(NewYork: CarnegieFoundation,1910).
45
HarryM.Marks,IdeasasSocialReforms:TheLegaciesofRandomizedClinicalTrials (PhDThesis,HarvardMedicalSchool,1983)HarryM.Marks,TheProgressof Experiment:ScienceandTherapeuticReformintheUnitedStates,19001990(Cambridge: UniversityPress,2000).
27
28
manycentressothattherewasnotanundueinfluenceofoneortwophysiciansineach centre.Heexaminedthemajorchemotherapeuticagents,includingSalvarsan, sulphonamidesandpenicillinandconcludedwithsomelaterworkonoralhypoglycaemic drugs,buthedidnotexaminehowindustrygottheirdrugstested.LikeQuirke,Iconclude thatthesysteminBritainwasmorecentrallycoordinatedbytheMRC,thanthe independentsystemofcollaborationsthatexistedinAmerica. InBritain,even afterBurroughsWellcomedemonstratedphysiologicalactivityof theirdrugs,testedthemforpurityandstandardisedthemintheirownlaboratories,theystill haddifficultyinestablishingclinicaltrials.WhereasinGermanytheclosecollaborations betweenfirmsandpharmacologistsledtoearlytestingofnewproductsinclinicaltrials,it wasdifficulttomakethesearrangementsinothercountries.GeraldGeisondescribedthisin
46 Dividedwestand andSwannreferredtolongstandingconflictsbetween laboratory
workersandclinicians.Mostofthehistoricresearchonthepharmaceuticalindustryhas focussedondrugdiscovery,tellinguswhatwasdiscoveredandwhen,andwithlittleon drugdevelopment. Thedevelopmentphasethathasevolvedsincenoveldrugswerepreparedwas initiallyasimpleprocess,buthasbecomeincreasinglycomplexitinvolvesturninganewly discovereddrugintoamedicinethatcanbeprescribedsafelytopatients.Itinvolves selectingthedose,formulatingthedrugasaninjection,tabletorsomeotherform,and testingitfirstinanimalsandtheninpatients,producingdatatoencourageotherdoctors totrythedrugandultimatelytomakeitacommercialsuccess.Anotherpartofdrug developmentoperatesatastrategiclevelandconcernsdecisionsregarding,whichdrugsto developandwhatresourcesandfacilitiesarerequiredtosupporteachpotentialdrug.This phaseofdrugdevelopmenthasreceivedlimitedattentionandIexploredthisthroughthe internalrecordsoftheBurroughsWellcomeScientificandTechnicalCommittee,andbased onmyownconclusionsofwhatothercompaniesproducedandhadtestedbythe TherapeuticTrialsCommittee.
46
G.L.Geison,DividedWeStand:PhysiologistsandCliniciansintheAmerican Contextin M.J.VogelandC.E.Rosenberg,TheTherapeuticRevolution:Essaysinthe SocialHistoryofAmericanMedicine(Philadelphia:UniversityofPennsylvaniaPress, 1979).
28
29
LiebenauconcludedthattheMRCstudiesoninsulinformedthemodelforfuture collaborativeresearch,andbothQuirkeandRobsonreferredtohisseminalwork.Thus, onthebasisofalimitedappraisalaviewhasbeenperpetuatedthatthiswasafoundation modeluponwhichtheMRCrefinedstudydesignsandadrugdevelopmentprocess culminatinginthefirsteverrandomisedcontrolledtrialofstreptomycinin1946.Toa degreethishasbeenfuelledbythewritingsofmanyoftheparticipantsinthoselater

47 trials.
Theconclusionthatasystemofclinicaltrialswasmodelledonthoseforinsulinand thattheMRCbuiltuponthisinanefforttocontroltheindustryhasnotbeenchallenged sinceLiebenausaccountinwhichhereferredmistakenlytoinsulinasapituitaryhormone.

48
BoothexaminedthegrowthofMRCsponsoredclinicalresearchcentres,butonlyby
49 referringtoMRCannualreports. Wastheinsulinmodelrepresentativeofotherstudies
performedbytheMRCintheperiodupto1946oristhismodelonlyapplicabletothe developmentofproductswheretheMRCheldthepatentandcouldcontrolthe collaborators?Intheirrecenttheses,bothDesireCoxMaksimovandthenVivianeQuirke tookinsulinastheacceptedmodel.Theimpressionisgivenintheseaccountsthatdrugs simplycameintogeneraluse,asifitwereobviousthatdrugsthatworkedinthelaboratory wouldbeefficaciousandsafeinman.Thismayhavebeenthecaseforinsulinandpenicillin, regardingtheirspectacularactivity,butthisfocusonmajorsuccessesgivesnoinsightinto theroutineresearchfornovel drugsthatwasthebreadandbutterofthepharmaceutical industry.Whataboutthosedrugsthatdidnotworkorcausedadverseeffects?The forefrontofthisresearchwasintheclinic.Evenattheendofthenineteenthcentury, Ehrlichrecognisedthattheonlytruetestofadrugwasinmanandcompaniesusedtheir earlyexperienceinpatientstomodifytheirproducts,toevaluatenewdosageforms,to
47
J.Liebenau,TheMRCandthePharmaceuticalIndustry:theModelofInsulinin JoanAustokerandLindaBryder(eds.),HistoricalPerspectivesontheRoleoftheMRC (OxfordUniversityPress,1989):163180.

48
J.Liebenau,TheMRCandthePharmaceuticalIndustry:theModelofInsulin (1989):169.
49
C.C.Booth,ClinicalResearchinJ.Austoker,L.Bryder(eds.)Historical PerspectivesontheRoleoftheMRC.(Oxford:OxfordUniversityPress,1989):205241.
29
30
modifythedoseordurationoftreatmentoreventosubstituteonedrugforabetter alternative,asindeedEhrlichdidwithneosalvarsan.
50 Quirke defendedtheprogressofBritishindustryindevelopingacollaborative
networkthroughtheworkoninsulin butitwasnotdifficultfortheMRCtofinddoctors readytotestinsulin,afterithadalreadybeenshowninCanadaandtheUSAto dramaticallylowerbloodglucose.ItwasquiteanotherthingforaBritishfirmtotesta novelchemicalinmanforthefirsttime.ThemorethatIlookedatthisproblem,themore surprisedIwasthatithadbeenignored.Itseemedtomethattheresearchtodatehadbeen fittedaroundthebestavailablesourcematerialratherthanconsideringthisfundamental question. DesireCoxMaksimovdescribedtheTherapeuticTrialsCommittee(TTC)asthe modelthatemergedfromtheearlierChemotherapyCommitteeforrandomisedcontrolled
51 trials. Herstudywascarriedoutinparallelwithmyownresearchandcoversmyperiod
ofinterest.BecauseshealsoexaminedtheTTC,herthesisbearstheclosestparallelsto mineandthereforedeservescloseattention.Inaseriesofcasestudiesshecontrastedthe effortsofpatentmedicinemanufacturerswiththescientificapproachesofthemedical establishmentandtheState,whichsupportedthemoreacceptablestandardisedmedicines

52 evaluatedbytheMRC. Sheexaminedtrialsofinsulinfordiabetes,trialsofpneumococcal 53 serum,andpatulinforthecommoncold.
Thus,herapproachwasverydifferent,ignoringtheproductsarisingfrom pharmaceuticalindustryresearchandconcentratingonthemethodologyofthelargertrials
54 ratherthantheprinciplesoftestingnewagents. Patulin,likeinsulinwasanaturalproduct
50 51
VivianeQuirke,(UniversityofLondon:PhDthesis,1999).
D.CoxMaksimov,TheMakingoftheClinicalTrialinBritain,19101945. Expertise,theStateandthePublic(Cambridge:PhD.Thesis,September1997):17130.
52
D.CoxMaksimov,TheMakingoftheClinicalTrialinBritain,19101945. Expertise,theStateandthePublic(Cambridge:PhD.Thesis,September1997):17130.
53 54
D.CoxMaksimov,(1997):183262. Ibid..
30
31
55 arisingfromacademicresearch ratherthanadrugfromindustryandthepatulinstudies
wereusedtodescribethemechanisationoftrialsandthekeyroleofthestatistician,Major
56 Greenwood,whohadbeeninvolvedinclinicaltrialdesignformanyyears. TheMRC
werebecomingarbitersofdrugevaluation,determininghowmedicalresearchwas reported,thecharacterisationandstandardisationofmedicines,therecognitionand authorityofexperts,howtheresearchwasreportedeventhecentresinvolved. AccordingtoCoxMaksimov,theTTCwasaboutpromotingacertaintypeof medicalresearch,butwasitreally?My argumentisthatbyselectingonlythewinning drugssuchasinsulinhistoriansmayhaveintroducedabias.Quirkealsoevaluatedthe impactoftheinsulinclinicalstudiesandconcluded,likeLiebenau,thattheseformedthe modelforallfuturetrialsandcollaborationswithindustry.Liebenau,QuirkeandCox Maksikovdonotaddresstheissueofmanufacturinginsulinorwhowasinvolved.Innot doingsotheymissedtheimportantlinkthatFrancisCarr,whohadpreparedSalvarsanat BurroughsWellcome,hadmovedfirsttoBootsthentoBritishDrugHouseswherehe establishedthecapacitytomanufacture95%ofBritishrequirementsforinsulin.Carr, amongothersledtherequestsfromindustryforasystemofclinicaltestingofnewdrugs andthecompaniesatthetimeclearlydidnotseeinsulintrialsasamodeltomeettheir needs. Thetrialofpneumococcalserumwasnotatallrepresentativeofthemainworkof theTTCasitwasalreadyplannedin1929,twoyearsbeforetheestablishmentoftheTTC in 1931.Furthermorethestudyaddressedquestionsabouttheneedtovaccinaterather thanbeingastudyofnewdrugs,andfurthermore,initialvaccinesuppliescamefrom America. CoxMaksimovexaminedinturnhowalloftheproceduralelementsof the randomisedclinicaltrialwereinplaceby1946andarguedthatthepneumococcaltrial definedprocedures.Iamnotconvincedthatthepneumococcalstudywasthemajor influencethatshesuggestsandwithoutintendingtoclaimanincreasedvalidityof afirst
55
H.Raistrick(firstofseveralpresentations),PatulinintheCommonCold. CollaborativeResearchonaDerivativeofPenicilliumpatulumBainierLancet (20 November1943):62534.

56
L.Hogben,MajorGreenwoodBiographicalMemoirsofFellowsoftheRoyalSociety 7(1950):13954.
31
32
handsource,herinterpretationconflictswiththeaccountrecalledtomebySirAustin BradfordHill,thefounderoftherandomisedcontrolledtrialandbyhissurviving
57 colleagues. Therewerequitedifferentobjectivesandalsoethicalconstraintsin
vaccinatingindividualsagainstthepossibilityofacquiringacommondiseasecompared withtreatingthemwithanovelchemicaltotreatadiseasealreadypresentandparticularly regardingwithholdingtherapyintheplacebogroup.CoxMaksimovmadetheimportant pointthatrecentaccountshavebeenwinnershistoriesofClinicalTrials,oneinwhich

58 statisticianssuchasPeterArmitage ,RichardDoll,59 RichardPetoandSirAustin
BradfordHilldominateandclaimownershipofclinicaltrials.Theirargumentsconcernthe qualityofthedesignofexperiments,theremovalofsourcesofbias,andacertainwayof reportingdataandinthisrespecttheirauthoritycannotbequestioned,butwasthislater modelofrelevanceinthe1930s?CoxMaksimovarguedforanaturalprogression throughtheTTCpneumococcalstudy,theMRCstreptomycinstudies,andpatulin

60 studies, arguingthatArmitagehadreferredtoBradfordHillhavingaroleintheTTC,
thoughsherecognisedtherewasnodocumentaryevidenceandIfoundlittleeitherthefirst
61 referencetohimwashisattendanceatthetenthcommitteemeetingin1939. Lilienfeld
tookanalmostgenealogicalapproachandtriedtotracethecontrolledtrialslinkback furthertostudiesofthegoldtherapy,sanocrysinin1925,andothershavealsoarguedthat
57
LettertomyselffromSirAustinBradfordHill(6October1988)P.DArcyHart, EarlyControlledTrialsBritishMedicalJournal 312(10February1996):37879A. BradfordHill,MeasurementinMedicine:TheClinicalTrialBrit.Med.Bull.7.4(1951): 27882A.BradfordHill,TheClinicalTrialNewEnglandJ.Med.247(1952):113P. Armitage,BradfordHillandtheRandomisedControlledTrialPharmaceuticalMedicine6 (1992):2337R.Doll,SirAustinBradfordHillandtheProgressofMedicalScience BritishMedicalJournal 305(1926December1992):152126I.Chalmers,M.Clarke,J. G.Scadding,inI.Chalmers,I.Milne,U.Troehler(eds.),TheJamesLindLibrary( www.jameslindlibrary.org)accessed7January2003.
58
P.ArmitageisEmeritusProfessorofAppliedStatisticsattheUniversityofOxford:P. Armitage,(1992):2337.
59 60
RichardDoll,(1992):152126.
J.M.Stansfield,A.E.Francis,C.H.StuartHarris,LaboratoryandClinicalTrialsof Patulin:MedicalResearchCouncil,ClinicalTrialofPatulinintheCommonCold(16 September1944)Lancet:37375.

61
BradfordHillwasonlyappointedtotheTTCforthetenthandfinalmeetingin1939: TTCMinutes10,(28March1939),MRCFile1523/15(TTC).
32
33
62 therewereevenearlierisolatedcasesofrandomisedcontrolledtrials. InthisthesisI
showthatmanyofthetrialsorganisedbytheTTCwereoflimitedscopeandstatisticians werenotinvolvedandthestudieswerejustlargeenoughtosatisfythecompanyneedfor somedata.AsubgroupofstudiesinareasofspecificinteresttotheMRCwaslarger,not bydesignbutonaccountofthetypesofpatientsselectedandtheexperienceofthecentres involved.AsitwasthepharmaceuticalfirmsthatrequestedtheestablishmentoftheTTC, weshouldseehowBritishfirmsjudgeditssuccess,orotherwiseratherthanacceptingthe accountoftheTTCSecretary,FrankGreen.Hencethereremainsmuchscopeforan evaluationoftheinteractionbetweentheBritishpharmaceuticalindustryandtheMRCin evaluatingnoveldrugs. CoxMaksimovdidnotrecognisethestrongpushfrommanufacturerstohavenovel drugstestedbytheMRC.Shesuggestedtherewasnotmuchdifferencebetween pharmaceuticalfirmsandpatentmedicinemanufacturersattheturnofthe(nineteenth)
63 century. TheachievementsoftheBritishinpurifyingandisolatingactiveingredientsand
intablettingtechnologywereignoredandachievementswereminimisedsothatratherthan emphasisingtheremarkabletechnicalachievementofthesynthesisandproductionof Salvarsan,sheemphasisedonlythat: SalvarsanproducedbyBurroughsWellcomeintheWarwastoxicandthere wereproblemswithitsquality duringthewarandhowtheBoardofTrade forcedcompaniestogetofficialcertificatestheembarrassmenttolegitimate companieslikeBurroughsWellcomeandMay&Bakershouldnotbe 64 underestimated. IproposethattheoriginsofclinicaltestinggobacktothoseearlydayswithSalvarsanand thattheTherapeuticTrialsCommitteeestablishedbytheMRCin1931evolvedoutofa morecomplexrelationshipwiththefirmsoveralongertimeperiod.Itwasthe pharmaceuticalcompaniesthatcajoledtheMRCintotheestablishmentoftheTTC,after
62
D.B.E.C.Gill,RandomisedMentalHealthTrialBeganin1935andM.Clarke. QuasirandomAllocationofTreatmentwasReportedin1930,bothin BritishMedical Journal 312(18May1996):1298A.M.Lilienfeld,Ceterisparibis,theEvolutionofthe ClinicalTrial. BulletinoftheHistoryofMedicine56(1982):118.

63 64
D.CoxMaksimov,(1997):21. D.CoxMaksimov,(1997):21.
33
34
twopreviousfailedattempts,justasBurroughsWellcomehadledthewayonbiological standardisationandhadrequestedthetestingofSalvarsan. Insummary,therehavebeenlimitedattemptstoreviewtheestablishmentofthe Britishpharmaceuticalindustryandinparticulartounderstandhowitdevelopedfrom preparingextractsatdoctorsrequeststosynthesisingnewdrugsandtherehashardlybeen anyattentiongiventotheproblemsfacedbyBritishmanufacturersingettingtheirownnew drugstestedclinically. 1.4SourcesandThesisOutline. Ihaveexaminedinformationfromdiversesecondarysourcesinchemistry, dyestuffs,chemicalengineering,pharmacy,medicine,clinicalresearch,therapeutics,
65 pharmacology,physiology,economics,businesshistories,andbiographies. However,I
alsoconcentratedonarchivematerial,particularlytherecordsoftheWellcomeChemical ResearchLaboratory,themanufacturingworks,andpersonalarchivesofstaffmembers, physiciansandresearchers.SomeFirstWorldWarmaterial,discussingthefirsttestingof BritishproducedsyntheticdrugsisbasedonfilesoftheMRCSalvarsanCommittee,the laboratorybooksfromBurroughsWellcome,theCommitteeandCouncilMinutesofthe MRC,andfilesoftheAssociationofBritishChemicalManufacturers.Theoriginalsource referencesaregiveninthebibliographyandreflectthereferencingsystemsinplaceatthe timeofmyoriginalexamination,andalthoughmuchoftheMRCmaterialhasbeen reclassifiedandisavailableattheNationalArchives,formerlythePublicRecordOffice, somewasdestroyedpriortothemove. Thethesisissetoutalongbroadlychronologicallinesbutitincludesrecurring themes,suchastheinteractionsbetweenthepharmaceuticalindustry,basicscientific research,medicine,andgovernment.Ishowhowclosetheserelationshipswere,whereas previousauthorssuchasMoonmanstated:itisonlysincetheendofthesecondwarthat
65
PietroCorsi,P.Weindling,InformationSourcesintheHistoryofScienceand Medicine(London:Butterworth,1983)P.Weindling,ResearchMethodsandSourcesin E.Clarke(ed.),ModernMethodsintheHistoryofMedicine(London:Athlone,1971): 173.
34
35
66 theideaofGovernmentshapingindustryhastakenroot. Amajoremphasisisplacedon
67 theroleofsignificantindividuals,andparticularlyFrancisCarr.
TheearlypartofthethesisaddressesthedominanceofGermanchemistrywithina researchorientedindustry.Dyestuffsandchemicalintermediateswereprimarilyimported fromGermany.Universitybasedchemists,manyofwhomwereconsultantstoindustrial firms,hadwarnedbeforetheFirstWorldWaraboutthefactorsleadingtothedominance

68 ofGermany. AgeneralthemethroughoutistheshortageofsuitablytrainedBritish
chemists,particularlythosewithmanufacturingexperience.Manyofthechemicalprocesses dovetailedintoeachotherandthemanycomplexinterdependenciesbetweenfirmsreliedon chemicalintermediates.LittlepreparationwasmadefortheoutbreakofWaranditis interestingtocontrasthowbetterpreparedBritainwasbetween19371939andhowmuch thecountrydependedontheinterwarefforts. ThethemesthatemergethereforeareofsustainedeffortstoensurethatBritainnever againhadtorelyonaforeignpowerforkeyresources.Thisinvolveddefiningwhatdrugs wereessential,whomadethem,whatchemicalintermediatesandsolventswereneeded, howthedrugscouldbestandardisedandhowtheirpotencycouldbemeasured. Additionallythesyntheticarsenicaldrugs,replacingthosehithertoonlymadeinGermany, werepotentiallytoxicandhadtobeshowntobesafeandeffective. TheMRCtookacentralroleintheevaluationof Salvarsanbutmanyoftheirstaff camefromindustryandparticularlyBurroughsWellcome.Giventhescarcityofchemists, pharmacologists,physicianresearchersandotherkeymembersofstaff,itisinterestingto charttheircareerstoseetheeffectthattheyhadonthedevelopmentofseveralBritish pharmaceuticalfirms.TheMRCandgovernmentcontinuedtosupporttheBritishindustry throughouttheperiodunderstudy,andanotherthemewhichemergesistheeffortmadeto protecttheevolvingresearchbasedBritishpharmaceuticalindustry,firstlyunderthe
66
EricMoonman,ReluctantPartnerships:aCriticalStudyoftheRelationshipBetween GovernmentandIndustry (London:VictorGollanez,1971):17.

67
JosephBenDavid,TheScientistsRoleinSociety (EnglewoodCliffs:PrenticeHill, 1979):16068.

68
W.M.Gardner,TheBritishCoalTarIndustry,ItsOrigin,DevelopmentandDecline (London:Williams&Norgate,1915).
35
36
artificialsituationofWar,butthenbyaseriesofdirectandindirectmeasures.Adistrustof foreignmedicines,hadbeensparkedbytheincreasingimportsofpatentmedicines,with exaggeratedorevenfraudulentclaims,butcontinuedintothetwentiethcenturythroughthe assayofantitoxinsandorganextractsinwhichmanyforeigndrugswerefoundwanting. EthicalBritishmanufacturerswantedtoshowthemedicalprofessionthattheirnoveldrugs werestandardised,pureandhadareliableandquantifiabledegreeofactivityinfactthat theywereasgoodorbetterthanGermandrugs.Assaysofimpuritiesinstartingmaterials, measurementoftotalalkaloidcontent,amountsofactiveingredients,impuritiesinthefinal drug,biologicalstandardisationandmeasurementofclinicalactivitywereallmeansof showingthebenefitsofdrugspreparedbyBritishfirmsandofhighlightingtheproblems inherentinforeigndrugs.HereitwastheinteractionbetweentheGovernment,theMRC, thePharmaceuticalSociety,individualfirms,theAssociationofBritishChemical ManufacturersandrelatedgroupssuchastheSocietyoftheChemicalIndustrythatbecame important.ThroughoutthisworkIhavetriedtotaketheholisticviewofwhatfirmswere tryingtoachieveintheirdailychallenges.Inadditiontoinsulin,thenewlydiscovered vitaminsandthemanyorganotherapiesarisingfromacademicadvanceswerebeneficialto thegrowthofBritishindustryBritishfirmswereattheforefrontofinvestigatingthese opportunities,involvingcomplexextractionandmanufacturingtechniques,buttheir successwiththesenoveltherapiesledtoincreasesofmanufacturingpotentialand commercialsuccessesandtheircloserelationshipwithphysiologistsanduniversitychemists ledtosyntheticformsofbothvitaminsandhormonesbeingdeveloped.FirmssuchasAllen &HanburysandGlaxoexpandedsignificantlyasaresultoftheseopportunities. Amajorrecurrentandpreviouslyignoredtheme,isthegraduallyacquiredexpertise insyntheticdrugmanufacture,firstseeninsomeofthealkaloidsandfurtherexemplifiedby Salvarsanduringthewarandotherdrugspostwar.Syntheticdrugsbroughttogether manyofthepreviousintertwinedissuessuchasthelackofchemists,theneedtotestnew drugsinanimalmodels,theunderstandinggainedinrelatingchemicalstructureto physiologicalfunction,andtheclinicalstudiesrequiredtoevaluatethesafetyandefficacy oftheseagents.HerewasakeydevelopmentoftheBritishpharmaceuticalindustry, perhapsignoredbecauseitdidnotturnonasingleeventoraparticularstudy.For companiesthiswasnotanissueofdemandingaspecifictypeofclinicaltrial.Thefirms evaluatedheresimplywantedtheirdrugstestedinwhatevermannerpossibleastheyhad
36
37
majordifficultiesinarrangingstudiesdirectly,atleastinBritain.Evenifthestudywasonly inahandfulofcases,thatwasenoughaslongastheMRCultimatelyvouchedforthedrug andgaveitapositiveappraisal.Evenmanyofthesuccessfuldrugsmentionedhereare longforgotten.Theyplayedtheirpartinthetherapyoftheperiodasevidencedbytheir inclusioninthepharmacopoeiaof1948butmanyhavebeenreplacedsincethen.The consequenceofthesestudieswastherecognitionthen,asnow,thatnotalldrugswouldbe marketedeitherbecauseinsufficientactivitywasdemonstrated,orthereweresomesafety issues,ortherewasinsufficientdataordemandtomakethedrugcommerciallyviable. ThefirmsandtheMRChadacommoninterestincollaboratingasthestudiesallowed theMRCtoexpandthenumberofcentresinvolvedinclinicalresearch.HowevertheTTC andtheearlytestsofbiologicalstandardisationprobablyhadasmuchofaneffectby excludingforeigndrugsasbyhelpingBritishdrugstosecureaplaceonthemarket.A constantfrustrationforboththeMRCandthecompanieswastheslowprogressofthe TTCsclinicaltrialsanditisnotsurprisingthatafterthesecondworldwar,whichbrought afurtherstimulustotheBritishpharmaceuticalindustrythroughpenicillinandincreased manufactureofsyntheticdrugs,companiesbegantoemploytheirownpharmacistsand
69 physicianstoestablishtheclinicaltestingofdrugs, andthistrendevenbeganinthelate
1930s. Despitethebroadchronologyofthethesis,inevitablytherearesomeslightoverlaps betweensections.ForexampleitseemedsensibletoincludealloftheWaractivities, includingproductionandtestingofSalvarsaninonechapter,soIalsoincludedthework thatcontinuedonSalvarsanafter1918asitinvolvedthesameindividuals. FollowingonfromthisIntroduction,Chapter2describesthevariedoriginsofthe Pharmaceuticalindustryin thenineteenthcenturyandassessesthepositionofthesmall Britishcompaniesinrelationtotheirlargerinternationalrivals,contrastingtheethical manufacturerswithproducersofpatentmedicines.
69
K.J.Williams,B.Gennery,TheHistoryofthePharmaceuticalIndustryinJ.Lloyd, A.Raven(eds.),HandbookofClinicalResearch (London:Churchill,1994):122K. Williams,ATenthAnniversaryfortheAssociationforClinicalResearchinthe PharmaceuticalIndustry(ACRPi)PharmaceuticalMedicine3(1988):219224.
37
38
Chapter3describesthemostresearchorientedBritishfirm,BurroughsWellcome, andhowtheycombinedthebestofGermansyntheticchemistrywithAmericanadvancesin drugformulation,especiallytablets.ItwastheonlyBritishfirminitiallyinapositionto rapidlytakeupthesynthesisofthemorecomplexGermandrugsandtodevelopthestrong linkswiththenewlyfoundedMRC.Iintroduceindividualswhoweretoplayanimportant roleinthedevelopmentandtestingofdrugsthroughouttheinterwarperiodof1919

70 1931.
Chapter4examineshowtheFirstWorldWarforcedtheBritishGovernmentto interveneinpharmaceuticals,firstbyestablishingcommitteestoestablishwhichdrugswere essentialandthenhowtoresolvetheirproduction.IexaminehowBritishfirmsbeganto collaborateformallyforthefirsttimeastheAssociationofBritishChemicalManufacturers, howBritishfirmsmasteredlargescalechemicalsynthesis,andhowtheMRCfirstgot involvedintestingSalvarsanasanextensionofthestandardisationworkcarriedoutbyits staff whentheywereatBurroughsWellcome. Thenfollow3chaptersthatbroadlycoverthesameperiod: Chapter5coverstwoaspectsofpostwarBritain.ItexamineshowBritish pharmaceuticalfirmssoughtprotectionpostwar,firstbytariffs,thenbystandardisationof biologicalandhormonalextracts.TheMRCassistedandindoingsoestablishedtheir internationalreputationfordrugstandardisation,whileextendingtheirinterestinclinical outcomes. Chapter6describeshowBritishfirmscampaignedforclinicaltestingofdrugsfrom 19221930anddemonstrateshowtheMRCwasanidealintermediarybetweenthefirms andresearcherstoestablishgroundrulesforearlyclinicaltrialsinBritain.Thespecialised MRCsubcommitteesandtheChemotherapyCommitteedidnotmeettheneedsofthe pharmaceuticalcompaniesandIdemonstratethedistinctionbetweenMRCresearchto supportindustryandtheirownmoreacademicallyorientedstudiesandtheutilisationof theiremergingnetworkofclinicalcentres.
70
FrancisJ.Griffin,Obituary,FrancisCarrChemistryandIndustry (15February 1969):196.
38
39
Chapter7examinesthestrategyofBurroughsWellcomepostwarandespeciallythe period1925to1931,uptotheestablishmentoftheTherapeuticTrialsCommitteethrough thestrategicdebateswithintheirScientificandTechnicalCommittee. Chapter8examinestheactualworkingsoftheTherapeuticTrialsCommittee,how theyinitiallyfavouredBritishdrugsandhowthestudiescomplementedtheirownresearch andinterests.Thisexaminationofallofthedrugstestedgivesaninsightintotheresearch strategiesof British(andsomeforeign)firmsandallowsanassessmentofthesuccessor otherwiseoftheTTCgivinginsightsintothetesting,bothfromtheMRCperspectiveand thatofBurroughsWellcome(fromSTCMinutes19311939)andotherfirms. Chapter9offerssomeconclusions,bothbyreviewingthekeytopicsidentifiedandby comparingthepositionofBritishmanufacturersattheoutbreakoftheSecondWorldWar withthepositionthattheyfoundthemselvesinattheoutbreakofWarinAugust1914. Someopportunitiesforfurtherworkarethenidentified. Afullbibliographyofsourcesisgivenattheend.
39
TheOriginsofthePharmaceuticalIndustry
40
CHAPTERTWO:TheOriginsofthePharmaceuticalIndustry.
2.1TheGrowthofthePharmaceuticalIndustryintheNineteenthCentury. Earlynineteenthcenturydrugtherapywasaimedatalleviatingsymptomssuchas
1 feverandpain. By1900twoparallelbutoverlappingsystemsofdrugmarketinghad
evolvedinallofthemainmanufacturingcountries.Patentmedicineshadbeenavailable
2 forovertwocenturies,buttheiruseexpandeddramaticallyduringthenineteenthcentury.
Theywerepreparationswhoseingredientswerekeptsecret,andwhichweresoldunder
3 brandnamesforawiderangeofillnesses. Theirsuccessdependeduponheavy
advertisinginthepopularpress,andthefactthattheysparedpatientstheexpenseofa doctor'sconsultationfee.Patentmedicineswereofvariablequality,wereoftenlacedwith opiatesoralcohol,oronlyincorporatedminutequantitiesofwhatdoctorsandpharmacists consideredactivedrugs.Doctorswereconcernedthattheywereineffectiveandeven

4 potentiallydangerous.
Ethicalmanufacturerstookadifferentapproach.Theidentification,extraction,and purificationofmorphineinParisin1803stimulatedtheestablishmentofseveralalkaloid manufacturingfirmsinFrance,followedbyBoehringer,Merck,andScheringin

1
A.Burman,TheHeroicApproachtoNineteenthCenturyTherapeuticsBulletinof theAmericanSocietyofHospitalPharmacists11(1954):32027DavidL.Dykstra,The MedicalProfessionandPatentandProprietaryMedicinesDuringtheNineteenthCentury BulletinfortheHistoryof Medicine29(1955):40119.

2
PatentMedicineTaxReceipts18291914Chemist&Druggist85.1(8August 1914):3536T.Hughes,ThePatentMedicineStampDuty:itsOriginandHistory BritishMedicalJournal (9January1932):3233RevenuefromPatentMedicineTax Stamps18001931Chemist&Druggist114(30May1931):639.

3
V.Coleman,TheMedicineMen (London:TempleSmith,1975)B.McNamara,Step RightUp:anIllustratedHistoryoftheAmericanMedicineShow(NewYork:Doubleday &Co.,1976)RoyPorter, Quacks,FakesandCharlatansinEnglishMedicine(Charleston: Tempus,2001)WilliamH.Helfand,TheSellersofNostrumsinPrints,Posters,Ephemera andBooks(Chicago:ChicagoUniversityPress,2002).

4
JamesH.Young, TheToadstoolMillionaires:aSocialHistoryofPatentMedicinesin AmericaBeforeFederalRegulationinAmerica16601850(Princeton:Princeton UniversityPress,1961)JamesH.Young,TheMedicalMessiahs:aSocialHistoryof HealthQuackeryinTwentiethCenturyAmerica(Princeton:PrincetonUniversityPress, 1967)M.Silverman,MagicinaBottle(NewYork:McMillan,1941)M.Silverman,The DruggingoftheAmericas(Berkeley:UniversityofCaliforniaPress,1976).
40
41
5 Germany. Suchmanufacturersdifferentiatedthemselvesfurtherbyproducingthenewly 6 discoveredchemicalelementsbromineandiodine,inrichsupplyinGermany. Luke

7 HowardinLondonproducedcalcinedmagnesium,bismuthandmercurysaltsfrom1801.
MorsonsandHowardssoldquininesulphateinsteadofcinchonafrom1821,andfirms wereabletocomparethebestsourcesofquinine.From1827firmssuchasMercksold
8 purifiedmorphine,insteadofopium,asdidT.H.SmithinEdinburghby1837. Firms
manufacturedplantextractsandinorganicremediesaccordingtothedemandsof
9 physicians. Inotherwords,doctorsdecidedwhichdrugswereneededandpharmaceutical
manufacturersprovidedthem. Somedoctorsproducedtheirownmedicines,butasextractionofalkaloidsbecame morecomplex,requiringsolvents,distillationandcrystallisation,manufacturerssaved themtheexpenseofpurchasingmachinery.Ascapacityincreased,standardpackswere preparedanddistributedwidelyfortreatingstandardandspecificdiseases.Manyfirms producedthesamebasicdrugs,butindividualfirmsdistinguishedtheirdrugsfrom competitorsbyassayingchemicalconstituentsandimpuritiesinsimplelaboratorytests.
M.Weatherall,InSearchofaCure:aHistoryofPharmaceuticalDiscovery (Oxford: OxfordUniversityPress,1990)WalterSneader, DrugDiscovery:theEvolutionof ModernMedicines(London:JohnWiley,1985):67,914C.D.Leake,AnHistorical AccountofPharmacologytotheTwentiethCentury (Springfield,Illinois:C.C.Thomas, 1975):1201JohnHarleyWarner,TheTherapeuticPerspective:MedicalPractice, KnowledgeandIdentityinAmerica18201885(Cambridge,Massachusetts:Harvard UniversityPress,1986) E.MerckofDarmstadt:aHistoryofChemicalAchievement 18271937(Darmstadt:Merck,1937).
6
7
WalterSneader,(1985):4142. D.L.Howard, Brit.Col.Pharmacist(August1926):241.
W.Bernsmann,ArzneimittelforschungundEntwicklunginDeutschlandinder ZweitenHlftedes19JahrhundertsPharmazeutischeIndustrie29(1967):6Mark Honigsbaum,TheFeverTrail:TheHuntfortheCureforMalaria(London:MacMillan, 2001).

9
E.Kremers,G.Urdang,TheHistoryofPharmacy (Philadelphia:J.B.Lippincott, 4thedition,1976)R.D.Mann,ModernDrugUse,anEnquiryonHistoricalPrinciples (Boston:MTPPress,1984)F.N.L.Poynter,TheEvolutionofPharmacy (London: PitmanMedical,1965):13149E.H.Ackerknecht, TherapeuticsFromthePrimitivesto theTwentiethCentury (NewYork:Hafner,1973):8889JonathanLiebenau,TheRise oftheBritishPharmaceuticalIndustryBritishMedicalJournal (3October1990):72428, 733.
41
42
Thepurityofdrugsproducedbyreputablefirmsimprovedastheirpharmacistsadopteda
10 moreprofessionalrole.
JacobBellofJohnBell&Co.wasoneofthefoundersofThePharmaceutical
11 SocietyofBritainin1841andwasPresident18569. WilliamAllenofAllen&
12 Hanburyswasthefirstpresident. TheSocietywasmodelleduponthePhiladelphia 13 CollegeofPharmacy,foundedinAmericain1821. WhereasFrenchfirmsmade
referencetoexperimentsinanimalsbyphysiologistssuchasFrancoisMagendieand ClaudeBernard,andGermansreferredtoEmil Fischer,HermannKolbeandothers,such assayswerecontinuouslyhamperedinBritainbytheantivivisectionlobbyfromthe1860s andthisinhibitedthedevelopmentofpharmacologyandinteractionsbetweenthe

14 pharmaceuticalindustryandexternalacademicsinBritain. Bythecloseofthe
nineteenthcentury,theBritishpharmaceuticalindustrywasstrugglingtokeepupwithits
15 counterpartsinGermanyandinAmerica. Pharmaceuticalsevolvedonalargescalein
Germany,whereasAmericanfirmsmadesignificantadvancesinnovelmeansof administeringdrugs.AnappreciationofthecompetitionfacedbyBritishfirmswillenable ustounderstandmuchaboutthewaysinwhichasectionoftheBritishpharmaceutical
10
J.K.Crellin,TheGrowthofProfessionalisationinNineteenthCenturyBritish PharmacyMedicalHistory 11(1967):215227F.A.Filby,AHistoryofAdulteration andAnalysis(London:GeorgeAllen&Unwin,1934)E.W.Stieb,G.A.Sonnedecker, DrugAdulteration,DetectionandControlin19thCenturyBritain (Madison:Universityof WisconsinPress,1966)J.A.Blake(ed.),(1970).

11
JohnBellaComingCentenaryChemist&Druggist52(11June1898):1605S. W.F.Holloway,RoyalPharmaceuticalSocietyofGreatBritain18411991:APolitical andSocialHistory (London:ThePharmaceuticalPress,1991):appendix.

12
L.G.Matthews,HistoryofPharmacyinBritain (EdinburghandLondon:E.&S. Livingstone,1962):11827L.G.Matthews,AnUnrecordedWilliamAllenCaricature MedicalHistory 15(1971):3056.

13
J.W.England(ed.), TheFirstCenturyofthePhiladelphiaCollegeofPharmacy 18211921(Philadelphia:PhiladelphiaCollegeofPharmacy,1922).

14
J.M.D.Olmsted,FrancoisMagendie(NewYork:Schumanns,1944)Claude Bernard,AnIntroductiontotheStudyofExperimentalMedicineTrans.H.C.Greene, (NewYork:Dover,1957)R.D.French,AntiVivisectionandMedicalSciencein VictorianSociety (Princeton:PrincetonUniversityPress,1975).

15
J.T.Mahoney,Merchantsof Life:AnAccountoftheAmericanPharmaceutical Industry (NewYork:Harper,1959).
42
43
industryadaptedandmadeuseoflaboratoryscienceasameansofdevelopingand
16 marketingcompetitivenewproductsinthe1880s.
2.2EvolutionfromSmallPharmacyFirmsinAmerica. IntheearlynineteenthcenturymostmedicinesusedintheUSAwereimported fromBritain.PhiladelphiabecamethecradleofpharmacyfortheAmericannation, famousfortheCollegeofPharmacyfoundedin1821,aroundwhichanAmerican pharmaceuticalindustrywasestablished.EarlygraduatesoftheCollegesuchasErnstR.

17 Squibbattackedthefraudulenceandadulterationassociatedwithpatentmedicines.
Philadelphiabasedfirmscreatedandeffectivelycontrolledalucrativenewsector
18 ofthepharmaceuticalmarket,ethicaldrugssoldsolelytomedicalprofessionals. The
termethicalmedicinecameintousein theUSAafterthe1847codeofethicsofthe AmericanMedicalAssociationforbadedoctorsfromprocuringapatentforaremedy,and

19 fromsellingpatentmedicinesornostrums,orgivingtestimonials. AsinBritain,there
20 wasahugemarketfortheseremedies,oftensoldwithfancynames. The1877byelaws
ofthePhiladelphiasectionoftheAmericanMedicalAssociationstated: Anyphysicianwhoshallprocureapatentforaremedyorforany instrumentofsurgery,orwhosellsorisinterestedinthesaleofpatent remediesornostrums,orshallgiveacertificateinfavourofapatentor proprietaryremedyorpatentedinstrument,orwhoshallenterintoagreement

16
ThePharmaceuticalIndustry'tovaryingdegreesincluded'theChemicalandAllied Trades'and'theFineChemicalIndustry':WhatisaFineChemicalChemist&Druggist 85.2(29August1914):51.

17
L.G.Blochman,DoctorSquibb:TheLifeandTimesofaRuggedIdealist(New York:Simon&Shuster,1958)J.T.Mahoney,Philadelphia,CradleofPharmacy:Smith, Kline&French,WyethandOthers(1959):3041.

18
J.F.Marion,TheFineOldHouse:Smith,KlineCorporation'sFirst150Years (Philadelphia:SmithKline,1980).
19
R.M.Shryock, TheDevelopmentofModernMedicine.AnInterpretationofthe SocialandScientificFactorsInvolved(NewYork:Hafner,1969)M.Fishbein,AHistory oftheAMA18471947(Philadelphia:W.B.Saunders,1947):3542Peter Temin,Taking YourMedicineDrugRegulationintheUnitedStates(Cambridge,Mass:Harvard UniversityPress,1980):2.

20
B.McNamara,(1976)D.Armstrong,E.M.Armstrong, TheGreatAmerican MedicineShow(NewYork:PrenticeHall,1991).
43
44
toreceivepecuniarycompensationorpatronageforsendingprescriptionsto 21 anyapothecaryshallbedisqualifiedfrombecomingamember.
AseriesoffurthergraduatesofthePhiladelphiaSchoolofPharmacygaverisetoanew breedofpharmaceuticalmanufacturersthathadtheskillstodevelopnoveldosageformsof ethicaldrugs.ThefirmofWilliamR.WarnerwasfoundedinPhiladelphiain1856andhis futurepartnerinWarnerLambertwasapharmacygraduateofPhiladelphiain1884,as weremanyotherfoundersofpharmaceuticalfirms,includingHenryWellcomein1874 andSilasBurroughsin1877. FrederickBeldingPower,wholaterjoinedBurroughs

22 Wellcomeasachemistalsotrainedthere.
ThefirmofJohnWyeth&Co.originatedfromapharmacyopenedbyFrankand JohnWyethin1860.JohnWyethgraduatedfromthePhiladelphiaCollegeofPharmacy withathesisonthechemicalconstituentsofvariousplantsandFrankWyeth,achemist,

23 alsoattendedthecollege. JohnWyeth&Co.prosperedbysellingproprietarymedicines 24 duringtheAmericancivilwarwithaturnoverofover$600,000. Buttheywerealsoan
innovativefirmthatintroducednewmarketingpracticesaswellasnewdrugformulations. Asearlyas1861theyjoinedthetwomostlikemindedfirms,H.K.MulfordandSmith& Kline,tofoundthePhiladelphiaDrugExchange,tocampaignfortheabolitionofstamp dutyonpatentmedicines,becausemanyoftheethicalfirmsstillsoldtheseinparallel.The Exchangealsoestablishedasystemforchemicallytestingimporteddrugs,particularly patentmedicines,whichenteredAmericadespitealawbanningtheimportationofpoor

25 qualitymaterials.
WyethandtheircolleaguesintheDrugExchangeactivelydistinguishedthemselves fromthemanufacturerswhomadeonlypatentmedicines,byalsoproducingpurifieddrugs ofknowncompositionsoldonlytodoctorsandpharmacists,oftenusingesotericscientific

21
JonathanLiebenau,MedicalScienceandMedicalIndustry:TheFormationofthe AmericanPharmaceuticalIndustry,(Basingstoke:MacMillan,1987):2627.
22
J.W.England(ed.),(1922):1378,200ff.,216,410.
23
J.T.Mahoney,Philadelphia:CradleofPharmacy:SmithKline&French,Wyeth andOthers(1959):3041L.G.Blochman,(1958)JonathanLiebenau,(1987):2223.
24 25
J.WyethtoBurroughsWellcome,(31October1887),WF:88/47:8. JonathanLiebenau,(1987):23J.W.England(ed.),(1922):132.
44
45
26 terminologysuchas'dialysed'iron. TheymetareadymarketamongAmericandoctors
whowishedtominimisethepracticeofselfprescribingbypatients.OtherUSfirmswith rootsinpharmacyincludedA.P.Sharp,foundedin1827inBaltimore,thefirstinAmerica
27 toproducealkaloids. CharlesErhardtandCharlesPfizerestablishedtheirfirmin
28 Brooklyn,NewYorkbetween18458afterPfizerhadbeenapprenticedtoanapothecary.
HarveyC.ParkeandGeorgeS.DavisformedParkeDavisasasmallmanufacturing businessinDetroitin1866,andW.E.UpjohnfoundedTheUpjohnPillandGranule
29 CompanyinKalamazooin1886toproducefriablepills.
TheprincipaladvancesbyAmericanfirmswereincreatingnoveldosageforms suchassugarcoatedpills,whichwereconvenienttocarry,andsugarmaskedanybitter
30 tastes. Large scalemanufactureofpillsdevelopedfrom1857,andelixirs(solubleliquid
31 forms)from1859. Wyethpreparedcompressedhypodermictablets,andtablettriturates
werefirstmadein1861.Thesecouldbereadilydissolvedforinjectionorfortakingas
32 solutions. Thefirstmouldedmedicinesandcompressedpillsweremanufacturedin 33 Philadelphiain1863andtabletsweremadecommerciallyfrom1869. Wyethemployees
designedandpatentedthefirstrotarytabletpressinAmericain1872toproduceopiates, digitalis,strophanthusandquininetablets.By1876patentsweresecuredontheprocess
26 27
28
J.WyethtoBurroughsWellcome,(28June1881),WF:88/47:8. J.T.Mahoney,Merck&Co.(1959):2012.
S.Miles,Pfizer,anInformalHistory (NewYork:Pfizer,1978)J.G.Lombardino, ABriefHistoryofPfizerCentralResearchBull.Hist.Chem.25.1(2000):1015.

29
LeonardEngel,MedicineMakersofKalamazoo (NewYork:McGraw Hill,1961) CecilRoberts,ACenturyofCaring,Upjohn:Achievement (Kalamazoo:Upjohn,1938).

30
C.Gunn,AHistoryofSomePharmaceuticalFormulationsinF.N.L.Poynter (ed.),(1965):13150.
31
L.F.Kebler,TheTabletIndustry itsEvolutionandPresentStatus:Compositionof TabletsandMethodsofAnalysisJournaloftheAmericanPharmaceuticalAssociation 3 (1914):82048,937,958,106299.

32
J.T.Mahoney,Philadelphia:CradleofPharmacy:SmithKline&French,Wyeth andOthers(1959):312.
33
NoteaboutBrockedon'sPatentPharmaceuticalJournal 3(1844):554T.H. Bishop,InventoroftheCompressedTablet,WilliamBrockedonChemist&Druggist 162(28August1954):209F.N.L.Poynter,(1965):13149.
45
46
34 andthemethodofcompressionofpills. Incontrast,Britainspillsweremadebyhand
untilAllen&HanburysboughttheirfirstpillmakingmachineatthePharmaceutical exhibitioninPhiladelphiain1876,buteventhennotabletswerebeingmadecommercially
35 inBritain. JohnWyethstated:Priorto1877theformula's(sic)thatweresoldintablet
formwereveryfew.Theyconsistedofsimplechemicalssuchaspotassiumchlorate,
36 ammoniumchlorideetc.andafter1877combinationsfollowed. Wyethalsostated:we
doclaimandweknowthatthepreparationswemanufactureareunsurpassedbyanyinthe
37 38 world. ParkeDavisformulatedsomeproductswithingelatinecapsulesfrom1887.
Dr.AbbottofChicagoprepareddosimetricgranules,atypeofpillwithaccurately
39 calibrateddoses,from1888.
Upto1880firmssuchasG.D.SearleofChicagoofferedhundredsofelixirs, syrups,powderedextractsandtinctures.SmithKline&Frenchhadacatalogueofabout
40 15,000items. Howevertheincorporationofexistingproducts,astabletsrequiredspecial
testinginalaboratorytodevelopthemostsuitablemethods,meantthatfirmsbeganto focusuponasmallerrangeofhighervalueproducts.ThefirstAmericanfirmstointroduce achemicalqualitycontrollaboratorytoassayrawmaterialspurchasedwereMulfordand ParkeDavisin1879.AchemistwashiredbyParkeDavisin1880todeviseamethodto standardisetheamountofextractedergotintablets.By1883ParkeDavisofferedtwenty normalliquids,andrecognisingthevariabilityofbatchestheyintroducedLotnumbersin April1886sothatanyproblemsarisingcouldbetrackedbacktoparticularmaterialsand
34
J.W.England(ed.),(1922):15456 Heritage:aBriefHistoryofWarnerLambert andtheEntrepreneursWhoShapedIt(NewJersey:WarnerLambert,1987).

35
G.Tweedale,AttheSignofthePlough:275YearsofAllen&Hanburysandthe BritishPharmaceuticalIndustry (London:JohnMurray,1990):6769,81,120.

36 37 38 39
J.W.England(ed.),(1922):156. J.WyethtoBurroughsWellcome,(28June1881),WF:88/47:8. F.N.L.Poynter,(1965):142.
H.Kogan,TheLongWhiteLine:theStoryofAbbottLaboratories(NewYork: RandomHouse,1963)WilliamD.Pratt, TheAbbottAlmanac:100YearsofCommitment toQualityHealth (Elmsford,NewYork:Benjamin,1987).

40
J.T.Mahoney,G.D.Searle(1959):14455J.F.Marion,(1980):103.
46
47
41 conditionsofpreparation. An1884pricelistofEliLillyCo.ofIndianapolisstated:
Eachlotofdrugisexaminedbyassaybeforemanufacture.Wemakenoextrachargeon thisaccountandweconsideritourhighestdutyto knowourpreparationstobeofuniform

42 andfullstrength. Lillyhiredachemistandbotanistforcontrolworkfrom1893and
SmithKline&Frenchanalysedeverythingmadeandorganisedaresearchlaboratoryin
43 1900andaphysiologylaboratoryfrom1911.
Attheendofthenineteenthcenturybiologicaldrugs,socalledbecauseantiseraor antitoxinswereraisedinanimalsbytheinjectionofbacteria,wererecognisedas important,buttheresponseproducedinthebloodwashighlyvariable.Thesameproblem appliedtohormonalextractspreparedfromanimalorgans.Thesecouldnotbeassayed chemicallyandabiologicaltestofactivityinanimalswasrequired.ParkeDaviswasthe firsttohireapharmacologist,intheircasefromtheUniversityofChicagoin1894,to

44 producestandardiseddiphtheriaantitoxinandadrenaline. Liebenauexplainedhow
standardisedproductscouldbedifferentiatedonstrengthandpurity,reliabilityand consistency,ratherthanhavingtocompetelargelyonpricewithmanyfirmsproducingthe
45 samedrugs.
ThusinAmericathemaindevelopmentswereinthetechnologyofpresentingdifferent formsofmedicinesandinstandardisingthese.Inselectingthebestmedicinesto incorporateintotablets,firmsreactedtochangesofmedicalpracticeandincreasing

46 knowledgeofphysiology. Theethicalpharmaceuticalfirmsestablishedlinkswith
universitiessuchasWisconsin,whereinfluentialclinicianssuchasJohnJ.Abeloffered
41
ParkeDavisat100,ProgressinthePast,PromiseintheFuture,1866 1966 (Detroit:ParkeDavis,1966)JohnP.Swann,AcademicScientistsandthePharmaceutical Industry:CooperativeResearchinTwentiethCenturyAmerica (Baltimore:Johns Hopkins,1988):201M.L.Hoefle,TheEarlyHistoryofParkeDavisandCompany Bull.Hist.Chem.25.1(2000):2834.

42
JonathanLiebenau,(1987):43. JonathanLiebenau,(1987):1045. J.W.England,(1922):6. JonathanLiebenau,(1987):5,20,25.
43
44 45
46
P.Starr, TheSocialTransformationofAmericanMedicine:theRiseofaSovereign ProfessionandtheMakingofaVastIndustry (NewYork:BasicBooks,1982).
47
48
47 advice. SomeUSfirmssuchasAmericanCyanamidhadoriginsinchemical
manufacture,butnotontheGermanscaleandtherewasaverylimitedindigenousdye industry,althoughin1913MonsantoChemicalmadevanillin,caffeine,phenacetinand phenolphthalein.AmericasindustrywasprobablymidwaybetweenBritainandGermany

48 insizeattheendofthenineteenthcentury. TheUSfirmswereprotectedbytariffson
finishedgoods,butlikeBritainreliedheavilyonGermanyforsyntheticdrugsanddyes. 2.3GermanyandtheSyntheticModelfromthe1860s. ThehistoriographyoftheGermanchemicalindustryiscapturedunderthehistory

49 ofdyestuffs,ofindividualpharmaceuticalfirmsandmoregeneralreviews. Whileolder
50 51 GermanfirmssuchasMerck(1668) andSchering(1851) withpharmacyrootsbecame
justlyrenownedforthequalityoftheiralkaloids:afurtherwaveofnewpharmaceutical firmsevolvedfromdyestuffsmanufacturers.Althoughthesyntheticdyestuffsindustryhad originatedinEnglandwiththediscoveryofmauvebyWilliamPerkin,Britishfirmsfaced ashortageofchemistsandemployedmanyGermantrainedchemists,andwereovertaken

52 bytherapidriseofGermanfirmsfromthe1860s. In 1862thedyefirm,Meister,Lucius
53 &Co.wasfoundedatHoechst,nearFrankfurt. TheFarbwerkeFriedrichBayerwas
47
J.Parascandola,(1982):51227JohnP.Swann,(1988)E.R.Brown,Rockefeller MedicineMen:CapitalisminAmerica(Berkeley:UniversityofCaliforniaPress,1979):8, 24,56,63,71,121JohnP.Swann,ArthurTatum,ParkeDavis,andtheDiscoveryof MapharsenasanAntisyphiliticAgentJ.Hist.Med.andAlliedSciences40.2(April 1985):16787.

48
L.F.Haber,TheChemicalIndustryDuringtheNineteenthCentury:aStudyofthe EconomicAspectofAppliedChemistryinEuropeandNorthAmerica(Oxford:Clarendon Press,1958):173,17681.

49
J.J.Beer,CoalTarDyeManufacturersandtheOriginsoftheModernResearch LaboratoryIsis49(1958):12331.
50
FromMercksAngelPharmacytotheWorldwideMerckGroup16681968 (Darmstadt:Merck,1968).
51
Schering:FromaChemistsShoptoaMultinationalEnterprise,aCurriculumVitae/ th DesignConcept(Berlin:ScheringAktiongesellschaft,4 edition1997).

52
A.Arora,R.Landau,N.Rosenberg(eds.),ChemicalsandLongTermEconomic Growth:InsightsfromtheChemicalIndustry (NewYork:JohnWiley,1998)M.R.Fox, DyeMakersofGreatBritain.AHistoryofChemists,Companies,ProductsandChanges 18561976 (Manchester:I.C.I.plc,1987).

53
F.Aftalion,AHistoryoftheInternationalChemicalIndustry transl.O.Theodor, (Philadelphia:UniversityofPennsylvaniaPress,1991):41D.Gericke,100Years
48
49
54 establishedin1863. LeopoldCassella,foundedin1812asadyeimporter,madeaniline 55 coloursfrom1867,andby1870hadastaffof18menincludingfirstrankchemists. The
chemistssystematicallystudiedtherelationshipsbetweenchemicalstructuresandthe propertiesofthedyesandproducedsyntheticvariantsofexistingdyesleadingtonovel coloursthatexploitedexpandingmarkets. JustusvonLiebig,thesonofadruggistin Darmstadt,studiedalkaloidsinParis,buthealsodevelopedaspecialinterestinhow chemicalsreactedquantitatively,andheappliedthisknowledgetodrugs.Afterhe discoveredchloroformin1851,hetrainedchemistsandencouragedthemtoworkclosely withbiologistsindevelopingnewsyntheticdrugs,baseduponthemanychemicals

56 containedintheplentifulwastecoaltarextractsofthedyestuffsindustry.
Chloralhydrate,discoveredbyLiebigin1832wasextractedandtestedclinicallyas ananaestheticin1869,andthediscoveryofetherandphenolphthaleinin1871gavefurther
57 earlyindicationsofthepotentialbenefitsofsyntheticdrugs. PasteurandListershowed
thatphenolhadantisepticpropertiesandthisstimulatedGermandyefirmstodevelop furthersyntheticdrugsfromphenol,whichwasamajorwasteproductofthedye
58 industry.
Thesameprinciplesappliedtoproducingsyntheticdrugsandsyntheticdyes,but onekeydifferencewasthatthedrugshadtobeevaluatedfirstbypharmacologistsandthen intheclinic.InordertoachievethisBayerforgedlinkswithaschoolinWrzbergandthe
ServicetoMan:MilestonesoftheHoechstPharmaceuticalCompanyFortschr.Med.102 .20(24May1984):7577.
54
E.Verg, Milestones(Leverkusen:BayerAG,1988) FromGermaninto Acylureidopenicillin:ResearchthatMadeHistory (Leverkusen:BayerAG,1980).

55
E.Bumler,PaulEhrlich:ScientistforLife(NewYork:Holmes&Meier,1984):
80.
56
J.B.Morrell,TheChemistBreeders:theResearch SchoolsofLiebigandThomas ThomsonAmbix19(1972):146H.M.Leicester,Davis,DavyandLiebigJournalof ChemicalEducation (1951):28.

57
th F.N.L.Poynter(ed.),MedicineandScienceinthe1860'sProceedingsofthe6 BritishCongressofMedicine(London:WellcomeInstitute,1967)M.Weatherall,(1990): 2930,357.
58
R.J.Dubos,PasteurandModernSciencein ThePasteurFermentationCentennial 18531957:aScientificSymposium (NewYork:Pfizer,1988):1732G.T.Wrench,Lord Lister:hisLifeandWork(London:Unwin,1913).
49
50
59 UniversityofGttingen,andAGFAhadsimilarlinksinHeidelberg. Meister,Lucius&
BrningcollaboratedwiththeMarburgtrainedpharmacologist,HermannKolbeinLeipzig in18734,resultinginsyntheticacetylsalicylicacid,usedfortreatingrheumatismin1875
60 andasanantipyreticin1876.
By1878,Germanfirmsheldover60%oftheworlddyemarketandtheir dominanceinmanufacturingcapacityandproductionofchemicalintermediatesallowed
61 themtotakeanearlyadvantageintheproductionofsyntheticdrugs. Thus,thechief
industrialisednation(Britain)andthemostpracticalpeopleintheworldhadbeenbeaten
62 intheendeavourtoturntoprofitableaccountthecoaltartheypossessed.
Adepressionindyestuffsmarketsbetween1881and1885ledGermandyefirmsto diversifyfurther.Meister,Lucius&Brningusedtheirchemicalintermediatesas precursorsfornewindustriessuchasexplosives,photographicchemicalsand pharmaceuticalsandBayersubmittedtheirfirstpharmaceuticalpatentin1882forthe

63 antipyretic,phenacetin. Germandyefirmsalreadyproducedtheirownsolvents,acids
andchemicalintermediatesthatwereessentialfordrugsynthesis:sulphuricacid,chlorine,
64 causticsoda,benzole,toluole,naphthalene,phenolandanthracene. Theysubdivided 65 plants,standardisedoutputsandindustrialisedtheprocessofinvention. Thenewhealth
59
T.Lenoir,AMagicBullet:ResearchforProfitandtheGrowthofKnowledgein GermanyAround1900:Minerva26(1988):6688.
60
M.Tainter, AspirininModernTherapy (NewYork:SterlingDrugCompany,1969) 100YearsofAcetylsalicylicAcid:theUniqueCareeroftheActiveIngredientinAspirin (Leverkusen:Bayer,1997).

61
G.MullerThurow,IndustrialisationofInvention:aCaseStudyfromtheGerman ChemicalIndustryIsis73(1982):36368.
62
E.W.Jenkins,FromArmstrongtoNuffield.StudiesinTwentiethCenturyScience EducationinEnglandandWales(JohnMurray:London,1979):8.
63 64 65
J.C.OgilvieWill,OnSalicylicAcidLancet(18December1875):87072. ThisappliedespeciallytoBadischeandHoechst:L.F.Haber,(1958):16,130.
A.J.Levine,IndustrialRetardationinBritain18801974 (London:Weidenfeldand Nicholson,1967)J.A.Hobson,TheEvolutionofModernCapitalism (London:Allen& Unwin,1949):126G.MullerThurow,(1982):36381.
50
51
66 insurancelegislationin1883directeddyefirmsfurthertowardspharmaceuticals. Inthe
1880sand1890sMeister,Lucius&BrningandtheBadischeAnilinundSodaFabrik
67 (BASF)competedfortheadviceofthepharmacologistAdolphvonBaeyer andhis
students,CarlGraebe,CarlLiebermann,EmilandOttoFischer,andLudwigKnorr. However,onedisadvantageofcollaboratingwithanacademicresearcherwasthatifhe publishedhisresultsopenly,otherfirmswouldbefreetotakeupmanufactureofaproduct. RevisionofthepatentlawinGermanyin1891extendedprotectionfromtheprocessof productiontocovertheproductitself,furtherencouragingsyntheticchemistryasnew

68 productscreatedexclusivityandmonopoly.
Asecondstrategywastoemploytheacademicdiscoverer.In1883Meister,Lucius &BrninghiredAugustLaubenheimer,ProfessorofChemistryatGiessenUniversityand
69 heremainedwiththefirmuntilhisdeathin1904. PaulEhrlichinFrankfurtcollaborated 70 withLaubenheimerfrom1885. In1884BayersecuredCarlDuisberg,whohadtrained
inGttingenandJena,andheldaparttimepostwithvonBaeyer,tosetupapharmacology laboratoryatElberfeldatatimewhenonly40%ofGermanuniversities,andfew
71 elsewherehadsuchadepartment. Meister,Lucius&Brningdevelopedtheir
pharmaceuticaldepartmentafterLudwigKnorr,aformerstudentofEmilFischerat Erlangenwaspersuadedtojointhemin1893,andestablishedthefirstfulltimelaboratory
66
L.F.Haber,(1958)Especiallychapter5:108134.OnBritainsee13549:forFrance 15060:Switzerland161172andotherEuropeancountriesandtheU.S.A:173J.J.Beer, (1958):12331.

67
WalterSneader,(1985):29,84,114,250.
68
J.J.Beer, TheOriginsoftheGermanChemicalIndustry (Urbana:Universityof IllinoisPress,1959):371W.J.U.Woolcock,SocietyofChemicalIndustry,Leeds Chemist&Druggist103.1(25July1925):1378.

69 70
E.Bumler,(1984):xii,43,11012.
H.Loewe, PaulEhrlich,SchoepferderChemotherapie(Stuttgart: WissenschaftlichenVerlagsgesellschaft,1950):8990,95,123T.Lenoir,(1988):6688 E.Bumler,(1984):xii,43,55Jonathan Liebenau,PaulEhrlichasaCommercial ScientistandResearchAdministrator Med.Hist.34.1(1990):6578.

71
C.C.Mann,M.L.Plummer,TheAspirinWars(Boston:HarvardPress,1991):23 31L.F.Haber,(1958):135M.Silverman,R.Lee,Pills,ProfitsandPolitics(Berkeley: UniversityofCaliforniaPress,1974)S.Miall,HistoryoftheBritishChemicalIndustry (London:ErnestBennLtd.,1931):124.
51
52
72 inindustry. In1897HeinrichDreserofDarmstadt,ProfessorofPharmacologyat 73 GttingenwasappointedDirectorofResearchofBayer. Theexpansiondescribedabove 74 encouragedothertopGermanchemistssuchasHeinrichCaroandAugustW.Hoffmann,
whohadgainedexperiencewithEnglishdyefirmstoreturntoGermanyandestablish
75 laboratoriesatBayer(1888),Meister,Lucius&Brning(1891)andBASF. Asaresult
76 77 ofthefocusonpharmaceuticals,Meister,Lucius&Brning, Kalle, andMerckprepared
78 furthersyntheticantipyretics,antisepticsandpainkillers.
AfterthePasteurInstitutewasestablishedinParisin1888,theKochInstituteof HygieneandInfectiousDiseaseswasestablishedinBerlinin1890:bothhadstrong
79 supportfromtheirrespectiveGovernments. IncontrasttheBritishInstituteof
PreventativeMedicine(ListerInstitute)receivedlittlesupportfromtheGovernment,the
80 BritishMedicalAssociationorindustrialists. Koch'sInstituteattractedtheattentionof 81 manyGermanpharmaceuticalfirms. OneofKoch'sassistantswasplacedinchargeof
72 73 74
E.Bumler,(1984):75 WalterSneader,(1985):84. WalterSneader,(1985):27, 73,82.
M.R.Fox,(1987):1718,20,23,989,111,126forCaro,and4,10,15,20,28,63, 66,70,945,106,114,141forHoffmann.
75
S.Miall,(1931):66,745J.J.Beer,(1959):3656 FromGermaninto Acylureidopenicillin (1980) 50YearsofBayerRemedies18881938 (Leverkusen:Bayer, 1938)M.R.Fox,(1987):13W.Bernsmann,(1967):7.

76
WiedieErstenHeilmittelnachHoechstKamenDokumentesHoechsterArchiven 8(Frankfurt:Hoechst,1965):8,15.
77
WalterSneader,(1985):86.
78
K.H.Beyer,Discovery,DevelopmentandDeliveryofNewDrugs(NewYork:S.P. MedicalandScientificBooks,1978):24,1789L.F.Haber,(1958):128F.Sherwood Taylor,AHistoryofIndustrialChemistry (London:Heinemann,1957)M.Silverman, (1941):192212C.D.Leake,(1975):15865.

79 80
E.Bumler,(1984):49 50.
TheBritishInstituteofPreventativeMedicineorListerInstituteremained underfundeduntilalargebequestbyLordIveagh.TheBrownInstitute,theRoyal CollegesofPhysiciansandSurgeonsandAlmrothWright'slaboratoryatStMary'swere theonlyothersignificantmedicallaboratoriesinBritainZ.Cope,AlmrothWright: FounderofModernVaccineTherapy (London:Nelson,1966):9899H.Chick,The ListerInstituteofPreventativeMedicineEndeavour(July1949):106 111.

81
T.D.Brock,RobertKoch:aLifeinMedicineandBacteriology (Madison&Berlin: Springer,1999).
52
53
82 thetuberculinproductionplantatMeister,Lucius&Brningin1891. WhenEhrlich
movedtoBerlin,hisongoingcollaborationwithMeister,Lucius&Brningplacedthemin apositiontotestbiologicalagentssuchasdiphtheriaandtetanusantitoxins,discovered
83 therebyEmilBehring.
Germanfirmsachievedsignificantcommercialsuccessinthenewfieldofsynthetic drugsbyexploitingthestrengthstheyhadalreadydevelopedinsellingdyes.Theyhad alreadyachievedeconomiesofscalebyutilisingbyproductsofthedyeindustry,bothas startingmaterialsandaschemicalintermediates.Thecustomersweredifferent,so extensivemarketingwascombinedwithclosecollaborationwithphysicianstosupportthe introductionofanincreasingrangeofsemisyntheticderivativesthathadnotpreviously beenadministeredtopatients.From1894Bayermarketedderivativesoftannicacidfor thetreatmentofdiarrhoea,andthephenacetinderivativeSalophenasanantipyretic.In September1898BayerwidelyadvertisedHeroin(diaminomorphine)asacough

84 suppressantandsafealternativetomorphine. E.MerckofDarmstadtevaluatedsynthetic
derivativesofmorphinewiththeAustrian,JosefvonMeringandintroducedDionin,the
85 ethyletherofmorphinein1898.
Germanfirmsadoptedahardsellingapproach,discountingtheirdrugsand promotingthemheavily,astheyhadwithdyestuffs,establishingpricingandquota
86 agreements. Aspirin,discoveredbyBayerwaspromotedfrom1899onanunprecedented
82
ArnoldLibbertzbecamethefirstDirectorofthebacteriologyplantatHoechstin 1906,E.Bumler,(1984):2501G.MullerThurow,(1982):36381J.D.Bernal,Science andIndustryintheNineteenthCentury (London:Routledge&KeganPaul,1953):151.

83
H.J.Parrish,AHistoryofImmunisation (Edinburgh:Livingstone,1965)E. Bumler,(1984):5556,63,68T.Lenoir,(1988):6669,734J.Liebenau,Marketing HighTechnologyinR.P.T.DavenportHines(ed.), History,BagmenandMarkets: StudiesintheHistoryofMarketingandBritishIndustry (Aldershot:Gower,1986):8889 A.S.MacNalty,E.BehringBritishMedicalJournal (20March1954):66870.

84
WalterSneader,TheDiscoveryofHeroinTheLancet352(21November1998): 169799.
85
J.VonMering,PhysiologicalandTherapeuticInvestigationsontheActionof SomeMorphiaDerivativesTheMerckReport7(1898):513.
86
W.J.Reader, I.C.I.AHistory:TheForerunners18701926 volume1(London: OxfordUniversityPress,1970):8,87.
53
54
87 scaleto30,000doctors. Toassisttheuptakeofthesecomplexnewdrugs,theyreplaced
complicatedchemicalnameswithpronounceableTradenames(suchasAspirin)that continuedtobereferredtolongafterthepatenthadexpired.Theylabelledproductsin foreignlanguagesforexport,builtanextensivenetworkofagents,andperformed sophisticatedmarketresearch.Theyconvinceddoctorsoftheworthofsyntheticdrugs comparedtonaturalproducts, bothbyreferencetopharmacologyexperimentsandtothe publicationofclinicalresults.DoctorsinGermanyhadfewerreservationsthantheir

88 counterpartsinBritainaboutsupportingcommercialproductsinwriting. Having
convinceddoctorsofthevalueofsyntheticdrugs,Germanfirmsenhancedtheirexisting productsbychemicalmodificationtopreparestructuralanalogueswhichwereevaluated bypharmacologistsinanimalexperiments,soBayerssuccessfulTrionalsuperseded Sulphonalwhichwaslesssoluble,andbothwereovertakeninturnbyBayersVeronalin

89 1904. Itbecameapparentthatsmallchangesofchemicalstructureledtoenhanced
activityorabetteroverallprofileandthatthesecouldbesoldastangiblebenefitsto doctors. AthirdstrategyfordealingwithexternalconsultantswasadoptedbyMeister, Lucius&Brning.Thiswasthenegotiationofexclusiverightstoaproductsuchastheir localanaestheticNovocain(procainehydrochloride),synthesisedin1905by

90 ProfessorAlfredEinhornofMunich. Meister,Lucius&Brningandtheirsisterfirm
CassellaconcludedasimilaragreementwithEhrlichinwhichhecededallproductsfor
91 themtoselluniquelyinreturnfor30%ofprofits.
87
F.SherwoodTaylor,(1957):23R.Alstdter(ed.), Aspirin:theMedicineofthe Century (Leverkusen:Bayer,1985):24WalterSneader,TheDiscoveryofAspirin PharmaceuticalJournal 259(1997):6147.

88 89
C.D.Leake,(1975):157,1667C.C.Mann,M.L.Plummer,(1991):2331.
Similarlyphenolwasreplacedbychlorphenol.Salolwasreplacedbyquinoline derivativesthatincludediodinesuchasLoretinfromHoechst(1893)andVioformfrom Bindstedtler(1899),andUrotropinein1904.BindschedlerisnowpartofSandoz.Sandoz 18821961:75YearsofResearchandEnterprise (Basle:Sandoz,1961):136B. Holmstedt,G.Liljestrand,ReadingsinPharmacology (Oxford:PergamonPress,1963): 12834.

90
WalterSneader,(1985):55,98C.C.Mann,M.L.Plummer,(1991):2331J.J. Beer,(1959):366C.D.Leake,(1975):1667T.Lenoir,(1988):6688.
91
E.Bumler,(1984):125.
54
55
Thusbytheturnofthecentury,Germanfirmshaddevelopedanefficientmeansof transformingwasteproductsofthedyeindustryintoextremelyprofitablenewlinesof drugs.Theyheldamonopolyintheproductionofchemicalintermediatesandcreateda scientificauraaroundtheproductsbycollaboratingclosely,andevenemployingwell knownpharmacologists.Theyextendedsalestechniquestoprovidefreesamplesto doctorsandperformedclinicaltrials,buttheyalsocontinuedtousetheiroldtechniques ofcartelsandpricefixingandpatentprotectiontocreatemonopolies,whichweredifficult tochallenge. In1899BritainwasfeelingthefullforceofGermanmarketing.N.H.Martinofthe NewcastlebranchoftheSocietyfortheChemicalIndustrywrote: Hardlyamonthpassesbutsomenewsubstitutioncompoundwithatrivial nametoindicateitsallegedmedicinalpropertiesandascientificnameto suggestprofoundresearch.Theycomewithlaboratoryandmedicinalreports 92 inalanguagecalculatedtodeceive.
SuchwastheflowofGermansyntheticdrugsthatacartoonintheNationalDruggiststated afewofthelatestspecimensoftheincreasingflowofforeignsyntheticsandasked,
93 Willtheyneverstop?
2.4Ehrlich:Collaboration,StructureactivityTests,BiologicalStandardisation,and ClinicalTrials. Insteadofeachfirmproducingthesameextracts,thedyemanufacturersprepared uniquesyntheticproductsthatcouldbeprotectedbyprocessandproductpatentsandby tradenames.Thesewerethentestedwithpharmacologistsandtheirmechanismofaction waswellunderstood.TherelationshipbetweenMeister,Lucius&Brning(andother firms)andPaulEhrlichofBerlintypifiedthisnewapproach.Ehrlichmadeseveralmajor contributionstounderstandingdrugactions.Hedevelopedanimalmodelsofinfectionsto demonstratetheefficacyofsyntheticdrugs,soencouragingMeister,Lucius&Brningto

92
N.H.Martin,SyntheticMedicinalChemicalsBritishMedicalJournal (23January 1915):16869.

93
TheadvertisementincludedResorlin(madeinGermany),AntiKol(carries testimonials),Solantol(ascientificcompoundliteratureonapplication),Pixol(sendfor reporton100cases).PyrogallopyrineChemist&Druggist46(26January1895):141.
55
56
94 preparemanynewchemicals. Herecommendedto:examineallpreparationswhose
potencycanbemeasuredonlywiththeaidofphysiologicalexperiments,andinMay 1901hetestedadyefromCassella,whichwasthefirstmanmadedrugtocurean infectionwithoutkillingtheanimalsthiswasdevelopedbytheDrmstdterChemische

95 Werke.
Whenpharmaceuticalmanufacturersfirstpreparedbiologicalsera,itwasEhrlich whoarguedthatitwasessentialtouseseraofpreciselydeterminedconcentrationandhe
96 providedthisserviceforthem. Ehrlichrelatedchemicalstructuretoactivity:
Ihavetriedtointroduceamidogroups,sulphoradicals,etc.intotrypanred incertainpositionsandtherebyimproveitsefficacy....Ithinkthefieldof 97 experimentalchemicaltherapywillexpandincreasinglyinthefuture.
Thisstructureactivitybasedchemicalapproachtodrugselectionfordevelopmentwas uniquetoGermany,eventhoughsomeBritishacademicsusedthisapproachonasmall
98 scaletostudypharmacologicaleffects. However,thisrationaltherapeuticapproachstill
leftproblems.CarlBrowningperformedresearchwithEhrlich andcontinuedtoexamine
99 acridineandtheneutralnonmethylatedproflavinewhenhereturnedtoBritain. Ehrlich 100 andhiscolleagueLudwigBenda examinedhundredsofacridinedyesontrypanosomes,
94
TheVereingteChemischeWerkeofCharlottenburgmarketedamodifiedversionof arseniousacid,Atoxyl:E.Bumler,(1984):109,187,249.
95 96 97
98
L.F.Haber,(1958):1167,130. E.Bumler,(1984):5962,7175H.Loewe,(1950):137. E.Bumler,(1984):117.
A.CrumBrown,T.R.Fraser,OnthePhysiologicalActionoftheSaltsofthe AmmoniumBasesDerivedfromStrichnia,Brucia,Thebeia,Codeia,MorphiaandNicotia Trans.Roy.Soc.Edin.25(1868):151 204D.B.Dott,R.Stockman,TheChemistry andPharmacologyofMorphineanditsDerivativesYearBookofPharmacy (London: Churchill,1888)34955J.M.FortescueBrickdale,RecentAdvancesintheRelation BetweenChemicalStructureandPharmacologicalActionBritishMedicalJournal (16 January1915):106W.D.M. Paton,TheEarlyDaysofPharmacologywithSpecial ReferencetotheNineteenthCenturyin ChemistryintheServiceofMedicine(London: Pitman,1963):789.
99
C.Browning,JournalofPathology andBiology 18(1913):144C.H.Browning, ProflavineandAcriflavineBritishMedicalJournal (8April1967):111.

100
E.Bumler,(1984):1426,171,192,216,229.
56
57
whichwereparasitesthatcausedsleepingsicknessintropicalcountrieswhereGermany
101 hadcolonialaspirations,andherelatedtheiractivitytotheirchemicalstructure. Alfred 102 Bertheim, DirectorofMeister,Lucius&Brningturnedthewholestaffontopreparatory
workforEhrlich,andBendaeventuallyjoinedtheirpartnerCassella,beforethefirms
103 mergedtoformHoechst. Optochin,(ethylhydroxycuppreine),aderivativeofquinine,
andTrypaflavin(acriflavine)werefoundtobeactiveinanimals,butneitherwassuccessful
104 inhumansandtheformerwastoxic. Thisraisedthequestionthatalthoughanimals
wereusefulforpreliminarytesting,theultimatetestscouldonlybeperformedinman. Ehrlichreemphasisedtheimportanceofclinicaltrialsastheonlyaccuratewaytofinally evaluateanewdrugandstressedtheneedforcliniciansandchemiststocollaborate closely. Acombinationlikethatsuggestedheremeetsarealrequirementofmedical research,anddonotdoubtthatthiscouldachievemuchforthebenefitand wellbeingofthesickandwouldcertainlyleadtoanexpansionofour 105 therapeuticexpertise,andthediscoveryofgenuinecurativeagents.
IfchemicalssuchasAtoxylandTrypanRedweretransformedfromtheadministered substancetoactiveprinciplesinthehumanbody,thentheireffectwouldonlybeseenin studiesinpatientsasopposedtoanimalstudies.Thuswiththephenylarsonicacid,

106 'Arsacetin',fromtheendof1906Ehrlicharrangedclinicaltrials.
ThecontinuedsupportfromBayer,HoechstandtheVereinigteChemicalCompany
107 wasessentialtoEhrlich. HisworkontheantisyphiliticSalvarsanhighlightsthe
101
H.Loewe,(1950):87,91,12425M.Wainwright,AcridineaNeglectedAnti BacterialChromophoreJ.AntimicrobialChemotherapy (2001)47:113.

102 103
E.Bumler,(1984):1213,142,144,147,161,1656,171,192,204,2167,244.
T.S.Moore,J.C.Phillips,TheChemicalSociety18411941.AHistoricalReview (London:TheChemicalSociety,1947):618E.Bumler,(1984):244L.F.Haber,(1958): 131.

104 105 106 107
E.Bumler,(1984):251M.Weatherall,(1990):148. E.Bumler,(1984):118. E.Bumler,(1984):127.
E.Bumler,(1984):123,126,143145 H.Loewe,(1950):100,1923,2001K.H. Beyer,(1978):24.
57
58
practicalissuesinvolvedinpreparingandtestingthisdrugthesewouldhavetobefaced byBritishmanufacturerswhenSalvarsanbecameunavailableasaresultofthewar,as describedinChapter4.WhenhediscoveredSalvarsan,EhrlichrequestedofHoechsta largesupplyofachemicalintermediateinJune1909,whichenabledhimtoarrange

108 clinicaltrialsinSeptember1909,whichgavepromisingtherapeuticresults. Ehrlichwas
wisetotheneedsofindustry: Themostimportantthinginthefirstinstanceistocoverthefieldby immediateandexhaustivepatenting,possiblyevenofsuperfluous substances.Itwillbeofespecialimportanceforustoobtainprotectionfor 109 ourproductshereinthedevelopedcountries.
ByNovember1910therewere25peopleworkingonSalvarsanatHoechstandalmost 400,000ampoulesweremadeinthelastquarterof1910.Therapidityandthescaleofits clinicaltestingofSalvarsanbeforegeneralreleaseofthedrugattheendofNovember 1910wereimpressive.Ehrlichrecalledthat: Inthepastdrugswereusuallytestedinonlyafewhospitals,andoftenon fewerthanahundredpatients.Inthefuture,however,suchaprocedure wouldnolongerbeadequatetorevealanypotentialdefectsorharmful 110 propertiesofacompoundpriortoitsintroduction.
Hoechstsupplied60,000freesamplestodoctorstotreat10,000patients,andyetEhrlich wasstillcriticisedinsomequartersforintroducingSalvarsantooearly,andbyothersfor
111 delayingtheintroduction. By1911Hoechst'spharmaceuticalbusinessaccountedfor
aboutaneighthofitsmassiveturnover.SalvarsanbecameHoechstsandtheworldsbest sellingdrug,assalesgrewfrom50,000inthefirstyearto150,000in1911.Normally otherfirmswouldimmediatelycopysuchasuccessfuldrug,andalthoughHoechstfeltit wasunlikelythatotherfirmswouldachievethecomplexproductionofSalvarsan,they

108
Hoechstproduced'606'on2June1909anditwaspatentedon10JuneinGermany andinothercountriesbyOctober.Resultswereannouncedon18April1910atthe CongressofInternalMedicineinWiesbaden.Ehrlich'scompoundlogendedwith696or sodiumSalvarsanon11January1912E.Bumler,(1984):144,155,1612,264.

109
110 111
E.Bumler,(1984):128. E.Bumler,(1984):169. E.Bumler,(1984):180,186.
58
59
112 neverthelesskeptdetailsofthesynthesisofSalvarsansecretuntil1912. Despitethe
unsurpassedactivityofSalvarsan,problemsofproductionmeantthatitwaseasily contaminated,sotheplanthadtoworkunderconditionsnotpreviouslyencounteredin largescaleoperations,andspecialmachineshadtobedesignedforfillingthepreparation intovacuumsealedampoules.Muchoftheapparatushadtobemadeofsilverandthe

113 wholeproductionhadtoberunveryquickly.
ThecomplexityofthesynthesisofSalvarsanmeantpotentiallydangerous consequencesifimpuritieswerenotremovedandiftoxicbyproductswereadministeredto patients.Ehrlichsoughtalesstoxicandmoresolublepreparation,andfound'914'or Neosalvarsan,whichwasthenalsodevelopedbyHoechst,somaintainingtheirprewar

114 dominance. Ehrlichwasconsciousofthepotentialsideeffectsandhebelievedthatthe
developmentofatreatmentwithcompletelyharmlesssubstanceswouldremainan
115 unfulfilleddream. Thus,Ehrlichcanbeseendevelopinganimalmodelsofinfection,
systematicallytestingcompoundsandselectingthebestandincollaborationwithindustry suggestingalternativechemicalstructures.Hewasinvolvedinbothstandardising biologicalsandarrangingtheclinicaltestingofSalvarsanandplayedhispartinpromoting itsuse. ThemodeldevelopedbyEhrlichofscreeningmanyhundredsofchemicalswastaken upnotonlybyotherGermandyefirmsbutalsopharmacybasedGermanfirmssuchasJ. D.Riedel,ScheringAGandE.Merckthatbegantousechemistrytomodifynatural alkaloidalpreparations,andtheywerejoinedlaterbyC.F.Boehringer,Gehe&Co., SchimmelandCo.andthefinechemicalsmanufacturersE.deHaenofSeeke,vonHeyden,

116 Th.SchuchardtandKnoll&Co. Theattractionofthismethodofresearchwasthatit
providedpreparationsuniquetothecompanyandthesecouldbemanufacturedonalarge scale,standardisedandprotectedbypatentsandtrademarks.Theseweredrugsthat Britishmanufacturersinparticularcouldnotcopy.

112
L.F.Haber, TheChemicalIndustry19001930:InternationalGrowthand TechnologicalChange(Oxford:ClarendonPress,1971).

113 114 115
E.Bumler,(1984):2079. E.Bumler,(1984):181,265. E.Bumler,(1984):169.
59
60
2.5TheScopeofChemicalResearchinGermanPharmaceuticalFirms. IntheprevioussectionIdemonstratedhowGermandyefirmswereabletodevelop syntheticdrugsandhowfirmssuchasHoechstengagedasignificantnumberofchemists tooptimiseaproduct,culminatinginSalvarsanandNeosalvarsan.TheGermandyefirms hadvastresourcesofchemistswhowereabletoturntheirskillstomanufactureof pharmaceuticalsfromwasteproductsofdyemanufacture. Carl DuisbergofBayer,inalecturein1896,explainedhowhisfirmhad100 chemistswithuniversityeducation,65%withPhDsand25engineersfromTechnicalhigh

117 schoolstothinkofallpossiblereactionsandtomakeproductsmorecheaply. In1897
EmilFischerclaimedtherewere4,000chemists(excludingUniversitystaff)intheGerman Reich,ofwhich3,000workedinindustry.In1900BASFatLudwigshafenhadatotal staffof6,000including148chemists,75engineersandtechnicalexpertsand303 mercantilestaff.Meister,Lucius&BrningandBayerproducedtentimesasmany

118 patentsasBritishfirms. ABritishConsularreportdescribed4,500Germanchemistsin
1901,ofwhich69%werePh.D.s,10%hadaTechnicalDiplomaandafurther5%had both.ThiscomparedwithlessthanhalfofthetotalinEngland,whereonly21%wereeven
119 graduatesandonly10%hadaDiploma. Bayer'sstaffdoubledeveryfiveyearsfrom
119in1875to5,000inMay1902,including160chemistsand260engineersplus680 clerks.By1913theyhadgrownto10,600.Badischehad2,500menandHoechsthad
120 1,600including54chemists. Attheendof1913Hoechstemployed8,100includinga
121 commercialandscientificstaffof871andCassellaemployed3,000menby1913.
116 117
W.Bernsmann,(1967):7681.
C.Duisberg,TheEducationofChemistsChemist&Druggist48(13June1896): 83132.
118
A.G.Green,TheRelativeProgressoftheCoalTarIndustryinEnglandand GermanyDuringthePastFifteenYearsinW.M.Gardner,TheBritishCoalTarIndustry, itsOrigin,DevelopmentandDecline(London:Williams&Norgate,1915):198.

119
SirJ.Dewar,AppliedChemistry,EnglishandForeignPresidentialAddresstothe BritishAssociationinBelfast,1902inW.M.Gardner,(1915): 2226J.J.Beer, Isis (1987):36381L.F.Haber,(1971):401,48,133,865.

120
R.Meldola,TheScientificDevelopmentoftheCoalTarIndustryinW.M. Gardner,(1915):136.
121
L.F.Haber,(1971):128.
60
61
Merckhadthelargestfactoryofthepharmaceuticalmanufacturersandevenin 1905employed800workers,50pharmacologistsanddoctors,andatotalstaffof1,500. Thirteenyearslaterthishadgrownto2,000.Scheringhad935workersandapermanent

122 staffofabout300in1913. Germanfirmsnotonlyhadoverallstafflevelsaroundten
123 timeshigherthanBritishpharmaceuticalfirmsbutalsowereincreasingatafasterrate.
IntheirsemiannualreportofApril1903,Schimmel&Co.,amakerofessentialoils stated: Therearenogroundsforfearingthatit(theGermanChemicalIndustry) willbeoutstrippedbycompetitionfromabroad,solongasGerman 124 universitiespossesssucheminentrepresentativesofchemicalsciences.
DespitetheiralreadymassivescalecomparedtoBritishfirms,Bayer,Badischeandthe AktiengesellschaftfrAnilinfabrikationofBerlin(AGFA)mergedcreatingthe Interressengemeinshchaft(laterknownas'LittleIG')on1January1906toremain competitivewiththefirmofHoechst,formedbythemergeroftheFrankfurtfirmsMeister, Lucius&BrningandCassellainAugust1904,towhichKallewasaddedbetween1907

125 126 8. Theypooledprocessesandpatentsandagreednottocompeteinpharmaceuticals.
DuisbergofBayerwantedpharmaceuticalmanufacturerstomerge,butinsteadtheyformed theinformalPharmaIGin1905,withMerck,Gehe,J.D.Riedel,KnollandC.F.
127 Boehringer. TheonlyimportantpharmaceuticalfirmoutsideofthePharmaIGwas
ScheringanditssubsidiaryC.A.F.Kahlbaum.PharmaIGfirmsagreedtopoolprocesses,
122
L.F.Haber,(1971):133.
123
T.I.Williams(ed.),AHistoryofTechnology:TwentiethCentury190050volume V1(Oxford:ClarendonPress,1978):479.
124
SirWilliamA.Tilden,TheSupplyofChemicalstoBritainandherDependencies inW.M.Gardner,(1915):325.
125
Germanfirmshadcollaborated(VereinChemischerFabriken)sincetheearly nineteenthcentury,H.Hollander,(1955)G.C.Allen,MonopolyandRestrictivePractices (London:Allen&Unwins,1968).

126
TheHoechstagreementwason1519October1904.Duisbergarrangedcross licensingwithAGFAandCassellaandurgedthemoveintopharmaceuticals.Bayer BadischeAGFAwereintheratioof43:43:14signedon1January1906:L.F.Haber, (1971):47,124.

127
L.F.Haber,(1971):132134J.Slinn,AHistoryofMay&Baker1834 1984 (Cambridge:HobsonsLtd.,1984):78 79.
61
62
andexperienceandupholdeachotherspatentsandkeptcloserelationswiththedyefirms.
128 BayerandMerckalsocametoanagreementconcerningproductionofsedatives. British
firmsreliedonparticipatinginGermanruncartelstogivethemaccesstoatleastsome
129 modernGermandrugs. ManyofthesearedetailedinSlinnsaccountofMay&Baker 130 andincludedcartelsforcamphor,bismuth,chloroformandmercurialpreparations.
OutputofGermandyefirmstrebledfrom1881to1900,andtheirmarketsharerosefrom 50%tobetween8090%.By1914theGermanfirmsrepresentedanoverwhelming
131 dominantforce.
AbriefmentionhowevermustbegivenaboutSwissfirms,whichoperatedasifan extensionoftheGermanindustry.SeveralSwissfirmssituatedaroundBaselevolvedfrom
132 dyemanufacturersinasimilarwaytoGermanfirms. TheGesellschaftfrChemische
IndustrieBaselortheSocietyfortheChemicalIndustryinBasel(abbreviatedCIBAonly since1945)wasfoundedin1884fromagroupofearlierBaselmanufacturersincluding onethathadtradedindrugsfrom1758.Bindschedler&BuschandEdouardSandozalso openedtheirownfactoryin1886(becomingSandoz&Co.in1893)andtheymergedwith A.Gerber&Coin1898.TheformercanbetracedbacktoadyefirmfoundedinBaselin

133 1859. HoffmannlaRochewasfoundedin1896specificallytoproducepharmaceuticals
andunlikeotherSwissfirmsdidnothavedyestuffsroots.Inordertogainpatent
134 protectionitsoriginalsitewaswithinGermany. ThefiveSwissfirmscentredinBasel
128 129
L.F.Haber,(1971):134.
JonathanLiebenau,TheRiseoftheBritishPharmaceuticalIndustryBritish MedicalJournal (3October1990)301:726.

130
JudySlinn,(1984):80.
131
DavidS.Landers,TheUnboundPrometheus(Cambridge:CambridgeUniversity Press,1969):276.PaulM.Hohenberg,ChemicalsinWesternEurope18501914 (Chicago:RandMcNallyandCo.1967)J.J.Beer,(1958):123131.

132
CIBALtd.TheStoryofChemicalIndustryinBasle(Lausanne:Graf,1959)Paul Erni,TheBaselMarriage:HistoryoftheCibaGeigyMerger(Zurich:NeueZuriche Zeitung,1979)HansConradPeyerwithforewordbyPaulSacher,Roche:aCompany History18961996(Basel:EditionsRoche,1996) Sandoz18821961(1961)P.Bousell, H.Bonnemain,F.Bove,Sandoz:HistoryofPharmacyandthePharmaceuticalIndustry (Lausanne:AsklepiosPress,1983)The50YearsofSandozPharmaceuticalProducts (19171967)J.Med.Lyon (January1968)49(135):1378.

133 134
J.T. Mahoney,(1959):2323. HansConradPeyer,(1996)J.T.Mahoney, (1959):216236.
62
63
(CIBA,Sandoz,J.R.Geigy,L.Durand,Huguenin,andtheBaslerChemischeFabrik)
135 employed1,326peoplein1901andoperatedprofitsharingpoolsbetweenthem.
CIBAhad1,600staffin1913,HoffmanlaRochehad550,Geigy400,Sandoz340and DurandandHuguenin100.CIBAbeganmanufacturingpharmaceuticalsintheearly
136 1900'sandsoonaseparatesectionwascreated. Switzerlandthushadastrongindustry,
butwasstillheavilydependentonGermanyandboughtalltheprocesschemicalsandupto
137 80%ofallintermediatesfromGermany.
2.6FailureofBritainandOtherCountriestoDevelopSyntheticDrugs. France,likeBritainreliedheavilyonGermanyanddidnotproducesyntheticdrugs. BothQuirkeandRobsonhavecomparedtheoriginsandcomparativescaleofFrenchfirms withBritain.Quirkedemonstratedthatmuchofthepharmaceuticalinnovationcamefrom

138 collaborationswiththePasteurInstitute. Thelargestfirm,theSocietdesUsinesde
Rhne,employed700staff,including27chemistsin1900.By1913theyspecialisedin organicchemicals,especiallypharmaceuticals,photochemicals,andessencesandwerethe firstinFrancetoproducephenol. ThemuchsmallerPoulencBrothersfirmisalsorelevant tothisaccountastheycollaboratedwithBritainsMay&Bakerbeforemergingwith

139 UsinesdeRhnein1928toformRhnePoulenc. TheFrenchdyestuffsindustrywas
basedonnaturalalkaloidsandmineralsandFrancedidnotrecognisemedicalpatents. MostBritishfirmsweresmallincomparisonwithGermandyebasedfirmsevenbeforethe latterbegantomergeprewar.In1884therewere8001,000manufacturersmakingupto

140 5,000medicineswith19,000employedinmanufactureanddistribution. Severalsmall
135 136
L.F.Haber,(1971):20,113and169,F.A.SherwoodTaylor,(1957):384.
A.Buergin,GeschichtederGeigyUnternutze17581939(1958)L.F.Haber, (1971):1634 Sandoz18861961 (1961):136:J.T.Mahoney,(1959):216 236.

137 138
L.F.Haber,(1971):19,163.
MichaelRobson,(UniversityofLondon:PhD,June1989)ThePharmaceutical IndustryinBritainandFrance19191939V.Quirke,ExperimentsinCollaboration. TheChangingRelationshipBetweenScientistsandPharmaceuticalCompaniesinBritain andinFrance,19351965(UniversityofOxford:PhDthesis,1999).

139 140
JudySlinn,(1984):92,95101. Chemist&Druggist36(1890):367 Chemist&Druggist50(23January1897):
125.
63
64
localfirmswithpharmacyrootshavelongsincedisappeared,butsomedidwellsuchas JamesWoolleySons&Co.,Manchester(founded1796),ThomasKerfoot,Ashtonunder
141 Lyne,(1797),ArthurCox &Co.inBrighton(1839) ,StaffordAllen&Co.London, 142 143 (1833) andWilliamRansom&Sons,Hitchin(1846). Thefinechemical
manufacturer,ThomasMorson&SonsLtd.,originatedfromabusinessestablishedby ThomasNewbornRobertMorsonasanapothecary inFleetStreet,Londonin1821,having learntaboutalkaloidmanufactureinFrancefortheprevious3years.Heproducedthefirst

144 quinineandmorphineinBritain. ThomasN.R.MorsonwasPresidentofthe 145 PharmaceuticalSociety18489andagain185961. ThomasWhiffenswasfoundedin 146 1819andconcentratedonfinechemicals. Evans,Lescher&Webboriginatedfroma
firmestablishedinWoodStreetinLondonin1828byJohnSidneyLescher,afounderof
147 thePharmaceuticalSocietyandJohnEvans. May &BakerfoundedinBatterseain
1834,producedbismuth,mercurials,etherandspiritsbutmostnoveldrugswereboughtin underlicense.TheypreparedphenacetinandSulphonalunderan1887contractwith
148 Bayer. By1900May&Bakeremployedabout100people.From1903they
manufacturedsaltsoflithiumhavingsecuredtherightsbytakingonachemistwhohad patentedtheprocess.Itwastheirsearchforasourceofmineralfromwhichtoextractthe lithiumthatledtoarelationshipwithPoulencFrres. By1910May&Bakerhadsalesof

149 250,000butgrossprofitsoflessthan22,000andnetprofitsofjustover7,000.
141
C.Fearon,TheHistoryofA.H.Cox&Co.(ArthurHawkerFox18131903) PharmaceuticalHistorian 23.2(June1993):46.

142 143
S. Miall,(1931):133.
AllanDuckworth,Chemist&Druggist(10November1959):127139John RichardsCo.claimedtohavethelargestpillfactoryintheworldhavingregistered22,000 typesofpill.TheirstocksofBlaudspillswereusuallyton:F.N.L. Poynter, (1965): 133K.Holland,WilliamRansom&SonsPlcThePharmaceuticalJournal (14 November1987):5789.

144 145
L.G.Matthews,(1962):227,2312S. Miall,(1931):133.
S.W.F.Holloway,RoyalPharmaceuticalSocietyofGreatBritain18411991.A PoliticalandSocialHistory (London:ThePharmaceuticalPress,1991)appendix.

146
ThomasWhiffen18191904inD.J.Jeremy,C.J.Shaw(eds.),Dictionaryof NationalBiography V(London:Butterworth,1956):846S.Miall,(1931):13940.

147 148 149
ThelateT.E.Lescher,PharmaceuticalJournal 140(30April1938):460. JudySlinn,(1984):4445. S.Miall,(1931):141JudySlinn,(1984):79.
64
65
DuncanFlockhardt,foundedin1806inEdinburgh,producednitrousoxideandthen
150 chloroformanaestheticsfrom1848andJ.F.MacFarlan wasfoundedin1864. T.H.
SmithwasfoundedinEdinburghin1827StaffordAllen&Sonsfoundedin1833prepared drugsandessentialoils.WilliamJohnBushfoundedthefirmknownasW.J.Bushin Hackneyin1851,initiallymakingflavouringessencesbythesteamdistillationofherbs

151 andspicesbeforedevelopingdrugs. Beechamsbeganin1848asapatentmedicine
manufacturer,anddidnotproduceethicalpharmaceuticalsuntilaftertheSecondWorld
152 War. In1851thepatentmedicinemarkethadaturnoverof250,000andthelargest
companywasThomasHollowayofLondon,whointhatyearproduced25,000worthof
153 pills. T.&J.Smith(laterSmith&Nephew,whenH.N.Smithjoinedin1896)was 154 establishedinHullin1856,butremainedsmalluntiltheWar. A.BoakeRobertswas 155 foundedin1865initiallyproducedbrewingchemicals,flavouringsandessentialoils.
GlaxohadoriginsinNewZealandasJ.Nathan&Co.,importingdairyproduceinto Britainandonlybecameestablishedasababyfoodmanufactureratthestartofthe
156 157 twentiethcentury. TheLondonDrugCompany,andTaylors concentratedonthe
retailtraderatherthanproducingtheirowndrugs.Boots,establishedin1877were
158 retailersandexpandedtoachainof200shopsbytheendofthenineteenthcentury.
150
C.G.Drummond,Pharmacy&MedicineinGeorgianEdinburghPharmaceutical Journal 192(1964):287293PharmacyinScotlandChemist&Druggist81(27July 1912):146.

151
S. Miall,(1931):141W.J.Bush&Co.Ltd:ACentenaryJ.Soc.Chemical Industry (3March1951):168.

152
T.A.B.Corley,TheBeechamGroupintheWorldsPharmaceuticalIndustry 191470GesellschaftfrUnternehmensgeschichte(1994)(1):1830.
153 154
PharmacyinScotlandChemist&Druggist(27July1912):146.
R.Bennett,J.A.Leavey,A HistoryofSmith&Nephew(London:Smith& Nephew,1981).

155
W.J.Bush,StaffordAllenandA.BoakeRobertsnolongerexistandweremerged aspartofagroupcalledInternationalFlavouringandFragrancesInc.,www.iff.co.us
156
R.P.T.DavenportHines,JudySlinn,Glaxo,AHistoryto1962 (Cambridge: CambridgeUniversityPress,1992):1745.

157 158
GeoffreyTweedale,(1990):50,78,83.
Chemistry&Industry (23February1963):303S.Chapman,JesseBootofBoots theChemist(London:Hodder&Stoughton,1974)C.Weir,JesseBootofNottingham, Boots1994) ARecordofFiftyYearsProgressofBootsPureDrugCo.Ltd:Jubilee1888 1938(Nottingham:Boots,1938).
65
66
EventwoofthelargestBritishfirms,BurroughsWellcomeandAllen&Hanburys,
159 employedlessthan200staffinthe1890's. Allen&Hanburyswasfoundedin1715
andexpandedgradually,movingtoBethnalGreenin1874andtoVereStreetin1880, adoptinglimitedliabilitystatusin1893.Bythenthefirmwasproducingtheirownsoluble coatedpills,disintegratingtabellaeandhypodermicinjections,buttheysoldtuberculinthat hadbeendevelopedinGermany,andthyroidextracts.Attheendofthenineteenth century,Allen&Hanburysremainedafamilyrunbusiness,withsharesownedby

160 CorneliusHanburyandhissonFrederickJansonHanbury. Atechnicalchemist,John
Fordredwasemployedfrom1878,butformorecomplexteststheyturnedtothe
161 PharmaceuticalSociety. Theyemployedapharmaceuticalanalyst,WilliamRalphDodd
(18561917),toperformassaysandhebecameheadofasmallmanufacturinglaboratory afterhefoundthenewsiteatWareinHertfordshireandhewaselected totheboardin

162 1904. FrederickWilliamGamble(18721948)wasappointedasmanageroftheVere
Streetpharmacyin1900.HehadjoinedatPloughCourtin1896andtransferredtoVere Streetthefollowingyear,havingqualifiedfromthePharmaceuticalSociety.Hehada geniusforfriendlyrelationswiththemedicalconsultantsoftheneighbourhoodandwe

163 willencounterhimfurther. ArapidexpansionatWareinvolvedthebuildingofpastille
andcapsuledepartmentsin1900tocomplementthejujubeandlozengedepartmentsat BethnalGreen,whichhousedadministrationandprintingworksforadvertising.In1903 Allen&Hanburydevelopedandbeganusingtheprototypeofthemodernrotarytablet

164 machine. AtWareboilersandnewmouldingmachinerywereinstalled,milk
evaporationunits,rollers,electricmotorsandstills,andthechemistWilliamRadford,a trainedbuilder,eventuallybecameworksmanager.Between1900and1914,16,500was
159
160
A.G.GreeninW.M.Gardner,(1915):132 136L.F.Haber,(1971):16. GeoffreyTweedale,(1990):86.
161
GeoffreyTweedale,(1990):7374,79W.R.Dunstan,A.F.Dimmock, EstimationofDiastasePharmaceuticalJournal 38(1879):773775AVisittoMessrs. A.&H.WorksChemist&Druggist22(1880):14.

162 163
GeoffreyTweedale,(1990):73,87,89,108,115.
FrederickWilliamGamblewasapharmacisttrainedatKensingtonandthe PharmaceuticalSociety(18721948).HejoinedthepharmacyofAllen&Hanburysin 1896.GeoffreyTweedale,(1990):99.

164
C.Gunn,inF.N.L.Poynter,(1965).
66
67
spentonexpansionsatWare.Althoughtheemphasiswasonmilkandfoodproducts,they madebulkgalenicalssuchascascaraandliquoriceaswellascastoroil,liquidparaffinand codliveroilandasignificantlineinsurgicalinstruments. 2.7FactorsInhibitingtheDevelopmentofBritishFirms. 2.7.1Introduction. AnumberoffactorshavebeenexploredtoexplaintherelianceuponGermanyfor

165 noveldrugsandchemicals. Britainhadmanysmallindependentfamilyownedfirms.
TheonlysignificantmergerinBritainwasofseveralsmallfirmsin1908toformBritish
166 DrugHouses. Theyproducedhighlypurifieddrugsandhadlaboratoriesforquality
control,advertisingthattheywerethefirsttoofferawarrantyofnotonlycompliancewith theU.S.FoodandDrugsActandBritishPharmacopoeiabutevenmorestringent
167 standards.
Britishdyestuffsfirmsfailedtoproduceinnovativedyesandsocouldnotadaptto manufacturefinechemicalsanddrugs.Therewasalackofavailablechemists,specifically thosewithmanufacturingscaleexperience,alackofavailablechemicalintermediates, limitedmarketingcapacity,andresistancetotestingdrugsinanimalexperiments.British pharmaceuticalfirmsmadestandarddrugsfordoctors,whowereevenslowtoadoptpure
165
SirW.A.Tilden,TheSupplyofChemicalstoBritainandherDependencies JournaloftheRoyalSocietyofArts(27November1914): 26SirWilliamA.TildeninW. M.Gardner,(1915):315 334I.Singer,TheCoalTarColourIndustryofEngland: CausesofitsProgressandRetardationinW.M.Gardner,(1915):280297.

166
ThegrandfatherofBDHchairmanCharlesA.HillwasArthurStephenHillwhohad enteredthepharmaceuticaltradeintheseconddecadeofthenineteenthcentury.Hisfirm amalgamatedtobecomeDavy,YatesandHillthenmergedwithHodgkinsons,Clarkeand WardtoformDavy,Hill,Hodgkinsonandthenin1908becameBDHincorporatingBarron Harveys&Co.andHearon,Squire&FrancisLtd British&ColonialPharmacist (October1943):254in2130B.CARR/IVPressCuttings.CharlesAlexHill,BSc,FIC, PhD,wasChairmanofBritishDrugHousesfromitsinceptionon1January1909.Hillwas anAssociateoftheInstituteofChemistryfrom1895.

167
C.A.Hill,H.S.Collins,AnEffectiveMethodofApplyingtheGutzeitTestfor ArsenicChemist&Druggist67(30September1905):548C.A.Hill,ThePurityof PharmaceuticalChemicalswithSuggestionsforCommerciallyObtainableStandards Chemist&Druggist72(23May1908):79297C.A.Hill,QuantitativeColorimetric TestsforLeadChemist&Druggist66(11March1905):388T.TustingCooking,(Davy, Hill,Hodgkinsons)TheContaminationofZincanditsCompoundswithLeadChemist& Druggist69(29September1906):507
67
68
168 alkaloids,preferringformanyyearstousetotal plantextracts. FewdoctorsinBritain
appliednumericalmethodstoevaluatenewtreatmentsandyettheywerepersuadedbythe scientificrationaleandmarketingofGermansyntheticdrugs,testedpharmacologically, patented,soldunderTradenamesandpromotedheavily.Britishfirms,partlybyvirtueof theirlackofinnovation,failedtocollaboratewithuniversityscientists,pharmacologists

169 andclinicians.
AneminentgroupofBritishUniversityprofessorsgaveearlywarningsofthedominance ofGermanyandtheneedtoaddressthis.TheseincludedSirWilliamTilden,former ProfessorofChemistryinBirmingham18804,thenProfessoroftheRoyalCollegeof ScienceinLondon,whowasamemberoftheCounciloftheInstituteofChemistryandthe

170 SocietyofPublicAnalysts FrederickM.Perkin,asonofthedyefounderWilliam
Perkin,andheadofPerkins&Sons,whobecameheadofchemistryattheBorough
171 172 PolytechnicInstitutionin1897 RaphaelMeldola(18491915) whostudiedatthe
RoyalCollegeofChemistryin1866beforeworkingattheBrooke,Simpson&Spillerdye worksinHackneyWick.HetookthechairofchemistryatFinsburyCollegein1885and wasProfessorofOrganicChemistryatLondonUniversityfrom1912.Meldolaandothers gaveevidencetothe1904enquiryintothedeclineofthedyestuffsindustryandhewasin turnPresidentoftheSocietyofDyesandColourists,theSocietyoftheChemicalindustry andtheInstituteofChemistry.WilliamRamsay(18521916)wasProfessorofChemistry atUniversityCollege,Bristol18807andthenatUniversityCollegeLondonuntilhisdeath

173 in1916 ArthurGreensucceededMeldolaattheworksofBrooke,Simpson&Spiller
168
D.McKie,Woehlers'Synthetic'UreaandtheRejectionofVitalism:aChemical Legend Nature153(1944):608610F.G.Hopkins,TheCentenaryofWoehlers SynthesisofUrea(18281928)BiochemicalJournal 22(1928):13418.

169
M.J.Allen,TheStatisticalMovementinEarlyVictorianBritain:TheFoundationof EmpiricalSocialResearch (NewYork:Barnes&Noble,1973):135146A.M.Lilienfeld, 'Ceterisparibus':theEvolutionofClinicalTrialsBulletinoftheHistoryofMedicine56 (1982):118L.Lasagna,HistoricViewpointofClinicalTrialsDrugInformation Journal (1982):8.

170 171 172
ForaseriesofarticlesonthisseeW.M.Gardner,(1915). M.R.Fox,(1987):100.
AlexanderFindlay,WilliamHobsonMills(eds.),BritishChemists(London:The ChemicalSociety,1947):96110.
173
AlexanderFindlay,WilliamHobsonMills(eds.),(1947):219246 J.Chemical Society (1917)111:36976.
68
69
andwasthenworksmanageratClaytonAnilineuntil1901,whenfor2yearshewasa
174 consultant,thenProfessoroftinctorialchemistryatLeedsUniversity. TheseBritish
chemistscomplainedofanegativeattitude toresearchwithinBritain,defectivepatent laws,andgeneralGovernmentapathy.IncontrastGermanfirmshadextensivefinancial supportfromtheirgovernmentandtherewasmorecentralplanningofrailwaysand

175 waterwaystostimulateexports. Itwasnotgoingtobepossibletorebuildthedye
industryovernightbutthereweresomefactors,whichwerebroughttotheattentionof governmentasareasthatcouldbeaddressed.Alloftheaboveexpressedtheirconcerns withintheSocietyoftheChemicalIndustry(SCI),whichhadintroducedthefirstjournal

176 devotedtothechemicalindustryin1882. TheSocietyhad1,140membersby1882 177 climbingto2,697in1891.
2.7.2TheLackofPracticallyTrainedBritishChemistsandChemicalEngineers. ChemistsinBritainwereinshortsupplyattheendofthenineteenthcentury,
178 especiallythosewithpracticalexperienceinpharmaceuticals. WhenWilliamPerkin
179 juniorinheritedhisfathersdyeworksinthe1850s,hehadonly4chemists. In1867the

180 ChemicalSocietyinBritain(founded1841)hadonly192members. Oneofthefew 181 sourceswasOwensCollegeinManchesterwhereEdwardFrankland wasProfessorfrom
1851,untilhemovedtoSouthKensingtonin1856,withHenryRoscoetakingupthechair inManchester.AnotherwasthelaboratoryofTheophilusRedwood,Professorof
174
J.Baddiley,ArthurGeorgeGreenObituaryNoticesofFellowsoftheRoyal Society 4(1943):251 270.

175
W.H.Perkin,TheAnilineorCoalTarColours(1868)inW.M.Gardner, (1915):1 45.

176 177 178
S. Miall,(1931):vii SocietyofChemicalIndustryChemist&Druggist(11July1891):415. AcademicChemistryinL.F.Haber,(1971):3467W.F.Furter,(ed.) Historyof
ChemicalEngineering (Washington:AmericanChemicalSociety,1980).
179
180
JournaloftheSocietyoftheChemicalIndustry (1885)4:437.
D.S.L.Cardwell,TheOrganisation ofScienceinEngland,ARetrospect(London: Heinemann,2ndedition1972):99100C.S.Gibson,Endeavour(1947):638:T.S. Moore,J.C.Phillip,(1947).

181
C.S.GibsonandT.B.Hilditch,EdwardFranklandArmstrongObituaryNotices ofFellowsoftheRoyalSociety 5(19458):61829.
69
70
182 ChemistryattheSchoolofPharmacyatthePharmaceuticalSocietyinLondon. Aseries
ofeminentGermanchemistsincludingA.W.Hoffmannperformedresearchandtaughtat
183 theRoyalCollegeofChemistryfoundedin1845. Franklandworkedalongsidehim
sincetheopeningandsucceededHoffmannin1865,andheledtheearlycampaignsfor bettereducationofchemists.SouthKensingtonbecameanimportantsourceofindustrial
184 chemists. JustbeforeHoffmannleftforBerlin,HenryEdwardArmstrongjoinedthe
185 laboratory,firstasastudent,thenasanassistant. ArmstronghadstudiedattheRoyal
CollegeofMines,foundedin1851,andfrom1867underKolbeinLeipzig,andBunsenin Marburg.ArmstrongreturnedasProfessorofChemistryattheLondonInstitution, FinsburyCircusin1870.TheRoyalCollegeofChemistryandtheSchoolofMineswere amalgamatedinKensingtonin1872.In1874ArmstrongpublishedhisIntroductionto OrganicChemistry.HewasafoundermemberoftheInstituteofChemistryin1877, whichaimedtoincreasetheacademicstatus ofindustrialchemistry.Entrantsrequired3 yearstrainingplus3yearsteachingorindustrialexperience.InOctober1879hebecame thefirstProfessorofAppliedChemistryattheCityandGuildsInstitutefoundedin

186 November1878. Armstrongandotherseniorchemists,manyofwhomhadtrainedin
Germany,werebehindtheformationoftheSCIin1881,whichlobbiedforpatentreform
187 andtechnicalandpracticaltrainingofchemists.
182
TheophilusRedwood,ObituaryJournaloftheSocietyoftheChemicalIndustry 11(1892):2289.
183 184
D.S.LCardwell,(1972):867.
E.Frankland,ChemicalResearchinEnglandNature 3(1871):445D.Layton, InterpretersofScience:aHistoryoftheAssociationforScienceEducation (Bath:John Murray,1984):P. Mathias,TheFirstIndustrialNation:anEconomicHistoryofBritain 17001914(London:Methuen,secondedition,1983):221,419R.M.Macleod,The SupportofVictorianScience.TheEndowmentofResearchMovementinGreatBritainin 18681900Minervaiv(27),(1971):197230D.S.L.Cardwell,(1972):87.

185
G.VanPraagh,H.E.ArmstrongandScienceEducation(London:JohnMurray, 1973)SirFrederickKeeble,H.E.ArmstrongObituaryNoticesofFellowsoftheRoyal Society 3(1941):238 H.E.ArmstronginE.F.Armstrong,ChemistryintheTwentieth Century:AnAccountoftheAchievementandthePresentStateofKnowledgeofChemical Science(London:ErnestBenn,1924):122H.E.Armstrong(6May1848to13July 1937)inAlexanderFindlay,WilliamHobsonMills(eds.),(1947):5895.

186
D.S.L.Cardwell,(1972):127132.
187
W.H.PerkininW.M.Gardner,(1915):1SirWilliamA.TildeninW.M. Gardner,(1915):332,377S.Miall,(1931):86:A.J.Levine,(1967).
70
71
TheCityandGuildsInstitutemovedtotheFinsburyTechnicalCollegein1883and from1884itbecamethemoreadvancedCentralTechnicalCollegeatSouthKensington. HenryArmstrongwasbythenProfessorofChemistryatthegreatestchemicalengineering

188 schoolinBritain. Armstrongtaughtchemistrythatwaslargelyanalyticalwithsynthetic
chemistryonasmallscaletoexaminetheoreticalchemicalstructuresofalkaloidsandcoal tarproducts.HislearninginGermanyinfluencedhiscontroversialcampaignsforpractical heuristicmethodsofteaching.HehadconsiderableinfluenceasaFellowoftheRoyal SocietyandasSecretary,PresidentandVicePresidentoftheChemicalSocietyalmost continuouslyfrom1875untilhisdeathin1937andasPresidentoftheChemicalSection oftheBritishAssociation. ArmstrongslectureswithGeorgeDavisformedthebasisofathreeyeardiploma

189 ofchemicalengineeringlaunchedin1885. GeorgeDavispublishedthefirstBritishtext
190 onchemicalengineeringin1901,basedonhisownlecturesinManchesterfrom1887.
Heparticipatedinthe19023TechnicalEducationBoardwithmanyfamouschemists includingLevinstein,Roscoe,Dewar,W.H.Perkin,Ramsay,andGreenalongwith ThomasTyrerrepresentingdrugs,whorecognisedthattheshortfallwasinpractical

191 chemistsandparticularlychemicalengineers. HenryArmstrongrecognisedthatinorder
tocompetewithforeigners,soundscientificeducationwasneededandhenotedthat
192 Americapromisedtobecomeamajorcompetitor.
T.H.HuxleywrotetoTheTimesin1886thatthelastyearsofthiscentury promisetoseeusembarkedinanindustrialwaroffarmoreseriousimportancethanthe
193 militarywarsofitsopeningyears. ThelimitedresourcesofBritishpharmaceutical
firmsweredescribedin1889:
188
G.VanPraagh,(1973):21,60P.E.Richmond,A.R.Quarishi,Armstrong's HeuristicMethodSchoolScienceReview45(1964):517J.V.Eyre,H.E.Armstrong 18481937 (London:Butterworth,1958).

189
F.W.Keeble,(1941):240. G.VanPraagh,(1973):56.
190
191
D.S.L.Cardwell,(1972):195201ThomasTyrer,ObituaryJ.Societyofthe ChemicalIndustry (1918):91.

192 193
L.F.Haber,(1971):63. G.VanPraagh,(1933):52.
71
72
Ourhistoricdrughouses,whohavealwaysactedmoreorlessas manufacturers,havemuchtotheirdetrimentneglectedresearch.Each establishmentshouldhaveitschemistengagedinthechemicalexamination ofnewremediesforthediscoveryofactiveprinciples,etc.whichmusthave tendedtohavekeptusoutofthearmsofforeignersformostofouralkaloids andotherorganicsubstancesnowinsuchincreasingdemandin 194 medicine. Giventhelackofchemicalengineers,itisimportanttointroduceonethattrainedwith HenryArmstrongandlaterenteredindustrywithBurroughsWellcomeandplayedamajor partinthedevelopmentofchemicalengineeringinthepharmaceuticalindustry. FrancisHowardCarr,astudentofArmstrongatFinsburybecameoneofthemost
195 importantchemicalengineersinthepharmaceuticalindustryintheinterwarperiod.
Carrplaysacentralpartinthisthesis,establishingmanufacturingsyntheticchemistryat BurroughsWellcome,BootsandBritishDrugHouses,aforerunnerofGlaxo.Hewasborn inCroydon,theseventhof12childrenofstrictBaptistparents.Afterleavingschoolat15 yearshewastohaveenteredaCityMerchantsoffice,butonthedayhewasduetostarthe pulledoutfortunatelyhisfatherrecognisedthathisloveofchemistrywouldberewarded byattendingFinsburyTechnicalCollege,wherehewastostudywithHenryArmstrong between188992.Althoughhehadtoleaveaftertwoyearseitherthroughillhealthorfor financialreasons,hecompletedhisDiplomaandArmstrongintroducedhim toW.R.

196 Dunstan,whohadrunthePharmaceuticalSocietylaboratorysince1879. FrancisCarr
thenbecameresearchassistanttoDunstanatthePharmaceuticalSocietyfrom18926, wherehewasawardedthefirstSaltersscholarship,andthenfollowedhimtotheImperial Instituteashisassistant,whenDunstanbecameScientificDirectorin1896.Armstrong furthersupportedhisprotgeandencouragedCarrtotakeupmembershipoftheInstitute ofChemistryin1895andtojoinhisownLondonclub,theAthenaeum,tointroducehimto

197 influentialbusinessmen.
CarrexplainedthattherehadbeeninsufficienttrainedchemistsinBritain:
194
C.Umney,PresidentialAddress,BritishPharmaceuticalCongress, PharmaceuticalJournal 49(14September1889):21418.

195
T.A.Henry,WyndhamRowlandDunstan(18611949)ObituaryNoticesof FellowsoftheRoyalSociety 7(1950):65.

196
T.A.Henry,(1950):62 81.
72
73
Itisnotsomuchmorecollegesandmorestudentsasitisbettermethods oftrainingwhichneedtobeconsideredinconnectionwiththe educationalquestionwhichisonlyoneofthemanyimportantsidesofthe problemofthechemicalindustryinthiscountry.Thetechnicalcollege shouldgobeyondtheprocessofdevelopingthemindtothatofthe 198 applicationofmentalprocessestotheproblemofindustry. CarrbecameactiveinpromotingpracticaltrainingofchemistsatFinsbury,buthealsohad asignificantdirecteffecthimselfintrainingothersonthejobashemovedfromfirmto firm. HejoinedBurroughsWellcomeatDartfordinJanuary1898asChiefManufacturing Chemist,andhisinfluencetherewillbediscussedinChapter3. 2.7.3.PatentProtection. SCImemberswerebehindchangesinthepatentlawswithIvanLevinsteinon
199 behalfofLevinsteinsandotherdyefirms,andThomasTyrerleadingthecampaigns.
IvanLevinsteinsfirmhadbeenfoundedagenerationearlier,butheexpandedthebusiness toBlackley,northofManchesterin1865andemployed20menbytheendofthe nineteenthcentury.LevinsteinwasPresidentoftheChamberofCommercein1903,but resignedhisposttotakepartinJosephChamberlainsTariffCommissionandhewas

200 VicePresidentoftheTariffleague. ThomasTyrerhadbeenapartneratMay&Baker
andwhentheoriginalpartnershipwasdissolvedhehadsetuphisowncompanyin1898by
201 acquiringtheStratfordChemicalWorksinEastLondon.
AsaresultofthedriveofTyrerandLevinstein,the1907PatentLawAmendment, cameintoforceinJanuary1908,compellingGermancompaniestotransferpartoftheir productiontoBritaininorderforpatentstoremainvalid.Thiswasanattempttostimulate thechemicalindustryinBritain,toprovidepotentialjobs,andstimulatethestudyof chemistry.FollowingtheAct,thegroupofBASF,AgfaandBayerboughtasiteat
197
F.H.CarrarchivesatImperialCollegeTranscriptsbyA.E.GuentherB.CARRFH
6.
198
F.H.Carr,PresscuttingsletterOpinionsonEducationPre1914,Carr2130 B/CARRIV.3
199
M.R.Fox,(1987):51 52W.J.Reader,I.C.I.AHistory:TheForerunners1870 1926 volume1:265.

200 201
M.R.Fox,(1987):216.
JudySlinn,(1984):54.HewasawardedthemedaloftheSocietyoftheChemical Industryin1910andremaineditstreasurerforthe10yearsbeforehediedin1918.
73
74
BromboroughontheRiverMersey,whileasecondgroupcomprisingmainlyHoechst
202 boughtasiteatEllesmerePort,Cheshire.
Whereastheoriginalintentionofthe1907Actwastoforcetheproductionofdyes neededfortheBritishmarket,acourtrulingtwoyearslateremasculatedtheActby allowingfirmstoimportmanyintermediatesandsemifinishedgoodstheyonlyneededto

203 sellaproportioninBritainanditwasimpossibletocheckwhatwasimported.
2.7.4AlcoholSuppliesandDuty Britishdyefirmshadcampaignedforlongperiodstohavetheexcisedutieson ethanolreduced.Alcoholwasneededasasolventinwhichtodissolvevariouschemicals inordertogetthemtoreact,andwasrequiredinthepreparationofsaltsandasachemical intermediateitselfinarelativelypurestate.Inadditionitwasessentialtohaveasupplyof cheapacetone,andaceticacid. However,thegovernmentbelievedthatifalcoholwerenot taxedheavily,itwouldbeusedfordrinkinganddistillationandinBritainspiritswere methylatedtopreventthis. Thegovernmentalsohadconcernsoverthehighamountsof alcoholusedinpatentmedicinesandtonics. However,boththeexcisedutyandthe purificationcostswereprohibitiveforindustry,andasaresultcertaindyesandchemicals couldnotbeproducedcosteffectivelyinBritain. Thegovernmentgavenoconcessionsto
204 industry incontrasttoGermanywhereitwasavailableatspecialratestoindustry. The
priceofetherwasthreefoldhigherinEnglandthaninGermany,althoughBritaindid
205 prohibittheexportofphenolfrom1901. Adepartmentalcommitteeonalcoholreported
onthesituationin1905,butdidlittletohelpasthegovernmentfailedtoreducethe
206 duty. Absolutealcoholwasespeciallyusedforthemanufactureofchloralhydrate,and 207 in1913weimported28,994proofgallonsfromGermany.
Theavailabilityofacheapsourceofmanufacturedalcoholasastartingmaterialfor drugproductionwasconstantlymentionedasoneofthemainhurdlestodrugdevelopment.
202 203 204 205 206
M.R.Fox,(1987):5152. M.R.Fox,(1987):3233. M.R.Fox,(1987):43 L.F.Haber,(1971):13.
DepartmentalCommitteeonAlcoholReportQ1378,(ed.)2477(London:HMSO, 1905).
207
Chemist&Druggist85.2(19September1914):489M.R.Fox,(1987):43.
74
75
AttheoutbreakofWaritwasstatedthattherewasfurtherdiscussiononalcoholsupplies
208 anditwasstatedthat: ifthiscountryhaddutyfreealcoholGermanywillnotbeina 209 positionforsometimeafterthewar,ifeveragaintoexporttheirpreparations.
2.8TheExtentofRelianceonGermanyforPharmaceuticalsandEspecially Synthetics. AlthoughtheproductionoforganicchemicalsincreasedinGreatBritainbetween 1880and1910,exportsofBritishchemicalsrosemoreslowlythanimportsbetween1900

210 and1914. Laterin1926whenFrancisCarrgavehispresidentialspeechhelookedback
totheperiodbeforethewar.HerecalledthatstatementstotheeffectthattheBritish chemicalindustrywasnegligiblewereexaggeratedasthenumberofworkersinthe
211 chemicalindustrieshaddoubledbetween1900and1914. Furthermoretheshortagesof
syntheticswere: Notsolelybecausetheywerenotmadehere,forseveralfirmshadachieved thatalreadybutantipyrin,aspirin,salicylicacid,phenacetin,chloralhydrate, salol,phenolphthalein,saccharin,veronal,sulphonal,trional,eucaineand novocainewerenotmanufacturedhereandtheseamountedtoover1m 212 worthofsyntheticdrugs. Thisapparentlymisleadingquotationmeantthatalthoughtechnicallymanyofthe chemicalscouldbemade,atleastonasmallscale,itwasnotpossibleforBritish manufacturerstopreparetheminbulkonacompetitivebasis.Owingtoourinferior organisationwethusbecameinameasuretheshuttlecockofGermanmenofbusiness. Itwasstated:beforethewaritwouldhavebeenverydifficulttoproducethesalicylates here.EvensimplesyntheticssuchastheunpatentedAspirinwerenotproduced
208 209
F.M.Perkin,inW.M.Gardner,(1915):298314.
EdwinJ.Tookey,MakingFineChemicalsChemist&Druggist85.1(29August 1914):63.
210
H.W.Richardson,ChemicalsinD.H.Aldcroft(ed.), TheDevelopmentofBritish IndustryandForeignCompetition18751940(1979)L.F.Haber,(1971):121,148.

211
F.H.Carr,textofhis1926SCIspeech,ManufactureofOrganicMedicinal ChemicalsinhisarchivesatImperialCollege.B/CARR/IIILectures192060.Hedidnot givetheactualnumbersofchemists.

212
F.H.Carr,SyntheticOrganicDrugs:TheirManufactureasAffectedbytheWar Chemist&Druggist88.4(29July1916):778779.
75
76
commerciallyinBritainbecauseitcouldnotbeproducedatpriceswhichcouldcompete
213 withthoseatwhichGermanywasabletoofferthem.
TheantifebrileeffectofAntipyrinhadbeendescribedandpatentedinJuly1883, buteventhoughallofthesyntheticpatentshadexpiredBritishfirmscouldnotprepareitto
214 sellcompetitivelyagainstGermanfirms,andthesamewastrueofLanolines. In
additionsomealkaloidsincludingatropine,cocaine,emetine,hyoscine,morphine, ergometrinewereonlymanufacturedinGermany.Carrcontinued: PreWarGermanystradewasverymuchenhancedbysellingcartelsand thedrawingtogetheroflargemanufacturingconcerns.Thefirst achievementsweretheeliminationofcompetitionwithinGermanyandthe organisationofconcertedeffectstoundersellrivalsinthoselineswhere dangerouscompetitionseemedlikelytoarise.Therewascertainlyplentyof evidenceofthesesalescartelsandthepracticeofsellingbelowcostatthe 215 leastthreatofcompetition. Insummary,aseriesoffactorsconspiredagainstBritishmanufacturingchemists.Firstly therewerelessuniversitytrainedchemistsinBritainthaninGermany,andmanyofthem weretrainedontheoreticalratherthanpracticalgrounds.ThesizeofGermanfirmswas muchgreaterthanBritishfirms,sothereweregreatereconomiesofscaleandGermany hadsubsidisedtransportandcheaperrawmaterials,particularlyethanol.Itwasnotbeyond thewitofBritishchemiststomakethedrugs,buttheycouldnotmanufacturethemas cheaplyastheGermanscould.However,althoughpriortothewar,themanufactureof organicfinechemicalproductsbysynthesiswastoaverylargeextentacontinental
216 monopolytherewasneverthelessabeginningmadewithinthiscountry.
Asfurtherevidenceof theimportanceofGermansynthetics,TheRoyal Commissiononvivisection,whichreportedin1912,listedthedrugsthathadrecentlybeen introducedasaresultofanimalstudies.Theseincludedthesoporificschloral,sulphonal andveronallocalanaestheticscocaine,eucaineandstovaintheanalgesicsand antipyreticsantipyrin,antifebrin,phenacetinandexalginphysostigmine(oreserin)for

213
F.H.Carr,textofhis1926SCIspeech,ManufactureofOrganicMedicinal ChemicalsinhisarchivesatImperialCollege.B/CARR/IIILectures192060TheWar andtheScarcityofSomeDrugsBritishMedicalJournal (27March1915):559561.

214 215
Chemist&Druggist 85.2(15August1914):37patent26429from22July1883.
Acartelexistedforiodineandotherdrugs:TheWarandtheScarcityofSome DrugsBritishMedicalJournal (27March1915):559561.

216
D.L.Howard,British&ColonialPharmacist(August1926):243.
76
77
glaucomaamylnitritesforanginaandthediureticscaffeine,theobromine,diuretinand
217 urotropin. OutofatotalofchemicalimportsfromforeigncountriesandBritish 218 possessionsof1.3m,morethan25%wasfromGermanyin1913. Figures,specifically
fordrugsarenotreadilyavailable,asdrugswereoftencombinedwithchemicals,polishes, glasses,gelatine,plastics,andartificialsilk. TheEmpirealsoreliedonGermany.Indiatook8.5mofproducefromGermany and3mfromAustriawhileAustralia,NewZealandandCanadaallreliedonGermanyfor

219 chemicalintermediates. ContemporaryaccountsshowhowBritainreliedonGermany
forthesyntheticalandotherdrugs,whichhaveinsomewaysrevolutionisedmedical
220 science,andalsomanyofthemoreimportantdisinfectants. Germansyntheticswere 221 seenby1914asaseriouscompetitiontoourtrade.
Britishfirmsmanufacturedprofitablelinessuchasmorphine,strychnineand caffeinewhileotheralkaloidswerelefttoGermanywhointurntooktheirrawmaterials fromBritishcolonies.Smiths,Morsons,Howards,Whiffens,andMacFarlanes betweenthemmademorphine,brucine,strychnine,quinine,caffeine,nicotineandsalicin andanumberofotheralkaloidsinBritain.Aswillbedescribedinthenextchapter, BurroughsWellcomeproducedpilocarpinesalts,hyoscine,atropine,emetine, apomorphine,aconite,colchicines,cotarnum,homatropine,hydrazolineandspaline.Pre WarBurroughsWellcomepreparedseveralofthesesynthetically,atleastonasmallscale

222 inordertoestimatethepurityoftheirextracts.
217 218
VivisectionVindicatedBritishMedicalJournal (16March1912):6267.
W.H.Perkin,DrugsUnenumerated,includingMedicinalPreparationsinThe AnilineandCoalTarColoursJ.RoyalSoc.ofArts (27November1916):76.

219
WarandBusinessChemist&Druggist88.4(29July1916):7989.
220
Prof.W.H.Perkin,ThePositionoftheOrganicChemicalIndustryinW.M. Gardner,(1915):408.
221 222
S.Chapman,(1974):96.
MalayFineChemicalsChemist&Druggist85.1(22August1914):46D.B. Dott,VegetableAlkaloidsHowtheWarhasAffectedProductionChemist&Druggist
77
78
2.9ConcludingRemarks. InthelatterhalfofthenineteenthcenturyBritainhadcometorelyonGermanyfor manydrugsandinparticularsyntheticdrugs.BritainexportedcoaltarstoGermanyand thenimportedfinisheddyesandasaresultfailedtodevelopitsdyeindustry,sobecoming reliantonGermanyforchemicalintermediates.Manyofthedrugswereneededurgently fortheWarpainkillers,anaestheticsandantisepticsplusantitoxinsandvaccines.The focusofBritishfirmswasmoretowardsextractionofoils,alkaloids,glucosides,thanthe preparationofsyntheticchemicals.Britishfirmsweresmallincomparisontotheir Germancounterpartsandcouldnotcompeteonefficiencyofproductionorprice,andif theytriedtotheGermanshadmanycartelsandpricingarrangementsthatitwasbestnotto competeheadtohead.Britishfirmsthereforeproduceddifferentalkaloidsandextracts. WhereasGermanyledthewayonsyntheticchemistry,itwasinAmericathatmostnovel dosingformswereinventedandthisbringsustoanexaminationofhowanAmerican importerofmedicinescreatedaniche,byestablishinghisownfirmofBurroughs Wellcome.Thesuccessofthisfirmanditsadoptionofchemicalsyntheticworkisthe subjectofthenextchapter.
88.4(29July1916):777T.A.Henry,ThePlantAlkaloids(London:J.andA.Churchill, 4thedition1949):xi,4R.Robinson,JournaloftheChemicalSociety 111(1917):876.
78
BurroughsWellcome:BritishOriginsofCollaborativeResearch.
79
CHAPTERTHREE: BurroughsWellcome:BritishOriginsofCollaborativeResearch. 3.1Introduction. InthischapterIexaminehowthefirstresearchbasedBritishpharmaceuticalfirm, BurroughsWellcome,restructuredthepharmaceuticalmarketinBritainbyincorporating novelalkaloidsandGermansyntheticdrugsintoAmericanstyletablets,andbytakingthe bestofbothcountriesmarketingtechniques:theuseofTradenamesandscientific advertisingfromGermany,andtheuseoftravellingrepresentativessellingdirectlyto doctorsasinAmerica.Withthecreationofscientificlaboratoriesemployingprominent physiologistsandchemists,BurroughsWellcomechangedtherelationshipsbetween industry,academiaandgovernmentinBritain,andbetweenlaboratoryscienceandmedical practice.BurroughsWellcomewasthefirstBritishfirmtorecognisethecommercial advantagesofadoptingscientificmethodsandbasingnewproductsonlaboratory investigationstheaimthroughoutwastodifferentiatetheirproductsfromthoseofother
1 firms. Whenthegovernmentthreatenedtaxingthemaspatentmedicineproducers,
becauseoftheiradvertisingandimportationofmedicinesfromAmerica,thefirm respondedbyproducingethicaldrugs,characterisedchemicallyandstandardisedby biologicaltestinginanimals. IwillshowhowBurroughsWellcomeutilisedsyntheticchemistryonasmallscale toconfirmthestructureofphysiologicallyactiveprinciplesisolatedfromplants,andhow theyinvestigatedtheactivityofsyntheticchemicalderivativestogainanunderstandingof therelationshipofchemicalstructuretophysiologicalfunction.Thishasnotbeen previouslyrecognisedasacharacteristicoftheBritishpharmaceuticalindustryattheendof thenineteenthcentury,anditwasthesechemicalskillsthatenabledthefirmtoeventually produceitsownsyntheticdrugs.EvenBurroughsWellcome,theBritishfirmwiththemost advancedchemistry,onlyrarelymanufacturedsyntheticdrugsonacommercialscale.In 1908FrancisCarrcitedthatproductionofsuprarenalhormonewasperformed chemically,whilecodeineandoutofpatentdrugssuchasAtoxylandisoquinoline
M.Weatherall,ResearchinthePharmaceuticalIndustry:19thCentury PharmaceuticalJournal 242(1989):543545.
79
80
2 derivativesofadrenaline(Suprareninsynthetic)weremadeinsmallquantities. However,
BurroughsWellcomechosenottocompetedirectlywithGermanfirmsinproducing syntheticdrugstheysolddifferentalkaloids,incorporatedGermandrugsintotheirown uniqueTabloidsanddifferentiatedtheirproductsbypurifyingandstandardisingthemin animaltestsagainstpuresyntheticchemicalstandards.Indoingsotheycreateda frameworkforestablishinganewtypeofdrugdevelopmentinBritain. ThischapteralsointroducesthemanyindividualsfromBurroughsWellcomethat playedamajorroleintheestablishmentoflaboratoriesattheMRC,thePharmaceutical Societyandinotherpharmaceuticalfirms,andhelpedtodeveloptheregulatoryframework fordrugdevelopmentintheinterwarperiod. ThehistoriographyofthefirmofBurroughsWellcomehaspreviously concentrated
3 onthefirmspharmacyorigins. Tanseyhasexaminedtheoriginsofphysiologicalresearch
4 indetail. Othershavefocusedonthepartnersthemselves,particularlyWellcome,because 5 ofhislastinglegacy. Thechemistryandmanufacturingsidehasreceivedlittleattention,
butwasequallyimportanttothedevelopmentofBurroughsWellcomeandtotherestof theBritishpharmaceuticalindustryIthereforelimitexaminationofthephysiology laboratoriestotheirrelationtothechemicallaboratories,thegrowthofthefirms manufacturingcapacity,andtheirdealingswithexternalcollaborators,particularlyrelating toclinicaltrials. Liebenauconcludedthatproductdevelopmentandresearchevolvedoutofearly

6 laboratoriesthatperformedassays,buthegavenoexamplesotherthanserumtherapies.
D.L.Howard,British&ColonialPharmacist (August1926):243.
J.Liebenau,TheRiseoftheBritishPharmaceuticalIndustryBritishMedicalJournal 301(1990):724728G.MacDonald,InPursuitofExcellence:OneHundredYearsof Wellcome(London:WellcomeFoundationLtd.,1980).

4

5
J.R.Vane,TheWellcomeCentenary.HenryS.Wellcome,hisResearchPhilosophy andCurrentExcitementsTrans.Med.Soc.London 97(19801):4150.

6
J.Liebenau,MedicalScienceandMedicalIndustry:TheFormationoftheAmerican PharmaceuticalIndustry (Basingstoke:MacMillan,1987):410.
80
81
HereIshowthatthesituationwasmorecomplex.Iarguethatthechemistryperformedin Britainhaspreviouslybeenverymuchunderestimated:techniquesandexpertisedeveloped beforetheGreatWarexplainhowBurroughsWellcomewereabletorapidlyproduce syntheticdrugswhentheybecameunavailablefromGermany. 3.2TheEstablishmentofBurroughsWellcome(1880). InordertounderstandthestrategiesadoptedbyBurroughsWellcomeitisessential tounderstandthefirmsoriginsasanimporterofAmericanmedicines.Althoughseveral authorshaveexaminedpartsoftheBurroughsWellcomestorythereisnocomprehensive overview.ThefollowingaccountisbasedmostlyonprimarysourcesattheWellcome FoundationandshowsthatbothBurroughsandWellcomebuiltupontheircontactsin Philadelphia,LondonandCambridgetoestablishtheirfirm.SilasMainvilleBurroughs (18461895)hadworkedinpharmaciesinLockportandBuffaloinAmericabefore graduatingfromthePhiladelphiaCollegeofPharmacyin1877.Hehadanearlyinterestin
7 tabletsandhisthesiswasonTheCompressionofMedicinalPowders. Hefirstcameto
Britainin1878toestablishaLondonofficeforthePhiladelphiapharmacybasedethical
8 manufacturingfirmofJohnWyeth&Co. Burroughsinitiallyintendedtoonlyspend612
monthsinEngland,butseeinganopportunitytosellnoveltablets,hesetuphisown businessfromApril1878inGreatRussellStreet,London,assoleimportingagenton
9 behalfofWyeth. ThenoveltyoftheirdrugswasemphasisedinWyethsBritish
advertisements:Purity,activityandbeauty.Elegantpharmaceuticalpreparations,
10 compressedpowdersorpillsandmedicinalfluidextracts.
J.W.England(ed.),TheFirstCenturyofthePhiladelphiaCollegeofPharmacy1821 1921(Philadelphia:CollegeofPharmacyandScience,1922):494Healsosuccessfully appliedforapatent,number20269forCompressedPeptonicTablets,dated8September 1879:TradeMarks.WF:85/16.

8
G.MacDonald,(1980):57,1921ObituaryofSilasBurroughsChemist& Druggist47(9&16February1895):213214,254258.
9
MissHunt,ARecollectionofEarlyDaysatBurroughsWellcome18807WF: 86/98:19.ACenturyofWyethProductsintheUKSlough,EtonChronicleandWindsor Observer(1December1978)inWF:Box38J.

10
J.WyethtoBurroughsWellcome,(31October1887):Correspondencebetween BurroughsWellcomeandJohnWyethWF:88/47:8.BurroughsadvertisedWyethproducts onhisfirstpricelist,(28May1878),WF:Box112.
81
82
Burroughsbusinessexpandedrapidly,partlybecauseofhispersonaldynamismandsales flair,partlybecauseofthenovelproductshewasselling.In1879hepurchasedtherightsto Keplersmaltextractbusiness,tookonRobertClaySudlow,andinMayhemovedthe

11 businessheadquartersofthefirmtoSnowHill,nearHolbornviaductincentralLondon.
In1880BurroughsbegantoimportthesugarcoatedpillsofLanmanandKemp,afirm
12 basedinNewYorksince1858. Toconsolidatethisexpansion,Burroughsoffereda
partnershiptoHenryWellcome,whohadalsograduatedfromthePhiladelphiaCollegeof
13 Pharmacyin1874. WellcomehadbeenapharmacistwithPoole&Geisingerfrom1866
to1870inRochester,theninChicagobeforejoiningtheNewYorkfirmofCaswell, Hazard&Co.asasalesrepresentative.From1876hehadtravelledextensivelyinSouth AmericaforanotherNewYorkfirm,McKesson&Robbinswhosebusinessincapsuled

14 pillshebroughttoEnglandwithhimasthesoleimportingagent. IntheLanceton 31
15 March1880,Burroughsproduceda27pageadvertoftheirwiderangeofproducts.
16 BurroughsWellcomeCo.wasfoundedon25September1880. InOctober1880
thefirmexpandedintotheadjacentsite,whichtheyusedasawarehouseandSudlow
11
Thisremainedtheheadquartersuntilburntdownfollowingbombdamageinthe SecondWorldWar.G.MacDonald,(1980):2430.
12
H.WellcometoS.Burroughs,Letterbooks188120May1897,(27July1883), WF:S/G/1482:76Lanman&Kempdatedfrom1858:H.W.Holcombe,PatentMedicine TaxStamps:aHistoryoftheFirmsUsingUnitedStatesPrivateDieProprietaryMedicine TaxStamps(Lawrence,Mass:Quartermann,1979):816,3213.

13
C.M.Wenyon,HenryWellcomeObituaryNoticesofFellowsoftheRoyalSociety 2(1938):229238A.R.Hall,B.A.Bembridge,PhysicandPhilanthropy:aHistoryofthe WellcomeTrust19361986(Cambridge:CambridgeUniversityPress,1986):3H.Turner, HenryWellcome,theMan,hisCollectionandhisLegacy (1980):58 SirHenryDale, ObituaryofHenryWellcome(18531936)TheTimes(1August1936)JamesR. Rhodes,HenryWellcome(London:Hodder&Stoughton,1994).

14
H.Turner,(1980):57ArticlesofAgreement,WF88/47:8H.J.Parish,The WellcomeResearchLaboratoriesandImmunisation:TheHistoryofInoculationand Vaccination (London:BurroughsWellcome,1913):1,WF:85/17.

15
Letterbooks18811897,H.WellcometoS.Burroughs,(30March1883),WF: S/G/1482:11012 Lancetadvertisement,WF:85/20:2.

16
ArticlesofAgreement,WF88/47:8G.MacDonald,(1980):5.
82
83
17 becameGeneralManager. By1881BurroughsWellcomeimporteddrugsforseveral
18 firms. However,tensionsdevelopedbetweenBurroughsWellcomeandWyeth,because
oftheexpandingcollaborationswithotherfirms,issuesaboutqualityandpricing,and BurroughsexploitationofthenoveltyofWyethsproductsbyregisteringthetrademarks
19 oftheirethicaldrugsunderhisownname. JohnWyethfeltBurroughsalwayshadwhat
wemightstylepatentmedicineimpulses.AsatravellingrepresentativeforWyethin America,althoughactiveandenergetichehadoftencausedmoretroublethanallthe othertravellersputtogether,bymakingtoohastyarrangementswithcustomers,often

20 prejudicingthefirmsinterestsbymakingstatementsnotpossibletofulfil. Wyeth
claimedthatBurroughstooktoomuchprofitinBritainandfailedtoreachsalestargets despitespendingtoomuchonadvertising,thoughasacounterargumentBurroughs complainedthattheroyaltyleviedbyWyethaddedtohisprices.JohnWyethfeltthatthey shouldobtainpremiumpricesbyemphasisingtheethicalnatureofhisproducts: Thereisnopossiblesimilaritywithpatentmedicines,hestressed:[We] gaveyoustandardpreparations,[including]ourcompressedpills... [which]...nooneelsecanmanufacture,atrade[which]onceestablished cannotbetakenfromyoucomparedwithproprietarymedicines,which 21 requirecontinuedadvertising. WyetharguedthattheirethicalvalueswerecompromisedwhenBurroughssoldsub
22 standardversionsofWyethsBeef,WineandIron. OntheotherhandWyethprepared
somedrugstothestandardsoftheAmericanratherthantheBritishPharmacopoeia,due
17
G.Pearson,AChronologyoftheHistoryofBurroughsWellcome&Co.18781936 (typescript,1936),WF:88/24:41d:1OriginsoftheChemicalWorksvolumeI,WF: 89/57:8MissHunt,ARecollectionofEarlyDaysatBurroughsWellcome18807,WF: 86/98:19ArticlesofAgreement,WF:88/47:1.

18
H.WellcometoS.Burroughs,(27July1883),WF:S/G/1482.
19
AfterWellcomesarrivalheaddedthe'TallyHo'rangeofperfumes,andMcKesson andRobbinscapsuledpills:TradeMarks187986,WF:85/16.
20 21 22
J.WyethtoBurroughsWellcome,(28June1881),WF:88/47:8. J.WyethtoBurroughsWellcome,(28June1881),WF:88/47:8.
ForafullaccountoftherelationshipbetweenBurroughsWellcomeandWyethsee FairchildBrothersandFostertoBurroughs,(5November1895),WF:88/47:8.
83
84
23 toourignorancethattheBritishhadastandard. ThisledBurroughsWellcometo
appointA.SearlfromHowardsandSons,astheworksmanagerwiththeresponsibilityfor
24 maintainingstandards,andsodefiningtheircommitmenttotheethicalapproach. Inthe
periodbetweenOctober1881andFebruary1884,Burroughswasawayalmostcontinually,
25 establishingthebusinessthroughouttheEmpire.
Meanwhile,HenryWellcometookoverthedailyrunningoftheBritishbusinessand
26 adoptedtheWyethethicalstrategiesandmarketingtechniques. Productswereadvertised
onlyinthemedicalpressasMedicinalFormulaeofnewandimprovedchemicaland pharmaceuticalpreparations,beingofhighquality,andwerepresentedusingthelatest
27 Wyethtablettingandpackagingtechniques. HenryWellcomeabsolutelyrefusedto
advertiseinnewspaperslikethepatentmedicinemanufacturers,ashebelievedthiscreated
28 prejudices,whichthemedicalprofessionhadtosuchacourse. Wellcomeintroduced 29 Americanstyletravellingrepresentativesin1881,sellingonlytopharmacistsanddoctors.
Healsoadoptedthepolicyofsendingoutaround200,000Americanstylecircularsand
23
24
J.WyethtoBurroughsWellcome,(28June1881),WF:88/47. LetterstoG.E.Pearson,WF:E2PFBox23.
25
Burroughstravelsaredocumented,S.BurroughstoH.Wellcome,(30March1883): 110,114,Letterbooks188120May1887,WF:S/G/1482BurroughsWellcometoJ. Wyeth,(22August1882),WF:87/33(18823)andLetterstoPearson,WF:E2G. MacDonald,(1980):23.

26
Radford&FranklandtoH.Wellcome(7January1885),WF:E2PFH.Wellcometo S.Burroughs,(25August1882),Letterbooks18811897,WF:S/G/1482.
27 28 29
G.Pearson,(1936):2. A.W.Haggis,TypescriptHistoryoftheWorks:56.
H.WellcometoS.Burroughs,(9July1885):381,Letterbooks18811897,WF: S/G/1482ForanaccountofanAmericanstyledetailmanseeP.Temin,TakingYour Medicine:DrugRegulationintheUnitedStates (Cambridge,Mass:HarvardUniversity Press,1980):84ff.J.Liebenau,MarketingHighTechnology:EducatingPhysiciansto useHighTechnologyMedicinesinR.P.T.DavenportHines(ed.),History,Bagmenand Markets:StudiesintheHistoryofMarketingandBritishIndustry (Aldershot:Gower, 1986):82101J.Liebenau(ed.), TheChallengeofNewTechnology.Innovationin BritishBusinessSince1850(Aldershot:Gower,1988).
84
85
30 15,000samplesoftheirproprietarybeefjuicetodoctors. Doctorswereprovidedwith
remindersofthefirmanditsproductsintheformofmedicaldiaries,pocketpens,pencil casesandpaperknivesbearingthecompanylogoanddrugnames.Pamphletsweresent
31 fromheadofficeandadvertisementswereplacedinthemedicalpress. Further
advertisingtodoctorstookplaceatmeetingsoftheBritishMedicalAssociationorthe PharmaceuticalSocietyandBurroughsWellcomereceivedindependentprizesawardedfor
32 noveldrugsandstandardsofexcellence. BurroughsWellcomehadastandatthe
33 InternationalMedicalandSanitaryExhibitioninLondoninthesummerof1881. Inthe
followingyearsWellcomeextendedtheseinfluencessignificantly,invitingeditorsof
34 scientificjournalsandinfluentialphysicianstoelaboratesocialevents. Someofthese
suchasJ.FletcherMoulton,initiallyadistinguishedmathematicianandbrilliantlawyerand laterLordChiefJustice,thenfirstchairmanoftheMRCwereimportantinsupporting
35 BurroughsWellcome.
PreviouslyIhavedescribedthetwoformsofmarketingpatentmedicines advertiseddirectlytothepublicandethicalmedicinesadvertisedtodoctors.Sincethe eighteenthcenturydoctorsandeditorsofmedicaljournalshadcampaignedagainstpatent
30
BurroughsWellcometoJ.Wyeth,(22August1882)and(1February1893),WF: 88/47:8.
31
G.MacDonald,(1980):11,23WellcomeChemistsDiary1906,WF90/19H.J. Parish,HistoryoftheFirmchapters56,WF:85/20:2:105.
32
H.WellcometoS.Burroughs,(8April1884):303,WF:S/G/1482Thesewere advertisedintwoBurroughsWellcomehandoutsAmericanandEuropeanNewsletter (1896):161162,ChronicleandDistrictTimes(24April1894).

33
Exhibitorscertificates,WF:130:973/112.
34
G.Pearson(1936)WF:88/24:41d:48G.MacDonald,(1980):11H.Turner, (1980):810H.J.Parish,Historyof theFirm:56,WF:85/20:2:105H.M.Stanleywas aguestspeakervisitedon21April1884withDr.Manson.ChronicleandDistrictTimes (24April1884).Healsovisitedon14July1900H.M.Stanley,BritishMedicalJournal (12January1890):3257A dinnerforPowerwasheldinJuly1886,WF:YLBox 18BB/86Dr.FrederickB.PowerChemist&Druggist49(25July1896)Letterbooks, WellcometoBurroughs(9July1885):381,WF:S/G/1482Alargecommemorationfor Balfourtookplaceon8December,1902,WF:90:14:2R.C.Sudlow'sretirementdinner wason14September1903,WF:90/14:3Box158.
35
WellcomeoftenconsultedJ.FletcherMoulton.LordMoultonofBank,Obituary BritishMedicalJournal (19March1921)(1):433 F.B.PowerFiles,WF 88/94:79a.
85
86
medicinesandtheunsubstantiatedyetextensiveclaimsmadeontheirbehalf,butthe
36 Governmenthaddonelittletoregulatesalesexceptforimposingtaxes. Therewere
concernsaboutlackofbeneficialeffectandthepossibilityofadverseeffects.Theincreasing flowofforeignpatentmedicinesintoBritain,especiallyfromAmerica,ledtheGovernment totrytorestrictimportswiththepassageoftheRevenueStampandInfringementofTrade MarksActofSeptember1882,whichimposedstampdutyof1215%oftheretailpriceson

37 importedpatentmedicines. Thoughthistaxwasnotaimedatethicaldrugs,the
boundariesbetweenethicalandpatentmedicinesweresomewhatconfused.Burroughs extensiveadvertising,andinparticulartheAmericanoriginoftheirmedicinescausedthe GovernmenttoinitiallyclassBurroughsWellcomeasapatentmedicinevendordespite theirpleathattheysoldonlyknowndrugsWellcomeremarkedthatTheGovernment solicitorprosecutedandfinedusforsellingforeignmedicinesunstampedandour

38 enemies[are]campaigningagainstus. Ifimposeduponthem,thetaxwouldhave
affectedBurroughsWellcomeinthreeways:inthefirstplace,they wouldhavehadtopay
39 dutyaswellasthelargeroyaltyalreadypaidtoWyethmakingthemunprofitable.
Secondly,theywouldhavebeenobligedtostamptheirproductsaspatentmedicines,and losetheadvantageofmarketingthemasethicaldrugs.ThirdlytheActwouldalsohave
40 requiredthemtodestroymanyoftheirexistinglabelsandcirculars. Theproposedstamp
dutycameataparticularlydifficulttimeforthecompanytheyhadalreadyoverextended
36
R.Porter,Quacks,Fakers&CharlatansinEnglishMedicine (Tempus:Stroud, 2001).

37
WilliamWyatt,TheActsofParliamentRelatingtoStampedMedicinesChemist andDruggist106.1(12February1927):201WellcomefoughtagainsttheRevenueStamp andInfringementofTradeMarksActofSeptember1882:BurroughsWellcometoJohn Wyeth,(22August1882),WF:88/47:8WellcometoBurroughs,(6September1882),(4 December1883)and(14December1883),Letterbooks18817,WF:S/G/1482.

38
H.WellcometoS.Burroughs,(6September1882),Letterbooks18817,WF: S/G/1482.
39
BurroughsWellcomepaid15%oninitialsalesand20%onthemajority.Inreturn Burroughsclaimedtravelexpenses,postage,rent,advertisingandsalaries:Burroughs WellcometoJ.Wyeth,(15August1887),WF:88/47:8.

40
H.WellcometoS.Burroughs,(14December1883),Letterbooks18817,WF: S/G/1482.
86
87
themselvesbyestablishingthebusinessinFranceandSpaintheprofitsforthelastquarter
41 wereonly600againsttheprevious1,800.
AsaresultWellcomehadtodelaypaymentofanoutstandingbillof$5,000toJ. WyethandhecautionedBurroughs:Ihopeyouwillnotarrangeanybusinessmattersin
42 Americathatwilldrawuponusforfundsduringthecomingyear. BurroughsWellcome
alsofacedgrowingcompetitionfortheethicalmarket,includingtheinitiationoftablet
43 manufacturebyotherBritishandforeignfirms. WellcomewrotetoBurroughs:our
competitorshaveneverbeensoaggressiveinpushingbusiness,especiallyinExtractof
44 MaltAllen&Hanburys,Savory&Mooreandothers[were]strikingoutveryboldly.
Secondly,BurroughsWellcomehadtochallengeanumberofinfringementsoftheirown
45 trademarks. Inordertomeetthecrisistheyhadtoextendtheirexistingloansand 46 decreaseadvertising.
TheonlywaythatBurroughsWellcomecouldconvincetheGovernmentthatallof theirmedicineswereethicalandnotpatentmedicines,wastobeginmanufactureofthe WyethdrugsinBritainandtoemphasisetheirstandards.Afterseveralfineshadbeen imposedonthem,WellcomesuggestedthepurchaseofWyethtradenames,thedetailsof
41
H.WellcometoS.Burroughs,(30March1883),(15October1883)and(19October 1883),Letterbooks18817,WF:S/G/1482.
42
H.WellcometoS.Burroughs,(26October1883)and(5November1883), Letterbooks18817,WF:S/G/1482.
43
H.WellcometoS.Burroughs,(6September1882),Letterbooks18817,WF: S/G/1482 BurroughsWellcometoJohnWyeth,(27September1882),WF:88/47:8.

44
H.WellcometoS.Burroughs,(6September1882),WF:S/G/1482:27(27January 1883),WF:86/98.
45
Lundbergpreparationsandtheir'Hazeline'brandwerecopiedbyafirmcalled Haseline(sic.).TheManchesterfirmofThomasKerfootusedthesametabletting machineryandpackagingasWyethtopreparetheir'Purechlorateofpotashpearls',anda GermanfirmbeganexportingcompressedtabletsathalfoftheBurroughsWellcomeprice: WellcometoBurroughs,(6,27September1882and30March1883),WF:S/G/1482 BurroughsWellcometoJ.Wyeth,(27July1883),WF:88/47:8.Germanfirmswereeven accusedofspyingandimpersonatingBurroughsWellcomerepresentativesinwhatbecame knownastheGravescase,WF:E2J.WyethtoBurroughsWellcome,(14September 1882),WF:88/47:8.

46
H.WellcometoS.Burroughs,(22and26October1882),WF:S/G/1482.
87
88
47 theirdrugconstitutionsandtheirtablettingmachinery. Wyethagreedonlytolendrather
thansellsomeoftheirtablettingmachinestoBurroughsWellcome,subjecttoa20%
48 royaltyonthesaleofWyethdrugs,andpaymentofthetransportcosts. Nevertheless,the
GovernmentagreedtosuspendstampingofimportedWyethproducts,conditionalupon manufacturingstartinginBritain.Itwasanarrowescapefortheyoungfirm,Henry WellcomeexplainedtoBurroughs:hadthey[theGovernment]rigidlyenforcedthelaw ourpenaltieswouldhavebeensomethingenormous,tosaynothingofthegreat inconvenienceandlossincurred.Thecrisisover,Wellcomecommented:wemaythank

49 ourluckystarswegotoffsoeasy.
BurroughssuggestedthecompanyshouldbuytherightstofurtherWyethlines. WellcomewasnotsokeenashefeltabetteroptionwastoseekindependencefromWyeth. AsthemainnoveltyofWyethsdrugslayintheirpresentationastablets,herealisedthey couldpreparethesamedrugsfromcheaperrawmaterialspurchasedinBritain,andhence avoidpayingroyaltiestoWyethteatoproducequercital,forexample,washalfthepricein

50 London. WellcomethereforecruciallypersuadedBurroughstobeginmanufacturingand
heinformedBurroughsinSeptember1882that:erectionofmachineryproceeds
51 rapidly. ThreetablettingmachineswerepurchasedfromWyeth,whosuggesteditwould
52 takethreemonthstoinstallthem. AlthoughWellcomeregrettedseparatingtheoffice
47
BurroughsWellcometoJ.Wyeth,(22August1882)andJ.WyethtoBurroughs Wellcome,(14September1882),WF:88/47:8.BurroughsWellcomewerefinedforselling unstampedHazelineandwereaskedtoremove'Burroughs'fromthelabels:Wellcometo Burroughs,(24November,4December1883),WF:S/G/1482:20024.

48 49 50
Letterbooks18811897,(27July1883),WF:S/G/1482. H.WellcometoS.Burroughs,(4December1883),WF:S/G/1482:224.
Otherdrugswereonaverage20%moreexpensiveinPhiladelphia.Burroughs WellcometoJ.Wyeth,(27September1882),WF:88/47:8H.WellcometoS.Burroughs, (27July1883),WF:S/G/1482JohnHenryEvans,(SCI)analyticalchemisttoBurroughs Wellcomere.Teasuppliesquercitannicacid:CostsmemotoJowettre.Tabloid manufacture,(2March1895),WF:89/29:2.

51
H.WellcometoS.Burroughs,(19September1882),WF:S/G/1482:2334.
52
H.WellcometoS.Burroughs,(6September1882),WF:S/G/1482:2334J. WyethtoBurroughsWellcome,(14September1882),WF:88/47:8.
88
89
andworks,amuchexpandedmanufacturingsiteinacleancountryatmospherewaschosen
53 atBellHouseWharf,Wandsworthin1883.
ThefinancialsituationremainedprecariousasWellcomespentmoreonequippingit
54 thanheoriginallyestimated. Furthermore,hehadbeenunabletoselltheoriginalSnow 55 Hillpremises. WellcometravelledtoAmericainMarch1883tonegotiatethepurchase
offurtherequipmentfromWyethforthenewfactoryandinAprilthefirstpillmachines
56 wereprovided. Howeverduring1883thetensionbetweenBurroughsWellcomeand
Wyethgrewtoanimosity. AfterhisvisittoAmerica,Wellcomedescribedhowthetwo companiesweregettingfurtherapart.HefoundtheWyethpeoplegushingandkind andfullofsoftsoapswhenhewaswiththembutstillgreedy,witheverydispositionto bleedus,andhecondemnedthehaughtyandoverbearingspiritwithwhich[Wyeth]have

57 dealtwithus.
WellcomerealisedthatGermanalkaloidsandsyntheticdrugsofferedadditional advantagesovertheWyethdrugs,astheywerechemicalswithawellunderstood mechanismofaction,whichcouldbesoldtodoctorswithascientificmessageasethical drugsFurthermore,BurroughsWellcomecouldcombineGermanscientificadvancesinto theirAmericanstyletablets.HesuggestedthatBurroughsWellcomemakeaoneoff paymenttosecurethepermanentrightstoallWyethlinesinwhichtheycurrentlydealt.
53
Theleaseranfrom9February1883until29September1889thoughthefirmstayed untiltheendof1889becauseofafirejustbeforetheendofthelease.G.Pearson,(1936) WF:88/24:41d:2H.WellcometoS.Burroughs,(27July1883),WF:S/G/1482H.J. Parishunpublishedmemoirs,WF:85/17.

54
WellcomesupervisedthechoiceofsiteandthemovementoftheworkstoBellLane, Wandsworthon9February1883:H.WellcometoS.Burroughs,(27July1883),WF: S/G/1482G.Pearson,(1936),WF:88/24:41d:2.

55 56
H.WellcometoS.Burroughs,(12June1883and27August1883),WF:S/G/1482.
Twopillmachines,alatheandportablefurnaceweretobesenttoBurroughs WellcomeduringApril,J.WyethtoBurroughsWellcome,(10April1883),WF:84/7:8.
57
WellcometoBurroughs,(13March1883,27July1883),WF:S/G/1482.
89
90
Wyethdemanded50,000forthisprivilegeand,whenagreementcouldnotbereached,
58 theyaskedforthereturnoftheirtablettingmachines.
Inresponse,BurroughsWellcomedecidedtobuildtheirowntablettingmachines, takingadvantage,asGermanfirmshadrecentlydone,ofthefactthatWyethhadnot patentedtheiradvanceddesignsinEurope.Inordertocreatetheirowntablet manufacturingfacility,specialisedengineeringstaffhadtobebroughtintoBurroughs Wellcome,principallyfromGermanfirms.Oneofthefittersdescribedhowhewasthe onlyEnglishchapamongtheengineersthereweretwoGermansandtheyusedGerman

59 machines,lathesetc. WellcomeevenarrangedfortheworkstoberunbyaGerman,Dr.
Witte:amaninwhomIhavefullconfidenceregardingmanagement.Wittewassentto visittheWyethsitetoevaluatetheirmethods.Afterthreetablettingmachineswereinstalled attheWandsworthsite,BurroughsWellcomeproducedtheirowntablets,butstillreliedon

60 Wyethfortheirmainbulkdrugsupplies. Howevertheyresistedpreparingtoomany
specialsattherequestofphysiciansandbegantoconcentrateonlargescaleproduction
61 ofasmallernumberoflines.
62 WyethcontinuedtocriticiseBurroughsexpensesasexcessive. Neverthelessduring 63 thefirst3yearsofbusiness,salesgrewfrom17,811in1881to57,156in1883. By 64 1884,10,000hadbeeninvestedinthecontinentalbusiness. Burroughsmeanwhile
58
AnaccountoftherelationshipwithWyethappearsinBurroughstoHorton(anagent ofWyeth),(12July1893),WF:88/47:8J.WyethtoBurroughsWellcome,(19April 1893),WF:88/47:8.AtthesametimetheyendedtheirfiveyeararrangementwithFellows &Co.,Letterbooks,(6September1882),WF:S/G/1482:227.

59
Mr.C.BargatetoH.A.D.Jowett,HistoryoftheWorks,(26November1930), WF:YLBox15WF84/7.
60
DrWittejoinedinsummer1882andwasplacedinchargeofdevelopingthe Wandsworthsitein1883,Letterbooks,(27July1883),WF:S/G/1482:98.
61
62 63
Letterbooks,H.WellcometoS.Burroughs,(26October1883),S/G/1482. J.WyethtoBurroughsWellcome,(28June1881),WF:88/47. Radford&FranklandtoH.Wellcome,(7January1885),WF:88/47(E2). H.WellcometoS.Burroughs,(4December1883),WF:S/G/1482:218.
64
90
91
65 becameincreasinglycriticalofWellcometowardstheendof1883. Wellcome,inturn
wasaggrievedthatinitialpromisesofanequalpartnershiphadbeenunfulfilledandthat Burroughsmademajordecisionswithouthim.Wellcomecriticisedhishastyflashesof
66 judgmentandimpulsiveandalltoohastydisposition. Theriftsimmeredthensettled 67 temporarilywhileanewpartnershipagreementwasdrawnup.
ThenewchemicalworksatWandsworth,includingBurroughsWellcomesown tablettingmachinery,formallyopenedon6October1884,establishingthecompanyforthe firsttimewithitsownlargescalemanufacturingcapacity.InadditiontotheoldWyeth lines,theWorksproducedotherfirmslicensedproductsandvariousinorganic preparations,enablingBurroughsWellcometoestablishtheirownidentity,distinctfrom

68 Wyeth,intheBritishmarketplace.
CentraltotheirstrategywastheadoptionofthetrademarkTabloidproposedby WellcomefortheirspecialtabletsregisteredfirstinBritaininMarch1884andthenin
69 variousoverseascountries. Tabloidwasinitiallyderivedfromacontractionoftheterms
tabletandalkaloidbutitwasalsoastrongBrandrepresentingaqualityproduct,easily recognisedasbeingonlyfromBurroughsWellcome.Theideaprobablycamefromthe increasinguseofGermantradenames,whichwereshortandeasilyrememberedand replacedcomplexchemicalnames.BurroughsWellcomeadoptedTabloidhavingearlier

70 soughttomonopolisethetermtabletuntilchallengedbyanAmericanfirm. Theywrote
65
BurroughscriticisedthetimespentbyWellcomeinliterarycircles,andthefailureof theMcKessonpartofthebusiness,suggestingallthatWellcomebroughttothefirmwas uselesspaperand40:S.BurroughstoH.Wellcome,(8March1888),WF:S/G/1482 WellcomeexpressedhischagrinasearlyasAugust1882whenBurroughssuggested delayingthefullpartnershipuntilfouryearslater.H.WellcometoS.Burroughs,(25 August1882)and(6September1882),Letterbooks188187,WF:S/G/1482.

66 67 68 69
H.WellcometoS.Burroughs,(6September1882),WF:S/G/1482:23 H.WellcometoF.B.Power,(9April1884),WF:86/98. H.WellcometoS.Burroughs,(6February1884),WF:S/G/1482.
TabloidwasregisteredbyHenryWellcomeasatrademarkinBritainon14thMarch 1884andinvariousothercountriesby1885:TradeMarks,187986,WF:85/16H. WellcometoS.Burroughs,(26October1883),WF:S/G/1482:164.

70
TabloidsandTabletsChemist&Druggist40(28May1892):785Tabloidsand TabletsChemist&Druggist40(4June1892):817BurroughsWellcome,Tabletsand
91
92
totheChemist&Druggist,thewordTabletswasappliedbyustothisclassof (compressed)drugsatthecommencementofourbusinessin1878.Thisformofmedication
71 hadhithertobeenknowninthiscountryascompressedpills. Tabloids,howeverwere
furtherdistinguishedbyemphasisingthatthetabletscontainedstandardiseddosesof
72 purifiedactivedrug,measuredwithgreataccuracy. Thisbecamethecentraldefining
conceptofBurroughsWellcomedrugs,emphasisingthattherewasgreateractivityandless variabilitythanotherfirmspreparations.Tabloidswerepromotedinthismanneratthe
73 annualBritishMedicalAssociationmeetingwithgreatsalesasaresult. Bytheendof
1884Henry Wellcomereported:Ourbusinessisprosperinghandsomelyandtheoutlook
74 moreencouragingthanever. BurroughsWellcomecontinuedtolicenseinnew 75 productsin1885actedasagentsforFairchildsDigestiveFerments.
ThenewpartnershipbetweenBurroughsandWellcomewasfinallyagreedon29May
76 1885. Buttheriftbetweenthemsoonwidenedagain,andinJuly1886Burroughssued 77 forbreachofpartnership. HeclaimedthatWellcomehadnotdiligentlyappliedhimself,
TabloidsChemist&Druggist40(11June1892):849BurroughsWellcome,Whatisa TabletChemist&Druggist40(11June1892):881Armour&Co.TabletsChemist& Druggist40(25June1892):913EvolutionandPresentStatus:CompositionofTablets andMethodsofAnalysisJournaloftheAmericanPharmaceuticalAssociation 3(1914): 820848,937958,106299A.W.Haggis,HistoryoftheFirm:56WF:85/20:2:278 279.

71
F.N.LPoynter,EvolutionofPharmacy (London:Pitman,1965):137. Dosesof1/1,000to60grainswereprepared:G.MacDonald,(1980):23. WellcometoBurroughs,(9July1885),WF:S/G/1482. WellcometoBurroughs,(1December1884),WF:S/G/1482.
72 73 74 75
WellcometoFairchilds,(16June1885),WF:E2.BytheendofOctober1885the firmheldabalanceof3,300,Letterbooks,(26October1885),WF:S/G/1482.
76 77
Radford&Frankland(solicitors)toWellcome,(7January1885),WFE2.
ForafullaccountofeventsleadinguptotheendofthepartnershipseeBurroughsto FairchildBrothers&Foster,NewYork,(11April1891),WFE2BurroughsWellcometo J.Wyeth,(26June1888),WF:88/47.
92
93
78 thathehadunpaiddebtsandthathehadwithdrawnexcessprofits. Incontrast,allofthe
evidencepointstoextensivedaytodayinvolvementofWellcomeinmanagingand reorganisingthebusiness,whileBurroughsplayedoutanequallyimportant,butquite
79 differentroleinopeningupnewoverseasmarketsandlicensingnewproducts.
Burroughswasthemostwidelyknownpersonalityintheranksofpharmacy,andwell
80 knownthroughouttheworld. Wellcomeretortedthatthefirmhadbeenanentangled
snarlwhenhetookoveroperations,whichifithadbeenleftwouldhavebeenruined.
81 HeindignantlytoldBurroughsyounolongerknowthebusiness. Wellcomeechoed 82 WyethwhohadalsocomplainedofBurroughswantofasystem. Nevertheless,
Wellcomehimselfhadbeenabsentfromworkformuchof18856,butonlybecausehehad
83 almostdiedwhileheroicallysavingaladyfromdrowning.
In1886Wellcomewrote:Businessisinthemostwretchedlydepressedstate throughoutEuropeandtheColonies,weareholdingourown,simplifiedbygivingupthe
84 McKessonRobbinspills,thelonglistofwhichhasbeensomethingofanencumbrance.
Thiswasthefirstsignificantsteptocurtailingtheproductrange.BynowtheTabloidrange wassuccessfulandBurroughsWellcomeextendedtheirtradenamestrategytoinclude othernoveldosageformssuchasValoids(valeriatesorcreams),Piloidsassmallround pillsin1886,Ovoids,aneasytoswallowshapeandElixoids,whichwerepalatable
78
InthequarteruptoJuly1885thetradebalancewas1,456whenitshouldhavebeen 3,000butthiswasduetoadepressionintrade.WellcometoBurroughs,(9July1885), WF:S/G/1482.

79
AnoverseasofficewasestablishedinSydneyin1886andothersfollowed.WestKent Advertiser(21March1924),WF:Box25.
80
Chemist&Druggist46SilasBurroughsObituary(9February1895):213(18May 1895):675.
81
H.WellcometoS.Burroughs,(25August1882),Letterbooks18811887,WF: S/G/1482.
82 83
J.WyethtoH.Wellcome,(28June1881):213,WF:88/47:8.
HewasawardedamedalfromtheRoyalHumaneSociety,Letterbooks,Burroughsto Wellcome,(27July1886),Letterbooks18811887,WF:S/G/1482G.MacDonald, (1980):17.

84
H.WellcometoJ.Wyeth,(8January1886),Letterbooks18811887,WF:S/G/1482: 438.
93
94
85 formsofnauseousdrugssuchaspotassiumiodide. Theyalsoincorporatedthelatest
fashionabletrendsforcodliveroilandmaltpreparations,andSaxinatomisersfor antiseptics,inhalersforammoniumchloride,andevenproducedartificialeardrums. Rarelyamonthwentbywithouttheintroductionofanewline,brandedaspartofthe

86 BurroughsWellcomerange. Nevertheless,theirmainUScompetitor,ParkeDavismade
suchinroadsintoourbusinesswedecidedtoundercutandWellcomedescribedavery activefightwithothermakersofcompresseddrugs,Merck,WarnerandotherAmerican, GermanandEnglishfirmswhoemploysteampower,andwethink,someAmerican

87 machines. Merckhadamonopolyintheproductionofcertainalkaloidsbasedupon
suppliesofrawmaterialsofcertainplants. By1880ParkeDavisofPhiladelphiawasprobablythemostsophisticatedAmerican manufactureroftablets,havingovertakenWyeth.Successinbusinesswasdeterminedby differentiationagainstotherfirmsproducts.Whileproducingbettertabletswasone possibility,ParkeDavisidentifiedanewmethodbyintroducingalaboratoryin1879asa majorcommitmenttopurityandstandards.UnlikeGermanlaboratories,whichfocussedon newproducts,theParkeDavisapproachwastoproducepurestandardiseddrugsfrom complexextracts.In1880theyhiredthechemistAlbertLyonswhodevisedamethodto standardiseergot,analkaloidcontainingproductofafungusthatgrewonrye.For centuriesergotextractswereknowntopreventbleedingafterchildbirth,butthedownside wasthatcontaminatedryewheneatencouldalsocauseepidemicsofgangreneand
88 convulsions,soitwasimportanttoknowthepotency. By1883ParkeDavishad
assignedpharmacologicalactivitytoaparticularcomponentwithinergotandbegan to
85
TradeMarks,187986WF:85/16.Itwasfollowedbyregistrationof'Valoids'in 1884,Elixoidsin1884,Piloidsin1886,Soloids(antisepticsolutions)andOvoids: WellcometoBurroughs,(26October1883):164,WF:S/G/1482.

86
Cuttingsfromadverts. Chemist&Druggist36(28January1888)G.MacDonald (1980):12,25SuccessfulPharmacy(1882)ProgressinPharmacy(1888):cuttings pagenumbersunknowninWF:89/29b:7.

87
88
H.WellcometoJ.Wyeth,(8January1886and18May1886),WF:88/47:8.
C.DeCosta,St.AnthonysFireandLivingLigatures:aShortHistoryof ErgometrineLancet(18May2002):176870.
94
95
89 standardisetheirproducts. From1886thesuccessfulpolicyofincorporatinghighly
activestandardisedpreparationsintheirtabletswasextendedtootherdrugs. InordertoremaincompetitiveBurroughsWellcomehadtoextricatethemselvesfromthe
90 arrangementswithWyethandtheyfinallyachievedthison5November1888. Bythis
timeBurroughsWellcomehadperfectedtheirtablettingandcouldmakealloftheoriginal Wyethlines,aswellassometabletsthatWyethcouldonlyprepareonhandmachines. HenryWellcomedeclaredthattheirnewlypatentedtablettingmachinesproducedbetter finishedgoodsthanWyeth,moreaccurately,at400to500perminute,withthecapacityto

91 riseto600perminute. Thislevelofefficiencywasimportantasothercompanies
enteredthemarket,forcingpricesdown. Insummary,BurroughsWellcomedevelopedadiverseproductrange,andledthe Britishindustryintablettingtechnology.Furthermoretheyhadadoptedpatentingof machineryandtheuseof Germanliketradenames.BurroughsWellcomelicensednovel syntheticchemicaldrugsfromGermanfirmsandincorporatedthemintotheirownunique Tabloidform.ExampleswereDiuretin(theobromine)fromKnoll,Phenacetinand SulphonalfromBayer,andAntipyrin(Hoechst),LanolinwasalsoimportedfromGermany

92 tomaketheointmentbasesthatdidnotgorancid. BurroughsWellcomewasatlast
creatinganichemarketwithinthegrowingpharmaceuticalindustry:thoughtheystilldid notmanufacturechemicalsonalargescale,asinGermany,theydidincorporate
89
ParkeDavisat100:ProgressinthePast,PromiseintheFuture18661966Milton L.Hoefle,TheEarlyHistoryofParkeDavisandCompanyBull.Hist.Chem.25.1 (2000):2834:by1883thefirmwasassayingover20biologicaldrugs.JohnP.Swann, AcademicScientistsandthePharmaceuticalIndustry:CooperativeResearchinTwentieth CenturyAmerica(Baltimore:JohnsHopkinsPress,1988):2021.

90
LegalnegotiationscontinueduntilJune1885:FairchildBros.andFoster(solicitors)to SilasBurroughs,(5November1888),WF:88/47:8.BurroughsagreedtosellsomeWyeth linesthroughanewagent,WilliamF.Horton:BurroughsWellcometoFairchildBros.& Foster(NewYork),(11April1895),WF:88/47:8.Wyetharrangedtoselltheirremaining linesinBritainthroughRoberts&Co.BurroughsWellcometoJ.Wyeth,(1February 1893),WF:88/47:8.

91 92
H.WellcometoJ.Wyeth,(5November1885),WF:88/47:8.
LanolinwasimportedfromBenroJaffeandDrmstaedterfromJuly1886,WF: 86/98/16IchthyolfromCordesHermanii&Co.from1888,G.Pearson,(1936)WF: 88/24:41d:3Instructions/MemosreDartfordWorks18931950,WF:89/29:1.
95
96
manufacturedchemicalsintotheirtablets.BurroughsWellcomewasstillsmallbyGerman
93 standardseventhoughtheirstaffincreasedsixfoldinthe7yearsupto1891.
Insummary,bythistimeBurroughsWellcomehadtheirownindependentsuppliesof drugsandtheirownmanufacturingfacilitiesinwhichtheypreparedtabletswithdefined dosagestrengthmedicinesandalsoincorporatedthelatestmedicaladvances,sellingtheir productsundertheTabloidname,whichsignifiedqualityandreliability. HowevertheirsuccesswithTabloidsencouragedtheopeningoffurthernewworksin

94 Dartfordon3July1889onthesiteoftheformerPhoenixpapermills. Duringtheperiod
1889to1893thefirm establishedtheirfirstcontractswithBritishdyemanufacturerssuch asClayton,ReadHollidayandLevinsteinsforthepurchaseofnitrites,toluidine,benzol, phenol,nitricacid,naphthol,anilineandotherfinechemicalstobeusedassolventsandas

95 intermediatesforsimplechemicalreactions. Asmanufacturingoutputexpanded,and
drugproductionbecamemoreefficient,drugpricesweresometimeslowered,but BurroughsWellcomeTabloidscommandedhigherpricesthanotherlesssophisticated tablets. ThetechniquesthatBurroughsWellcomeusedtodevelopnewformulationswere increasinglyinnovative.In1891theyintroducedsugarcoatedCascaratabletsaspurgatives

96 andin1892theylicensedaprocessformakingtabloidsoftea. Inthesameyearthey
introducedconcentriccoatedtabletswithapeptonicinnerkernelsurroundedbypepsin, andfilmcoatedwithsugartomakethempalatable.Therationalewasthatthisdoublecoat couldresistbreakdownofthetabletsinthestomachsothattheycouldexerttheireffecton
93
Balancesheet(30November1887),WF:E2(Box23).By1900theyemployed115 girlsforpackingincontrasttoonly23in1884HistoryoftheWorksofBurroughs WellcomeandCo.WestKentAdvertiser(21March1924),WF:Box25.By1891there were400staffi.e.sixtimesthe1884figureandtherewere500in1892.By1900there wasastaffof4,300:StaffRecords,WF:90/14:3.

94
95
Chemist&Druggist37(14September1889):392. Purchaseofchemicalsanddyes(1October1889to31October1893),WF:84/710 G.E.Pearson,(1936),WF:88/24:41d:4.
11.
96
96
97
97 theintestine. In1892theircompetitorsAllen&Hanburysintroducedsolublecoated
pills,disintegratingtabellaeofcompresseddrugs,andeasilysolubletabellaeforthe
98 preparationofhypodermicinjections.
HenryWellcomecontinuedtoadoptnovelmarketingtechniquesandspecialities
99 weresoldtoprestigecustomersinconvenientmedicinechests. Heproudlyboastedthat
they:haveequippedeverycommercial,military,mining,exploringandotherexpeditionof
100 importancewhich haslefttheseshoresformanyyearspast. ByAugust1893,four
yearsafterthemovefromWandsworth:thenewworkswereconsiderablyenlargedand fittedupinamostelaboratescale,onalevelwithanysimilarfactoryintheWorld.Itwas
101 awellventilatedfactorywithaconstantatmosphereof60degrees.
WithTabloidsandtheemphasisonpurityandreliabilityBurroughsWellcomehad hituponasuccessfulformula,butintherapidlydevelopingfieldofpharmaceuticalsthere wasnoroomforcomplacency.AmajorissueconstantlyfacedbyBurroughsWellcome wasthat,duetothesuccessofTabloids,witheveryinnovation,nosoonerdidtheyrelease newtabletsandformulations,severalcompaniescopiedthem:PerhapsthereisnoEnglish specialtywhichhasbeensopersistentlyimitatedonthecontinentastheBurroughs

102 WellcomeTabloids. AlthoughWellcomefoughtthreatsofcopieddrugswithcourt
103 actions,thiswascostlyandtimeconsuming.
Bythe1890smanyfirmswereabletoperform alkaloidalextractionsandtoprepare tabletsbutthatdidnotmeantheywereallofthesamequality.HenryWellcomeandhis staffrecognisedthatextractionofmixturesofalkaloidsfromplantscouldresultindrugs withvariableeffectsintheclinic.Drugsoftencamefromunreliablesourceswheredifferent

97
Anexternalphysiciansuggestedthistechnique,TradeNotesMessrs.Burroughs Wellcome&Co.Chemist&Druggist40(11June1892):847.
98
GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen&Hanburysand theBritishPharmaceuticalIndustry17151990(London:Murray,1990):102103.
99
100 101
G.MacDonald,(1980):29,43. AnnualMuseumBritishMedicalJournal (3August1895)ii:2945. WestKentAdvertiser(5August1893)WF:E2Cuttingsfromnewspapers. Chemist&Druggist(1891)39:516,554,585,608.CuttingsfoundinWF:89/29:7. G.MacDonald,(1980):12.
102
103
97
98
speciesofplant,grownunderdifferentconditionsandharvestedatdifferenttimeswere mixedtogether.Thestrengthcouldonlybecomparedbymeasuringthetotalalkaloid content,astheactiveingredientswereunknownbuteventomeasurethetotalalkaloidal strengthrequiredlaboratoryexpertise. HenryWellcomeestablishedtheWPRLin1894tostandardisethepreparationof diphtheriaantitoxin.Hesoughtameansbywhichhecouldshowthathisfirmsextracts werethemostpotentandheappliedthesamethinkingtoergot.Hewasimpressedwith ParkeDavisclaimsofstandardisingergotbyabiologicalreaction,recognisingthatdoctors wouldalsobeimpressedinbeingprovidedwithareliableproductfreeofthesideeffects causedbyotheralkaloidspresent.Wellcomedeterminedtofollowtheirleadandemployed furtherchemistsandphysiologistsinestablishingtheWellcomePhysiologicalResearch
104 Laboratories(WPRL)in1894. ThismajorcommitmentwouldsetBurroughsWellcome
apartfromcompetitorsinBritainasithadforParkeDavisinAmericaincreatingmarket exclusivityotherswouldonlybeabletocompeteiftheyalsodevelopedlaboratories. Wellcomewasgraduallyassertinghisinfluenceontherunningofthebusiness,while BurroughscontinuedtotravelextensivelyuptohisdeathontheRivieraon6February

105 1895. InMarch1895itwasannouncedthatthebusinesswouldcontinuetotradeunder
thedirectionofHenryWellcomebutwouldretaintheBurroughsWellcomename. Wellcomenowhadhisunhinderedchancetostamphisstrategyofpurifiedstandardised medicinesonthefirm,buttherewereseveralchallengesahead. Wellcomestrengthenedthecommercialsideofthefirmfollowingthelossof

th Burroughs.On10 June1895,EdgarLinsteadjoinedastheheadoftheAdvertising
Department,andon8July1895WellcomesecuredtheexperiencedGeorgeEPearson, whohadbeenaseniorassistantwiththeLondonpharmacyfirmof JohnBell&Co.since 1889.HejoinedBurroughsWellcomeasatravellingsalesman,initiallyinWestLondon,
104
C.M.Wenyon,HenrySolomonWellcomeObituaryNoticesofFellowsofthe RoyalSociety 2(1938):230231.

105
BurroughsWellcome&Co.sTripChemist&Druggist (18July1891):7071 Mr.BurroughsintheEastChemist&Druggist39(24October1891):625Burroughs willWF:E2SilasBurroughsObituaryAmericanJ.ofPharmacy (1895):4334.
98
99
butthenhetravelledextensivelyasBurroughshadandestablishedthebusinessinAustralia,
106 SouthAfrica,Italy,CanadaandtheUSA.
BurroughsWellcomewantedtoincorporatelaboratorytechniquesthatothers wouldnotreadilybeabletocopy.InitiallyanalysisofextractsintheParkeDavismanner wasachievedbycollaboratingwithWilliamRowlandDunstan,whowastherecognised

107 expertatanalysingalkaloidsinBritain. In1886DunstanhadbecomeProfessorof
ChemistryattheSchoolofPharmacyofthePharmaceuticalSociety,andin1887he becametheDirectoroftheSocietysnewresearchlaboratories,wherehisassistantswere H.A.D.JowettandFrancisCarr.DunstanwasanactivememberoftheChemicalSociety andhestandardisedpreparationsfortheBritishPharmacopoeiaandanalysedthevery variablecontentofcommercialpreparationsderivedfromvariousbotanicalspeciesand

108 differentsources. ThecollaborationwithDunstanslaboratorywasusefultohelpto
identifyweaknessesinrivalproducts.Wellcomethereforeestablishedthefirmonaresearch footing,takingthebestapproachesofGermanandAmericanfirmsandcombiningthemto producetheirownuniquerangeofdrugs. 3.3ChemicalLaboratoriesforResearchandChemicalWorksforManufacturing. IntheirfirstdecadeatRussellStreetandSnowHillinLondon,BurroughsWellcome

109 hadonlylimitedlaboratoryfacilitiesatWandsworth,andlaterDartford. Theyreliedon
110 Wyethforbasictestsonchemicals,drugsandplantspurchasedexternally. Initial
manufacturinginBritaininvolvedonlyincorporationofdrugsprovidedbyWyeth,though
106
G.E.Pearson,(1936)WF:88/24:41d:5G.Pearson,WF:YLBox23E2PF.
107
T.A.Henry,(1950):6380D.Read,JournaloftheChemicalSociety 77(1900):49. Dunstanalsoexaminedsalicinderivativesofphenol:W.R.Dunstan,Pharmaceutical Journal 40(18801):809W.R.Dunstan,F.H.Carr,TheDetectionofAconiteChemist &Druggist48(1896)24850.

108
H.King,F.L.PymanBiographicalMemoirsofFellowsoftheRoyalSociety 4 (1944):681697,onp.682Dunstancollectedsamplesfromthecoloniesforanalysis:T. A.Henry,W.Dunstan(1950):64,74.

109
ProgressinPharmacyChemist&Druggist36(28January1888)pageunknown foundinWF:89/29:7.
110
ForexampletheytestedExtractumpancreatitisofSavoryandMoore.H.Wellcome toFairchilds,(16June1885),WF:88/47:8.
99
100
111 from1886limitedresearchontabletproductionwasperformed. Unlikepills,which
weresimplyrolledinanoutercoating,tabletsweremorecomplexandhadtobeprepared aschemicalsaltswhichwouldresistbreakdowninthestomach,retainanacceptabletaste anddissolvereadily.ThissectionshowshowHenryWellcomeattractedkeystaffwiththe requiredchemicalskillstoestablishtheWellcomeChemicalResearchLaboratories

112 (WCRL). Asdescribedpreviously,littleattentionhasbeengiventothissideofthe
business. WellcomewrotetoFrederickBeldingPowerwithindaysofBurroughssdeathand hisestablishmentinthekeypostasDirectorofChemicalResearchon30May1896wasa

113 keyappointmentindevelopingchemicalresearchatBurroughsWellcome. Powerwasa
longtimefriendofWellcomeandhadaccompaniedhimonhisfirstvisittoBritainin1880. PowerhadachildhoodinterestindrugsandworkedinalocaldrugfirminHudson,New York,fromtheageof13years,andthenatapharmacyinChicagowhereheperformedhis firstexperiments.Wellcometookoverfromhimin1872,andfollowedhimtothe PhiladelphiaCollegeofPharmacywherePowermadeaninstantimpressiononhis ProfessorswhosupportedhisapplicationtotheAmericanPharmaceuticalAssociationin 1872.HegraduatedinthesameyearasWellcomeandwiththehighestprizeinChemistry (1874)hewasdescribedasthebeststudentinthecollege,boundtoexcelallothers...a

114 naturalchemist.Hisfirstpublicationswereonchinchonaalkaloidsin1875. Powers
professorsintroducedhimtotheinfluentialworksofDanielHanburyandtoProfessorF.L. FlckigersfamousPharmacographia,whichpromptedhimtoseekaresearchpostinthe pharmacognosylaboratoryofFlckigerinBernein1876.Flckigerlaterdescribedhimasa
111
112
TradereportsBritishMedicalJournal (3August1895):294295.
E.M.TanseyandR.C.E.MilliganTheEarlyHistoryoftheWellcomeResearch Laboratories,18941914inPillPeddlers,EssaysontheHistoryofthePharmaceutical Industry.(Monograph13)J.Liebenau,ElaineC.Stroud,GregJ.Higby,(eds.)(Madison, Wisconsin:AmericanInstituteofPharmacy,1990):91106.

113
HistoryoftheWCRL,PowertoJohnson,22January1907and27December 1912,WF:88/94 PharmaceuticalJournal (24May1913):721ObituaryChemistry& Industry (8April1927):324.Adinnerfor50washeldtocelebratehisarrival.Dr. FrederickB.PowerChemist&Druggist49(25July1896):163.

114
PowerArchives,WF:88/94:59.
100
101
115 geniusinresearch. PowerthenworkedwitheminentGermanscientistsincluding
BaeyerinChemistry,andSchmiedeberginPharmacology,andhisthesisontheresinsof PodophyllumgainedhimaD.Phil.In1880PowerreturnedtoAmericaanddirectedthe pharmacyofFritzscheBrothersofNewJersey,becomingProfessorofAnalytical ChemistryatPhiladelphiaCollegeofPharmacy,andfrom1883,ProfessorofPharmacyat

th WisconsinUniversity.PowerparticipatedintheCommissionappointedin1890forthe7
116 revisionoftheU.S.Pharmacopoeia. BythetimeofhisappointmenttoBurroughs
Wellcome,Powerhadareputationasaworldauthorityonplantalkaloids.Wellcomehad keptintouchwithhisfriendPowerandvisitedhisresearchlaboratoryinStrasburgand
117 knewhewastheidealmantoleadBurroughsWellcomeintonewavenuesofresearch.
Powersappointmentopenedupnewpossibilitiesforpreparingextractsandorganic chemicalderivativesofplantalkaloidsandattractingnewstaff. Hisknowledgeofbotany wasimportantwhenthefirmestablisheditsownmateriamedicafarmsothatplantsofa uniformspeciescouldbegrownunderstandardconditionssothatthefirmdidnothaveto

118 dependonthevagariesofthemarketplaces.
WithPowerinplace,theWCRL,occupyingthreefloorsandindependentofthe Workswasformallyestablishedin1896tomanufactureseriesofchemicalstoassistinthe identificationofextractedplantalkaloids.Powerdescribedhow:thematerialsavailable fortherapeuticuseconsistedforthemostpartofsimplechemicalsandgalenicals preparations,withafewactiveprinciplesofnaturaldrugs.Littlewasknownregardingthe compositionofmanyofthenaturaldrugsincommonuse,theproductionof syntheticdrugs wasjustbeginningandfewchemistshadthetemeritytoworkatsuchbiological
115
GeoffreyTweedale,(1990):6165. G.MacDonald,(1980):7.
116 117
F.B.Power,F.Hoffmann,Examination ofMedicinalChemicals(Philadelphia:H.C. LeasSons,1873)H.WellcometoS.B.Power,(9August1883),WF:88/47:8.

118
A.W.Haggis,HistoryoftheWorks:56,WF:85/20:2:123127 Powersrolein thestandardisationofmedicineswasrecognisedin1902attheInternationalConferencefor UnitofFormulaeofpotentmedicamentsinBrussels,whentheU.S.SecretaryofState appointedhimasadelegate:InternationalConferencefortheUnificationofformulaeof potentmedicamentsinBrusselson15September1902,WF:88/94:26and84G.Pearson, (1936),WF:88/24:41d:7.
101
102
119 problems. On1September1896WellcomesecuredtheemploymentofDunstans
assistantH.A.D.JowettfromthePharmaceuticalSocietylaboratory.Jowetthadrecently gainedhisD.Sc.fromLondonUniversityafterworkingonthesmallscaleextractionand
120 characterisationofalkaloids. Hehadcarriedoutnoteworthyinvestigationsofnatural 121 productsofmedicinalinterestunderProfessorW.R.Dunstan. UnderPowerhe
soughttoachievebettermeansofextraction,purificationandstandardisationofexisting andnovelalkaloids.ThesewerethenpatentedasinventionsusingtheGermanstyletrade namesthatotherscouldnotcopy.Powerrecruitedadditional staffuntilhewasassistedby

122 alargestaffofwelltrainedyoungchemists. Oneofthefirstchemists,Dr.S.B. 123 Schryverjoinedon4April1898,thoughheonlystayeduntiltheendoftheyear.
Thefirmhaddifficultyobtainingyoungpharmacistsandchemistswhoare thoroughlyqualifiedtoworkindependentlyandtoorganise.Burroughs Wellcomeareextendingtheirmanufactureinsuchdirectionsthatthey constantlyrequiremoremenpossessingpharmaceuticalandtechnicalskills andknowledgesucharenecessaryforsupervisingprocessesanddevising 124 methodsamongapplicantsarefew100%men.
TheanalyticallaboratorywasestablishedasanindependentsectionwithintheWCRLin
125 February1897,headedbyDr.F.H.Lees. E.F.Harrison,whohadalsotrainedunder
119
F.B.Power,WCRLWF:88/94.
120
H.A.D.Jowett,ObituaryChemist&Druggist125.1(15August1936):177 The Times(14August1936),WF:Box22F.B.Power.HistoryoftheW.C.R.L.(1907and 1912),WF:90/14:1G.Pearson,ALocalIndustry,HistoryoftheWorksandBurroughs WellcomeWestKentAdvertiser(21March1924),WF:YLBox25D3DW.

121
H.King,FrankLeePyman(1944):682T.A.Henry,WyndhamRowland Dunstan(1950):6381.
122 123
WellcomeResearchLabsDinnertoF.B.Power,(21July1896),WF:88/94:79a.
Dr.S.B.SchryverbecameProfessorofBiochemistryatImperialCollegeofScience andTechnology,WCRLStaff,WF:YLBox25F.B.Power,HistoryoftheWCRL (1907and1912),WF:YLBox25.

124 125
ADayinDoverChemist&Druggist52(25June1898):954.
LeesmovedtotheWCRLinJuly1899,andtheninAugust1905hebecameHeadof theAnalyticalDepartmentatDartford.HeresignedfromBurroughsWellcomeafter prolongedillnessinOctober1915,WorksRecordsWF:90/15:2F.H.Carr,Harrison MemorialLecture,PharmaceuticalJournal 103(26July1919):9399.
102
103
DunstanatthePharmaceuticalSociety,andlikehisgoodfriendFrancisCarr,performed researchonalkaloidsofaconite,assistedLees.HarrisonremainedatBurroughsWellcome forsixyearsbeforetakingonaconsultancyroleandachievingfameforhisexposofthe contentsofpatentmedicinesintheBMAcampaignsagainstSecretRemediesandthenasa

126 consultanttotheWarOfficeregardingprotectionagainstpoisonousgases. Ontheone
handtheanalyticallaboratoryformalisedtheimportanttaskofcheckingthepurityand compositionofpurchasedrawmaterials,chemicalproducts,intermediatesandcompetitor drugsontheotherhanditassessedthequalityofeachbatchofmaterialproducedbytheir ownchemicalresearchlaboratory,checkingthepurityandtheyieldsofchemicalreactions.

127 128 Thusithadbothanalyticalandresearchfunctions. HenryWellcomeemphasisedto
theanalyststhat:Thesecuringofchemicalsofthefinestqualityandofthehighestpurityis
129 theprimeraisondtre,butthequestionofprofitmustneverbelostsightof.
Wellcomewasmeticulousinhisinstructionstolaboratorystaff.Brandedproducts hadtobesealedbyaresponsiblepersonandsignedforwhensupplied,andallbrokenseals hadtobereportedtoheadoffice.Companylabelshadtoberemovedfromreturnedvials. Precautionsweretakenagainstintermixingdrugpreparations,andarsenicalswerebanned fromthequinineproductionsection.Wellcomepreparedaseriesofstandingorders coveringsuchaspectsasavoidanceofglasssplintersinvials,performingtablettallychecks
126
J.K.Irvine,TheParttheChemistPlaysinNationalHealthInsurance PharmaceuticalJournal (1February1930):101102 Pharmaceutical Journal (8February 1930):12930E.F.Harrison.LaboratoryBook,WF:88/94:26MetallicImpurities:Tests ofBlaud'sPills,WF:89/29/1(1887)L.G.Matthews,HistoryofPharmacyinBritain (Edinburgh:E.&S.Livingstone,1962).HarrisonbeganasaJacobBellscholarin1890, qualifyingthenextyearandgainingaBScfromLondonUniversityin1892andthe AssociatedexamoftheInstituteofChemistry.In1905hebecameafellowoftheInstitute ofChemistry,WF:88/94:26.
127
HistoryoftheWCRL,PowertoJohnston,(22January1907and27December 1912,WF:YLBox25LaboratorybooksWF:85/9,whicharenowretainedatGlaxo SmithKline.

128
G.Pearson,(1936)WF:88/24:41dMr.Hogg,OrganisationoftheWellcome ChemicalResearchWorks,Dartford18971934,WF:89/57:13.
129
H.Wellcome,ChemicalDepartmentalInstruction18(29November1898)volumeii, inWF:S/G/145inHogg,OrganisationoftheWellcomeChemicalResearchWorks,WF: 89/57:2.
103
104
130 andnotleavingmaterialsunsupervised. In1898Wellcomewrote:
theaimisforimprovedqualityandnottorelyontheproductsofothersandunderno circumstanceswhatevermaydrugsetc.purchasedoutsidebeuseduntiltheyhavebeen
131 passedbytheanalyst. ItisclearthatthepromotionofBurroughsWellcomeproducts
accordingtostandardisationandpuritywasnotonlyapromotionaltool,butwastaken veryseriouslyinternally. HenryWellcomerecognisedthattherewerevariousmeansbywhichhecouldclaim hisproductswerebetterthancompetitorextracts.Thefirstwasbyensuringareliable sourceofrawmaterialsupply.InthisrespectPowerwasimportantincheckingthespecies, sourceandqualityofpurchasedalkaloids.Evenbetterwastogrowtheplantsrequired locally.Thesecondwastostandardisechemicallytheconditionsofextractionandtouse reliablestrengthsofsolventsfortheprocess.Leescheckedtheseintheanalytical department.Athirdmeanswastopreparedifferentsaltsofthealkaloidstoimprovetheir physicalpropertiesandtheircompressibilityintotablets.Thiswaspartoftheworkofthe Chemicallaboratory.Afurthermeanswastoimprovetheassayofalkaloids.Inthepastthe totalamountsofalkaloidsextractedhadbeenmeasuredbutaschemicalconstitutionswere definedtheindividualalkaloidscouldbemeasured. PowerandJowettandtheirstaffpurifiedandcharacterisedthechemicalstructures ofthemanyalkaloidstheyextractedandworkedouthowtosynthesisethem.Subsequent extractscouldthenbecomparedagainstasyntheticstandardtoshowhowmuchactive ingredienthadbeenextracted,inaclosecollaborationbetweentheWPRLandWCRL From1898Schryver,PowerandJowettpreparedmanyalkaloidssyntheticallysothat alkaloidalextractsfromplantscouldbestandardisedagainstanabsolutestandardbefore
132 incorporationintotablets. Thefinal stepwastoscaleuptheseprocessessothatstaffat
133 theWorkscouldperformextractionsonamanufacturingscale. Oncethiswasinplace,
130 131
Ibid.
WF:89/57IIIIH.Wellcome,ChemicalDepartmentalInstruction3(29 November1898)volumeii,inWF:S/G/145.
132
StaffWCRL,WF:YLBox25.
133
B.CARRF.H.LaboratoryNotebooks.ImperialInstituteofScienceandTechnology 2132B/CARR/1vols.IandII.
104
105
itsimplybecameaprocessthatcouldberepeatedtimeandagaintoextract,synthesiseand standardiseawholeseriesofalkaloids.JowettproducedthefirstBurroughsWellcome semisyntheticgoldsaltsofthealkaloidshyoscine,hyoscyamineandatropine,whichwere

134 incorporatedintotabletsandmadeonacommercialscalefromAugust1897. An
135 engineer,Mr.Raisin,preparedthenecessaryequipmenttosupporthim. Thenitwasa
matterofpublicisingthescience.PowerjoinedtheChemicalSocietyandbecameclosely involvedwiththeSCI.HewasontheirCouncilandPublicationsCommittee,wherehe wasaclosefriendofSirWilliamTildenandotherinfluentialdyemanufacturingchemists andProfessorsofChemistry,alreadydescribedinchapter2suchasWilliamPerkin,

136 WilliamRamsey,RaphaelMeldola,andJamesDewar. ManyoftheBurroughs
WellcomecharacterisationsofnaturalproductswerepublishedintheJournalofthe SocietyoftheChemicalIndustry. Initially,thechemistryattheWCRLinvolvedonlysimplehydrolysis,condensation orsubstitutionreactions,butoverthenextdecadethecomplexity ofchemistryperformed increaseddramatically.TheWCRLstaffcharacterisednaturalproductssuchasthebarkof Cascarasagrada,(Rhamnuspurshianus),extractsofwhichhadbeenusedasapurgative, andevaluatedthechemistryofresins,volatileoilsandcrystallineextractstoestablishwhat wasresponsibleforthebiologicalaction.137 AsthisworkincreasedtheWCRLexpandedfurthertooccupyanadditionalfloorof theSnowHillsite,whichremainedthelocationuntilthemoveon24May1899to completelynewpremisesat6KingSt.,SnowHill.Thenewlaboratorieswereequipped withpumps,vacuumfilters,electricsupplies,distillers,analyticalbalances,adarkroomand adrymill.Thelibrarywasstockedwiththekeyjournalsreportingadvancesin chemistry, suchastheJournaloftheChemicalSociety,BerichtederDeutscheChemische
134
H.A.D.Jowett,SomeNewGoldSaltsofHyoscine,Hyoscyamine,andAtropineJ. ChemicalSociety 71(1897):860Mr.Hogg,OrganisationoftheWellcomeChemical ResearchWorks,WF:89/57IIII.

135 136 137
G.Pearson,(1936),WF:88/24:41d:7. WellcomeResearchLabsDinnertoF.B.Power,(21July1896),WF:88/94:79a.
H.A.D.Jowett,ANewGlucosideFromWillowBarkJ.Chem.Soc.(1900):707 12R.Bentley,ATextbookofOrganicMateriaMedica(London:Longmans,Green& Co.,1887):99.
105
106
138 Gesellschaft,ChemicalNewsandtheJournaloftheSocietyoftheChemicalIndustry.
Astheworkbecamemorespecialisedadepartmentwasestablishedforthe preparationofalkaloidsandsynthetics,separatefromthoseproducinginorganicchemicals
139 andgalenicals. Jowettsworkthereonthealkaloidsof Jaborandifrom1899was
describedaspioneeringandledtotheisolationandproposalofthechemicalstructureof theactiveingredient,pilocarpinein1902andvariousfurtherchemicalderivativeswere
140 isolatedandinvestigatedforphysiologicalactivity. Jaborandileaveshadenteredusein
medicinein1874,slowingtheheartandincreasingsalivarysecretions,buttherehadbeen
141 someconfusionoverthebestspeciesofplanttousetoprepareextracts. Theworkof
JowettandsubsequentlyPymanmeantthatthepharmacologicalactioncouldbebetter understoodandpreparationscouldbestandardisedforthecontentofeachactive ingredient,improvingexistingalkaloidsandalsonewerdrugs. Thusbythecloseofthenineteenthcenturythefirmhadestablishedchemical laboratorieswhereresearchworkofconsiderablecommercialimportancewasperformed butinsteadofproducingsyntheticdrugs,thetechniqueswereusedtoimproveexisting productionofalkaloids.Inadditiontoplantextractsthefirmbegantoextractanimal

142 tissuessuchasadriedthyroidextractfollowingthenewconceptsoforganotherapy.
Manynaturalextracts,syntheticderivativesofmorphine,newcreosotecompoundsand
138
C.L.Oakley,A.T.GlennyBiographicalMemoirsofFellowsoftheRoyalSociety 12(1966):163180F.B.Power,HistoryoftheWCRL,(22January1907)and supplement(27December1912),WF:YLBox25.D3DWAphotographoftheKing StreetlaboratoriesappearsinH.Turner,(1980):19TheWCRL,WF:88/94:80.

139 140
G.Pearson,(1936),WF:88/24:41d:7.
H.A.D.Jowett,YearBookofPharmacy 36(1899):435 JournalofChemical Society 77(1900):474,851 JournalofChemicalSociety 79(1901):581,1331H.King, F.L.Pyman(1944):682H.A.D.Jowett,PilocarpineandtheAlkaloidsofthe JaborandiLeavesJ.Chem.Soc.(1900):47398H.A.D.Jowett,TheAssayof PreparationsContainingPilocarpineandtheCharacteristicsofPilocarpineNitrateand HydrochloridePharmaceuticalJournal (29July1899):9193.
141
H.A.D.Jowett,J.ChemicalSociety 83(1903):438H.A.D.Jowett,J.Chemical Society 83(1903):442T.A.Henry,(1939):54958.

142
W.Sneader,DrugDiscovery:theEvolutionofModernMedicines(London:J.Wiley, 1985):192M.Borell,Organotherapy,BritishPhysiology,andtheDiscoveryofthe InternalSecretionsJ.Hist.Biol.(1976)9:23568.
106
107
newsaltsofolderagentsrequiredbiologicalstandardisationinanimalsattheendof
143 1900. ThisworkcouldnotbeperformedwithinBurroughsWellcomeuntiltheHome
144 OfficelicensedtheWPRLlaboratoriesin1901.
LargescaleextractionstookplaceattheChemicalWorksinDartford,whichwere
145 considerablyenlargedwithafloorspaceof100by45feetinJuly1896. TheWorkshad
aconstanttemperatureandwerecrammedwithcostlymachineryandonalevelwith anysimilarfactoryintheworld,andthefirstGermaninorganiclineswereproducedin August1896withJowetttemporarilyincharge,whileretaininghisresearchroleatthe

146 WCRL. InordertorelievethestrainonJowett,anapproachwasmadetoDunstanto
recruitFrancisHowardCarraschiefmanufacturingchemistfortheChemicalWorksandhe tookupthisroleon3January1898. Carr,likeJowetthadathoroughgroundinginbothanalyticalchemistryand pharmaceuticalscience,andparticularlyinstudyingtheefficiencyandyieldsofchemical reactions.HisearliertrainingwithHenryArmstrong,oneofthefoundersofchemical engineering,wasdescribedinChapter2.CarrwasDunstansstudentfrom18926, performingresearchonthealkaloidsofaconite,ergot,hyoscyamine,andipecacuanha.He wasthefirsttomakethealkaloidspyracotinine,exotinine,ergotoxine,andnorhyosyamine. DunstanandCarrcoauthoredseveralresearchpapersonaconitepreparationsarisingfrom

147 IndiaandAsia,andthenCarrfollowedDunstantotheImperialInstituteearlyin1896.
CarrsroleatBurroughsWellcomewastoimprovethemanufacturingprocesses,increase efficiencyofproductionandtocollaboratewith researchersattheWCRL,tocharacterise activeingredientsbycomparingtheextractswithsynthesisedsubstances.Hecamewithan excellentpedigree,havingalreadyestablishedhimselfasanassistantexamineratthe
143
H.WellcometoRt.Hon.CharlesThompsonRitchie,(25February1901),WF: 86/92:1S.B.Schryver,F.H.Lees,ResearchesonMorphinept2J.Chem.Soc.(1901): 563580.

144 145
E.M.Tansey,(1989):141. G.Pearson,(1936)WF:88/24:41d:7.
146
SilasBurroughsObituaryChemist&Druggist46(8February1895):213A.W. Haggis,HistoryoftheWorks:56,WF:85/20:2:1.
147
Carr'sarchivesareatImperialCollege,B.CARRFH6includingnotesofa conversationwithbyA.E.GuentherT.A.Henry,W.Dunstan(1950):6281.
107
108
148 InstituteofChemistryunderPercyFaradayFrankland. Carrsecuredtheassistanceof
furtherformercolleaguesfromDunstanslaboratorywhohadtrainedatFinsburyCollege,
149 includingW.C.ReynoldsandW.E.Thompson. Theyperformedbiochemicaltestson 150 Soloids,assayedchaulmoograoils,glycerophosphates,samplesfromthecolonies, plants 151 grownatDartford,andtestedmanufacturedbatchesagainstsyntheticstandards.
FivefurtherchemistryassistantsjoinedtheWorksbetweenNovember1897and October1899,includingonewhotransferredfromthePharmacydepartment,butthese
152 wereunqualifiedboys. BurroughsWellcomeopenedanothernewFinechemical
buildingon6June1898toproducechemicalintermediatesandinorganicsaltsand BurroughsWellcomehadjustcompletedalargebuildingand(were)layingfoundationsof
153 another58feetby130feetwith3storeys. InDecember1898amaltbrewingplant
openedtoproducetheKeplerrangeofproducts,andinJanuary1899erectionofanew Tabloidbuildingbegan,whichwasreadybyOctober1900.CarrattendedInternational exhibitionsoflaboratoryequipmentinParisandGermanytopurchasethelatest
148
A.Findlay,WilliamHobsonMills(eds.),BritishChemists(London:TheChemical Society,1947):5897.
149
WilliamColebrookReynoldsjoinedtheworkson1April1899andreportedtoCarr. Helefton3November1911:Mr.Hogg,OrganisationoftheWellcomeChemical ResearchWorks,WF:89/571III.W.E.Thompsonjoined1August1899.Previouslyhe hadworkedasalabboyatthePharmaceuticalAssociationbeforegoingtotheImperial Institutewherehedidnoformaltrainingexceptfor3yearsunderCarr.AtBurroughs Wellcomehepreparedalkaloids,eserine,andpilocarpineattheExperimentallaband WCRLanddepartedinJanuary1916 JohnAugustusGoodsonwhojoinedtheTropical InstituteinKhartoumin1906andlaterworkedattheWCRLalsotrainedatFinsburyunder RaphaelMeldola,WF:YL Box25.
150
W.DunstantoBurroughsWellcome,(17February1906),WFBusiness correspondence18951940,WF:D3DWEG.E.Pearson,(1936),WF:88/24:41d:7.
151
152
Laboratoryreports18891893,(10October1889),WF:84/7.
Hogg,Organisation oftheWellcomeChemicalResearchWorks,WF:89/57II (S/G/145)StaffRecords.TayloreventuallytookoverasheadoftheWorkswhenCarrleft in1914.

153
Anotereferringtothefirmsoutingof700stafftoDoverexplainedhow2yearsago thestaffwasjust500.Theyhadjustcompletedalargebuildingandwerelayingthe foundationsofanother3storeyshigh,ADayinDoverChemist&Druggist52(25June 1898):954.
108
109
154 manufacturingequipment. HeenhancedtheWorksequipmentandevenpatentedhis 155 ownfurnacedesign. Between1901and1908heoversawtheintroductionofmains
electricpower,anelectriccrane,motorvans,workstelephonesandapackaging
156 conveyer. Anewchemicalbuildingwasopenedin1901,afurtherTabloidbuildingin
1903,achemicaldepartmentofficein1904,anengineeringshopandaplanttoproduce chloroform.ThelaboratoriesimpressedvisitingSocietyoftheChemicalIndustrymembers
157 on15July1905andanotherplantforarsenicalsopenedin1908. Intheperiodfrom
1896totheoutbreakoftheFirstWorldWar,theWCRLandthemanufacturingcapacityat theWorksweresignificantlyenhanced. 3.4TheWellcomePhysiologicalResearchLaboratoriesupto1901. InthissectionontheWPRLpriorto1901Iwillintroducethekeycharactersand showhowtheWPRLandWCRLinteractedtoutilisechemistrytodifferentiateBurroughs Wellcomeproductsbaseduponpurityandstandardisation.Ihavedemonstratedalready thatBurroughsWellcomehadbeenpursuingachemicalapproachsincetheinceptionof Tabloidsin1884. EmilvonBehringsdiscoveryofdiphtheriaantitoxininGermanyin1890was recentlydescribedbythehistorianWilliamBynumasprobablythesinglemostimportant catalystinthecreationofthemodernpharmaceuticalindustry,becauseitstimulatedthe searchforabetterunderstandingoftherelationshipbetweenthestrengthandpurityofa
158 preparationanditsaction. Diphtheriaantitoxincouldbeproducedinanylaboratorythat
hadthefacilitiestoraiseandassayitinanimals.Nothavingalicence,BurroughsWellcome
154
InSeptember1900CarrandRaisin,bynowheadofengineering,attendedan internationalmeetinginFrance:B.CARRFH6Mr.Hogg,WF:89/57IIIIWellcome himselfvisitedEuropeancentrestostudythelatestequipment:H.Turner,(1980):12.

155 156
B.CARRFH6Mr.Hogg,WF:89/57IIII.
Thedramaticexpansionoftheworksstaffbetween1884and1907,wasreflectedby thenumbersof'girls'employedonly23in1884,with115in1890,121in1894,278in 1898,467in1901,502duringwartimein1902and412in1907:Mr.Hogg,WF:89/57I IIIWF:YLBox25:G.Pearson (1936),WF:88/24:41d:810.

157
WFBox77,51D3DWandMr.Hogg,WF:89/57IIII.
158
W.F.Bynum,ScienceinthePracticeofMedicineintheNineteenthCentury, (Cambridge:CambridgeUniversityPress,1994):164165.
109
110
triedtonegotiatetherightstodistributediphtheriaantitoxinproducedbytheBritish InstituteofPreventativeMedicine(BIPM)butwhiletheyprevaricatedandAllen&
159 Hanburystookupthatrole,BurroughsWellcomedecidedtomaketheirownsupplies.
However,theantitoxinrequiredsophisticatedbiologicalstandardisationinanimalsinorder toensuresafetyandpotency,andthismadecommercialproductionexclusivetotechnically orientedfirmssuchasLederle,ParkeDavis,andMulfordandsomegovernment

160 laboratories. However,the1876CrueltytoAnimalsActdidnotallowcommercialfirms
toperformsuchworkinBritain.TanseydiscussedindetailtheimplicationsoftheActfor BurroughsWellcomeandthedeterminedeffortstoovercometheinitialrejectionofthe
161 BurroughsWellcomeapplication. 162 TheyproducedtheirowndiphtheriaantitoxinfromApril1894. Anindependent
physiologistandHomeOfficelicenseholder,ThomasJessopBokenham,atSt. BartholomewsHospitalin London,assistedthemwithassaysfromSeptember1894and

163 th becameanemployeeofthefirmfrom27 April1895. Togreatacclaim,commercial
productionofdiphtheriaantitoxinbeganinthefirstweekofJanuary1895,aheadofthe
164 BIPM. BurroughsWellcomeinitiallyprovideditfreeofchargeduringtheperioditwas 165 166 underthetrial. Theyalsopreparedaconvenientdriedconcentratedversion.
159
160
GeoffreyTweedale,(1990):120. J.Liebenau,(1987):72,75,100,110.
161 E.M.Tansey,(1989):141.
162
G.Pearson,(1936),WF:88/24:41d:4.
163
E.M.Tansey,(1989):141onp.4Staffrecordbook,(18791902):35,WF:P2 T.BokenhamtoBurroughsWellcome,(19August1896),WF:86:92:1TheSupplyof DiphtheriaAntitoxininEnglandBritishMedicalJournal (10November1894):1063G. Pearson,(1936),WF:88/24:41d:45TradeNotes,DiphtheriaAntitoxinChemist& Druggist44(24November1894).

164
DiphtheriaantitoxinwasalsoproducedbyEvansSons,Lescher&Webb,the GoldsmithCo.,RoyalCollegeofPhysiciansandSurgeons,BritishInstituteofPreventative Medicine(BIPM)andRoyalVeterinaryCollege,Chemist&Druggist44(24November 1894):736H.Chick,M.Hine,M.MacFarlane,BIPMWaronDisease:aHistoryofthe ListerInstitutePharmaceuticalJournal (1898)61:4624TheAntitoxinTreatmentof DiphtheriaLancet(5January1895)TheAntitoxinTreatmentofDiphtheriaBritish MedicalJournal (12January1895):1012G.Pearson,(1936),WF:88/24:41d:5.

165
A.W.Haggis,HistoryoftheWorks:56,WF:85/20:2:4(14January1899),WF: 86/92:1TheDiphtheriaCureChemist&Druggist46(16February1895):238Trade
110
111
Wellcometookadvantageoftheacclaimregardingtheantitoxintoemphasisethe importanceofhislaboratories,whichofferedadiagnosticservicetoanalysethroatswabs fordiphtheriaandtuberculosisatatimewhenmostphysicianshadlimitedaccessto laboratoryfacilities.DrBousefield,apathologistatSt.BartholomewsHospitalperformed theserviceonbehalfoftheWPRLandwasallowedtochargeafeebutfromthishehadto

167 coverthetubes,medicalcostsandpostage,anddrawupaccountseachmonth.
AssalesofantitoxinincreasedHenryWellcomeappliedtotheHomeOfficefora licencetoperformphysiologicaltestswithinthefirm,buttheirapplicationwasturned
168 downinAugust1896onthegroundsthatitwouldcreateamonopoly. TheWPRLat 169 CharlotteStreetinLondonwasextendedtoincreaseproductionofantitoxin.
BokenhamcouldnotcopealonewiththeincreasingworkloadandWellcomesought assistanceinitiallyfromFrederickGowlandHopkins,whodecidedtopursuehisacademic
170 career.
InsteadWellcometurnedtoProfessorMichaelFosterinCambridge,theforemost
171 physiologistinBritainforadviceonstaff. Fosterrecommendedhisownresearch 172 pathologistA.A.Kanthack, butWellcomesecuredtwoCambridgegraduates.Walter
NotesChemist&Druggist46(22June1895):870AngloAmericanNewsletter(1896): 1612,WF:E2.
166 167
TradeNotesChemist&Druggist45(1894):857WF:YLBox23(E2).
WPRLDiagnosticFeesMemo's,(1May1901),andH.WellcometoDrBousefield (21December1903),WF:YLBox84.
168 169
E.M.Tansey,(1989):141,especiallyonpp.1718,23.
ForanearlyaccountoftheWPRLseeHistoryofImmunologicalAdvances1895 1972WF88/15EarlyprintedmaterialonBW. BusinessCorrespondence18951940, WF:E2DW.ThemovetoCharlotteStreetwasapprovedon20July1896:G.E.Pearson, (1936),WF:88/24:41d.Howeverthelaboratorieswerestillbeingfittedouttwoyears later,T.BokenhamtoH.Wellcome,(23August1898),WF:86/92:1.

170
171
A.W.Haggis,TheLifeandWorksofHenrySolomonWellcome,WF:89/72IIII.
BurroughsWellcometoW.Dowson,(5December1900),WF:HSWLetterbooks 19001,WF:S/G/148/1:607W.DowsontoM.WhiteRidley,(15February1900),WF: 86/92H.J.Parish,HistoryoftheFirm:56,WF:85/20:2:6.

172
A.A.Kanthack18631898wasDirectorofthePathologicalDepartmentatSt. Bartholomew'shospital,succeedingC.S.Roy:Obituary,AlfredoAntunesKanthack BritishMedicalJournal (31December1898):19412MarkWeatherall,Gentlemen,
111
112
Dowson hadstudiedunderHuxleyatSouthKensington,hadbeenaGeneralPractitionerin BristolandwasaFellowoftheIncorporatedSocietyofMedicalOfficersofHealth.He wasdoing3monthsresearchontetanusunderKanthackinthepathologydepartmentof

173 Prof.G.SimsWoodhead,whorecommendedhimtoBurroughsWellcome. Theother
174 wasthebacteriologistLouisCobbett. DowsoninitiallyassistedBokenhamandlater 175 replacedhimasDirectoroftheLaboratoryinOctober1897.
Despitetheproblemofgettingassaysdone,BurroughsWellcomesoldnotonly diphtheriabutalsoantisyphiliticandantityphoidantitoxins,andantistreptococcus
176 sera. InanticipationoffurtherexpansionoftheWPRL,atBrockwellHall,asiteat 177 HerneHillwasleasedfromNovember1898. Inthespringof1899theWPRLmoved 178 thereandDowsonrecruitedyoungscientistsfromthelocalschoolinDulwich. The
headmaster,HerbertBreretonBakerwasachemistwithahighreputation,whowaslater
ScientistsandDoctors:MedicineatCambridge18001940(Cambridge:BoydellPress, 2000):1526,16365,172,196.
173
DaleReminiscencesin93HD143.6SimsWoodheadhadaspecialinterestin tuberculosis,L.Bryderin TuberculosisandtheMRCinJoanAustokerandLindaBryder (eds.),HistoricalPerspectivesontheRoleoftheMRC(Oxford:OxfordUniversityPress, 1989):57.

174
ObituaryofLouisCobbett,BacteriologistLancet(22March1947):3912.Walter Dowson 18561919studiedscienceatChrists,CambridgeH.H.Dale,93HD143.6 MarkWeatherall,(2000):155,163,171,182,200.

175
W.DowsontoM.WhiteRidley,(15February1900),WF:86/92:1H.J.Parish, HistoryoftheFirm:56,WF:85/20:2DaleArchives,93HD143.6E.M.Tansey, (1989):141onpp.716.

176
Medicaldiary,(1899):115,WF:86/92:1.SeealsoA.E.Wright.OntheResults WhichHaveBeenObtainedbyAntityphoidInoculationLancet(6September1902):651 654Z.Cope,AlmrothWright:FounderofModernVaccineTherapy (London& Edinburgh:ThomasNelson,1966).

177 178
G.E.Pearson,(1936),WF:88/24:41d:7.
DowsonlivedinAlleynRoadoppositeAlleynsschool,whichwasassociatedwith DulwichCollege.Dowsoncontactedtheheadmasterregardingboyswithpromisein science:W.S.Feldberg,H.H.Dale,BiographicalMemoirsofFellowsoftheRoyal Society 16(1970):95W.DowsontoWells,(27July1900),WF:86/92:1.
112
113
179 ProfessoratImperialCollege,London. Hisstudents,AlexanderThomasGlennyandH.
J.SudmersenjoinedBurroughsWellcomeasassistantsinthebacteriologylaboratoryand
180 continuedtheireducationintheevenings. Afurtherchemist,ArthurJamesEwinswas 181 recruitedtotheWPRLfromthesameschool.
WellcomedescribedthebacteriologylaboratorywithintheWPRLasbeinginclose association withmyphysiologicallaboratory.Itwasforresearchinbacterialchemistry,a classofworkdistinctfromthatcarriedoutinmychemicalresearchlaboratories(WCRL)in

182 KingStreet. Glennygaveanaccountofthebacteriologicalsectionofthelaboratory 183 whereheperformedresearchtoincreasetheefficiencyofserumproduction. Whena
HomeOfficeinspectorvisitedthesitehedidnotattempttoconcealhissatisfactionhe
184 hadnotseenanythinglikeitinBritain.
TheapplicationfortheHomeOfficelicence
wasfinallyacceptedon5September1901makingthephysiologicaltestingofantitoxins
185 preparedattheWPRLfinallypossibleonsite. Onlyoneotherfirm,JohnRichardson&
Co.,whoestablishedtheBacteriologicalInstituteinLeicester,appliedsuccessfullyfora
186 licenseanditwasnotuntil1905and1908thatfurtherlicensesweregranted. TheHome
179
BakerlaterbecameProfessorofInorganicChemistryattheUniversityofLondon:J. F.Thorpe,H.B.BakerObituaryNoticesofFellowsoftheRoyalSociety 1(1935):523 526.

180
C.L.Oakley,A.T.Glenny(18821965)BiographicalMemoirsofFellowsofthe RoyalSocietyofMedicine12(1966):163180.GlennystudiedmathematicsatUniversity College,London.Hislaboratorynotes(18991900)giveaninsightintohisworkunder Dowson,WF:84/7:7.HenryJ.SudmersenwasattheWPRL18981901and19051925: StaffRecordBook1571WF:YLBox46In19015heresearchedaPhDinBerne.

181
BothGlennyandEwinsweremadepermanentstaffwhentheygraduated.H.H. Dale,ArthurJ.Ewins(18821958)BiographicalMemoirsofFellowsoftheRoyal SocietyofMedicine4(1958):8191DaleArchives,93HD143.6:26.

182 183
H.WellcometoC.T.RitchieM.P.,(25February1901),WF:86/92:1:5.
C.L.Oakley,A.T.Glenny(1966):16380H.J.Parish,HistoryoftheFirm:56, WF:85/20:2:6.
184
WellcomePhysiologicalResearchLaboratoriesChemist&Druggist55(11 November1899):780781.
185
186
C.S.MurdochtoBurroughsWellcome,(21May1900),WF:86/92:1. E.M.Tansey,(1989):141.
113
114
OfficelicensegaveBurroughsWellcomeaclearadvantageoverEvans&SonsandAllen& Hanburyswhostillreliedonexternalsuppliesofantitoxinorhadtohaveeachbatchtested
187 elsewhere. ThesalesofdiphtheriaantitoxinbyBurroughsWellcomerosedramatically 188 from84,000vialsin1905to239,000in1910,and627,000in1915. Themainpointsto
emphasisefromthisdiversionintotheWPRLarethatBurroughsWellcomecontinuedto employscientists,theirscientificreputationwasenhancedandtheycontinuedtheirdrive towardsstandardisedmedicines.Inadditiontoantitoxins,thelicensingofthelaboratories allowedthemtofurtheradvancetheirworkonpurifying,andcharacterisingalkaloidsand glucosidesextractedfromplantsandorganextractsfromanimals,sotheycouldcompare thebiologicallystandardisedpreparationswithsyntheticallypreparedequivalents. 3.5InteractionsBetweentheBurroughsWellcomeLaboratoriesandWorksafter 1901. BurroughsWellcomeobtainedtheirvivisectionlicense,conditionalupontakingonan additionalphysiologist,whichWellcomeagainarrangedthroughhiscontactsatCambridge University.JohnMellanbyofEmmanuelCollege,Cambridge,qualifiedinphysiologyand chemistryin1900underMichaelFoster,J.N.LangleyandF.G.Hopkinswho
189 recommendedhisappointmenttothestaffoftheWPRLinOctober1901. Afurther 190 pathologist,Dr.W.V.ShawfromSt.MarysHospitalwasappointedinJanuary1902.
BurroughsWellcomealsocollaboratedwithaDr.HamiltonofDartfordandthepreviously mentionedDr.Bousefield,apathologistatSt.BartholomewsHospitalinLondon,where
187 188
AnEpitomeofTherapeuticsWyeth (Philadelphia:Wyeth,1901). H.J.Parish,TheWellcomeResearchLaboratoriesandImmunisation,WF:85/20:2.
189
J.B.Leathes,JohnMellanbyBiographicalMemoirsofFellowsoftheRoyal Society 3(1940):173195H.WellcometoC.T.Ritchie,(25February1901),WF: 86/92:1GeraldL.Geison,MichaelFosterandtheCambridgeSchoolofPhysiology:the ScientificEnterpriseinLateVictorianSocietyJ.N.Langley,SirMichaelFosterin MemoriamJ.Physiology 35(1907)W.H.Gaskell,SirM.Foster18361907Proc. Roy.Soc.Biol.1380(1908)lxxilxxxiW.S.Feldberg,HenryHallettDale18751968 (1970)77174onp.95.

190
ShawwasappointedinJanuary1902:E.M.Tansey,(1989):356.
114
115
191 Dowsonhadtrained. Wellcomehadanuncannyknackforselectingstaffthatwereto 192 achieveoutstandingreputations. SeveralofhisstaffwentontobecomeFellowsofthe 193 RoyalSociety.
Specialprovisionshadtobemadeinordertoattractpromisingyoungscientiststo workinacommercialenvironment.WellcomehadtoconvinceJohnMellanbythathis independencewouldbemaintainedandhehadtoslackenthestricttermsofemployment

194 regardingreviewofpublications,secrecyandhoursofwork.
ThegrantingoftheHomeOfficelicenceopenedthefloodgatesforthefirmto
195 evaluateabacklogofpreparationsrequiringassayinanimals. Thisencouragedthefirm
topursuefurtheractiveprinciplesandtocharacterisechemicallythem,whichinturnledto anexpansionofthechemicalstaffoftheWCRLfromtwoin1896tofourin1898,whereas in1900therewereseven.Intheperiodbetween1901and1914anewkindof pharmaceuticalindustrywascreatedinBritain.BurroughsWellcomeestablishedasystem wherebytheextractionandpurificationofnovelalkaloidsandglucosidessuchasemetine
191
W.P.R.L.DiagnosticFees,19034andW.DowsontoDr.Hamilton,(1May1901), WF:YLBox84.ProductionoftuberculinlikewiseenabledAllen&Hanburytoestablish goodcontactswiththemedicalprofession:GeoffreyTweedale,(1990):102.

192 193
G.MacDonald,(1980):35.
TheBurroughsWellcomestaffelectedFRS(withdateinparentheses)arelistedin WF:85/20:1givenwiththedatestheywereatthefirm:JohnMellanby190004(1940),P. Laidlaw190913(1927),A.Glenny18991909(1944),H.King19111919(1933),G. Barger190309(1919),A.J.Ewins18991947(1943),J.H.Burn1914(1942),P.Hartley 191921(1937),C.Kellaway194452(1940),C.Wenyon19071944(1927),H. Wellcome18801936(1932),F.L.Pyman19061919(1922),C.L.Oakley,19341953 (1957),H.H.Dale19041914(1914).

194
Toughcontractswerestillinuseupto1911whenFrederickAlfredPickworth workedatBurroughsWellcome.Hehadtotakenootherbusinessandkeepasasolemn secretallformulaeandprocesses,structureandworkingofmachinery,andnotdivulge these,buyorsellcopiedmachineryafterleaving.Allimprovementsrightshadtogoto BurroughsWellcomeObituaryofFrederickAlfredPickworthBritishMedicalJournal (11November1967):363.

195
Dr.Ponthieu,achemistatParkeDavisinDetroitacknowledgedthedifficulties causedbytheCrueltytoAnimalsActinBritain:StandardisationChemistandDruggist 59(7September1901):412.SimilarActs,onthestatuteinsomestates,didnotaffect firmsinAmerica.TestsperformedattheWCRLWF:88/94:89WF:WPRLDiagnostic fees19034,YLBox84.
115
116
andhyoscyaminefromplants,wascontrolledbydevelopingmethodstoassaythe concentrationsofactiveingredients.Firstlythiswasbysimplytestingtheextractsin animals,butthencruciallythiswastakenonestepfurtherbysynthesisingtheproposed activeingredientstoprovetheiridentitytotheextracts.Oncethiswasachievedthe chemicallysynthesisedpreparationweremaintainedasatechnicalstandard.Thiswas importantbecausetheextractionmethodusedbyotherfirmsproducedextractsofvariable activity,despiteattemptstostandardiseproceduresandconditions.Furthermorethepure chemicalcouldthenbeusedtoevaluatethemoresubtleactivitiesofthedrugin physiologicalexperiments.Becauseofitspurityitcouldbeusedatlowerdosesand untowardreactionsfromadditionalalkaloidsinanextractcouldbeexcluded.Furthermore, chemicalhomologuescouldbepreparedtotesttherelationshipofchemicalstructureto activity.ForthefirsttimeaBritishfirmsoldorganicdrugsaccordingtothestrengthof theirpureactiveprinciplesratherthanthetotalalkaloidcontentwithouthavingtorelyon externalsupportforassaysastheyhadwithDunstan.Thewholeprocesswas commerciallydriven,aimingtoproducenovelpreparationsthatweremoreactive,more concentrated,morepotentormorepure,givingBurroughsWellcomeadifferential advantageoverotherfirms.Encouragedby earlysuccessesthefirmpreparedfurtherde novosyntheticchemicals,whichwerealsotestedforphysiologicalactivity. Inadditiontoplantextracts,Jowettpreparedthehumanhormone,adrenaline,for
196 testingintheWPRLin1903. Howeverinsteadof sellingadrenalineincompetitionwith
otherfirms,BurroughsWellcomepreparedandsolditsownuniquestandardisedsynthetic isoquinolinederivativeofadrenaline,collaboratingwiththechemistsRobertRobinsonand WilliamH.Perkinjnr.attheLiverpoolMedicalInstitutionandManchesterSchoolof

197 Chemistry. FurthercollaborationswerearrangedwithchemistssuchasWilliamTilden,
EmeritusProfessorattheRoyalCollegeofScienceinKensingtononresearchregarding
196
G.Barger,H.A.D.Jowett,TheSynthesisofSubstancesRelatedtoEpinephrineJ. ChemicalSociety 87(1905):967G.Barger,H.A.D.Jowett,SynthesisofCompounds SimilartoAdrenalinefromPiperonalJ.ChemicalSociety 93(1908):563.

197
Thisappliedespeciallytothesearchforasyntheticsystemicallyactiveantiseptic:R. Robinson,W.H.Perkinjnr.,HarmineandHarmalineJ.ChemicalSociety 103(1913): 197385LiverpoolMedicalInstitutionBritishMedicalJournal (29March1913):667F. L.Pyman,F.G.P.Remfry,IsoquinolineDerivativesVII.ThePreparationofHydrastine fromCotarnineJ.ChemicalSociety 101(1912):1595.
116
117
198 terpenesandvariousoils. FredPowerwasintouchnotonlywithBritishchemists
throughhisroleontheSocietyfortheChemicalIndustrybutalsowithtopchemists
199 throughoutEurope. CarrsmentorHenryArmstrongturnedtothefirmforassistancein 200 workinguparatherlargequantityofmaterialforwhichIhavescarcelytheappliance.
AsBurroughsWellcomeincreasedtheirfocusonchemistrytheycorrespondedwithSir WilliamRamsay,ProfessorofChemistryatUniversityCollege,LondonSirJamesDewar, ProfessorofChemistryatCambridgeRaphaelMeldola,ProfessorofChemistryatFinsbury TechnicalCollege,LondonJocelynFieldThorpeatOwensCollege,ManchesterFrederick StanleyKippingatNottinghamUniversity,andArthurGeorgePerkinatLeeds

201 University.
Thenovelchemicalsorroutesofsynthesiswerepatentedtosecureprotectionfrom
202 otherfirmscopyingthem. Patentingandtestingtheseproductsinanimalsgave
BurroughsWellcomeanewformofmonopoly,especiallyintheformofsynthetic derivatives,althoughatthisstagethesyntheticpreparationswereprimarilyusedas standardsasitwascheapertopreparestandardisedextractsonalargerscale.Outside Germanyfewfirmsheldpatentsinthemedicalfield,becausemanyproducedthesame drugswithlimitedinnovation.IntheUSApatentingslowlyincreasedonlyafterthe ShermanActof1907,whichforbaderestraintoftradebysharingmarketsandbyprice fixingbutnotbymakingexclusivearrangementsfortheuseofpatents,secretprocesses

198 199
W.A.TildentoF.B.Power,(13June1906),WF:88/94:41.
DiscussionsontherecruitmentofchemistsmaybefoundinW.RamsaytoF.B. Power,(20March1907),WF:88/94:40A.G.PerkintoF.B.Power,(5May1907):WF: 88/94:41J.F.ThorpetoF.B.Power,(2October1905),WF:88/94:41Tildenenquired aboutpostsfor2chemists,W.TildentoF.B.Power,WF:93:37.

200
201 202
H.E.ArmstrongtoF.B.Power,(11July1907),WF:88/94:41. AlexanderFindlay,andWilliamHobsonMills(eds.),BritishChemists(1947).
FrankPymansnameappearedwiththatofWellcomeonseveralpatentse.g. ManufactureofNewTherapeuticCompounds(PhenylarsonicAcids)BritishPatentBP 855(1908)ManufactureofaNewTherapeuticCompound(fromLaudanosine),BP314 (1909)ManufactureofNewTherapeuticCompounds,BP11108,13828,14633(1909) TherapeuticCompound,Thiolaminomethylglyoxaline,BP25,873(1910)physiologically activebase4(or5)betaaminoethylglyoxyline,BP28,538(1910).Wellcomepatented withF.H.Carr,Manufactureofemetine,BP14,677and17,483(1913)Wellcomealone patentedaminophenylselenonicacid,BP2787(1914),C.M.Wenyon,HenryWellcome, ObituaryNoticesofFellowsoftheRoyalSociety 2(1938):229238.
117
118
203 andtechnicalknowledgegenerally. TheAmericanfirmofE.R.Squibbhadonlyone 204 patentbefore1920. Wewillseelaterhowpatentsweretobecomecentralincontrolling
medicaldiscoveriesandhowthisonoccasionswasassociatedwithcontroversy. Anothermeansofcontrollingthequalityofdrugswastoensurethecorrectstarting materialsforextractswereused.BurroughsWellcomealreadyhadonebotanicalexpertin FrederickPowerandtheygrewsomeoftheirownmedicinalplantsunderstandard conditionsbuttheytookonanotherexpertinGeorgeBarger,whotrainedinchemistryand biologyatUniversityCollege,London(1896)andKingsCollegeinCambridge(1898).He gainedaPh.D.afterresearchinBotanyattheUniversityofBrusselsandjoinedtheWPRL

205 in1903afterconsiderablereflectionoverhisconcernsaboutcommerciallinks.
BargersbotanicalandchemicalexpertiseenabledresearchersattheWPRLtoexaminethe chemicalconstitutionoffurtheralkaloidsandglycosideshisfirstpublishedresearchat
206 BurroughsWellcome(withW.V.Shaw)wasontheconstitutionofdigitalisextracts.
ThescientificstatureoftheWPRLwascementedbytheappointmentofHenryHallett Dalein1904.Dowson,Barger,MellanbyandDaleallcamefromWellcomesconnections
207 withFrederickGowlandHopkins,whoactedasaconsultantandWalterFletcher. Dale
hadstudiedexperimentalphysiologyinMichaelFostersprestigiousdepartmentat
208 Cambridgebetween1894and1900. HeknewBargerfromCambridgeasamemberof
theNaturalScienceclub.SincethenDalehadperformedresearchinEhrlichslaboratoryin
203
W.J.Reader,ImperialChemicalIndustriesaHistory.TheForerunners18701926 volume1(London:OxfordUniversityPress,1970):199.
204
JohnP.Swann.(1988):31RichardHarrisonShryock,AmericanMedicalResearch PastandPresent(NewYork:TheCommonwealthFund,1947):140.
205
206
H.H.Dale,GeorgeBarger(1940):6383.
TheChemicalandPhysiologicalAssayofDigitalisTincturesPharmaceuticalJournal 19(1904):249.
207
H.H.Dale,Reminiscences:WPRL19041914,DaleArchives,93HD143.6.
208
G.L.Geison,MichaelFosterandtheCambridgeSchoolofPhysiology:The ScientificEnterprisein LateVictorianSociety (Princeton:NewJersey,Princeton UniversityPress,1978)J.N.Langley,SirMichaelFosterin MemoriamJ.Physiology 35(1907)W.H.Gaskell,SirMichaelFoster18361907Proc.Roy.Soc.Biol.1380 (1908)lxxilxxxHopkinsrecommendedDaletoDowson:H.H.Dale,'Reminiscences, WPRL190414.DaleArchives,93HD143.6143.3.
118
119
209 Germany. HereturnedtoEnglandtoperformresearchatUniversityCollegeHospital 210 (UCH)inLondonin1900, andenjoyedfruitfulcollaborationswithThomasRenton

211 Elliott,bothinCambridgeandlateratUCH.
WhenDaleconsideredtheBurroughsWellcomeposthefeltmychancesinacademic physiologyrevealedsoblankaprospect.HeknewlittleaboutBurroughsWellcomes researchlaboratoriesbutknewthatinadditiontofamiliarremedies,thefirmhadsomeof greaternovelty.WellcomeexplainedtoDalethatherequiredresearchofaseriousand permanentnatureliketheworkontheactionofstrophanthusbySirThomasFraserin Edinburgh.HealsoreferredtoergotandaccordingtoDalehadasounderandmore

212 enlightenedappreciationofresearchthanIhadbeeninclinedtoexpect.
Academiccolleaguesreactionswerelessfavourable:someyoungerresearchers weregenuinelyscandalised.DalehadasimilarreactionwhenhemetProf.Arthur Cushny,thefirstProfessorofMedicineatUCH,whowasinterestedinhisworkuntilhe foundoutwherehewasfromandDalewascrestfallenbythisattitudetopharmaceutical

213 industryassociations. DalewasplacedintwogroundfloorlaboratoriesatBrockwell
Parkfittedforchemistryandbacteriologyresearchandsetaboutaresearchcareerthat eventuallybrokedownsuchbarriers.
209
DaleliaisedwithT.R.Elliottandtaughtattheuniversitywhereoneofhisstudents andafutureemployeewasLaidlawH.H.Dale.PatrickPlayfairLaidlawBiographical MemoirsofFellowsoftheRoyalSociety 3(1941):427447DaleArchives,93HD143.3.

210
In190002underGeeandT.LauderBruntonhewasindailycontactwithWilliam BaylissandE.H.StarlinganditwasduringthisperiodhefirstmetOttoLoewiwithwhom helatersharedtheNobelprizein1936:W.S.Feldberg,H.H.Dale(18751968):79 174:H.H.Dale,F.Himmelweit(eds.),TheCollectedPapersofPaulEhrlich (London: Pergamon,1956).

211
SirHenryDale,ThomasRentonElliott(18771961)BiographicalMemoirsof FellowsoftheRoyalSociety (1961)7:5374H.H.DaletoT.R.Elliott,(22July1958), DaleArchives,RoyalSociety93HD143.6.

212
H.H.Dale.Reminiscences:WPRL190414,DaleArchives,RoyalSociety93HD 143.6:23
213
H.H.Dale,ReminiscenscesWPRL190414,DaleArchives,RoyalSociety93HD 143.6:8.
119
120
In1904MarmadukeBarrowcliffjoinedtheWCRLfromNottinghamUniversityand
214 workedonthechemicalconstitutionofvariousessentialoils. AtSudlowsretirement
dinnerin1905,WellcomestatedthatsinceSudlowhadstartedin1879,thepremisesofthe
215 firmhadincreased800foldandthestaffwasnowat4,300. Inordertodealwiththe
increasingspecialisationofwork,theWCRLestablisheditsownExperimentaldepartment inDecember1905.AlthoughJowettwasitsmanager,itwasPymanwhoranthe
216 laboratoryonadailybasis. FrankLeePymanwasanexperiencedchemistwhojoinedthe
laboratorystaffoftheExperimentallaboratoryinFebruary1906.Hehadgraduatedfrom VictoriaUniversity,Manchester,andafteraperiodofresearchinZurichUniversitytook
217 upashorttenureinthelaboratoryofThomasEdwardThorpe,theGovernmentchemist.
218 Aprewarmaximumofninechemicalstaffwasreachedin1906.
Thisdepartmenttookonanincreasinglyacademicandyetpracticalrole, investigatingthepropertiesofnewdrugs,findingefficientroutesofsynthesisforthe standards,bettermeansofisolationandbettermeansofscalinguptheextractsto manufacturingcapacity.Jowettsencouragementoforiginalscientificenquiryand publicationsreflectedhisownacademicbackground: thelaboratorywasspaciousandwellequippedwithalibrarynextdoor,and twoorthreeassistantsavailableforthepreparationofintermediatesrequired insynthesesandforanalyses,butmostimportantofallweretheresearch
214
M.Barrowcliff,TheConstituentsoftheEssentialOilofAmericanPennyroyalJ. ChemicalSociety (1907):87587M.Barrowcliff,F.B.Power,TheConstitutionof ChaulmoogricandHydnocarpicAcidsJ.ChemicalSociety (1907):55778M.R.Fox, DyemakersofGreatBritain18561976(Manchester:ICIplc,1987):200note6 LaboratoryNotebook13,WF:85/9.

215
R.C.Sudlow'sretirementdinnerwason14September1905,WF:90/14:3.
216
JowetttookuptherolebeforetheopeningofanewlaboratoryinFebruary1906:Mr. Hogg,WF:89/57IIIIG.E.Pearson,(1936),WF:88/24:41d:10Private,Dr.Jowett, WF:85/9:88H.King,FrankLeePyman(1944):68197onpp.682683.

217
SirThomasEdwardThorpe18451925wastheGovernmentscientificofficer.From 18851894hehadbeenProfessorattheRoyalCollegeofScienceinLondon.Hewrote severaltextsonchemistryincludingA DictionaryofAppliedChemistry,AManualof InorganicChemistry,QualitativeChemicalAnalysisandLaboratoryPractice ObituaryJ.ChemicalSociety (1926)1031.

218
Mr.Hogg,WF:89/57IIII.
120
121
atmospherefosteredbythefirmandthemagnificentopportunitiespresented 219 tothosecapableofgraspingthem.
Pymansteamimmediatelypreparedsyntheticderivativesofsalicylicacid,whichBurroughs Wellcomepatented,exploredinanimalexperimentsandsoldaspotentialalternativesto
220 BayersAspirin. Aspirinwasagreatsuccess,butthereweremanypoorsubstitutes,
whichBurroughsWellcomedemonstratedwereveryvariableinfreeacidnumber,iodine
221 absorptionandmeltingpoints,especiallythosefromtheGermanmarkets. Pyman
synthesisedberberine,andphenacetinbeforetakingupJowettspioneeringinterestin glyoxylines,(thealkaloidsofthePilocarpussp.)andisolatedjaborine,pilocarpidine,
222 pilosineandpilocarpine,extendingtheresearchintosyntheticmodifications. Asthe
workoftheWCRLexpandedoverthenext10years,asteadystreamofnewrecruits
223 joined.
WellcomesrelationshipwithDunstan,alreadyclosethroughthehiringofJowett, CarrandothercolleagueswasextendedwhenWellcomeagreedtocollaboratewiththe Imperial InstituteinNovember1905,todevelopanydrugsarisingfromresearchthere. Jowetthadabsolutediscretionaboutwhichproductstotakeup.However,Wellcomewas
219 220
H.King,FrankLeePyman(1944):683.
F.L.Pyman,H.S.Wellcome,H.A.D.Jowett,Manufactureofanewsalicylicacid cinnamylderivative,(cinnamylsalicylicacid)B.P.7125(1906)F.L.Pyman,H.A.D. Jowett,SomeDerivativesofSalicylicAcidJ.ChemicalSociety 22(1906):317.

221
C.EdwardSagetoF.B.Power,(10June1904),WF:88/94:58(quote)W.Dowson toBurroughsWellcome&Co.,(23January1901),WF:94:36.
222
H.King,FrankLeePyman(1944):681697 PharmaceuticalJournal (8October 1927):375F.L.Pyman,TheSynthesisofGlyoxalineDerivativesAlliedtoPilocarpineJ. ChemicalSociety 101(1912):530G.Pearson,(1936)WF:88/24:41d:10Pymans laboratorybooksdatingfrom7February1906areinWF:85/9.

223
ThenamesaregiveninseveralpublicationsfromthelaboratoryandincludedF.H. Shedden,B.Sc.andMrH.W.Clewerin1899,C.E.Potterin1901,F.H.Gornallin1902, andMr.FrankTutinin1903,Mr.A.C.O.HanninAugust1904,MarmadukeBarrowcliff inOctober1904,Dr.H.Rogersonin November1905andMr.W.Thomaswhoworkedon AtoxylinDecember1905,Dr.A.H.SalwayinOctober1906,C.W.MooreinDecember 1907,Mr.H.W.CatoninSeptember1907,Dr.T.CallaninOctober1910,Mr.H. BrowningM.Sc.inNovember1911,Mr.W.J.S.NauntonB.Sc.inJanuary1912,andMr. S.J.GreenM.A.inNovember1913,StaffWCRLBox25andS/G/145.
121
122
keentopreservehismonopolyofnewdrugsandsoughtassurancefromtheGovernment thatotherfirmswouldnotprofitfromnewdrugsarisingfromthecollaboration,seekingto withholddetailsoftheactiveingredientsandmanufacturingprocesses,whiledelaying reportsuntilthefirmcouldprocuresufficientrawmaterialsforthesaleslaunch. Although theImperialInstitutewaspreparedtodelaypublication,Dunstanstatedthat:neitherthe ImperialInstitutenortheColonialOfficewouldbeinapositiontoguaranteeyourfirm

224 shouldenjoyanythingapproachingamonopoly. Jowettrecognisedfromthisdialogue
that:Wecanonlyhopetobethefirstinthefieldandgetthecreditofthescientific
225 investigationandwecannotobtainamonopolysuchaswecouldwithasyntheticdrug .
ThisquotesummarisestheemergingBurroughsWellcomestrategytoextractnew drugs,chemicallycharacterisethemandstandardisethem,butalsotopreparesynthetic versionsoratleastsemisyntheticsalts,whichcouldbepatentedandprotectedand increasinglysomeoftheseweresoldassyntheticproducts.Dunstansentaseriesofraw materialstotheExperimentallaboratory,wherePymanisolatedvariousglucosidesand alkaloidsthatwereassayedforphysiologicalactivity,andsomeledtoisolationofnovel

226 chemicalstructures. Thesecontributedtoaseriesofnewproductsfrom1908including
arsenicals,Orsudan,pituitaryextract,bismuthsalts,mercurysuccinate,Epinine,asynthetic haemostaticandthealkaloidalextracts,Brucine,EpicineandErgamineandextractsof KurchiBarkfromIndia,togetherwithferriglycerophosphatesandsomefurther

227 proprietarypreparations.
Tropicalmedicineplayedanimportantroleincolonialexpansiontowardstheendof thenineteenthcenturyasseveralcausativeagentsofinfectionwereidentified,togetherwith
224
HenryWellcometoW.Dunstanandreplies(17,20,27,28February1906),Business Correspondence18951940,WF:D3DWE.Thequoteisfrom27February.
225
H.A.D.JowetttoG.Pearson,(22February1906),re.InterviewwithHenry Wellcomeon28November1905,WF:BusinessCorrespondence18951940,WF:D3 DWE.

226 227
H.King,FrankLeePyman(1944):68384.
ListofProductsinOrganisationoftheWellcomeChemicalResearchWorks,Mr. Hogg,WF:89/57IIII.
122
123
228 thespecificmeansofkillingthem principallythroughresearchinGermany.
ThroughouthislifeHenryWellcomemaintainedahealthyinterestincolonialdevelopment andtropicalmedicine,andevenintheearlyyearsofthefirm,they hadregularrequestsfor

229 drugsfromtropicalcountries,leadingtoimportantclinicalcollaborationsinBritain. The
WellcomeTropicalResearchLaboratorieswereestablishedattheGordonMemorial
230 CollegeinKhartoum,Sudanin1902. AswiththeWPRLandWCRL,HenryWellcome
attractedtopscientists.ThefirstDirectoroftheTropicallaboratorieswasDr.(laterSir)
231 AndrewBalfourwhohadtrainedinEdinburgh. Afloatinglaboratorywasaddedin1907
232 underDr.CharlesMorleyWenyon,whoreturnedtoEnglandin1908, andafurther 233 tropicaldiseasesexpert,Dr.CecilA.Hoarewasemployed. Wenyonstudiedzoologyat
YorkshireCollegeinLeeds,andzoologyandchemistryatUniversityCollege,London,and completedamedicaleducationatGuysHospitalin 1904.AfterashortcareerasaGeneral PractitionerhewasappointedasHeadoftheProtozoologicalDepartmentoftheLondon SchoolofTropicalMedicinein1905.Hestudiedtheactionofdrugsontrypanosomesat thePasteurInstitute,andattheZoologicalInstituteinMunichbeforemovingtoKhartoum
228
M.Worboys,TheColonialWorldasMissionandMandate:LeprosyandEmpire, 19001940Osiris15(2000):20718M.Worboys,BritishMedicineanditsPastat QueenVictoriasJubileesandthe1900CentennialMed.History 45.4(2001):46182M. Worboys,TheComparativeHistoryofSleepingSicknessinEastandCentralAfricaHist. Sci.32(1994)(95pt1):89102.

229
SirJohnKeithofZanzibarcorrespondedwithBurroughsWellcomeaboutsuppliesof thedrugstrophanthusin1885H.WellcometoS.M.Burroughs,(17December1885), Letterbooks,WF:S/G/1482:381,4302.

230
ForageneralbackgroundseeH.HaroldScott,(1939)Gen.SirReginaldWingate Bart.Khartoum TheStoryofGordonCollegeanditsWorkundated,WF:PB/86A. A.AbdelHammeed,TheWellcomeTropicalResearchLaboratoriesinKhartoum1903 1934Med.Hist.41(1997):3058.

231
WellcomesupportedtheexplorationofH.M.Stanley.Worldattention wasdrawnto thewarinSudanin1898andWellcomevisitedin1900toseewardamageandlevelsof disease.H.Turner,(1980):212.

232
C.A.Hoare,CharlesMorleyWenyon(18781948)BiographicalMemoirsof FellowsoftheRoyalSociety 6(1949):62742.Wenyonbecametheprotozoologisttothe MetropolitanAsylumsBoardin1922,MRCMinutesII(1922):376.In1932Wenyon becameDirectoroftheWellcomeResearchInstitute.

233
C.A.Hoarecontributed179papersin60yearswithBurroughsWellcomeupto 1980,PapersatWI/GC/57G.MacDonald,(1980):4951.
123
124
234 in1907.
NewbotanicaldiscoveriesweresenttotheBurroughsWellcomeheadquartersfrom India,AfricaandSouthAmerica,eitherthroughtheColonialOfficeandJowettslinkswith Dunstan,orthroughthefirmscolonialhousesestablishedinSydneyandinCapeTownin

235 1902,Montrealin1906,andNewYorkin1907. Plantspecimenswouldbeidentified 236 andsentforfurthertestingofphysiologicalactivityattheWPRL Oneproductarising
washyoscyamine,isolatedamongotheralkaloidsfrom DaturametelbyReynolds,Carrand
237 PymanandreleasedontothemarketinMarch1908.
Followingthesuccessinthepreparationofpilocarpinesalts,scientistsbasedatthe WCRLandattheWPRLcollaboratedonanumberofprojects.WellcomeaskedBargerto followtheleadofParkeDavisinpurifyingandtestingactiveingredientsofergotalkaloids, derivedfromthefungususedinmedicineforhundredsofyears.Extractsofergotwere preparedattheexperimentallaboratoryoftheWCRLandweresenttoDaleattheWPRL forphysiologicaltestingifanyindividualpurifiedalkaloidsshowedpromisingactivitythey werefurtherinvestigated.CarrandReynoldsthenmadesuppliesonalargescaleatthe WorksandselectedbatchesofthismaterialweresentbacktoDaletocheckthepurityand

238 physiologicalactivity.
234
CecilA.Hoare,CharlesMorleyFletcher(1949):627642.
235
HistoryoftheFirmofBurroughsWellcomeWestKentAdvertiser(21March 1924),WF:YLbox25D3DW.
236
P.A.FelixPerredespreparedaseriesofarticlesontheplantsoftheLondon tropicalgardens:ComparativeanatomyofthebarksoftheSalicaceae Pharmaceutical Journal (1August1903).HewashonouredbyPhiladelphiaCollegein1906andbyAm.J. Pharmacyforaseriesofarticlesonbotanicalgardens,WF:88/94:41.(12Marchand14 November1906)F.B.PowertoPhiladelphiaCollege,(12March1906).Bargeralso trainedinbotanyinadditiontochemistry:H.H.Dale,G.Barger18781939(1940):63 83.

237
T.A.Henry,(1939):6971.
238
W.S.Feldberg,H.H.Dale(1970):945H.H.Dale,G.Barger(1940):66H. Dale,F.Carr,TheAlkaloidsofErgotJ.ChemicalSociety (1907):337B.J.ClarkinJ. Bruinvels,M.J.Parnham(eds.),Haemodynamics,HormonesandInflammation (Oxford: Elsevier,1984):333.W.Sneader,(1985):106108.
124
125
BargerandCarrpreparedtheactiveprinciplesofergotincludingacomplexof
239 alkaloids,calledergotininwhichDaleassayedinanaesthetisedcats. Hisfindingsopened
240 upnewavenuesofresearchonthephysiologicalcontrolofbloodpressure. Theteamof
Barger,Dale,ReynoldsandCarrthenisolatedseveralseparateactiveprinciplesfromergot includingchrysotoxin,whichreversedthestimulatoryactionofadrenalineontheheart,and ergotoxine,enablingittobeassayedasasinglealkaloid.Daleshowedthatcommercial preparationsofergotfromotherfirmswereveryvariableandonlyhadaround2%

241 ergotoxineinthem. Inasampleofordinary ExtractumergotineliquidumB.P.from
anothercompanyDalefoundthataminutequantitycausedstoppageofanimalhearts,and thisalarmingconsequencewasduetoanimpurity,whichEwinsidentifiedas
242 acetylcholine.
Bycombiningsyntheticchemistryandphysiologicalassays,BurroughsWellcome createdastandardisedpreparationofergotoxine,theactivityofwhichwasdemonstratedin theiradvertisementsusingkymographtracestocreateascientificimagetoconvince

243 doctorsofthequalityoftheirergotpreparation. Thisscientificrationale,offeringthe
benefitofsaferprescribing,gavetheirproductaclearcompetitiveadvantageoverrivals suchasParkeDavisandH.K.Mulfordwhosepreparationswerestandardisedonlyagainst thetotalalkaloidcontent,wheremanyofthealkaloidsdidnotcontributetothedesired
239
H.H.Dale,AdventuresinPhysiology (London:Pergamon,1953)H.H.Dale, GeorgeBarger18781939(1940):6383W.Sneader,(1985):106108G.Barger, F.H.Carr,NoteonErgotAlkaloidsChemicalNews94(1906):89.

240
H.H.Dale,TheActivePrinciplesofErgotBritishMedicalJournal (19November 1910):1610.

241
Daleemphasisedtheeffortsover2yearsbyCarrandReynoldswhenhereceivedthe acclaim:W.S.Feldberg,H.H.Dale(18751968)(1970):128H.H.Dale,OnSome PhysiologicalActionsofErgotJournalofPhysiology 34(1906):163206H.Dale,G. Barger,ErgotoxineandSomeOtherConstituentsofErgotBiochemicalJournal 2 (1907):240299.

242
A.J.Ewins,Acetylcholine.ANewActivePrincipleofErgotBiochemicalJournal,8 (1914):44.
243
J.Parascandola,TheSearchfortheActivePrincipleofErgot.LaboratoryScience andClinicalMedicineinConflict:in'NeueBeitragezurArzneimittelgeschichte. FortschrittefrWolfgangSchroeder,VeroeffentlicheungenderInternationalenGesellschaft fuerPharmazie (Stuttgart:WissenschaftlicheVerlagsgesellschaftfrPharmazie1982).
125
126
244 activityandsomemightbetoxic. Thispolicywasappliedtootherproductsandenabled 245 BurroughsWellcometoobtainprestigepricesfortheirdifferentiatedproducts.
EwinsandBargerthenidentifiedthealkaloidthatseemedtoberesponsibleforthe obstetriceffectsofergot.Takingtheirideafromthestenchthataccompaniedthelarge scaleproductionofergotderivativesbyCarrattheWorks,theyfoundsimilaractivityin

246 extractsofputrefyingmeat. DaleandBargerfoundthathistaminewaspresentinboth 247 ergotandinanimalgut. ThisinturnledBargertocharacterise,thenchemically
synthesise,otheramineslikeadrenaline,whichrepresentedthefirstsyntheticanalogueofa
248 naturalhumanhormone. Puresamplesoftheseaminesstimulatedanimalsheartsin 249 Dalesstudies. OverfiftychemicalderivativesweresynthesisedattheWCRLallowing
Daletogainathoroughunderstandingoftherelationshipbetweenphysiologicalactivity
250 andchemicalstructure. Theergotexamplerepresentsthemostlastingandimportant
244
J.Liebenau,(1987):43.ParkeDavisdidnotattempttoseparateoutthevarious alkaloidsandarguedthatsecondaryprincipleswouldbepresentinthesameratiothough thiswasknownnottobetrueforipecacuanha,G.Ponthieu,StandardisationChemist& Druggist59(7September1901):412WF:84/7:14H.H.Dale,GeorgeBarger(1940): 67H.H.Dale,G.Barger,TheWaterSolubleActivePrinciplesofErgotJournalof Physiology 38(1909):Proc.lxxvii.

245
G.MacDonald,(1980):26PriceListofPharmaceuticalProducts,1917:WF: DB/68H.H.Dale,F.H.Carr,Ergotandits'Preparation,aCriticalReviewofthe RequirementsoftheBritishPharmacopoeiaPharmaceuticalJournal 37(1919):130.

246
G.Barger,A.J.Ewins,TheAlkaloidsofErgotIIJ.ChemicalSociety 97 (1910):284.
247
G.Barger,H.H.Dale,4Betaaminoethylglyoxymine(betaiminazolylethylamine) andotherActivePrinciplesofErgotJ.ChemicalSociety 97(1910):2592G.Barger,H. H.Dale,J.Physiology 41(1910):318344 J.Physiology 43(1911):182195,499.

248
G.Barger,H.H.Dale,ChemicalStructureandSympathomimeticActionofAmines J.Physiology 41(1910):1959G.Barger,G.S.Walpole,FurtherSynthesesofp hydroxyphenylethylamineJ.ChemicalSociety (1909):1720G.Barger,G.S.Walpole, PressorPrinciplesfromPutridMeatJ.Physiology 38(1909):23,343H.King,A.J. Ewins,TheSynthesisofSomeNewDimethyltetrahydroquinolinesJ.ChemicalSociety 103(1913):104H.A.D.Jowett,J.ChemicalSociety 93(1908):563.
249 250
W.S.Feldberg,H.H.Dale(18751968):128.
G.Barger,IsolationandSynthesisofpHydroxyphenylethylamine,anActive PrincipleofErgot,SolubleinWaterJ.ChemicalSociety 95(1909):1123G.Barger,H. H.Dale,AThirdActivePrincipleinErgotJ.ChemicalSociety (1910):128G.Barger,
126
127
contributiontothisnewformofknowledge,butthereweremanydozensoffurther exampleswhereplantextractswerecharacterisedallowingBurroughsWellcometogofar beyondthestandardslaiddownbytheBritishPharmacopoeia,whichonlydefinedawide rangeofstrengthsfortotalalkaloidalextracts,evenwhentherewasmorethanoneputative

251 activeingredient. Inthepharmacopoeiathestrengthofalcoholusedtoextractalkaloids
252 wasnotevenspecifiedandvariedmarkedlyinstrength.
AsecondrolefortheWCRLwastoevaluatenovelGermansyntheticdrugsarising primarilyfromthedyefirms.Thesewerestandardisedinasimilarwaytothealkaloids, buttofacilitatethecompressingandtablettingasTabloids,saltsoftheactiveingredients

253 wereprepared. Pymanproducedacetosalicylates,quininesaltsandaversionof
254 phenacetinforincorporationintoTabloids. ThegrowinginfluenceofGermanchemistry
attheWCRLwasreadilyapparentinreferencestoGermanpublicationswithinmany
255 BurroughsWellcomecompanydocuments.
AthirdfunctionoftheWCRL,thespecialsynthesisofchemicalswithpotential medicalusesisgiveninPowersannotationonacopyoftheBritishMedicalJournal, commentingontheworkofProfessorWernerinHeidelberg,whohadsuggestedthatthe beneficialeffectofradiotherapyonanimalcancerswasduetoproductionoftheamine,
H.H.Dale,ThePresenceinErgotandPhysiologicalActivityofBeta iminazolylethylamineJ.Physiology 40Proc.:34.DalepresenteddataattheInternational PhysiologicalCongressinViennain1910,93HD143.6:3236H.H.Dale,W.E.Dixon, TheActionofPressorAminesProducedbyPutrefactionJ.Physiology 39(1909):25.

251
P.A.FelixPerredes,TheAnatomyoftheBarkofRobiniapseudacacia PharmaceuticalJournal (3August1901),apaperreadattheBritishPharmaceutical conferenceinDublin,July1901F.B.Power,TheChemistryoftheBarkofRobinia pseudacaciaChemist&Druggist59(3August1901):2245.

252
TheB.P.Cannabisindicawas5%whilethatintheUSAwas15%,Pharmaceutical Journal 69(1902):245Ipecacuanhastrengthsvariedaccordingtosource,Pharmaceutical Journal 69(1902):2567,asdidalcohol:R.B.Wild,TheClinicalUseofIpecacuanha AlkaloidsLancet(6September1902):654Wellcomecascaradifferedfromothers,WF: 90/14:1:99.

253
254
G.Pearson,(1936),WF:88/24:41d:8. PymanLaboratoryNotes,(7February1906),WF:85/9Book1.
255
DemandforsulphonalroseafterLauderBrunton'sCroonianlecturedescribing sulphonalastheidealsedative:SulphonalaNewHypnoticBritishMedicalJournal (21 April1888):864.
127
128
choline. PowerthereforeaskedJowetttoprepareasimilaraminefrom Apocynum,anda

256 supplyof155gwassenttoProf.CushnyatUCHforclinicalexperiments.
Jowett,HannandPymanpreparedaseriesofsyntheticchemicalscalledtropeinesfor
257 physiologicalstudiesbyDaleandMarshallattheWPRL. Someoftheseweremirror
imagesofthesamechemicalstructureandtheydevelopedtechniquestoresolvethese differentopticalisomersoftropeineandhyoscyamine,andmadetheimportant observationthatoneformcouldbemanyhundredsoftimesmoreactivethanitsmirror image.ThismeantthatifBurroughsWellcomecouldprepareandpurifythemostactive form,itwouldbesignificantlybetterthantheextractcontainingamixtureofthetwo.They

258 foundthatthistechniquecouldalsobeappliedtoanumberofalkaloids. HaroldKing,
256
ReportfromH.A.D.JowetttoF.B.Power,F.B.PowerNotes18831921,WF: 88/94:58H.MacGillivray,APersonalBiographyofArthurRobertsonCushny,1866 1926Ann.Rev.Pharmacology.(1968)124W.B.Fey,ArthurCushnyClin.Cardiol. 18(1995):3601J.Parascandola,ArthurCushny,OpticalIsomerism,andtheMechanism ofDrugActionJ.Hist.Biol.8.2(1975):145165.

257
H.A.D.Jowett,A.C.O.Hann,PreparationandPropertiesofSomeNew TropeinesJ.ChemicalSociety (1906):35765F.L.Pyman,H.A.D.Jowett, RelationshipsBetweenChemicalConstitutionandPhysiologicalActionintheTropeines J.ChemicalSociety 91(1907):92 J.ChemicalSociety 95(1909):1020F.Pyman, RelationshipBetweenChemicalConstitutionandPhysiologicalActioninCertain SubstitutedAminoalkylEstersJ.ChemicalSociety 93(1908):1793 J.ChemicalSociety 111(1917):167(onthebasisofalecturegiventotheChemicalSociety,6December 1917).
258
M.Barrowcliff,F.Tutin,TheConfigurationofTropineand[psi]Tropineandthe ResolutionofAtropineJ.ChemicalSociety 95(1909)196677F.H.Carr,W.C. Reynolds,TheSpecificRotatoryPowerofHyoscyamineandtheRelationBetweenthatof AlkaloidsandtheirSaltsJ.ChemicalSociety (1910)T1328:180H.King,The PossibilityofaNewInstanceofOpticalActivityWithoutanAsymmetricCarbonAtomJ. ChemicalSociety (1914):249.Itwasknownin1815thatsomecompoundsexhibited differentialrotationoflight.Pasteurdemonstratedthisclearlywithtartaricacidin1848. VantHofandLeBelrealisedthatitwaswithcarbonattachedto4differentgroupsE.S. th Taylor,AHistoryofIndustrialChemistry (London:Heinemann,4 edition1933):220224 H.King,TheResolutionofHyoscineanditsComponents,TropicacidandOscineJ. Chem.Soc.115(1919):476H.King,TheStereochemistryofHyoscineJ.Chemical Soc.115(1919):974.
128
129
whowewillmeetagainlater,hadjoinedtheexperimentallaboratoryinNovember1912
259 andhebecamemuchinvolvedinthiswork,beforehetransferredtotheWCRLin1914.
ManyexamplesexistwhereBurroughsWellcomecharacterisednaturalproductsto identifytheactiveingredientandpreparedstandardisedmedicinessuchasstrophanthus,
260 willowbarkextracts,andnovelextractsincludingApocynum,diuretics,andtyramine.
FrankTutinjoinedtheWCRLinDecember1903andexaminedthechemicalconstitution
261 ofvariouschemicallysubstitutednaturalproducts. From1908Pyman,Reynolds,
BarrowcliffandRemfry,influencedbyEhrlichssuccesswithAtoxyl,anarsenicderivative fortreatingsyphilis,preparedaseriesofsyntheticaromaticarsonicandarsinicacidswhich
262 263 werepatented. Theyanalysedironarsenatetocharacteriseit. However,onlyone
completelysyntheticproduct,giventheBurroughsWellcometrademarksofSoaminor Kharsin,wasasignificantcommercialproductforthefirm.Thiswasastraightcopyofthe Germandrug,freedofitspatentbecausetheactivemercurialproductrepresentedby
259
SirCharlesHarrington,HaroldKingBiographicalMemoirsofFellowsoftheRoyal Society 2(1956):157171.

260
H.H.Dale,P.P.Laidlaw,C.T.Symons,AccelerationoftheMammalianHeartby StimulationoftheVagusNerveJ.Physiology 39(1909)Proc.xiiiP.P.Laidlaw,An ActivePrincipleofApocynumCannabicumJ.Physiology 38(1909):76P.P.Laidlaw, H.H.Dale,TheActionofanActivePrinciplefromApocynumHeart1(1909):138H. H.Dale,P.P.Laidlaw,ThePhysiologicalActionofbetaIminazolylethylamineJ. Physiology 41(1910):318344H.H.Dale,P.P.Laidlaw,ThePresenceinErgotand PhysicalActivityofbetaIminazolylethylamine J.Physiology 40(1909)Proc.xxxviiiH. H.Dale,P.P.Laidlaw(18811940)ObituaryNoticesofRoyalSocietyofLondon 3 (1941):444P.P.Laidlaw,H.H.Dale,TheActionofSomeDiureticsProceedingsof theRoyalSocietyofMedicine3(1909)TherapeuticPharmacologysection:38.
261
F.B.Power,F.Tutin,SomeObservationsRegardingOleuoropeinfromOlive LeavesPharmaceuticalJournal (5December1908):71421F.Tutin,F.W.Caton,J. ChemicalSociety 97(1910):252434.

262
F.L.Pyman,W.C.Reynolds,AromaticArsonicandArsinicAcidsJ.Chemical Society 93(1908):1180F.L.Pyman,W.C.Reynolds,ANewSolanaceousAlkaloidJ. ChemicalSociety (1908):2077F.L.Pyman,M.Barrowcliff,F.G.P.Remfry,Aromatic ArsonicAcidsJ.ChemicalSociety 93(1908):1893.

263
F.B.Power,HaroldRogerson,TheCharactersofOfficialIron Arsenide PharmaceuticalJournal 81(19September1908):34244.
129
130
264 Soamin,hadbeenpreparedinGermany. BurroughsWellcomerecognisedthatthey
couldnotcompetedirectlyonamanufacturingcapacitywiththeGermanfirmsin producingsyntheticdrugs,buttheycreatedtheirownmarketnichewiththeirpurifiedand standardiseddrugs. 3.6Conclusions:TheImpactoftheLaboratories. IntheperiodcominguptotheFirstWorldWar,BurroughsWellcomewasa diversifyingpharmaceuticalcompany.Notonlydidtheyproducetheoriginalsuccessful Wyethbrands,inorganicdrugsandalkaloidalextracts,buttheyalsoproducednovel chemicalcompoundsandnonsterilesera,whichwerecontrolledforstrengthandpurity. ThisbecameincreasinglyimportantandDowsonwasbothblamedandsackedonan occasionwhenheallowedpoorlystandardisedbiologicalmedicinesontotheAmerican
265 market,leadingtoDalebecomingheadoftheWPRL. DalerecalledthatGlennywas 266 makingthebestthathecouldofwhatheknewnottobereallysuitableconditions.
Processing,labellingandbottlingweremovedtoanewbuilding,speciallydesignedand constructedandwithventilationbysterileair,andwithGlennyastheHeadofthe
267 Immunologydepartment.
264
B.Moore,TheHistoryofOrganicCompoundsofArsenicintheTreatmentof ProtozoanDiseasesBritishMedicalJournal (29April1916):6168.Kharsinwas producedfrom17March1908,Mr.Hogg,WF:89/57IIII.

265
Dalewasofferedatemporarypostat800p.a.increasedto1,000whenhebecame Director.Incomparisonauniversitylecturerreceivedaround600:DaleArchives93HD 143.8W.S.Feldberg,H.H.Dale18751968(1970):79174F.B.PowertoHenry Wellcome,(31January1902),WF:88/9428aE.M.Tansey,(1989):1116E.M. Tansey,WhatsinaName?HenryDaleandAdrenalineMedicalHistory 39.4(October 1995):45976H.O.Schild,DaleandtheDevelopmentofPharmacologyBr.J. Pharmacology (February1997),120(4Suppl):5048Obituary,DrW.C.FowlerBritish MedicalJournal (24June1967):84647.
266
ThequoteisfromW.S.Feldberg,H.H.Dale18751968(1970):165Outputof diphtheriaantitoxininmillionsofunitswas86in1900,130in1905,240in1910,480in 1915and640in1920.From1909itwasavailableinconcentratedform,WF:84/71213 GlennyNotebook(August18991900)LaboratoryReports(October1889October 1895)ChemicalsUsedSeptember1903March1905,WF:84/7:11.

267
H.H.Dale,Reminiscences93HD143.6H.J.Parish HistoryoftheFirm:56, WF:85/20:2:14.
130
131
AfurtherconsequenceofthelaboratorieswasthattheybroughtBurroughs Wellcomescientiststotheforefrontofeffortstostandardisedrugs.Unstandardised preparationsofsomefirmsremainedinthepharmacopoeiasimplybecausecertaindoctors wereconvincedofthebenefitofthetotalextract,andbecausethepharmacopoeiahadnot

268 beenupdatedsince1898. AnewCodexwaspreparedin1907toaidthepractitioner:
perplexedbynumerouscircularsfromdifferentsourcestobetoldongood authoritythatmostofthefancifulnames(ofdrugs)refertoonearticlewith whichhehasbeenfamiliar....itmaysaverepeatedtrialsofadruguponwhich 269 hemayhavealreadyformedadefiniteopinion. Asaresultoftheirexpertiseindrugdevelopmentandstandardisation,Burroughs Wellcomewererepresentedonseveralcommittees.FredPoweronthestandards committeesadvisedontheuseoftradenames,allowablelevelsofimpuritiesandhe detailedtheteststhatwereimpossibletoperformandthestandardsthatitwasnotpossible

270 tomeet. Heprepareda5pagelistofdifferencesbetweentheBritishandAmerican
Pharmacopoeias,emphasisingtheneedforbiologicalstandardsandassayofactive principlesratherthantotalalkaloids.Allethicalmanufacturersaimedtodifferentiatetheir
271 productsfromthosewithlesserstandards. SeveralfirmscontributedtotheCodexandto 272 themedicalliteratureondrugpurity. Theemphasisonpurityandstandardsrecognised
268
E.Blbring,J.M.Walker,J.H.BurnBiographicalMemoirsofFellowsoftheRoyal Society (1981):4589.

269
TheCodexwascoordinatedbythePharmaceuticalSocietyandsupplementedthe BritishPharmacopoeia.TheCodexwasmoreauthoritativebutdidnotcarrythesame authorityasconferredtotheB.P.bythemedicalacts:TheB.P.Codex:anImperial DispensatoryfortheUseofMedicalPractitionersandPharmacistsLancet72(2 November1907):1247.

270
BritishPharmaceuticalCodex,commentsandreportsbyF.B.Powerandothers, WI/GC/5Acc35.
271
D.L.Howard,wholecturedtothePharmaceuticalSocietyin1907,C.A.HillandT. D.Morsonwerekeyfigures.Allwereinfavourofofficialmeasuredlimits,atthehighest practicablelevel,balancingpublichealthwiththeincreasedcostsofstrivingforagreater purity.Ethicalfirmsallobjectedtosubjectivetermssuchas'pure','commerciallypure'C. A.Hill,ThePurityofPharmaceuticalChemicalswithSuggestionsforCommercially ObtainableStandardsChemist&Druggist72(23May1908):792797.

272
CharlesA.Hill,TheEssential OilsoftheB.P.Chemist&Druggist77(12February 1910):271TheMostSuitableLimitTestsforArsenicinOfficialSubstancesand PreparationandtheLimitsforArsenicthatmaybeReasonablyAdopted.Chemist&
131
132
thattheseweremeasurable,whereastheclinicalbenefitwasnotreadilyquantified,apoint towhichIwillreturn. Intheperioduptothewarattitudestodrugmanufacturersbecamepolarised.Those thatemphasisedpurityandstandardiseddrugs,andinvokedsciencecametorepresentthe ethicalsideofdrugdevelopmentandweresupportedbyphysicians,whereaspatent medicinemanufacturersbecamethefocusofgovernmentactivity.Dalechairedan

273 internationalconferenceonphysiologicaldrugstandardisationon29November1906.
Theemphasisonpurestandardiseddrugscontrastedmarkedlytothewavesofprotest concerningadulteratedmedicinesinBritainandinAmerica,whichledtolegislative controlsontheadvertisingofsecretorpatentremedies.Eventheethicalpharmaceutical industrywasheldatlengthfromthemedicalprofession.TheAmericanMedical

274 Associationbannedmemberswhojoinedthepharmaceuticalindustry. InBritainthe
medical journalswouldnotallowreprintsofpublishedpaperstobeusedaspromotional
275 items.
WhilethePharmaceuticalSocietyfavouredpreparationanddispensingofdrugsby pharmacists,doctorsresentedtheinfluenceofpharmacistsonprescribing,sohelpingto forgeacommonbondbetweenthemselvesandproprietarymedicinemanufacturers,though unwittinglytheyoftenprescribedGermanbrands.Thecommongroundbetweenthe medicalprofession,theregulatorsandtheethicalfirmswasthecampaignagainstpatent
Druggist67(30September1905):348 ThePurityofPharmaceuticalChemicalswith SuggestionsforCommerciallyObtainableStandardsChemist&Druggist72(23May 1908):7927B.P.ArsenicTest,Chemist&Druggist81(29July1912):122123T. TustingCocking,TheContaminationofZincanditsCompoundswithLeadChemist& Druggist69(29September1906):507PharmaceuticalChemicalStandardsChemist& Druggist85.1(4July1914):4955TheBritishPharmaceuticalCodex:anImperial DispensatoryfortheuseofMedicalPractitionersandPharmacists,PharmaceuticalSociety ofGreatBritainLancet (2November1907):982.
273
TheUnificationofOfficialFormula'sforPotentMedicamentsLancet(23February 1907):527andLancet(27April1907):1178.
274 275
JohnP.Swann,(1988):3134.
P.W.J.Bartrip,MirrorofMedicine:aHistoryoftheBritishMedicalJournal (Oxford:BritishMedicalJournal:ClarendonPress,1990).
132
133
276 medicinemanufacturers. BurroughsWellcomewantedtoestablishhighreference
standardsfortheirpreparedproprietaryproductsandoneoftheiranalysts,E.F.Harrison,
277 contributedsignificantlytothecampaignsoftheBritishMedicalJournal.
Thelaboratoriesandthestaff employedsignificantlyenhancedthereputationof BurroughsWellcome,notonlyfromthediscoveriesandpublicationsemanatingfromthe laboratories,butalsothegoodwillcreatedbybeingthefirstBritishsupplierofdiphtheria antitoxinandbyofferingalaboratoryservicetodoctors.WhereasTabloidsdefined BurroughsWellcomeinthenineteenthcentury,asreliablemedicinesineasytoadminister tablets,thenewcenturybroughtafocusonpurifiedactiveingredients,whichwere chemicallycharacterisedandstandardised.Theworkonergotderivativesmadeatthe WCRLandtestedattheWPRLcreatedaworldwidereputation,particularlyforBargerand

278 Dale. Inthefieldofphysiologythefirmproducednopublicationspriorto1903,yetin
thenextelevenyears99paperswerepublishedonthechemicalstructureofalkaloidal extracts,mostlybyBarger,Burn,Carr,Ewins,Laidlaw,MellanbyandWalpole.Afurther 9paperswerepublishedbybacteriologystaffsuchasGlenny,SudmersenandOBrien, whowereinvolvedmoreinroutineproduction,maintenanceofsterilityandstandards relatingtoantitoxins.LinkswiththeListerInstituteweregoodthroughG.S.Walpoleand

279 thebacteriologistR.A.OBrienwhocamefrom there.
276
ConventionofHomeRepresentatives,Dartford(31December1907):9,WF: 90/14:5.Therepresentativeswereconcernedaboutthepoorquality(small)leaflets produced(p.8),thelackofcomparativestudieswithNizinantisepticandzinc sulphocarbolate(p.40),andthepoordefinitionssuchas'slightreaction'orjusta'trace'in tests.

277
SecretRemedies:WhattheyCostandWhattheyContaintheCompositionofCertain SecretRemedies,XXIIMedicinesforGeneralUse (London:BritishMedicalAssociation, 1909) MoreSecretRemedies (London:B.M.A.,1912).Aselectcommitteeonpatent medicineswasestablishedin1912G.Urdang,Bull.W.H.O.4(1951):577603.

278
Aswellasimmediatescientificrecognitionandinadditionforhisworkon chemosynaptictransmissionofnerveimpulses,DalewasawardedtheNobelPrizein1936. G.Barger,H.H.Dale,Journal ofPhysiology 41(1911):17W.S.Feldberg,H.H.Dale 18751968(1970):77174.

279
W.S.Feldberg,H.H.Dale18751968(1970):95HarrietChick,Margaret Chick,MargaretHume,MarjorieMacFarlane,WaronDisease,aHistoryoftheLister Institute(London:ListerInstitute1971)JennerInstituteofPreventativeMedicine PharmaceuticalJournal (1898)61:4624.
133
134
Dalerecalledtenyearslatertherewassomethingofapioneeringcharacterin thosedaysinthiscreationoflaboratorieswithseriousresearchinview,inconnectionwith
280 aBritishpharmaceuticalbusiness.
ThescientificacclaimachievedbyBurroughsWellcomewasadoubleedgedsword. Thedownsidewasthatitmadethestaffattractivetootherfirmsandtoacademiccentres. GeorgeBargerreturnedtoacademiain1909aftersixyearsatBurroughsWellcome,to becomeheadofChemistryatGoldsmithCollegeintheUniversityofLondon.In1913he

281 tookthechairofchemistryatRoyalHollowayCollege. Suchwasthesuccessin
establishingWellcomesresearchlaboratoriesthatmanyofthekeyresearchersweresought tojointhenewlyformedMedicalResearchCommittee,ofwhichmoreinthenext
282 chapter. LaidlawleftBurroughsWellcomein1913fortheSirWilliamDunnlectureship
inPathologyatGuysHospitalandcontinuedhisworkonergotinhisnewroleandfrom1 January1914,heandDalebegantestingthepotencyofposteriorpituitarylobeextractsas
283 wellasamides,alkaloids,andfurtherextractsofergotanddigitalis.
Itisclearthatbycreatinglaboratorieswheresciencecouldflourish,Wellcomewas abletoattractintoindustrystaffofthecalibrethatotherwisemaynothaveconsideredsuch acareer.Manyofhisrecruitscametohimviapreexistingnetworksofyoungscientists,
280 281
W.S.Feldberg,HenryHallettDale18751968(1970):92.
H.H.Dale,G.Barger(1940):66.HecontinuedtocollaboratewithBurroughs WellcomeP.vanRomburgh,G.Barger,PreparationoftheBetaineofTryptophanandits IdentitywiththeAlkaloidHypamorphineJ.ChemicalSociety 99(1911):268G.Barger, E.Stedman,Physostigmine(I):AlkylationProductsofEserolineJ.ChemicalSociety 123 (1923):758 J.ChemicalSociety 125(1924):1373.

282
A.LandsboroughThompson,HalfaCenturyofMedicalResearch:OriginsandPolicy oftheMedicalResearchCouncil volume1(London:HMSO,1973)J.Austoker,Walter MorleyFletcherandtheOriginsofaBasicBiomedicalResearchPolicyinJ.Austokerand L.Bryder(eds.),(1989):2333.

283
ThisbeganamajorinterestforBurnwhobecameinvolvedinbiologicalstandardsat theM.R.C.J.H.Burn,H.H.Dale,OnthePhysiologicalStandardisationofExtractsof thePosteriorLobeofthePituitaryBodyMRCReportontheBiologicalStandards, number69(1922).E.Blbring,J.M.Walker,J.H.Burn(1981):49.
134
135
notablyfromCambridge.Hopkinsformerstudent,PatrickP.Laidlawbasedatthe
284 physiological laboratoryofGuysHospital,wasattractedtojoinDale.
InsummaryBurroughsWellcomedidnotattempttocompetewithGermanyinthe largescalemanufactureofsyntheticdrugsthoughtheywereabletoproducesomeofthese, atleastonasmallscale.ThelargerGermanfirmsbasedtheirsyntheticdrugsonthereadily availablewastematerialsfromthedyeindustry,whereasBurroughsWellcomeandGerman pharmacybasedpharmaceuticalmanufacturerssuchasMerckconcentratedonplant extracts.InBritaintherewasnotsuchareadysupplyof manufacturingchemistsand chemicalengineerstoproducedrugsefficientlyonalargescale,butthemaincommercial disadvantagewasthatthescaleofchemicalproductionatBurroughsWellcomeremained smallincomparisontothedyefirms. Ihaveshownthatconsiderablechemicalexpertisewasdevelopedinproducing syntheticalkaloidsonasmallscalesothatextractscouldbestandardisedagainsttheir activeingredientsinordertoproducereliableactivity.ThestrengthsofBurroughs Wellcomewerechemicalcharacterisation,smallscalechemicalsynthesis,biological standardisationandtheproductionofTabloidsorothernoveldosageforms.Thegrowing expertiseinchemistryandlargescalemanufacture,however,enabledthemtosorapidly manufactureSalvarsanandothercomplexsyntheticdrugswhenthewarbrokeout. In1913HenryWellcomeconsolidatedallofhislaboratoriesunderoneumbrella, creatingtheWellcomeBureauforScientificResearch(WBSR)underBalfour,leaving WenyonasDirectorofResearchintheTropics.WalterM.FletcheroftheMRChad concernsaboutfirmssupportingresearchwheretheycouldinfluencepublishingofresults asfirmsaretiedhousesbuthesuggestedthattheapparentfreedomconferredbythe
284
Laidlaw,previouslyDunnProfessorofPathologyatGuyshospitaltookupa permanentpostattheN.I.M.R.ataninitialsalaryof750p.a.:MRCAnnualReports 19141920:MRCCommitteeMinutesII,(16December,1921):167H.H.Dale,P.P. LaidlawBiographicalMemoirsofFellowsoftheRoyalSociety (1941):427447.Laidlaw didworkonhistidineandtoxinsP.Laidlaw,A.Glenny,DetectionandConcentrationof AntigensbyUltrafiltration,PressureDialysisetc.withSpecialReferencetoDiphtheriaand TetanusToxins:BiochemicalJournal 9(1910):298TheCambridgeconnectionincluded Mellanby,Barger,Dale,Laidlaw,Burn,Dowson,KanthackH.H.Dale,PatrickPlayfair Laidlaw,18811940ObituaryNoticesofFellowsoftheRoyalSociety 3(1941):427447.
135
136
285 WBSRwasoptimal. Soonafteritsestablishment,WarbrokeoutandtheWBSRwas
placedatthedisposaloftheWarOffice,offeringtrainingandsupportonTropical
286 Research. HenryWellcomemaintainedaninterestinTropicalMedicinethroughouthis
lifeandthiswasimportanttothefirmsabilitytotesttheirnewdrugsinthecolonieswhen theyhaddifficultyingettingdrugstestedinEngland.Iwillreturntothisinchaptersix. InthenextchapterIwillexaminethechallengesthatBurroughsWellcomefacedin replacingGermandrugsaftertheoutbreakofthewar,andtheproblemsthatwerecreated bythelossofseveraloftheirkeystafftotheM.R.C.andtootherpharmaceuticalfirms.
285
MaisieFletcher,TheBrightCountenance:aPersonalBiographyofWalterMorley Fletcher(London:Hodder&Stoughton,1957):187.
286
CecilA.Hoare,CharlesMorleyWenyon18781948(1949):62742.
136
WarandtheEstablishmentofaBritishSyntheticDrugIndustry
137
CHAPTERFOUR WarandtheEstablishmentofaBritishSyntheticDrugIndustry Wecannotrecoverwhatwehaveneverhad...theproductionoffine 1 chemicalshavefromthefirstbeenaGermanindustry. 4.1Introduction:theRelianceonGermanDrugsandChemicals. ChapterTwoshowedthatBritainreliedonGermanyforsyntheticdrugs,chemical intermediatesandcertainalkaloids.TheRoyalCommissiononVivisection,whichreported in1912,listedthedrugsthathadrecentlybeenintroducedasaresultofanimalstudiesand mostwerefromGermany:thesoporifics,chloral,sulphonalandveronallocalanaesthetics, cocaine,eucaineandstovaintheanalgesicsandantipyretics,antipyrine,antifebrin, phenacetinandexalginphysostigmine(oreserin)forglaucomaamylnitritesforangina
2 andthediuretics,caffeine,theobromine,diuretinandurotropine.
ThisrelianceonGermanyforsyntheticdrugsin1914wasnotapparentintheBritish Pharmacopoeia.Theversioninuseupto1914(i.e.thatproducedin1898)onlylisted3 syntheticdrugseventhedraft1914versiononlylisted7syntheticdrugs.Thiswasbecause standardsofspecificationhadnotbeenagreedformanyofthenewerdrugs:Britaindidnot

3 haveasystemforassayingdrugs. ButitisclearbyreviewingtheBritishMedicalJournal
andChemist&DruggistthatGermansyntheticdrugsheldadominantpositioninthe
4 Britishmarket. Furthermore,becausetheuseofGermantradenameswasfrownedupon,
F.H.Carr,RecoveryofTradeLosttoGermanyChemist&Druggist85.2(29 August1914):51. 2 FinalReportoftheRoyalCommissiononVivisectionBritishMedical Journal (16 March1912):62627. 3 Thesewereacetylsalicylicacid(Aspirin),barbitone(Veronal),benzaminelactate( Eucainelactate),chloralformamide,dicimorphinehydrochloride(Heroin),hexamine (Urotropine),phenolphthalein(Purgen)British MedicalJournal (17October1914):672 73 BritishPharmacopoeia1914(London:Constable&Co,1914)TheBritish PharmacopoeiaChemist&Druggist85.2(3October1914):4958TheBritish Pharmacopoeia1914PharmaceuticalJournal (3October1914):45255. 4 SyntheticMedicinalChemicalsBritishMedicalJournal (23January1915):168169 MedicalNewsReplybyBurroughsWellcomeBritishMedicalJournal (6February 1915):257.
137
138
Britishdoctorsoftenuseddrugs,distributedbywholesalers,notevenrealisingthatthey
5 wereGerman.
FiguresfromtheCommercialIntelligenceBranchoftheBoardofTradeshowthat importsfromGermanyin1912includedsmallquantitiesofnaturalproducts24,500of opium,237,100ofPeruvian barkandrhubarbroot,andalargerportion,(264,600)of purifiedquininebutalso895,500ofpreparedmedicinesand742,500ofchemical

6 productsformedicine. AlthoughGermansyntheticswereseenasathreatasdescribedin
chaptertwo,therewashowever,arecognitionthatsomeeffortswerebeingmadein Britain:Althoughpriortothewar,themanufactureoforganicfinechemicalproductsby synthesiswastoaverylargeextentacontinentalmonopoly,therewasneverthelessa

7 beginningmadewithinthiscountry.
Inchapter3,IdemonstratedthatBurroughsWellcomehadthechemicalskills requiredtopreparemanyalkaloidssyntheticallyonasmallscale,inordertoestimatethe purityofextractedalkaloidsandtocarryoutcomplexstructureactivityrelationship

8 studies. However,theonlysyntheticstheyproducedcommerciallywereAtoxyl,
isoquinolinederivativesofadrenaline(Suprareninsynthetic)andcodeine,whileMay& BakeronlypreparedphenacetinandSulphonalundercontractfrom Bayer,afterimporting

9 latestageintermediates.
Smiths,Morsons,Howards,Whiffens,andMacFarlanesdidnotperformany chemicalsynthesis,butbetweenthemextractedvariousalkaloids,concentratingonthe mostprofitablelines,morphine,strychnineandcaffeineandsotheystillreliedonGermany

10 forothers. BurroughsWellcomeproducedpilocarpinesalts,hyoscine,atropine,emetine,
ForexampleJohnBelldistributedMarlesenforBayer.BritishMedicalJournal (5 September1914):55. 6 DrugsandMedicinalPreparationsChemist&Druggist85.2(3October1914):34. 7 D.L.Howard,British&ColonialPharmacist (August1926):243. 8 BurroughsWellcomeletter.Chemist&Druggist85.1(22August1914):46B. Dott,VegetableAlkaloidsHowtheWarhasAffectedProductionChemist&Druggist 88.4(29July1916):777T.A.Henry,ThePlantAlkaloids(London:J.&A.Churchill,3rd edition,1939)R.Robinson,J.ChemicalSociety 111(1917):876. 9 JudySlinn,AHistoryofMay&Baker18341984(Cambridge:Hobsons,1984): 4445. 10 BoardofTradeNotesChemist&Druggist85.2.(5September1914):40F.H. Carr,presscuttingsin2131B/CARR2No.143,ImperialInstitute(5September1914):1 D.Bolton,TheDevelopmentofAlkaloidManufactureinEdinburgh18321939
138
139
11 apomorphine,aconite,colchicines,cotarnum,homatropine,hydrazolineandspaline.
Therewereshortagesofformamine(hexamine),quinineandsanatogen,andthese
12 amountedtoover1m.worthofsyntheticdrugs.
The1907patentlawhadaimedtostimulatesyntheticmanufactureofpatented (henceGerman)drugsinBritain,andtherebystimulatethetrainingofchemists.However, itbecameapparentthatafteramodificationofthelawin1909,onlythelatterchemical stagesofsynthesiswerebeingperformedinthiscountryandnearfinishedgoodswere beingimported.Asaresult,chemistsheredidnotgainmuchexperience,butpriceswere keptlowduetoGermanefficiencyoflargescaleproduction. ThepatentsofmanyoftheearliestGermansyntheticdrugs,suchasAntipyrin, patentedinJuly1883hadexpired,butBritishfirmsstillcouldnotprepareitcompetitively

13 againstGermanfirms. Itwasstatedthat:beforethewaritwouldhavebeenvery
difficulttoproducethesalicylateshere.EvensimplesyntheticssuchasAspirinwerenot manufacturedcommerciallyinBritainbecauseitcouldnotbemanufactured:atprices
14 whichcouldcompetewiththoseatwhichGermanywasabletoofferthem.
Germanfirmscreatedaseriesoftrustsandcartelstomaintainmonopoliesand
15 discouragecountermeasures. Thus,thelackofcompetitivenesswasalsodueto:
Enhancedsellingbycartelsandagradualdrawingtogetheroflarge manufacturingconcerns.Thefirstachievementsweretheeliminationofcompetition withinGermanyandtheorganisationofconcertedeffortstoundersellrivalsinthose lineswherethereseemedtobealikelihoodofdangerouscompetitionarising:owing toourinferiororganisationwethusbecametheshuttlecockofGermanmenof 16 business. Britishfirmsfoundthatcartelswerenottheonlyanticompetitivepractice:
Chemistry&Industry (1976):701708LondonPharmaceuticalIndustryChemistry& Industry (1933):667698. 11 T.A.Henry,(1939). 12 F.H.Carr,SyntheticOrganicDrugs:theirManufactureasAffectedbytheWar Chemist&Druggist(29July1916):7789. 13 ManufactureofAntipyrinChemist&Druggist 85.1(15August1914). 14 Acartelexistedforiodineandotherdrugs.TheWarandtheScarcityofSome DrugsBritishMedicalJournal (27March1915):55961. 15 L.F.Haber,TheChemicalIndustry19001930:InternationalGrowthand TechnologicalChange(Oxford:ClarendonPress,1971):110,118,2756. 16 F.H.Carr,textofhis1926SCIspeech,ManufactureofOrganicMedicinal ChemicalsinhisArchivesatImperialCollege.B/CARR/IIILectures192060.
139
140
Internationaltradingisnotonareciprocalbasis...foreignchemicalsand pharmaceuticalpreparationsareadmittedintothiscountry,practicallyduty freewhilstgoodsexportedfromthiscountrytocountriesabroadaresubject toanexceedinglyhigh'advalorem'duty.Onevastcountry (America)... directlyprohibitstheimportofpharmaceuticalpreparationsofother countrieswhileotherimmensestatesdosoindirectlybymeansof(the)high 17 duty. ThroughoutthenineteenthcenturyBritainhadmaintainedafreetradepolicyinmarked contrasttoincreasingprotectionisminFrance,Italy,theUnitedStates,NewZealandand
18 Canada.Allen&HanburysfoundthisparticularlycostlyinAustralia. Americantariff
protectionhadeffectivelykilledoffBritishalkaliexportsandnowprohibitedimportationof
19 somepharmaceuticalsandcontrolledadvertisingtophysicians.
InthischapterIwillexaminehowBritainreactedtothelossofGermandrugsatthe outbreakofthewar.Iexaminethecollaborationsestablishedtodeterminewhichdrugswere essentialandhowthesecouldbemadeorreplaced,andhowtheshockoftheWarbrought hometheneedforfirmstocollaboratetomakethebestuseofresources.Thischapterwill showhowtheprewareffortsofBurroughsWellcomedescribedinchapter3formeda valuabletechnicalbaseforthepreparationandanalysisofnewdrugs,bothinternallythrough theirexperiencedstaffsuchasPymanandJowett,andexternallythroughHenryDaleand ArthurEwins,whojoinedtheMedicalResearchCommittee(MRC)andarrangedstudiesby theirSalvarsanCommitteetoshowthatBritish produceddrugswereassafeastheGerman versions.Thesestudieswerethefoundationforfurtherdevelopmentsinbiological standardisationofdrugsandofclinicaltrials.FrancisCarr,ArthurEwinsandothersspreadthe BurroughsWellcomemodelofchemicalresearchanddevelopmentandlargescale manufacturingtootherpharmaceuticalfirms.Finally,Iwillexaminesomeofthecollaborations thatestablishedtheBritishpharmaceuticalindustryonamoresecurefooting.
17 18
BritishChemicalIndustriesBritishMedicalJournal (5March1921):347. L.F.Haber,(1971):239BritishDyestuffsChemist&Druggist94.2(8October 1921):39D.ChapmanHustonandE.C.Cripps,ThroughaCityArchway:TheStoryof Allen&Hanburys17151954(London:JohnMurray,1954):245. 19 W.J.Reader,ImperialChemicalIndustriesLtd.AHistory:TheForerunners1870 1926volume1(London:OxfordUniversityPress,1970):169B.E.ReubenandM.L. Burstill,AGuidetotheTechnologyandEconomicsoftheChemicalIndustry (London: Longman,1973)J.Bishop,DrugEvaluationProgramsoftheA.M.A.190566Journalof theAmericanMedicalAssociation 196(1966):496.
140
141
4.2GovernmentResponsestotheConditionsofWarandDrugShortages TheoutbreakofWarledtoamassivedemandfordyestomakeuniforms,anddrugs,
20 especiallyantiseptics,anaesthetics,painkillersandantitoxins. Manyofthesame
chemicalswererequiredbothfortheproductionofexplosivesandofdrugs.However, syntheticdrugs,manychemicalintermediatesandsomealkaloidsweresoonnolonger available.Miallrecalled:Thechemical manufacturersofthiscountrywereveryill

21 preparedforsuchacatastrophe. TheBritishgovernmenthadtomakerapiddecisionsto
managethissituation.Theyhadtoensurethatnoessentialmaterialswereexported,and theyhadtofindalternativesourcesofGermandrugs,chemicalintermediatesandraw
22 materials.LongertermsolutionsincludedgrowingsomemedicinalplantsinBritain or
importingdrugsfromalliedcountries,butthereweremanyurgentrequirements.
th InpassingtheTradingwiththeEnemyActofAugust5 1914(undersection8of
theCustomsandInlandRevenueAct),theGovernmentimmediatelyspecifiedalistof essentialchemicalsincludingdrugs,whichcouldnottobeexportedtothecontinent withoutaspeciallicence:glycerine,lead,saltpetre,nitrateofsodium,carbolicacid,ethyl andmethylalcohols,alkaliiodides,belladonnaanditspreparationsandalkaloids,bismuth anditssalts,boricacid,bromineandalkalbromides,castoroil,chloroform,cinchona, quinineandsalts,cocapreparations,andalkaloids,colloidin,corrosivesublimate,cresol andpreparations,nitrocresol,digitalis,ether,ethylchloride,formicaldehyde,henbaneand preparations,iodineandpreparations,Lysol,mercuryandsalts,morphiaandother alkaloidsofopium,nuxvomicaandalkaloids,paraffin,protargol,salicylicacid,Salvarsan andallfinechemicals. CertificatesoforiginwererequiredforNorway,Sweden,Denmark,ItalyandThe
23 Netherlands. Beforeanexportlicencewasgranted,applicantshadtospecifythenature
20
EffectoftheWaronDrugSupplyPharmaceuticalJournal 93(12December1914): S.Miall,HistoryoftheBritishChemicalIndustry (London:ErnestBennLtd.,1931):
797.
21
36.
22
Prof.H.G.Greenish,DrugCultivationinEffectoftheWaronDrugSupply PharmaceuticalJournal 93(12December1914):797. 23 CustomsandInlandRevenueActChemist&Druggist 85.1(15August1914): 34TradingwiththeEnemy itsLimitationsandPossibilitiesChemist&Druggist85.2 (22August1914):47TradingwiththeEnemyChemist&Druggist85.2(17October
141
142
andquantityorweightandvalueofgoods,whereitwasgoingandwhy,andwhichports
24 andshipswouldbeused. TheArmyimmediatelyrequisitionedallquinine,phenacetin, 25 andformaldehydeproduced,aswellasseveralchemicalintermediates. TheGermans
immediatelyreciprocated,banningexportstoBritainofchemicalsrequiredformaking
26 munitions,dyestuffsanddrugs. Thismadeabadsituationevenworse.Forexample,
BritainhadreliedonGermanyforphenol,useditselfasanantiseptic,butalsoneededfor
27 theproductionofdrugssuchasAspirinandPhenacetin.
TheGermansdidnotbelieveitwaspossibleforBritishfirmstoproducesynthetic drugsonacommercialscale.PerkinquotedaseniorfigurewithintheGerman Chemical Industry,probablyDuisbergofBayerasstating: Englandtalksnotonlyofholdingherowninthewar,butofbeatingusin thechemicalindustry.Shecannotdoit,becausethenationisincapableofthemoral efforttotakeupsuchanindustry,whichimpliesstudy,concentration,patience,and 28 fixingtheeyeondistantconsequences,andnotmerelyonthemonetaryresult. Britishdrugfirmshadreliedonthedyeindustryforchemicalintermediatesbuteventhe largerBritishdyefirmssuch asClaytons,ReadHollidayandLevinsteinsreliedonimports
29 fromGermanyofchemicalintermediatessuchasbenzene,toluene,andcarbolicacid. 30 Britishfirmsweremuddlingthrough. Therawmaterialsupplyofinorganicchemicals
suchasbromides(usedforepilepsy)andpotashfrommineraldepositsinGermanywas immediatelycompromisedbytheWar,butatleasttherewerealternativesourcesinSouth
31 32 America. HoweversuppliesallovertheworldwerecorneredbyGermany.
1914):33TradingwiththeEnemyProclamationChemist&Druggist85.2(12 September1914):34AbsolutealcoholChemist&Druggist(19September1914):48. 24 ProclamationonExportationofMedicinesChemist&Druggist 85.2(3October 1914):335. 25 MedicalNewsBritishMedicalJournal (5May1917):603. 26 F.H.Carr,SyntheticOrganicDrugs:theirManufactureasAffectedbytheWar Chemist&Druggist87(29July1916):778779. 27 TradePriortotheWarChemistandDruggist85.1(15August1914):48W.J. Reader,MinistryofMunitions(1970):2501,2867. 28 QuotedbyW.H.PerkininW.M.Gardner,(1915):407427quoteonp.415. 29 L.F.Haber,(1971):121,148. 30 W.J.Reader,(1970):267. 31 B.Dott,VegetableAlkaloids:HowtheWarhasAffectedProductionandF.H. Carr,TheManufactureofDrugsAffectedbytheWarfrom BritishandColonial Pharmacist(June1915):4367.AcopyofthispaperisintheArchivesofFrancisH.Carr:
142
143
Manychemicalintermediatessuchasorganicacids,alcoholsandaldehydeswere sooninshortsupply.Chemicalsrequiredforthemanufactureofdrugsincludedliquid chlorine,sulphurdioxideandtrioxides,phosphoricanhydride,chloridesandoxychlorideof phosphorus,aceticanhydride,acetylchloride,carbonylchloride,thechloroaceticacids,

33 monochlortoluene(benzylchloride),acetoaceticacidester,andphenylhydrazine. Other
essentialintermediatesfromdyemakerswereamidophenols,dimethylalanine, dimethylsulphide,betanaphthol,andphthallicanhydride. SomeBritishcompanieshadmadeeffortsincaseofwartoavoidshortages.Sir EdwardEvansofEvansSons,Lescher&WebbhadattendedtheBritishPharmaceutical CongressasPresidentin1912inwhichthegeneraltopicofdrugtradeinwarwas discussed.HisfirmboughtupsuppliesofGermandrugsfromSpainandPortugalthey cultivatedherbsandplannedincreasedeffortstomakedigitalis,henbane,colchicum, olearin,belladonna,peppermint,lungwortandaromatics.BurroughsWellcome,likemost otherswereillpreparedforthesuddenoutbreakofwar. Insummarythewarbroughtanimmediateshortageofsomenaturalplants, inorganicdrugs,alkaloidsandbiologicalsandanabsolutelackofGermansyntheticdrugs. Thefirststrategyadoptedwastoseekalternativesourcesoralternativedrugs.Thesecond wastotrytomaketheGermandrugs.Althoughsomeshortageswereimmediately obvious,therewerealsomoresubtlerequirementsforchemicalintermediates,someof whichwerenotimmediatelyrecognised.
4.3WhichDrugswereRequiredandCouldTheybeManufacturedinBritain? Beforelegislationcouldbeputinplacetoalleviatetheshortages,theGovernment hadtodecidewhichdrugsandchemicalintermediatesweremostneededfortheWarOffice
B.CARR2130B/CARR:3atImperialCollege,LondonTheWarandtheScarcityof SomeDrugsChemist&Druggist85.2(5September1914):4BoardofTradeReturns to31AugustBritishMedicalJournal (3September1914):47. 32 C.A.Hill,T.D.Morson,ManufactureofFineChemicalinRelationtoBritish ChemicalIndustryfrom BritishandColonialPharmacist(June1915):4367.Acopyof thispaperisintheArchivesofFrancisH.Carr:B.CARR2130B/CARR:3atImperial College,London. 33 F.H.Carr,TheWarandBritishProductionofFineChemicals,SyntheticOrganic DrugsandAlkaloidsBritish&ColonialPharmacist(June1916):4367in2130B.CARR PresscuttingsIV.
143
144
34 andthiswaspoorlyunderstooduntilMoultonbegancollatingdata. Fortunately,the
PharmacopoeiaCommissionhadjustcompletedworkonthenewPharmacopoeia,which
35 wasduetobepublishedinDecember1914. TheCommissiononPatentMedicines,which
metbetweenMay1912andJune1913,alsoreportedjustbeforetheoutbreakofWar. Theirextensivereportof782pagesincludedmanyrecommendationstoover14,000
36 37 questions. TherehadalsobeenarecentProprietaryMedicinesInquiry. Togetherwith
theBritishPharmaceuticalCodexof1907,theseformedagoodbasisfordefiningessential
38 drugs. PreparationofthePharmacopoeiaandCodexhadincludedpharmaceutical
39 industryinput. ThenextstepwastocheckwhichdrugscouldbemadeinBritain,what
chemicalintermediateswouldbeneededandwheretherewereshortages. ReturnsofthecommercialintelligencebranchoftheBoardofTradeinAugust1914 confirmedactualshortagesofnaturalandsyntheticalkaloids,thelocalanaesthetics, EucaineandNovocaine,andothernaturalextractssuchasThymol(oilofajowan)usedas anantiseptic,andlanolin(hydrouswoolfat)neededforthepreparationofointments. However,thefigureswerenotdetailedenoughtoidentifyshortagesofspecificchemical intermediatesorindividualsyntheticdrugsandthismadeitdifficulttopredict

40 requirements.
Inordertoassesswhichdrugswereneeded,whocouldmakethemandwhat intermediateswererequiredaseriesofinterrelatedcommitteeswereestablished,ledbythe BoardofTradeandtheNationalInsuranceCommissionandwithcontributionsfroma numberofChemicalSocieties.Broadly,theycoveredthechemicalintermediatesrequired tomakenotonlydrugs,butalsodyesandexplosives,thedrugsrequired,thepossible alternatives,whichfirmsmadethesedrugsandhowmuchofeachwasavailable.Inorderto

34 35
A.J.P.Taylor,EnglishHistory19141945(Oxford:Clarendon,1988):45. TheBritishPharmacopoeia(1914). 36 AHugeRevenueThreatenedBritishMedicalJournal (11May1912):1090. PatentMedicineCommitteeChemist&Druggist85.1(24October1914):47. 37 ProprietaryMedicineInquiryPharmaceuticalJournal 93(8August1914):218. 38 TheBritishPharmaceuticalCodexLancet (22November1907):1247. 39 TheBritishPharmacopoeiaBritishMedicalJournal (13August1914):8845 TheBritishPharmacopoeia1914BritishMedicalJournal (3October1914):4958.It cameintoforceon31December1914. 40 F.H.Carr,SyntheticOrganicChemicalIndustryNottinghamJournal (October 1918)ChairmansaddressbyF.H.CarrtotheNottinghambranchoftheSCI.CopyinF. H.CarrarchivesatImperialCollege.B/CARR/IIILectures192060.
144
145
makemanyofthedrugs,acomplexwebofchemicalintermediateswasrequiredfrommany differentfirmsandmanyofthesamestafffrompharmaceuticalfirmswasrepresentedon severalcommittees. WalterRunciman,educatedinSouthShieldsandCambridgewasthesonofaship ownerwhomhesucceededasBaronhewasaLiberalM.Pfrom18991900andfrom1902

41 onwards(until1918andthen192431). AsnewlyappointedPresidentoftheBoardof
Trade,heestablishedaCommitteeonDrugSupplywithinthreeweeksoftheoutbreakof Wartoquantifytherequirementsofvariouschemicals,toestablishwhichfirmsproduced them,andtosetprioritiesfortheallocationofchemicalintermediatesrequiredfordrug production,andsotocoordinatesuppliesthroughasubcommitteeondrugschairedbyJ. FletcherMoulton.Asearlyas23November1914,RuncimancalledforaGovernment sponsorednationaldyeindustry,notonlytobenefitdyeproduction,butalsoasasourceof

42 chemicalintermediates. Moulton,whohadalongstandinginterestinscienceandhad
campaignedagainsttheantivivisectionistssupportinghisgoodfriendHenryWellcomewho wroteofMoultonin1896:He,morethananyotherman,rousedthiscountry(England)to arealisationofthevitalimportanceofscientificmethods,researchinmedicineandinevery

43 branchofindustry. Moultonhadplayedasignificantroleindefendingscientificpatents
inthechemical,electricalandotherindustries.Hewasamemberofparliamentanda memberofthejudiciarycommitteeofthePrivyCouncil,andhadpreviouslylecturedonthe issuesfacedbychemistry,includinga1904addresstotheSocietyoftheChemical Industry,Thetrendofinventioninthechemicalindustry.Inhis1914Redelectureon TheManufactureofAnilineDyesinBritainhestated:Wenomoredaretoleaveour greatindustriesatthemercyofaforeigncountrythanwedaretrusttoaforeigncountry

44 ourgunsandourammunition.
41
RuncimanremainedattheBoardofTradeuntil1916,whenhewasreplacedbySir AlbertStanley,(laterLordAshfield):A.J.P.Taylor,(1988):15,326K.Middlemass,J. Barnes,Baldwin:ABiography (London:C.Tinkling&Co.,1969):567,65,654.

42
H.FletcherMoulton,TheLifeofLordMoulton (London:Nisbet,1922)F.B. Power,Nature(13January1923):44M.R.Fox,DyeMakersofGreatBritain18561976: aHistoryofChemists,Companies,ProductsandChanges(Manchester:I.C.I.plc,1987): 38,48,53,85,889,91,146. 43 J.FletcherMoultonobituarybyF.B.Power,WF:88/94:6263. 44 ibid.
145
146
Moultonscommitteeaimedtointegrateandcoordinateoverallsuppliesandthis involveddevelopinganunderstandingoftheinterrelationshipsbetweenfirmsandtheir relianceoneachotherforchemicalintermediates.Thecommitteeincludedthreeprofessors ofchemistry WilliamHenryPerkinjunior,FRS,ProfessorofChemistryatOxford

45 University andthesonofthefounderoftheBritishdyestuffsindustry Prof.Arthur
GeorgeGreenatLeedsUniversity,whohadbeenassociatedwiththedyestuffsfirms,
46 Brooke,SimpsonandSpillerandwithClaytonAniline andRaphaelMeldola,FRS, 47 ProfessorofChemistryattheRoyalCollegeofChemistry,thenatFinsburyPark. The 48 49 representativesof dyestuffsincludedHerbertLevinstein ofLevinsteins:JosephTurner,
chairmanofReadHollidayofHuddersfield,andMiltonS.SharpoftheBradfordDyers
50 Association. Italsoincludedtwopharmaceuticalmanufacturers,DavidL.Howard,head
ofHowardsofIlford,andpastpresidentoftheInstituteofChemistryandoftheSociety oftheChemicalIndustry,andThomasTyrer,theexperiencedheadofT.Tyrer&Co.,and pastpresidentoftheSocietyfortheChemicalIndustry.HowardandTyrerrepresented

51 twoofthelargestpharmacybasedmanufacturersproducingalkaloidsandfinechemicals.
Thecommitteequicklyorganisedincreasedsuppliesofsulphuricandnitricacids,liquid
52 chlorine,syntheticbenzolandphenol,toincreasedrugproduction.
Itbecameimperativetodefineexactlywhichdrugswereessentialandwhat constitutedareasonablealternative.Itwasclearthatanaesthetics,painkillersand
45 46
M.R.Fox,(1987):92 Chemistry&Industry (1929)7:1009. J.Baddiley,ArthurGeorgeGreenObituaryNoticesofFellowsoftheRoyal SocietyofMedicine4(1943):25170. 47 ForbackgroundseeAlexanderFindlayandWilliamHobsonMills(eds.),British Chemists(London:TheChemicalSociety,1947):96,1767,2478W.J.Reader,(1970): 278L.F.Haber,(1971):3535M.Hainsworth,WhowasRaphaelMeldola?Biologist 39(1992):72ObituaryofRaphaelMeldolaProc.Roy.Soc.Lond.93(1917):2937. 48 HerbertLevinstein,J.Soc.Chem.Ind. Jubileeedition(1931):92. 49 M.R.Fox,(1987):4243. 50 M.R.Fox,(1987):7692. 51 ThecommitteealsoincludedGeorgeBeilbyJP,F.R.S.,apastpresidentofthe S.C.I.,MaxMusprattofthePatentOffice,SirArthurTedderofCustoms&Excise (ChemistryandPharmaceuticals)andProf.JamesJohnstonDobbie,F.R.S. BritishMedical Journal (5September,1914):40W.J.Reader.(1970):26670W.H.PerkininW.M. Gardner.(1915):345,407,419. 52 F.H.Carr,TheManufactureofSyntheticOrganicDrugsAffectedbytheWar, BritishandColonialPharmacist(June1915)4367,(quote)in2130B/CARRcuttingsIV: 3,ArchivesatImperialCollege.
146
147
antisepticswouldbeneededingreatquantities.TheNationalHealthInsurance Commission,createdin 1911,andresponsibleforcivilianGovernmentspendingon healthcare,tookacentralroleindefiningtheproblemsofdrugsupply.Thehealthinsurance providedBritishworkingmenearninglessthan16peryearandsomeworkingwomen

53 withhealthbenefits. BecausetheGovernmentwastopayformedicines,italreadyhadan
increasedinterestinensuringthatthemostappropriatedrugswereprescribed.
54 SirRobertMorant, acivilservantpreviouslyattheBoardofEducation,became
chairmanoftheNationalHealthInsuranceCommissionandsetuptwoadvisory committees.TheCommitteeonDrugSupplydecidedwhichspecificdrugsweremost
55 needed itsmembersincludedthePresidentofthePharmaceuticalSociety,MrEdmund
White,theVicePresident,MrE.T.Neathercott,56 andtheSecretary,MrW.J.U.
57 Woolcock,whowasemployedattheWarOffice. JohnC.UmneyofthePharmaceutical
53
S.W.F.Holloway,RoyalPharmaceuticalSocietyofGreatBritain18411991.A PoliticalandSocialHistory (London:ThePharmaceuticalPress,1991):52,32440. 54 SirRobertMorantwasnamedasthefirstCommissioneroftheNHIon28 November1911:S.W.F.Holloway,(1991):338foralifehistoryofMorantseeD.Cox Maksimov,TheMakingoftheClinicalTrialinBritain,19101945.Expertise,theState andthePublic(Cambridge:PhD,September1997):9097. 55 MembersofthecommitteeincludedtheNHICommissionerMrJackSmith Whitaker,aschairmanSirThomasBarlowBartSirThomasLauderBruntonBartDr.A. Cox,MedicalSocietyofBMAProf.A.R.Cushny,ProfessorofPharmacologyat UniversityCollege,LondonDr.E.RowlandFothergill,CouncilofBMADr.B.A. Richard,SecretaryofLondonPanelCommissionDr.F.J.SmithDr.WilliamHaleWhite PresidentoftheRoyalCollegeofPhysiciansDr.E.W.Adams,medicalofficer,NHI CommitteeonDrugSupplyChemist&Druggist85.1(22August1914):33and(29 August1914):59and(5September1914):4042. 56 PharmaceuticalSocietyofGreatBritainChemist&Druggist99.1(28July1923): 117E.T.NeathercottwasPresidentofthePharmaceuticalSociety192024,S.W.F. Holloway,(1991). 57 WilliamJamesUglowWoolcockwasoneoftwopharmacistsrepresentedonthe firstNationalAdvisoryCommitteeonInsurancecreatedaftertheNationalInsuranceActof 1911.HewasappointedasLocalAssociationsOfficerandfrom1913wasSecretaryand registrarofthePharmaceuticalSociety,untilhisappointmentasGeneralmanagerofthe AssociationoftheBritishChemicalManufacturersformedin1916.InDecember1918he wasreturnedasCoalitionLiberalM.P.forCentralHackney:S.W.F.Holloway,(1991): 337,339,355,392.
147
148
SocietyandCharlesA.HillofBritishDrugHouses,whohadbeeninvolvedinproduction
58 ofboththe1898and1914Pharmacopoeia,werealsomembers.
Inparallel,representativesoftheLondonChamberofCommerceincluding
59 Pharmaceuticalmanufacturers,metwithJohnAnderson(laterViscountWaverley) ofthe
NationalHealthInsuranceCommissionandSirRobertMoranttoestablishthesecond committeeasanEmergencyCommitteeofTradeSectionto considerandadviseusastothebestmeansofobtainingfortheuseof Britishindustries,sufficientsuppliesofchemicalproducts,coloursand dyestuffsofkindshithertolargelyimportedfromcountrieswithwhichweare 60 presentlyatwar. JohnAndersonwasoneofthefewseniorofficialswhounderstoodchemistry, havingreadscienceinScotlandandGermanybeforejoiningthecivilservicehebecame instrumentalindirectingBritishfirmstoproducesyntheticdrugs. JohnC.UmneyofthePharmaceuticalSociety(whowasalsoontheCommitteeon DrugSupply)chairedthisEmergencyCommitteeofTrade,whichincludedthe pharmaceuticalmanufacturersDavidLloydHowardofHowards,CharlesA.HillofBritish
61 DrugHouses,T.D.Morson,ThomasTyrer,withT.E.Lescher, andE.A.Webbofthe
firmEvansSons,Lescher&Webb. Overall,theNationalHealthInsuranceCommissionwascharacterisedbyalackof redtapeithelpedtoavoidfaminesofalcohol,glycerineandsugar,andyetmanufacturers
58
J.C.UmneywasaBoardmemberofthefirmWright,LaymanandUmney PharmaceuticalJournal (22August1914):294JohnCharlesUmney,Publicationofthe PharmacopoeiaChemist&Druggist83.2(26July1913):53Obituary,CharlesUmney Chemist&Druggist88.5(25November1916). 59 LordBridges,JohnAnderson,ViscountWaverleyBiographicalMemoirsof FellowsoftheRoyalSociety 4(1958):307325. 60 ExportationofMedicinesChemist&Druggist85.2(19September1914):33for backgroundseeMajorGeneralSirW.G.MacPherson. HistoryoftheGreatWarVolume 1.(LondonH.M.S.O.,1921):178179.
61
ThomasE.LescherjoinedthefirmofEvansSons,Lescher&Webbin1895.After takingthePharmaceuticalSocietyexamhetravelledextensivelytotheFarEast,Australia andNewZealand,establishingtheinternationalbusiness.Hebecameapartnerin1900.T. E.Lescher,BritishPharmaceuticalCongress:PharmacyToday itsResponsibilities Chemist&Druggist127.1(31July1937):1189TheLateT.E.LescherPharmaceutical Journal 140(30April1938):460.
148
149
62 stillhadtobegtheWarOfficeforsuppliesofsulphuricandnitricacids. Atthestartofthe
War,thePresidentoftheBoardofTrade,andthePresidentandSecretaryofthe PharmaceuticalSocietywereindailycontactwiththeWarOffice,NationalHealth InsuranceCommissionandotherGovernmentdepartments.TheSecretaryoftheMedical ResearchCommittee,WalterMorleyFletcher,alsowasconstantlyattendinginnumerable meetingsattheWarOffice,attheHomeOfficeandwiththeRoyalArmyMedicalCorps,

63 theAirForceandtheRoyalSociety. TheMedicalResearchCommitteehadbeen
establishedin1913,andwastoplayanimportantrole,particularlyrelatingtotheassayof
64 newly producedSalvarsanaswillbedescribedlaterinthischapter.
Inadditiontothecentralquestionofwhichdrugswereneededandwhocould providethem,oralternatives,aseriesoffurthercommitteescontributedtothemore detaileddiscussionsrequiredregardingchemicalintermediatesneededandsourcesofthem. EventhesupplyofsomeofthedrugsalreadymadeinBritainwaspotentiallycompromised bythelackofessentialintermediates.ThustheChemicalSocietywereconcernedwiththe preparationofinorganicandorganicchemicals:mostimportantofthesearemedicinal drugs,anilineetc.,sotheysetupacommitteeinvolvingacademicchemists,andthe SocietyofChemicalProductsforIndustrialPurposes,todiscusssyntheticchemicals.The pharmaceuticalmanufacturers,DavidHowardandThomasTyrer,gavecontinuitywiththe

65 othercommittees, andwerejoinedbyHill,Hewitt,White,andevenJowettofBurroughs
Wellcome,andwerealsorepresentedonacommitteewithmembersoftheInstituteof ChemistryandtheSocietyofPublicAnalyststoaddressthesupplyoflaboratoryresearch chemicals.AfurtherLaboratoryAgentsCommitteeconcerneditselfwithmaterialsrequired
62 63
C.A.Hill,T.D.Morson,TheBritish&ColonialPharmacist(June1915):4367. MaisieFletcher,TheBrightCountenance:aPersonalBiographyofSirWalter MorleyFletcher (London:Hodder&Stoughton,1957):128T.R.Elliott,WalterMorley Fletcher(18731933)ObituaryNoticesofFellowsoftheRoyalSocietyofMedicine (1934)I:153163. 64 LindaBryder,TuberculosisandtheMRCinJoanAustokerandLindaBryder (eds.),HistoricalPerspectivesontheRoleoftheMRC (Oxford:OxfordUniversityPress, 1989):121. 65 BoardofTradeNoticesTheManufactureofSalvarsanChemist&Druggist85.2 (5September1914):40.
149
150
formanufactureas,forexample,glasswareforperformingreactionswasalsoinshort
66 supply.
SirRobertRobertsonwastheGovernmentchemistwhotookchargeofwartime researchinchemistry.Hedealtmostlywiththeheavychemicalindustrymemberssuchas BrunnerMond,theUnitedAlkaliCo.,andAlbright&Wilson,whoallmadetremendous effortstomeetdemandsformunitions.BrunnerMondandtheSouthMetropolitanGas

67 Companyproducedlargesuppliesofphenolandthishelpedthepharmaceuticalindustry.
Alcoholsupplieswereimprovedfurtherbythemergeroftheprincipalwhiskydistillersto formtheDistillersCo.Ltd,withasubsidiaryBritishIndustrialSolventsmakingacetoneat
68 Hull.
4.4CallsforFurtherGovernmentIntervention. Asdescribedpreviously,pharmaceuticalfirmsinBritainwereverysmallandhadno representativeTradeAssociation.However,itwasimmediatelyrecognisedthattheWar

69 offeredanopeningforBritishmanufacturers. Themainprotestsaboutthereliance
uponGermanyandcalledupontheGovernmentforassistancewereUniversitychemistry professorswhoconsultedwidelyforthedyefirms,andweremembersoftheSocietyofthe
70 71 ChemicalIndustry. SirWilliamTilden wasalsoamemberoftheCounciloftheInstitute
ofChemistryandtheSocietyofPublicAnalysts.Hehadwarnedsincethe1880saboutthe
72 potentialconsequencesofaweakBritishchemicalindustry. Justweeksbeforethewar
66
TheLaboratoryAgentsCommitteeincludedR.Meldola,C.A.Hill,DavidHoward, H.A.D.Jowett,J.T.Hewitt,Sir.WilliamTildenandEdmundWhitewhiletheGlassware committeeincludedMeldola,Tilden,andProfessorH.B.BakerBritishSalicylicAcid Chemist&Druggist85.2(3October1914):35. 67 RobertsonwasmadeFRSin1917andChiefGovernmentChemistin1921:R.C. Farmer,RobertRobertsonObituaryNoticesofFellowsoftheRoyalSociety 6(1949): 53961S.Miall,(1931):3856. 68 S.Miall,(1931):110. 69 AnOpeningforBritishManufacturersPharmaceuticalJournal 93(22August 1914):292. 70 ArthurMarwick,TheDeluge:BritishSocietyandtheFirstWorldWar(Boston LittleBrown,1965)A.FindlayandWilliamHobsonMills(eds.),(1947). 71 In1912hewasProf.ofAppliedChemistry,RoyalCollegeofScience,1913Chairof ChemistryatFinsburyTechnicalCollegeandin1919becameMasonProfessorof Chemistry,Birmingham:Minerva8(1970):406. 72 ForaseriesofarticlesonthisseeW.M.Gardner,(1915).
150
151
TildengaveaseriesoflecturesasProfessorofChemistryattheRoyalCollegeofScience,
73 TheProgressofScientificChemistryinourOwnTimes andon14August1914he
wrotetoTheTimes: ProbablytheBritishpublicisnotawarethatnearlyallthesocalled syntheticdrugsaremadeinGermany....andtoaconsiderableextentalsothe alkaloidsquinine,morphine,eucaine,etc.[British]manufacturerswillnot failtotakeadvantageoftheirpositionstopreventafamineinthese necessarymedicalmaterials.Indoingsothereseemsnosufficientreason whythemanufactureofthesesubstancescannotbeperformedhereforthe 74 benefitofourselvesandourdependencies. InhisaddresstotheRoyalSocietyofArtson27November1914onTheSupplyof ChemicalstoGreatBritainandherDependencies,heaskedthattheprotectionalready promisedtothedyeindustry,intheformofdefinitefinancialaidfromtheGovernment, shouldbeextendedtofinechemicals,andchemicalintermediatesandheexplainedthat: Theestablishmentofwhatwillbeapracticallynewindustryinthiscountry willrequireconsiderationandassistancefromtheStateifitistosurvivethe 75 periodfiercecompetition,whichwillfollowtheconclusionofthewar. TildendescribedhowBritishfirmsmightproducesomeofthealkaloidsand syntheticdrugs,hithertoonlycommerciallyavailablefromGermany.Theycouldnotyetdo soonacostefficientbasisandwouldcertainlynotbeabletocompetewithGermanyafter theWar.TheGermansmight: keepanymarketstheycanretainoutsidetheBritishEmpire,buteveryman whocaresforhiscountrywillsurelydemandthatbusinessathomeshallbe limitedtoBritishgoods.Existingconditionsofferagreatopportunitytothe BritishDrugManufacturingtrade:itwouldbenotonlyprofitablebutalso patriotictotakeadvantageofit.Thereisnoreasonwhythemajorityatleast ofthesyntheticdrugsmostgenerallyusedshouldnotbemanufacturedinthis countryifthenecessaryenterpriseandcapitalbeforthcoming.Thehome 76 demandwouldatoncebeveryconsiderable. TildendescribedtheorganisationofGermancompanies,wheremanagementwasby competentspecialists,whowereconstantlyonthelookoutfornewdiscoveriesandwho
73
ChemistryPastandPresentChemist&Druggist85.1(25July1914):197. th Tildensletterwrittenon14thAugust1914wasprintedon18 August:Tradein DrugsandChemicalsChemist&Druggist 85.1(22August1914):3334. 75 W.TildeninW.M.Gardner,(1915):315334. 76 DrugStocksandtheDrugTradeBritishMedicalJournal (15August1914):379.

74
151
152
hadalargetechnicalstafftomakediscoveriescommerciallyviablebysecuringcheap materials,improvingprocessesandcreatingademand.Theyhadalegalstaffthatpatented allimprovementsanddescribedthemvaguelytopreventcopying.Germancompanies influencedtheirGovernmentonaspectsoftaxandfreightcosts,andtheyhadagencies spreadaroundtheworldthatencouragedanextensivecreditsystem.TheGermansusually

77 aimedtocreateamonopolysituationandthentoincreaseprices.
78 ProfG.Henderson spokeonthesubjectofBritishChemicalIndustryandthe 79 War. FrederickM.Perkin,bynowafreelancechemistryconsultanttothedyeindustry,
alsosummarisedthepositionofBritishmanufacturers.Henoted:Thestartingofchemical manufacturingrequiresgreatexperienceandspecialplant.Severalmanufacturershad approachedhimwillingtohelpbutasking:WilltheGovernmentassisttheminfounding thesenewindustries.Onehadsaid:Weshallbeestablishinganewindustryatatimeof

80 greatstresswilltheinfantbegivenachancetobecomeahealthychild?
TheGovernmentintroducedthePatents,DesignsandTradeMarks(Temporary Rules)Act1914amendment,whichallowedfortheweeklynotificationinTradeMark
81 th JournalsofthenamesofGermandrugsthathadbeensuspended. From8 September
1914,theGovernmentabrogatedpatentsofGermandrugsincludingAspirinandHeroin (Bayer),Lysol(Schuelke&May),Stryphrin(E.Merck),Urotropine(E.Schering),and Sanatogen(Bauer&Co.),offeringtherightsofproductiontoBritishfirms.Eventually

82 mostofthesyntheticpatentswereabrogatedincludingSalvarsan. However,Britishfirms
77
78
F.H.Carr,(29July1916):77880L.F.Haber,(1971):129. SirJamesIrvineandJ.L.Simonson,GeorgeGeraldHenderson(18621942) ObituaryNoticesofFellowsoftheRoyalSociety 4:490.HendersonwasProfessorof ChemistryattheGlasgowandWestofScotlandTechnicalCollegeandwasPresidentof theSocietyoftheChemicalIndustry191518. 79 Prof.G.G.Henderson,BritishChemicalIndustryandtheWarPharmaceutical Journal 93(7November1914):615. 80 F.M.Perkin,inW.M.Gardner,(1915):298314. 81 TradeMarksofAlienEnemiesChemist&Druggist85.2(19September1914):52 MrD.B.Dott,AlkaloidsTheBritishandColonialPharmacist(June1916):4367. 82 GermanPatentsinBritainPharmaceuticalJournal 93(15August1914):246 Patents,DesignsandTradeMarksAct,1914PharmaceuticalJournal 93(29August 1914):31921GermanChemicalPatentsPharmaceuticalJournal 93(19September 1914):4068ThePatentsandTradeMarksofAlienEnemiesPharmaceuticalJournal 9 (26September1914):419GermanPatentsandTradeMarksPharmaceuticalJournal 93 (26September1914):436German PatentsandTradeMarksSalvarsanPharmaceutical
152
153
alsowantedfulluseofthefamiliartrademarksbywhichthedrugswerewidelyknown.For example,BurroughsWellcomewantedtorefertoHexamine,astheirformofurotropine ratherthanthecomplexchemicalnameofhexamethylenetetramine,whichdoctorswould

83 notrecogniseorremember,andtheyachievedthisaim. Aseriesofdrugsrelatedto
hexamine,includingUrodonal,andUrotropineweresaidtosteriliseacidurineandbenefit rheumatismandgout.Suspensionofthepatentsencouragedmanufactureby Britishfirms. LongertermpromisesofsupportingBritishmanufacturerscamefromRuncimanin1915: TheActpassedlastautumnasanemergencymeasureprovidedthatthe operatorsofGermanpatentsinthiscountryshouldhaveafullchanceof conductingthemunderlicenseanditwastheintentionoftheGovernment nottocripplethiscompanywhenthewarwasover,buttogivethemthe 84 opportunityofmakingthemostofGermanpatents. InadditiontoreplacingGermandrugs,alternativesweresought.Alcoholcouldreplace someoftherolesofphenol,buttheGovernmentcontinuedtoplacestrongrestrictionson
85 theuseofalcohol,asitwasalsorequiredforthemanufactureofexplosives. Companies
continuedtocomplainabouttheshortagesofalcohol,asitwasessentialasasolventfor
86 crystallisingdrugsandforpreparingChloral. Highgradecastoroil,glycerine,sugarand
87 lanolinwererequisitionedandfirmshadtokeepaccuraterecordsofuse. EvenaRoyal
Journal 93(10October1914):53031SalvarsanBritishFirmObtainsLicense PharmaceuticalJournal 93(24October1914):569.

83
TradeMarksofAlienEnemiesChemist&Druggist (19September1914):52F. H.Carr,TheWarandBritishProductionofFineChemicals,SyntheticOrganicDrugsand AlkaloidsTheBritishandColonialPharmacist(1915):4367,cuttingsin2131B/Carrat ImperialCollegeTradeMarksofAlienEnemiesChemist&Druggist(26September 1914):66SyntheticMedicalChemicalsBritishMedicalJournal (23January1915):168 AdvertBritishMadeHexamineTabloidChemist&Druggist85(17October1914):31 ConfiscatedDrugs,UseofTradeNames(14May1915),WF:85/31:12. 84 W.H.PerkininW.M.Gardner,(1915):422. 85 W.M.Gardner,(1915):322S.Miall,(1931):8486. 86 DutyFreeAlcoholintheChemicalIndustriesandCommercialUsesofAlcohol PharmaceuticalJournal 93(29August1914):31617,AlcoholandtheWarwith GermanyPharmaceuticalJournal 93(29August1914):33928,994proofgallonshad beenimportedfromGermanyin1913.AbsoluteAlcoholChemist&Druggist85.2(19 September1914):48.M.Fox,(1987):43. 87 F.H.Carr,FineChemicals,theirManufactureinRelationtotheBritishChemical Industry,presentationtotheSocietyoftheChemicalIndustry,Chemist&Druggist88.4
153
154
Commissiononsugarsupplywasestablished,andthishadaneffectondrugsassugarwas
88 neededtoproducepillcoatings. AccordingtoThomasE.LescherofEvans,Lescher&
Webb,whowashonorarysecretaryoftheWholesaleDrugTradeAssociation,greatstress waslaidonlargescaleproductionofsaccharinsothatpeoplecouldstilldrinktheirtea
89 andcoffee.
Inadditiontofinancialandimmediatefiscalhelp,thepharmaceuticalcompanies soughtassurancesfromGovernmentthatitwouldbeworthwhileinthelongertermto investinnewmanufacturingplant.Considerableinducementsweremadetoencourage

90 firmstoproducephenacetin. Inreturn,theGovernmentsoughtassurancesthatprices
wouldbeheldfirmuntiltheendoftheyear.Therehadbeensomepanicbuyingandsharp
91 increasesin thepricesofdrugsandsurgicaldressingsandsomespeculativebuying. Two
pharmaceuticalmanufacturersservedonthepricescommittee,whichtriedtofixrealistic
92 pricesaccordingtosupplyanddemand.
Runcimanexpressedsympathyforthepleafrom thepharmaceuticalfirmsfor
93 protection,thoughasaLiberalheremainedafreetrader. Inordertoencourage
production,theGovernmentofferedaccesstorestrictedbuildingsupplies,promisedto defraycostsandassuredaguaranteedmarketduringthewarwithsignificantenhanced
(29July1916):778MajorGeneralSirW.G.MacPherson,(1921):1789:Burroughs WellcomeStandingOrders,WF:85/31:12W.J.Reader,(1970):285287. 88 SugarFurtherGovernmentActionChemist&Druggist85.1(31October1914): 33:LaterGlycerine,usedforflavouringdrugsandexplosiveswasbannedfromusefrom February1917bytheMinistryofMunitions(untilJanuary1919)soithadtobereplacedin pillsbyglucoseortreacle.W.J.Reader,(1970):2501. 89 T.E.Lescher,BritishPharmaceuticalCongress:PharmacyToday its ResponsibilitiesChemist&Druggist127.1(31July 1937):1189. 90 TheManufactureofPhenacetinChemist&Druggist85.2(12September1914): 38TradeMarksTheWarandtheShortageofDrugsChemist&Druggist85.2(19 September1914):512. 91 AProclamationRelatingtoTradingWiththeEnemyChemist&Druggist85.1(15 August1914):34TheWarandtheDrugTradePharmaceuticalJournal 93(8August 1914):219BuySpeculativePharmaceuticalJournal 93(15August1914):255Prices ofDrugsandMedicinesPharmaceuticalJournal 93(15August1914):2467,291War PricesChemist&Druggist85.1(1August1914):48. 92 ExportationofMedicinesChemist&Druggist85.2(19September1914):33. 93 L.F.Haber,(1971):188191.
154
155
94 salestothearmedforces. Furtherlongertermpromiseswerelessforthcoming.Early
BritisheffortsatreplacingGermandrugsweredescribedbyRuncimantotheGovernment
rd on23 Novemberaspartofacombinednationaleffortonascalewhichrequiresand
95 justifiesanexceptionalmeasureofstateencouragement.
DespitevaguepromisesofGovernmentassistance,companieswereinitially reluctanttoenlargetheirownmanufacturingplants.W.J.BushwasthefirstfirminBritain tomakesalicylicacidanditsderivatives:thebeginningofanewepochinthemanufacture

96 97 offinechemicalsinthiscountry. WhenW.J.Bush wasaskedtoproduce5tonsof
salicylicacidtheystated: thatisaveryseriousconsideration,notonlyasregardssalicylicacidbut manyotherproducts,whichwecouldundoubtedlymanufactureprofitably, justaswehavebeenmanufacturingsyntheticperfumesformany 98 years. Towhatextentisafirmjustifiedinspendingcapitalonplantinthe presentcircumstances?Moneyisscarce.Noonehascouragetomakean expensivedrugonasmallscale.18monthsprewarweputdownnewplant formanufacturingat40,000p.a.Fewarethepeopleinthiscountrywho 99 arewillingtobeinterestedinfinechemicalsasactualmanufacturers. Thegovernmentagreedthattheexpensesofplantdevelopmentandadvertisingcouldbe offsetagainstroyalties,buttherewasstillreticencetoputdownplanttopreparecomplex drugsespeciallyif,asexpected,theabrogatedGermanpatentsmightnotremainworkable postwar. CharlesA.HillofBritishDrugHousessummarisedthecomplexityoftheissues facedbyBritishfirmsinpreparingsyntheticdrugswhenhewrote: Asregardssyntheticremedies,onecannotexpecttobuildupinafew months,anindustry,whichbystressofcircumstances,hasgrownupin Germanyduringtwogenerations.Thegreatdifficultyisthateachproduct hangsonothers,therawmaterialsforonesyntheticsubstancebeingtheby productinthemanufactureofanother.Notonlydoesthisdovetailingapply
94
TheManufactureofPhenacetinChemist&Druggist85.2(12September1914):
38.
95
96
Hansard(HouseofCommons),fifth,68,(23November1914),cols,75962. WarPricesChemist&Druggist85.1(1August1914):48. 97 CentenaryAlbum:aPictorialRecordofBushWorldwideDevelopment, EstablishmentsandPersonalitiesDuringOneHundredYearsofProgress18511951 (London:W.J.Bush,1951). 98 ExportationofMedicinesChemist&Druggist85.2(19September1914):33. 99 MakersandBuyersChemist&Druggist85.1(24October1914):58.
155
156
totheproductsthemselvesbuttheapparatusandplantemployedare commontomanyproducts.Itwouldobviouslynotpaytoputdown expensiveplantforthemanufactureofafewproducts,thewhole consumptionofwhichisonlyamatterperhapshundredweights,butitwould easilypayafactorywhichwouldturnoutahundredproductseachwitha 100 consumptionofsomehundredweights. Maintainingsuppliesofessentialdrugsandchemicalswastoovitaltobelefttothe uncoordinatedactionsofindividualpharmaceuticalfirms,sothecontrolofsupplieswas coordinatedunderMoulton,initiallywithintheMinistryofSupply,thenundertheMinistry
101 ofMunitions,createdbytheMunitionsofWarActof9June1915. Oneofthechief
achievementsoftheMinistrywastherationalisationofdyemanufacturingbyestablishing BritishDyesLtd.inJuly1915,withthepurchaseofanumberofdyefirmsincludingRead Holliday.Withamarketcapitalisationof 2m.themergedcompanystillrepresentedonly onefortiethofthevalueofthelargeGermanfirmsandexcludedthelargestBritishfirmof

102 Levinsteins,forwhichthelowgovernmentbidwasrefused. BritishDyesLtd.
providedthechemicalsrequiredformunitions,whileLevinsteinsconcentratedondyes, treblingtheirassetsintwoyears.LevinsteinsalsosecuredtheservicesofProf.ArthurG. GreenfromLeedsUniversity,whoperformedresearchattheCollegeofTechnologyat ManchesterUniversity,andsetupsmallresearchcoloniesattheUniversitiesofCambridge, Oxford,Sheffield,BristolandtheTechnicalcollegesofGlasgow,Finsburyand

103 Huddersfield. Gradually,furtherpoliticiansweredraftedintotheMinistryofMunitions,
includingtheCabinetmemberandfreetradesupporter,SirAlfredMond,asthefirst
104 CommissionerofWorksin1916.
4.5BritishProductionofSalvarsanMRCTestingofQuality.
100
C.A.Hill,SyntheticMedicalChemicalsBritishMedicalJournal (23January 1915):168. 101 W.J.Reader,(1970):25051,258,26870A.J.P.Taylor,(1988):3031,34. 102 MondwasLiberalMPforSwansea,andamemberoftheABCMlaterW.J. Reader,(1970)I:272,447E.Hutchison,Minerva8(1970):392411. 103 M.R.Fox,(1987):4953. 104 A.J.P.Taylor,(1988):249KeithMiddlemassandJohnBarnes,(1969):8990.
156
157
Salvarsanwasthebesttherapyforsyphilis,whichwasdescribedastheworst
105 scourgeofwarasvenerealdiseaseaffectedoneinevery5ofthetroops. Inthecaseof
Salvarsantherewasnoquestionoveritsefficacy,onlywhetherBritishfirmscouldever producethesyntheticdrugtothesamedegreeofpurityandactivityastheGerman product.WhenwarbrokeoutsuppliesofSalvarsanfromGermanysoonbecame

106 unobtainableinBritain.
SalvarsanhadbeenpatentedinGermanyon10June1909andinBritainon22 December1910.Itwasproducedaccordingtotherequirementsofthe1907Patentlawby theSwissfirmCIBAinManchesterandbytheGermanfirm,Meister,Lucius,&Brning

107 (Hoechst)atalargeplantinEllesmerePort,alongwithNovocain,alocalanaesthetic.
Thefirmstookadvantageofthe1909rulingthatonlythelatterstagesofproduction neededtobeperformedinBritain,usinglatestageintermediatesimportedfrom
108 Germany. Meister,Lucius&BrningwarnedattheendofAugust,whenthepatent
cameunderthreatthat: (Salvarsan)isextremelydifficulttoprepare.Ithastobepreparedbyvery scientificmen,insilvercrucibles.Eachdosehastobeverycarefullysterilised andverycarefullyweighedandispassedbythefirmMeister,Lucius& 109 Brningwhogiveaguaranteewitheverydosetheysendout. Mr.E.H.Scholl,theBritishbornmanagerofthepharmaceuticaldepartmentofMeister, Lucius,BrningatEllesmerePort,hadbeenbasedattheworksinGermanybeforemoving totheLondonofficein1907.HeofferedtomakealloftheSalvarsanrequiredbyBritain andgaveinformationonstockstoRobertMorantattheNationalHealthInsurance Commission.MembersoftheCommitteeonthesupplyoflaboratoryreagents,including
105
A.J.P.Taylor,(1988):121. ManufactureofSalvarsanProductsinEnglandandFranceBritishMedicalJournal (10April1915):649650W.H.Willcox,J.Webster,TheToxicologyofSalvarsan BritishMedicalJournal (1April1916):473,492493ReportoftheRoyalCommission ofVenerealDiseaseBritishMedicalJournal (30September1916):477. 107 W.J.Reader,(1970):2656 ChemicalTradeJournal 57(1916)no.1534: 329 1535:3523,358 ChemicalTradeJournal 61(1917),1589.367:ChemicalTradeJournal 65(1919)no.1676:1351. 108 M.R.Fox,(1987):50,52. 109 Chemist&Druggist(29August1914):41.
106
157
158
stafffromtheNationalHealthInsuranceCommission,weresenttoEllesmerePortto
110 evaluateproductionmethods. Theyreportedbackthatthesynthesiswouldnotbeeasy.
GermanpatentsforSalvarsanweresovagueastobeunhelpfulwithregardto
111 methodsofsynthesis. Furthermore,theGermanworkers,anticipatingwar,departedin
thesummerof1914leavingonlyM.Dnchmann,theWorksengineer,andamannamed Hummerichwhosabotagedtheplant,anddestroyedalltherecords.TheEllesmerePort plantwasputupforsale,butitwasNovember1916beforethedyemanufacturerHerbert

112 Levinsteinboughtit.
ThePresidentoftheAmericanbaseoftheFarbwerkeHoechstemphasisedthathe considereditimpossibleforeitherAmericaorBritaintosynthesiseSalvarsan: Idonotthinkthereisanypossibilityofengaginginthemanufactureof theseproductshere,eveniftherewerepatentlawstocompelthecarrying outofpatentsinthiscountryandmanufacturegoodsprotectedundersuch patents.EnglandhastriedthiswiththeresultthattheGermansestablished plantsinEngland,wherethey carriedoutjustenoughoftheprocesstocover thepatent,dependinguponGermanyforallrawmaterialsandintermediate products.TheresultisthatinspiteofitslawsEnglandislefthighanddry. OnlytodayIreceivedacablefromtheManchesterbranchoftheGerman plant,askingifwecouldsendanySalvarsantoEuropefortheBritish 113 army. HehadnoideathatBurroughsWellcomehadalreadyachievedthesynthesisofSalvarsan. Theoutbreakofthewaron4August1914changedtheimmediateresearchplansof BurroughsWellcome.Theydivertedresourcestoemergencyproductionofextratyphoid vaccines,tetanusanddiphtheriaantitoxinsandantigasgangreneseraunderAlexander
114 Glenny.Therewasanimmediateshortageoftetanusantitoxin. BurroughsWellcome
alsopreparedandstandardisedbiologicalpreparationsofdigitalis,ergot,squillsand
115 strophanthin.
110 111
NewPatentRulesChemist&Druggist85.1(29August1914):41. TheSalvarsanPatentsChemist&Druggist85.2(19September1914):51. 112 M.R.Fox,(1987):42,4952,55. 113 AmericanDruggistBritishMedicalJournal (26August1914):85.Thequote statesManchesterbutmustrefertoEllesmerePort. 114 H.J.Parish,WF:85/20:2:12. 115 Chemist&Druggist84.3(23May1914)EvansadvertSxiiEvansadvert PhysiologicalStandardisationChemist&Druggist85.1(15August1914)suppliii.
158
159
TheyalsorecognisedthatthesinglemostimportantsyntheticdrugdeniedtoBritain
116 wasSalvarsan,onwhichworkcommencedimmediately. HenryWellcomeappliedfor
thesuspensionofthreeSalvarsanpatentson17September1914,bywhichtimehis chemistsattheWCRLhadalreadysynthesisedasmallsupplyof10gramsofSalvarsan.He insistedonbeinggrantedthefulltermofthepatentsoastorecouptheexpenseoflaying

117 downplant. TheGermansweredisbelievingwhentheyheardthatBurroughsWellcome
hadappliedfortheSalvarsanpatents,complainingofunauthoriseduseandthatitwouldbe adangertothepublic.Theyrequestedroyalties,insistingthatitwasnotsoldunderits
118 tradenameofSalvarsanorreferredtoas606. Moreover,theywereveryeagerto
knowhowtheEnglishfirmwillsurmountthegreatdifficultiesinthepreparationand whetherthepatientswillhavetopayforthebusinessthoroughnesswithgrievousbodily
119 harm. TheyknewthatBurroughsWellcomehadbegunincorporatingGermanlinesas
TabloidsinAugust1896andthatthelaboratorystaffhadsynthesisedseveralalkaloidsona smallscale,buttheonly previousevidenceoftheskillsrequiredtoproduceanarsenicalon acommercialscalewaslimitedproductionofaversionofAtoxyl,brandedasKharsin,

120 producedcommerciallyfromMarch1908. Nevertheless,Pyman,Reynolds,Barrowcliff
andRemfryhadpreparedfurtheraromaticarsinicandarsonicacidsduring1908andmany
121 otherworkerswereinvolvedinsmallscalesyntheticprojects.
TheGovernmentwerekeentosecurefurthersuppliesofSalvarsan,butnoother Britishfirmswereyetabletomakeit,reflectingthefactthatothershadnotinvestedin syntheticchemistryasBurroughsWellcomehad.Duringthehearingsforthenext applicationinOctober,thecommentwasmadebytheGermanrepresentativethat:if incompetentmenweretomakethedrug,thechiefindustrytobenefitwouldbethatof
116
A.Duckworth,RiseofthePharmaceuticalIndustryChemist&Druggist172 Centenarynumber(10November1959):127139Diphtheriaantitoxinincreasedfrom240 mUnitsin1910to480mUin1915and640mUin1920,WF:84//7:1213. 117 TheSalvarsanPatentsChemist&Druggist85.2(19September1914):51. 118 ibid. 119 Quotedfrom Chemist&Druggist85.2(14November1914):49. 120 MrHogg,HistoryoftheWorksvol.III,WF:S/G/145. 121 H.King,FrankLeePymanBiographicalMemoirsofFellowsoftheRoyalSociety 4(1944):684.
159
160
122 gravedigging,suchwastheconcernoverimpuritiesandsideeffects. AfurtherBritish
licensefortheproductionofSalvarsanwasgrantedtotheSocietAnonymedes EtablissementsPoulencFrresofParis,thelargestFrenchfirm,on11November1914,on theconditionthattheirproductwassoldthroughMayandBakerinEnglandunderthe

123 namesofArsenobenzolBillonandNovarsenobenzolBillon. TheFrenchpatentlaw
specificallyexcludedprotectionofmedicinesandasaresultworkersatthePasteur
124 Institutehadalreadypreparedthesyntheticarsenical,Atoxylin1907. Thisexperience
helpedPoulenctoproduceSalvarsan. AresearchteamwasestablishedatBurroughsWellcomespecificallytomanufacture
125 Salvarsancommercially. Thefirstfullbatchof46gramswasproducedon23October
126 1914,thoughitwaspoorlysoluble. By7November1914acontinuousproduction
processwasinplace.PymanandhisteamattheExperimentallaboratoryoftheWCRL testedearlysamplesforsolubilityandtoxicity,while2vialsofthefirstbatchwere deliveredtotheHeadOfficeinJanuary1915andsenttoWilliamHenryWillcoxFRCP, whowasLt.ColonelintheRoyalArmyMedicalCorps,headoftheoutpatientclinicatSt.

127 Marys,andSeniorScientificAnalysttotheHomeOffice. DrJowettreceivedasmall
sampleforfurthertestsand6vialsweresenttoadoctorforac.(clinical)trial.Overthe
122
GermanPatentsandTradeMarksPharmaceuticalJournal 93(24October1914):
601.
123
May&BakercollaboratedwithPoulencprewarconcerningthepricingofiodides, bismuth,mercurialsandquinine,GermanPatentsandTradeMarksSalvarsan PharmaceuticalJournal 93(14November1914):675.May&BakeralsosoldEpsomsalts, bathsalts,sodiumsulphateandseveralGermanimports.BritishMedicalJournal (13 August1914)SupplF.H.Carr,FineChemicals:TheirManufactureinRelationtothe BritishChemicalIndustryChemist&Druggist88.4(29July1916):7789C.A.Hill,T. D.Morson,TheBritishAssociation TheSyntheticChemicalIndustryChemist& Druggist88.4(9September1916):9512. 124 WalterSneader,DrugDiscovery:theEvolutionofModernMedicines (London: JohnWiley,1985):2523. 125 TheseincludedFrankPyman,RobertFargher,HubertWilliamBentleyClewer, EdwardJones,AlfredBacharach,HaroldKing,RobertReginaldBaxter,EdwardCharles SnellJones,WF:Box25.PymanandClewerworkedonneosalvarsanfromNovember 1914.WF:YLBox46WorksRecords. 126 G.E.Pearson,AChronologyoftheHistoryofBurroughsWellcome&Co.1878 1936(typescript),WF:88/24:41d:12. 127 TheToxicologyofSalvarsan:Dioxydiamidoarsenobenzol(Salvarsanor Kharsivan)British MedicalJournal (1April1916):4738.
160
161
nextyearandahalf,over130furtherbatchesweresenttoDrLeesintheanalytical
128 department.
BatchesofSalvarsanwerepreparedattheWorksunderthedirectionofFrancis Carruntiltheendof1914.However,justwhenBurroughsWellcomewasgettingtogrips withsynthesisofSalvarsanonalargescale,severalof thestaffinvolvedleftthecompany. AttheendofNovember1914Dr.PowerretiredasDirectoroftheWCRLtoreturntothe USAasDirectorofthePhytochemicallaboratoryattheGovernmentsBureauof

129 Chemistry. PowerwasawardedagoldmedalbyHenry Wellcomeforover18years
outstandingserviceasDirectoroftheWPRL.FrankPymanfromtheExperimental DepartmentwasgiventheaddedresponsibilitytotakeoverthepreparationofSalvarsan
130 andneosalvarsanfrom1December1914.
FrancisCarrdecidedtoleaveBurroughsWellcomeatthesametime.Inhisown accountCarrhadwrittentoHenryWellcomewithoutsuccessonseveraloccasionsasking foragrantof10,000toextendtheWorks,formakinggoodtheabsenceoffine

131 chemicalsthenonlyobtainableinGermany. Thefinalstimulusmayhavebeenthathe
wasupsetattheappointmentofPymanasthereplacementforPower.CarrcontactedJesse Bootwhowaspreparedtoofferwhateverheneededtoestablishasyntheticdrugcapacity atBootsPureDrugCompany.CarrwasappointedasDirectorofBootsanalytical departmentandChiefChemistandhetookasignificantnumberofkeystafffrom BurroughsWellcomewithhim.IwillreturnshortlytoexaminehisworkatBoots,and detailsofthestaffthatmovedwithhim,andtheimplicationsforBurroughsWellcome. HavingresolvedthemeansofproducingSalvarsan,JowettandPymanturnedtheir
128
WF:90/31KharsivanQArecordbook(23October1914to17November1915), AccessionBox160. 129 StaffatWCRL,WF:Box25EvansChemist&Druggist88.4(29July1916): 775. 130 PersonalitiesFrederickB.PowerRetirementChemist&Druggist85.2(7 November1914):15WF:Box25Powermaintainedcontactwithhisformercolleagues, Dale,HenryandTutinaslateas1925e.g.DaletoPower,(25June1924).HenrytoPower, (27January1925)FrankTutin(UniversityofBristol)toPower(7July1925),WF:88/94: 49. 131 ConversationswithF.H.CarrbyA.E.Guenther,B.CARRFH6,ImperialCollege.
161
162
132 attentiontoneosalvarsanfrom1November1914to7January1915. Someofthe 133 batchesofSalvarsanmadeinDecemberwerekeptforproductionofneosalvarsan.
WithPowerdepartingandthelossofCarr,BurroughsWellcomehadtoredeploy stafftofillthegaps.JohnAugustusGoodson,whohadreceivedhischemicaltrainingat FinsburyTechnicalCollegeunderRaphaelMeldola,hadworkedattheWellcomeBureauin Khartoumsince1906.HetransferredtotheWCRLinDecember1914tocontinue productionofSalvarsanaswellasbenzylchloride,andthecinchonaderivative,

134 hydroquinone. Anewchemicalbuildingwascompletedin December1914toextendthe 135 drugproductionfacilities. ThechemistsattheWCRLwereorganisedintoteamsto
136 preparereplacementsofGermandrugs. Oftheteamremaining,onlyafewwere
specificallynamedasinvolvedinSalvarsanproduction.TheseincludedRobertFargher D.Sc.andRobertR.Baxter,bothofwhomhadtrainedinManchesterunderW.H.
137 Perkin. HubertWilliamBentleyClewer(atBurroughsWellcome191418)andEdward
C.S.Jones(191318)wereinvolvedinneosalvarsananalysesbetweenNovember1914and
138 January1915.
AteamofoperativeshadsupportedCarrattheWorksanditseemsthatthisteam wasunaffectedbyhismove.Jowett,whohadoriginallybeenlinemanageroverCarrwas giventhetaskofoverseeingtheWorksinadditiontohisotherdutiesandherepresented thefirmindetaileddiscussionswiththeBoardofTradeoverthequalityofSalvarsan preparations,thoughitwasultimatelytheresponsibilityofGeorgePearsonasGeneral Manager.

132 133
WorksHistory,StaffRecords,WF:YL46. WF:RecordsofKharsivan thiswasuncataloguedatthetimeofmyresearch. Recordofbatches1132. 134 WorksHistory,StaffRecords,WF:YL46. 135 ThisalsoproducedsalicylicacidfromJanuary1915,sodiumsalicylatefromMarch 1916,phenacetinfromMayandAspirinfromSeptember1916:G.E.Pearson,(1936), typescript,WF:88/24:41d:12. 136 TheLaboratorybooksof41chemistsdetailtheextentofchemicalsyntheticwork undertaken:WF:85/9bundles58Accessionbox5. 137 StaffatWCRL,WF:Box25. 138 HubertCleweralsoworkedondigitalis,chaulmoograoil,emetineandpyramidone andJonesalsoproduceddigitalisandsalicylicacid.Fargherproducedalkaloids,pilosine derivatives,hydroquinone,benzylchloride,lysidineandsalol,WorksHistory,Staff Records,WF:YLBox46.
162
163
AlthoughBurroughsWellcomeachievedthemanufactureofSalvarsan,thequestion remainedastowhethertheyhadavoidedthenoxiousimpuritiesandhadsecuredaproduct withsimilarefficacytoGermanpreparations.ThesyntheticprocedureforSalvarsanwas complexanditwasnoteasy topreventtheformationofintenselypoisonousbyproducts. EhrlichinBerlinhadroutinelytestedtheactivity,strengthandsafetyinanimalsofeach

139 batchofSalvarsanmadebyHoechst. BurroughsWellcomerealisedthattheywouldalso
havetoperform suchtestsbeforehumanuse.However,manyoftheirexpertstaffhad movedtothenewlyestablishedMRCandtheyhadtoturntothemtoperform

140 physiologicaltesting.
4.6TheMRCandtheFirstSalvarsanCommittee. TheMRChadbeenfoundedin1913asaresultofresearchfundingarisingfromthe 1911NationalInsuranceAct.TheMRCExecutiveCommitteeappointedin1914,included sixprofessionalandthreelaymembers:itwaschairedbyLordMoultonofBathand includedChristopherAddisonM.P.,formerlyProfessorofAnatomyandDeanofSt.

141 Bartholomews, whowastobecomethefirstMinisterofHealthin1919WaldorfAstor,
whochairedtheDepartmentalCommitteeonTuberculosisfrom1913T.CliffordAllbutt, RegiusProfessorofPhysicattheUniversityofCambridgetheLeicestersurgeonMr CharlesJohnBondWilliamBullochF.R.S,ProfessorofBacteriologyattheUniversityof

142 London andattheLondonHospital MatthewHay,ProfessorofForensicMedicineand
PublicHealthattheUniversityofAberdeenFrederickGowlandHopkins,founderof
139
W.S.Feldberg,HenryHallettDale18751968BiographicalMemoirsofFellows oftheRoyalSociety 16(1970):106. 140 BritishMadeSalvarsanPharmaceuticalJournal 94(17April1915):536. 141 Dr.ChristopherAddisonwasM.P.forHoxtonandProfessorofAnatomyat UniversityCollegeandSheffield.IntheWarhewasMinisterforReconstructionfrom1917 andPresidentoftheLocalGovernmentBoard.Hewentontoarrangethecharterforthe MRCandwasthefirstMinisterofHealth,establishingaCommitteewithLordAthloneon theprovisionofpostgraduatemedicaleducation.JoanAustokerandLindaBryder(eds.), (1989):24,222. 142 SirJohnLedingham,WilliamBullochObituaryNoticesofFellowsoftheRoyal Society 3(1941)81952.
163
164
143 BiochemistryattheUniversityofCambridge andthebacteriologistSirWilliamBoog
Leishman.WalterMorleyFletcherfromCambridgewasappointedasSecretary.144 AtFrederickHopkinsssuggestion,HenryDalewasproposedforthepostof DirectoroftheDepartmentofBiochemistryandPhysiologyatthenewMRCcentral laboratories,theNationalInstituteofMedicalResearch(NIMR)whereherejoinedGeorge

145 Barger. AlthoughDalehadenjoyedhistimeatBurroughsWellcome,hewasdispleased
withWellcomesreorganisationin1913,placingAndrewBalfourasDirectorofthe WellcomeScientificBureauwithoverallresponsibilityforallofthelaboratories.Dalefelt
146 thatasaresultthelaboratorieswouldbelessindependent.
NosoonerwastheMRCestablishedon1JulythanthewarbrokeoutinAugust
147 withwhatatthetimeonlyseemedafewdaysnotice. BargerandDalereturnedrapidly
fromavisittoGermany,andsoonafterBargermovedtoEdinburgh.AlmrothWright
148 decidednottomovefromSt.MarystotheNIMR. OfhisstaffonlyLeonard 149 150 151 Colebrook movedtotheNIMR,underCaptainS.R.Douglas. W.E.Gye,
previouslyattheImperialCancerResearchFund,wasadded.
143
SirH.Dale,FrederickGowlandHopkinsObituaryNoticesofFellowsoftheRoyal Society 6(1948)115145. 144 L.BryderinJ.AustokerandL.Bryder(eds.),(1989):56. 145 BargerwasProfessorofChemistryatGoldsmithsCollege,NewCrossfrom1909 andatRoyalHollowayCollegefrom1913.HeservedtheCounciloftheChemicalSociety 19137.In1919hetooktheChairofChemistryinRelationtoMedicineatEdinburgh whereheremaineduntilayearbeforehisdeathwhenhebecameRegiusProfessorof ChemistryattheUniversityofGlasgow.SirH.H.Dale,G.Barger,Biographical MemoirsofFellowsoftheRoyalSociety (1940)3:6385. 146 LieutenantColonelAndrewBalfourhadbeenfirstDirectoroftheTropical laboratoriesinKhartoumfrom1902.DalequestionedPearsononhisplans:DaleArchives, RoyalSociety,HD143.6:67. 147 DaleArchives,RoyalSociety,HD47.13.144. 148 CommentsonalecturebySirC.Harrington,23November1963. DaleArchives,RoyalSociety,HD47.12.12. 149 C.L.Oakley,LeonardColebrookBiographicalMemoirsofFellowsoftheRoyal Society 17(1971)17:91138. 150 P.Laidlaw,StewartRankenDouglasBiographicalMemoirsofFellowsofthe RoyalSociety (1935)1:56976. 151 C.H.Andrewes,WilliamEwartGyeBiographicalMemoirsofFellowsoftheRoyal Society 8(1953):41930J.AustokerandL.BryderinJ.AustokerandL.Bryder(eds.), (1989):42.
164
165
ThemovementofBurroughsWellcomestafftotheMRCdecimatedthefirms capacitytoperformstandardisationwork,butleftthemwellplacedtocollaboratewiththe
152 MRC. Fortunately,thepreviousworkattheWellcomelaboratoriesattractedfurther
highcalibreresearchers. JoshuaHaroldBurnjoinedBurroughsWellcomefromCambridge
153 inJanuary1914 andcontinuedJowettandPymansresearchonnicotineand 154 pilocarpine. However,withtheoutbreakofwar,Burnalsolefttoregisterasamedical 155 student,andtoserveinFrance.
Fromtheirfoundation,theMRCplannedacentralinstitutefortestingdrugs,along thelinesofthePasteurInstituteinParis,foundedin1888,theInstituteRobertKoch foundedinBerlinin1891,andRockefellerInstitutefoundedin1901inNewYork.One possibilityconsideredandrejectedwasattheListerInstituteforPreventativeMedicine, foundedin1891.WiththeoutbreakoftheWar,therequirementfortestingbiologicaland syntheticdrugstookonanewurgency,butasMountVernonHospital,theplannedsitefor theNIMRwasusedasamilitaryhospital,Dalehadtotakeuptemporaryresidenceatthe ListerInstitute.DaletookwithhimArthurJ.EwinsandPatrickP.Laidlawandevenhis

156 administratorfromBurroughsWellcome.
In1909thePharmacopoeiaCommitteehadsuggestedthatthereshouldbeapublic institutionforthepharmacologicalstandardisationofpotentdrugsandserums.Whereas thePharmacopoeiawasbaseduponsimpleteststhatanalystscouldperform,thenewer drugscouldnotbeassayedbychemicalmeans.TheMRCgaveanearlyindicationthatthey wantedtobecomeinvolvedinbiologicaltestingofdrugswithAproposalthatthe CommitteeshouldundertaketheexaminationofSalvarsanmanufacturedinEnglandunder
152
Afurtherresearcher,HaroldKingjoinedtheMRCfromBurroughsWellcomein 1919 SirCharlesHarrington,H.KingBiographicalMemoirsofFellowsoftheRoyal Society 1956)2:15771. 153 BurnstudiedphysiologyatEmanuelCollege,Cambridgein1909underF.Gowland HopkinsandjoinedtheWPRLon1January1914:E.Buelbring,J.M.Walker,J.H. BurnBiographicalMemoirsofFellowsoftheRoyalSociety (1981):4589. 154 J.H.Burn,H.H.Dale,TheActionofCertainQuaternaryAmmoniumBases, JournalofPharmacology 6(1915):305. 155 E.Blbring,J.M.Walker,J.H.Burn(1981):4589. 156 Laidlaw'spostattheNationalInstituteofMedicalResearchcamewithasalaryof 750perannum:MRCAnnualReports191420MRCCommitteeMinutesII,(16 December1921):167.
165
166
licensefromtheBoardofTrade,andthisrequestwasreferredtoasubcommittee includingFletcherMoulton,FrederickGowlandHopkins,andWilliamBullochasaresult
157 theSalvarsancommitteemetforthefirsttimeon29October1914. Theproposalfor
MRCinvolvementwasacceptedon10December1914withtheconditionthattheMRC nameappearedonanyvialstestedbythem.ThissuitedBurroughsWellcomeasitcouldbe
158 exploitedintheiradvertisements. PreWartherehadbeennoformalisedtestingof
drugsinBritain.TheMRCstaffmaderesponsibleforthetestingofSalvarsanandthe analogousgroupofarsenicalswereHenryDale,whowrote:withEwinsIwas immediatelyplungedintoinvestigationsrequiredtoenableaBritishmanufacturerto

159 producetheimportantdrug,whichhadformerlybeensuppliedentirelyfromGermany.
EwinsconcentrateduponexaminingarsenicimpuritiesinsamplesofSalvarsanandother
160 organicarsenicals.
FromtheoutsetDaledoubtedthevalidityofthesimpletestsperformedbyEhrlichon Salvarsan,inwhichastandardamountofdrugwasinjectedinto10miceandaslongas8 ormoresurvivedthebatchwaspassed.Dalefoundthatvariableresultswereachievedeven byinjectingthesamebatchintomultiplegroupsofrats,sohemodifiedtheassaystotake moreaccountofbiologicalvariationandappliedthestatisticaltechniquesthatGlennyhad establishedatBurroughsWellcomein191012duringworkonthevariableresponseof guineapigstodiphtheriaantitoxin.Healsomeasuredtherapeuticeffects,especiallyforthe lesstoxicneosalvarsan,forwhichclinicalrelapseshadbeennoted,despitepassingEhrlichs tests.DalelearnedhowtoproduceaninfectioninmicethatwassensitivetoSalvarsanso

161 thatcurativeactioncouldbedetermined.
OccasionalbatchesweresubstandardandthisfurtherestablishedthecaseforMRC
162 controlofthequalityofthesophisticatedsyntheticandbiologicaldrugs. ByApril1915
theMRCwereabletostate:atanearlydatetheexperimentalworkwhichhasbeendone
157 158
MRCMinutesI,(29October1914):4. MRCMinutesI,(10December1914). 159 DaleArchives,93HD143.11:3. 160 A.J.Ewins,TheEstimationofArsenicinOrganicCompoundsJ.Chemical Society 109(1916):1355. 161 W.S.Feldberg,HenryHallettDaleBiographicalMemoirsofFellowsoftheRoyal Society 16(1970):1067. 162 DaleArchives93HD,NIMR47.13.144.
166
167
undertheirdirectionshowedthattheproblemofthesuccessfulmanufactureofSalvarsan
163 compoundsinEnglandandFrancehadbeensolved. TheMay&Bakerversionof 164 Salvarsanpassedeverytime,butoccasionallytheBurroughsWellcomeversionfailed.
TheMRCwerekeentogainabetterunderstandingoffactorsinfluencingthepotencyand safetyofthenewBritishsyntheticdrugsandwhenbatchesofBurroughsWellcomes
165 Kharsivanwerereleased,thedrugwastestedinalargenumberofpatients. Willcoxat
theHomeOfficeemphasisedthatKharsivanwaspracticallyidenticalinitsphysiological andtherapeuticeffectswithSalvarsan(theGermandrug).However,heacknowledged thatsubstitutionsthatarejustasgoodastheoriginalarticlesarelookeduponwith disfavourinthiscountrybecauseweregardGermanchemistsassuperiorinabilitytoour

166 own. Inotherwords,furtherworkwasneededtoconvinceBritishdoctorsthatthe
BritishsyntheticdrugswereasgoodastheGermanversions.Followingtheirexperience withSalvarsan,theMRCextendedtheirlaboratorytestingtoincludevariousseraand
167 antitoxins,whichhadpreviouslybeenimported. However,thequestionsthatcontinued
tobeaskedrelatedtotheclinicalefficacyandsafetyofSalvarsan,andIwillreturntothis asthereasonbehindtheestablishmentofasecondSalvarsanCommittee.Inthemeantime thereweresignificantchangesinthestructureoftheBritishPharmaceuticalIndustry.
4.7TechnologyTransferfromBurroughsWellcometoBootsandMay&Baker. Aswehaveseen,attheoutbreakoftheWaronlyBurroughsWellcomehad significantexperienceofcomplexchemicalsynthesisandeventhenprimarilyonasmall scale.BurroughsWellcomehadexperiencedchemistssuchasPower,BargerandPymanto workoutthesyntheticroutes,buttheyalsohadgainedexperienceinscalingupprocesses throughCarrandJowett.OthercommercialfirmsinBritainwererelativelysmallconcerns unableindividuallytobearthecostsofhiringalargespecialisedanddedicatedresearchand
163 164
BritishMadeSalvarsanPharmaceuticalJournal 94(17April1915):536. DaleArchives,93HD143.11. 165 H.C.Lucey,TheTherapeuticandReactionEffectsofKharsivan.ARecordof600 InjectionsBritishMedicalJournal (29April1916):6146. 166 W.H.Willcox,J.Webster,ToxicologyofSalvarsanBritishMedicalJournal (1 April1916):4738. 167 MRCAnnualReport,191415,(London:HMSO,1916):4244.
167
168
168 drugdevelopmentstaff. Eventhelargerfirmshaddifficultyinattractingthefew
availablechemistswithexperienceoflargescaledrugproduction.Chemistryinindustry didnotofferarewardingcareeraspaywasgenerallyinadequateandtheemployerlooked
169 toooftenonlyforimmediateprofit. Thus,itwasasignificantlossevenwhen
supportingstaffsuchasMr.H.Browning,whohad3yearsexperienceattheWCRL,left inSeptember1914.Hiringexperiencedchemistsfromotherindustrieswasnotan attractiveoption,astheydidnothavetheexperienceoftablettingorworkingundersterile conditions. TheretailtradeofBootsPureDrugCo.hadexpandedrapidlyfrom33shopsin 1893to250bytheturnofthecenturyandassistedbythepassingofthePharmacyActin 1908andtheNationalInsuranceActof1911,ithad560shopsin1913,withtakingsof 2.5mperannum.However,theyexperiencedacontractionofcertainareasoftheir businessattheoutbreakofthewar.JesseBootwasaveryrichandinfluentialman,friendly

170 withbothLloydGeorgeandChristopherAddison,andadonortoLiberalPartyfunds.
BootrealisedthatthevoidleftbytheexclusionofGermandrugs,especiallysyntheticsand theincreasedneedsofWargavethepotentialforlargeprofitstobemade. However,inordertoachievethishehadtofindanexperiencedmanufacturing chemist.FrancisCarrwaspersuadedtojoinBootsandherecruitedfiveotherBurroughs Wellcomestaff,includinghiscloseassistantMarmadukeBarrowcliff,aplantengineeranda

171 foreman. FrancisCarrhadfirstmetJesseBootwhenFrankPymansdaughtermarried
hissonJohnBoot.Asrecentlyas1909Carrhadbeenonasalaryofonly250p.a.and hadtwodaughtersundergoingeducation,sohehadtosupplementhissalarybywithfees asanexternalexaminerfortheUniversityofLondon.BootofferedCarrnotonlyan increasedsalary,butalsoafreehandinthelaboratoryandproductiondesign,whereasat BurroughsWellcome,CarrhadbeenunderJowettandalsoPower,andfromNovember 1914wastohavebeenunderPyman.
168 169
SyntheticMedicinalChemicalsBritishMedicalJournal (23January1915):168. W.Tilden,BritishMedicalJournal (23January1915):168. 170 Chemistry&Industry (23February1963):303. 171 S.Chapman,(1974):9698S.A.B.Kipping,TheResearchDepartmentofBoots PureDrugCo.Ltd. Chemistry&Industry (23February1961):30210W.H.Sims, Notes,8November1963Bootslibrary.CorrespondencefromBootslibrarian.
168
169
AtthestartofthewarBootshadbeenheavilyadvertisingwarrelatedlow technologyproductssuchasantiflyspray,verminpowdersandcompressedmedicinals
172 forthemenatthefront. CarrwasagoodfriendofE.F.Harrisonwhohadperformed
researchwithhimunderDunstan,beforetakingontheanalystroleatBurroughsWellcome andthenactingasaconsultantandanalysingpatentmedicinesfortheBMA.Harrisonhad joinedthearmyasaprivate,butwaspromotedtocorporalwhentheRAMCrequiredan analystatMillbanktoquantifythethreatsofgaswarfareandHarrisonbecame SuperintendentoftheAntigasDepartment,thatwasasectionoftheChemicaland WarfareDepartment.Histeamtestedaseriesofwiderangeofgasesincludingchlorine, cyanogenbromide,phosgene,andmustardgasandthemeansofneutralisingthem.Boot

173 puthisstaffbehinddevelopinggasmaskscontainingabsorbentmaterials. Atleast900
girlswereemployedinmanufacturingboxrespirators,packedwithabsorbinggranulesand atonestagetheyproduced90,000aweek.ChapmanwrotethatElatedwiththesuccess insecuringCarr,BoottookthefrontpageoftheDailyMailon15Octoberandboasted:

174 Germanscienceknowsnosecretsfrommyanalysts. Whetherheknewbythenthathe
hadsecuredCarrisnotclear,buttherecordsatBurroughsWellcomeshowthatCarrdid
175 notdepartuntil10November1914. Attheendof1914Bootsextendedtheir
laboratoriesandbuiltanewfinechemicalmanufacturingplant,whichopenedunderCarrs guidancein1915andproducedaspirin,disinfectants,saccharinandiodinetinctures.Boot proclaimedwehavemademoreprogressthananyotherfirm....notpreviously manufacturinginthiscountry.

176
Inordertofuelthisexpansion,CarrsoughtoutBurroughsWellcomestaff members thatwerefamiliarwithallofhisformerfirmskeysecretprocesses.Carrhimselfknewthe constitutionofthefirmsbases,thesolutionsusedintheTabloiddepartment,andthe
172 173
C.Weir,JesseBootofNottingham (Nottingham:Boots,1994):5559. F.H.Carr,HarrisonMemorialLecture,PharmaceuticalJournal 103(26July 1919):9399. 174 S.D.Chapman,(1974):96. 175 StaffRecords,WFS/G/145. 176 S.D.Chapman:(1974):96.
169
170
177 processesusedhehadpracticalexperienceinmanufacturingofalloftheirmainlines.
ManystaffmemberswereloyalsupportersofCarr,whoappearstohavebeenpopular.W. F.ThompsonhadbeenatBurroughsWellcomefor17yearsasalaboratoryassistantto CarrandhadalsofollowedhimfromthePharmaceuticalSocietyandtheImperialInstitute,

178 wheretheyhadcollaboratedforafurther3years. S.C.Fidler,anengineerwhojoined
BootsinFebruaryof1915,hadrepairedandbuiltnewcompressingmachines,punchesand eyesatBurroughsWellcomefrom1907andwasfamiliarwiththeorganisationofthe compressingroom,andwhichmachinestouseforthevariousdrugs:H.E.Wilson,who becameHeadoftheBootsChemicalDepartmentinMay1915hadbeenatBurroughs Wellcomesince1903producingquininesalts,hexamines,cinchona,phenacetinandsome

179 basicsalts. F.C.ChapmanwasawarehousemaninthedrugstockroomofBurroughs
Wellcomefrom1897andhesawalltheformulaeforcompresseddrugsandknewthe numbercodesofthebasesandsolutions.Hepreviouslyworkedinthegranulatingsection beforemovingtoBootsinJuly1915.W.H.Porterwasanexperiencedteatester, responsibleforcompressionofteaintotabletsusinguniquerotarymachinery.Hehadbeen atBurroughsWellcomesince1896untilhemovedtoBootsinOctober1915.Adocument inthearchivesatBurroughsWellcomeentitledFormulaeandsecretprocessesdiscusses theimpactthatthelossofCarrandhishandpickedcolleagueshadonBurroughs

180 Wellcome.
TheacquisitionofChapmanandPorter: Enablesacompetingfirminwhoseservicestheyaretoobtainalmost completeinformationastothefirmssecretprocessesandspecially knowledgeinthemanufactureofcompresseddrugs.Thecombinationof CarrwithChapmanenablesthemtoproducegranulesaccordingto BurroughsWellcome&Company formulaeandtheacquisitionofFidler enablesthemtousesimilarmachinesandpunchesandeyeswhilstthe additionofPorterenablesthemtoobtainteaofasimilarcharactertothat usedbyBurroughsWellcome&Companyandtocompressitonamachine,
177
H.A.D.JowettMemoonSecretProcesses,BAS/G/49,(13January1916),File 85ReportfromVariousSourcesre.'B'affairBootsHeadhuntingBurroughs WellcomeStaff,1915,WFBox10. 178 WorksRecords,WF:Box25. 179 Re.SecretProcesses,Mr.CarrmightdenythisknowledgebutH.E.Wilson couldnot,havingactuallymadethesolutions.WF:D3:DWBox15,BAS/G/49.Hehad chargeoftheformulaebooks,(12January1916).WFBox10WF:D3. 180 Re:FormulaeandSecretprocesses,WF:YLBox25,WorksRecords.
170
171
thedesignofwhichisentirelyduetoBurroughsWellcomeand 181 Company. TheinternalenquiryheldbyBurroughsconcludedthat: TheacquisitionofCarr,WilsonandThompsonbyafirmwould enablethemtoobtainandworkthemoreimportantsecretprocesses workedoutbyBurroughsWellcome&Co.Mr.Carr,havingthe generalknowledgeofalltheprocesses,Wilsonbeingacquaintedwith themanufactureofquininesaltsandglycerophosphates,chloroform andpossiblyorganics,whileThompsonwouldsupplythedetailed 182 practicalknowledgeforthemanufactureofalkaloids. BythistimeBurroughsWellcomehadproducedseveralalkaloidsandsynthetic
183 drugs. Thompsonhadproducedsolanaceousalkaloids,eserine,emetine,pilocarpine, 184 hydrastine,homatropine,cocaine,andergotoxine. Bootswouldnowbeabletomakeall
ofthese.BootsthemselveshadbeenhithardbythelossofstafftotheWar,butthe acquisitionsfromBurroughsWellcomeallowedthemtorestructuretheirbusinessalongthe BurroughsWellcomemanufacturingmodel,thoughnotasyetestablishingtheirown

185 laboratoryresearchfacilities. TheDirectorofBootsandmanagerofthechemical
departmentatthetime,Mr.H.B.Holthouse,recruitedfurtherchemistsin1916,including
186 Belgianrefugees. HealsorecruitedW.H.Simswhogaveavividaccountofhisearly
timeatthecompany.SimsworkedinitiallyasanassistanttoThompson,preparing
187 alkaloidsandglucosidesofDigitalis.
IttooktimeforBootstoestablishtheirnewmanufacturingcapacitybutthey producedtheantisepticChloramineTin1916andexpandedtheirfactoryfurtherduring
181 182
ReportsfromVariousSourcesre.'B'Affair1915,WF:Box10. ReportsfromVariousSourcesre.'B'Affair1915,WF:Box10. 183 Fargherproducedalkaloids,pilosinederivatives,hydroquinone,benzylchloride, lysidineandsalol.EdwardJonesproduceddigitalisandsalicylicacid.HubertWilliam BentleyClewer,(191418)workedondigitalis,chaulmoogra,emetineandpyramidone. PymanandClewerworkedonneosalvarsanfromNovember1914,WF:YLBox25,Works Records. 184 F.L.Pyman,WarWorkattheWCRL,WF:Box25DW. 185 C.Weir,(1994):56. 186 SimsworkedwithC.A.Hudson,F.R.Parkin,andF.A.H.Stowellprepared hyoscineandhomatropine.W.H.Sims,Notes,8November1963,Correspondencefrom J.M.Leverton,LibrarianatBootsDrugCompanyS.D.Chapman,(1974):96C.C. Weir,(1994):59. 187 W.H.Sims,Notes,(8November1963).
171
172
1917whentheyspent200,000onnewbuildingsandlaboratoriesandapparatus,built undergovernmentlicensetoproduceaspirin,phenacetinandatropine,claimingthat phenacetinproductionwouldsoonbelargeenoughtosupplyalmostentirelythenormal

188 Britishdemand. Thefirstofthreelargeextractorswasinstalledinthechemical
departmenttoextractatropinethewartimeproductionreached400ouncesperweek.In ordertomeetthesedemandsitwascommonforstafftowork12hourseachdayandat
189 weekends. InpreparingsyntheticAdalin(diethylbromoacetylurea)andFlavineas
safewoundantiseptics,CarrcollaboratedwithProf.F.S.KippingatUniversityCollege,
190 Nottingham,whosesonwasachemistatBoots. Carrinitiallytriedtomakethe
antisepticsbymethodsnotcoveredbythepatents,butafterfailingtodosoheaskedtobe allowedtoworkthepatents.Heinitiallymadeafewpoundsandfoundthemchemically andphysiologicallythesameastheGermanversionshewaseventuallyabletomake4050

191 lbs.perweek. Oncesuccessful,BootappliedtotheBoardofTradeforpermissionto 192 adoptthepatentedtechniquestoproducefurthernewdrugs. Thus,acriflavinecream
(Burnol)wasproducedaswellaslargequantitiesofsyntheticaspirin,phenacetin,atropine, saccharinandvariousalkaloids,chloroform,andLysol.BootsproducedLewisite, formaldehydeandfinelydividedbismuth andbecamethemostsignificantBritish

193 pharmaceuticalmanufacturerafterBurroughsWellcome.
AsBootswereencouragedbyearlywartimesuccess,Carrattractedfurther BurroughsWellcomestaffincludinganexpertintabletmanufacture,anauthorityon
188
TheReportoftheRoyalCommissiononVenerealDiseasesBritishMedicalJournal (11March1916):3867. 189 W.H.Sims,Notes,(8November1963):2:Bootslibrary. 190 S.A.B.Kipping,TheResearchDepartmentofBootsPureDrugCo.Ltd. Chemistry&Industry (23February1961):30210C.H.Browning,R.Gulbransen,E.L. Kennaway,L.H.D.Thornton,FlavineandBrilliantGreen,PowerfulAntisepticswith LowToxicityfortheTissuestheirUseintheTreatmentofInfectedWoundsBritish MedicalJournal (20January1917):7378. 191 F.H.Carr,BritishChemicalIndustryChemist&Druggist 88.4(29July1916): 799800. 192 TheManufactureofAdalinChemist&Druggist89.1(27January1917):106. 193 H.D.Dakin,J.B.Cohen,J.Kenyon,StudiesinAntisepticsII:onChloramineits Preparation,PropertiesandUseBritishMedicalJournal (29January1916):1602:H.D. Dakin,E.K.Dunham,AHandbookonAntiseptics(NewYork:MacMillan,1918):46
172
173
pharmaceuticsandfivemorechemistsfromLeedsUniversityincludingA.NutterSmith (tablets),B.A.Bull(pharmaceuticals)andDr.MarshallwhohadtrainedunderProfessor
194 ArthurG.Green. AttheendofthewarFrancisCarrwasawardedtheC.B.E.forhis 195 teamswartimecontributions.
BurroughsWellcomehadtriedtoprotectthemselvesfromfurtherstaffpoachingby ensuringthatindividualspreparingTabloidsreceivedtheingredientsasAandBandwere notfamiliarwiththedrugconstitutions. ThecontractofFredericPickworth,whoworked brieflyasananalystatDartfordin1913beforegoingtomedicalschool,exemplifiesthe caretakenbyBurroughsWellcomeitforcedhimtokeepasasolemnsecretallformulae andprocesses,structureandworkingofmachinery.Hehadtopromisenottosellor copymachinery,andondeparturehadtosurrenderallbooksanddocuments,anddrawings

196 ofapparatusandagreenottoimitateproducts. Theyhadnotenvisagedthewholesale
plunderofstaffledby theformerWorksmanager.FrankTutinmadesalicylicacid,but wenttotheMRCinOctober1915.AlfredLouisBacharach,whohadjoinedtheWCRLin February1916andpreparedantisepticcresols,localanaestheticsandsalicylicacid,was persuadedtojoin Glaxoin1920. HaroldKing,whofilledthegapvacatedbyEwins,hadgraduatedwithfirstclass honoursinchemistryfromUniversityCollege,BangorandjoinedtheWPRLin1912, collaboratingwithDaleandEwinsonalkaloidsandwithBarger,whohadjustleftfor

197 GoldsmithsCollege. KingmovedtotheExperimentallaboratoryoftheWCRLat
DartfordunderPymanon30September1915andproducedsalicylicacid,andAspirinby
TheReportoftheRoyalCommissiononVenerealDiseasesBritishMedicalJournal (11 March1916):3867. 194 S.Chapman,(1974):9697. 195 CarrreceivedtheC.B.E.whileotheruniversitychemistswereawardedanM.B.E. orO.B.E.C.Weir,(1994):59. 196 F.A.Pickworth,born31August1889,B.Sc1913,qualifiedanalyst1914,died22 October1967,WF:86/68Obituary,F.A.PickworthBritishMedicalJournal (11 November1967):363Obituary,F.A.PickworthBritishMedicalJournal (2December 1967):559Obituary,F.A.PickworthBritishMedicalJournal (10February1968):387. ThequoteisfromChemists,F.A.Pickworth191117,WF:86/68
197
H.H.Dale,G.Barger,(1940)3:6385.
173
174
198 aneconomicprocess. Heproducedmethanolfromacetone,andprepared
glycerophosphatesandtheirsalts,acetylsalicylicacidanddigitalis. ThefirstcommercialbatchoftheKharsivanversionofSalvarsanproducedat TempleHillwasinJanuary1917,andtheMRCteamofFletcher,DaleandHarrisonvisited

199 thesiteinMay1917. R.L.OBrienattheWPRLwroteinFebruary1917,Iamsorry
thatIamagainwithoutanypharmacologicalassistantanditisimpossibletodoanytests
200 forseveralweeks.
May&BakeralsobenefitedfromtheexpertiseofaformerBurroughsWellcome memberofstaffwhentheybegantheirownproductionofarsenicals.May&Bakerasked thepermissionofDaletoapproachhisinvaluableEwinswhohadanexceptional promptitudeinrecognisingpossibilitiesofpracticaldevelopmentsfromnewdiscoveries

201 madeelsewhere. FollowingtheirsuccesswithSalvarsan,May&Bakerbuiltafactory
atBellLane,Wandsworth,withthehelpofPoulencofFrance,specificallyforthesynthesis ofSalvarsan.InJuly1917ArthurJ.Ewins,whohadspentfifteenyearsatBurroughs Wellcome,wasappointedaschiefchemistandDirector,responsiblefortheirnewly

202 establishedresearchlaboratories. From1917themanufacturewasunderthesupervision
ofapharmacist,CharlesGillingwhospenttimeinFrancelearningtheprocedures.As agreedwithBurroughsWellcome,batchesthatpassedwerealsogivenlabelsbearingby
203 authorityoftheMRC.
Thus,thewarmarkedaturningpointofnewcareeropportunitiesandBurroughs Wellcomescientistswerefoundtobeindemand,beingoffereduniversityposts,important positionsattheMRC,butalsokeypositionsatrivalpharmaceuticalfirmssuchasGlaxo, May&BakerandBootsPureDrugCompany.
198
C.R.Harington,H.King(1956):158.KingstayedatBurroughsWellcomeuntil hismovetoSouthAfricain1947. 199 G.E.Pearson,(1936),typescriptWF:88/24:41d:12. 200 O'BrientoTaylor,StandingOrders,(1February1917),WF:85/31:12. 201 H.H.Dale,ArthurJamesEwins(1958):88. 202 Judy Slinn,(1984):923HenryDale,ArthurJamesEwins(1958):8191.
174
175
4.8ProductionofFurtherSyntheticDrugsandAlkaloidsinBritain.
Manyexampleshavealreadybeengivenofsyntheticdrugsandpreviously unavailablealkaloidsmanufacturedbyBritishfirms.Ofthedrugswherethepatentswere abrogated,manywerealkaloids,antisepticsorbarbituratesthatwererelativelyeasyto prepareaslongasrawmaterialswereavailable.BurroughsWellcomepreparednew alkaloidscommerciallyin1914andexpandedtherangein191516.FargherandBaxter, whohadpreparedSalvarsan,werealsoaskedtopreparederivativesofphenacetinand Aspirin,arsenicals,alkaloids,resins,andlysidine,hydroquinone,benzoylchloride, hydrochloricacidandSalol.Pymandirectedproductionofneosalvarsan,emetine,digitalis, cocaextracts,alkaloidsofipecacuanha,histidine,acetylsalicylicacid,lanolin,and

204 chaulmoograoil.
Byearly1915manyBritishfirmsproducedawiderangeofnewalkaloidsand
205 206 chemicals. A.BoakeRobertsproducedtheoils,cineol,menthol,andoenanthicether.
Suppliesofether,chloroform,quininesalts,ethylchloride,andnitrousoxidewere increaseddramatically.T.H.SmithandDuncanFlockhardtproducedtheanaesthetic gases,chloroform,etherandopiumalkaloidsandmedicinalglucosides,whileJ.F.

207 MacFarlanproducedchloroformandether,surgicaldressingsandgalenicalsinScotland.
In March1915,W.J.BushofHackneyandThomasKerfootinManchesterwerethefirst
208 inBritaintoproducesalicylatesusedforrheumatism,influenzaandneuralgia. At
203
204
MRCMinuteBookI,(10&13December1914). WF:YLBox25. 205 Howard'sJ.F.McFarlan,Morson's,T.H.Smith,DuncanFlockhardtandMay& Bakerproducedemetine,digitalisandcocaine,andnewalkaloidsofipecacuanha.In1915 theyproducedsynthetichistidine,lysidine,cresols,localanaesthetics,glycerophosphates andpilocarpine:SocietyoftheChemicalIndustryChemist&Druggist86.2(6March 1915):53W.J.Reader,(1970):258,2678M.R.Fox,(1987):4849,8688Evans PhysiologicalStandardisationChemist& Druggist85.1(15August1914),Suppliii. 206 SocietyoftheChemicalIndustryChemist&Druggist86.2(6March1915):53. 207 Evansadvertin Chemist&Druggist85.2(29August1914):33WhatisaFine Chemical?Chemist&Druggist85.2(29August1914):51G.Tweedale,AttheSignof thePlough:275YearsofAllen&Hanbury'sandtheBritishPharmaceuticalIndustry1715 1990 (London:Murray,1990):78,85DuncanFlockhardtadvertsChemist&Druggist 88.4(29July1916):147. 208 ManufactureofSalicylicacidChemist&Druggist85.1(22August1914):3738 A.H.Cox,ThePatrioticPosterChemist&Druggist85.2(5September1914):1.
175
176
Howards,eventhoughonlytheseniorpartnerswerechemists,theymadeAspirinbya
209 batchprocesseasytoproduceonalargescale, intheirsplendidrangeofuptodate
210 laboratories. Howardsmadeasmuchquinineastheycouldwithavailablesuppliesof 211 bark.
Thereafter,BritishfirmswenttogreatlengthstoemphasisetheBritishoriginsof theirgoods.BritishDrugHouseswerethefirsttoofferguaranteesofconformitytodefinite specificationsofpurity,morestringentthantheFoodandDrugsActandtheBritish

212 pharmacopoeiaof1898. Theyinfluencedprescribersbyproducingaguidetothe1914 213 Britishpharmacopoeia. Afterhisappealforgovernmentsupport,CharlesHillinvested
heavilyinmanufacturingfacilitiesaroundGrahamStreetinLondon.Afurther3acreswere boughtontheoppositesideoftheRegentsCanal.Inadditiontoshortagesoffundsand buildingmaterialstherewerealsostaffshortages.BDHhad150enlistedmenandthese werereplacedby150womenandbyasmanyoldermen.AnewUStelephonesystemwas installedandanextendedautomatedpilldepartmentwith facilitiesforfinishingandcoating. Hillwrote:OurpolicyinregardtotheproductionofsocalledGermanchemicalshasbeen tomanufacturethosearticleswhichwouldotherwisebeunobtainable.Hexaminewas madeatthestartofthewarbutwasdiscontinuedwhenthereweresufficientsupplies. Manytonsofsalicylicacidandsodiumsalicylateswereproducedbutthelimitingfactorhad
214 beenplantcapacityasincreasedmanufactureisdoneattheexpenseofsomethingelse.
ArthurH.CoxadvertisedinhisPatrioticPosterthat:Wecannottakeuparmsagainst ourcountrysenemybutwecan....putupagrandfightforourcountrybyrefusingtobuy
215 Germangoods. BritishwholesalerswhohadpreviouslydistributedGermandrugssuch
209
QuotedfromAfterOneYearofWarTheSupplyofFineChemicalsChemist& Druggist87.1(14August1915):45foraphotographofHowardsofIlfordfactorysee Chemist&Druggist88.4(29July1916):127. 210 HowardsofIlfordChemist&Druggist85.1(1August1914):suppl.iiiii. 211 H.S.Abrahamson,TheWarContract,Chemist&Druggist99.2(3November 1923):62526. 212 WhatisaFineChemical? Chemist&Druggist85.1(29August1914):51. 213 TheBDHGuidetotheBritishPharmacopoeia1914 (London:BritishDrugHouses, 1915)atWellcomelibrary. 214 AQuinquennialRecord.HowtheBDHhavegrownsincethe4ConstituentHouses MergedintoOne,Chemist&Druggist88.4(29July1916):78889. 215 Quotedfrom BritishMedicalJournal (12September1914):43C.Fearon,The HistoryofA.H.Cox&Co.Ltd.PharmaceuticalHistorian 23(1993):46Aphotograph
176
177
asLysol,forScheringnowemphasiseditwasmadebyaBritishfirmwithBritishcapital,
216 byBritishlabour,usingBritishrawmaterials. EvansSons,Lescher&Webbgrew
herbsbutalsoextendedtheirmanufacturingcapacitytoproduceSalvarsanandotherdrugs atRuncorninCheshire,appointingDr.W.A.CaspariasResearchDirector.Hewasa sciencegraduateoftheVictoriaUniversityandofJenaUniversityinCzechoslovakia.They

217 alsoproducedserumsandvaccinesinthebacteriologylaboratories. 218 Academicresearchersalsodealtwithpracticalproblemsofnationalimportance.
Within3weeksofthestartoftheWar,ImperialCollegeofSciencemade23synthetic
219 drugsonasmallscale. DuncanFlockhardtdistributedmedicalanddieteticpreparations,
vaccinesandtuberculinmadebystaffattheRoyalCollegeofPhysicians,Edinburghunder
220 221 Prof.Ritchie, andtheListerInstituteproducedadditionalvaccines.
RobertRobinson,whohadtrainedunderW.H.PerkinjunioratManchester, securedthenewlycreatedHeathHarrisonchairofOrganicChemistryatLiverpool Universityin1915.BeforethewarRobinsonhadcontributedsignificantlytotheliterature onalkaloidsynthesis,proposingthechemicalstructuresofstrychnine,andbrucine,and

222 from1916hepreparedbetaeucaine,novocaineandatropine. HisteamatLiverpool
collaboratedwithEvansSons,Lescher&Webbthroughanadvisoryboardestablishedin
223 July1917. ThelaboratoriesatLiverpool,likethatatOxfordwereoccupiedby
colonistsfromindustrytakingadvantageofuniversityfacilitiesforproduction.Oxford
224 hadrepresentativesofBritishDyes,W.J.BushandBoakeRoberts. HenryDakin
oftheA.H.Coxlaboratoriesisshowninanadvertin Chemist&Druggist88.4(29July 1916). 216 LysolChemist&Druggist86.2(6March1915):8. 217 ACheeryChatwithSirEdwardEvansontheWarsEffectonBritishPharmacy Chemist&Druggist88.4(29July1916):7756. 218 TrevorI.Williams,(1990):91. 219 TheImperialCollegeofScienceBritishMedicalJournal (3June1916):800The WarandtheSupplyofDrugsBritishMedical Journal (10March1917):339. 220 MedicinalandDieteticPreparationsVaccinesandTuberculinsDuncan FlockhardtBritishMedicalJournal (17March1917):367. 221 TheListerInstituteBritishMedicalJournal (20May1916):728. 222 LordToddandJ.W.Carnwath,RobertRobinson18861975Biographical MemoirsofFellowsoftheRoyalSociety 22(1976)415527. 223 LordTodd,J.W.Carnforth,RobertRobinson(1976)GeoffreyTweedale, (1990):120. 224 TrevorIWilliams,(1990):91.
177
178
producedflavinestomakeChloramineTinassociationwithProf.J.B.CohenatLeeds,as partofhisworktodevelopantisepticsthatdidnotbreakdownoncontactwithwounds,as
225 hypochloritesdidandBrowningandothersinvestigatedthese. W.E.S.Turneratthe 226 UniversityofSheffieldofferedtosupplyauthoritativeinformationonpatents. Etherwas 227 alsopreparedatGovernmentfactoriesinquantitiesupto5,000tons.
AftersecuringtheEllesmerePortfactory,Levinsteinsdyefirmbuiltuparesearch departmentof30chemistsandmadeNovocainandAcriflavinefromNovember1916as wellasTrypaflavine,ProflavineandEuflavine.Substantialamounts(254kg.)weregiven freetotheGovernment.Forthisworktheirchiefchemist,ArthurWilliamBurgerreceived

228 theCertificateofMerit. SomeGermandrugs,suchasprocaineandbarbitolwere
availableinBritainfromAmericanfirmssuchasAbbott,whileSmith,Kline&Frenchsold
229 antiseptics. Thewartransformedtheproductionofalkaloids,syntheticchemicals,and
chemicalintermediatesinBritainintheabsenceofGermancompetitionthoughconcerns remainedaboutthecompetitivepositionofBritishfirmspostwar. 4.9TheTrainingofChemistsandtheCoordinationofthePharmaceuticalIndustry.
4.9.1EstablishmentoftheAssociationofBritishChemicalManufacturers(ABCM).
225
MedicalResearchCommitteeTheAntisepticFlavine(Acriflavine)British MedicalJournal (9June1917):76970E.K.Dunham,H.D.Dakin,ReporttotheMRC, ObservationsonChloraminesasNasalAntisepticsBritishMedicalJournal (30June 1917):8657DakinsDiChloramineTintheTreatmentoftheWoundsofWarBritish MedicalJournal (25August1917):24951.ChloraminewassoldbyBurroughsWellcome asHalozane,H.D.Dakin,E.K.Dunham,TheDisinfectionofDrinkingWaterBritish MedicalJournal (26May1917):682HealthofMunitionsWorkersBritishMedical Journal (7July1917):13C.H.Browning,R.Gulbransen,L.H.D.Thornton,The AntisepticPropertiesofAcriflavin,ProflavineandBrilliantGreen,withSpecialReference totheirSuitabilityforWoundTreatmentMRCReport,BritishMedicalJournal (21July 1917):7075C.H.Browning,R.Gulbransen,E.L.Kennaway,L.H.D.Thornton, FlavineandBrilliantGreen.PowerfulAntisepticswithLowToxicitytotheTissues:their UseinInfectedWoundsBritishMedicalJournal (20January 1917)I:7378. 226 Chemist&Druggist85.2(12September1914):40. 227 ThePharmaceuticalJournalandPharmacist(14February1910)inB.CARR 228 W.J.Reader,(1970)I.:266,276. 229 L.F.Haber,(1971):144.TheAmericans,inthesamesituationpassedasimilarlaw in1917.
178
179
UnlikeGermanyin1914,Britainhadnotradeassociationrepresenting
230 pharmaceuticalmanufacturingfirmstocoordinatewithcentralgovernment. Inpartthis
functionhadbeentakenupbythemoreacademicallyoriented,SocietyoftheChemical Industry.Attheirannualconferenceon7November1914theSocietydiscussedthe
231 PresentandFutureoftheBritishChemicalIndustryasAffectedbytheWar.
Sincetheoutbreakofwar,severaloftheseniorstaffofBritishfirmswereforcedto collaboratecloselyonthevariousgovernmentcommitteesinordertoevaluatewhichdrugs theycouldmakeandwhichchemicalintermediateswereneeded.Insharingtheproblems andchallengesthesekeyindividualsrecognisedthepotentialadvantagesofestablishing moreformallongertermcollaborationsin whichtheindustryhadacollectivevoice. Previouslymanyfirmsproducedthesamelinesandeachcoordinatedtheirownsuppliesof rawmaterials.Theyreliedindividuallyondyefirms,includingthoseinGermanyfor chemicalintermediatesandalsoreliedontheBritishdyestuffsconsultantsasacampaigning voice. MembersoftheChemicalSociety,theSocietyofDyeists&Colouristsandthe SocietyfortheChemicalIndustryestablishedaJointCommitteetoorganisethechemical manufacturerstoaddresstheissuesnotcoveredbyothercommitteessuchaswhichless commonchemicalintermediateswereneeded,investmentinmanufacturingplant, coordinationofproductionandthelackoftrainedchemists.Thefirstjointmeetingforall memberswasheldon27May1916intheroomsoftheChemicalSociety,underthe
232 chairmanshipofthePresidentoftheChemicalSociety,AlexanderScott whoexplained:
Itisessentialthatintheirownintereststhereshouldbeformedan AssociationofChemicalManufacturerspowerfulenoughtoinfluence legislationandtoindicatetotheGovernmentwhatisnecessaryinthe 233 nationalinterests.
230
231
L.F.Haber,(1971):232. TheProductionofFineChemicalsinBritainPharmaceuticalJournal 93(14 November1914):696. 232 ScottwasalsoamemberoftheSocietyoftheChemicalIndustry:T.S.Moore,J.C. Phillip,TheChemicalSociety18411941.AHistoricalReview(London:TheChemical Society,1947). 233 ThequoteisfromABCMChemist&Druggist88.3(27May1916):3941, FurtherbackgroundontheABCMisgivenonpage87.
179
180
The16membersoftheorganisingcommitteeoftheABCMincludedoneFellowofthe
234 RoyalSociety,twoDScsandfiveFellowsofRoyalInstituteoftheChemicalSociety.
FrancisCarr(Boots)wasafoundermemberwiththepharmaceuticalindustry representativesRalphDoddandKennethAllen(Allen&Hanbury.)Mr.G.A.Pearson (BurroughsWellcome),C.A.Hill(BritishDrugHouses),W.A.H.Naylor,T.D.Morson, L.J.Morson,(ofMorsons),E.T.Brewis,E.J.Boake(ofBoakeRoberts,Stratford,

235 London)aswellasProf.HenryE.ArmstrongandDr.EdwardFranklandArmstrong .
ThefirstDirectoroftheABCMwasW.J.UglowWoolcock,formercommitteememberof theSocietyoftheChemicalIndustryandofthePharmaceuticalSociety.Boakesuggested
236 thattheABCMshouldbelimitedtoBritishfirms.
TheABCMaimedtopromoteclosercooperationbetweenchemicalmanufacturers, toactasamediumforplacingbeforetheGovernmentofficials,itsviewsuponmatters affectingtheBritishchemicalindustryandtopromoteindustrialresearchthereby facilitatingthedevelopmentofanewBritishindustry.Theyadvocatedclosercooperation withuniversitiesandtechnicalcolleges,financingandsupervisingresearch,advisingits membersinregardtoparticularresearchtoundertakeandonthemostsuitableinstituteor

237 authoritytoworkwith.
234
OrganisingChemicalIndustryChemist&Druggist88.3(27May1916):3941.At themeetingon22June1916thefollowingwerecooptedSirA.Mond,Mr.F.W.Brock, Mr.G.B.Merrian,Mr.MaxMusprattF.R.S.ofLiverpool,Mr.R.B.Pullar,MrA.T. Smith,MrNormanHolden,MrJohnGray,MrW.J.Wilson. 235 E.F.ArmstronghadstudiedattheRoyalCollegeofScienceinLondon,thenthe CentralTechnicalInstitute,gaininghisPhDatBerlinUniversityandD.Sc.fromLondon University.HehadbeenaDirectoroftheSouthMetropolitanGasCo.,thenscientific advisortotheMinistryofWorksandMinistryofHomeSecurity.Hehadmanagedother firmsbeforebeingappointedManagingDirectoroftheBritishDyestuffsCorporationin 1925,C.S.Gibson,T.B.Hilditch,EdwardFranklandArmstrongObituaryNoticesof FellowsoftheRoyalSociety 5(1948)619633. 236 Chemist&Druggist88.3(27May1916):39,41,87. 237 Chemist&Druggist88.3(24June1916):665ABCMChemist&Druggist88.3 (1July1916):35ABCMChemist&Druggist88.4(22July1916):36British ChemicalIndustry:OneYearOnChemist&Druggist88.4(29July1916):45Afterthe WarHowStandOurChemicalIndustries(ChemicalSectionoftheLondonChamberof Commerce)Chemist&Druggist88.4(4November1916):1110SecretsofChemical Manufacturers,ABCMChemist&Druggist88.4(11November1916):1134Salvarsan SeveralFatalities,AlcoholPrices(18November1916):1148,SecretChemical ProcessesChemist&Druggist(18November1916):1160.
180
181
238 JohnT.Brunner ofBrunnerMondemphasisedtheneglectoftechnicaleducation
andlackofchemicalknowledgebyGovernmentofficials,andpointedoutthattheImperial
239 CollegeofSciencehadmanybuildingsunequippedthroughwantoffunding. The
ABCMbelievedthattheseproblemscouldbeovercomeiftheABCMfinancedand supervisedresearchincooperationwithteachinginstitutions,intheinterestsofthe chemicalindustryasawhole,andmakingthisavailabletomembers.Itwouldorganise systematicconferencesbetweenmanufacturersandteachers.Regardingwartimesupplies, theABCMhadtoensurethateventheunusualbutimportantchemicalswerefreely available.Theyappointedachemicallytrainedadministratortoworkwithagoverningbody ofacademicprofessionalstokeeprecordsofallBritishchemicalproductsandtheir manufacturers,avoidingduplicationandunnecessarydevelopmentofplant. Pharmaceuticalmanufacturerswarnedthat:TherealestablishmentofaBritishfine chemicalindustryuponanadequatescalecannottakeplaceuntilthenaturalresourcesin
240 materials,plant,labourandchemicalknowledgearefreelyavailable.
OneoftheleadingABCMmen,FrancisCarrgaveapapertotheSocietyofthe ChemicalIndustryon20July1916inwhichherecalledhowcapitalistsandbankerswere reluctanttoinvestinthepharmaceuticalindustry.TheGermanstrategywastochargehigh pricesforintermediates,arrangelongtermcontractsandsystematicdumpingofdrugs. Hecontinued: Representativesofeachbranchofthechemicalindustrymustdefine theextentoftheirrequirementsfromotherbranches.Welooktothe ABCMtotaketheleadinthesemattersandtosetafootthenecessary organisationtopreventoverlappingandgaps,toarrangebymutual concessionsthattoomanydonotmanufacturethesamechemicals, andtosecurethemanufactureofthosechemicalsalreadyprovided for.AfurtherfunctionoftheAssociationwastocalluponcertain branchesofchemicalmanufacturertosupplyrawmaterialssuchas
238
JohnTomlinsonBrunnerstartedtheammoniabusinessinNorthwich,Cheshirein 1873andthisfirmwasoneoftheprecursorsofI.C.I.,M.R.Fox,(1987):3435W.J. Reader,(1970):111:L.F.Haber,(1971):101,157,189. 239 J.T.Brunner,OrganisingChemicalIndustryChemist&Druggist88.3(27May 1916):3941.RegardingdebatesonImperialCollegethereareextensiverecordsatthe archiveincludingthoseofF.H.Carr. 240 C.A.Hill,T.D.Morson,ManufactureofFinechemicalsinRelationtoBritish IndustryandD.B.Dott,VegetableAlkaloidsHowtheWarhasAffectedTheir ProductionBritishandColonialPharmacist(June1915)4367,(quote)in2130B/CARR cuttingsIV:3,ArchivesatImperialCollege.
181
182
sulphate,chlorsulphonicacid,carbonylchloride,phenylhydrazine, acetoaceticether,phosphoruspentachlorideetc.eventhoughon accountofthequantitiesatfirstdemandedsuchundertakingscould onlyberegardedasbusinesspropositionsonlybythose observerswhosemotivesaretemperedbytheneedsofthechemical 241 industryasawhole. Heconcluded: whetherornotthemanufactureofsyntheticdrugswilldeveloptoa largeindustryabletoholditsownintheworldsmarketswillbe determinedbytedyeindustry.Withalargedyeindustrythesupplyof intermediateswouldbeassured.Attheconclusionofthewarthenew cokeovenplantsthathavebeenestablished,will,wehope,beableto 242 supplyimmensequantitiesofbyproducts. However,oneoftheperceivedproblemsofcollaborativeprojectsasawartimemeasure wasthatindividualsfromrivalfirmswouldbegrantedaccesstoeachotherscompany secretsbecausetheMinistryofMunitionshadpowers,torequireanypersonto
243 communicatetoaperson...allknowledgeof hisprocess. Becauseofthisandbecause
oftheirexperienceofhavingstaffpoached,BurroughsWellcomerefusedtosend
244 representativestomanycommittees,despiteanapproachbyMoulton. Thusthe
pharmacybasedmanufacturersdominateddiscussionsbetweenthepharmaceuticalindustry andtheGovernment.245 AstheWarprogressed,thepriceofcertaindrugsincreasedby50%dueto decreasedavailabilityandincreasedtransportcosts.Thisespeciallyappliedtosalicylates, Aspirin,bromides,Phenacetin,potassiumpermanganate,morphine,quinine,atropineand cocaine,eitherbecausetheywereoriginallyfromGermany,ormadefromchemicalsfrom Germany,andbecauseoftheincreaseddemand.TheExcessProfitsActwaspassed

241
F.H.Carr,SyntheticOrganicDrugs:TheirManufactureasAffectedbytheWar Chemist&Druggist88.4(29July1916):77879. 242 F.H.Carr,(29July1916):778. 243 TradeMarksAppliedForChemist&Druggist,88.5(4November1916):44. 244 AlthoughOBriendidserveonacommitteeregardingvaccineproduction:H.J. Parish,WF:85/20:20chapter3. 245 UnderSirRobertMorantthiscommitteeconsistedofEdmundWhite,Chairmanof thePharmaceuticalSociety.C.A.Hill,andJohnC.UmneywhotogetherwroteThe EssentialOilsoftheB.P.Chemist&Druggist(12February1919):271.Bothcontributed totheB.P.of1914.Chemist&Druggist85.2(3October1914):30,4958.Italso includedW.J.U.WoolcockhewasSecretaryoftheBritishPharmaceuticalConference
182
183
becausesomefirmstookadvantagebyonlyproducingthemostprofitablelines,whilethe
246 aimwastoensurethatallessentialdrugsweremade. TheABCMlobbiedthe
GovernmentabouttheExcessProfitsTaxthatthreatenedtoleavemanufacturerswithout thecashtoextendtheirresearchfacilitiesandplantcapacity.TheAssociationwasalsovery activeintheassessmentofnewlegislationonfactories,tradeagreements,patents,trade marksandvarioustechnicalaspectswiththeaimofpromotingBritishinterests,butkept awayfromlabourrelationsortradedisputes.TheABCMwasaBritishattempttocounter theclosecollaborationalreadyexistingbetweenlargefirmsinGermanywherestrategic alliancesofthegroupreferredtoastheLittleIG(BASF,BayerandAGFA)wasfurther

th extendedon18 August1916whentheymergedwithHoechstCassellaKalleplusWeiler
247 terMeerandGriesheimElektronunderthedirectionofCarlDuisbergofBayer. The
reactiontotheGermanmergerwasthat: anenormousengineofcommercialwarfarehasbeencreated expresslyfortheexpectedwarafterthewar,andthatitisintendedto undertakestillmoreefficientlyandonalargerscale,the variousmethodsbywhichGermanattacksuponallcompetitionwere 248 carriedout. JustbeforethemergerwasfinalisedtheCounciloftheBritishMedicalAssociationsummed uptherecognitionthat:Thecountryandprofessioncannotaffordtobeleftatthemercy

249 offoreignsupplyofsubstancesmanyofwhichareessential .
TheABCMrepresentedamixedgroup,includingtheheavychemicalmanufacturing companies,andthereweresignsitwillbeconfinedtorepresentativesofthelarger
250 firms. ThemaincommitteeincludedMr.C.A.HillofBritishDrugHousesand
in1913.NationalInsuranceActChemist&Druggist(5July1913):5558BernardM. Allen,SirRobertMorant:aGreatPublicServant(London:MacMillan,1934). 246 ThePriceofDrugsBritishMedicalJournal (3April1916):420A.J.Taylor (1971):40ExcessProfitsActChemist&Druggist(27April1918):43. 247 W.J.Reader,(1970):256,321,4512,476. 248 ReportsoftheAlienPropertyCustodianJournalofIndustrialChemistry (April 1919):355. 249 ImportedSyntheticDrugsBritishMedicalJournal (10June1916):828,868. 250 BritishChemicalIndustry Chemist&Druggist(19June1915):467.
183
184
subsequentlyfromNovember1916twomorepharmaceuticalmen,FrancisCarrfrom BootsandMr.DavidHowardfromHowards,251 formingafinechemicalssubgroup. TheABCMhelpedtocoordinatemattersofimportancetothechemicalindustry, butitwasnotanimmediatefixforthechronicshortagesofchemists,generallabour shortages,highrawmaterialprices,andthelackofavailabilityofsomechemical

252 intermediates. TheestablishmentoftheBritishDyestuffsCorporationhadnotreally
253 helpedasmuchashadbeenhoped. Despitethemassiverisesinproductionofsome
chemicals,therestillremainedalackofcheapandreliablesourcesofsuchbasic commoditiesasmethylandethylalcoholsandaceticacid. Andyetbythemiddleof1916theABCMclaimedwithpridethat:wehavepassed thestageofmakingfinechemicalsbecauseweareobligedtoandarenowlayingthe foundationofanextensiveindustry.Theirlisthadextendedby7080articlesinthelast yearandmorethantwiceasmuchwasbeingmade.TheABCMstressedtheneedfor

254 strongsupportofthisKeyindustryinBritain. FrancisCarroftheABCMgavea
rallyingcallforprotectionoftheinfantindustryinhis1916speechtotheSCIwhenhe stated: asofthefuturesomeformofprotectionisofvitalnecessitytoour chemicalindustry,forwithoutitanythingaccomplishedwillbe demolishedrapidlyandcompletelybycompetitionfromabroad...no opportunityshouldbelostofimpressinguponthenationanditsrulers thatthepossessionofapowerfulandselfcontainedchemicalindustry hadthesamedegreeofimportanceasthegreatengineeringindustry hadproventobe...wemustasanationdosomethingtosafeguard 255 newindustries. HewasconcernedthatGermancompetitionwilladopteveryskilfulmanoeuvretocombat newdevelopmentsinthiscountrysuchascharginghighpricesforintermediateproducts,
251
ABCMChemist&Druggist88.3(1916):37,41,(665,683,)ABCMCarrand HowardElectedChemist&Druggist88.5(18November1916):36. 252 J.DavidsonPratt,TheEconomicsoftheFineChemicalIndustryChemistryand Industry (20January1951):38. 253 L.F.Haber(1971):234. 254 BritishChemicalIndustryChemist&Druggist88.4(22July1916):799800. 255 F.H.Carr,SyntheticOrganicDrugs:theirManufactureasAffectedbytheWar Chemist&Druggist(29July1916):778.TranscriptofapapergiventotheSCIon20July 1916.
184
185
offeringlowtermsforfinishedproducts,orlongperiodcontracts,systematicdumping
256 etc.
Carrsuggestedthatthereshouldbeanimmediatedeclarationthattherewouldbea periodofprotectionfromGermanimportsaftertheWartogiveconfidenceforfurther capitalinvestment.Herecognisedthatscientificefficiencyinproductionwilldeterminein

257 thelongrunwhichnationshallbethestrongest. CarrsalsoaddressedtheChemical
SectionoftheBritishAssociation,callingfortheeducationandthetrainingofmento conductworkinsyntheticfactories,bothastechnicalmanagersandexpertoperatives.As thewarprogressedCarrcautionedthattheGermanshadalreadyrecognisedthegrowing importanceoftheBritishfinechemicalindustry.Heconsideredthattheywould concentratemoreonwipingoutthisnewcompetitionthanintherecoveryoflostcolonies,

258 andherecalledthelossofanearlyleadinboththedyeandcamphorindustries. France
proposedexclusionofallGermanproductsandwasnotallowingGermanmanufacturingin
259 France,andRussiawasconsideringthesame.
CarrconsideredthatinordertounderstandtheseproblemstheBoardofTrade
260 neededsomebodyfromthechemicaltradesonitsReconstructioncommittee. Initially
theBoardofTradeexcludedABCMrepresentativesuntiltheyrecognisedtheirgrowing contributiontochemicalmanufacture,asthegroup,whichwasthemostrepresentative...at
261 presentinexistenceinthecountry.
Runcimanscommitteeseventuallyagreedtoprotection,notonlyinchemicals,but alsofortextiles,ironandsteel,andengineering.AttheBritishAssociationmeetingin
262 September1916,Prof.G.G.Henderson presentedapapertothechemicalsection
256
257
Ibid. Ibid. 258 Ibid 259 SirWilliamRamsay,SocietyoftheChemicalIndustryChemist&Druggist86.2 (6March1915):53. 260 TheMinistryofReconstructioncommitteewassetupaddressthepotentialpostwar tradewars,andsocialandeconomicproblemsoffacingastrongGermanyandcentral European'Zollverein'orcustomsunion.A.J.Taylor,(1971):93. 261 Nature102(1918)no.2562:2723 Nature103(1919)no.2568:383. ChemicalTradeJournal 63(1918)no.1647:38. 262 SirJamesIrvine,J.L.Simonsen,GeorgeGeraldHendersonObituaryNoticesof FellowsoftheRoyalSociety (1944)4:491502.
185
186
summarisingtherecommendationsofthesubcommitteeofanadvisorycounciltotheBoard ofTrade.Thisrelatedtoscientificindustrialresearchandtraining,suggestinglargerfunds forthePrivyCouncilforextendingindustrialresearch,tariffprotectionforarticlesofvital importancetothenationalsafety,uniformityofpatentprotectionacrosstheEmpire,and rigorousenforcementoftheworkingofpatentsinBritain.Oneproposedmodelwasthe AustralianCommonwealthInstituteforScienceandIndustry,whichwasrunbyscientific

263 menofhighstandingwiththehopeofestablishingaNationalPhysicalLaboratory.
In1917theMinisterforReconstruction,ChristopherAddisonheardfromthe ABCMthatthepharmaceuticalanddyestuffsfirmswantedspecificprotectionsandfrom15 May1918theyweregrantedtenyearsprotectionundertheKeyIndustriesAct,which togetherwiththelossofthemostfavourednationstatusandtheTradingwiththeEnemy

264 (Amendment)Act,restrictedGermanimports. InJune1918theEconomicDefenceand
DevelopmentCommitteewassetupwiththeaimofpromotingpharmaceuticalsandother keyindustries.ClearstrategieswerethereforeputinplacetoallowtheBritishindustryto consolidateandtobecomecompetitivepostwar.
4.9.2TheDepartmentofScientificandIndustrialResearchandtheTrainingof Chemists. WhenRaphaelMeldolawrotetoTheTimeson20January1915,hismainworry abouttheproposedcreationofBritishDyesLtd.wasthatthedirectorshipsuggesteddid notincludearepresentativeofscientificchemistrytheninJulyofthatyearhewasinvited tochairtheAdvisoryCouncilofBritishDyes.MeldolaurgedtheBoardofTradetosetup acommitteeregardingchemicalsupplyandproposedaschemefortheorganisationand developmentofScientificandIndustrialresearch.Howeverhediedon15November1915 beforeseeingthistocompletion. TheRoyalSociety,theBritishScienceGuild,theSocietyoftheChemicalIndustry, andtheInstituteofChemistryacknowledgedtheproblemofalackofsufficientscientific education.TheAdvisoryCounciloftheCommitteeofthePrivyCouncilwasformedin July1915andtheDepartmentofScientificandIndustrialResearch(DSIR)inDecember
263
TheBritishAssociationpresidedoverbyProfG.G.Henderson:F.H.Carr,The SyntheticChemicalIndustryChemist&Druggist88.4(9September1916):457. 264 L.Haber,(1971):24145.
186
187
265 1916,baseduponthemodeloftheNationalPhysicalLaboratory. TheRoyalSociety 266 establishedtheconjointboardofScientificSocietiesin1916. Thecommonaimofthese
groupswastoincreasetechnicalexpertiserelatedtoscienceandparticularlychemistryand itsapplicationtoindustry.The(DSIR)calledfor: alargelyincreasedsupplyofcompetentresearcherssecondlya heartyspiritofcooperatingamongallconcerned,menofscience, menofbusiness,workingmen,professionalmenandscientific societies,universitiesandtechnicalcolleges,localauthoritiesand 267 Governmentdepartments. Aparticularemphasiswasplacedonindustriesthathadbecomelocalisedabroadand particularlyinGermanyandconcernsaboutthedifficultiestobefacedpostwarunless
268 269 therewasgrowthandorganisationofscientificresources. GeorgeBeilby ,amember
ofthePrivyCouncilstated:
265
SirHaroldMelville,TheDSIR:DoesitPayOff? (London:GeorgeAllen&Unwin, 1961):26IanVarcoe,Scientists,GovernmentandOrganisedResearch:theEarlyHistory oftheD.S.I.R.191416Minerva8(1976):192217I.Varcoe,OrganisingforSciencein Britain:aCaseStudyoftheDepartmentforScientificandIndustrialResearch(DSIR) 191664(Oxford:UniversityPress,1974)R.McLeod,E.K.Andrews,TheOriginsof theD.S.I.R.ReflectionsonMenandIdeas,19156PublicAdministration 48(1970): 2348E.Hutchinson,ScientistsasanInferiorClass:TheEarlyYearsoftheD.S.I.R. Minerva8(1970):396411J.D.Bernal,ScienceinHistory (London:C.A.Watts&Co., 1965)C.E.K.Mees,ThePathofScience(Chichester:JohnWiley,1946)J.Jewkes,D. Sawers,R.Stillerman,TheSourcesofInvention (London:MacMillan,1955)A.C. Seward(ed.),ScienceandtheNation (Cambridge:CambridgeUniversityPress,1971)A. Marwick,(1965)especiallychapter7.
266
ReportoftheCommitteeonthePositionofNaturalScienceintheEducational SystemofGreatBritain.(London:HMSO,1918),Cd9011:53,57,64DavidLayton, EducationinInstitutionalisedSocietiesin AHistoryofTechnology,vol.1,TrevorI. Williams(ed.),(Oxford:ClarendonPress,1978)IanVarcoe,CooperativeResearch AssociationsinBritishIndustryMinerva19(1981):43363E.F.Armstrong,Chemistry inthe20thCentury:anAccountoftheAchievementandPresentStateofKnowledgeof ChemicalScience(London:ErnestBenn,1924):88.V.E.Coslett(ed.),Scientific ResearchinUniversitiesandIndustry.AReportontheConditionsinGreatBritain (London:AssociationofUniversityTeachers,1955). 267 R.C.Cochrane,MeasuresforProgress(Washington:NationalBureauofStandards, 1966):231,559. 268 Ibid. 269 Beilbyhadbeeninvolvedinthecyanidebusinessandpatentedamethodofmaking potassiumcyanideusedbyCasselJudySlinn,(1984):61.
187
188
Theplaceofchemistryinthenationallifehasbeenfarmore importantthanthemajorityofeducatedpeoplehaveimagined,and thisplacebidsfairtobecomeofvastlyincreasedimportanceinthe nearfuture.Thespecialmessageforparentsandteachersis, therefore,thattrainedchemistswill,inthenearfuture,beinincreased 270 demandforindustrialandofficialoppositions. TheGovernmentrecognisedthat:aspecialneedexistsatthepresenttimefornew machineryandforadditionalstateassistanceinordertopromoteandorganisescientific researchwithaview,especiallytoitsapplicationtotradeandindustry.TheHaldane committee,whichwasestablishedin1908,wasproposingtoincreasethefundingof scientificresearchandtrainingofchemistsaftertheeffortsoftheBritishAssociationfor
271 theAdvancementofScience.
AttheSocietyof theChemicalIndustrymeetingin1916furtherpointsaddressedby FrancisCarrwereeducationandtrainingandheidentifiedtwoclassesofworkers:technical andexpertoperatives: Thefirst(class)consistsofresourcefulwelltrainedchemists directingonthespot,operativesofthesecond.Hereferredtothe specialqualificationsofthesefirstclassmenandsaidthatinsynthetic chemicalmanufactureandaboveallotherbranchesofchemical manufacturemenofthiskindcombiningbusinessandscienceare 272 indispensable. Hesuggestedoneormoretechnologicalcolleges,withmanufacturingcapabilitiessothat chemistscouldspendaconsiderabletimeproducingsyntheticdrugsunderexpertguidance, focusingonproducingthoserequiredinsmallquantitiesofthesortnotcosteffectivefor Britishindustrytoproduce. Thecollegewouldhavealargepermanentstaffandwouldbeconductedalongstrict businesslines.Theaimwouldbetocreaterealisticmanufacturingconditionswhere studentscouldworkinchemical,physicalandengineeringlaboratories,withdrawing rooms,joinersandfittersshopsandaplantgeneratingsteam,gasandelectricity,allof whichcouldbemeteredandexpressedquantitativelysothatstudentsgainedthevalueof
270
AlexFindlay,inR.B.Pilcher,F.ButlerJones.WhatIndustryOwestoChemical rd Science(Cambridge:W.Heffer,3 edition1945)Introduction:viii. 271 D.Layton,InterpretersofScience:aHistoryoftheAssociationforScienceEducation (Bath:JohnMurray,1984):21.
188
189
rawmaterials,yieldsofreactions,theheatandpowerabsorbed,thetimeandlabour expended.Studentswouldbegivenacommercialperspectiveandwouldundergo instructioninaccountancyandcosting.Studentswouldspendtimeintheanalytical laboratoryin whichintermediatesandthefinalproductwereexamined.Theywouldhave instructioninphysicalandelectrochemistry,appliedmathematics,constructionanddesign andpreparationofsteamjoints,chemicalengineering,machinedrawing,repairs,useof specialmachineryandplant,stokingandenginedriving,makingsteamjointsandwood turning.Theseweretheskillsrequiredtorunamodernpharmaceuticalbusinessworks. Thesecondyearwouldcoverengineeringincludingsteamraisingandpowerproduction
273 andanalysisofwasteandfluegases.
Thesuccessorotherwiseoftheeffortstoincreaseemphasisonchemicalresearch willbedealtwithinthesubsequentchapteronpostWarBritain,whichwilladdtheimpact oftariffprotection,thesuccessofBritishdyestuffsandtheexclusionofGermandrugs.In subsequentchaptersIwillexaminehowtheinteractionsbegunduringtheWarbecamethe modelsforfurtherinteractionsbetweenthepharmaceuticalindustryandtheGovernmentin bothbiologicalstandardisationandclinicaltrialsasBritishfirmspreparedfurthersynthetic drugs. Thewarmarkedaturningpointforthestandingofscience,inrelationtoits potentialimportanceinwarasinpeaceandthiswasevidentinthechemicaland

274 pharmaceuticalindustry. Companiesrationalisedthewayinwhichtheyproduced
drugs.
275
Indoingsotheycreatednewchallengesofhowthemodelwouldbeextended
intopeacetimeandhownewproductsarisingwouldbetested.
4.10TheMRCProposeClinicalTesting
272
Editorial,Science,EducationandGovernmentBritishMedicalJournal (5February 1916):20910. 273 F.H.Carr,SyntheticDrugIndustryChemist&Druggist(9September1916):457. 274 S.M.HArmitage,ThePoliticsofDecontrolofIndustry:BritainandtheUnited States(London:Wadenfeld&Nicholson,1969)P.B.Johnson,LandFitforHeroes:The PlanningofBritishReconstruction19169 (Chicago:ChicagoUniversityPress,1968). 275 A.J.P.Taylor,(1988):45,49,91,176,321,3716,426W.J.Reader,(1970): 132L.F.Haber,(1971):173.
189
190
TheMRCrecognisedthathavingtakeupacentralroleinthetestingofSalvarsanin ordertoensurethequalityandstrengthofBritishpreparations,theyneededtoextendthis rolefurtherbyhelpingtoconvinceconservativeBritishphysicianstouseBritishsynthetic drugs.SalvarsanwasevaluatedaspartofacoordinatedattackonVenerealdisease.The RoyalCommissionraisedtheageofconsentfrom13to16yearsandendorsedthe conclusionsoftheSelectCommitteeonPatentMedicines,thatmosttreatmentsmaking unsubstantiatedclaimsofferednobenefit:itwasimportantthereforetoshowthat

276 Salvarsan,ascientificdrugendorsedbytheMRCwaseffective. EditorialsintheBritish
MedicalJournalwerescathingintheircontemptofefficacyfiguresgeneratedinprisons, bythePoorlawauthoritiesandinvoluntaryhospitals.Theycalledinparticularforarecord ofhowmanytimesSalvarsanoritssubstituteswasprovidedatthepublicexpenseand urgedtheuseofmodernscientificmeasuresunitingtheeffortsofdoctorand bacteriologist.Theaimwastoshowclearlythebenefitsasopposedtotheeviland

277 unqualifiedtreatmentatthehandsofchemists,herbalistsandquackspecialists.
TheMRChadgainedsomeexperienceofclinicalevaluationbyperformingasmall trialofbismuthiodidedoublesaltofemetineatamilitaryhospitalforthetreatmentof
278 amoebicdysenteryandthisbecamethestandardtherapy. Salvarsanwasmorecomplex
asthedrugwaswidelyavailable,patientswerewidelyscatteredandrecordingofdatawas notasgood.Theytriedtocorrelateclinicaloutcomeswithlaboratoryresultstoassess whethertherewasaneedtoaddtoormodifythesystemofcontrols,appealingtomembers

279 ofthemedicalprofessiontofurnishitwithaccuraterecordsoftheresults.
276
TheRoyalCommissiononVenerealDiseaseswasappointedinNovember1913with theaimtoinquireintotheprevalenceofvenerealdiseasesintheUnitedKingdom,their effectsuponthehealthofthecommunity,andthemeansbywhichthoseeffectscanbe alleviatedorprevented.(HMSO:Cmnd.8189,1916) 277 RoyalCommissiononVenerealDiseaseRegulationsBritishMedicalJournal (11 March1916):3806. 278 H.H.DaleArchives,RoyalSocietyNIMR,93HD47.13.144. 279 TheManufactureofSalvarsanProductsinEnglandandFranceBritishMedical Journal (10April1915):649BritishMadeSalvarsanBritishMedicalJournal (17April 1915):689690J.E.R.McDonagh,TheManufactureofSalvarsanProductsinEngland andFranceBritishMedicalJournal (17April1915):697J.E.R.McDonagh,D.Watson, TheManufactureofSalvarsanProductsinEnglandandFranceBritishMedicalJournal (24April1915):7423EhrlichsRecentModificationofSalvarsanBritishMedical Journal (24April1915):979TheManufactureofSalvarsanProductsinEnglandand
190
191
TheCommitteeventuretourgethatmembersofthemedical professionwouldbeperformingaserviceofnationalimportance,in thepresentemergency,bykeepingaccuraterecordsofcasesinwhich thenewpreparationsareused,andbyplacingsuchrecordsatthe disposalofthecommitteefortheirprivateinformationandguidance. Particularstressmustbelaiduponthedesirabilityofrecordingin everycase,thenameofthepreparationusedandtheserialnumber appliedbythemanufacturertotheparticularbatchemployedtogether withsuchdetailsastodosage,theprecautionstakentoensurepurity ofthewaterusedandfinallytheresultsoftheadministration,bothas regardstherapeuticefficacyandthepresenceorabsenceofspecial 280 incidentalsymptoms. Someauthors,lessconvinced,consideredthateffortstoproducedrugssuchasSalvarsan wouldbebetterspentpreparingT.N.T.(trinitrotoluene)andtheywereconcernedabout
281 toxicityduetothearsenicpresentinSalvarsan. Oneofthearmyphysicians,H.C.
Lucey,basedattheRoyalHerbertHospital,Woolwichwrote:IbelieveKharsivantobe everybitaspotentastheoriginalGermanpreparationintheincidenceofadversereactions
282 cataloguedandthebactericidalpoweroftheblood. TheBritishMedicalAssociation
wereclearlynotconvincedbyBritishmanufacturerswhentheystatedthat:wehavemuch tolearnandalongwaytotravelbeforeourchemistscanputabeautifulpacketofsodium
283 salicylateat3shillingsapoundonthemarket(AstheGermanscould). Salvarsanwas
clearlyimportanttotheArmyandreservesofdrugsatWoolwicheventuallyincluded250
284 milliontablets. TheMRCalsoofferedsupport:
theCommitteeareconfidentthatsofarasthestrictestlaboratory controlscanensureit,theprofessionandthepublicarenowreceiving fromEnglishandFrenchsourcescompoundsfullyuptothestandard 285 ofthebestGermansuppliespreviouslysold. France(26June1915):1087BritishandFrenchSalvarsanProductsBritishMedical Journal (26June1915):1091. 280 TheManufactureofSalvarsanProductsinEnglandandFranceBritishMedical Journal (10April1915):649. 281 TheChemicalConstitutionofCertainProprietaryDrugsBritishMedicalJournal (10July1915):75. 282 H.C.Lucey,RAMC,RoyalHerbertHospital,Woolwich,BritishandFrench SalvarsanProductsBritishMedicalJournal (10July1915):7576. 283 ImportedSyntheticDrugsBritishMedicalJournal (17June1916):868. 284 SirW.G.MacPherson,(1921). 285 ManufactureofSalvarsanProductsInEnglandandFranceBritishMedicalJournal (26June1915):1087.
191
192
Butthissummarisedthekeyissue.MRCargumentswerebasedonlaboratorydatarather thanclinicaloutcomes.WhentheMRCannouncedtheirresultstheywerestrongly supportivefortheBritishmanufacturerseffortstomanufacturesyntheticSalvarsan: theCommitteearesatisfiedthattheproductstestedbiologically undertheirdirectionwerenotinferior,insafetyorinefficacy,tothe originalGermanpreparations.Itmayberemarkedherethatthe satisfactoryresultsofclinicaltrials,aswellastheresultsoflaboratory testsfortoxicity,wereinthehandsoftheCommitteebeforetheissue 286 oftheseproductswasauthorised. H.C.LuceyattheRoyalHerbertHospital,Woolwichrecordedindetailtheeffectsofa
287 further600injectionsofKharsivanin1916. StudiesofKharsivanandGalylwere
reportedfromFrance.Of96cases,84hadnoreactions,11onlyslightandonehada
288 significantreaction.
Andyettherewereconcernsaboutsafetyandtherewasasecondenquiryin
289 Germanyin1917onthesafetyofSalvarsan. Col.L.W.Harrison,oftheRoyal Army
MedicalCorps.(RAMC)reviewedover40,000casestreatedintheArmyandbelieved
290 thatKharsivan,SalvarsanandArsenobenzolwereequallyefficaciousandsafe. Major
LloydJones,(RAMC)performedtestson200patients.Of1,320injections,only37%did
291 notgiveanadversereaction. Haslarhospitalproduceddataon1833injectionsof 292 arsenicals,allofBritishmanufacture. Itwasagainstthisbackgroundofcontinued
286
J.E.R.McDonagh,ManufactureofSalvarsanProductsinEnglandandFrance BritishMedicalJournal (10April1915):64950. 287 H.C.Lucey,TheTherapeuticandReactionEffectsofKharsivanBritishMedical Journal (29April1916):6148. 288 TreatmentofSyphilisBritishMedicalJournal (1January1916):16. 289 MRCReportoftheSalvarsanCommittee66II.ToxicEffectsFollowingthe EmploymentofArsenobenzolPreparations(London:HMSO,1922). 290 ToxicEffectsofArsenobenzolPreparationsMRCSpecialReportSeries41 SpecialCommissionupontheManufacture,BiologicalTestingofSalvarsanandits Substitutes,MRCSpecialReportSeries44(1919):35. 291 JohnAdam,SalvarsanTreatmentofSyphilisBritishMedicalJournal (17February 1917):234anotherreportofover200injectionsgaveamorefavourablereaction.The ProphylaxisofVenerealDiseasesBritishMedicalJournal (17February1917):2434. 292 SirArthurMay,MedicineandtheSeaAffairBritishMedicalJournal (28April 1917):5335ofthese1522werekharsivan,55Galyland256arsenobenzolbillon.
192
193
scrutinythatasecondMRCSalvarsanCommitteechairedbyMajorFrederickAndrewesof St.Bartholomews,Londonwassetupattheendof1917toexamine: manufacture,testingmethodsofadministrationandclinicaleffectsofSalvarsanandthe

293 analogousgroupofantisyphiliticremedies. TheArmywantedProfessorGunn,Reader
inPharmacologyatOxfordandDr.Turner,ReaderinMorbidAnatomyattheUniversityof Londontotestthechronicorultimateeffects[ofSalvarsan]inexperimentson
294 animals.
WhenArthurEwinslefttheMRC,DalehadlittlehelpfortheassayofSalvarsanand withalltoolittlelikelihoodatthatstageofthewaroffindinganybodywhowouldgiveme thekindofhelpwhichIrequired.HelpeventuallymaterialisedintheformofMiss FlorenceDurham,andtheBelgianrefugee,Mlle.JulietteMarchalbutboth eventually

295 followedDaletotheNIMR.
TheMRCrecognisedthesignificanceoftheproductionofSalvarsanbyBritish firmsandtheyemphasisedtheirownpartinorganisingtheeffort: Inthisundertaking,intheemergencycreatedbythewar,adutyoutsidethe strictlimitsofmedicalresearch,thecommitteearesatisfiedthattheyhave assisted,notonlyinmeetinganimmediatenationalneed,butinfoundingan industrywhichwillbeofincreasingimportancetothepracticeofmedicine andtothehealth ofthecommunityasprogressiveeffectisgiventothe 296 recommendationsoftheRoyalCommissiononVenerealDiseases. Thus,alladvertisingbypatentmedicinemanufacturersforthisdiseasewasbannedand therapyhadtobeadministeredbyaGeneralPractitioner,sodiscouragingconcealment, continuedspreadofdiseaseandselftreatmentastrongendorsementforethicalmedicines
297 overpatentmedicines. TheVenerealDiseasesBillwaspassedon25May1917,and
293
MajorFrederickAndrewes(Chairman,PathologyLaboratory,StBartholomew's), SurgeonGeneralHumphreyRollestonofCambridge,ColonelL.W.HarrisonandMajorC. J.White,bothoftheRAMC,MilitaryHospital,RochesterRow,F.J.H.Coutts,Professor W.Bulloch,ofTheLondonHospital,J.W.McNee,UniversityCollegeMedicalSchool, andDr.H.H.Dale.MRCSalvarsanCommitteeMinutes,MB22,(14February1918):1. 294 MRCSalvarsanCommitteeMinutesMB22(14February1918):1. 295 W.S.Feldberg,HenryHallettDale18751968 BiographicalMemoirsof FellowsoftheRoyalSociety 16(1970):107. 296 th 5 MRCAnnualReportin BritishMedicalJournal (14January1922):74. 297 TheProphylaxisofVenerealDiseasesBritishMedicalJournal (24February1917): 27881WilliamOsler,TheCampaignagainstVenerealDiseaseBritishMedicalJournal (26May1917):6946.
193
194
centreswereestablishedacrossthecountrywherepeoplecouldbediagnosedandtreated
298 freeofcharge.Itbecameacriminaloffenceknowinglytocommunicatethedisease.
Havingrecommendedcontrolledtherapywitharsenicalsitbecameincumbentonthe GovernmenttoensurethatSalvarsanandsimilardrugswereusedsafely.
4.11TheSecondSalvarsanCommittee. ThesecondSalvarsanCommitteemeteveryweekfrom14February1918totheend of1924toexaminemanufacture,testing,methodsofadministrationandclinicaleffectsof

299 Salvarsanandtheanalogousgroupofantisyphiliticremedies. Althoughthisextends
beyondthechronologyofthischapter,theirworkfollowedfromthewarworkon Salvarsanandsoisincludedinthischapter.Theireffortscanbedividedintothreemain stages.Firstly,theyaskedforchemicalstandardsontheassumptionthattoxicitywouldbe relatedtothequalityofeachbatchofdrug.Thentheycollateddatatoassesssideeffects reportedtothemfromthearmyandnavyhospitals.Thirdly,theycompareddataonBritish

300 preparationswiththeGermanoriginalsandtheFrenchGalyl. Fromtheoutsetthey
301 arrangedplannedtoreviewArmyandNavyrecordsfromHaslarandRochesterRow.
Indefiningstandards,theSalvarsanCommitteedependedheavilyupontheco operation andexpertiseofscientistsfrompharmaceuticalfirms,especiallyFrankPyman

302 whohadbeenresponsibleforitsproductionatBurroughsWellcome. Theworks
managerofBurroughsWellcome,H.A.D.Jowettdescribedtheprecautionstakeninthe
303 synthesisof Salvarsanfromarsenic. Theprocessinvolvedacomplexseriesof
reactions,purifications,analyses,crystallisations,andprecipitations.Thefinalproducthad tobeprotectedfromoxygenbysealingvialsundersulphurdioxidegas.Itwasthen
298
CriminalLawAmendmentBillTheTreatmentofVenerealDiseasesBritish MedicalJournal (17March1917):3723. 300 299 InitialmembershipwasthesurgeonH MRCSalvarsanCommitteeMinutes MB22,(undated,February1918):2. 301 MRCSalvarsanCommitteeMinutesMB22,(14February1918):2. 302 MRCSalvarsanCommitteeMinutesMB22,(5March1918):3. 303 MRCSalvarsanCommitteeMinutesMB22,(22March1918):5.
194
195
assayedbothchemicallyandinabiologicaltest.TheMRCconcluded:theproductseems
304 uniform,theonlymarkedvariationisastotheresultofthebiologicaltest.
TheothercommonlyusedSalvarsanpreparationwasMay&Bakers Novarsenobenzolbillon,sotheCommitteealsocheckedthefacilitiesofMay&Bakerat Dagenham.On11March1918theM&Bpharmacist,Gilling,explainedthatthecomplete manufactureofSalvarsanhadnotyetbeenachievedbythemintheU.K.astheintermediate 'nitro'compoundwaspreparedbyPoulencBrothers,theirFrenchcolleagues,andsentto

305 them. IncontrasttoBurroughsWellcome,May&Bakertooknoprecautionstoprotect
theproductfromair,buttheirpharmacistGillingfeltthiswassuitableiftheydidnottake
306 toolonginthepreparationandaslongasmaterialsremaineddry.
However,afteroneincidentwhereafirmcircumventeditstestingproceduresby usingrejectedbatchesofSalvarsantoprepareneosalvarsanwithoutfurthertesting,the SalvarsanCommitteeinsistedthatbatchnumbersappearedoncommercialpackagessothat

307 anyproblemscouldbetracedbacktothebatchproduced. TheCommitteewerekeento
produceasetofcommonstandardsofpurity,butnottolaydownstandardsthatweretoo stringentfortheBritishmanufacturers.However,Jowettwantedthemoststringent conditionssothatonlyBurroughsWellcomecouldmeetthem:theuseofpurechemicals, recrystallisingintermediates,andassessmentofthepercentageconcentrationsofarsenic

308 andof waterinthepreparations.
Jowettemphasisedtheneedforcontrolsofvacuumdrying,forcomplexsolvents, filtrationandprecipitationandinertsealingoftubesofthefinalproduct.Standardsof solubilityanddissolutionwerealsotobespecified. Heinsistedthatpoorbatchesof Salvarsanshouldnotbereusedtoproducegoodbatchesofneosalvarsanandhecautioned thataddingsaltcouldunscrupulouslylowerthearsenicconcentration,thoughthiswasnot
304 305
MRCSalvarsanCommitteeMinutesMB22,(22March1918):5. FordetailsontheagreementbetweenPoulencandMay&BakerseeJudySlinn, (1984)MRCSalvarsanCommitteeMinutesMB22,(11March1918):4. 306 MRCSalvarsanCommitteeMinutesMB22,(19February1919):25. 307 MRCSalvarsanCommitteeMinutesMB22,(5March1919):27the novarsenobenzolpreparation,glucarsenolwasfromtheAngloFrenchDrugCompany. 308 MRCSalvarsanCommitteeMinutesMB22,(22March1919):30.
195
196
309 permittedinhisowncompany. DuringMarch1919theMRCvisitedtheBurroughs

310 WellcomeWorksinordertoseefirsthandtheprogressmadeinpreparingSalvarsan.
TheMRCindirectlyacknowledgedJowettsexpertinput,butonlybywritingthatthe Committeeareindebtedtoanoutsideauthority formoredetailedsuggestionsastosuitable

311 standardsforSalvarsanandneosalvarsan. Theywerecautiousinspecifyinglinkswith
anygivencompany. ThroughouttheseearlydevelopmentstheMRCstaunchlydefendedtheBritish products.TheMRCTrenchFeverCommitteeaskedin1918:whichofthepresent preparationsmostnearlyapproachestheoriginalGermanpreparation?TheSalvarsan Committeeconfidentlyrepliedthatanymightbeused,suchasKharsivan,Arsenobillon,

312 Diarsonal,orSalvarsanproducedbyMay&Baker.
HenryDaleinvestigatedNovarsenobillonandNeokharsivaninrabbits,in
313 comparisonwiththeoriginalGermanNeosalvarsan. Allthreegavesimilarresultsand 314 heconcludedonlythattherewasaninterestingcomparativefatality. TheCommittee
wantedtocomparetheBritishandFrenchdrugswithCanadianandGermandrugs,which
315 hadbeenassociatedwithjaundice. However,intryingtoobtaindatafromArmycentres,
theyreceivedvariablefeedback.CherryHintonreportedseveralfatalcases,whereas anothercentresawnojaundicefrom108,000injections. TheMRChypothesisrelatingpurityofthedrugstothesafetyprofilegainedfurther credencewhenProf.W.BullochreportedthataCommitteeofinvestigationinGermany hadconcludedthatalthoughSalvarsanpassinganimaltestsproducedjaundice,later

316 batchespassingevenmorestringenttestsdidnot. AsaresulttheMRCappliedtheir
309
MRCSalvarsanCommitteeMinutesMB22,(26March1919):31TheAngloFrench drugcompanyappliedtotheM.R.C.toimportGalylwithalowerarseniccontent. 310 G.E.Pearson,(1936),TypescriptWF:88/24:41d:12. 311 MRCSalvarsanCommitteeMinutesMB22,(8October1919):50. 312 MRCSalvarsanCommitteeMinutesMB22,(1May1918):10. 313 MRCSalvarsanCommitteeMinutesMB22,(17April1918):9. 314 MRCSalvarsanCommitteeMinutesMB22,(18May1918):11. 315 MRCSalvarsanCommitteeMinutesMB22,(31May1918):12(4October1918): 20(4December1918):21(30April1919):37. 316 MRCSalvarsanCommitteeMinutesMB22,(15May1918):11(17July1918):16.
196
197
317 strictguidelinestonewproductsemergingfromGermanysuchassilverSalvarsan.
Thus,whereastheinitialaimoftheMRCwastoensurethatthepurity,strengthandsafety oftheBritishproductswereasgoodasthosefromGermany,astimemovedonthey effectivelyreversedthetestingrequirements,establishingaprotectionistpolicy,and excludingforeignimportsifnotuptothenewlyestablishedhighstandards.Theytested Galyl,importedbytheAngloFrenchdrugcompanyandSilverSalvarsan,andcompounds '1495'and'1496'fromMeisterLucius&Brning,(Hoechst)ofGermany,whichwere

318 promotedascontaininglessarsenic. ThereremainedconcernsaboutBritishSalvarsan,
arisingfromdeathsandadverseeffectssuchasdermatitisandjaundiceinBritishandallied
319 hospitals,butthesecontinuedtobedifficulttoquantifyunderconditionsofwar. Inorder
togainwiderexperienceDalecorrespondedwithDrReidHuntofHarvardUniversityin Bostonandcomparedhisresultsinrats,usinglowerdoseswithhisownstudiesin
320 rabbits.
TheMRChadproblemsingettingtheclinicaldatatheyneededtosupporttheir hypothesis.Civiliancaseswereinadequatelyreportedeventhoughalldeathswere followedupandinvestigatedhistologicallyandasagreedmanufacturerswerenotifiedof

321 theoffendingbatchnumbers. PaulFildes,thenewSurgeonGeneral,responsiblefor
summarisingtheArmyexperiencewithSalvarsanwasunabletoprovideanycomparative
322 data,thoughhereportedthatthearmyinFrancewasalreadyusingSilverSalvarsan.
Inprivate,theSalvarsanCommitteeacknowledgedthatitwasimpossibleto properlydefinetherelativetherapeuticvaluefromarmyreturns,thoughthedatadidenable
317
MRCSalvarsanCommitteeMinutesMB22,(18December1918):22. MRCSalvarsanCommitteeMinutesMB22,(18December1918):22. 319 MRC.SalvarsanCommitteeMinutesMB22,(14February1918):1 MRCReportof theSalvarsanCommittee66II.ToxicEffectsFollowingtheEmploymentof ArsenobenzolPreparations(London:H.M.S.O.,1922)TheToxicEffectsofSalvarsan, BritishMedical Journal (18December1920):945 MRCSpecialReportSeries41(1917) ToxicEffectsofArsenobenzolPreparationsinSurgeryII,aClinicalStudyoftheToxic ReactionsFollowingtheIntravenousAdministrationof914Lt.ColR.J.G.Parnell,P. Fildes,SpecialCommissionUpontheManufacture,BiologicalTestingetc.ofSalvarsan anditsSubstitutesMRCSpecialReportSeries44(1919).
318
320
MRCSalvarsanCommitteeMinutesMB22,(17July1918):16,(24July1918):17, (11September1918):18. 321 MRCSalvarsanCommitteeMinutesMB22,(17January1919):23.
197
198
323 somecomparisonofrelativetoxiceffects. Giventheircentralroleinevaluating
Salvarsan,itwasonlynaturalthattheMRCSalvarsanCommitteewouldbeasked searchingquestions.WalterMorleyFletcheransweredonequerywiththeopinionthat probablythesafestisHoechst'sNeosalvarsan('914')bysyringe.Healsostatedthat: theCommitteehadcometotheconclusionthattherewasno appreciabledifferencebetweenthevariousneosalvarsanpreparations andthosefromBritain,FranceandCanadaseemequallyefficacious withtheoriginalGermanNeosalvarsan,andnotmorelikelytobe 324 followedbyilleffects. Prof.SimsWoodheadinvestigatedadversereports,andProf.W.Bullochwasaskedto collectfurtherstatisticson'606'and'914'attheLondonHospital.IncontrasttoFletcher's publicsupportforBritishdrugs,thenextmeetingoftheCommitteeagreedthatitwasnot evenpossibletomakean accuratestatementaboutthenumbersofpatientstreatedwith eachpreparation,letalonethepercentagesuccessrate,withoutwhichno'statistical'
325 comparisonswerepossible. TheMRCagaintriedtodistinguishwhatthereportsof
toxicityweredueto:chemicalimpurities,oxidationofthedrugorevenduetotheuseof contaminatedwater.YetagainFletcherreemphasisedtothecommitteethatareporton therelativemeritsofBritishproductscomparedwithGermanproductswouldbeagreat

326 help. HowevertheMRCstruggledtopiecetogetheranykindofareportonthe
efficacyofSalvarsanfromtheirdiverse,incomplete,andprimarilyarmysources.Instead theycouldonlyreportonstandardisednomenclatureandchemicaltestingofthevarious
327 preparationstocontroltheirsale. Giventheexigenciesoftheperiod,itisperhapsnot
surprisingthatreliableretrospectivelycollecteddatawasdifficulttoobtain.Therewere twoissues,thelackofconsistentdatarecordformsandthewayinwhichcontemporary
322 323 324 325
MRCSalvarsanCommitteeMinutesMB22,(17January1919):23. MRCSalvarsanCommitteeMinutesMB22,(26February1919):26. MRCSalvarsanCommitteeMinutesMB22,(19March1919):29. MRCSalvarsanCommitteeMinutesMB22,(19March1919):29(22March1919): MRCSalvarsanCommitteeMinutesMB22,(2April1919):33. MRCSalvarsanCommitteeMinutesMB22,(7April1919):34.
30.
326 327
198
199
328 datawascollectedwithastrongemphasisonindividualcasehistories. DuringtheWar
theMRCwereunabletoimposeamoresystematicapproachontheorganisationand collectionofmedicaldatathattheywanted.Theyroutinelytestedbatchessubmittedby Britishfirms,agreedlicensesforimportingfirmsandsearchedoutforeignbatchesthat wereobviouslyinadequateorunsafe. Asaresultoftheirproblems,theCommitteewishedtomakethecontrolofthese substancescompulsory.Both'606' and'914'cameundertheheadingofarsenicandits medicinalpreparationsinpartIofthePharmacyActof1908andhadtobelabelledas 'Poison'.HoweveroneMemberofParliament,inanswertoquestionsasked: Itwasnotclearwhoshouldtakeactiontoseetoenforcementofthe requirementsorinwhatwaytheseobligationswouldassistin obtainingpropertestsorwouldpreventthesaleofpreparationsnot conforming.Itmightbedesirabletoempowersomecompetentbody 329 toschedulecertaindrugssothatdefinitetestscouldbeenforced. ThiswasthefirstsuggestionofanationaldruglicensingsystemandtheMRCweretobe responsibleforrecommendinglicenses. InFebruary1918,theCommitteefirstdiscussedthepossibilityofFrankPyman, helpingthemwithsafetystudies.PymanhaddepartedBurroughsWellcometotakeupthe postofProfessorofTechnologicalChemistryintheUniversityofManchesterandHeadof theDepartmentofAppliedChemistry.Pymanwaswillingtoperformfurthertestson GermansubstancesonbehalfoftheMRC,butaslateasFebruary1919hislaboratorywas
330 notyetinorder.
AttheendoftheWar,GeorgeBargerlefttheMRCtotakeuptheChairof ChemistryinRelationtoMedicineattheUniversityofEdinburgh,buttheMRCacquired hisformercolleagueHaroldKingfromBurroughsWellcomeasareplacementin1919.
328
SeeU.Troehler,QuantificationinBritishMedicineandSurgery17501830,with SpecialReferencetoitsIntroductionintoTherapeutics.(UniversityofLondon:PhD Thesis,1978). 329 MRCSalvarsanCommitteeMinutesMB22,(11April1919):35. 330 MRCSalvarsanCommitteeMinutesMB22,(11April1919):35.Thelaboratory referredtomusthavebeenintheDepartmentofAppliedChemistryintheCollegeof TechnologyinManchesterwherehewasappointedProfessorbeginningon1March1919: H.King.FrankLeePymanBiographicalMemoirsofFellowsoftheRoyalSociety 4 (1944):687.
199
200
KingstudiedtheimpuritiescontainedincommercialpreparationsofSalvarsanand
331 identifiedthemainproblematiccomponentwhichwastwiceastoxicasSalvarsanitself.
WhenSalvarsanagainbecameavailablefromGermanypostwar,theSalvarsan CommitteesuggestedthatBoardofTradelicencesshouldbeamendedtorequirethesame biologicaltestsandbatchlabellingforGermanSalvarsanderivatives,andtheBoardof Trade,MRCandLocalGovernmentBoardmetinMay1919andagreedtorequirethis

332 beforeissuingimportlicences,effectivelyexcludingmanyforeignpreparations. The
SalvarsanCommitteeconsideredthatimportationofforeigndrugswithouttestingmight leadtorisktothepublicandunfaircompetitionwithBritishmanufacturerswhoare
333 compelledtosubmittheirproductsfortesting. Ifforeignpreparationsweretobe
excluded,therewasastillgreaterneededtoprovetheefficacyofBritishpreparations. ThereweretwofurtherdisappointmentsfortheMRCintheircontinuedstriveto collectclinicaldatatosupporttheirstatementsinsupportofBritishdrugs.Attheendof thewaritwasrecommendedthatthecardsofthemilitaryvenerealdiseaseclinicsshouldbe collectedastheycloseddown,butagainthisdecisioncametoolateandtheMRCfound

334 thatmanyrecordshadalreadybeensenttotheBritishMuseum. Furthermore,Dalehad
toadmitthatanimaltestsfailedtopredictforproblemsinclinicaluse,andthisrecognition
335 ledtheMRCtoconcludethattheydefinitelyneededcomparativeclinicalresults.
Fildes'spapersummarisingarmydatawasstillonlyindraftforminJuly1919and hisfindingswerequitegeneral:hestressedhewasprovidingonlyresultsandnotaguideto
336 therapy. Incontrasttothepatchyandlargelyincompletedataavailable,theCommittee
hadquitegrandioseplansforanalysiswiththeillnesstobeclassedintooneof12groups, withresultssubdividedbythebrandofdrugs(therewerearound13),thenumberof
331
MRCSalvarsanCommitteeMinutesMB22,(11April1919):35H.King, DerivativesofSulphurinCommercialSalvarsanpartsIandII.J.ChemicalSociety 119 (1921):1107,1415. 332 MRCSalvarsanCommitteeMinutesMB22,(30April1919):37(28May1919): 40. 333 MRCSalvarsanCommitteeMinutesMB22,(4February1920):52. 334 MRCSalvarsanCommitteeMinutesMB22,(2July1919):43. 335 MRCSalvarsanCommitteeMinutesMB22,(8July1919):44. 336 MRCSalvarsanCommitteeMinutesMB22,(23July1919):46.
200
201
injections,thetotaldose,theamountofmercurycontained,toxiceffects,theirduration,
337 andclinicalresults.
TheMRCclearlysetouttopositionitselfthroughtheSalvarsanCommitteeasa centralsourceofindependentknowledgeofthenewsyntheticcompounds,andasan arbiterofgoodprofessionalstandards.Theirproposalforacentralisedtestingfacility advisingtheBoardofTradeplacedtheminapositionwherebytheybecamethefocalpoint ofrequestsforinformationonrelativesafetyandactivityofthedrugsforwhichtheyhad takenresponsibility.In1919DalecreatedaNationalLaboratoryforBiologicalStandards, analogoustotheNationalPhysicalLaboratorytomaintainstandardsamplesofotherdrugs

338 suchasantitoxins,andmorebroadlytobecomethecentreformaintainingstandards.
WiththeincreasingworkloadDalerequiredareliableassistantandoncompletionofhis medicalstudiesJoshuaH.Burn,anotherexBurroughsWellcomeresearcherrejoinedhim
339 attheNIMRon1September1920andtheywerelatersupportedbytwotechnicians.
WalterFletcherwantedtheMRCtobethatcentralauthoritativebodyandinsisted thatfiguresonSalvarsanhadtobegivenasanincidenceperthousandinjectionsratherthan justasthenumberofcases,buthisCommitteecontinuedtofinditimpossibletoraisesuch figuresandasaresultaskedifgirlscandotheworkattheMRCStatistical

340 Department. FletcherwasparticularlyinfluencedbyGermanreportsthatgaveadefinite 341 airofprecisione.g.20deathsafter225,000injections. Specialinterestgroupsin
Germanyusedfiguresimaginativelytosupporttheircasesortocampaignagainstthenew remedy,whetherbecauseofitshighprofits,becauseitwasdangerous,becauseitwasused forprostitutesorforantiSemiticreasons,becauseofitsassociationwithEhrlich,whowas
337
MRCSalvarsancommitteeMinutesMB22,(26November1919):51MRCReport ontheultimateresultsofthetreatmentofsyphiliswitharsenicalcompounds(1919)(2): 867. 338 J.AustokerandL.Bryder,TheNationalInstituteforMedicalResearchandRelated ActivitiesoftheMRCinJ.AustokerandL.Bryder(eds.),(1989):3557. 339 MRCMinutesII,(7July1920):72.Hebecameapermanentmemberfrom1July 1921at500risingby25p.a.to750A.N.RichardsandDaleoninsulinandhistamine alsoE.Buelbring,J.M.Walker,J.H.Burn,(1981):50DrHinestayedfor6months thenwenttoSt.BartstobereplacedbyMrH.C.Sayer,MRCMinutesII,(18March 1921):38(22July1921):127. 340 MRCSalvarsanCommitteeMinutesMB22,(10March1920):54. 341 MRCSalvarsanCommitteeMinutesMB22,(19May1920):56.
201
202
aJew.Thisairofaccuracyhadbeenseenin1914,whenitwasreportedthatatotalof353 authoritieshadtreated74,018patientswith92%cured.FurtherpreciseGermanreports in1917showedthat254authoritiesreportedthat265,158patientshadreceived1,268,946

342 injections.
InmarkedcontrasttotheapparentaccuracyofreportinginGermany,itwas impossiblewiththeBritishdatatoclassifyeventheadministrationmethodthoughthere
343 wasanimpressionthatarsenobillonwaslosingitseffectiveness. Italsobecameclearthat 344 thereweresignificantfailingsinthefollowupofpatients. Anyclinicalsuspicionsthat
efficacywasdecreasingpresentedadilemmafortheMRCaftertheyhadsovigorously
345 supportedtheBritishdrugs. FurtherconcernsabouttheefficacyofBritishDrugscame
afterDale'sanimalexperimentsin1921,whichshowedMay&Bakers NovarsenobenzolbillonandBurroughsWellcomesNeokharsivanwerelesseffectivethan
346 BayersNeosalvarsan. TheyquestionedPearsonandJowettofBurroughsWellcome,
whofranklyadmittedthatowingtoproblemsoftoxicityandsolubility,theformulationhad beenchanged.TheMRCadvisedareturntotheoldform.Incontrast,theMay&Baker representativesBlenkinsopp,HaythornthwaiteandEwinshadnotmadeanyrecentchanges

347 sothedeficiencyoftheirproductcouldnotbeexplained.
WithgrowingquestionsabouttheefficacyandsafetyofBritishSalvarsan,theMRC facedafurtherdilemmainJune1921.TheMinisterofHealthreceivedanapplicationfrom aGermanfirmtomarketSilverSalvarsanatpricesconsiderablylowerthantheBritish preparations.ThiswasexactlywhatCarrhadpredictedwouldhappen.TheMRC SalvarsanCommitteedeliberatedthat:onthegroundsofeconomyitcouldbean advantagetoapproveit....[But]itwasfeltthatthepositionoftheBritishmanufacturer
342 343
MRCSalvarsanCommitteeMinutesMB22,(21July1920):59. MRCSalvarsanCommitteeMinutesMB22,(29September1920):61. 344 MRCSalvarsanCommitteeMinutesMB22,(19January1921):64. 345 MRCSalvarsanCommitteeMinutesMB22,(1December1920):63. 346 MRCSalvarsanCommitteeMinutesMB22,(18February1921):67. 347 MRCSalvarsanCommitteeMinutesMB22(3March1921):69RichardBlenkinsopp wastheeldestsonofWilliamwhodiedin1916whowasoneofseveralBlenkinsoppsthat hadmanagedthefirmsinceanewpartnershiphadbeenestablishedin1876.Richardtrained inchemistryattheCity&GuildsCollegeinKensingtonfrom18981900:JudySlinn, (1984):8231,86,91,94.
202
203
348 shouldbeborn inmind:afurtherexampleoftheirsupportfortheBritishindustry. In
Octoberof1921therewasafurtherapplicationforsulpharsenol,whichthereforehadto
349 undergoDale'sanimalexperimentsforapproval.
WhentheMRCSalvarsanreportwasfinallypublishedin1922,itrecognisedthat thereweresafetyissuessuchasasmalldegreeofliverimpairment.Theyarrangedagrant sothatSurgeonLt.CommanderW.J.GerrardatHaslarcoulddoexperimentsusingthe

350 vandenBerghtesttolookforearly signsoftoxicjaundice. HoweverSalvarsan
preparationsweremoreefficaciousthananyothertreatment.Deathsarefaroutweighedby
351 those,whichwouldoccurwithothermethods. Oneofthereportsprincipal
conclusionswasthattheespeciallyhigh incidenceofjaundiceinmilitaryhospitals,was verymuchrarerthanonthecontinent,especiallyinGermany,indicatingthatBritishand Frenchpreparationsmayhavebeenbettertolerated.Itcommentedonespeciallyreliable armyrecordsandthatlessreliancecanbeplacedontherecordsofcivilvenereal

352 clinics. However,asIshowedpreviously,andastheSalvarsanCommitteemeeting
minutescontinuedtoshow,theMRCwereunsurehowgoodtheirdatawastosupportthe Britishindustry.TheattemptsoftheMRCSalvarsancommitteetoassessclinicalefficacy quantitativelyinpatientswasfrustratingcomparedtotheirearlierworkwithantitoxinsand vaccines,whereadefineddosecouldbegiventoananimalandthedegreeofimmunity conferredcouldbemeasurednumericallyandpresentedstatistically.Alsothecollectionof datawaseasierastheadministrationwascentrallycoordinated.InthecaseofSalvarsan thedosestrengthsvaried,thepreparationsvaried,thedurationoftreatmentandfollowup variedandtheMRChadlimitedcontroloverthequalityofdatacollected.
348 349
MRCSalvarsanCommitteeMinutesMB22,(30June1921):79. MRCSalvarsanCommitteeMinutesMB22,(6October1921):89. 350 P.Fildes,R.J.G.Parnell,AClinicalStudyoftheToxicEffects,whichFollowthe IntravenousAdministrationof'914':MRCSpecialReportSeries41Reportofthe SalvarsanCommittee(London:HMSO,1922)MRCSalvarsanCommitteeII(1922) ToxicEffectsFollowingtheEmploymentofArsenobenzolPreparations:Reportofthe SalvarsanCommitteeBritishMedicalJournal (29July1922):184MRCMinutesII,(17 November1922):383. 351 ToxicEffectsFollowingtheEmploymentofArsenobenzolPreparations:Reportof theSalvarsanCommitteeBritishMedicalJournal (29July1922):184. 352 Ibid.
203
204
FrustratedbythelackofprogresstheMRCprovidedgrantstoinvestigatorsin LiverpoolforstatisticsandclinicalinvestigationofresultsofdifferentformsofSalvarsan andmercurialtreatments.InvestigatorsatStBartholomewsstudiedtheeffectsonhepatic adequacy,andagroupatTheRoyalNavyhospitalatHaslarnearGosportwereaskedto

353 studytheearlysignsoftoxicjaundice.
Thenalongcameanotherthornychallenge.J.E.R.McDonaghwasaLondon physicianwithyearsofexperienceintreatingsyphiliscaseswithSalvarsanandsimilar
354 drugs wemethimpreviouslyasoneofthedoctorsunconvincedbytheMRCthatthe
BritishsubstituteswereasgoodastheirGermanoriginals.InreplytotheSecretaryofthe NIMR,McDonaghexplainedthathehadperformedexperimentsandreadallofthe literature,includingpatents.HeexplainedhisconcernsaboutcomparingBritishand Germanpreparations:becausetheyarechemicallyidenticalitdoesnotfollowthattheyare similarinotherrespectshegavetheexamplethatsyntheticsalicylicacidlooksandacts differentlytoextractsandthatadrenalinandsuprareninarediametricallyopposed.Healso explainedthatthepatentswerewritteninsuchamannerastodeceivesohowcould Britishfirmsbesuretheypreparedthedruginthesameway?Heobservedthatthe SalvarsanproducedbythetwoBritishfirmshadalowyield,andthissuggestedto McDonaghalesscompletelinkage.HecontendedthattheGermandrugsproducedafter 1912wereactuallyofbetterqualitythanwhenthepatentswerewritten.Hedismissedthe MRCbiologicalcontrolsasvaluelessanimalswerenotassensitiveasman.Furthermore, hearguedthatthetoxiceffectwasverymuchgreaterincatscomparedtodogs.Hewent on: IamfairlyoftheopinionfromtheseveraltoxiceffectsIhaveseen followingtheuseofthenewproductsthatthesuccessfulmanufacture hasnotbeensolvedandthatthemedicalprofessionwouldbewell 355 advisedtoawaitthereportsofcliniciansbeforeusingtheproduct. McDonaghsstarkcriticismawakenedaflurryofcorrespondenceandeditorialcommentin theBritishMedicalJournalincludingarebuttalhedoesnotconvinceusthattheyare
353
MRCMinutesII,(28February1921):28(17November1922):383.
354
J.E.R.McDonagh,SalvarsaninSyphilisandAlliedDiseases(London:Hodder& Stoughton,1912).
204
205
wellfounded.NobodyunderstoodwhatMcDonaghmeantwhenhewrotebyhis referencestoincompletelinkagesandcolloidalarsenic.TheMRCconcededthatSalvarsan shouldbehighlyreducedbuttheydisagreedthattherewasadifferencebetweennaturaland syntheticsalicylicacidorbetweenadrenalinandsyntheticSuprarenin. TocountertheseargumentsMcDonaghgaveanevenmoretechnicalexplanationas towhyhebelievedtheBritishproductspreparedinadifferentwaymightbemoretoxic. HepointedoutthattheamountofreductionrequiredwasnotspecifiedintheGerman patentsandchallengedtheMRCwhydidEhrlichdeemitnecessarytohavethereportsof certainmedicalmenbeforeallowingthedrugtocomeuponthemarket.Ehrlichtookthe samepositionin1912withneosalvarsan,althoughhewasfullyawareonapriorigrounds thatthepreparationwaslesstoxicthenSalvarsan.FromhisownexperienceMcDonagh reported6casesofexfoliativedermatitisand2casesofjaundicetreatedwiththe BurroughsWellcomeKharsivan.Onediedandthreelostalloftheirhairandallcaseshad hyperkeratosisofthenails.Nonehadmorethan2injectionsandtwohadonlyone injection.Onehaddermatitisonlyaweekafterinjection.In contrasthearguedthathehad giventhousandsofinjectionsofGermanproductsinupto16dosesandhadonlyeverseen
356 onecaseofdermatitisexfoliate. ThisroundofcorrespondenceintheBritishMedical
JournalwasacutelyembarrassingfortheMRCasitchallengedtheirauthorityinseveral ways.CloserinspectionofMcDonaghscareerhowevershowsthatheclaimedtohave discoveredFerrivineandIntamine,theironsaltofsulphanilicacid,andasubstituted derivativeusedforacuteandchronicsyphilisrespectively,andperhapsthisinterestto criticiseBritishSalvarsan.AmoreindependentviewfromProfBaylissofferedacaution againstexaggeratedoptimism anyreasonablysafetherapeuticprocedurewill,inthis
355
J.E.R.McDonagh,TheManufactureofSalvarsanProductsinEnglandand FranceBritishMedicalJournal (17April1915):697. 356 QuotefromJ.E.R.McDonagh,TheManufactureofSalvarsanProductsinEngland andFranceBritishMedicalJournal (17April1915):697furthercorrespondence:J.E.R. McDonagh,DavidWatson,TheManufactureofSalvarsanProductsinEnglandand FranceBritishMedicalJournal (24April1915):7423EditorialcommentBritish MedicalJournal (24April1915):697ParenchymatousSyphilisBritishMedicalJournal (30January1915):198
205
206
countrysecureanunbiasedtrial,especiallyifthereissoundexperimentalevidenceinits
357 favour.
4.12Conclusions. TheWarmarkedawatershedintherebirthoftheBritishpharmaceuticalindustry. In1920aneditorialinthePharmaceuticalJournalsummarisedthat:InBritainthe manufactureoffinechemicalsduringthewarwascarriedonunderthemostadverse conditionsastobuildingplant,labourmaterialandotherfactors.Sothatitishighly

358 creditablethatmuchgoodresultswereachieved. Manufacturersfrompreviously
diversebackgroundsrestructuredtopreparesyntheticGermandrugsandalkaloids.The Governmentsupportedtheindustrybylegislation,throughaccesstoscarcecommodities, andbyhelpingtocoordinatesuppliesofimportantchemicalintermediates.Firmsmadeuse ofthescarcechemicalmanufacturingresourcesandexpandedproductionsignificantly,but soughtreassurancesthattheirinvestmentswouldbesecure.Hundredsofthousandsof pounds(weight)oftheanaestheticsweremade1,080milliontabletsofmedicinesby1916

359 atotalof66milliondosesofquininesaltsandby1917amonthlysupplyof12,500lb.
AfterBurroughsWellcomelostresearcherstotheMRC,theyturnedtothemforassistance inthebiologicalstandardisationofSalvarsan.Thus,theMRCsupportedBritishsynthetic drugproductionandbecamethearbitersofdrugsafetyandextendedtheirroletoalso arbitrateondrugefficacy,butfoundthattheirdatacollectionmethodswereinadequatedue tolimitedcontroloverwartimedatacollection.Theyweredeterminedtocollateaccurate dataandestablishedasecondSalvarsancommitteefrom1918to1924,duringwhichtime theMRCestablishedtheirownclinicalresearchsitestheseweretoperformlaboratory research,butalsocouldbecalleduponforclinicalresearch.Thiswillbeevaluatedfurther inthenextchapter.
357
J.E.R.McDonagh,TheRationaleandPracticeofChemotherapyBritishMedical Journal (22April1916):5912and(10June1916):8201.Thisreportcontinuedthe debatethatMcDonaghhadinitiatedinhisfirstpublicationinAprilandwascarriedoutata meetingoftheDermatologicalSectionoftheRoyalSocietyofMedicine. 358 ChemicalIndustryinGermanyandtheUnitedKingdomPharmaceuticalJournal 104(21February1920):162. 359 MajorGeneralSirW.G.MacPherson,HistoryoftheGreatWarvolume1(London: HMSO,1921):1789.
206
PostwarProblems,PatriotismandProtection:
207
CHAPTERFIVE: PostWarProblems,PatriotismandProtectionism:Industryled CampaignsandtheRiseofFrancisCarr. 5.1Introduction. AsaresultoftheWaritwasrecognisedthatBritainwastooreliantonGermanyfor drugs,dyesandchemicals,evidentinthefactthatmanyBritishfirmsmanufacturedGerman drugsinthespecialconditionsofwartime.CarraddressedtheNottinghambranchofthe SocietyfortheChemicalIndustryinNovember1918anddescribedthat:anindustrythat hadbeendevelopingprewarhasgrowntoconsiderableproportionsproducingorganics,

1 antiseptics,sedativesandlocalanaestheticsanddiureticsofEnglishmanufacture.
However,pharmaceuticalfirmsexpectedsomeformofprotectionfromthereturnof Germancompetitionpostwar,andtheincreasinglyinfluentialAssociationofBritish ChemicalManufacturersledthesecampaigns. Thischapterdealswiththenewchallengesofpeace:ontheonehandexport marketsreopened,ontheotherhandhugewartimesalestothearmedforcesdisappeared. MarketswerefurthercompromisedbytherapidreturntoproductivityoftheGerman industryandthereparationsimposedonGermany.Britishfirmshadtoaddresstheseshort termcompetitiveproblems,whileestablishingthelongertermsupplyofchemicalengineers andclinicaltrialists.Thischapteristhefirstofthreechaptersaddressingtheperiod1921 31bothfromtheindustryandtheMRCperspectiveastheytriedtoexcludeunsafe foreigndrugs,withaprotectionistpolicy therequirementforbiologicallystandardised drugsbytheNIMR.Chapter6addressesthecampaignforclinicaltrials,whichiskept separatebecauseitoccurredinthreemainwavesin1922,1926and1931.Chapter7is thenacasestudyofpostwardevelopmentsandstrategicdiscussionsthattookplacewithin theseframeworksintheScientificandTechnicalCommittee(STC)atBurroughsWellcome 19251939,andthatchaptersetsthesceneandgivesanindustryinsightforchapter8on theestablishmentandworkingoftheTherapeuticTrialsCommitteefrom193139,in whichinsightsfromtheSTCarecontinuedthroughto1939.
FrancisCarrtoSCI,reportedinNottinghamJournal,(October1918)CarrArchives. 2130B/CARRIVPressCuttings:6.
207
208
PostwarBritishpharmaceuticalfirmslookedtothegovernmentforassistanceand protectionandwerepartiallysuccessful.Theirinitialgains,however,weretemporary, resultinginadownturnintheirbusiness.FortunatelyforBritishfirms,newtherapeutic opportunitiesallowedthemtoexpandinnewdirectionswithoutdirectlyhavingto challengetheincreasingcompetitionfromthemergerofseveralGermanfirms. Nevertheless,Britishfirmscontinuedtomanufacturesomesyntheticdrugsanimportant interwardevelopmentinBritain,whichhasbeenunderestimatedbyhistorians. 5.2PostWarCampaignsfortheProtectionofthePharmaceuticalIndustry. Britishcompaniestookadvantageofmarketsthatopenedupasaresultofthe endingofhostilities,leadingtoaboomperiodof18monthsasexportrestrictionswere removed,butthisonlydelayedtheproblemsofovercapacityofprewarstandarddrugs, aheadofanabrupteconomicdownturn,coincidingwiththeminersstrikeandrising
2 unemployment.
TheendoftheWarrapidlydecreasedthedemandforpainkillers,antiseptics,
3 vaccines,serumsandanaesthetics. ItalsobroughtrenewedcompetitionfromGermanyin 4 theproductionofsyntheticdrugs. EventoremaincompetitivewithMerckandSchering
inproductionofalkaloidsrequiredtechnologicaladvances.Therecommendationsofthe newBritishPharmacopoeiaof1914,onlypartlyimplementedduringtheWar,hadthe
5 effectofreplacingmorealkaloidsbypureactiveprinciples,someofwhichweresynthetic.
ThemarketchallengeswerecompoundedbythesurplusofGermandrugsastheTreatyof
A.J.P.Taylor,EnglishHistory19141945(Oxford:ClarendonPress,1988):1425, th 163G.C.Allen,BritishIndustriesandtheirOrganization (London:Longmans,4 edition 1959). 3 In1918BurroughsWellcomeproducedoveroneandahalfmillionpacksofseraand vaccines.H.J.ParishWF:85/20:2.

4
FromGermanintoAcylureidopenicillin:ResearchThatMadeHistory (Bayer: Leverkusen,1980):18.

5
Cantharideswasreplacedbycantharadine,cocabycocaine,jaborandibypilocarpine andphysostigminebyeserine.B.P.1914BritishMedicalJournal (10October1914): 634.
208
209
VersaillesallowedtheReparationsCommitteetoseizeonehalfofGermanstocksheldon
6 15August1919,and25%ofaveragemonthlyproductionupto1January1925.
ThecampaignforprotectionoftheBritishpharmaceuticalindustryhadbegun duringtheWarwiththefoundationoftheABCMin1916.Justbeforethis,in1915,inhis paperTheManufactureofOrganicDrugsAffectedbytheWarFrancisCarrwrote: Nolongercanwebesatisfiedtobeexternallydependentforsuppliesofvital importance.Itisourdutytoadmitfranklytodaythatsomeform ofprotection isofvitalnecessityduringthecoming10years,whilewedevelopacomplete organisationandrectifyeducationalshortcomings.Withoutthisprotection, whathasalreadybeenachievedwillrapidlyandcompletelybedevastatedby competitionfromabroad.Therecanbenodoubtthattheindustryunprotected 7 wouldbecomethebuttofheavyGermanartillery.
Asaresultoftheirpoorcompetitiveness,theBritishpharmaceuticalfirmssoughtthesame tenyearperiodofprotectionpromisedfordyestuffsfrom15May1918,toallowaperiod ofconsolidationinordertoestablishmoreefficientdrugproductionandresearchfacilities. TheBritishDyestuffsCorporationwasestablishedinNovember1918,bringingtogether

8 mostofthemajorBritishdyemanufacturers. Thisofferedthepotentialfuturebenefitsfor
pharmaceuticalfirmsofbetterprovisionofchemicalintermediatesandsolvents,which remainedinlimitedsupplyasaresultofthecontinuedTradingwiththeEnemyActandits
9 Germanequivalent.
InNovemberof1918theBoardofTradeissuedaWhitePaperpromisinggrantsin aidforexpansionandresearch,andthiswasofficiallyannouncedastheCustoms
A.J.P.Taylor,(1988):127,149.Thiswaslatermodifiedin1924undertheDawes plan:L.F.Haber,TheChemicalIndustry19001930(Oxford:ClarendonPress,1971): 2489.

7 8
F.H.Carr,TheBritish&ColonialPharmacist(June1915):4367.
SchemefortheAllocationandAdministrationoftheFundsProvidedbyParliament fortheDevelopmentoftheDyeIndustrybyMeansofFinancialAssistancetoCompanies andFirmsinAidofDevelopment,ExtensionsandResearch(London:H.M.S.O.,1918) Cmnd9194M.R.Fox,DyeMakersofGreatBritain18561976(Manchester:ICIplc. 1987):5557,60,86,156,158,168.

9
A.J.P.Taylor,(1988):1718W.J.Reader,BritishDyestuffs:theStrugglefor Survival19191926ImperialChemicalIndustriesLtd.AHistory:TheForerunners1870 1926volume1(London:OxfordUniversityPress,1970):425445.
209
210
ConsolidationAct(Dyestuffs:ProhibitionofImportsProclamation),whichcameintoforce
10 on24February1919tobegintheperiodofprotection. Thiswasatemporarymeasure,
initiallytotheendof1919,butwiththesuggestionofatenyearextension. 5.3TheABCMMissiontoGermanManufacturingSites. In1915WilliamTildenhaddescribedtheorganisationofGermanchemical companies.Managementwasbycompetentspecialists,whowereconstantlyonthe lookoutfornewdiscoveries,andwhohadalargetechnicalstafftomakediscoveries commerciallyviable,bysecuringcheapmaterials,improvingprocessesandcreatinga demand.Theyhadalegalstaff,whichpatentedallimprovementsanddescribedthem

11 vaguelytopreventcopying. GermancompaniesinfluencedtheirGovernmentonaspects
oftaxandfreightcostsandtheyhadagenciesspreadaroundtheworldthatencouragedan
12 extensivecreditsystem. Littlewasknown,however,aboutthewayinwhichGerman
firmsstructuredtheirmanufacturingcapacityuntiltheinvasionandoccupationofpartsof GermanyallowedadirectevaluationofGermanfactoriesandprocesses.Thefirstaction organisedbytheABCMin1919wasthearrangementforachemicalmissiontotravelto GermanytoevaluatewhatcouldbelearnedfromthestructureandworkingsofGerman

13 pharmaceuticalmanufacturingplants.
TheABCMpartyof20membersplus5GovernmentofficialsthatvisitedGermany inMaytoJune1919includedFrancisCarrofBoots,whohadbeenresponsibleforthe earlyBritishmanufactureofSalvarsanatBurroughsWellcomeandofFlavineatBoots,and IvanLevinsteinofLevinsteinsdyefirm,whohadtakenovertheEllesmerePortfactoryto produceNovocaineandotherGermandrugs.InJune1919theABCMreportedonthe BritishChemicalMissiononChemicalFactoriesintheOccupiedareaofGermany.The aimof thevisitwas:
10
11
L.F.Haber,(1971):173W.J.Reader,(1970):280.
WilliamA.Tilden,TheSupplyofChemicalstoBritainandHerDependencies,inW. M.Gardner,TheBritishCoalTarIndustry:itsOrigin,DevelopmentandDecline(London: Williams&Norgate,1915):315334.

12
F.H.Carr,SyntheticOrganicDrugsChemistandDruggist88.4(29July1916): 77880L.F.Haber,(1971):129.
210
211
Notsomuchtoascertaindetailsastotemperatures,pressuresandquantities ofchemicals)used(but)todeterminethebasicprincipleswhichmustbe adoptedifBritishchemicalmanufacturersaretocompetesuccessfullywiththe 14 establishedGermanundertakings.
TheABCMvisited39worksandfoundthatGermanplantsweredesignedtooperate continuouslyinregularsequence,startingfrominitialreactionsonupperfloorsdownto crystallisationandpackingonthelowerfloors.Largescaleoperationscouldbeoperated independentlyofotherschemicalsusedoncewererecoveredandreused.Equipment suchasglassware,autoclaves,stirringandliftingmachineswereallofamuchhigher standardinGermanythaninBritain.TheABCMalsoconfirmedthegreatercommercial awareness,withaspecialdevelopmentsectionwithinBayerbringingtogetherchemists,

15 engineersandaccountants. InthesalespropagandadepartmentofBayertherewere70
graduatesqualifiedinbiology,pharmacology andchemistrywhowereactivethroughout Germany,dividedinto12districts,eachincludingabout4universities.Eachonereported toLeverkusen,theheadoffice,whichproducedpropaganda.Freesamplesofdrugswere givenout,butnotindiscriminately onlywhenaskedforbydoctorsinterestedinagiven subject. ThevisitstoGermanfactoriesmadetheABCMawareofwhattheywereup against,notonlyregardingdrugsbutalsokeychemicalintermediates.However,therewere nofactoriesintheoccupiedareathatproducedmethanol(bywooddistillation), formaldehydeorformicacid,althoughplantsmakingaceticacid,sodiumacetate,acetic anhydride,chloraceticacidandalcoholwerevisited.ThefactoriesofBayeratElberfeld andMerckatDarmstadtwerejustoutsidetheoccupiedarea.Nevertheless,processesfor theproductionofsalicylicacid,sodiumsalicylate,phenacetin,antipyrin,Salvarsanandits
13
ChemicalIndustryinGermanyandtheUnitedKingdomPharmaceuticalJournal 104(21February1920):162.
14
AssociationofBritishChemicalManufacturers,ReportoftheBritishChemical MissiononChemicalFactoriesintheOccupiedAreaofGermany (London:ABCM,June 1919):101.

15
AssociationofBritishChemicalManufacturers,(1919):14,36,1013J.F.Thorpe, inE.F.Armstrong(ed.),ChemistryintheTwentiethCentury:AnAccountofthe AchievementandthePresentStateofKnowledgeofChemicalScience (London:HMSO, 1929),Cmnd.3282:315ff.
211
212
derivatives,lacticacid,chloral,chloroform,cholicacid,opiumalkaloidsandcocaine hydrochloridewereseen.ThesuccessofGermanfirmswasattributedtothescientific equipmentandcontrol,massproduction,efficiencyandsufficiencyofplant,cooperation withothermanufacturersineliminatingwastefulcompetition,whilecontinuingtostimulate theintroductionofnewmethodsandnewproducts.Laboratoriesweredividedinto researchfornewproductsandseparatesectionsfortechnologicalresearchdirectedat improvementandcontrolofprocesses,especiallytheintermediatestagesofnewdrug manufacture.Thelaboratorieshadahighpercentageoftrainedspecialists:atBoehringer, whereopiateswereprepared,10%werechemists.Somemanufacturewasrestrictedto largecapacityfirmsforefficiency.Examplesgivenincludedtheproductionof2tonsper dayofglacialaceticacidatKnapsack,20tonsamonthofantipyrinatHoechst,andthe smallbutspecializedworksofBoehringerproduced4080oz.ofcocainehydrochlorideper day,80tonsamonthoftartaricacidand3tonsadayoflacticacid.Importantbyproducts wererecoveredduringmanufacture:inthecaseofantipyrinthesewerebenzene,sodium bromide,andsodiumacetateandinthecaseofSalvarsanthesewereetherandmethyl
16 alcohol.
Germanfirmsdealtdirectlywithcustomersratherthanthroughwholesalersand agents:Theyseemtohavepossessedauniquecapacitytoexcite,andinvolvingordinary peopleintheiraffairs.InGermanythewholecommunitytakesinterestinthechemical industryandthisisperhapsoneofthepredominatingfactorsinpromotingthewelfareof

17 thatindustry.
TheABCMrecognisedthat: Britishchemicalmanufacturersmustnotonlypossessthenecessaryfinancial means,butmustbewillingtospendfreelylargesumsofmoneyinextending thescientificsideoftheiractivities.Librariesandlaboratoriesmustbefittedup orextended,astaffofchemiststrainedforthesupervisionofdifferent processes,andadequatebuildingsandplanterectedinordertocompetewith foreigncountries.
16 17
AssociationofBritishChemicalManufacturers,(June1919):101103.
QuotedinLeeNiedrighausDavis,TheCorporateAlchemists:thePowerand ProblemsoftheChemicalIndustry (London:TempleSmith,1984):56.
212
213
AndItisevidentthatBritishchemicalmanufacturerswillnotbeabletocompete
18 successfullywiththeGermanindustryuntilsomesuchcooperationhasbeeneffected.
TheABCMstatedthat: Itisofimportancethatchemicalengineersinthiscountryshoulddevotetheir attentiontothequestionofbeingabletosupplystandardplant,suchastile linedironvesselsasusedforcorrosiveacids,etc.,autoclaves,stills,avarietyof enamelware,earthenwareandfilteringapparatusquicklyandeconomically (and)toequiptheirworksonthese[German]lines,Britishchemical manufacturerswillrequirealargesupplyofwelltrainedchemistswhoarenot 19 onlyablebutwillingtospecialiseintheparticularbranch . Germanfactorieswereinsplendidconditionswithalargeandhighlytrainedforceof employees,andmoreoverwithadditionalopportunitiesforincreasingtheirproductionby utilizingtheextraequipmentaddedforwarmaterialproductiondescribedasa
20 dangerousfactorinthestruggleforcommercialsupremacy. Theclearmessagestaken
homeweretheneedforbetterorganisationoffacilities,andgreaterefficiencyof manufacture.Inshorttherewasasignificantroletobeplayedbychemicalengineers.While Levinsteinreturnedprimarilytodyestuffsmanufacture,FrancisCarr,asoneoftheserare chemicalengineerstookupthegauntlettocampaignforbettertrainingofthisparticular typeofchemistforthepharmaceuticalindustryandthiswillbeaddressedlater,buttowards theendof 1919amoreimmediatechallengethreatenedtheBritishpharmaceutical manufacturers. 5.4TheSankeyJudgmentanditsConsequences. TheprotectioninitiallyaffordedtoBritishmanufacturers,restrictingdyeimports wasfoiledwhenLordJusticeSankeyconfirmedon17December1919thattheDyestuffs ProhibitionofImportsProclamationsetuptoofferprotectionwasillegal.Ithadbeen basedonthe1876CustomsConsolidationAct,whichprohibitedarms,ammunition, gunpowderandanyothergoods.FollowingGermanprotestationsSankeyruledthatlaw didnotgivetheGovernmentthepowertoinvokerestrictiononthetradeofdyes,sohehad
18 19
20
AssociationofBritishChemicalManufacturers,(1919):103. AssociationofBritishChemicalManufacturers,(1919):102103. GermanPoisonGasFactoriesChemist&Druggist91.3(28June1919):55.
213
214
21 nooptionbuttoallowGermanimports. Thisjudgmentquicklyledtotheswampingof
22 themarketwithGermandrugs. AttheannualdinneroftheChemicalIndustryClubin
1920,LordMoultonrecounted:Weareatthispresentatacrisisofourhistory.If
23 Englanddoesnotrealisethatitmustbeagreatchemicalnation,itsfutureisgone.
ImmediatelyaftertheSankeyjudgment,Britishfirmscampaignedforfurther protectionintheshortterm.FirmsrepresentedbytheSalicylicAcidAssociationclearly realisedthattheycouldonlysucceedinthelongtermifpricescamedowndueto efficienciesandtheybecamemorecompetitiveratherthanjustrelyingonprotection. However,theyneededsomeprotectiontogettimetodevelopthisefficiencyof

24 production. TheSocietyofDyersandColouristslobbiedforextendedprotectionofthe
dyestuffsindustry,suggestingthattheGermanshadtooeasilycircumventedthe1907 PatentAct(discussedpreviously),andthattheBritishdyeandrelatedchemicalindustries wereofkeystrategicimportance.TheysuggestedthattariffprotectionwouldallowBritish firmstimetoestablishchemicalplantsandresearchfacilitiesandtobecomecompetitive. Protectionwaseventuallygrantedfordyesin1920intheformoftheBoardof TradeDyestuffs(ImportRegulations)Act,whichcameintooperationon15January

25 1921. ImmediatelytheABCMlobbiedforanextensionoftheprotectiontoinclude
syntheticorganicchemicals,analyticalreagents,allotherfinechemicalsexceptsulphateof
26 quinine,exceptofvegetableoriginsorfromfermentationprocesses.
21
SocietyoftheChemicalIndustryChemist&Druggist93.3(11December1920): 57S.Miall,HistoryoftheBritishChemicalIndustry (London:ErnestBennLtd,1931):95 96M.R.Fox,(1967):5660(quote),85,89W.J.Reader,(1970):280,4301,439.

22
Editorial,TheFineChemicalIndustryBritishMedicalJournal (22January1921):
133.
23
ThequoteisfromWarfareandtheDyeIndustryChemist&Druggist93.3(27 November1920):92.Moultondiedthefollowingyear,LordMoultonofBankBritish MedicalJournal (19March1921):433.

24
F.H.Carr,SocietyofChemicalIndustryChemist&Druggist93.1(17July1920) at4 ABCM.

th
25 26
M.R.Fox,(1987):60.
J.DavidsonPratt,TheEconomicsoftheFineChemicalIndustryChemistryand Industry (20January1951):38.
214
215
LobbyingfromtheInstituteofChemistryalsobeganin1920,withFrancisCarr, nowatBritishDrugHouses,oncemoreinvolvedsupportinglegislationtoprotectthe manufactureofchemicalsandchemicalglasswareaskeyindustries.Carremphasisedthe socialbenefitsofchemistry,theraisingoftheskillsofthecountry,anditsstrategic importance,notonlyintheproductionoffinechemicalsanddrugsbutalsoT.N.T.and poisonousgases.HeurgedthatEnglandshouldbeagreatmanufacturingnationanda shopkeeper.HeparticularlypointedtoprotectionisminGermanyandAmericaandthe

27 effectonpricessuchastheextortionatelyhighpriceforsaccharin. Hediscussedthe
necessityofretainingtheholdonorganicsandalsoreferredtoimportantnew
28 developmentsofnovelhormoneextractssuchasthyroxinin1918
CharlesHill,ChairmanofBDH.emphasisedthattheindustrywantedprotectionfor analyticalandresearchreagents,pharmaceuticalsandphotographicmaterials,arguingthat theexpansionofanorganicchemicalindustryisintimatelyassociatedwithdevelopments

29 inbiochemistryortherapeutics. TheKeyIndustriesActwasextendedeventuallyto
pharmaceuticalsastheSafeguardingofIndustryActin1921,andleviedatariffof33.3% onimports.PearsonofBurroughsWellcomewrotetotheTimesabouthisfirmsapproval oftheSafeguardingofIndustryActthoughtherateoftaxwaslessthanhehadhopedfor. Heclaimed: Theadverseconditionswhichheforesawin1918havesincebecomerealities andthecompetitionfromGermany andothercountriesisnowsuchthatunless theS.C.I.obtainssomeassistanceatsometime,thiscountrywillsinkbackinto theconditionthatitwasinbeforethewarintheeventofanotherwar,this countrywillagainbedependentforoursuppliesofvitalchemicalsonforeign andpossiblyhostilenations. Hereferredtotherecentcaseoftheclosureof14manufacturersofchemicalglasswarein
30 thiscountryand6,000employeesbeinggiven7daysnotice. SamuelRideal,Fellowat
27
NoteshandwrittenbyCarrinpreparationforalectureFilesofFrancisHoward Carr,B.CARR.attheImperialInstitute,London2131B/CARRIII,1920
28
Dyestuffs(ImportRegulation)BillChemist&Druggist93.3(11December1920): 589.
29
C.A.Hill,(SocietyoftheChemicalIndustry)TheFineChemicalIndustryBritish MedicalJournal (22January1921):133.

30
IndustrialProtectionChemist&Druggist94.2(9April1921):3334.
215
216
UCHwroteintheprefacetoBarrowcliffandCarrsbook,OrganicMedicinalChemicals publishedin1921:Creditablethoughtheaccomplishments,Britishmanufactureisnot
31 especiallycosteffective. CarrgaveapresentationinLondoninFebruary1921entitled
Industrial research importanceagainstfutureattackbyaforeignpowerinwhichhe emphasisedthatitwasonlybytheallianceofchemicalresearchthatwecouldhopetomeet

32 effectivelythefloodofGermancompetition.
Somewartime(andearlier)problemsremained.TheGovernmentstilldemanded thepaymentofwhatmanufacturersconsideredtobeexcessivedutytobepaidonindustrial alcohol,thoughitsavailabilityinBritainwasatleastguaranteedbymergerstoformthe DistillersCompanyimmediatelypostwarandbythePureMethylatedSpiritsregulation

33 of1921. Capitalgrants,buildingmaterialsandfuelremainedinshortsupply.The
situationworsenedin1921whentherewasanationaltradinglossof204,159.After depreciationandtaxrefundsthelosseswereinexcessof1milliononsales,whichwerea
34 quarterofthe1920level.
TheEconomistdescribed1921asoneoftheworstyearsofdepressionsince
35 industrialrevolution. FortheBritishpharmaceuticalindustrytosurviveithadto
increasetheefficiencyofitsprocesschemistryoflargescaleproductiontobecompetitive orithadtochangefromimitationtoinnovation.GeorgePearsonofBurroughsWellcome commentedthatBritishfirmshadthecapacitytobecomeamajormanufacturerof

36 syntheticdrugsifgiventhechancetodevelopitsindustry.
InaBritishScienceGuildbookletpreparedin1921Carrwrotethat:
31
S.Rideal,prefaceinM.Barrowcliff,F.H.Carr,IndustrialResearch:Organic MedicinalChemicals(London:Ballire,Tindall&Cox,1921).
32
F.H.Carr,IndustrialResearchImportanceAgainstFutureAttacksbyaForeign PowerChemicalAge(12February1921)summaryof paperisintheCarrArchiveat ImperialInstitute,London.2131B/CARR2IVPresscuttings:7

33 34 35 36
E.F.Armstrong,(1924):20. L.F.Haber,(1971):247. A.J.PTaylor,(1988):144,163. IndustrialProtectionChemist&Druggist94.2(9April1921):3334.
216
217
Futureprogressliesinextendingtheuseinourindustry,inclosestpossible relationshipwiththatcarriedoutinacademicinstitutionsandundertheaegisof theM.R.Candsecondlybyfindingemploymentforgreaternumbersof scientificallytrainedstaffsandworkerstowhomisgivenresponsibilityanda 37 livinginterestistheworktheyareperforming. BritainalsosoughtnovelwaysofexcludingGermandrugsthe1921British PharmaceuticalConferenceexecutivecommitteecontinuedtheprocessofdefiningessential drugsandincludedthepharmaceuticalmanufacturers,CharlesHillofBDHandE.T. Neathercott 38 ofSavory&Moore,whiletheresearchsubcommitteeincludedbothFred
39 GambleofAllen&HanburysandCharlesHill. In1922theABCMtookthisastep
further,producingalistofover2,000finechemicalsalreadymanufacturedinBritain,
40 emphasisingthatweoughttobeindependentofforeignsupplies.
StanleyBaldwintookupthiscampaigninOctober1922ashefeltthatBritaincould onlyfightunemploymentwithprotection,whichbecameoneofthekeyelectionissues.
41 However,theelectionofDecember1923wentagainstprotection. Nevertheless,the
changehadbeendramatic,astheKeyIndustryActatleastgavecompaniestheconfidence toforgeaheadproducingGerman styledrugs.TheSocietyofPublicAnalysts,including Carr,campaignedformorestringenttestsbeforedrugsweresold,andtheymetwiththe RetailPharmacistsUnionrepresentedbyFrederickGambleofAllen&Hanburysatthe

42 InstituteofChemistryon12thJune1923todiscusstheSaleofFoodsandDrugsAct.
GamblesentalettertotheMinisterofHealthaboutthevariableanalysisofprescribed
43 medicines. Bythetimeoftheir1923annualreport,theincreasinglyinfluentialABCM
hadexpandedtorepresent150firms,andproducedadirectoryinFrench,Spanish,
37
F.H.Carr,BritishScienceGuildbooklet,1921intheCarrarchives2130B/CARR, ImperialInstitute,Londonpage77.
38
G.E.Pearson,WF:E2PFYLBox23:28. GovernmentChemistryChemist&Druggist95.2(5November1921):59 BritishFineChemicalsBritishMedicalJournal (22April1922):666.
39 40
41
A.J.P.Taylor,EnglishHistory19141945(Oxford:ClarendonPress,1988):206, 208,2201. 42 SaleofFoodandDrugsActChemist&Druggist99.1(4August1923):183184.

43
TheConferencePastandPresentChemist&Druggist99.1(28July1923):129
133.
217
218
Portuguese,ItalianandGerman.Theyclaimed:Wecanproduceirrefutabledatathatthe KeyIndustrydutyhasbeeninstrumentalinpromotingthedevelopmentofthisimportant
44 keyindustry. Aneditorialin Chemist&Druggistagreedthatmanufacturershadbeen 45 assistedinasmallwaybytheAct.
Apatterncanbeseenemergingwhichparalleledthecontinuedactionsofthe governmentintheircampaignsagainstpatentmedicinesandintheirquestforbiological standardisationofdrugsthatcouldnotbeassayedbychemicalmeans.IftheGermandrugs couldnotbeexcludedbytariffs,thentheycouldbeexcludedbyraisingthebarriersto marketingthem,namely,requiringfurtherchemicalandbiologicaltestsandultimately clinicaltrials.Standardisationwithcheckingofpuritybecameimportanttoolsinexcluding substandardforeignpreparations. ThedebatesaroundProtectionwithinthepharmaceuticalfirmsmirroredthosein widerpoliticalcircles.ThreeelectionsbetweenOctober1922andOctober1924were

46 foughtontheseissues. Attheendof1923,justbeforeanothergeneralelection,Charles
HillwroteinalettertotheTimes: Itiswellthatcandidatesofwhateverpoliticalpartyandeveryvotershould understandtheposition.Circumstanceshaveconspiredtominimisethe usefulnessoftheSafeguardingofIndustryAct.Thecountryoverflowedwith stocksofforeignchemicalsbroughtinimmediatelypriortotheActcominginto 47 force.Thedepressedcurrencymadethe33.3%dutyoflittleavail.
CharlesHillconsideredthatitwasessentialtomaintaintheActonthestatuteandifitwas droppedorreplacedbysomeotherprotectionwouldmeangivingbacktoGermanythe
48 supremacyinthefinechemicalindustrywhichshepossessedbeforethewar. Theaim
44 45
ABCMBritishMedicalJournal (9June1923):1003. TheFineChemicalsMarketChemist&Druggist99.2(3November1923):621.
46 47
A.J.P.Taylor,(1988):195,197,2067,230. TheTimes(27November1927).TheletteralsoappearedinC.A.Hill,Fine ChemicalIndustryOutlookChemist&Druggist99.2(1December1923):751.

48
Ibid.
218
219
wastoextendthedurationoftheprovisionsoftheSafeguardingIndustriesAct,whichwas
49 th duetolapseon19 August1924.
TheABCMandSCIcollaboratedcloselythroughoutthisperiodandmanyofthe committeememberswerecommontobothSocieties.EdwardFranklandArmstrong,who spokeattheABCMannualmeetinginJuly1924,alsochairedtheSCImeetingand discussedthepossibilityofsharingthesamebuildingfortheChemicalSociety,Societyfor theChemicalIndustry,AssociationofBritishChemicalManufacturers,Instituteof

50 ChemicalEngineersandInstituteofChemistry,thuscementingtheircollaboration.
5.5BritishPharmaceuticalFirmsPostWar. Fallingsalesandtheassociatedexcesscapacitybroughtadecreasingreturnonthe Britishpharmaceuticalfirmsexpandedfixedassets.Small,geographicallyisolatedfirms, dependentonothersforintermediateswereafeatureofmanyBritishindustriesintheinter

51 warperiod. AspecificexampleofthishadbeencitedintheABCMdocumentin1919.In
Britainamixtureofgascompanies,dyefirms,finechemicalmanufacturersandothersused lowefficiencymethodstomakesalicylicacid.Becauseofthedecreasingmarketand increasedcompetitionfromGermany,Britishfirmshadrapidlytorationalisetheir productionanddecidewhichofseveralpathstofollow.TheSCImeetingon17September

52 1921discussedsyntheticwaysofmakingnaturalproductsasonepossiblewayforward.
ForfirmssuchasBurroughsWellcome,Boots,BritishDrugHousesandMay& Bakerthathadpreparedsyntheticdrugs,evenifonlytoalimiteddegree,thechoicewas mostdifficult.Theycouldreturntotheirlargerangesofsimpledrugs,or,havinginvested inexpensivemanufacturingplant,couldattemptfurtherproductionofanarrowerrangeof

49
WestminsterWisdom SafeguardingIndustry,TherapeuticSubstancesBill Chemist&Druggist100.2(12April1924):526.

50
TheAssociationofBritishChemicalManufacturersChemist&Druggist101.1(26 July1924):124.
51
T.H.Burnham,G.D.Hoskins,IronandSteelinBritain (London:Allen&Unwin, 1943):149190.

52
SocietyoftheChemicalIndustryChemist&Druggist95.2:(17September1921) 4243.
219
220
morecomplexsyntheticdrugslikeSalvarsan,withhigherprofitmargins,butincompetition withGermanfirms.Inpracticemostcompromisedandcontinuedproducingbiological drugsasnewopportunitiesaroseinthefield.ThefirmofEvansSons,LescherandWebb, whichhadpreparedsomesynthetics,decidedinsteadtoconcentrateonphysiological standardisationofnaturalextractsandalsocontinuedtopreparevaccinesandantitoxinsat theirBiologicalInstituteinassociationwiththephysiologistCharlesSherringtonof

53 Liverpool(andlaterOxford), andattheirfinechemicalsdepartment,establishedin1916
54 atRuncorninCheshire.
IwillnowdescribethesizeofBritishfirmsandespeciallytheirlaboratorystaff,and howfirmsacteddifferentlyandthisbackgroundwillaidanunderstandingofthe interactionswiththeMRCTherapeuticTrialsCommitteeaswillbedescribedinthefinal chapter.ThestrategicdilemmasfacedbyBurroughsWellcomearediscussedingreater detailinthenextchapter,asdirectevidenceisavailablefromtheminutesoftheirScientific andTechnicalCommittee(STC). 5.5.1May&Baker:May&Bakerproducedfinechemicalsandinorganicssuchaslithium beforetheWar.Theirgeneralmanager,WilliamBlenkinsoppssonRichard,waswell suitedtoweighupthepossibilitiesashehadstudiedchemistryattheCity&GuildsCollege inSouthKensington.HisfatherhadbuiltupaninformalrelationshipwithPoulencof Francefrom1909,whichwasformalisedinSeptember1916afterPoulencreceiveda licensetoprepareSalvarsanderivatives.May&BakerboughtafactoryatBellLane, WandsworthandacquiredArthurEwins,theexBurroughsWellcomechemistfromthe MRCaschiefmanufacturingchemist.EwinsappointedGeorgeNewberry,agraduateof theRoyalCollegeofScience,whohelpedduringthewarandjoinedpermanentlyinMarch 1918,andCapt.R.W.E.Stickings,agraduateofKingsCollegewasappointedWorks manager.InSlinnsaccountshefoundthatfewrecordssurvivedtodocumentwartime
53
E.G.T.Liddell,CharlesScottSherringtonObituaryNoticesofFellowsof the RoyalSociety 8(1952):24170M.W.Weatherall,Gentlemen,Scientists,andDoctors: MedicineatCambridge18001940(Cambridge:BoydellPress,2000):139,170,173,221.

54
TheStoryofEvansMedicalSupplies18091959 (LiverpoolandLondon:Evans MedicalSupplies,1959):Dr.H.WolferstanThomas,theirfirstDirector,firstdescribedthe valueofAtoxylfortrypanosomiasiswhileworkingattheschoolofTropicalmedicinein Liverpool.C.Turner(ed.),GoldontheGreen:FiftyGlaxoYearsatGreenford, (Greenford:Glaxo,1985).
220
221
difficulties.May&Bakerdidwelloutofthewar.Theirnetprofitsrosefromasteady6 7,000prewartoapeakof209,000in1916.However,withthedeathoftheGeneral Managerin1918theywerecautiousinextendingtheleaseofthefactory,withtheoption topurchaseitfor25,000bytheendof1922.May&Bakerstruggledandmadeatrading lossof10,888in1921comparedwithaprofitof31,606thepreviousyearandturnover

55 felltoitslowestlevelin1922. Intheperiodfrom1923,Poulencarrangedtopurchase
sharesinMay&Bakerandin1927thefirmeffectivelybecameasubsidiaryoftheFrench firmandthefollowingyearPoulencmergedwiththeSocietChimiquedesUsinesdu Rhne.Thus,althoughMay&Bakerappearedtofailtoinvestandcommitstronglyto

56 synthetics,theyacquiredexperienceofsyntheticdrugsbytheirmerger. Inadditionto
57 EwinstherewereonlythreeotherchemistsatM&Buntil1925. In1924DrT.B.
MaxwelljoinedM&Basanassistantmanager.By1927May&Bakerexpandedtheir researchfacilitiesandemployedfourchemistsandtwopharmacists. HarryJamesBarber

58 joinedasaresearchchemistin1927andbecameproductionmanagerfrom19291934.
5.5.2Boots:HavinglostFrancisCarrin1920,Bootsregressedintotheiroldproduction methods.AfterthewarJesseBoot,sufferingfromarthritis,decidedtosellhiscompanyto theAmericanbasedUnitedDrugCompanyin1920.Duringthe1921Minersstrike,many manufacturingprocesseswereshutdownandonlyaskeletonstaffworkedinthechemical departmentatBootswithonly34chemists,includingDr.J.MarshallandH.H.L.Levene,

59 whoplayedprominentrolesintheinterwarperiod. JesseBoot,inamannersimilarto
HenryWellcome,madehugephilanthropicpaymentstowardstheestablishmentofthe
55
JudySlinn,(1984):9596G.Tweedale,AttheSignofthePlough:Allen& HanburysandtheBritishPharmaceuticalIndustry17151990 (London:Murray,1990): 125C.Turner(ed.),(1985):14.

56
J.Slinn,(1984):99126. J.Slinn,(1984):100101. H.J.Barber,HistoricalAspectsofChemotherapy:SixEssays(May&Baker,1978).
57
58
59
W.H.SimsNotes(8November1963):2Dr.J.Marshallretiredin1950andMr. H.H.L.Leveneretiredinthe1960'sCarr'sdepartureisdiscussedinS.Chapman,Jesse BootofBootstheChemist:AStudyinBusinessHistory (London:Hodder&Stoughton, 1974):127.
221
222
UniversityCollegeofNottingham,whilehisretailfirmexpandedfurtherinthehandsofhis sonJohn.Bootsdidhoweverextendtheirmanufacturingcapacitytoprepareinsulin. Manychemicalsweremadeinsmallquantitiesandweresoldtothephotographic industry,butthisbecameunprofitableaftertheremovalofimportdutiesandBootsbegan screeningofnewchemicalsagainin1923,nodoubtstimulatedbythesuccessofinsulinand arsphenamine(Stabilarsan).InsulinwasproducedfromJune1923,afterDr.Marshall visitedToronto,andarsphenaminewaslicensedfromanAmericanuniversity.Asbothwere injected,Bootshadtomasternewtechniquessuchassterilemanufacture.Inorderto

60 achievethis,bacteriologicalandpharmacologicallaboratorieswerefounded. However
thelaboratoriesweresmallandJohnBoot,sonofthefoundertookupthechallengeto developanewsiteatBulwelljustoutsideNottinghamearlyin192761 allowinga significantexpansion,astheybegantomaketheirownprocesschemicalssuchasthe oxidisingagentssodiumandpotassiumdichromate.Dr.FrankLeePyman,whohadbeenat BurroughsWellcomeuntil1914,andthenProfessorofTechnologicalChemistryatthe UniversityofManchester,joinedBootsinJuly1927asDirectorofResearch,bringingwith

62 himfivepostgraduatechemists,takingthetotaluptonine. Pymandirectedsynthetic
workonsomeglyoxalines,solubleglycerophosphatesaltsandaseriesofantiseptics.C.E. Coulthard,andJ.MarshallsupportedPymanindevelopingahomologousseriesofphenols,
63 leadingtothedescriptionofnamylmetacresolasanantiseptic. During1927Boots
producedsaccharin,finelydividedbismuth(Bismostab),potassium iodide,Glauberssalt, sulphostab,quininesalts,hexylresorcinol,aspirin,chloroform,acriflavine,insulinandliver extract,dimethylsulphate,butylchloralhydrate,benzylchloride,phthalicanhydride,and
60
61
J.Slinn,(1984):95110.
ChristopherWeir,JesseBootofNottingham.FounderoftheBootsCompany (Nottingham:TheBootsCompany,1994).
62
LeonardAndersonofBootsfinechemicaldepartmentrecommendedPymanasthe bestresearchchemistinthecountryafterSirRobertRobinson.Pymanwasinitially involvedindeterminingthestructuresofnaturalagents,mostlyalkaloidsandhormonal extractsH.King,FrankLeePyman,18821944ObituaryNoticesofFellowsofthe RoyalSociety 4(1944):681697.

63
F.L.Pyman,C.E.Coulthard,J.Marshall,TheVariationofPhenolCoefficientsin HomologousSeriesofPhenolsJ.Chem.Soc.(1930):280.
222
223
vanillin.Itwasthroughworkonpatentsforhexylresorcinolandpreparationofalkyl
64 phenolsthatamylmetacresolwasdiscovered,extendingBootsmaininterestinantiseptics.
5.5.3Howards:Howardsproducedtabletsofalkaloidsandestablishedaresearch departmentin1919,hiringDr.JohnWilliamBlagdenfromC.F.Boehringer&Sonsof Mannheim.DavidHowardwasachemist,wholikeWilliamPerkinhadtrainedunder

65 AugustWilhelmHofmannattheRoyalCollegeofChemistryinLondon.
5.5.4Glaxo: IntheearlypostwarperiodonlyAllenandHanburysandGlaxowereadded
66 tothosewhobegantoproducedrugs. ThecompanylaterknownasGlaxostartedas
Nathans.TheyhadoriginatedfromaNewZealandfirmthathadimporteddairyproduce andtooktheirnewnamefromtheirmilksubstituteadvertisedas:Glaxobuildsbonnie
67 babies. Nathans(Glaxo)grewinnichemarketsthroughdramaticallyincreasedexport
salesofnutritionalproducts,anddriedmilksubstitutesandhadalargerangeofmalted
68 productsduetoconcernsovertuberculosisinfectednaturalmilk. However,they
incorporatedscientificthinkingintopromotionalmaterial: Biologistshaveshownthatsunlightactsaseffectivelyascodliveroilin respecttothecureandpreventionoftuberculosisandricketsanditincreases phosphorusandcalciumcontent.Milkofperfectcompositioncanbeproduced onlybycowswhichareproperlysunlitandfeedinggreengrass,itselfthe productofsunlight.SuchmilkisbroughttothiscountryintheformofGlaxo 69 driedmilk. Glaxohadaturnoverofonlymin1918andtheywerejustbeginningtodevelop pharmaceuticalssimplybyaddingvitaminstotheirmilkproducts.Salesincreasedupto

70 1921beforefallingbackbetween1921and1925. Theirearlylaboratoryresearchbegan
64 65
S.A.B.Kipping,ChemistryandIndustry (25February1963):3034.
A.W.Slater,Howard'sChemicalManufacturers17971837:aStudyinBusiness History,(UniversityofLondon,M.Sc1956)Blagdenhadbeeninterredduringthewar Howards17971947(London:Howards,1947).

66
R.P.T.DavenportHinesandJudySlinn,Glaxo:AHistoryto1962(Cambridge: CambridgeUniversityPress,1992):68134G.Tweedale,(1990).
67 68 69
70
C.Turner(ed.),(1985):17R.P.T.DavenportHines,J.Slinn,(1992):29,33. G.Tweedale,(1990):9197,127,157,182,184. AdvertSunlightinMilkChemist&Druggist100.1(1924):126. R.P.T.DavenportHines,J.Slinn,(1992):46,99.
223
224
whentheyhireda17yearoldmancalledTedFarmer,whowouldplayanimportantrolein theirlaboratory.Theyalsohiredanexperiencedanalyst,NormanRadcliffe,andinJanuary 1920theytookontheCambridgegraduate,AlfredLouisBacharach,fromtheanalytical laboratoriesatBurroughsWellcomeandG.P.DoddsfromtheOxfordpublicanalysts laboratory.GlaxotookonHarryJephcott,ayoungmanwithaPharmaceuticalSociety

71 diplomaandafirstclassdegreeinchemistry. Togetherthissmallteambeganto
investigatethevitamincontentoftheirmilkproductsundervariousconditions.Davenport HinesandSlinngaveadetailedaccountoftheearlyworkonvitaminsintheirGlaxo
72 history. DiseasesduetodietdeficiencieswererecognisedbyBlandSuttonin1889and
CasimirFunkoftheListerInstitutecoinedthetermvitamin(e)in1912.Ricketswas
73 knowntobeduetoafatfreedietandcodliveroilwasbeneficial.
BacharachandHarryJephcottdiscoveredthattheirdriedmilkwasdeficientinfat solublevitamins,performingstudiesinanimalsafterthefirmwasgrantedaHomeOffice license.BacharachwasamemberoftheSocietyofPublicAnalystsfrom1919and

74 presenteddataonvitaminsatseveraloftheirmeetings. HarryJephcott,visitingan
InternationalDairyCongressinWashingtonD.C.in1923,tookthechancetovisitthe JohnsHopkinsHospitalinBaltimorewhereProf.ElmerV.McCollumclaimedtohave identifiedtheantirachiticfactor,whichhecalledvitaminD,andin1924negotiatedwith ColumbiaUniversityaprocessforextractingvitaminD,withwhichGlaxofortifiedtheir milkproducts1,000fold. TheythenproducedtheirfirstpharmaceuticalOstelinDinAugust1924,theearliest standardisedvitaminconcentrateontheBritishmarket,withanactivity2,000timesthatof codliveroil.ItwasrecommendedbytheLancetandsoonreplacedcodliveroilasa therapyforrickets,thoughcodliveroilremainedusefulasitalsocontainedvitaminAand

71
R.P.T.DavenportHines,J.Slinn,(1992),47,4950,64,667,71,87,97,114,124, 1578 C.Turner(ed.),GoldontheGreen.50YearsofGlaxoatGreenford(Greenford: GlaxoPharmaceuticalsLtd.,1985):5859.

72 73
R.P.T.DavenportHines,JSlinn,(1992):6897.
F.G.Hopkins,ThePresentPositionoftheVitaminProblem.(II)RicketsBritish MedicalJournal (27October1923):74850.

74
R.P.T.DavenportHines,JSlinn,(1992):7273A.L.Bacharach,Nutritionin RoyalInstituteofChemistry,WhatIndustryOwestoChemicalScience(Cambridge:W. Heffer,1945):1012.
224
225
iodine.In1924anAmericanresearcher,HarrySteenbockdiscoveredthatirradiation increasedtheyieldoftheantirachiticfactorfromvariousoilsandhepatentedthisprocess, securingroyaltiesfortheUniversityofWisconsin.Manyfirmspaidtoacquiretherightsto thisdiscovery,includingAbbottlaboratories,MeadJohnson,ParkeDavis,E.R.Squibb andWinthropMedicalCo.,whichforcedGlaxotodothesame,andtheypreparedtheir

75 firstirradiatedergosterolin1929.
BacharachbroughtmuchtoGlaxoincludingstatisticalanalysisofbiologicalresults andcolorimetricassaysutilisingnewultravioletspectrophotometers,andby1929Harry
76 JephcottwasaDirector. Glaxosalessufferedinthepostwardepressionandtheirprofits 77 reachedtheirlowestpointin1932beforerecoveringagain.
5.5.5Allen&Hanburys: GeoffreyTweedalecontributedahistoryofAllen&Hanburys
78 fromwhichIcansummarisetheinterwardevelopments. ReginaldHanbury,likehis
grandfatherCorneliusqualifiedasasurgeonandledthesurgicalinstrumentsdivision.The firmhadgrownsignificantlyfromastaffof20in1850to500in1915.Turnoverdoubled duringthewartoreach1m,althoughtheywereleftwithadamagedfactoryatBethnal Green.Theyreliedheavilyonthemilkandmaltedfoodbusiness,butthisplacedthemina positiontotakeadvantageofthediscoveryofvitamins,whichwereaddedtotheirexisting products.Muchoftheirotherproductsarosefromprocessingrawmaterialsintofine chemicals.Allen&Hanburyswereasmallfamilyrunfirmatthestartofthewar,having justhadthesetbackofthedeathsofCorneliusHanburyin1916andtheirchemistWilliam RalphDodddiedin1917. DespitetheirlonghistoryAllen&Hanbury'sturnoveronly reached1millionin1920withover50%duetoitsmilkandfoodproducts,despitea tenfoldrisesince1913.Theyfailedtopayadividendin1919forthefirsttimeandprofits of93,129hadtobesetagainstthelossoftheirRussianfactoryasaconsequenceofthe
79 revolution,andtheirBethnalGreensite,damagedbybombshadtoberebuilt. Theyhad
75
R.P.TDavenportHines,JSlinn,(1992):7579 Dalenotes,NIMR.(5May 1950)attheRoyalSociety,HD47.13.144underVitaminD.

76 77 78
C.Turner(ed.),(1985):18. R.P.T.DavenportHines,JSlinn,(1992):47,66,712. G.Tweedale,(1990):11559. G.Tweedale,(1990):123,248L.F.Haber,(1971):251
79
225
226
theirownexpertsciencegraduateinchemicalanalysis,NormanEvers,whojoinedthefirm in1912,havingbeenapublicanalystinBirmingham.HehadtrainedattheInstituteof
80 ChemistryandreceivedhisdegreefromKingsCollege,London. In1922theDangerous
DrugsActnecessitatedtheemploymentoftrainedandqualifiedmenandincreasedtheuse ofanalyticalmethods.Separateanalytical,research,bacteriologicalandexperimental manufacturingdivisionswereestablishedatAllen&HanburysalongtheBurroughs Wellcomelinestocheckthepurityofpurchasedmaterials.Theyalsoestablishedresearch, bacteriologicalandexperimentalmanufacturingdivisions.Thelaboratoriesoccupied120by 40feetofthetopflooroftheBethnalGreenbuilding. TheDirectorofthelaboratorieswas NormanEvers,supportedby7chemistsandanumberofassistants. Accordingto Tweedalesaccount: intheresearchandexperimentalresearchlaboratoriesworkiscarriedout withaneyetothefuture:newpreparationsaremadeinsmallbatcheswith theobjectofdiscoveringhowbesttheycanbemanufacturedonalargescale: oldmethodsofmanufactureareexaminedinthelightofrecentknowledge: investigationsaremadeupon vexedandtroublesomeproblemsinchemistry, 81 pharmacyandpharmacology,andnewmanufacturingplantistested. Asdescribedpreviously,Allen&HanburysplayedasignificantroleintheBritish manufactureofinsulinandestablishedalargemanufacturingunitatGrahamStreet,under thedirectionofFrancisCarrofBritishDrugHouses,theircollaborativepartner,andinsulin contributedsignificantlytoprofits.Glaxogrewasamajorcompetitorinthemilkbusiness andespeciallyafteraddingvitaminstoitsproductsfrom1924,atechniqueinwhichA&H followedfrom1928.A&Hwerebeingmarginalisedintheirpreviouslystrongestareaand thereforesoughtnewchannels,buthadtodowithdecliningincome.
5.5.6BritishDrugHouses: BeforethewarBritishDrugHousesofferedpurifieddrugsin
82 differentforms. Theirchairman,CharlesA.Hill,hadbeenacontemporaryofFrancis
80
NormanEvers,G.D.Elsdon,(ofAllen&Hanburys),TheAnalysisofDrugsand Chemicals(London:Charles&GriffenCo.,1919)N.Evers,ChemistryofDrugs (London:ErnestBennLtd,secondedition1933)EversbecameDirectorofResearchat Allen&Hanburysfrom1922,remainingthereuntil1952.NormanEversChemistryand Industry (25October1952):1060.

81
G.Tweedale,(1990):127. Chemists&Druggist85.1(29August1914),nearp.51adverts.
82
226
227
CarratthePharmaceuticalSocietyandacampaignerforpureandstandardiseddrugs.At theendoftheWarheturnedtohisfriendforadviceonhowBritishDrugHousescould
83 enterthesyntheticdrugarea.CarrfirstvisitedBDHinNovember1919. Hesubmitteda
detailedmemorandumofrecommendationsfortheplannedreorganisationofthefirm's researchincludingstaffingdetails,amountsofdrugstobemadeandintermediatesand
84 equipmenttobepurchased.
Theymovedforwardambitiously.FrancisCarrwasaskedtogiveanopinionof whatwouldberequiredtosetupamodernplantforBDH.InamemowrittentoHillin November1919,Carrpromisedthat:withfirstclassequipment,giventimeanychemical canbeproduced.Heestimatedthat: Areasonabletargetforachemistworkingwithtwoboyswouldbetomake15 chemicalpreparationsinayearonascaleof20kg.Withfoursuchchemists andassistantsthe60preparationswouldprobablybeaccompaniedby40 intermediatesandotherscouldbepurchasedfromdyestuffsfirms.Capitalof around8,000wouldbetiedupinstocksandthat3,200wouldbesetaside forpurchasesofintermediates.Thewagesfortheboyswouldbe2perweek togetherwiththechemistssalarybillof1,432.Inordertoattractasuitable technicaldirectorwouldrequireafurther500p.a.Afurther2,500would beneededforthepurchaseof materialssuchasreactionvessels,autoclaves, 85 mechanicalstirrers,vatsandfilters.
However,insteadherecommendeddevelopingboldly,investing0.25mandbuildinga smallscalelaboratoryandcontrolfacilities,removingthesteamplantstoasitewithrail andcanalconnections,adumpinggroundandcheappower.Thesitechosenwasat

86 GrahamStreetinLondon. WhenaskedifhecouldfilltheroleofDirector,hewasalso
boldinhisownsuggestedsalary:
83
PharmaceuticalJournal 104(14February1920).ThetextofthespeechisinCarrs archives,(8July1919),ImperialInstitute.

84
F.H.CarrtoC.AHill,(19November1919),B.CARRatImperialInstitute personalnotesofFrancisHowardCarr.
85
F.H.CarrtoC.A.Hill,(23November1919):B.CARRatImperialInstitute personalnotesofFrancisHowardCarr.
86
Helaterconfirmedtheydidspend1/4m.inChemistryintheProgressofMedicine BritishMedicalJournal (6August1927):2334.
227
228
"Myservicesmightbedear,even2,000,anddisproportionatetoother Directors.GivenasuitablefieldIamconfidentofbeingabletomakemyself worthover2,000....andwithfirstclassequipmentanychemicalcouldbe 87 producedandthedeliverytimedependedonthescaleoftheoperation". ThiswasafantasticsumatthetimeanditallowedhimtomovehousetoHampsteadand educatehistwodaughters.Hisotherconditionsincludedthecontrolofmanufacturingand

88 powersofappointmentanddismissal. Carrwouldhavealottoliveuptoandhedid.
BDHdecidedtoexpandandaimforsyntheticdrugswithFrancisCarrdrivingthem forward.TheBDHlaboratoriesdoubledtheirsizeandtheyacquiredCurling,Wymanand J.Warrenwhoemployed30trainedchemistsandabout40pharmacistsinapayroll ofover

89 1,200.
Carrcontributedtotheproductionofthyroxinandalsoinsulin,asdiscussed previously.Healsoledtheeffortstopreparepreparationsofthenewvitaminsand followinghisdiscoveryofameansofestimatingthestrengthofvitaminA byacolour reactionusingatintometer,hegavekeynotelecturesreviewingdevelopmentsin

90 preparationofvitamins.
InsummaryBritishfirmsfolloweddifferenttracksaftertheWar,butthecommon themewastodevelopnoveldifferentiateddrugs.Somedidthisbyusingvitamins, particularlyGlaxoandAllen&Hanburys,andsomedidsobyfocusingonhormonesand glandextracts.Theonlyfirmtosignificantlyenterintosyntheticdrugmanufacturewas BritishDrugHouses,buttheytoodevelopedtheirinfrastructurebaseduponlargescale productionofhormonesandAllen&Hanburyslearnedagreatdealbycollaboratingwith them.BootsandMay&Bakerturnedincreasinglytochemistryinthelaterinterwarperiod.
87
F.H.CarrArchive2130B/CARRIVPresscuttings:41.F.CarrtoC.A.Hill,re: ResearchChemists.(23November1923).
88
Chemist&Druggist92.1(14February1920):57.AtthistimeM.R.C.researchers typicallyreceived400500perannum.
89
TheBritishDrugHousesLtd.Chemist&Druggist(20February1926):254Still ProgressingChemist&Druggist(5July1919):46.
90
F.H.Carr,VitaminsPharmaceuticalJournal (18December1926):72934.
228
229
5.6ProtectingtheBritishPublic:TheMRCandNationalInstituteofMedical ResearchBiologicalStandardisationandGovernmentLegislationofDrugs. WehaveseenhowtheGovernmenttriedtoofferassistancetoBritish pharmaceuticalfirmsintheformofcapitalgrantsduringthewarandtariff protectionpost war.TheGovernmentalsoexpressedconcernsaboutthegrowingsalesofpatentmedicines toagulliblepublic,andthebiologicals,trustedbydoctorsasbeingofreliablestrengthsand yetcapableofcausingseriousharm.IhavedescribedpreviouslyhowtheBMAbroughtthe patentmedicineissuetoaheadwiththeirpublicationsSecretRemediesandMoreSecret Remedies.ThelatestBritishPharmacopoeiahadbeenpublishedaftertheoutbreakofthe war,andithadnotbeenpossibletofocusontheseissuesuntiltheendofhostilities.The wartimelegislationoftheVenerealDiseasesActbeganthisprocessandwasaimedatthe mostflagrantbreaches,suchasquackclaimstotreatsyphilis.AcommitteefortheControl ofPatentMedicineswasalsoannouncedfollowingtotherecommendationsoftheSelect Committeeonpatentmedicinesof1914tofocusonlegislationonthecompositionof patentmedicines,theiradvertisingofclaimsandwhethertheycontravenedthePoisonsAct. ThestancetakenfittedinwellwiththestringenteffortstoprovethatBritishmade
91 Salvarsanwasavalidtherapy.
WhentheMinistryofHealthwasestablishedin1920,thegovernmentimmediately tookamoreactiveroleintheHealthoftheNationandthecontrolofdrugs.Acommittee wasestablishedtoconsiderandadviseonthelegislativemeasurestobetakenforthe effectivecontrolofthequalityandauthenticityofeachtherapeuticsubstanceofferedfor

92 saletothepublicascannotbetestedadequatelybydirectchemicalmeans. The
governmentalsoenactedtheDangerousDrugsActin1920tospecificallycontrolthesale
93 ofnarcoticssuchasopiumandheroin. Addisonsoughttocontinueprotectionof
91
MinistryofHealthEnquiry.SelectCommittee1914Chemist&Druggist92.3(1 May1920):83.
92
TheControlofTherapeuticSubstancesNotAmenabletoChemicalAnalysis BritishMedicalJournal (5March1921):35758.

93
DangerousDrugsAct1920BritishMedicalJournal (15January1921):96S.W. F.Holloway,RoyalPharmaceuticalSocietyofGreatBritain18411941:aPolitical& SocialHistory (London:ThePharmaceuticalPress,1991):3925.
229
230
abrogatedforeignpatentsundertheDefenceoftheRealmActinordertomaintaindrug
94 synthesisbyBritishfirms.
ViscountAstorexplainedduringthesecondreadingoftheproposedProprietary MedicinesBillin1920thattherehadbeencompromises,butallweweretryingtodowas
95 protectthelifeandhealthofthepeople. Theissuesweretheunreliablecontentofsome
drugs,thefactthatselfprescribingledtodelaysinseekingmedicalconsultation,andthat somemedicationswereadvertisedascuringallmannerofdiseases,someofwhichwere consideredincurableinshort,dealingwiththeissueofreliabilityofclaimsmadeby manufacturers. OnewayofprotectingtheBritishpublicwouldbetoexcludeforeigndrugs.The SocietyoftheChemicalIndustry,appealedtothemedicalprofessiontouseBritish rather thanforeigndrugs: Wedonotadvertisetothepublic,nor'prescribe',norinanywaytrespasson therightfulprovinceofthemedicalpractitioneronthecontrary,werelyonthe positionthatthechemist,sofarasthemedicaluseofchemicalsisconcerned,is thehandmaidofthemedicalman,andwemightadd,ratherbluntly,wedonot recommendforeignmedicalmenandhealthresorts.Whyshouldthemedical manrecommendforeignpharmaceuticalpreparations?Thescientificstaffsin ourlaboratorieswelcomesuggestionsfrommedicalmen,andwillcarryout investigationstoelucidateproblemsconnectedwithchemistry,materiamedica 96 andthelike,whichmayproveofassistanceintheartofhealing.
Inafollowupletter,theABCMdescribedhow,attherequestoftheSecretaryofState, firmshadextendedtheirresearchandtheirmanufacturingplantinordertosecurethe productsofscienceforthewareffort.Theywrote:
94
MRCSalvarsanCommitteeMinutesMB22,(18February1920):53MaisieFletcher, TheBrightCountenance:aPersonalBiographyofWalterMorleyFletcher(London: Hodder&Stoughton,1957):320.OnAddison,seeWorksoftheMinistryofHealth BritishMedicalJournal (24July1921):135.

95
TheProprietaryMedicinesBillBritishMedicalJournal (7August1920):2149. BritishChemicalIndustriesBritishMedicalJournal (5March1921):347.
96
230
231
WehavereceivedfromanumberofoldestablishedBritishfirmsmore particularlyconcernedwiththeproductionofdrugs,anappealtomedicalmen 97 oftheBritishEmpiretosupportBritishindustry. Inhis1921addressasPresidentoftheSocietyoftheChemicalIndustry,SirWilliam

98 JacksonPope ofCambridgeUniversity calledupon
TheChemicalSociety,TheSocietyoftheChemicalIndustry,andtheInstituteof ChemistrywithperhapsthenewlyfoundedABCMto.setupawatchfuland alertjointcouncil,withdirectionstoconsidernationalquestionsinwhichanyof the variousinterestsofchemistryareconcerned,andtomakesuchrepresentationsto 99 ouradministratorsaswouldvoicethecorporateviewofthewholebody. FollowingthiscombinedlobbyingtheKeyIndustriesBill waspassedandcameinto operationon 1October1921.Itimposedadutyonimportsofallsyntheticorganicagents, andaroundseventhousanddefinedfinechemicalsaswellasdyestuffs,opticalglass, wirelessparts,laboratorywares,tungstenandfermentedchemicalsforafiveyearterm.It was: Anacttoimposedutiesofcustomsoncertaingoodswithaviewtothe safeguardingcertainspecialindustriesandthesafeguardingofemploymentin industriesintheUKagainsttheeffectsofdepreciationofforeigncurrencies, 100 andthedisposalofimportedgoodsatpricesbelowthecostofproduction. TheimpositionoftariffsinBritainpolarisedtheBritishpharmaceuticalindustry.The BritishChemicalTradeAssociation,whosememberssoldalltypesofdrugs,wasopposed totheKeyIndustry Billasitdecreasedtheiroveralltrading,manyoftheirproprietary
97
ThePositionoftheFineChemicalIndustryBritishMedicalJournal (16February, 1921):315thequoteisfromBritishChemicalIndustriesBritishMedicalJournal (5 March1921)347.

98
PopehadabackgroundsimilartoFrancisCarr.HehadbeenanAssistantProfessor attheCentralTechnicalInstitutioninLondon,thenfrom1897HeadofChemistryat GoldsmithsCollege,from190108ProfessorofChemistryattheMunicipalCollegeof Science&TechnologyinManchesterandfrom1908ProfessoratCambridge.Hewas PresidentoftheSCI19201,C.S.Gibson,WilliamJacksonPopeObituaryNoticesof FellowsoftheRoyalSociety 3(1941):290324.

99
SirWilliamJacksonPope,TheChemistsPartinTherapeuticProgressJ.Soc. Chem.Ind.(15September1922).
100
QuotedfromSafeguardingofIndustryActChemist&Druggist95.2(10 September1921):3840SeealsoTheKeyIndustryBillChemist&Druggist95.2 (24 September1921):5769MedicinalChemicals Chemist&Druggist95.2(12November 1921):6263.
231
232
101 medicinesbeingofforeignorigin. ButStanleyBaldwin,whothefollowingyearwould
havetohandlethecontroversyaroundthebillinofficeattheBoardofTrade,pointedout thattheexperienceofwaryearsshowedthegreatdangerofdependenceuponforeign
102 sources. Theethicalpharmaceuticalcompaniesacclaimedthetariffs,whichprotected
theirproductionofhighvalueproducts.Asadirectresult,inNovember1921,EvansSons, Lescher&Webbcompletelyrelinquishedtheirtradeinproprietarymedicinesinfavourof
103 ethicalmedicines.
However,protectionintheformoftariffswasnotenoughtoshieldtheBritish pharmaceuticalindustryasitstruggledthroughtheeconomicrecessionofthe1920'sand
104 founditincreasinglydifficulttoexportdrugs. EvenafterthepassingoftheKey
IndustriesscheduleoftheSafeguardingofIndustriesActin1921,itwasclearthatmany hospitalswerestillusingcontinentalremediesand:thatowingtothedutynowimposed
105 wouldhavetopaymore. Thereasonsrangedfromignorancethattheproductswere
German,throughtheuseoftradenamesandpurchasesfromwholesalers,toreluctanceon thepartoftheendusertoacceptthattheBritishproductwasasgoodasthatproducedin Germany. AttheendoftheWarthegreaterroleofgovernmentinorganisingandsetting

106 nationalprioritiesforsciencewasconfirmed. TheMRCwereplacedunderthePrivy
101 102
SafeguardingofIndustryActChemist&Druggist95.2(24September1921):57.
Dr.Murray,questiontotheBoardofTrade,MedicinalChemicalsChemist& Druggist95.2(12November1921):6263.
103 104
TheRelinquishmentChemist&Druggist95.2(5November1921):57.
OverseastradebegantoimprovebetweenJulyandSeptember1921,Chemist& Druggist95.1(15June1921):51.
105
Dr.MurrayMedicinalChemicalsChemist&Druggist95.2(12November1921): 6263.
106
ReportoftheMachineryofGovernmentCommittee,iv,Cd9230,(London: H.M.S.O.,1918)H.Himsworth,TheDevelopmentandOrganisationofScientific Knowledge(London:Heinemann,1970)A.LandsboroughThompson,HalfaCenturyof MedicalResearch,vol1.OriginsandPolicyoftheMedicalResearchCouncilUK (London:HMSO,1973):368.
232
233
107 Council,ratherthanreportingtotheMinisterofHealth. Theconnectionbetweenthe
originalMedicalResearchCommitteeandNationalInsurancefundingceasedon31March 1920,offeringgreaterindependence,andreestablishmentastheMedicalResearch
108 Council.(IcontinuetousetheabbreviationMRCforconvenience) Havingbeen
temporarilydisplacedduringtheWar,theMRCestablishedtheNationalInstituteof MedicalResearch(NIMR)atthesiteoftheoldMountVernonHospital(Hampstead)with departmentsofBacteriologyandExperimentalPathology,Biochemistryand Pharmacology,AppliedPhysiology,andStatistics.AformalDirectoroftheInstitutewas notannounced,butDalechairedtheCommitteeofdepartmentaldirectorsandwasfinally

109 appointedasthefirstDirectorin1928.
Henry DalehadalreadybeenmuchinfluencedbyhisvisittothelaboratoryofPaul Ehrlichin190304ayearpriortojoiningBurroughsWellcomepreviously.Hewrote:I cameawaywithmystoreofideas,andmyrepertoryofwaystoapproachproblemsgreatly

110 enriched. CentraltoEhrlichsthinkingwasthatisolatedactivesubstancesshouldbe
biologicallystandardised.IpreviouslydescribedhowthePharmacopoeiaCommitteeof 1909hadfirstaddressedthestandardisationofbiologicaldrugs,andtheGeneralMedical CouncilapproachedtheGovernmentaboutlegislationasearlyas1909withthe

111 concurrenceofresponsibledrugmanufacturers. Dalehadexploredtheseapproachesat
107
ThefirstmeetingoftheMRCtookplaceon7July1920,MRCCouncilMinutesII, (1920):41TheProposedMinistryofHealthBritishMedicalJournal (21April1917): 51718.

108
MedicalResearchCouncilBritishMedicalJournal (27March1920):447.The newCommitteeincludedViscountGoschenC.B.E.,MrWilliamGraham,MPfor EdinburghCentral,Hon.E.F.L.WoodMPofRipon,C.J.Bond,F.R.C.S.,Consultant Surgeon,LeicesterRoyalInfirmaryWilliamBullochMD,FRS,ProfessorofBacteriology atLondonHospital,T.J.Elliott,FRSPhysicianatUCH,HenryHeadMD,FRS,formerly physiciantotheLondonhospital,F.GowlandHopkinsFRS,Prof.ofBiochemistry, UniversityofCambridge,MajorGeneralSirW.B.Leischman,MB,FRS,Directorof PathologyintheArmyandDrNoelPaton,MD,FRS,Prof.ofPhysiology,Universityof Glasgow.BritishMedicalJournal (10April1920):51011.
109
W.S.Feldberg,HenryHallettDale18751968BiographicalMemoirsof FellowsoftheRoyalSociety 16(1970):116.

110
W.S.Feldberg,HenryHallettDale(1970):116.
111
BiologicalStandardsandtheTherapeuticSubstancesBillBritishMedicalJournal Suppl.(12September1925).
233
234
BurroughsWellcome,achievingthepostofDirectorafterDowsonwassackeddueto poorly standardisedbiologicaldrugs.AllcountrieshadbeendependentonPaulEhrlichs InstituteforExperimentalTherapyforstandardisationofbiologicaldrugsuntilAugust

112 1914. Thelackofanenforceablebiologicalstandardattheoutbreakofthewarleft
BritainbehindGermanyandAmericaastheonlygreatnationwithnosuchsystem.Dale addressedthisduringthewarwithhisworkonthestandardisationofSalvarsan,and recruitedformercolleaguesfromBurroughsWellcome,includingGeorgeBargerand ArthurJ.Ewins.However,EwinswaspoachedbytheManagingDirectorofMay&Baker in1917andBargeracceptedaChairatEdinburghUniversitytowardstheendoftheWar, leavingDalewithlimitedsupportandrelyingontrustingthefirmstodotheirown testing. Thiswasnotasoundbasisforthescrutinyofdrugs,especiallythoseofforeignorigin. EwinsreplacementwasalsosecuredfromBurroughsWellcomeon30May1919Harold King,anorganicchemistfromtheWCRLrejoinedDaleattheMRCandhispermanent
113 appointmentattheNIMRwasconfirmedinMarch1922.
ItwasDalesinitiativethatledtotheappointmentofaGovernmentCommitteeon BiologicalStandardisationasannouncedbyAddison.Hewasinstrumentalinwritingthe sectionoftheMRCreportof191920suggestingthatthereshouldbemoreresearchon standardsofbiologicalpreparationsandsera,andthatsubmitteddrugsshouldbetested

114 againstdefinedstandards,ratherthanrelyingontestingbythecompaniesthemselves. In
112
MRCMinutesII,(16December1921):181.
113
HaroldKinghadstudiedchemistryunderK.J.P.OrtonatUniversityCollege, Bangor,graduatingwithfirstclasshonours.HejoinedtheWPRLin1911andalsoworked intheExperimentallaboratoryattheWorks,andduringtheWarhemanufacturedsalicylic acid.StaffRecords,WF:Box25Kingwasappointedatasalaryof800,increasingto 900.MRCMinutesII,(24March1922):266andMRCMinutesII,(27November1923): 161SirCharlesHarrington,HaroldKing18811957BiographicalMemoirsofFellows oftheRoyalSociety 2(1937):157171.HaroldKing,ObituaryTheTimes(18February 1957)HewastheonlyfulltimerattheNIMRuntilaseparatedepartmentwasestablished in1927NIMRearlyhistory,1968,DaleArchives93HD.143.11.
114
MRCReport191920BritishMedicalJournal (10April1920):510511.
234
235
April1920Addisonappointedacommitteetoconsidernewlegislationandadministrative
115 measurestodealwithstandardsfor:
a)Agroupof'biologicproducts'asdescribedintheU.S.regulationsof1919i.e.vaccines andantitoxins. b)Potentsyntheticse.g.Salvarsananditsanalogues,ordinarydrugse.g.digitalis,

116 strophanthus,ergot,cannabisindicaandpituitarygland.
DaleestablishedaCommitteeonBiologicalStandardsandAssaytocoordinate
117 researchondeterminationandmaintenanceofbiologicalstandards, whichincluded
Prof.WilliamBulloch,ProfessorofBacteriologyoftheLondonHospital,Prof.George DreyeroftheDunnSchoolofPathologyinOxford,C.J.MartinoftheListerInstituteand MRCSecretary,WalterM.Fletcher.TheCommitteeawardedgrantstoresearchers

118 standardisingbiologicaldrugs.
TheprincipalcentreforbiologicalstandardisationbecametheDepartmentof BiochemistryandPharmacologyattheNIMRledbyDaleandheattractedseveralmore formerBurroughsWellcomecolleaguesincludingJoshuaBurn,whojoinedhiminJuly

119 1921. In1920justbeforetheirownreorganisation,theMRChadofferedagrantof 120 600toBurnforstudiesofbiologicalstandards. By1920hehadservedinthearmy
115
TheadvisorycommitteeconsistedofSirGeorgeNewman,Chairman,Ministryof Health,Mr.JohnJeffrey,ScottishBoardofHealth,SirThomasHouston,Ministerof HomeAffairs,NorthernIreland,Dr.HenryDaleoftheMRCSirNestorTizzard,G.M.C., Dr.C.U.Hawthorne,B.M.A.,Dr.J.H.Burn,PharmaceuticalSocietyandProf.J.F. Tucker,InstituteofChemistry.EdmundWhiteandF.W.Gamblewereappointedas witnessesTherapeuticSubstancesBillChemist&Druggist99.1(4August1923):183.

116
ReportoftheDepartmentalCommitteeonControlofCertainTherapeutic Substances(London:HMSO,1921)TheControlofTherapeuticSubstancesnot AmenabletoChemicalAnalysisBritishMedicalJournal (5March1921):3578.

117
118 119
MRCMinutesII,(7July1920):82,101. MRCMinutesII,(15October1920):138(10December1920):192.
BurnwasappointedtothestafffromJuly1921ataninitialsalaryof500p.a. MRCCouncilMinutesII,(18March1921):105.
120
MRCCouncilMinutesII,(20March1920):72.
235
236
121 andcompletedamedicaldegreeinCambridge. In1921PercivalHartleywasrecruited
fromBurroughsWellcometotheNIMRasDirectorofBiologicalStandards.Hartleyhas notbeendescribedpreviouslybecauseheonlyjoinedBurroughsWellcomein1919, workingondiphtheriaantitoxinfor2years. HehadafirstclassdegreefromThe YorkshireCollegeoftheVictoriaUniversity(laterLeedsUniversity),studyingand researchingorganicchemistryunderJ.B.Cohen,andafterabriefperiodinOxford,hewas attheListerInstitutein190608,andthenperformedresearchandlecturedinphysiology atSt.ThomasHospitalinLondon.HartleythenperformedresearchinIndiafrom1909, returningtotheListerin1913,whereheworkedwithDaleuntilhiswarpostingabroad

122 withtheRAMCin1915. DalealsosecuredanotherformerBurroughsWellcome
colleague,Dr.PatrickP.LaidlawtoruntheNIMRbacteriologydepartmentinDecember 1921.DalethensecuredHaroldW.Dudley,achemistwhohadbeenworkinginDakins laboratoryinNewYork. ThefirstworkonbiologicalstandardsattheNIMRwastocharacteriseextractsof posteriorpituitarylobe,aglandfoundatthebaseofthebrain,andofneoarsphenamine, anotherarsenicalfortreatingsyphilis.JustpriortotheWar,Dalehaddescribedthe stimulatoryactionofpituitaryextractsontheuterusandsuchextractshadbeenusedto controlcontractionsduringchildbirth.InMay1921theObstetricSectionoftheRoyal

123 SocietyofMedicineestablishedaCommittee,includingDaletoevaluateitsuse. Assays
performedagainststandardsbyBurnshowedveryvariablestrengthsofthedifferent manufacturersbrandsofpituitaryextractandsometimesthisvariabilityledtouterine
124 rupture. Thecommitteeagreedthatitwasimportanttohavetherightstrengthof
preparation:aremedyofgreatvaluewhenaccuratelyused,maywheninaccurately
121 122
A.S.Milton,BurnOxfordforaStartBrit.J.Pharmacology 119(1996):12939.
H.H.Dale,PercivalHartley,18811857BiographicalMemoirsofFellowsofthe RoyalSociety 3:81100P.Hartley,Obituary,TheTimes(18February1957),HD 38.16.16SirPercivalHartley,ObituaryBritishMedicalJournal (23February1957)466.

123
MRCMinutesII,(27May1921):78W.S.Feldberg,HenryHallettDale(1970):
120.
124
J.H.Burn,H.H.Dale,StandardisationofPituitaryExtractBritishMedicalJournal (2December1922):1087OnthePhysiologicalStandardisationofExtractsofthe PosteriorLobeofthePituitaryBodyMRCReportsonBiologicalStandardsSpecial ReportsSeries69.
236
237
125 employed,producedangerousandevenfatalconsequences. Othertestsperformedby
theMRCshowedthatbiologicalextractssuchasstrophanthin,thecardiacglycoside
126 extractedfromtheseedsof Strophanthusgratus,byThomasFraserinEdinburgh, (and
previouslyusedbyIndiansforpoisonarrows)alsovariedinstrengthbyupto80fold.127 AsaresultoftheseveryvariablefindingsandwiththeMRCobtainingthepatent rightstoinsulinfromtheUniversityofToronto,(ofwhichmoreinthenextchapter),Dale campaignedforlawstogivetheNIMRtheauthoritytocontrolbiologicalstandardsand therapeuticsubstancesbylicensingofmanufacturers,inspectionofplant,premisesand processesandtestingmarketedproducts.128 Oneplanwastolicenseforeignfirmsto ensureeachconsignmentattainedtherequiredstandards.However,Addisonrecognised

129 thatitwasnotpracticableandthattheMRCshouldsupervisewhatevertestsrequired.
Dalewaskeentoextendtherequirementforstandardisationtootherbiological drugsandtocreateasystemofInternationalstandards.Dr.ThorvaldMadsen,Directorof theStateSerumInstituteinCopenhagen,whohadrecentlybecomethePresidentofthe HealthCommitteeoftheLeagueofNations,arrangedameetinginLondonon12 December,1921todiscussthepossibilityofcreatinganinternationallyrecognisedcentre

130 fromwhichreferencesamplesofallantitoxinseracouldbedistributed. Thefirst
125
StandardisationofPituitaryExtractBritishMedicalJournal (2December1922): 1087.

126
TheLateT.R.FraserChemist&Druggist92.1(17January1920):65.
127
ReportonBiologicalStandards.PituitaryExtracts.I.PituitaryExtractsSpecial ReportSeries69(London:HMSO,1922)J.H.Burn,J.W.Trevan,TheStandardforthe BiologicalAssayofStrophanthusPharmaceuticalJournal (1928):117:439J.H.Burn, U.J.GrewalTheStrengthoftheTinctureofStrophanthusB.P.andofSamplesof StrophanthusRelatedtotheInternalStandardOuabainQuart.J.Pharmacology 2(1921): 1W.Sneader,DrugDiscovery:theEvolutionofModernMedicines,(London:John Wiley,1985):138.

128
ReportofDepartmentalCommissiononControlofcertainTherapeuticSubstances, Ministry ofHealth(London:HMSO,1921)

129
130
StandardisationofSerumsetc.BritishMedicalJournal (12March1921):399.
A.A.Miles,BiologicalStandardsBritishMed.Bull.7(1951):283E.Buelbring, J.M.Walker,JoshuaHaroldBurn(18921981)BiographicalMemoirsofFellowsofthe RoyalSociety (1981):4589.
237
238
InternationalstandardswereagreedbetweenFrance,theUSA,GermanyandBritainfor
131 diphtheriaandtetanusantitoxinsataconferenceinParisin1922.
Earlyin1922theMRCcreatedaseriesofsubcommitteestoestablishstandardsfor variousbiologicaldrugsandsera,includingantituberculosis,antimeningococcalandanti pneumococcalsera,antidysentericfeverandafourthforantidiphthericandantitetanic

132 sera. R.A.OBrien ofBurroughsWellcomewasincludedinthelasttwocommittees. 133 LeonardColebrook oftheNIMRstaff,whowasamemberoftheantimeningococcal
andantipneumococcalteam,wassecondedtoworkandlectureatSirAlmrothWrights
134 unitatSt.Marysfortwoyearstolearnmoreaboutvaccines.
Followingtherevelationsofseveralantitoxinsandseraofvariablestrengthand especiallytheimplicationthattheseweremostlyofforeignorigin,theTherapeutic SubstancesActsweredraftedtomakeitobligatoryforsamplestobetested.Itwasalso recognisedthattheultimatewayinwhichtostandardiseabiologicalextractwasasstated intheMRCReportof1922: Theabsenceofofficialstandardsofvalueandauthenticityfordrugsofthis kindandfornumerousbiologicalpreparations,suchasserumsandthelikeused ingeneralpracticehasbeenpubliclydenouncedasdiscreditabletoournational positionintheworldofscienceandasourceofgravedangertothe community.Itwouldbeagreatadvantageifastablechemicalsubstancecould bepreparedofknownchemicalcompositionwhichactedontheuterusinthe 135 samewayasthepituitaryextract.
131
MRCCouncilMinutes(1922.):385DalechairedameetinginGeneva.International standardswereadoptedforpituitary(posteriorlobe)extract,neoarsphenamine,digitalis andinsulin.StandardsatLeagueofNationsH.H.DaleArchives,RoyalSociety,93HD 143.3.

132 133
MRCMinutesII,(20January1922):189.
C.L.Oakley,LeonardColebrookBiographicalMemoirsofFellowsoftheRoyal Society 17(1971):91138.

134
MRCMinutesII,(24March1922):272(22February1924):116Z.Cope,Almroth Wright,FounderofModernVaccineTherapy (London:Nelson,1966).

135
ReportonBiologicalStandards.PituitaryExtracts.I.PituitaryExtractsMRC SpecialReportSeries69(London:HMSO,1922) BritishMedicalJournal(2December 1922):1087.
238
239
MeanwhiletheTherapeuticSubstancesActtargetedtowardsforeigndrugswasstillbeing guidedthroughparliament.AstatementfromdiscussionsintheHouseofLordsinAugust 1923emphasisedthat: Itisessentialthatdoctorswhenwritingprescriptionsshouldbesurethatthe patientwillhavewhatheintendshimtohavewiththeaimtoensurethatthe standardofgoodscominginshouldbeashighasthearticleswhichwe 136 ourselvesmanufactureinthiscountry. InfactsomegroupssuchastheNorthBritishBranchofthePharmaceuticalSocietysaw noreasontothinkthatthepresentmethodsbywhichthesesubstancesareproducedand placedatthedisposalofthemedicalprofessionandpharmacistsgaveanyoccasiontofear
137 thatadequateprecautionswerenottakentoprotectthepublicintent. Yetby1924the
MRCwasoverrunwithassaystoperformandfrom17July1924theInsurance Commissionagreedtoallowatrialperiodofaround2months,duringwhichBritish manufacturerswereallowedtoperformtheirowntestsontheinsulin,whichtheywerethen producing,withcontrolbatchesbeingsenttotheNIMR.AsmallamountofUSinsulinwas importedbuttheUStestsweretrusted. ArowoccurredbetweentheMRCandtheCanadiansoverthestandardunitsof insulinafterthelattergroupchangedthem.Dalechairedaheateddebateatameetingin Edinburghin1923aboutwhethertouseratormouseunits,andeventuallytheMRC definitionwasupheld. ThemuchdebatedTherapeuticSubstancesBillwasfurtherdelayedin1924bythe attentionfocusedupontheeconomy.TheBillrecommendedthatsubstancesthatcouldnot betestedchemicallyshouldbesupervisedunderacommitteeofthePrivyCouncilassisted byanadvisorycommittee:ItisrecognisedthattheMRCwhichalreadypossessesthe requisiteorganisation,shouldberesponsibleforthiscentrallaboratory. EthicalmanufacturerssoughttocollaboratewiththeMRCtodefinestandardsfor biologicals,tofurtherdistinguishtheirethicaldrugsfrompatentandproprietarymedicines andtobeabletoexportdrugstoAmericaandEurope,wheretightlawsonbiological
136 137
TherapeuticSubstancesBillChemist&Druggist99.1(4August1923):198. TherapeuticSubstancesChemist&Druggist100.2(19April1924):568.
239
240
138 standardisationofbiologicalproductsalreadyexisted. TheMRCwastoactasa
regulatorandprotectortopreventthesaleinBritainofproducts,whichhadalreadyfailed
139 testsinothercountries,includingGermany. Theywereparticularlyconcernedaboutthe 140 toxicityofthearsenobenzols.
In ordertorelievethealreadyoverworkedlaboratoriesoftheNIMRitwas proposedattheendof1924thatthePharmaceuticalSocietywouldestablishalaboratoryif
141 theTherapeuticSubstancesActbecamelaw. DaleandFletchersupportedthe
TherapeuticSubstancesAct,whichwaspassedon23June1925,tomarkthebeginningof formalisedStatemonitoringofdrugs.Itcoveredsubstancesthatcouldnotbechemically analysedandneededindirecttestsi.e.vaccines,sera,toxins,antitoxins,antigens,Salvarsan,

142 insulin,andpituitarylobeextracts. LiketheAmericanguidelines,itaskedfor
manufacturerstokeeprecordsofdistributionofbatches.Dalewasopposedtoaclausein theguidelinesallowingindividualdoctorstobeabletoimport.Hewasconcernedthat unscrupulousforeignmanufacturersmightusetheirmachinerytogetobjectionable

143 substancesintothecountry.
Inparallel,theGeneralMedicalCouncil(GMC)invitedadditionsandamendments totheBritishPharmacopoeia,followingsuggestionsfromProfessorsofPharmacologyand MateriaMedica,pointingoutpreviousdefectsthatneededtoberemedied.TheMRC
138
B.G.Rosenkrantz,PublicHealthandtheState(CambridgeMass1972):1236J. Liebenau,MedicalScienceandMedicalIndustry:ChangingViewsinMassachusetts1842 1936,theFormationoftheAmericanPharmaceuticalIndustry (Basingstoke:Macmillan, 1987):325ff,396.

139
Of75remediesanalyzedearlier,asmanyas48weredangeroustolifeand11more wereinjurious.SecretRemediesandtheGermanMedicalPressBritishMedicalJournal, (30April1921):649.

140
InMarch1924HarrisonvisitedthePasteurInstitutetodiscussanobserveddecrease oftheefficacyofStovarsolMRCSalvarsanFileMB22,(6March1924):89
141
MRCMinutesII,(24October1924):136BiologicalStandards,Therapeutic SubstancesBillBritishMedicalJournal (7August1925),suppl.and(12August1925): 105.

142
TherapeuticSubstancesBillBritishMedicalJournal (1925):176,234,273Dale Archives,93HD21.293HD126.

143
TherapeuticSubstancesRegulations,DaleArchives93HD21.2.126)1925.
240
241
establishedasubcommitteeinvolvingElliott,Wallace,DaleandFletcher,whichmetwith theGMCtoreviewthesetherapeuticguidelines.144 Dalecontinuedtopushfor

145 InternationalStandardsandafurthermeetingtookplacein1925.
JoshuaBurnwasappointedDirectoroftheLaboratoryatthePharmaceutical
146 Societyon24October1925,whichbecameoperationalatthestartof1926. Rather
thanjustperformroutinetests,heexploredthereasonsfortheirvariationandrecognised thatdifferenceswerenotonlyduetovariationinthemechanismofextraction,butalsoan inherentbiologicalvariabilityofactionandresponse. Burnwrote: Thesurprisingfactwasestablishedthatthedoseperbodyweightrequiredto produceoestrusin50%ofovariectomisedmicewasthesameasforrats,when resultswereexpressedasameaneffectinagroupofanimalsandarevolution ofthinkingwasrequiredbeforeitwasrealisedthatallresponsesmustbetaken intoaccountincludingtheoddonesandthatthecorrectresponsewasthemean 147 ofallthesevaryingresponses. InDecember1926,thenumericalmethodsappliedtobiologicalstandardisationwere strengthenedfurtherbytheappointmentofJohnHenryGaddum,anotherformer BurroughsWellcomeman,tothebiochemistryandpharmacologysectionoftheNIMR. GaddumhadqualifiedatCambridgeinMathematicsandMedicineandstudiedinthe famousphysiologydepartment,andthenatUCH,London.GaddumthenworkedunderJ.
148 W.TrevanattheWellcomeResearchLaboratoriesfromJanuary1925.
BurncollaboratedcloselywithTrevanandrecognisedthatamathematicalmodel couldbedevelopedtounderstandthestatisticsofbiologicalvariation.Heproposedthat differencesofstrengthinanimaltestswereduetotheinherentvariabilityoftheanimalsor
144
MRCMinutesII(16October1925):151MRCMinutesII(29January1926):11(5 March1926):32and(28May1926):94.
145
InternationalCongressofBiologicalStandards,DaleArchives,93HD146.4II.
146
BurntestedmanufactureddrugswithhiscolleaguesDr.KatherineCowardandH. W.Ling,whobeganasaboywithDale.HisappointmentwasdiscussedintheMRC MinutesII(1924):136.Burnbuiltupadepartmentbetween1926andSeptember1937, whichledtheworldinbiologicalstandardisation.

147
TheVariation intheUnitoftheOestrusProducingHormone,J.H.Burn,K.H. Howard,JournalofPhysiology (London)63(1927):270.

148
W.Feldberg,JohnHenryGaddum19001965BiographicalMemoirsofFellows oftheRoyalSociety 13(1967):5777.
241
242
organs,andthesealsovariedfromdaytodayinthesameanimals,formingthebasisfor
149 alwaysneedingtocomparetheresultsagainstaknownstandard. BoththeMRCandthe
PharmaceuticalSocietyadoptedBurnandTrevan'srevolutionaryconceptsastheyfitted intotheirownschemesofindependenttestingandthedevelopmentofinternationally
150 definedstandards.
Justaheadofthe1927TherapeuticSubstancesAct,NormanEversgavea presentationtotheRoyalSocietyofArtsonChemistryandtheSupplyofDrugsinwhich heemphasizedthegrowinginfluenceofchemicalapproachestodrugdevelopment. Whereasattheendofthenineteenthcenturytherewaslittlestandardisation,afirmnow producing1,000drugsneededtohavechecksinplace: Themedicalprofessionmustbeprotectedandthepublicmustbeprotected againsttheintroductionofnewdrugswithexaggeratedstatementsof efficacy.Theliteratureofsyntheticdrugmanufacturesofthesetimesindeed remindoneofrosecataloguesratherthanscientificproductionsinthe 151 unstintedpraise. Chemistrynowcontributedtotheisolationoftheactiveprinciplesofnaturaldrugs,the elucidationoftheconstitutionofnaturaldrugs,thesynthesisofnaturaldrugs,the modificationofthestructuretochangethephysiologicalaction,preparationofpure suppliesofinorganicdrugs,thepreparationofdrugsinaformsuitableforadministration andanalyticalcontrols.AnewdepartmentwasestablishedatthePharmaceuticalSociety
152 fortestingvitaminsfromAugust1927. Despitetheestablishmentofformalisedtesting,
theTherapeuticSubstancesActcouldonlypreventovertmalpracticeandcarelessness. SubsequentlytherewereminorchangestotheTherapeuticSubstancesActfrom21st
149
ThestatisticalmethodsinJ.K.Trevan'spaperwerediscussedextensivelywithDale priortopublicationandwereroutinelyappliedtothetestingofthepotencyofvitamins, digitalis,cocaine,anddysenterytoxintoestablishdoseresponsecurvesStatistical MethodsforEstimationofBiologicalVariationsinToxicityDetermination,Proceedings oftheRoyalSociety(Biology)101(1927):483512.

150
TheyalsohadagreatinfluenceuponthethinkingofotherMRCstatisticianssuchas GaddumandespeciallyAustinBradfordHill,whowastoplayamajorroleindeveloping clinicaltrialsmethodology.A.B.Hillpersonalcommunications,including6October1988.

151
N.Evers,ChemistryintheSupplyofDrugs,PharmaceuticalJournal 106.1(12 February1927):16466.

152
Standardisationofremedies,Lancet(10March1928):508.
242
243
February1927,andeffectivefrom6February1928.Thesecoveredpracticalities,suchas moredetailedconditionsconcerningthetypeof containersandthelabeling,includingthe dateofmanufacture,potency,andlikelydateofexpiry.Boththeproprietaryandscientific namehadtobegivenonthelabel.Therewerenewrulesconcerningtheneedforadequate staff,premisesandplant,properhousingofanimals,andkeepingrecordsofbatchesof

153 drugspreparedandtested. Thelawstatedthatnewsampleshadtobeforwardedtothe
MRCfortestingandnomaterialscouldbesoldafterreachingtheirexpirydate.Resales wereprohibitedinthesamecontainersanddetailsofthepurityandmicrobiologicalcontent
154 hadtobeestablished.
Markedvariationofstrengthsofstrophanthinandpituitaryextractremainedan
155 issuein19289,yetthenumberoffirmsproductsbeingtestedwasstilllimited. The
AnnualReportofthePharmacologicalLaboratoriesofthePharmaceuticalSocietyfor1929 showedthatonly153sampleswereassayed,andthemajorityofthetestsweredoneon
156 fourofthemostdifficultmedicinestostandardisebutalsothemostimportant.
ThepublicationMethodsofBiologicalAssay,byJ.H.Burnin1928begantobe
157 referredtoas'thebible'forbiologicalstandardisation. In1930Burnsummarisedthe
principlesofbiologicalstandardisation:thetestsmustbecomparative,andtheymustbe basedonaquantitativedeterminationoftheanimalvariation...theseprincipleshavebeen
153
TherapeuticSubstancesRegulations(21February1927)(31May1927)Dale Archives93HDBox21.2126147(192562).
154
TherapeuticSubstancesActBritishMedicalJournal (16April1927):737The TestingofTherapeuticSubstancesChemist&Druggist(23April1927):499502.

155
U.G.Bijlsma,J.H.Burn,J.H.Gaddum,AComparisonoftheOxytocicPressor andAntiDiureticActivitiesofCommercial SamplesofPituitaryExtractQuarterlyJournal ofPhysiology 1(1928):494.

156
Testswereperformedonpituitaryextract46,digitalis39,squill30,ergot23, strophanthus6,ovarianextract3,insulin2,andothers4:alsoonnewgrowthfactors, vitaminA39,vitaminB1andB218,vitaminC3,vitaminD72,andothers4.,Reportof thePharmacologicalLaboratoriesofthePharmaceuticalSociety (1929).

157
Prof.H.R.Hausler(whohadworkedatNIMR)toH.H.Dale,(21December 1945),DaleArchives,HD38.16J.H.Burn,MethodsofBiologicalStandardisation (Oxford:OxfordUniversityPress,1937).
243
244
showntobecapableoftransformingthewholesubjectfromtheplaneofaninsidious
158 meansofselfdisciplinetothatofawellorderedandprogressivescience.
Duetothepracticalimpossibilityofmaintainingoverseasstandardsforeach
159 medicine,insteadtheimporterwaslicensed,andin1930sixlicenseswerecancelled.
Regionalmedicalofficerscollected555suspicioussamples,ofwhich 44wereofbelow strengthdiphtheriaantitoxinandtwo'foreign'preparationswerewithdrawn.Three samplesofvaccinelymphwerewithdrawnbecauseofconcernsaboutsterility,andafter furtherproblemsofsterilitytheTherapeuticSubstances(Catgut)regulationsofJanuary 1930wereintroducedbecauseoftheuseofunsterilisedcatgutinsurgery,anda consolidatedsetofRegulationswasissuedin1931withaddedguidelinesstandardisinggas

160 gangreneantitoxin.
Theworkonbiologicalstandardisationreflectedacontinuityofoperationincluding
161 Dale,Brown,Burn,Gaddum,TrevanandUnderhill. EventuallythePharmaceutical
SocietyLaboratoriesbecamepartoftheCollegeofPharmacy,withBurnbecomingthefirst Prof.ofPharmacologyandsubsequentlyin1933,DeanoftheCollegeofPharmacy, renamedtheSchoolofPharmacyofLondonUniversityin1937.In1937hesucceeded

162 GunnatOxford,remainingthereuntilhisretirementin1959.
Inconclusion,inthedecadeaftertheWar,firsttheMRCandthenalsothe PharmaceuticalSocietyestablishedlaboratoriesfortheroutinetestingofbiological
158
J.H.Burn,TheErrorsofBiologicalAssayPhysiologicalReviews10(1930): 14661.
159
DifficultyRegardingAdoptingStandardsofProductsfromOverseasLicensethe ImporternottheManufacturerBritishMedicalJournal (27June1931):588.

160
Therewerespecificguidelinesforvaccinesofantityphoid,antiTAB(typhoidand paratyphoid),TABC(typhoid,paratyphoidandcholera),plague,dysentery,whooping cough,tuberculosis,theSchicktest(toxinandcontrol),diphtheriaprophylactic,tuberculin, tuberclevaccine,diphtheriaantitoxin,andtetanus,arsenobenzenes,novarsenobenzeneand Sulpharsan.StateControlofTherapeuticSubstancesBritishMedicalJournal (27June 1931):588TheMRCtestedover300kindsofcatgut,vaccinelymph,antiserafortoxinof B.welchii,antidysentaryserum,strophanthustincturesandeverybatchofarsenobenzines: MRCReportSeries192930(London:HMSO,1930) BritishMedicalJournal (14March 1931):4468:DaleArchives,93HD21.2.1289.
161 162
Quart.J.Med(1932)5:33. A.S.Milton,BurnOxfordforaStartBrit.J.Pharmacology 119(1996):12939.
244
245
substances.Thestaffinvolved,manyfromBurroughsWellcome,alsoperformedresearch onthefundamentalprinciplesofbiologicalvariation,andplayedanimportantrolein establishingtheTherapeuticSubstancesActs.Thusaseriesofmeasureswerebeingputin placetoprotecttheBritishpublicfromunscrupulouspatentmedicines,frominadequately controlledpharmacopoeialdrugsandfromunstandardisedbiologicals,particularlyfrom abroad.ThesemeasuresalsoprotectedthedevelopingBritishpharmaceuticalindustryand Britishscience.
5.7ChemicalWorkersinBritainFrancisCarrandChemicalEngineering. SomeofthelongertermproblemsfortheBritishpharmaceuticalindustrythat weredescribedinchapter4hadbeguntobeaddressed,butmuchmoreneededtobedone.

163 Theintroductionofscientifically trainedpoliticianssuchasAlbertMond, chairmanof
BrunnerMond,intotheGovernmentin1916hadhelpedtodrawattentiontotheurgent needfortechnicallytrainedprocesschemists,andplantmanagers.Therehadbeenaclear movementduringthewartorecognisetheimportanceofscience,withthecreationofthe

164 DSIRandaCommitteeontheNeglectofScience,formedinMay1916.
Experienceinsome'unitprocesses'hadbeengainedintheOrdnancefactories,laid outinarationalmanner,withorganisedmaterialshandling,standardvessels,andefficient production,butmostchemistshadnopreviousexperienceofpreparinghighlypurified sterilesyntheticdrugsonamanufacturingscale.Thepharmaceuticalindustryneeded chemicalengineerswhocouldnotonlyperformchemicalsynthesis,butalsohadthe

165 engineeringskillsrequiredtoscaleuptomanufacturingcapacity. J.Lewskovitsch,
163
AlbertMondwasthechairmanofBrunnerMondfrom18941916,retiringin1923.J. Chem.Soc.(1931)II:332439W.J.Reader,(1970):4823.
164
D.S.LCardwell,TheOrganisationofScienceinEngland(London:Heinemann,2nd edition1972).
165
L.F.Haber,(1971):359.
245
246
whoactedasaconsultanttoBurroughsWellcome,hadusedthetermchemicalengineer
166 inBritainasearlyas1906butsuchchemistswererarities.
BythetimethatCarrjoinedBritishDrugHousesin1920hewasoneofthemost importantchemicalengineersinthecountry.ThefourpresidentsoftheChemicalSociety, InstituteofChemistry,SocietyoftheChemicalIndustryandPharmaceuticalSociety selectedCarrtogivetheprestigiouslecturecommemoratingtheworkofE.F.Harrisonat

167 theBritishPharmaceuticalConferenceinJuly1919. Shortlyafterwards,hewas
awardedaC.B.E.forhiswartimedrugproductions.In1921hecapturedthisexperience bypublishinganimportanttextonorganicmedicinalchemicals,whichdetailedmethodsof
168 productionofmanynewdrugs. Carrdevelopedaspecialinterestinthetrainingof
chemistsandgavealectureonthesubjecttotheSocietyoftheChemicalIndustryin1921. Inhiskeynoteaddressonthesubjectofpostgraduatetraining,fortheopeningofImperial CollegeofScienceandTechnology,Carracknowledgedthatastrongalliancebetween

169 universitiesandindustrywasessential. Thenumberofchemistsenteringmanufacturing
firmswasinsufficientforagrowingindustry,requiringprocesscontrol,researchand
170 analysis. Carrplayedanactiveroleonthecommitteesofvariouschemicalsocietiesand
usedthisplatformtocampaignforbettertrainingofchemistsandforchemicalengineering
166
J.LewskovitschtoF.B.Power,(9August1906),WF:88/94:41. HarrisonMemorialLecturePharmaceuticalJournal 103(July1919):34,53. MarmadukeBarrowcliffandFrancisH.Carr,(1921).
167 168 169
F.H.Carr,PostgraduateTraininginIndustrialChemistry,J.Societyofthe ChemicalIndustry (16May1921fromatranscriptat2130B/CARRF.H.6atImperial College.SeveralhundredthousandpoundswasstillneededtoequiptheDepartmentof ChemicalTechnologyofImperialCollege.TheSouthKensingtonsiteincorporatedthe RoyalCollegeofScience,theRoyalCollegeofMines,andtheCityandGuildsInstitute CentralTechnicalCollege,leadingtothefoundingofImperialCollegein1908. D.S.L. Cardwell,2ndedition1972):1978,228.

170
ReportoftheUGC,(London:HMSO,1921),Cmd1163:12:M.Sanderson,The UniversitiesandBritishIndustry18501970(London:Routledge&KeganPaul,1972).
246
247
tobeaffordedacademicstatus.171 Thefirstchairinchemicalengineeringwasassignedin
172 1923atUniversityCollegeLondon.
ThelargestlaboratoryinBritainwasthatoftheBritishDyestuffsCorporation (BDC),whichhadaresearchstaffofaround150byJanuary1923,butthisstillcompared
173 withover1,000inthelargestGermanconglomerate. Britishdyefirmshadnottakenup
thechallengetoinvestforthefuture.BDC'sresearchstaffactuallyfellfrom50to30over
174 theperiod19201923andwas19in1924.
Carrwaspartofagroupadvocatingtheunionofchemistrywithchemical engineeringasanacademicdiscipline.Carrfeltthatathreeyearacademiccoursedidnot adequatelyqualifyachemistforpracticeandthatafurtherpostgraduateyearwas required.Trainedchemistsneededtoknowhowtoreactifchemicalreactionsproceeded alongunexpectedlines.Theyneededtoincreaseyields,andreducelabourcosts,suggest appropriatematerials,understandthermodynamics,chemicalkinetics,fueleconomy, constructionofplant,andengineering.Theserequirementswereespeciallyacuteinthe pharmaceuticalindustry,wherecontinuousproductionprocessescouldnotbeused,sofine chemicalstendedtobebatchprocessed.Quitesmallchangesofconditionscouldresultin largechangesofyields,andhencecosts.Inaddition,themodernmanufacturingchemist neededtolearnsomeaspectsofmanagement,costingandaccountancy.Carrhadastrong platformforhiscaseashisfamespreadinternationallyfollowinghislargescaleproduction
175 ofinsulin,makingBritainselfsufficientin1923(discussedinchapter6).
171
F.H.CarrarchivesatImperialCollege,LondonB.CarrFH6 notesmadebyA.E. GuentherafteraconversationwithF.H.Carr,Winter19667.

172
D.B.Keyes,HistoryandPhilosophyofChemicalEngineeringEducation,Chemical EngineeringProgress49(1952):635G.G.Haselden,ChemicalEngineeringandits EducationalChallenge(Leeds:LeedsUniversityPress,1961)W.F.Furter(ed.),History ofChemicalEngineering (Washington:AmericanChemicalSociety,1980).

173 174
175
M.R.Fox,(1967). L.F.Haber,(1971):355.
TheChemicalAge(24April1926):405 NatalMercury (30June1927) DailyNews (5July1927),Columbia,Ceylon.CuttingsandnotesfromCarrArchivesatImperial College,2130B/CARRIVInsulinanditsManufactureRoyalSocietyofArts(26 February1927):263.
247
248
IvanLevinsteinrecognisedsimilarrequirementsfordyestuffschemists,sayingit
176 required5yearstrainingplus2yearsacquaintanceinordertobefullyfunctional. He
requiredcompetentworksmanagerswithknowledgeofscience,engineering,and quantitativethinkingonquestionsofenergyandhewasloathtotakeonforeignchemists
177 insteadofourown. However,Britishuniversitychemistscontributedmostlyto 178 theoreticalratherthanthemoreurgentlyneededpracticalknowledge.
Carr,alreadyanexamineratLondonUniversity,foughtlongandhardagainstthe closureofFinsburyTechnicalCollegeunderSirWilliamJ.Pope,afteritwasannouncedin
179 May1924thatitwouldcloseinJuly1926. InOctober1926CarrwaselectedPresident
oftheSocietyofthePharmaceuticalIndustry,andgavehisinauguraladdresstotheAnnual meetinginManchester: Theengineerwhohasanadequateperceptionofthenicetiesofthe requirementsfromthechemistsangleofvisionisasrareastheDodoanda chemistwithsufficientknowledgeisrare.Chemistsblameengineers,plant 180 makersandprocessworkers.
Therewasanabundanceofchemists,butalackoftrainedengineers.TheInstituteof Chemistryheldengineeringexaminationsfrom1926,soprogressbegantobemade,butfor alongtimethemainmethodofgainingexperiencedstafffortheimmediatefuturewasto trainthemonthejoborpoachexperiencedstafffromanotherfirm.Suchhadbeenthecase withCarrhimself. Inorderthatanindustrymayobtainpracticalvalueforscientificresearch,itis absolutelynecessaryforatleastanadequateproportionofthosewhooccupy responsiblepositionsintheindustrytohaveascientifichabitofmindtheir
176
SocietyoftheChemicalIndustryChemist&Druggist93.3(11December1920): M.R.Fox,(1987):2934. E.F.Armstrong,(1924):16,95.
57.
177 178
179
TheFinancialNews(17June1926)inCarrArchivesF.H.CarrlettertoTheTimes (5December1925).
180
2130B/CARRhandwrittennotesofFrancisHowardCarr,ImperialCollege,1926
248
249
mindsshouldbereceptiveoftheresultsofsuchresearchandalerttoits 181 practicalbearings.
Reportsontherelationshipbetweentechnicaleducationandtherequirementsoftradeand industryemergedin1925and1927butitwastheReportoftheCommitteeonTradeand Industryin1929,whichrecognisededucationasafactorinindustrialandcommercial

182 efficiency.
5.8PostWarGermanyandOtherForeignCompetition. Postwaritwashopedthatcompetitionin drugproductionfromdefeatedGermany wouldbereduced.InsteadGermandyeandchemicalmanufacturersexpandedtheir

183 activitiesintophotographicmaterialsandespeciallypharmaceuticals. Germanylost
coloniesthathadprovidedmedicinalplants,leadingherfirmstofocusevenmoretowards
184 syntheticdrugsashighervalueproductswithlesscompetition. Withfavourable
exchangerates,lowerwagecosts,longerworkinghours,muchgreatereconomiesofscale, androyaltiesfromBritishfirmsproducingtheirdrugs,Germanywasabletoofferverylow pricesforchemicalsanddyes.Itsenormousengineofcommercialwarfare,createdfor

185 theWar,increaseditsefficiencystillfurther. Germanfirmsinitiallypricedtheirproducts
artificiallylow,createdamonopolyandthenincreasedprices.Theybecameevenmore dominantwhentheygainedwindfalloverseasprofitsduringtherunawayinflationof1921 to1923,whichallowedthemtoeasilypayofftheirborrowingsandplantexpenseswith
181
FinalReportoftheCommitteeonIndustryandTrade(London:H.M.S.O.,1928) Cmnd.3282:217218.
182 183 184
E.Moonman,ReluctantPartnerships(London:VictorGollenz,1971):66. W.J.Reader,(1970):317.
SirWilliamPope,TheManufactureofChemicalProducts,Societyofthe ChemicalIndustrymeeting.Chemist&Druggist95.2(17September1921):4243.
185
ReportoftheAlienPropertyCustodianJ.IndustrialEngineeringChemicals(April 1919):335G.Stopler,K.Haueser,K.Borchardt,translatedbyT.Stolper,TheGerman Economy:1870tothePresent(London:Weidenfeld&Nicholson,1967):3435.
249
250
186 worthlessReichMarks. Amajorconcernwasthatpoliticalchaosofrunawayinflationin
GermanywouldleadtorisesinpricesofcertaindrugssuchasAspirinbyforcingsomeof
187 thesmallerfirmsoutofbusiness. Recollectionsoftheperiodwerearapidrecoveryof 188 theGermanchemicalindustry.
FromtheGermanperspective:DerKriegwarzwaroffiziellbeendet,wurdeaberin
189 andererformweitergefhrt. Overproductionpostwarledtoanexpansionofcartels.
In1905,Germanyhad23chemistryanddyecartelsincluding7inpharmaceuticalsby 1923
190 therewere93cartelsinplace. Inretaliation,theABCMinitiallyofferedarangeof
191 drugsatorbelowcosts,butcouldnotcompeteonpricesinthelongerterm.
ExtendingthewartimemergersbetweenGermanfirms,in1923J.D.RiedeltookoverE. D.deHaen,afirmthatspecialisedinfinechemicals,andScheringmergedwithKahlbaum andbecamepartofalargechemicalconglomerate,KokswerkeandGemischeFabriken. TheGermanstriedtoextendtheirinfluencefurtheratthestartof1925byaskingthethree

192 majorSwissfirms,CIBA,GeigyandSandoztoexchangeshareswiththem. Aswillbe
describedlaterthiswasnottheendofthemergeractivity,whichcametoaheadin1926. AfurtherthreattoBritishfirmscamefromAmericanfirmsestablishingofficesin Britain.ParkeDavishadbeenestablishedinLondonsince1891,andwasfollowedby
186
ExchangeratesarequotedinL.F.Haber,(1971).Thevalueofthemarkfellfrom 20/in1900toaworthless4.2bn.marks/$by1923W.J.Reader,(1970):444.TheAct waspassedat240M/butbyOctober1921,240Mwereworth6s8d(onethird).

187
TheFineChemicalMarketChemist&Druggist99.2(3November1923):621P. Frankland,TheChemicalIndustriesofGermanyinW.M.Gardner,(1915):379388.
188 189
GermanTradeandtheMarkChemist&Druggist95.2(8October1921):5657.
Withthewaroveritwascarriedoninanotherform.(Mytranslation.)H.Tammen, DieIGFarbenindustrieAktiengesellschaft,192533.EinChemiekonzerninderWeimar Republik(Berlin:T.O.M.,1978):15.

190
A.Arora,R.Landau,N.Rosenberg(eds.),ChemicalsandLongTermGrowth: InsightsFromtheChemicalIndustry (NewYork:J.Wiley,1998):56.

191
Editorial,TheFineChemicalMarketChemist&Druggist93.2(11December 1920):6465.
192
L.F.Haber,(1971):2745.
250
251
193 Abbottin1915,astheysoughtincreasedexportmarkets. J.Wyeth&Brothers
establishedtheirownfirminHavantin1926,Sharp&DohmeinHoddesdonin 1927,W. R.WarnerinEastleighin1932,EliLillyinBasingstokein1934.SmithKline&French establishedasalesbaseherethroughMenleyJames.However,evenin1936SKFs researchanddevelopmentdepartmentconsistedofeightpeoplewithabudgetof$70,000,

194 whilethefirmemployedabout180andhadsalesof$89m. OftheSwissfirms,Roche
wereestablishedinWelwynin1908,CIBAinHorshamin1919,SandozinLondonand
195 Bradfordin1921andGeigy,inManchester,butnotuntil1940.
AstheBritishchemicalanddyeindustrycameundergrowingpressurefrom Germany,BDCbegantodiscussmarketshareswithI.G.Farbenasnooneelsecould
196 makedyestuffs,socheaply,soplentifully,norhadthesalesandtechnicalbackup. Had
BDCacceptedtheirterms,thenIGwouldhavedominatedthemanufactureofchemical
197 intermediatesintheUnitedKingdombuttheBritishgovernmentblockedthis.
However,inNovember1923theGovernmentsoldsharesinBDCallowingreorganisation underanewchairman,LordAshfield(SirAlbertStanley)whowasjoinedontheBoardby
198 AlfredMondandDr.E.F.Armstrong.
Towardstheendof1924theLabourGovernmentwasconsideringwithdrawalfrom itsassociationwiththeBritishDyestuffsCorporation,butMcDonald'sGovernmentfellin
199 Octoberbeforeadecisiononmarketshareswasagreed. Labourministerswereopposed
tosuchanagreementbutweredividedonhowtoreorganiseBDCuntillatein1925. BaldwinrecommendedsellingBDCandusingtheproceedsofthesaletodevelop,through
193
JournaloftheSocietyoftheChemicalIndustry (1915):151Medicines,Drugsand PreparationsChemist&Druggist85.2(3October1914):46L.F.Haber,(1971):123.

194
JohnF.Marion,TheFineOldHouse,SmithKlineCorporationsFirst150Years, (Philadelphia:Smith,Kline,1980):130.
195
AllanDuckworth,RiseofthePharmaceuticalIndustryChemist&Druggist156 (10November1959):127139.
196 197 198
199
Thisreferstothe'LittleIG'mergerof1916,W.J.Reader,(1970):512. L.F.Haber,(1971):274. W.J.Reader,(1970):4447.
K.Middlemass,J.Barnes,Baldwin:aBiography (London:C.Tinkling&Co., 1969):3136.
251
252
theDSIR,facilitiesforpursuingchemicalinvestigationsnotnecessarilytothemakingof drugs,butofvaluetothefightingservicesandtothechemicalindustrygenerallytoensure
200 thatBritainwasselfsufficientinimportantchemicalintermediates.
By1925,inadditiontothedyefirms,therewere1219establishmentsinGermany with24,000employeesinpharmaceuticals,dominatedbyMerckandtheotherfivelargest firms.Thechemicalindustrywasgoingthroughaveryserioustimeandinthefirst5

201 monthsoftheyearimportsintoAmericadoubled. BritainreturnedtotheGoldstandard
withinterestsetatprewarrates,makingBritishexportsexpensive.Inthesummerof 1925EdwardFranklandArmstrongtoldtheABCMannualmeeting:Thepenetrationof theGermansintomatterschemicalwasevenwider,morerapidandmoreserioustoday

202 thanitwasin1914.
ThethreattotheBritishindustryincreasedinSeptember1925withthe announcementoftheplannedmergersofthemajorGermansyntheticdyeproducers,who
203 alreadydominatedthesyntheticpharmaceuticalsindustry. Incontrast,theBritish
chemicalanddyestuffsindustriesremainedwidelyfragmented.InhisStreatfieldMemorial lectureof3December1925FrancisCarrdiscussedthe'scientificbasisofindustry'and
204 urgedclosercollaborationinBritain. By1926theGermanmergerswerecompleted
200
PRO,CAB/24/165ReportoftheBDC,26July1924:5CAB/24/175Reportby ChairmanofCommitteeonCivilResearch,(16October1925)P2.
201
th ABCM9 AnnualmeetingChemist&Druggist103.1(25July1925):105the samepatternwasreportedbytheSocietyfortheChemicalindustry,Chemist&Druggist 102.1(6June1925):803. 202 th ABCM,9 AnnualMeetingChemist&Druggist103.1(25July1925):105.
203
By1925Britishexportswereonly84%of1913levelsandimportswere120%,A. J.PTaylor,(1988):238.AchangeinGermanlawin1923encouragedmergers.The originalDreibundofBASF,Bayer,andAGFAamalgamatedwiththeHoechstgroupon18 August1916.In1925theyaddedKalle,Cassella,GriesheimElektronandWeilerterMeer tobecomethefourthlargestfirmintheworldafterGeneralMotors,U.S.Steel,and StandardOil,withaannualturnoverof20mI.G.comprised48%oftheGerman chemicalindustryand66%ofitsprofitsPeterHayes,IGFarbenintheNaziEra:The NascentConcern18601933 (Cambridge:CambridgeUniversityPress,1987)L.F. Haber,(1971):123,andChapter10:27991.
204
F.H.CarrarchivesatImperialCollege,LondonB.CarrFH6notesmadebyA.E. GuentherafteraconversationwithF.H.Carr,Winter19667F.H.Carr,Streatfield MemorialLectureChemist&Druggist103.3(3December1925):829.
252
253
creatinganextendedInteressengemeinschaft,knownasI.G.Farben,employing7,200and
205 withaturnoverof50mthatthreatenedtoengulfBritishindustry. Themergerallowed
therationalisationofpurchasing,patents,research,andsaleswithcentralofficesin Leverkusen.ThethreepharmaceuticalfirmsMerck,C.F.Boehringer,andKnollalso
206 formedtheirownseparate'Interressengemeinschaft'inGermany.
Inresponse,1926alsobroughtmomentouschangesintheBritishchemicaland pharmaceuticalindustry. ManagementoftheBritishpharmaceuticalfirmschangedasthe

207 organisationsthemselvesbecamemorecomplex. Atthestartof1926,BDHwere
woundupwithacapitalof100mtoprotecttheirname,andthenextweekwerere
208 establishedasBDHplc. SirAlfredMondcombinedtheBritishchemicalindustries,
BrunnerMond,Nobel,UnitedAlkaliandtheBritishDyesCorporationtoformImperial
th 209 ChemicalIndustries(ICI),announcedpubliclyon26 October1926. Thusanall
embracingnationwidechemicaltrustwascreatedinBritainandcombinedallthemost
210 importantchemicalbranches. SirAlfredMondspoliticalcareerhadendedwiththefall
ofthecoalitiongovernmentin1922helosthisseatin1923andtookoverasChairmanof
211 BrunnerMond.
Anotherwayinwhichcompetitionwaseliminatedafterthemergerswasthrougha
212 seriesoffurtheragreementsonmarketsharebetweenIGFarben,ICIandDuPont.
SimilarmergersoccurredintheUSAwhereDuPontandAlliedChemicalcombinedin
205
M.R.Fox,(1987):16971. L.F.Haber,(1971):289.
206 207
A.J.Levine,IndustrialRetardationinBritain18801974(London:Weidenfeldand Nicholson,1967):53.
208 209
TheBritishDrugHousesLtdChemist&Druggist104.1(20February1926):254
In1926ICIwasaboutthesamesizeasI.G.Farbenwithamarketcapitalisationof about56.8m.L.F.Haber,(1971):291ff.,302W.J.Reader,especiallychapter19The foundationofICI(1970).Theamalgamationof45smallfirmstoformtheUnitedAlkali Co.beganthisprocessin1890andBrunnerMondacquiredfirmsbetween19171920S. Miall,(1931):61.

210 211
A.Arora,R.Landau,N.Rosenberg(eds.),(1998):241,245. W.J.Reader,(1970):2201,371 OnMondseeA.J.P.Taylor,(1988):249. H.Tammen,(1978):19.
212
253
254
213 1926, andinFrancewhereRhnePoulencandtheSocietChimiquedesUsinesdu 214 Rhne,combinedin1928
ArnoldRenshawM.D.oftheLaboratoryofAppliedPhysiologyandPreventative MedicineinManchesterwrotethatthe:recentmergingoftheoutstandingBritishchemical companiesintoasingleorganisationishailedbyscientificmenasoneofthegreateststeps towardstheeconomicprosperityofthechemicalindustry.Hefeltthatthenewcompany ofICIcouldrestore'nationalhonour'andthattherewasnownolongeranobstacleto competingwithGermanrivalssothat: WhilstcongratulatingtheGermaninvestigatorsupontheirachievementin theintroductionofdrugsofthetypeofSalvarsanandBayer205,wemay 215 envythefacilitiesandresourcesuponwhichtheyareabletodraw. BythishemeantthatBritainwouldnolongerbedependentonGermanyforchemical intermediates,andthiswouldbenefitthepharmaceuticalindustry.Therewasstillalotof progresstobemadeinestablishingresearchandmanufacturingcapacityontheGerman lines. 5.9Conclusions. Duringthe1920s,Britishfirmsthathadembarkedondrugsynthesisbeganto producesimpleorganicchemicals.Manyofthenewcompoundswerevariantsonnew agentsappearingelsewhere.TheDangerousSubstancesActof1922mandatedthe employmentoftrainedstafftodealwithpoisonsandotherdangerousdrugsandthisfurther stimulatedthedevelopmentoflaboratories.Processesandmanufacturingcapacitywere improved:anexampleofasmallstepwiseimprovementwasthepreparationofbetaeucaine (Benzamine)ratherthanthenaturallyoccurringalphaeucaine.Thismaynotseeman excitingdevelopmentbutthenewpreparationwasimportantatthetimebecauseitwasfar
213
G.D.Taylor,DuPontandtheInternationalChemicalIndustry (Boston,Mass: Twayne,1984)W.H.A.Carr,W.H.Alexander,TheDuPontsofDelaware(London: Muller,1965).

214
JudySlinn,AHistoryof May&Baker18341984(Cambridge:HobsonsLtd., 1984):99.

215
A.Renshaw,ChemicalResearchinBritainBritishMedicalJournal (6November 1926):857.
254
255
216 lessirritantandtoxicthantheparentsubstance. SimilarlyatBoots,afterthechemical
departmentwasexpandedin1929,workonhexylresorcinolledtothesignificantly improvedantiseptic,amylmetacresolandseveralfurtherderivatives,whichweremore
217 solubleandbettertolerated. Severalcompaniesexpandedtheirfacilitiestoproduce
insulin,vitaminsandhormones. Duringtheperiodunderreviewthereweremanysuchadvancesbutpreviously historianshaveconcentratedonlyonmajordevelopments,concerningthemselveswith drugssuchasinsulinorpenicillin,whichhavemadeamorelastingimpressionandwhich arebetterdocumented.InhisthesisRobsonwentasfarasdenigratingchemistswiththeir

218 obsessionwithobscuretechnicaldetailsoflittleoverallimportance. Contemporary 219 writersdidnotseetheinterwarperiodasthe'barrenperiod'ascribedbylaterauthors.
WhereasinotherindustriestheWartimecollaborationbetweenGovernmentandindustry wastransitory,Iarguethatthisremainedfruitfulinthecaseofthepharmaceutical industryandthattherelationshipcontinuedintheinterwarperiod,formingasolid

220 foundationforproductionof drugsinWorldWarTwo.
Protectionistmeasureswererecognisedasonlystopgapsuntiltheavailabilityof chemicalengineersandchemicalintermediatesimproved,anduntilfirmsdevelopedmore innovativedrugsandbettercollaborationwiththemedicalprofession.Britishfirmsfaced difficultchoicesintheinterwarperiod.Thosethathadinvestedinextendingtheir manufacturingcapacitywereespeciallyvulnerable.Therewasnowaythattheycould competewithGermanyonpriceandefficiencyofproduction.However,inorderto survive,Britishcompanieshadtomakeprofitsinthecontemporaryausterefinancial climate.Beinginnopositiontorelyentirelyuponsyntheticchemistry,theycontinuedto
216
J.Chem.Soc.125(1924):46. S.A.B.Kipping,ChemistryandIndustry (25February1963):3034.
217 218
M.Robson,ThePharmaceuticalIndustryinBritainandFrance19191939: (London:PhD,June1989):7.
219
ScientificandIndustrialProblemsofHormonesBritishMedicalJournal (24July 1926):167.

220
J.V.Pickstone,WaysofKnowing.ANewHistoryofScience,Technologyand Medicine(Manchester:ManchesterUniversityPress,2000):164.
255
256
producebiologicallystandardisedhormonesandvitamins,inorganicdrugs,andalkaloids andtheirsyntheticeffortswereprimarilythose,whichCarrproposed,ofgradual improvementsofmethodologyforpurifyingtheactiveprinciplesinbetteryields.Whilethis chaptershowedthatingeneralBritishpharmaceuticalfirmsexpandedtheirchemistry efforts,furthersupportisgiveninthechapteronBurroughsWellcomeandtheirScientific andTechnicalCommittee,whichexaminesinmoredetailthedilemmascausedbythe alternativepotentialstrategies. Thedearthofchemistsintherespectivecompaniesupto1927mayexplainthe apparentlackofinnovationsbyBoots,May&Baker,EvansandBurroughsWellcomein thisperiod,althoughanotherstrongreasonwasthesuccessoftheorganotherapiesand hormones,whichofferedanalternativetodirectcompetitionwithGermany.Furthermore, severalofthesecompaniessufferedthelossofkeymembersofstaff. Nevertheless,significantimprovementshademergedintheBritishpharmaceutical industryfrom1922and1926suchthatby1931MiallcoulddescribetheCooperation, whichistakingplacebetweenthechemistandbiologist,thechemistandphysicistand
221 betweenthechemistandengineer.
SoonaftertheTTCwasannounced,DrPercivalHartley,exBurroughsWellcome andbynowHeadoftheStandardsDivisionoftheNationalInstituteofMedicalResearch recountedthedifficultyinapplyingstandardsofproductsfromoverseasinapaperon StateControlofTherapeuticSubstancestotheAnnualmeetingoftheFeverhospitals groupinJune1931.Withlimitedresourcestochecksamples,ahighproportionof biologicaldrugshadbeeneithercontaminatedorunderstrengthandpotenciesvaried

222 widely,pointingtoaneedfornewchemicaldrugstobetestedclinically. These
commentsreflectedanongoingsuspicionaboutthepotencyofforeigndrugs. ThegovernmentassistedBritishfirmsbyfirstexcludingandthenraisingtariffs againstimportsandthenrequiredchemicalorbiologicalstandardisation.Accordingtotheir rhetoric,seeminglybackedupbythefigurestheyproduced,themainproblemwaswith

221
S.Miall,HistoryoftheBritishChemicalIndustry (London:ErnestBennLtd., 1931):237.

222
P.Hartley,StateControlofTherapeuticSubstancesBritishMedicalJournal (20 June1931):1072.
256
257
foreigndrugs.MuchoftheinitialexpertiseattheMRCcamefromBurroughsWellcome andtheycontinuedtosecurestafffromBurroughsWellcomesuchthatconcernswere raisedatonestage. However,basedupontheclosecollaborationofBurroughsWellcomewiththe MRC,Britainemergedfromapositionofweaknesstotakeasignificantinternationallead inbiologicalstandardisation.TheTherapeuticSubstancesActconfirmedtheimportant centralroleoftheMRCandlaterthePharmaceuticalSocietyheadedbyJ.H.Burnindrug standardisationandhelpedtoprotectBritainfromimportationofdrugsthathadnotbeen tested.By1928Dale,bynowtheoverallDirectoroftheNIMR,andFletcherwere increasinglyinfluentialindecidingthefateofmedicines,andbothwereinvitedtositonthe
223 PharmacopoeiaCommission. TheMRChadbecomeapowerfulcentralbodyforthe
evaluationofnovelmedicines.Howevertherewasasyetnoformalmeansofhavingdrugs testedinclinicaltrialsandthishadbeenanissueforBritishfirmsformanyyears. Inchapter8IwillexplorehowDaleandFletcherwerealsoinfluentialinassisting firmstoarrangefortheclinicaltestingofnewdrugsandsuggestthattosomedegreethis becameafurtherbarriertotheimportationofforeigndrugs.Clinicaltestingcouldbedone inGermanybutBritishphysicianswouldbemorelikelytouseamedicineifithadthe approvaloftheMRC.
223
MRCMinutesIII,(22June1928):83.
257
TheCampaignforClinicalTrials
258
CHAPTERSIX:TheCampaignforClinicalTrials.
1 Interestingnewcompoundsarediscovered.Interestingnewdrugsaredeveloped.
6.1Introduction. Thisisthesecondchapterofthreecoveringtheperiod19191931.Chapter5dealt withthegeneralproblemsfacedbythepharmaceuticalindustryintheinterwarperiod, Chapter7isacasestudyofBurroughsWellcomestrategyinthisperiod.Thischapter dealswiththespecificproblemofhowBritishfirmscampaignedtogettheirnewdrugs testedclinically. Havingcollaboratedcloselywiththepharmaceuticalindustryduringthe war,particularlyregardingSalvarsan,theMRCbecamethefocusofmedicalresearchin Britain,developingaseriesofclinicalresearchcentreslinkedtopatientcare,and establishedthemselvesasarbitersofdrugquality.AftertheWar,withtheestablishmentof theNIMRatHampsteadin1919,theroleoftheMRCinthestandardisationofnovel medicineswasformalised,toensurethatdrugscouldbeusedreliablywithknownpotency (chapter5).Inadditiontobiologicalstandardisationofdrugs,theMRCclinically evaluatedsomenewdrugs,firstretrospectivelyandthenprospectivelyandshapedthe regulatoryframework.AttheendoftheWartheworkofthesecondSalvarsan CommitteecontinuedasdescribedinChapter4.FromtheirfirstmeetingoftheMedical ResearchCouncilinJuly1920,Fletcherintroducedtheconceptofsmall,specialised coordinatingsubcommittees,whichrecommendedresearchgrantstoindividualsand
2 institutions,andwhichoversawresearchstudies. Theywerealsothemeansbywhich
theMRCconsideredsmallclinicalstudiesofanypromisingnewagents,usuallyarising
3 fromacademia.
WilliamOsler,(18491919)Aequanimitas,1900quotedfromC.D.Leake,An HistoricalAccountofPharmacologytotheTwentiethCentury (UniversityofCalifornia: Springfield,IllinoisC.C.Thomas,1975):2.

2
W.M.FletchertoSirGeorgeNewman,ChiefMedicalOfficerattheMinistryof Health,(7May1918),MRC1381/1.
3
MRCMinutesII,(7July1920),CommitteeonBiologicalStandards:82 CommitteeonCinchonaDerivativesandMalaria:83CommitteeonRickets:84 CommitteeonAccessoryFoodFactors:85.
258
259
Pharmaceuticalfirmshadprevioustriedwithlimitedsuccesstoorganisetheirown clinicaltrials.AtBurroughsWellcome,bothWPRLandWCRLscientiststriedto establishclinicaltrialsofnovelextractsandwhenavailable,thepublicationssupported

4 commercialactivity. Whentheyhadlimitedclinicaldata,aswasthecasewiththeir
throatTabloids,alltheycouldsaywasthat:SirMorrellMacKenzielikestheideaorthat theirmaltextractwassubmittedtomanytherapeutistsandageneralopinionhasbeen
5 expressed. DuringtheWartheMRCtestednotonlySalvarsan,butalsosomeother
productsthatshowedpotentialbenefitsforthetroops,buttheyemphasisedthattheir interestswerescientificratherthansupportingfirms.Oneexamplewasthetestingof collosolcocaineonbehalfofCrookesCollosolsLtd.Dalewrote:itisimportantthat thisstatementshouldnotbemisunderstoodasindicatingthattheMRC,oranymembersof

6 theirstaff,undertaketheexaminationofproprietarymedicinesattherequestofmakers.
FirmssawachancetocollaboratewiththeMRCthroughthesubcommitteestoperform clinicaltrialsoftheirnewdrugs.However,ultimatelythesearrangementsweretoo specificandlimitedandthepharmaceuticalfirmscontinuedtocampaignforasystemof testingdrugsuntilthecreationoftheTherapeuticTrialsCommitteein1931.
6.2TheMRCandClinicalResearchCentres. Followingtheirinitialwartimeresearchefforts,theMRCestablishedanetworkof centrestoencouragethedevelopmentofacademicclinicalresearcherswithlaboratory researchandaccesstopatientbeds.Thenetworkofclinicalresearchcentreswaswider thanpreviouslydescribedbyJoanAustoker,whoexaminedtheroleofWalterMorley

7 Fletcherandtheoriginsofaresearchpolicy. Similarly,ChristopherBoothbasedhis
conclusionsthattheacademicclinicalresearchbasewasquitelimitedbyreviewingonly
4
Atotalof58casesofconstipationtreatedwithCascaraTabloidswithsuccessin44. Chemist&Druggist39(1891):554 cuttinginWF:89/29:7.

5
6 7
Chemist&Druggist39(1891):13439,625,cuttingsfoundinWF:89/29:7. BritishMedicalJournal (1917)ii:710.
J.Austoker,WalterMorleyFletcherandtheOriginsofaBasicBiomedical Research PolicyinJ.Austoker andL.Bryder(eds.),HistoricalPerspectivesontheRoleofthe MRC(Oxford:OxfordUniversityPress,1989):23 33.
259
260
8 summariesoftheMRCannualreports. ThebiographyofWalterMorleyFletcherandthe 9 MRChistoriesarealsoinstructive ,buttheMRCMinutesdocumentfullythelevelof
supportgivenandidentifyfurthercentres.SteveSturdystudiedthedevelopmentof
10 clinicalscienceindetail,particularlyEdwardMellanbysdepartmentatSheffield. More 11 recentlyHelenValierexaminedresearchinManchester andMalcolmNicolsonin 12 Glasgow.
Postwar,theresearchactivitiesfinanciallysupportedbytheMRCexpandedto includecerebrospinalfever,influenza,pneumonia,rheumaticfever,venerealdisease,child lifeproblems,growthdisorders,accessoryfoodfactors,disordersofthecardiovascular

13 system,biochemistry,chemotherapy,andstatuslymphaticus. Wartimeinterestsinseptic
14 shock,woundsandtrenchfeverwerecontinued. TheMRCperformedworkontyphoid
andparatyphoidvaccinesandontropicaldiseasesincludingbilharziaandcholera.
8 9
C.C.Booth,ClinicalResearchinJ.Austoker andL.Bryder(eds.),(1989):205241.
MaisieFletcher,TheBrightCountenanceaPersonalBiographyofWalterMorley Fletcher (London:HodderandStoughton,1957)A.LandsboroughThompson,Halfa CenturyofMedicalResearch,volume1.OriginsandPolicyoftheMedicalResearch Council (London:HMSO,1973)A.LandsboroughThompson,HalfaCenturyofMedical ResearchvolumeII.TheProgrammeoftheMedicalResearchCouncilUK(London: HMSO,1975).

10
S.Sturdy,MedicalChemistryandClinicalMedicine:Academicsandthe ScientisationofMedicalPracticeinBritain19001925inIlanaLwy(ed.),Medicineand ChangeHistoricalandSociologicalStudiesofMedicalInnovation,ColloquiaINSERM 220(Montrouge:JohnLFurstadt,1993):371394S.Sturdy,ThePoliticalEconomyof ScientificMedicine:Science,EducationandtheTransformationofMedicalPracticein Sheffield18901922MedicalHistory 36.2(1992):12539.

11
HelenKathrynValier,(UniversityofManchester:PhDthesis,2002)ThePoliticsof ScientificMedicineinManchesterc1900 1960.

12
D.Smith,M.Nicolson,Paton,CathcartandFindlay:aConservativeStancein ScottishNutritionSocHist.Med.Bull 40.6(1987):4547D.F.Smith,M.Nicolson, ChemicalPhysiologyversusBiochemistry,theClinicversustheLaboratory.The GlaswegianOppositiontoEdwardMellanbysTheoryofRicketsProc.Roy.Coll. PhysiciansEdinburgh 19.1(1989):5160.

13
14
ReviewofMRCMinutesIII,(192027).
Shock:itsNatureandPreventionBritishMedicalJournal 1917(2):7713.The researchersinvolvedincludedProf.F.Bainbridge,Prof.W.M.Bayliss,Prof.W.B. Cannon,Dale,Elliott,Capt.JohnFraser,C.S.Sherrington,E.H.Starling,andCol. CuthbertWallace.
260
261
ProfessorWarringtonYorkewasresponsibleforresearchattheTropicalResearchUnitin
15 Liverpool.
TheMRCgainedsomefurtherlimitedexperienceinperformingclinicaltrialsof variouspotentialtreatmentssuggestedbyphysicians.In1921 theytestedaSwissspecific

16 treatmentfortuberculosis. InreviewingtheliteratureWilkinsonshowedthatonedoctor,
A.H.CroucherofEastbourne,whoclaimedhehadusedthemethodsince1896gavethe MRCaclearinsightintohowhethoughtitshouldbestudiedinclinicaltrials. Ipersonallywelcomeanyfairandopentrialofanymethodofspecific treatment,whichismostsurelythemethodofthefuture.Butitmustbeareal trialoftherelativemeritsofoursystembycompetentjudgeswhohavemade 17 themselvesauthoritiesbyworkandnotbyofficialposition. Croucherarguedthathehadsetdowntherequirementsforatrialdesignasearlyas1912. Hestatedthattheremedyshouldbetheonlyremedyusedintreatment: Itshouldbeexploitedinaconsecutiveseriesofcasesofallkinds(notmerely especiallyselectedcases)andallthecasesfullytreatedshouldbepublished. Aftertreatmentthecasesshouldbecarefullywatchedandexaminedforat leastthreeorfouryearsbeforeafinaljudgmentisgivenuponthevalueofthe remedy.Theresultsshouldbearrangedinthesegroupsorbetter,asinmy ownrecordsinfivegroups,accordingtothecharacteranddegreeofthe 18 changesinthelungs. InfactthequestionsabouttheSpahlingertreatmentremainedandtheMRCwereaskedby agroupofMPsforastatementonitsmeritsandalthoughtheyreferredthequestiontothe
19 TuberculosisCommittee,intruththeyhadnoconclusivedata. AsIwilldemonstrate
suchelaborateclinicaltrialsremainedonlyatheoreticalconceptforalongtime.British
15
MRCMinutesIII,(26April1929):69.AlsoBengerlaboratories,asubsidiaryof BritishDrugHousesprovided2,000towardsnewlaboratoriesfortheManchester UniversityMedicalSchool.Times(12July1929)ToxicologicalEffectsFollowingthe EmploymentofArsenobenzolPreparationsMRCSpecialReportsSeries(London: HMSO,1920)66J.Austoker andL.Bryder(eds.),(1989):110 11,117,120.

16
TheSpahlingerTreatmentforConsumptionBritishMedicalJournal (5March 1921):360SpahlingerTreatmentBritishMedicalJournal (2May1921):683.

17
W.C.Wilkinson,TheSearchforaSpecificTreatmentforTuberculosisBritish MedicalJournal (26February1921):308.

18
19
Ibid. MRCMinutesII,(16October1925):178. 261
262
firmssimplywantedaquickratificationinsimplestudiesandinsmallgroupsofpatients sothattheycouldselltheirproductsandtheMRCappearedtohavetheinfrastructureto achievethis. AlthoughtheMRCestablishedacentralroleinclinicalresearch,thereweresome opponents.AustokerdiscussedthebattlegroundbetweentheRoyalCollegesandthe emergingspecialitiesintheinterwarperiod.LordsMoynihanandDawson,representing theRoyalCollegesofSurgeonsandPhysiciansrespectively,sawtheMRCasathreatto theircentralcontrolandwereconcernedatseeingadivergencebetweenresearchand medicalandsurgicalpractice.Theyfeltthatphysiciansratherthanscientistsshoulddirect researchandtheysawsomeoftheresearchsponsoredbytheMRCaslackingclinical relevance.However,FletchersviewthatAcommitteeofeminentclinicians...will...be perfectlyuselessaswellashighlyembarrassingindirectingclinicalresearchantagonised
20 hisopponents. LordMoynihanmadeaseriesofcomments:physiologistscouldnot
21 introducenewmedicinesandtheywerealooffrommedicine. Moynihanand
Dawsonbothsawscienceasapartoftheroutinedailypractice,whereasFletcherdivorced sciencetothelaboratoriesforlaterapplicationinmedicine.In1920Moynihanhadpushed forresearchrelevanttosurgeryandchidedtheMRCforalackofcliniciansontheir Council,andyetthemainCommitteemembersincludedSirThomasCliffordAllbutt,the ConsultantsurgeonC.J.Bond,whowasaFellowoftheRoyalCollegeofSurgeonsand ConsultantatLeicesterRoyalInfirmary,plusT.R.ElliottofUCH,F.R.FraserofSt.

22 Barts,andDrW.W.S.TopleyofCharingCross.
FletcherwantedtoencourageMRCresearchin allbranchesofmedicine,butthis alsobroughtconflictwiththephysiciansandsurgeonstreatingcancer,whoseresearchwas alreadyfundedbytheImperialCancerResearchFund,establishedin1902thoughthe
20
21
W.M.FletchertoF.G.Hopkins,(12April1923),MRC1383:I. W.M.Fletcher,TheScienceofMedicineLancet(11October1930):77985. MRCMinutesII,(7July1920):114and116and(28January,1927):17.
22
262
263
Council didstudytheeffectsofRadium.In1923afurtherfundingbody,theBritish
23 EmpireCancerCampaignwassetup,toworkwithoutconflict.
FletcherinvitedDawsontojointheMRCCommitteein1931,thoughthisdidnot
24 stopfurtheroutbursts. AclinicalcommitteeincludingDawson,Trotter,Edward
25 MellanbyandLewiswasappointedtoadvisetheCouncilregardingclinicalresearch.
DawsonwasinfluentialandhadbeenPresidentoftheRoyalSocietyofMedicineandhe becamePresidentoftheBMAin1932. Fletcherfundedaninternationallyrenownedresearchnetworkofphysicians, physiologists,bacteriologistsandsurgeons,manyarisingfromCambridgeandUniversity CollegeHospital,butalsoothermajorLondonhospitalssuchasSt.Bartholomews,and St. ThomasaswellasSheffield,ManchesterandGlasgow.26 Thenetworkexpandedas investigatorsmovedfromUCHandCambridgetoestablishresearchcentreselsewhere. In1919St.BartholomewswasthefirsttoappointaProfessorofMedicine, ArchibaldGarrod,thoughhemovedtoOxfordtosucceedSirWilliamOsler.Francis RichardFraserwasappointedProf.ofMedicineatStBartholomew'sin1920,wherethe MRCalreadysupportedC.H.AndrewesandE.A.Carmichael,respectively thefuture DirectorsoftheCommonColdUnitinSalisburyandaresearchunitattheNational
27 HospitalinQueensSquare,andMrF.H.K.Green.
23
J.Austoker, AHistoryoftheICRF Chapter3,(190286),(Oxford:Oxford UniversityPress,1988)D.Cantor,TheMRCsSupportforExperimentalRadiology DuringtheInterWarYearsinJ.AustokerandL.Bryder(eds.),(1989):181 204.

24
J.Austoker,WalterMorleyFletcherandtheOriginsofaBasicBiomedical ResearchPolicyinJ.AustokerandL.Bryder(eds.),(1989):2333.
25 26
MRCMinutesIII,(21October1932):160.
WalterMorleyFletcher'spapersmaybefoundattheWellcomehistoricallibrary PP/WMFMaisieFletcher,(1957):30A.LandsboroughThompson,(1975)Richard Glazebrook, ScienceandIndustry:thePlaceofCambridgeinanySchemeforTheir Combination (Cambridge:CambridgeUniversityPress,1971).

27
FrasertrainedatCambridgethenEdinburgh,RockefellerandColumbiaUniversity, S.SturdyinIlanaLwy(ed.),(1993):371394C.C.BoothinJ.AustokerandL.Bryder (eds.),(1989):211MRCMinutesII,(22October1926):181MRCMinutesIII,(23 November1928):167.
263
264
ThomasLewiswasfundedbytheMRCandbecamethefirstfulltimechairand DirectorofClinicalResearchattheDepartmentofClinicalResearchandExperimental
28 TherapeuticsatUCHin1920. Col.T.R.Elliott,itsnewProfessorofMedicine 29 collaboratedwithDaleduringhistimeatBurroughsWellcomeandtheMRC. Dale
wroteT.R.Elliott,ThomasLewisandWilfredTrotterweregiantsofUCHwherethe firsttentativeessayswerebeingmadeintheapplicationofscientificmethodstoclinical
30 problems. Elliottdemonstratedthatanacademicunit,combiningteaching,research 31 andcareofpatients,couldactuallybemadetowork. ArthurRobertson Cushnywas
ProfessorofPharmacologyatUCH,andlatercontinuedhisstructureactivitystudiesin
32 Edinburgh.
SirArthurEllis,33 thefirstProfessorofMedicineatTheLondonHospital,was supported,aswasworkatSt.ThomassinLondonandattheResearchInstitutesetupby SirJamesMacKenziein1922attheDepartmentofTherapeuticsatEdinburghandrunby
28
Lewissalaryroseto2,000MRCMinutes,(30January,1925):11Hestudied atropineforatrialfibrillationandquinidine,MRCReport110(1922)W.R.Merrington, UCHanditsMedicalSchool:aHistory (London:Heinemann,1976):118,192 MRC Report19201 (London:HMSO,1922):2328ArthurHolman,SirThomasLewis, PioneerCardiologistandClinicalScientist(Godalming:SpringerVerlag,1986)C.C. BoothinJ.Austoker andL.Bryder(eds.),(1989):208210.
29
Elliottperformedresearchonadrenaline,W.R.Merrington,(1976):856,118,125 126ThomasRentonElliott,GC/42TherapeuticTrialsCommitteeCorrespondenceFiles 13/1,13/2SirWilliamGrantMacPherson,SirWilmotParkerHerringham,T.R.Elliott, SirAndrewBalfour(eds.),HistoryoftheGreatWarvolume1MedicalServices, DiseasesoftheWar(London:HMSO,19223)SirHenryDale,ThomasRentonElliott BiographicalMemoirsofFellowsoftheRoyalSociety 7(1961):53 74T.R.Elliott, ObituaryLancet(11March1961):56768.

30 31
93HDBox36.4.31. T.R.ElliottObituaryBritishMedical Journal (11March1961):7524.
32
A.R.Cushnypapers,WellcomeInstitutePR/ARCJamesColeman,The Hammersmith19351985.TheFirst50YearsoftheRoyalPostgraduateMedicalSchool atHammersmithHospital (London:M&PPress,1985)J.Parascandola,ArthurCushny, OpticalIsomerism,andtheMechanismofDrugActionJ.Hist.Biol.(1975)8:14565 H.MacGillivray,APersonalBiographyofArthurRobertsonCushny,18661926 AnnualRev.Pharmacology.(1968):1 24.

33
A.LandsboroughThompson,(1975):27.
264
265
34 Prof.J.C.Meakins. EdinburghwasalsothenewhomeoftheformerBurroughs
Wellcomechemistandbotanist,GeorgeBarger,whotookupthefirstChairofChemistry inrelationtomedicinein1919andhelditfor18years. Fletcheralsodevelopedinternationalconnectionsatmeetingssuchasthe

35 InternationalRedCrossMeetinginGenevainJuly1920. Thisledtofundingfromthe 36 Carnegie,DunnandRockefellerInstitutes. Lewiswasalsoinvolvedinnegotiatingthe 37 RockefellergrantsforUCH. WithfundingfromtheSirWilliamDunnandRockefeller
trustees,furthergrantswereawardedbyasubcommitteeinvolvingC.H.Andrewes(who joinedthepathologyandbacteriologydepartmentoftheNIMRin1926),ThomasElliott, FrederickHopkinsandthesurgeon,CuthbertWallace,(laterchairmanoftheRadiology

38 Commission). BoothalsoidentifiedtheWelshNationalSchoolofMedicineinCardiffas 39 animportantcentre.
Twofurtherresearchers,whohadcollaboratedwithLewis,movedtoCambridge.
40 Thepathologist, AlanN.Drury, hadbeensupportedatUniversityCollegeandhis
34
MRCMinutesII,(24March1922):250(4May1923):63.
35
FletchermetFlexner,Roux,Calmette,Bernard,BordetandMadsenandtraveledto theU.S.A.onseveraloccasions,visitingMcGillUniversity:MaisieFletcher,(1957).
36
E.R.Brown,RockefellerMedicineMenMedicineandCapitalisminAmerica (Berkeley:UniversityofCaliforniaPress,1979)MaisieFletcher,(1957):30,147,197 Mr.RockefellerandMedicalResearchBritishMedicalJournal (1917):130R.E. Kohler,WalterFletcher,F.G.HopkinsandtheDunnInstituteofBiochemistry:aCase StudyinthePatronageofScience(1978)Isis69:301,33155W.H.Schneider, RockefellerPhilanthropyandModernBiomedicine.InternationalInitiativesfromWorld War1totheColdWar(Bloomington:IndianaUniversityPress,2002).

37
W.R.Merrington,(1976):123AbrahamFlexner,MedicalEducationintheUnited StatesandCanada(NewYork:CarnegieFoundation,1910):116.
38
MRCMinutesII,(20July1923):91(17July1925)D.CantorinJ.AustokerandL. Bryder(eds.),(1989):199.
39
HelenKathrynValier,(UniversityofManchester:PhDthesis,2002)ThePoliticsof ScientificMedicineinManchesterc1900 1960:168C.C.BoothinJ.Austoker andL. Bryder(eds.),(1989):205.

40
Druryjoinedthescientificstaffonasalaryof850,MRCMinutesIII,(25January 1925):8.,andlatertransferredworkfromUCHtoCambridge,MRCMinutesIII,(24June 1927):106.
265
266
41 fundingcontinuedattheDepartmentofPathologyattheUniversity ofCambridge. R.
T.GrantwasappointedtotheDepartmentofExperimentalMedicineon11May1928,but heleftforCambridgeinOctober1928(andsubsequentlyheadedthenewclinicalresearch
42 unitatGuysHospital,thefirsttoemergedirectlyfromLewisdepartment. In 43 44 Manchester,E.J.Wayne workedonthemetabolismofinsulin. GeorgeW.Pickering
receivedsupportatSt.ThomassandwaslaterProfessorofMedicineatSt.Marysthen RegiusProfessorofMedicineatOxford.TheMRCalsosupportedGeorgeDreyeratthe DunnSchoolofPathologyinOxford,workingonbacterialdiseasesincludinghis

45 DiapylitevaccineforTuberculosis.
FromCambridge,FletcherknewCharlesSherrington whobecameProfessorof PhysiologyatOxford.Archibald.V.Hill,aphysiologistwasFletcher'sownstudentat Cambridgefrom1909beforehewenttoManchester.TheMRCprovidedagrantforJ.B.

46 Bateman toworkunderProf.A.V.HilllateratUCH andtoHenry.StanleyRaper(ex
Leeds)andJohnBeresfordLeathes(exSheffield,exToronto)asProfessorsof
47 PhysiologyinManchester,afterHillwenttoUCH.
Thesewerethemenwhoweretobecentralintheclinicaltestingofnewdrugs. TheMRCresearchattheCentralResearchInstitute,MountVernon,Hampsteadwas
41 42
MRCMinutesIII,(24June1927):106.
MRCMinutesIII,(26October1928):129C.C.BoothinJ.Austoker andL. Bryder(eds.),(1989):220,226,234.

43
EdwardJ.Wayne,ObituaryLancet(13October1990):932.Wayneobtainedhis degreeinchemistryatLeedsbeforestudyingmedicine,andhelatermovedtothe UniversityofManchesterandreceivedanMRCgrantof125toworkonfatand carbohydratemetabolismandinsulin,MRCMinutesII,(1May1925):87.Hejoined Lewisdepartmentin1931thenwenttoSheffieldasProf.of Pharmacology,andthenon toGlasgow.E.J.WaynewaslaterProfessorofMedicineatStMarysthenRegius ProfessoratOxford.HewasamemberoftheMRCandchairedtheBPC.

44
MRCMinutesII,(22October1926):181.
45
PapersbyL.BryderandJ.AustokerinJ.AustokerandL.Bryder(eds.),(1989):10, 46,53,63.
46
MarkWeatherall,Gentlemen,ScientistsandDoctors:MedicineatCambridge1800 1940.(Cambridge:BoydellPress,2000).
47
266
267
closelylinkedtobacteriologythroughAlmrothWrightandLeonardColebrook,bothof whomhadcollaboratedinclinicaltrialswiththeWarOffice.TheMRCsupportedbedsfor WrightatStMarysHospital.LeonardColebrookfolloweduphisvaccineworkwith

48 furtherMRCstudiesonpuerperalfeveratanewbuildingatQueenCharlottesHospital. 49 HejoinedtheMRCCommitteeinNovember1930. Biochemistryandpharmacologyat
50 theNIMRwereunderHenryDalewhowasappointedDirectoron1June1928.
TheMRCestablishedsubcommitteesforthestudyofrickets,(includingHopkins,
51 Paton,andEdwardMellanby) ,ahaemoglobincommittee(JoshuaH.Burn,52 D.Murray 53 LyonofEdinburghInfirmary), ananaestheticscommittee(includingProf.H.B.Dixon
fromtheUniversityofManchester),54 acommitteeonCinchonaderivativesandmalaria (includingDale,A.Balfour,Col.S.J.James,MajorH.W.Acton),andaYellowFever committee. AlthoughFletcherfoughtagainsttheestablishmentoftheBritishEmpireCancer campaign,GowlandHopkinsandC.J.BondwerepartoftheMinistryofHealth

55 DepartmentalCommitteeonCancer.
48 49
MRCMinutesIII,(11April1930):49. MRCMinutesIII,(28November1930):179. M.R.CMinutesIII,(2March1928):59 MRCMinutesII,(24March1922):243. MRCMinutesII,(1May1925):87.
50
51 52 53
MRCMinutesII,(4May1923):63.Murray LyonwassponsoredbytheMRCin 1927.Hewasthefirsttogivesyntheticthyroxintoapatient,M.Weatherall,InSearchofa Cure:AHistoryofPharmaceuticalDiscovery (Oxford:OxfordUniversityPress,1990): 89.

54 55
MRCMinutesII,(19October1923):101(12December1923):150bothwereon theMRCMRCMinutesII,(10April1920):51011.OntheBECCseeJ.AustokerinJ. AustokerandL.Bryder,(eds.),(1989):29.
267
268
56 FrederickGowlandHopkins, chairedanAccessoryFoodFactorsCommittee,
establishedjointlywiththeListerInstitutein1918,includingHarrietteChick,Jack
57 58 DrummondatUniversityCollegeHospital , thebiochemistArthurHarden andEdward
Mellanby(whowemetpreviouslyinatemporarylaboratoryroleatBurroughsWellcome
59 withhisbrotherJohn). From1923EdwardMellanby wasProfessorofPharmacologyat 60 Sheffield,andthenUCH. TheMRCalsosupportedfurthernutritionalresearchbyNoel
61 Paton,RegiusProfessorofPhysiologyattheUniversityofGlasgow. Amoregeneral
62 63 Nutritioncommittee wassetupin1929withProf.EdwardProvan Cathcart
(chairman),JohnBoydOrr,andcontinuedsupportfromHopkins,DrummondandChick. TheMRCstatistician,MajorGreenwood,ProfessorofEpidemiologyandVitalStatistics
56
H.Kamminga,F.G.HopkinsandtheUnificationofBiochemistryTrendsIn BiologicalSciences (22May1997):1847H.Kamminga,M.W.Weatherall,The MakingofaBiochemist(I)FrederickGowlandHopkinsConstructionofDynamic BiochemistryMedicalHistory 40(1996):269292M.W.Weatherall,H.Kamminga, MakingofaBiochemist(II)TheConstructionofFrederickGowlandHopkins ReputationMedicalHistory 40(1996):415 436F.G.Hopkins,ThePractical ImportanceofVitaminesBritishMedicalJournal (26April1919):50710J.Needham, E.Baldwin(eds.),HopkinsandBiochemistry18611947:PapersConcerningSir FrederickGowlandHopkins,FRS, (Cambridge:W.Heffer&Sons,1949):5MRC MinutesII,(9September1920):113.
57
F.G.Young,JackCecilDrummondObituaryNoticesofFellowsoftheRoyal Society 9(1954):99 129WalterSneader,DrugDiscovery:theEvolutionofModern Medicines (London:JohnWiley,1985):227247.

58
F.G.HopkinsandCharlesMartin,ArthurHardenBiographicalMemoirsof FellowsoftheRoyalSociety (1942)4:314.

59 60
R.P.T.DavenportHines,J.Slinn,(1992):75.
SirHenryDale,EdwardMellanbyObituaryNoticesofFellowsoftheRoyal Society 1(1955):193 222.

61
62
MRCMinutesIII,(24May1929):90foranaccountofitsworkseeC.Petty, PrimaryResearchandPublicHealth:thePrioritisationofNutritionResearchinInterwar BritaininJ.AustokerandL.Bryder(eds.),(1989):83 108.

63
G.M.Wishart,EdwardProvanCathcartObituaryNoticesofFellowsoftheRoyal Society 9(1954):33 53.CathcartasChairmanoftheCommitteeonQuantitative ProblemsofHumanNutritioncarriedoutseveralnutritionalsurveysonbehalfoftheMRC between192261932.
268
269
64 attheLondonSchoolofHygieneandTropicalMedicinewasaddedtothisteam ,andhe 65 waschairoftheMinistryofHealthsAdvisoryCommitteeonNutritionfrom19314.
TheSexHormonesCommitteeincludedDr.F.H.A.Marshall(chair),Dr.V.
66 KorenchevskyattheListerInstitute,andDr.A.J.ParkesoftheNIMR.
Inadditiontoestablishingcommittees,theMRCfundedfurtherresearch:
67 WarringtonYorkes colleagues,Dr.A.AdamsandDr.F.Murgatroydtostudyanti
malarialremediesandpotentialtrypanocidesProfA.E.BoycottandProf.F.J.Browneat
68 UCHtostudy thebacteriologyofpuerperalinfection Dr.J.F.WilkinsonatManchester 69 RoyalInfirmaryforchemicalworkonperniciousanaemia Prof.W.W.C.Topleyofthe 70 UniversityofManchester (laterProfessorofBacteriologyattheLondonSchoolof
HygieneandTropicalMedicine)andProf.HenryStanleyRaper,ProfessorofPhysiology atManchesterUniversityreceivedfundingforworkfortheanaestheticscommittee,71
72 Prof.EdwardCharlesDodds attheMiddlesexhospitalforworkontesticularhormones 73 Dr.R.CruickshankattheUniversityofGlasgowforserumtreatmentofpneumonia and 74 DrDerekN.Dunlop ofEdinburghworkonmetabolism Prof.J.C.Meakinsatthe
UniversityofEdinburghwasgiventwograntstosupportDrs.J.S.MurrayandC.G. Lambie(fromMarch1923)andProf.R.T.Leiperperformedstudiesonimmunityof
64
J.AustokerandL.Bryder(eds.),(1989):52,99,107L.Hogben,Major GreenwoodBiographicalMemoirsofFellowsoftheRoyalSociety (1950)7:137154.

65
MRCMinutesII,(22February1924):111C.Petty,inJ.AustokerandL.Bryder (eds.),(1989):83 108.

66 67 th TheSexHormonesCIBAHandbook4(Horsham:CIBA,4 edition,reprinted1954).
C.M.Wenyon,WarringtonYorkeBiographicalMemoirsofFellowsoftheRoyal Society (1944)4:523545.

68 69 70 71 72
MRCMinutesIII,(2June1929):110. MRCMinutesIII,(11April1930):68. J.AustokerandL.Bryder(eds.),(1989):712,74,79,81. MRCMinutesIII,(25January1927):17(27January1928):18.
F.Dickens,EdwardCharlesDodds,Biographical MemoirsofFellowsofthe RoyalSociety 21(1975):227 267.

73 74
MRCMinutesIII,(11April1930):73,74. MRCMinutesIII,(24October1930):150.
269
270
75 76 helminths L.W.HarrisonatStThomasontheabsorbabilityofbismuthcompounds 77 R.D.LawrenceandR.A.McCanceatKingsCollegeHospitalforworkonfoodstuffs.
EvenwiththisincreaseincliniciansfundedbytheMRC,theprobleminassessing newtherapiesfortreatmentwasthatfewindividualdoctorssawsufficientcasesandfewer stillwerescientificallytrainedorresearchminded.Fewoftheaboveoperatedlarge clinicalcentres. Thebenefitsofsyntheticdrugswerenotapparenttoalldoctorsandapproaches suchasdiet,exercise,andmassage,wereseenasalternatives.Acontemporaryeditorial speltoutthat:onlyinexceptionalcircumstancesshouldthey(drugs)beconsideredas

78 curative. DuringthewartherehadbeennoalternativebuttousetheBritishsynthetic
drugswhentherewerenonaturalreplacementsforGermandrugssuchasSalvarsan, Veronal,andAspirin,despitetheoccasionalreluctanceofBritishdoctorstoacceptthe
79 qualityoftheBritishversions.
TheMRCdidinvoketheuseofstatisticstoadegree,butmostlyfortheirpublic health,epidemiologyandvaccinationstudies.MajorGreenwoodcollaboratedwithDr. LeonardHillonaventilationstudy.Thisinteractionprofitedinthelaterinteractionswith HillsthirdsonAustinBradfordHill,whobecameanMRCstatistician.In1920John BrownleewastheleadingstatisticianattheMRCandtogetherwithGreenwoodandProf. E.C.CollisestablishedtheIndustrialHealthStatisticsDepartmentattheIndustrial

80 FatigueResearchBoard. ThiscommitteeextendedagranttoAustinBradfordHillin
January1923tocollectinformationforthenutritioncommitteeonthediseasemortality
75
P.C.C.Garnham,RobertThompsonLeiperBiographicalMemoirsofFellows oftheRoyalSociety (1970)16:385404.

76 77
MRCMinutesIII(22March1929):54
MRCMinutesIII(24May1929):90R.A.McCanceObituary,BritishMedical Journal (27March1993):851.

78
ReforminMedicalEducationBritishMedicalJournal (1January1921):20.
79
J.E.R.McDonagh,TheManufactureofSalvarsanProductsinEnglandand FranceBritishMedicalJournal (17April1915):697.

80
MRCMinutesII,(27May1921):76.
270
271
81 relatedtomigrationfromruraltoindustrialareas. Astatisticsdepartmentwas
establishedinMay1922withUdneyYuleaddedandinFebruary1925theIndustrial HealthStatisticsCommitteewasrenamedastheStatisticsCommittee.Howeveritwasnot untilthefinalprewarmeetingin1939thatBradfordHillattendedTherapeuticTrials Committeemeetings. ThissectionhasdiscussedhowtheMRCtookacentralroleinestablishingclinical researchcentresandincollaboratingwithotherinstitutessuchastheDSIR,theLister

82 Institute,BritishEmpireCampaign,andtheColonialOffice. Thisandthewartimework
oftheMRCprovidethebackgroundtowhypharmaceuticalcompaniesweresokeento collaboratewiththeMRC.
6.3TheABCMApproachtotheMRCforaClinicalTestingSchemein1922
Theextensionof theKeyIndustryActin1921toincludepharmaceuticalsand otherfinechemicalsofferedonlypartialprotectionforuncompetitiveBritish pharmaceuticalfirms.Whiletheywelcomednewrestrictionsontheimportationofdrugs fromabroadthathadnotbeenbiologicallytested,onlyclinicaltrialsinpatientscould offerconclusionsabouttheclinicalefficacyandsafetyoftheirownnewpowerful,andyet potentiallytoxicdrugs,butthesewerenotmandatory.TheFoodandDrugsActof1899 andDangerousDrugsActof1920onlyrequiredthestrengthandcontentofnewdrugsto bespecified.Therewasnolegislativerequirementtoproveefficacy.Intheorynothing preventedacompanyfromplacingnewproductsonthemarket.However,without supportingdatafromleadingpharmacologistsandcliniciansanewdrugwouldbeunlikely tobeacommercialsuccess. JoshuaBurn,theformerBurroughsWellcomeresearcher whowasresponsibleforbiologicalstandardisationattheNationalInstituteofMedical ResearchandthenatthePharmaceuticalSociety,latersummarisedthedifficultiesof performingtrials: Clinicalresearchworkisdifficultbecausetheexperimentalanimalisthe patient,whoisnotatthedisposaloftheexperimenter,andwhosewelfare
81 82
J.Beinart,TheInnerWorldofImperialSickness:theMRCandResearchin TropicalMedicineinJoanAustokerandLindaBryder(1989):109135.
271
272
mustremain amoreimportantconsiderationthantheoutcomeofthe research.Norcanthepatientsusuallybecollectedinlargegroupslike 83 mice. Intheabsenceofclinicaltesting,manufacturingcompaniesinsteadfollowedmedical publicationsandwhenanewconceptormethodoftreatmentwasdescribedtheyrushedto produceadrugwiththerelevantcharacteristics.Examplesincludethemultitudeof antisepticsmarketedafterListersdiscovery,includingalsobismuthsalts,calomel, mercuricsulphate,salol,betanaphtholandnaphthalenetetrachloride,andtheplethoraof phosphates,hypophosphates,andglycerophosphates,whentheywereshowntodecrease demineralisationofbones. Furtherexamplesfollowedthediscoveryofvitamins.Clinical trialswerenotalwaysneededinsuchcasesasthecompanycouldrefertothescientific proofalreadyestablished.Thefirmswerejustprovidingtheirversionofaprovenactive ingredientandtheydifferentiatedtheirdrugsonpurityandstrength.Theproblemwith thisapproachwasthatthenewtherapywasnotexclusiveandcouldbepreparedbymany firms.Fornoveldrugs,pharmaceuticalfirmsneededatleastafavourableclinical opinionpublishedinamedicaljournal,evenifittookonlyafewpatientstoachievethis aim.Britishfirmsthathaddifficultyinarrangingclinicaltestsfeltthatiftheirproducts weregivenasealofapprovalfromtheMRC,thiswouldgivethemanadvantageover Germanfirms. ThefewBritishfirmsthatinvestedinsyntheticchemistryhadmajordifficulties arrangingforclinicaltrialsoftheirnewdrugsasmostBritishdoctorswerenot accustomedtodealingdirectlywithpharmaceuticalmanufacturersandremained suspiciousofBritishsyntheticdrugs.Previouslyclinicaltrialshadnotbeenperformed becausecompaniesweresimplymanufacturingextractsrequiredbyphysicianstotreat patientsaccordingtotimehonouredtraditions.Assemisyntheticorsyntheticdrugshad neverpreviouslybeengiventohumans,firmshadtheadditionalhurdleoffirstconvincing thescepticalmedicalprofessionoftheirpotentialvalue,whereaspreviouslytheyhad simplyproducedalkaloidalextractsorinorganicmedicinesofknownefficacythatdoctors requestedandhadprescribedfordecades.Physicianswerealsoawareofthe contemporarylegalpositionwhileitisthedutyofaphysicianorsurgeontokeepup
83
J.H.Burn,TheBackgroundtoTherapeutics(Oxford:OxfordMedicalPublications, 1948):preface.
272
273
withtheadvancementmadebyhisprofessionitisalsohisdutynottoattempttoforge
84 aheadofitbytryingexperimentsonhisregularpatients.
In1922theMRChadjustacquiredtherightstoinsulinandwereabouttoestablish clinicaltrials.TheAssociationofBritishChemicalManufacturers(ABCM)thathad becomethecollectivevoiceofthepharmaceuticalindustryfollowingitscampaignsfor collaboration,forthetrainingofchemistsandasaresultofitschemicalmissionto Germanyin1919,approachedtheMRCaboutfacilitiesfortestingnewmedicinesatthe endof1922.TheywererepresentedbyfourleadingindustrymenFrancisCarr,whohad developedthechemicaldepartmentsatBurroughsWellcomeandBootsCharlesHill,the ManagingDirector,whohadrecentlyrecruitedCarrtoBritishDrugHousesGeorge Pearson,GeneralManagerofBurroughsWellcome,andFrederickGamble,pharmacist

85 andseniormanageratAllen&Hanburys. Theyrepresentedthemajorscientifically
basedBritishcompanieswhichhadexpandedduringthewar,butwhichmostfeltthe impactofasqueezeonprofitsin192122.TheABCMargued,astheyhadsincetheir inceptionin1916,thattheBritishindustryoughttobeindependentofforeign

86 supplies.
ThefirstmeetingwiththeMRCtookplaceon15February1923followinga
87 memorandumfromWoolcock, secretaryoftheABCM,whichsummarisedtheproblems,
whichPearsonandhisstaffhadexperiencedatBurroughsWellcome: Therearetwomaindifficultiesinsecuringthemedicalcooperation requiredunderthepresentconditions:thescarcityofmedicalresearch
84
Quotedfroma1918legalencyclopediabyK.LawrenceAltman,WhoGoesFirst? theStoryofSelfExperimentationinMedicine(NewYork:RandomHouse,1987):12.
85
G.E.PearsontoW.J.UlneyWoolcock,(18December1922)andW.J.U. WoolcocktoM.R.C.,(19February1923),MRCFile1523.
86
87
BritishFineChemicalsBritishMedicalJournal (29April1922):666.
W.J.UlneyWoolcockCBE,waspreviouslyactiveintheSocietyoftheChemical Industry.WoolcockhadstudiedatUniversity College,andtheSchoolofPharmacyin London.Between191318hewasRegistrarandSecretaryofthePharmaceuticalSociety. HewasGeneralManageroftheABCMfrom1918to1928.Laterhetookmanagement roleswithMondandICIW.J.U.WoolcockChemistry&Industry (27December 1947):807.
273
274
workers,[and]theprofessionalpositionofmedicalmenwhomaybecome associatedwithmanufacturingfirms. Whenamanufacturerhadevolvedbyresearch,asubstancewhichwas believedtobeoftherapeuticalvalueithadtobefirsttriedbya pharmacologisttomakesurethatitwouldbesafeforclinicaltrials.Such pharmacologistswerescarceinEnglandandfew,ifany,hadassistantsin training.Thepharmacologistswerealsoengagedintheirownlinesof researchfromwhichtheydidnotwishtobediverted.Asaresultofthisitis onlybyaluckychancethatthemanufacturerscangetanewproducttried pharmacologicallyinthiscountryandcontinuouscooperationinalong researchsuchasthatwhichinthecourseofsomethinglike15yearsworkin 88 Germanyledto'Bayer205'issimplyoutofthequestioninEngland. Bayer205ortryparsamide(Germanin)wasanewGermandrugfortreatingsleeping
89 sickness. Itwassignificantnotonlyforitsmedicalimpact,whichwouldbelimitedto
thecolonies,butasafurtherexampleofthesuperiorityofGermansyntheticchemistry andpharmacologyincombatingapreviouslyuntreatabledisease.Pharmacologyhad developedasanimportantscience,firstinFranceandGermanyandwasthenexportedto AmericabydoctorstrainedinGermany.PharmacologistsinGermanyworkedclosely withpharmaceuticalordyemanufacturers,whoprovidedthechemicalstogainabetter understandingofdrugaction.ThesciencewasnotasdevelopedinBritain,partlybecause oftheearlierAntivivisectionlaws,butalsobecauseofthelimitedavailabilityofnovel compounds,limitedfellowshipsallowingphysicianstoperformresearchandfewclinical

90 researcherswithaccesstopatientbeds,asdescribedpreviously.
TheWoolcock/PearsonnotefromtheABCMcontinued: Assumingthemanufacturerisfortunateenoughtoovercomethe pharmacologicaldifficultyheisthenfacedwiththemoreseriousmatterof gettingclinicalreportsonhisnewproduct.Hereagainthenumberofmen competenttodosuchworkisextremelysmallanditisnot toomuchtosay thattheaverageclinicalreportobtainableinthiscountryisworthless.What themanufacturerreallywantsisatrustworthyreportshowingwhat advantageanddisadvantagesthenewdrughaswhencomparedwith

88
W.J.U.WoolcocktoW.M.Fletcher(19February1923)basedonanotefromG. E.PearsontoW.J.U.Woolcock,(18December1922).ChemicalManufacturersandthe MRC19221949(13February1923),MRCFile1523.

89
FromGermanintoAcylureidopenicillinResearchthatMadeHistory.(Leverkusen: Bayer1980):13 19 50YearsofBayerRemedies18881938 (Leverkusen:Bayer,1938).

90
MRCMinutesII,(17July1925):122,and(30April1926):63.
274
275
existingremediesandcallingattentiontoanyunexpectedfeaturesinthe natureofitsaction.Itissafetosaythatsuchreportsareonlyobtainablein exceptionalcircumstancesinEnglandtoday.Whatusuallyhappensisthata medicalmanundertakestofurnishaclinicalreportandafterlongdelaysays thatowingtopressureofotherdutieshehasbeenunabletoundertakethe workortofinishareport,whichmerelystatesthatthedrugisorisnot satisfactory.Thisdifficultycanonlybeovercomeinthelongrunbythe provisionofmorepharmacologistsandexpertclinicalobserversandthis canonlybedonebythemedicalcollegesinthiscountrygivingmore attentiontothesesubjectsandencouragingstudentstospecialiseinthemat afairlyearlystageintheircareers.Butinadditiontothissomearrangement isrequiredwherebymanufacturerscanobtainasamatterofcourse, pharmacologicalandclinicalreportsonnewdrugs,justastheycanalready obtainreportsfromchemists,lawyersandotherprofessionalmenon chemical,legalandotherquestions.PerhapsthiscouldbedonebytheMRC formingapanelofpharmacologists,cliniciansandothermedicalexperts whommanufacturerscouldconsulteitherdirectorthroughtheCouncil.It ispossiblethattheCouncilcoulditselfarrangeforsomeofthisworkto doneinitsownlaboratoriesbutitwouldnodoubtbenecessaryto supplementsuchfacilitiesveryconsiderablyinordertocopeadequately withtheworkandtheformulationofapanelofmenwhomthecouncil considersuitableforsuchworkwould,itisthoughtbeofgreatassistance, notonlyasregardstheimmediatedifficultybutalsointhewayof stimulatinginterestinthesesubjectsandencouragingstudentstospecialise inthesedirections. 2)Professionalroleofmedicalmenwithmanufacturers Itisclearfromtheforegoingthatifthiscountryistotakeitsproperplacein chemotherapeuticalresearchandinthefinechemicalmanufactures,which shouldresultfromit,therewillhavetobeamuchcloserassociationof medicalmen(usingthatterminthebroadsensetoincludepharmacologists, physiologists,etc.)withmanufacturersthanhashithertobeenthecasein Englandandthequestionhasbeenraisedwhethermenwhothusbecome associatedwithindustrialfirmsforsuchpurposeswilllosecasteintheeyes oftheirprofessionalbrethrenandmayevenruntheriskofbeinglookedat askancebytheauthoritiesofthemedicalcolleges.Itisnoteasytostatethis difficultypreciselyandpossiblythenearestapproachtoaccuracymaybeto saythatthereseemstobeafeelingamongcertainmedicalmenthat professionalassociationwithafirmisregardedbytheleadersofthe medicalprofessionasnotquitetherightthing.Thisisaratherintangible matterandadmittedlydifficulttodealwithbutitwillberealisedthatina countrylikeEnglandwherethe'correctthing'inconductisafactorofno smallimportance,suchafeeling,ifitexists,maybeaseriousobstacleto progress.OnthismatteritishopedthattheM.R.C.maybeabletoafford manufacturerssomeguidanceandpossiblytoissuesomestatementonthe generalquestionsdealtwithinthismemoranduminwhichwouldbe incorporated,shouldtheyseefit,todoso,someexpressionofopinion, indicatingthattheywillbegladtoseeclosecooperationbetweenmedical 275
276
expertsandmanufacturersforthecommonobjectofsecuringprogressin therapeutics.Inthisconnectionitmayperhapsbementionedthatthereare alreadyinexistenceinthecountryinstitutionseitherendowedorsupported bynationalfundswhichhaveontheirstaffseminentscientificandmedical menandwhichundertakepurelycommercialinvestigationsandworkin closeassociationwithindustrialfirms.Theprestigeofsuchinstitutions seemstobeinnowayinfluencedbysuchassociation,noristhestandingof theirstaffsaffectedandinviewofthisthereseemstobenoreasonwhythe directassociationofmedicalmenwithindustrialfirmsshouldactinany 91 waytotheirdetriment. Thestigmaofliaisonswiththepharmaceuticalindustryregardingadvertisingandselling ofdrugsremainedinBritainfollowingthecampaignsagainstthepatentmedicine producers.DoctorsreliedonLondonbasedconferencesandoneditorialswrittenbythe medicalelitefortheirinformationonnewdrugs.Onlyrarelyweredogmaticclaims substantiatedwithextensiveclinicaldata.IndividualcasereportspredominatedinBritish medicaljournals.Towhatextentthisreflectededitorialpolicy,thephysiciansprecept thattherapyhadtobetailoredtotheindividual,orthedifficultiesofarrangingtestsofnew drugsisdifficulttoassess.Tradenamesofdrugswerefrowneduponandtheroleofthe manufacturingcompany wasrarelyacknowledged. Clinicaltrialshadbeenperformedinthepastwithvaccinesandantitoxins,but
92 localhealthboardsorganisedtheseinaccordancewithGovernmentpolicy. Allofthe
availablevaccinesweretheresultsofacademicresearchratherthancommercial enterprise.FirmssuchasEvansLescher&WebbcollaboratedwiththeLiverpoolSchool ofHygieneandTropicalMedicine,whileAllen&HanburyscollaboratedwiththeLister

93 Institutetoproducevaccines. Thefirmsthenactedinamanufacturingcapacityand
offeredsalesanddistributionservicesforvaccines.Nowthatsomepharmaceuticalfirms
91
G.E.PearsontoW.J.U.Woolcock,A.B.C.M.,(18December1922),MRCFile 1523.
92
A.I.Stolly,W.H.Birk,StudiesonImmunisationVersusRespiratoryDisease.VII. ReportontheProphylacticVaccinationof1536PersonsAgainstAcuteRespiratory Diseases19191920JournalofImmunology 6(1921):10315.

93
GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen&Hanburysand theBritishPharmaceuticalIndustry17151990(London:Murray,1990):120Walter Sneader,(1985):2301,233,235,244,265,280,332.
276
277
weredevelopingtheirowndrugstheysoughtwiderinteractionswithmedicalresearchers andhavinglimiteddirectsuccesstheyhadturnedtotheMRC.
6.4Insulin:anMRCPreoccupationandaProductionChallenge AlthoughthefirstcontactbetweenrepresentativesoftheMRCandtheABCM regardingclinicaltrialstookplaceattheendof1922,noimmediateprogresswasmade. ThereasonseemstobethattheMRCbecamepreoccupiedwiththeirworkonbiological standardsandespeciallyontheBritishdevelopmentofinsulin,followingtheapproach fromTorontoUniversitywithanofferoftheBritishrightstoinsulinandthis

94 overshadowedtheimmediateplanstoarrangestudiesoftheBritishfirmsproducts. The
MRCagreedtotesttheextract,knownasinsulinaslongasnorestrictionswereplaced
95 uponthem.
Insulinwasapurifiedhormone,initiallyextractedfrompancreaticglandsofcattle, whichappearedtocontrolbloodglucoselevels,soofferinghopeforthelifethreatening conditionofdiabetics.TheTorontoteamhadalreadycollaboratedwithEliLillyof

96 IndianapolisintheUSAforproductionofinsulin, whichhadalreadybeenshowntobe
remarkablyactive,heldfarmoreinterestfortheMRCthantheuntried'new'synthetic drugsavailablefromBritishfirms.Bythesametoken,iftheycouldobtainit,insulin offeredtheBritishfirmsthechanceofmuchlargerprofitsthananyoftheirotherlinesasit wasnotinitiallyavailableinGermany.TheinsulinstoryhasbeentoldindetailbyBliss andbySinding,soIwillfocusonlyonsomekeyissueswhichaffectedtheBritishfirms

97 andthetestingoftheirowndrugs. BothQuirkeandCoxMaksimovtookinsulinasone
oftheirthesiscasestudies.BothreferredtotheseminalstudybyLiebenau,thoughthis wasbaseduponalimitedappraisaloftheMRCsourcerecords,referringtoinsulinasa
94 95
M.R.C.MinutesII,(17November1922):375(8December1922):389.
Thefirstdiscussionsaboutinsulinwereon24March1922,MRCCouncilMinutesII, (21July1922):318.
96 97
MichaelBliss,TheDiscoveryof Insulin (Edinburgh:Faber&Faber,1983). C.Sinding,TheMakingofInsulinBull.Hist.Med.76(2002):23170.
277
278
98 pituitary(ratherthanapancreatic)hormone. InSeptember1922HenryDaleandhis 99 chemistHaroldWardDudley visitedU.S.manufacturersatAnnArbor(ParkeDavis)
100 andIndianapolis(EliLilly)todiscussthestandardisationofinsulin. Aswithother
extractsitcouldbeofvariablestrengthandgivenitsroleincontrollingbloodglucose,the doseadministeredhadtobeaccurate.DaleandDudleymetAmericancliniciansinvolved inearlyclinicaltrialsofinsulin,butalsodiscussedAmericanstudiesofinfluenza, bacterialchemistry,andvitaminsandtheyvisitedtheU.S.hygieniclaboratoriesin

101 WashingtontodiscussstandardsofSalvarsan,pituitaryextractsandantitoxins. 102 TheMRCsecuredBritishpatentsoninsulin. However,thischangeoftheir
103 policyregardingpatentswashighlycontroversialandtroubledthemformanyyears.
ProtestsappearedfromSirWilliamBaylissofUniversityCollege,London.104 The
98
J.Liebenau,TheMRCandthePharmaceuticalIndustryinJoanAustokerandLinda Bryder(eds.),HistoricalPerspectivesontheRoleoftheM.R.C. (Oxford:Oxford UniversityPress,1989):163180onp.169.

99
H.H.Dale,HaroldWardDudleyObituaryNoticesofFellowsoftheRoyalSociety 1(1935):595 606.

100
H.H.Dale,H.W.Dudley,ReporttotheMedicalResearchCouncilofourVisitto CanadaandtheUnitedStates(30October1922):318,MRCFile1092/15.
101
H.H.Dale,H.W.Dudley,ReporttotheMedicalResearchCouncilofourVisitto CanadaandtheUnitedStates(30October1922):318,MRCFile1092/15MRCMinutes II,(8December1922):389MRC1092/25M.Bliss,(1983):166TheNewTreatment ofDiabetesbyInsulinLancet(18November1922):1086J.AustokerandL.Bryder, TheNationalInstituteforMedicalResearchandRelatedActivitiesoftheMRCinJoan AustokerandLindaBryder(eds.),(1989):4445.

102
MRCMinutesII,(21July1922):318Amethodofconcentrationofinsulin,granted toDudleyandtheCouncilMRCMinutesII,(25March1923):26.
103
TheMRCdebatedpatentsextensivelyanddraftguidelinesonpatentsweredrawnup in1928MRCMinutesII,(1927):24,56,84,208(1928):4,131,161A.Landsborough Thompson,Volume2(1975):236.

104
BaylisswasthecodiscovererofSecretin,andalongwithE.H.Starlingthefirstto usethetermhormoneW.Bayliss,Insulin,DiabetesandRewardsinDiseasesNature (10February1923):188191.
278
279
educationalist,ProfessorH.E.Armstrongalsosentastronglywordedletterofcomplaint
105 toTheTimesaboutthepatentingofmedicaldiscoveries.
FletcherarguedthatpatentingwasinlinewiththeMRCpolicyofensuringthe qualityofnewmedicinesandthatproperstepstowardsstandardisationandtowardsthe helpandguidanceoftheprofessioninthetherapeuticuseofthesubstance(aregiven),

106 preventingimproperexploitationbycommercialinterests. Insulinwasalsoprotected
bytariffsandFrancisCarrlaterfoughtagainstremovalofthetariffonDanishinsulinand
107 thepossibilityoflowpricedimports. Insulintariffswerediscussedupuntil1933,when
aparliamentarytribunalwasestablishedundertheSafeguardingofIndustriesAct. Insulinwasclearlyanimportantadvance,butitinvolvedacomplexextraction processandwithoutpharmaceuticalindustrysupport,supplieswouldhavebeenlimited. HoldingthepatentswouldenabletheMRC: toexerciseamoralcontrolovermanufacturersandwouldinducethelatterto submittoasystemofsupervision,asregardsthisproduct,whichthelawdoesnot enabletheCouncilatpresenttoenforce(and)wouldregulariseanddefinethe council'sauthority.Thereforemanufacturerswouldsubmittocontrolasper 108 Salvarsan. IthadalwaysbeenthepolicyoftheCouncilnottocountenancepatentingwitha viewtopecuniaryprofitandyettheyhadinthepastacceptedassignmentof patentrightswithaviewtosecuringcontrolinthepublicinterestandinspecial circumstancespromotedpatentingpurelyasadefensivemeasureagainstimproper exploitationofamedicaldiscovery theyhaddeclinedpatentsinthecaseof 109 Streptococcalantitoxinandscarletfever.
105
H.E.ArmstrongtoTheTimes(21November1922)replybyH.H.Dale,Nature (24 February1923):2534W.M.FletchertoW.Bayliss(14February1923)W.Baylissto WalterM.Fletcher(15February1923)MRCFile1092J.LiebenauinJ.AustokerandL. Bryder(eds.),(1989):1712.

106
107
MRCFile1092,(30August1922).
J.Liebenau,inJ.AustokerandL.Bryder(eds.),(1989):176BDHstatement (January1934),MRC1092.
108 109
ReportofTriptoAmerica,H.W.Dudley,(30October1922),M.R.C.File1092. MRCMinutesIII,(29April1927):56.
279
280
TheMRCwerehowevercriticisedinsomequartersfortheirpolicy,forexample,Bayliss wrote:thereisastrongfeelinghereagainstpatentingtheproductsofvalueintheareaof
110 disease.
TheMRClaterarguedthathadtheynottakenupthepatentrightsinBritain, manufacturingbyourfirmscouldnothavebeenachievedhere:ifwehadlet manufacturersbegin2monthsagotheywouldprobablyhavemadelittleprogressand

111 wouldnowbescrappingtheirplantforchangedmethods. Theyrecognisedthatin
ordertoproduceinsulin,firmsrequired:elaborateequipment,biologicallaboratories (licensedbytheHomeOffice)andhighlyskilledpersonnelandthat:aprocesswhich succeedsonanexperimentalscaleinthelaboratory,presentsnewandmuchmoreserious

112 difficultiesonamanufacturingscale.
EarlytrialsofinsulinintheUSAhadgivenresultsofbrilliantpromisecreatinga hugedemandbeforetheactiveprincipleanditsmanufacturewereidentified.TheMRC cameunderpressuretoreleaseinsulinratherthantoperformfurthertests,butthey defendedtheteststhatweretopromote: whateverenterpriseororganisationisbestfittedforsecuringtheearliest productionoftheinsulinextractunderproperconditionsofsafetyand control.Inthiswaythenecessaryscientifictrialsofthetreatmentcanbe 113 mostreadilyobtained. TheMRCsecuredsuppliesofpancreasglands 114 andthiskeptthepriceofinsulinlow. Threealternativestrategieswereconsidered: a)Patentingthenlicensingouttovariousfirmswithspecificationofquality,safetyand priceandtestingattheNIMR.
110
SirWilliamBaylissInsulin.DiabetesandRewardsforDiscoveriesNature(10 February1923):18891.
111
H.H.DaleandH.W.Dudley,(8January1923),MRCFile1092. W.M.FletchertoC.J.Bond,(11January1923),MRCFile1092. TheTreatmentofDiabetesbyInsulinLancet(18November1922):10812.
112 113 114
W.BaylisstoW.M.Fletcher,MRC1092:23SirWilliamBayliss,Insulin. DiabetesandRewardsforDiscoveriesNature(10February1923):18891H.H.Dale, InsulinNature(24February1923):253254.
280
281
b)ProductionofinitialsuppliesattheNIMRorothernoncommercialcentres.
115 c)Studiesatselectedfirmseachwithlocalmanufacture.
TheMRCSecretarywrotetoBurroughsWellcome,BDH(actingtogetherwith A&H),Boots,EvansSonsLescher&Webb,andDuncanFlockhardtregardinginsulin
116 supplies. TheirpreferredchoicewasBurroughsWellcomeforThevastexperienceof
thesepeopleinmakingsuchpreparationsasadrenalin,iodothyroglobulin,pituitrin,etc. it
117 ismorelikelythattheywillhituponimprovements. Theyrealisedtherewouldbethe
jealousyofothermanufacturersbutthepositionofsuchafirmasBurroughsWellcomeis sooutstandingfromthescientificaspectthatthismaybedismissed.Regarding Wellcome,Bondfeltthat:'everypoundofhisisworthtwoofeverybodyelse'sowingto

118 theuniquefacilitiesathisdisposal. Iftheyhadgoneentirelytowardsaregionalpolicy
withonlyonefirminLondontochooseitwouldhavetobeBurroughsWellcome,giving
119 themtheopportunitytobeaheadoftherestoftheBritishfirms.
Dale,asHeadofthePhysiologySectionoftheNIMRandhischemist,Harold WardDudleyadvisedtheMRCtogoaheadwithsmallscaleproductionatseveralcentres, buttheMRClaboratoriesfirstaddressedsomeoftheproblemsofproduction.They achievedan8foldincreaseofyield,decreasedalcoholrequirementsby80%,decreased

120 theproductiontimeandfoundameansofheatsterilisation. Theyfeltthisjustified
delayingcommercialproduction,butonceproductionissueswereresolvedtheywereable
115
116 117
H.W.Dudley,(30October1932),MRCFile1092:15. MRCCouncilMinutesII,(12January1923). N.Paton(Glasgow)toW.M.Fletcher,(23November1922),MRCFile1092:15. C.J.BondtoW.M.Fletcher(12January1923),MRCFile1092:15. J.Liebenau,inJ.AustokerandL.Bryder(eds.),(1989):1734. InsulinMinutes,(8January1923),MRCFile1092.
118
119 120
281
282
121 tograntlicences. MeanwhiletheMRCtookoutfurtherpatentsonDudleysimproved

122 methodofproduction.
AnInsulinCommitteewassetupandestablishedtrialsatMRCsponsored
123 laboratoriesthathadappliedforalicensetoperformtrialsinNovember1922. Fiveof
thesecentreswereinLondon(St.Bartholomews,(Fraser)Guys(DrPoulton),St. Thomass,UniversityCollegeHospital,andTheLondon)andotherswereinSheffield (MellanbyandLeathes),andtwoinEdinburgh(Meakins,andMurrayLyon)andthese beganinDecember.LaterJ.A.NixinBristolandProf.NoelPatoninGlasgowjoined

124 in. TrialswerearrangedontheconditionthattherewasnoextracosttotheMRC 125 thoughtheylaterallowedthepurchaseofequipmentandhiringoflaboratoryassistants.
PatonrecommendedthatBurroughsWellcomeshouldbeinvolvedandtheymade
126 enquiriesaboutgainingalicenseatthestartofDecember1922. Afterinitial
discussionswithtenfirms,threeLondonfirmsestablishedcommercialproductionof insulinearlyinMay1923.FletchersatonacommitteewiththeMinistryofHealthto
127 discussthebestmeansofdistribution.
121
122
W.M.FletchertoW.M.F.Paton,(23November1922),MRCFile1092.
AMethodofConcentrationofInsulin,grantedtoDudleyandtheCouncilMRC Minutes,(25March1923):26OverseasPatents,MRCMinutes,(15June1923):79(20 July1923):85USPatents,(14January1924):27and(14March1924):35.

123
Acommitteewasestablishedtomonitorinsulinclinicaltrialswhichbeganin December1922MemberswereWilliamLeischmannupto23January1923(replacedby SirF.Andrewes),TheBaronMildmayofFlete,T.R.Elliott,LordGoschenwhowentto Madras12December1923,andH.H.Dale.(ProductionwasbyDrs.Babkin(London),T. A.Hughes(UCH),Poulton(Guys),DrGrahamandProf.Fraser(St.Barts)C.H. Kellaway,T.A.Hughes,ObservationontheEffectofInsulinonNormalMetabolism BritishMedicalJournal (28April1923):737.

124 125
126 127
MRCMinutesII,(17November1922):376(12January1923):3. MRCMinutesII,(17November1922):376(8December1922):389. J.Liebenau,inJ.AustokerandL.Bryder(eds.),(1989):1723. MRCCouncilMinutesII,(23March1923):26,53.
282
283
Allen&HanburysandBritishDrugHousesworkedtogetherandBurroughs
128 Wellcomeworkedalone. Therewerealsosubsequentlythreefirmsinvolvedfromother
partsofthecountry,namelyBoots,EvansSons,Lescher&Webb,andDuncan
129 Flockhardt. Everybatchofinsulinhadtoundergoindependenttests,uponpaymentof
afeeandcouldnotbesolduntilcertified.HowevertheNIMRwereunabletocopewith allofthetesting,sofromJuly1924foratrialperiodofaround2months,British manufacturersperformedtheirowntestsontheinsulinthattheyproduced,withcontrol batchesbeingsenttotheNIMR.AsmallamountofUSinsulinwasbeingimportedbutthe UStestswere trusted.Forapreliminaryperiodallsaleshadtobedirectedthroughthe Council.Amaximumnetsellingpricewasfixed,andonlythenameinsulincouldbeused. NomisleadingorexaggeratedclaimsofefficacywereallowedandtheCouncilfurnished statementsonthemodeofadministrationandprecautions.Activityhadtobestatedin plainfigures,instandardunits,withabatchnumberandreferencetotestsandanominal
130 royaltywastobepayabletotheMRC. Bysettingdowntheserigorouscontrolsthe
MRCbecamethearbitersofdrugsafetyandefficacyofinsulin. Althoughinsulinwasnotsynthetic,itsproductiononamanufacturingscalewas complex.Thepancreashadtobeisolatedfromcattlewithinhoursofdeath,andalcohol hadtobeaddedtopreventdestructionbyenzymes.Extractshadtoberefrigeratedinacid conditionstopreventbreakdownandinsulinwasthenpurified,andprecipitatedunder

131 exactconditions.Onetonofpancreasproducedonlyonegramofinsulin.
128 129
H.H.DaletoW.M.Fletcher,(4May 1923):53,MRCFile1092.
MRCMinutesII,(12January1923):43.Onthe23February1923,theMRC announcedthatinsulinwasbeingproduced'standardised'andon23Aprilitwasfurther statedthatB.D.H.(inassociationwithA&H)andBurroughsWellcomehadsatisfiedall therequirementsandtestsoftheCouncilforauthenticityandstandardvalue,therapeutic activityandsterility:D.C.HustonandE.C.Cripps,ThroughaCityArchway:TheStory ofAllenandHanburys17131953(London:Murray,1954).Asimilaragreementwas reachedwithBoots.

130
W.M.FletcherletterManufactureofinsulin,MRCMinuteBookII,(17July 1924):109J.Liebenau,inJ.AustokerandL.Bryder(eds.),(1989):170
131
F.H.Carr,H.W.Dudley,ScientificandIndustrialProblemsofHormonesBritish MedicalJournal (24July1926):167.
283
284
Insettingthetermsof manufacture,thestrategyoftheMRCforthefuture developmentofnoveldrugswasevident.Firmswantingalicencehadtohavethe manufacturingplant,equipmentandstaffforbiologicaltestsandsterilityexperiments,and somefirmshadapplicationsturneddown.Thisgaverealincentivestofirmstoimprove theirfacilities.CarrofBDHarrangedfortheerectionofalargescaleproductionplantat GrahamStreet,inLondonsothatincombinationwithAllen&Hanburys'InsulinAB' wasfirstsoldinMarch1923andupto50,000dosesperweekwereproducedbyJuly

132 1923.Itwasahighlyprofitablebusiness. BetweenAprilandOctober1923theirA.B.
brandsold2,525thousandunitscomparedtoBurroughsWellcome's490thousandunits. Bytheendof1923, theABbrandheld95%ofthemarketandestablishedBDHasamajor

133 forceintheBritishpharmaceuticalindustry. Asaresult,pricesdropped
134 dramatically. BritainwasselfsufficientandstoppedimportinginsulinfromAmerica
inthesummerof1923.Perhapsbecauseoftheiruncertaintyofthebenefitsofinsulin,or inordertoperformworkindependentofothercompanies,BurroughsWellcomearranged theirowntrialsofinsulin.Foroncethiswasnotadifficulttaskconsideringthedemand forthenewtreatment,buttheyhadclearlylosttheinitiative,whichhadbeentakenupby BDH.DalewasfurioustofindthatO'BrienoftheWPRLhadarrangedindependenttrials atSt.BartholomewsHospitaloftheearlybatchesofinsulin,behindthebackofthe

135 MRC. Hewasevenmoreconcernedaboutimitationproductsfromsmallcompanies, 136 poorlystandardised,butgivensimilarnamestoinsulintocreateademand.
132
ThecloserelationshipbetweenBDHandAllen&Hanburyswasunusualatthe time,butitmadethemostofCarr'sexperience,themanufacturingcapacityofBDHand theanalyticalfacilitiesandpackinganddistributionnetworkofA&H.Geoffrey Tweedale,(1990):129130H.H.DaletoW.M.Fletcher,(21March1923,3April1923) MRCFile1092AllenandHanburysprofitedfrompreviousexperiencewithparathyroid hormoneMRCMinutesII,(23March1923):53.

133
GeoffreyTweedale,(1990):129130InsulinTrialsBritishMedicalJournal (22 December1923):110.

134
J.Liebenau,inJ.AustokerandL.Bryder(eds.),(1989):175. H.H.DaletoW.M.Fletcher,(1January1923),M.R.C.Files1092.
135 136
SuchproductsincludedArmour'sInsulase,Philadelphia'sInsulans,Harrower's PanSecretin.Pancreatokinase,BritishMedicalJournal (16December1922):1194.
284
285
BurroughsWellcomeandotherfirmswereeventuallyallowedtoselltheiroral brandofinsulinassteriletablets,withoutanyspecifictesting,afterDalereviewedtheir plansformanufacture.Yet,theMRCrefusedtograntalicensetotheDanishcompany,

137 Leo,attheendof1923. TheMRCalsoexcludedtheoriginalEliLillypreparation,
despitethefactthatatonetimetheycouldsupplytheworldneeds,andthefirmspent 2,500to3,000perweekontestingandutilisedover100,000animalsinthefirstmonth tomeetthestrictU.S.qualityrequirements.EliLillycouldhavecompletelyoverrunthe Britishmarket.TheMRCarguedthatsufficientinsulinwasalreadyinproduction,made byBritishfirms.LiebenaumadethissamepointthattheMRCwasprotectingthe

138 industry. ThispointisnotableforthesewerethefirsttimesthattheMRCovertly
139 turnedawaynonBritishproducersexceptforqualitydefects. Attheendof1923
BritainwasfaraheadofGermanyintheproductionofhormonesandvitamins.Itwas wellinto19245beforelargescaleproductionofinsulinwasachievedinGermanyor
140 France,andthentheMRCalsoinhibitedtheimportationofinsulinfromBayer.
TheMRCremainedpreoccupiedwithinsulintrialsforthetwoyearsandresults
141 werepublishedintheirannualreports. Thearrangementoverinsulinworkedwell
becausethepharmaceuticalcompanyprofitswerebalancedbyachievingeconomical synthesisinthenationalinterest.Thefirmsinvolvedextendedtheirmanufacturingplant considerablyandgainedvaluableexperienceoftheproblemsoflargescaleproduction.In paralleltheMRCextendedtheirroleofoverseeingthepurityofbiologicalstandardsand arrangedclinicaltrialsofanimportantnewsubstance.Itshouldbenotedoncemorethatit

137 138
MRCCouncilMinutesII,(17July 1924):109. J.Liebenau,inJ.AustokerandL.Bryder(eds.),(1989):171. MRCCouncilMinutesII,(17July1924):109M.Fletcher,(1957):3301.
139
140
MichaelBliss,(1983):165J.Liebenau,inJ.AustokerandL.Bryder(eds.), (1989):175.
141
TheMRCstatisticalcommitteepreparedareportontheeffectofinsulinonthe mortalityofdiabetes.Howeverofthe1161privatepatients,61%werelostsightof,half inthefirstyearoftreatment,andaboutaquarterofpatientshadbeenseenonlyonce: InsulinBritishMedicalJournal (24February1923):341InsulinforSale(21April 1923):6901InsulinAvailableinthisCountryConditionsofSaleandPrecautionstobe Observed(21April1923):695SomeClinicalResultsontheUseofInsulin aReport oftheMRC(28April1923):73740EstimationofSugarinBlood(5May1923):777.
285
286
wasattheendof1922,intheearlystagesofcollaborationoninsulin,thatmanufacturers askedforsupportfromtheMRCinarrangingclinicaltrialsoftheirownproductsbutthe systemputinplacewasspecificforinsulin.
6.5FrancisCarrandhisGrowingInfluence. LiebenaucreditedtheMRCwithtakingonaconservativeresearchprojectto standardiseproductionandlowercosts,whichby1924succeededincuttingpricesby

142 almost75%. ItwillberecalledhoweverthattheMRCinitiallyconsideredlimiting
manufacturetocertainfirmsandtheirclearfavouritewasBurroughsWellcome.However, thebalanceofpowerintheBritishpharmaceuticalindustrywasshiftingsignificantly towardsBritishDrugHouses. Aswehaveseen,FrancisCarrwasalreadyawellknownfigureintheBritish pharmaceuticalmanufacturingindustry.HehadcollaboratedwithDunstanatthe PharmaceuticalSocietybeforetakingoverasWorksmanageratBurroughsWellcomein 1898.Havingestablishedamanufacturingcapacityforsemisyntheticdrugsandalkaloids, hemanufacturedSalvarsanin1914andwasheadhuntedtojoinBootstoestablishtheir manufacturingcapacityduringtheWar.ImmediatelyaftertheWarhewasenticedfora largesalarytojoinBritishDrugHouses.Ineachcasehewasabletoattractasignificant numberofhiscolleaguestomovewithhim.In1919hewaspartoftheABCMmissionto visitGermanfactoriesandin1921hecoauthoredatextbookthatoutlinedforBritish chemiststhemethodsofsynthesisingorganicdrugs.Hewasalsoanactivememberofthe SocietyofPublicAnalysts,andamemberoftheCounciloftheSocietyoftheChemical Industryfrom192023.Hehadpreviouslycontributedtosignificantlyimprovingthe manufacturingyieldofthyroxin,butitwashisachievementsinmakingBritainself sufficientininsulinthatbroughthimworldwidefame:F.H.Carr,whohasplayeda distinguishedpartinthedevelopmentoftheBritishfinechemicalindustry,closely
143 associatedwithearlyproductionofinsulininthiscountry, andhehasexhibited,asin
thenotablecaseofinsulin,averypracticalcapacityformasteringtheengineeringand
142 143
J.LiebenauinJ.AustokerandL.Bryder(eds.),(1989):171. TheFinancialNews(17June1926),ChemicalIndustryCongress,London.
286
287
144 othertechnicaldifficultiesoflargescaleproduction. Carrusedhischemical
engineeringskillstoincreaseyieldsofinsulinby20fold.Thepriceofinsulinfellfrom25
145 shillingsto2shillings8dper10dosesover12months. Itfellfurther:Thescientific
industryofthiscountryhadreasontobeproudofthefactthatwithin18monthsofits introduction,productionhadincreasedsogreatlythatabalancewasavailableforexport
146 andtheoriginalpricedecreasedto1/11d.
Althoughinsulincouldbeassayed,itsmechanismofloweringbloodsugarwas unknown.CarrdidnotsupportEhrlich'stheoryofthedirectactionofdrugsarguing althoughthechemicalconstituentsofatherapeuticagentdeterminesitsaction,thebody

147 mechanismalsoparticipatesintheresultantchemicalchange. Thisimpliedtohimthat
theonlywaytoproperlytestdrugswasinthehumanbody,hencehisstrongurgefora definedsystemofclinicaltests. CarrbelievedthatdoctorsintheU.K.wereconcerned aboutpecuniaryinterestswithpharmaceuticalfirms,andalthoughFraseroftheMRC disputedthis,Carrarguedfortrialstobearrangedthroughacentralindependentbody.He suggestedthataftersuch officialtests,individualmedicalmenwouldbelessafraidof performingtheirownpersonaltrialsandofpublishingtheresults.Carrdescribedhow individualmedicalmengenerallymadetestsinGermany,wherethemanufacturersquoted findingsinadvertisements.OnlythepreviousyearaneditorialintheBritishMedical JournalreferredtomedicalresearchonnewremediesinBritainwherethosecarefulof
148 theirreputationsmuststepwarily.
144
TheTimes(16June1926),B.CarrarchivesIVcuttings,ImperialCollege.
145
DailyTelegraph (12July1927).F.H.Carr'spersonalarchivesattheImperial InstituteincludecuttingsfromtheNatalMercury (30June1927)andDailyNews Colombo(5July1927).Thepricesofinsulinwerekeptcloselyinlinethroughoutthis timeThePriceandUnitValueofInsulinAnnouncementbytheMRCBritishMedical Journal (22December1923):1232.BurroughsWellcomepricesfor100units(10doses) wereinitially25/,then17/8,12/6andwerereducedto6/9from25February1924andan extratradediscountof20%BDHandA.&H.reducedpricesonthesamedays.
147
AddresstotheSocietyoftheChemicalIndustryBritish&ColonialPharmacist (August1927):268. 148 RobertGeorgeHogarth(Surgeon,Nottingham)TheMedicalPracticeandthe Public:BMAPresidentialAddressBritishMedicalJournal (24July1926):14550.
287
288
CarrgaveseveralkeynotelecturesonthestateoftheBritishpharmaceutical industryinthemid1920'sincludingtheStreatfieldMemorialLectureattheendof
149 1925. By1926BritishDrugHouseswereprobablytheleadingfinechemicalcompany
inBritain(aheadofBurroughsWellcomeandBoots.)Muchoftheirprogresscamefrom
150 thesuccessinmanufacturinginsulin,whichCarrrecountedinFebruary1926. Healso 151 playedaprominentroleinthemanufactureofvitamins. By1926Carrhadbeenelected
PresidentoftheSocietyfortheChemicalIndustry.Heacknowledgedtherelianceupon physiologistsforthetestingofdrugsbutemphasisedthatitwasalsonecessarytoknow thelimitsofstabilityoftheagentstotemperature,acidoralkali,andtheamountsof

152 impurities.
InhisPresidentialaddressinEdinburghin1927,onChemistryintheProgressof Medicine,Carrreemphasisedthat:inthiscountryforonereasonandanotherthereare almostinsuperabledifficultiesinthewayofgettinglikelysubstancesadequatelytested, norwasthereanyorganisation bywhichtheclinicaltestingofsuchsubstancescanbe carriedoutinourhospitalsandelsewhere.SimilarlyhespokeasPearsonhadfouryears earlieroftheproblemthat:medicalmenhesitateforprofessionalreasonstobeassociated withmanufacturingconcernsinmakingknowntotheircolleaguesthepropertiesofnew

153 substanceswhichtheyhavetested.
Inmostofourlaboratoriesdevotedtopharmacologythereisbutasmallband ofworkers,andtheyaregenerallyfullyoccupiedwithacademicresearchofa natureconsideredtobemoreacceptabletothosewhoseopinionscountmost. Sotheroutinetestingofsubstanceslikelytohavevaluabletherapeutic propertiesreceivesscantattention.Noristhereanyorganisationbywhichthe clinicaltestingofsuchsubstancescanbecarriedoninourhospitalsand

149
PharmaceuticalSocietyMeetingTheApplicationofScientificMethodtothe SolutionofIndustrialProblemsChemist&Druggist(12December1925):8358.
150
F.H.Carr,InsulinanditsManufacturetoRoyalSocietyofArts,(23February 1926)inB/CARRF.H.,CarrArchive,ImperialCollege.
151
F.H.Carr,VitaminsintheirRelationshiptoMedicalSuppliesChemist& Druggist(1926)89799.
152
F.H.Carr,ThePositionandProspectsoftheOrganicChemicalIndustryinthis CountryChemist&Druggist105.1(24July1926):170.
153
F.H.Carr,ChemistryintheProgressofMedicineChemist&Druggist106.3(9 July1927):233
288
289
elsewhere.Inparticularmedicalmenhesitateforprofessionalreasonstobe associatedwithmanufacturingconcernsinmakingknowntotheircolleagues 154 thepropertiesofnewsubstanceswhichtheyhavetested. Carrconcludedthattherehadtobeclosercooperationbetweenmanufacturers,and researchdepartmentsassomeformofresearchassociationtodecreaseoverlapsbetween

155 firmsandallowconstructivecriticism.
AlfredRenshawoftheLaboratoryofAppliedPhysiologyinManchestermadea pleaformultidisciplinarycollaborationbetweenbiochemists,medicsandorganicchemists andhequotedtheconclusionsoftheAmericanSocietyofChemistry: Medicalmenmustrealisethatthetaskofbuildingupnecessarilycomplex substances,whichaloneseemtohavetherapeuticvalueisamatterforcareful thoughtandpatientexperiment,thechemistsmustrealisetheintense difficultiesofobtainingandcorrelatingmedicalandclinicaldata,andabove all thecommercialorganisation,whichendorsessuchaproduct,mustbe preparedtowait,notmonths,butyearsforthefruitfulresults,whichmustof 156 necessityarisefromsuchacombinationofresources. Inparticulartherewasaneedtobridgethegapbetweenwhatitwaspossibletopreparein theresearchlaboratoryandinaproductionplant.HefeltthatBritainhadtobecome strongineverypartofthechainfromobservation,throughexperiments,development,
157 pilotplantscaleup,clinicaltestingandmarketing.
WhenBurroughsWellcomewereapproachedbytheDSIRtocollaboratein1926, ThomasHenrywrote: Itisalmostimpossibletocarryonworkofthisdescriptionwithout pharmacologistsandclinicalresearchers.Inthiscountryitisalwaysdifficult toobtaintrainedpharmacologistsandresearchinstitutesgenerallyhaveto

154 155
Ibid.
Ibid. CarrsaddresstotheSocietyoftheChemicalIndustrywaswidelyreported: British&ColonialPharmacist(August1927):268 ManchesterGuardian (14July1927)

156
A.Renshaw,ChemicalResearchinBritainBritishMedicalJournal (6November 1926):857.

157
F.H.Carr,'ManufactureofOrganicMedicinalChemicals,lecturetoS.C.I., Chemist&Druggist105.1(24July1926):170Thelecturewaswidelyreported, The FinancialNews,(17June1926):TheTimes(16June1926):BritishandColonial Pharmacist(August1926):Cuttingsofthesereportsandnotesinpreparationforthe lectureareinF.H.CarrArchives,2130B/CARRIVPressCuttings:8,
289
290
traintheirown.Itisequallydifficulttogetclinicaltrialsofnewdrugsmade. ThesedifficultiesdonotseemtooccurinFrance,GermanyandtheU.S.and thisgivesthesecountriesaconsiderableadvantage.Thedepartmentmight, actingincorrespondencewiththeMRC,usefullyseeifanythingcanbedone toincreasefacilitiesforpharmacologicalandclinicalresearchofnewdrugsin 158 thecountry. CarrgaveafurtherkeynotespeechtotheRoyalSocietyofArtson23February1927with

159 HenryDaleinthechair. Returningtohis1927lectureontheChemistryinthe
ProgressofMedicine,Carrdescribedtheprogressmadeinsynthesisingadrenaline,
160 histamineandthyroxine, givinghisinterpretationofchemotherapyalongthelinesof
Ehrlich.Hereferredtothechangesundergoneinthebodybytrypanocidalagents,Bayer 205andFourneau309,bothcolourlessandthoughactiveinvivo,hadlittleinvitro activity,aswithbismuthandhecitedthedepoteffectsoflonglastingformsofbismuth andarsenicals,andtheeffectofsunlightonergosterol.Hefeltthat: progressliesinthedirectionofbiochemistryandmoreeffectiveworking contactbetweenindividualsinchemistry,bacteriology,physiologyand clinicalmedicinetoavoidoverlapping.Chemicalexperimentmustproceedin theveryclosestassociationwithanimalexperimentationandwithclinical trials.Therearemanyconditions,whichcanonlybestudiedinmanhimself andtheimportanceofproperlyorganisedclinicaltrialsandtheproperinter relationofalltheseelementsofprogresscannotbetoostrongly 161 emphasised. Hesawthisastherationalefortestingdrugsinman.Carrreemphasisedtheneedforboth pureandappliedresearchincollaboration,forthemajorityofantiinfectivecompounds developedhadbeenforprotozoalinfectionsforwhichanimalexperimentalmodels existed,suchasinthedevelopmentbyBargerofthequinolinederivative,plasmoquine,
158 159
T.HenrytoA.W.Crossley,(9July1925),WF:STCS/G/49. F.H.Carr,HowInsulinisIsolatedfromInsulinanditsManufactureChemist &Druggist106.2(26February1927):263.

160
ChemistryintheProgressofMedicinepresentedattheSCIinEdinburgh,Chemist &Druggist106.3(9July1927):233 DailyTelegraph (12July1927).

161
F.H.Carr,ChemistryintheProgressofMedicine,Chemist&Druggist106.3(9 July1927):233AddresstotheSocietyoftheChemicalIndustryBritish&Colonial Pharmacist,(August1927):268.
290
291
162 (Pamaquin). Hefeltthepreparationofsyntheticinsulin,forexamplewastheway
forward. Inadditiontohisworkinimprovingproductionmethods,Carrdevelopedtests
163 forthepotencyofthefirmsproducts,suchasether. Healsoexaminedthepotencyof
vitaminsalongwithotherindustryrepresentatives,describingthedifficultiesof performingassaysthatinvolvedcomparingratsfedonstandardanddeficientdietsofa6 weekperiod,concludingthatasyntheticversioncouldsavealloftheeffort ondiettesting.

164 OneoftheproblemsnotedwithvitaminAwasalossofpotencyonstorage. Norman
EversofMay&BakercomplimentedCarronhismodificationoftheonlypracticabletest
165 availabletodate. Heshowedthesuperiorityofhisfirmsproductsoverandabovethe
requirementsofthepharmacopoeia.CarrwasawardedaD.Sc.fromManchester Universityin1929inrecognitionofhiscontributionstothedevelopmentofmedicines.In hisspeechofacceptancehestatedOncetheworldhadproclaimedvictoriousanalysis:

166 thecryisnowvictorioussynthesis.
6.6MRCExtendedRoleinClinicalTrials: IndividualMRCSubcommittees
162
F.H.Carr,ChemistryintheProgressofMedicineChemist&Druggist106.3(9 July1927):233asreportedintheDailyNews,Colombo,Ceylon:Carrarchives.B.CARR atImperialCollege.

163
F.H.Carr,EtherclonusBritishMedicalJournal (8October1927):664.
164
F.H.Carr,VitaminsinRelationtoIndustryBritishMedicalJournal (18 December1926):1194F.H.Carr,VitaminsintheirRelationshiptoMedicalSupplies Chemist&Druggist105.2(18December1926):89799.Carrsuggestedthatinsteadof timeconsuminggrowthtestsusinganimals,vitaminAcouldbeassayedusingcolourtests.

165
F.H.Carr,E.A.Price,ColourReactionsAttributedtoVitaminABiochemical Journal 20(1926)497501.

166
ManchesterGuardian:ChemistryandIndustry (26July1929):7258:TheTimes (12July1929):929.
291
292
167 TheMRCcontinuedtoaddfurthersubcommitteesasnewopportunitiesarose.
SomewereestablishedundertheauspicesofotheracademicbodiesbutunderMRC guidance,suchasthatappointedbytheObstetricSectionoftheRoyalSocietyof
168 Medicinetoevaluatepituitaryextracts. Inadditiontosupportingworkoncancer, 169 previouslydescribed,theMRCalsosupportedresearchbytheColonialOffice. MRC
subcommitteesinvolvedseveralcurrentandformerBurroughsWellcomestaffincluding HenryDale,AndrewBalfour,EdwardMellanby,R.A.O'BrienandC.M.Wenyon. Onceclinicaltrialswereunderwaywithinsulin,theMRCbegantolinksomeof theirotherresearchprogramsintotheclinicaltestingofdrugs.Prof.GeorgeDreyer, DirectoroftheStandardslaboratoryattheDunnSchoolofPathologyinOxford,joined theMRCCouncilinJune1923.TheCommitteediscussedtestinghisnewdiaplytevaccine fortuberculosisandestablishedasubcommitteewithWalterFletcher,Capt.Stewart

170 Douglas,DirectoroftheDepartmentofBacteriologyattheNIMR,andC.J.Bond and 171 ArthurMacNaltytodrawupaschemefortrials. MacNaltysuggestedthatDreyers
workwaslikelytorevolutionalisenotonlytuberculosis,butalsootherbacterialdiseases.
167
CommitteeonRheumatismMRCCouncilMinutesII,(10December1920):191 CommitteeonthePhysiologyofRespirationandtheCardiovascularSystem(18March 1921):30CommitteeonAntimeningococcusandAntipneumococcusSera, CommitteeonAntidysentericSeraandCommitteeonAntidiphtheriaandAntitetanic Sera(20January1922):190CommitteeontheClinicalUsesofOxygen(24March 1922):273CommitteeonHaemoglobin(8December1922):396Committeeon Anaesthetics(29January1926):8VaccinationCommittee(29January1926):10 tuberculinandbacteriologicalcommitteesL.BryderTuberculosisandtheMRCinJ. AustokerandL.Bryder(eds.),(1989):910.

168
Useofpituitaryextract CommitteeappointedbytheObstetricSectionoftheRoyal SocietyofMedicine,MRCCouncilMinutesII,(27May1921):78.

169 170
MRCCouncilMinutesII,(22July1921):112.
SirPatrickLaidlaw,StewartRankinDouglasObituaryNoticesofFellowsofthe RoyalSociety 2(1936):175 182.

171
MRCCouncilMinutesII,(15June1923):73(20July1923):88(12December 1923):152(22February1924):27L.BryderTuberculosisandtheMRCinJ. AustokerandL.Bryder(eds.),(1989):810A.S.MacNalty,BritishJournalof Tuberculosis22(1928):1618.
292
293
Althoughthetreatmentturnedouttobenomoreeffectivethanavailabletherapies,Dreyer
172 wasappointedDirectoroftheStandardsLaboratoryinOxfordinFebruary1924.
UndeterredbytheirdisappointmentwithDreyersvaccine,theMRCagreedtodo furtherclinicaltrialworkintuberculosiswithSanochrysinorsodiumaurothiosulphate. ThistherapydiscoveredbyHolgerMoellgaard,Professor ofAnimalPhysiologyin

173 Copenhagenin1923,hadagoldcontentof37%togetherwithaserum. TheMRCwere
askedbyhimtoarrangeclinicaltrialswithaviewtoconfirmingresultsinDenmark. FletcherplannedatrialalongthefollowinglinesinDecember1924.Herecountedthat (Moellgaard): isprovidingsuppliesofthegoldcompoundandoftheserumtobeusedin conjunctionwithitforthepurposesofthisworkandnonewillbeavailablefor generalusebytheprofessioninthiscountryuntiltheseconfirmatorytrials havebeensuccessfullyperformed.Thetreatmenthasnotbeenfoundsuitable forcasesofsurgicaltuberculosisanditisproposedtolimitthepresentstudies tocasesofpulmonarytuberculosis,towhichsomecasesoftuberculous meningitismaybeaddedineachoftheclinicsdiagnosishasbeenconfirmed byproofofthepresenceofbacilli.174 TheCouncilsubcommitteesuggestedrecruitingnotmorethantencasesineachcentre,
175 restrictingcasestopulmonarytuberculosisprovenbythepresenceofbacillus.
Prof.H.ArthurEllisattheLondonHospitalwaspreparedtotakeupto10patientsintoa study,alongwiththeProf.ofMedicineinEdinburgh(SirRobertPhilip),theChief MedicalOfficeratKingEdwardVIIMedicalAssociationofWalesinCardiff(Prof.S. LyleCummins)andDirectorsoftheUniversityMedicalclinicsinLondon:thus,T.R.

172
MRCMinutesII,(22February1924):21.
173
MRCMinutesII,(24October1924):132W.M.FletchertoH.MacLean,(St. ThomasHospital),(1December1924)Sanochrysin(Sodiumaurothiosulphate),MRC File1380/3L.Bryder,TuberculosisandtheMRCinJ.AustokerandL.Bryder(eds.), (1989):121MRCSpecialReportSeries96,(London:HMSO,1925)M.Fletcher, (1957):337B.Smith,GulliblesTravails:TuberculosisandQuackery18901930J. ContemporaryHistory 20:73356.

174
W.M.FletchertoArthurEllis,(1December1924),MRCFile1380/3.
175
Theorganisingcommitteewere,GeorgeDreyer,CuthbertWallace,HenryDale, CaptainDouglas,andArthurMacNalty:MRCFile1380/3W.M.Fletcher,MRCMinutes II,(24October1924):132W.M.FletchertoA.Ellis,(1December1924),MRCFile 1380/43.
293
294
176 ElliottatUCH,G.MarshallatGuys,DrL.S.T.BurrellatBromptonHospital.
SanochrysinwassenttoDrGeoffreyEvansatSt.BartholomewswhoinvolvedF.R. FraserandC.F.HarristoProf.FrederickLangmeadatSt.MarystoProf.Hugh
177 MacLean, achemicalpathologistatSt.ThomasHospital:DrF.R.E.HeafatWarwick
KingEdwardVIIHospital,andDrA.Trimblewhocoordinatedworkin NorthernIreland. FletcherlaterclarifiedtoLangmeadthattherewasnoneedforall10patientstobetreated inparallel,andthathecouldtreattwoorthreeandincreaseasexperienceindicated.Evans

178 reportedthatitwashighlytoxic. Ellisreportedthathehadtreated7casesand3had 179 violentreactions. MacLeanrecounted:ItseemstomethattheCouncilhavehardly
appreciatedthedifficultiesconnectedwiththisinvestigation.CertainlywhenIpromisedto
180 carryoutthetestsIdidnotappreciatethemmyself.
Researchershaddifficultydistinguishinganyeffectsoftherapyfromthevariable
181 backgroundcauseofthedisease. Dr.Sechar,presumablyrepresentingtheDanish
group,reviewedthecasesselectedathiscentreandallwereexcludedasbeingofthe wrongtypeofpatient:acertainkindofpatientisrequired,anditseemsquiteimpossible thatanyUnitofotherInstitutionshouldbeabletogetalargenumberofthistypeat

182 once. Thetherapywasdangerousinadvancedcases,whichwerecommonin
Institutions.Ifontheotherhandonlyearlycaseswithlittletissuedamagearetreated,the resultslookedgood,butthensodidothertherapies.MacLeanfinallygaveananecdotal
176 177
W.M.FletchertoH.A.Ellis,(1December1924),MRC1380/3.
MacLeodhadbeensenttoFrancebytheMRCin1915toinvestigateacutetrench nephritis.J.AustokerandL.Bryder(eds.),(1989):66,212.
178 179
MRCFile1380/3,(17March1925).
G.EvanstoW.M.Fletcher(17March1925)H.A.EllistoW.M.Fletcher(9 February1925),MRC1380/3.EllishadpreviouslyappliedtotheMRCforagrantto performworkonthechemotherapyoftuberculosis.

180
H.MacLeantoW.M.Fletcher,(8February1925),SanochrysinMRCFile 1380/3.
181
L.Bryder,TuberculosisandtheMRCinJ.AustokerandL.Bryder(eds.),(1989): 12MRCFiles1380/3onsanocrysin.
182
H.MacLeantoW.M.Fletcher,(8February1925),SanochrysinMRCFile 1380/3.
294
295
hopelesscasewhichwassaidtobetoofaradvancedfor treatmentwithsanochrysinand wasnotallowedintothestudy: Thesocalledhopelesscaseisnowapparentlywellandalready(within5 weeks)showspracticallynosymptoms.HadwetreatedhimbytheGold methodwewouldnaturallyhaveascribedtheextraordinaryimprovementto 183 thegoldinjections.Theresultwouldhavebeenentirelymisleading.

184 FurtheradversereportscamefromotherLondonhospitals. Thecomplexnatureof assessingthenewdrugisgiveninthereportsofoneoftheinvestigatorswhoonly 185 managedtotreat2cases. Ultimately,itwasconcludedthatSanochrysinwasoflittle 186 benefit.
In1925theMRCreportedstudiesinwhichtheyhadcomparedquinineand
187 quinidinefindingthelatterfarsurpassesothers. However,upto1925themajority
ofnewproductsfromindustrywerevariantsofalreadyavailabledrugsandtheMRChad littleinterestinthem,preferringtoconcentrateonimportantphysiologicalquestions,
188 hormonalextracts,tropicalmedicineandstandardisationofbiologicaldrugs.
183
H.MacLeantoW.M.Fletcher,(8February1925)forquotes,andfinalreport(27 March1925),MRCSanocrysinFile1380/3.
184
ReportsfromProf.FredLangmeadatSt.MarysandH.J.MacLeanatSt.Thomas' wereinProf.Elliottsreport,MRC1380/3MRCMinutesII,(27March1923)H.J. MacLeantoW.M.Fletcher,(8February1925),MRCFile1380/3.

185
H.J.MacLeantoW.M.Fletcher,(8February1925),SanochrysinMRCFile 1380/3.
186
StudiesonSanocrysinwereinconclusiveuntilonestudyfromMichiganstudied matchedpairsrandomlyallocatedfrom1926:J.BurnsAndersonJnr,B.T.McMahon,M. Pinner,AClinicalTrialofSanocrysininPulmonaryTuberculosisAmericanReviewof Tuberculosis24(1931):401435Prof.H.R.Dean,ScienceandMedicineBritish MedicalJournal (10October1931):668SecondReportoftheGoldTreatmentofTB, MRCBritishMedicalJournal (24July1926):15860.

187
QuinineandQuinidineBritishMedicalJournal (12September1925):488 CommitteeonCinchonaderivativesandMalaria:ClinicalComparisonsofQuinineand QuinidineMRCSpecialReportSeries96(London:HMSO,1925):110T.J.Lipkinof Liverpoolinvestigatedquinine,MRCMinutesII,(15October1920):154.

188
In1922thefirstsuchM.R.C.reportwaspublishedJ.H.BurnandH.H.Dale, ReportonBiologicalStandards(I)PituitaryExtractsMRCSpecialReportSeries69
295
296
6.7LobbyingforClinicalTrials:TheABCMandTheChemotherapyCommittee. Bayer205(Germanin)wasdiscoveredduringtheFirstWorldWarandunderwent clinicaltrialsin1920fortreatingsleepingsicknessinAfrica,andgavepromiseofnew therapeuticagentsagainstbacterialandparasiticdiseasesandsoanincreasingamountof

189 MRCfundingwasputintoresearchonchemotherapy. HenryDale,(chairman)C.H. 190 Browning andAndrewBalfour,fromtheMRCcollaboratedwithGeorgeBarger(ex 191 192 BurroughsWellcome),Prof.GilbertThomasMorgan andProf.RobertRobinson
fromtheDSIR.AttheCouncilmeetingof22October1926,aCommitteewasestablished jointlywiththeDSIRtoreportbeforeMarch1927onthescopeofworkrequiredin
193 Chemotherapy. In November1926theABCMGeneralmanager,W.J.U.Woolcock
formallyapproachedtheCouncilaboutclinicaltrialsagainwhenhewrote, Doyourememberhowthreeyearsagoasmalldeputationfromthe Association(visitedyou)...withregardtochemicalfirmsobtainingassistance fromyouingettingintouchwithcertainscientificworkers.Itaroseoutofour firmsmakingnewchemicalproductsandrequiringexpertassistanceinhaving
(London:HMSO,1922)StandardisationofPituitaryExtract BritishMedicalJournal (2 December1922):108788.

189
FromGermanintoAcylureidopenicillin:ResearchthatmadeHistory (Leverkusen: Bayer,1980)

190
C.L.Oakley,CarlHamiltonBrowningBiog.MemoirsofFellowsoftheRoyal Society 19(1973):173 215.

191
MorganhadtrainedunderMeldolaattheFinsburyTechnicalSchool,andthe InstituteofChemistry.HestartedasanassistantatReadHollidaydyefirmthenperformed researchattheRoyalCollegesofScienceinLondonandDublinHegainedhis professorshipthereandbecameProfessorattheFinsburyTechnicalCollegethen BirminghamUniversity.HedirectedtheChemicalResearchlaboratoryatTeddington. JamesIrvine,GilbertThomasMorganObituaryNoticesofFellowsoftheRoyalSociety 3(1941)355 362.

192
LordToddandJ.W.CarnwathRobertRobinsonBiographraphicalMemoirsof FellowsoftheRoyalSociety 22(1976)415 527T.I.Williams,RobertRobinson, ChemistExtraordinary (Oxford:ClarendonPress,1990).

193
MRCCouncilMinutesII,(2October1926):151.
296
297
themtestedclinically.Myrecollectionisthatthequestionofinsulinbecame 194 veryprominentjustatthattimeandnothingfurtherwasdone. Fletcherrepliedthat: TheMRChaveforlongbeenanxioustoseebetterprovisionmadefor coordinatedresearchinchemotherapyandtheyhavehadthisunderdiscussion 195 withtheDepartmentofScientificandIndustrialResearch. HandwrittencommentsinthemarginofthisfilebyLandsboroughThompsonoftheMRC confirmedtheprincipalreasonsofwhythecollaborationontrialsofnoveldrugshad faltered(lackof)clinicalworkers,shortageofpharmacologists,medicalethics,anduse
196 ofanimals. Thistiedinwithongoingcontroversiesrelatingtodoctorsputtingtheir
197 namestodrugadvertisementsandtoarticlesinthelaypress. TheCouncilrespondedin
linewith thenewfocusonchemotherapyasaresultoftheproposedcollaborationwiththe DSIR,whichaimedtoprovidetheMRCwithasourceofnewsyntheticcompoundsof

198 possibletherapeuticvalue.
6.8CollaborationwiththeDSIR EstablishmentoftheChemotherapyCommittee. AsaresultofthereportoftheJointCommitteeoftheMRCandDSIR,the ChemotherapyCommitteebecameoperationalinJuly1927,includingProf.JohnBerend

199 200 Cohen, WarringtonYorkeofLiverpool, Prof.ThomasElliott,andSirHughKerr
194
W.J.U.WoolcocktoW.M.Fletcher,(17November1926),TherapeuticTrial CommitteeMRCFile1523/15K.H.Beyer,Discovery,DevelopmentandDeliveryof Drugs(NewYork:S.P.Medical&Scientific,1978):153.

195
W.M.FletchertoW.J.U.Woolcock,TherapeuticTrialCommittee,(19November 1926),MRCFile1523/15.
196
A.L.ThompsonhandwrittennotesonW.J.U.WoolcocktoW.M.Fletcher, TherapeuticTrialCommittee,(17November1926),MRCFile,1523/15.
197
AndrewA.G.Morrice,TheMedicalPundits:DoctorsandIndirectAdvertisingin theLayPress19221927,MedicalHistory 38(1994):25580.

198
199
M.R.C.CouncilMinutesIII,(15July1927):155.
H.S.Raper,JuliusBerendCohenObituaryNoticesofFellowsoftheRoyal Society 1(1935):503 513.
297
298
201 202 Anderson. Prof.R.T.Leiper, whotheMRChadsupportedtostudybilharziasin 203 EgyptduringtheWar,wasaddedinNovember1927,toadviseonantihelminthics.
ChristopherH.AndrewesbecamesecretaryoftheChemotherapyCommitteeinJanuary
204 1928. TheMRCprovided2,800totheDepartmentofScientificandIndustrial
Researchtoperformresearchinsyntheticchemotherapysothatpromisingcompounds
205 weretobeputforwardtoclinicaltrialsattheteachinghospitalsonaninformalbasis.
TheChemotherapy Committeealsoaimedtoassistwiththebiologicalandclinical testingofsyntheticcompounds,preparedattheNIMRbyHaroldKingandhiscolleagues. Theynotedthedesirabilityofprovidingfacilitiesforclinicaltrialsofnewremediesunder statedconditionsagreedbetweenthejointcommitteeandrepresentativesofABCM.Its guidelinesforhandlingapplicationsfortestnewdrugswere:thatdetailsoftheapplicant wouldnotbeprovidedtothosedoingthetesting,andthattheCouncilhadtherightto refusethetestingofanyremedieswithouthavingtostateareason.Theapplicanthadto giveanundertakingthatnoalternativetrialarrangementswouldbemadeuntilthe Committeetrialswerecomplete,andthenatureandcompositionofthecompoundshadto bedisclosedinconfidencetogetherwithdetailsofanyrelevantpublications,experiments carriedoutinthemanufacturersownlaboratoriesandthepatentsobtainedorappliedfor. ThearrangementsfortestingwereentirelyamatterbetweentheCommitteeandthe expertsundertakingtheresearch.TheCommitteedecidedthattheywouldnotpublish
200
C.M.WenyonWarringtonYorke. BiographicalMemoirsofFellowsoftheRoyal Society 4(1944):523545.

201
SirCharlesScottSherrington,HughK.AndersonObituaryNoticesofFellowsof theRoyalSociety ProceedingsB104(1929):xxxxv.

202
P.C.C.Garnham,RobertThompsonLeiperBiographicalMemoirsofFellowsof theRoyalSociety 16(1970):385 404.

203
MRCMinutesII,(22October1926):151MRCMinutesIII,(15July1927):127 (14October1927):155MRCMinutesIII,(11November1927):181.
204
MRCCouncilMinutesIII,(27January1928):7.Christopher(laterSir)wasthe sonofSirFrederickAndrewesF.R.S.Hebecameagreatauthorityonviralresearch, workingtogetherwithPatrickLaidlawondogdistemperattheNIMR:J.Austoker, L. Bryder,inJ.AustokerandL.Bryder(eds.),(1989):41 43.

205
TheD.S.I.R.laboratoryworkwastobeperformedbyProf.R.Robinson,Prof.G. Barger,andDr.G.J.Morgan.M.R.C.MinutesII,(1927):127,155,187,227.
298
299
informationifitmadenoscientificcontributionandmightcausedamagetotheinterests oftheapplicant.Allexpenditurehadtobemetbytheapplicant,butiftheexperts proposedteststhatrequiredsignificantexpenditureonequipment,salariesortravelling expenses,detailsofproposalswouldbesenttotheapplicantforconsideration. TheChemotherapyCommitteeinitiallyarrangedtestsofantihelmintics, antimalarials,andtrypanocidals,whichfittedinwellwiththeresearchinterestsofthe MRCandtheirTropicalInstitutes.InJune1927ajointColonialMedicalResearch Committeewassetup,combiningmembershipoftheMRCwiththeColonialOffice.The chairwasRightHon.WilliamG.A.OrmsbyGoreandhisdeputywasSirGeorge Maxwell,togetherwithDr.JohnWilliamWatsonStephens,whowasoriginallybasedat theTropicalMedicineInstituteandperformedresearchonmalariaandblackwater
206 207 208 fever, SirLeonardRogers ,Dr.AndrewBalfour,Dr.CharlesTodd ,Dr.PhillipE. 209 210 MansonBahr ,Dr.CharlesM.Wenyon ofBurroughsWellcome,andMRCSecretary, 211 WalterM.Fletcher.
TheABCMalsointeracteddirectlywiththeColonialResearchCommitteeasthey sometimesreceivedremediesfromoverseas,whichtheyforwardedtotheMRCfor consideration:oneexamplewasanewremedy,superiortoallothersagainstmalaria feverandsyphilisfromaDr.LouisJohnstonofBucharest.Itwasalsosaidtobe efficientagainstallformsoftuberculosis.Itrequiredonlyafewinjectionsandwas

206
SirRickardChristophers,JohnWilliamWatsonStephensObituaryNoticesof FellowsoftheRoyalSociety 5(1947)525 540.

207
SirJohnBoyd,LeonardRogersBiographicalMemoirsofFellowsoftheRoyal Society 9(1963)261285.

208
C.H.Andrewes,CharlesToddBiographicalNoticesofFellowsoftheRoyal Society 4(1958)281290.

209
SirPhillipMansonBahr,ObituaryBritishMedicalJournal (26November1966): 1332ObituaryTheLancet(26November1966):11989P.E.MansonBahr,S. Willmott,DermatologyandtheRoyalSocietyofTropicalMedicineandHygieneInt.J, Dermatology 20(JulyAugust1981):42930.

210
C.A.Hoare,CharlesMorleyWenyonObituaryNoticesofFellowsoftheRoyal Society 6(1949)62742M.Worboys,TheComparativeHistoryofSleepingSicknessin EastandCentralAfricaHist.Sci.32(1994):89102M.Worboys,TheMansonRoss Controversy:TropicalMedicineandImperialismSoc.Hist.Med.Bull.21(1977):379.

211
MRCCouncilMinutesIII,(29April1927):58,(24June1927):101. 299
300
absolutelynotpoisonous.However,theChemotherapyCommitteediscounteditasan obviousquackremedyandpointedoutthattheclaimsaboutsyphiliswouldbeillegalin thiscountry.TheMRCarrangedthebiologicaltestingofanysuitablecompoundsinits

212 ownlaboratories.
Meanwhile,pharmaceuticalfirmsandespeciallyBurroughsWellcomeplayedan increasingroleintropicalresearch,asdescribedinthechapterontheirScientificand TechnicalCommittee.May&Bakerclearlyreceivedsupportintheirdevelopmentsfrom theLondonSchoolofHygieneandTropicalMedicineandtheycontributed150towards

213 expenditureonchemotherapyinvestigations.
6.9Further MRCTrials:Synthalin,PneumococcalSerumandLiverTherapy In1927theMRChadanofferfromScheringtotestSynthalin,asyntheticoral guanidinecompoundwhichhadundergonetrialsandbeenintroducedinGermanyfor diabetesthepreviousyear.TherecommendationfortestingcamefromtheInsulin

214 Committee,butonlyontheconditionthatitschemicalformulawasprovided. The
rationaleforthiscompoundwasthatithadpreviouslybeenshownthatremovalofthe parathyroidglandledtoasuddendropofbloodsugarandthatthiswasduetoabnormal levelsofguanidineintheblood.Guanidineitselfwastootoxictobegiventodiabetics, butanalkaloidcharacterisedbyBargerandWhitein1923wasshowntobeaguanidine derivative,andaseriesofchemicallysubstitutedguanidinesmadeinGermanywere

215 showntobesafer. ItwasevaluatedinavarietyofcentresincludingtheManchester
RoyalInfirmary,theSalfordRoyalandAncoatsinManchesterbuttheresultswere
216 patchyandthemethodsemployedtoobtainthemoftenlessthanrigorous. Despitethe
212
213
MRCCouncilMinutesIII,(15July1927):127,155(11November1927):190. MRCCouncilMinutesIII,(26April1929):69. MRCCouncilMinutesIII,(18March1927):26. WalterSneader,(1985):217,256.
214
215 216
HelenKathrynValier, (UniversityofManchester:PhDthesis,2002)ThePoliticsof ScientificMedicineinManchester1900 1960:168.
300
301
introductionofasecondversionknownasSynthalinB,therewerecontinuedproblemsof
217 livertoxicity.
Aswithinsulin,theinitialconceptforlivertherapyfortreatingperniciousanaemia camenotfromindustry,butfromtheworkGeorgeMinotandWilliamMurphyatHarvard in1926.Twoyearslaterthechemistandbiologist,EdwinCohnofHarvardidentifiedan extractoflivercontaininginsmallbulk,theunknownfactorwhichproducesthe

218 amelioratingeffect. HarvardUniversitysharedresultswiththeMRCandinvitedthem
tosetuptrials.AperniciousanaemiacommitteeincludingElliott,Dale,andFraserwas
219 appointedtoarrangetrialsofthisnewlivertreatment. FrancisFraseroftheMRCand
St.BartsHospitalpreparedthefirstBritishliverextracts,whichtheMRCpassedonto severalfirms.By1928theBootsPureDrugCompany,BritishDrugHouses,and BurroughsWellcomehadprovidedtheMRCwithsufficientmaterialbyamodificationof

220 theAmericanmethodstoestablishtrialsat8centres.
JohnFrederickWilkinsonhadestablishedtheManchesterUniversityDepartment ofClinicalInvestigationin1925attheRoyalInfirmaryandwasacentralfigureinthe MRCtrialsofperniciousanaemia.However,accordingtoValierwhoexaminedhis careerindetail,theMRCstestingofliverextractswasabandonedafterafewmonths withWilkinsonidentifiedastheculprit,seeminglybecauseofhisdirectcollaborationwith

221 industry(Boots). TheMRChadcollaboratedwiththeAssociationofClinical
217
Thecompoundscontinuedtobesoldanduseduntilthe1940swhenbetteroral antidiabeticsbecameavailable.SynthalininterestedtheMRCfurtherafteritwas discoveredtohaveantitrypanosomalactionandbothHaroldKingattheNIMRandlater ArthurEwinsatMay&BakermadefurtheranaloguesfortestingbyWarringtonYorkein Liverpool.WalterSneader,(1985):217,256Synthalin,Lancet(3March1938):482.

218
LiverExtractintheTreatmentofPerniciousAnemia:aReportbytheMedical ResearchCouncilBritishMedicalJournal (3March1928):380.

219 220
MRCCouncilMinutesIII,(15July1927):156.
The8centresincludedmanyoftheresearcherssupportedbytheMRC(T.R. Elliott,UCHE.C.Dodds,TheMiddlesex:ArthurEllis,TheLondon:StanleyDavidson, whohadbeensupportedbyMRCgrantsinbothEdinburghandthenlaterasProfessorof MedicineatAberdeenandEdwardMellanby(Sheffield)butalsoThomasHouston (Belfast),W.EHume,NewcastleonTyneandJohnCowan,ofGlasgow:HelenKathryn Valier,(UniversityofManchester:PhDthesis,2002):173,19596.

221
HelenKathrynValier,(UniversityofManchester:PhDthesis,2002):164198.
301
302
222 Pathologists(ACP)inidentifyingsuitablecentrestoperformbiochemicaltests. Valier
arguedthatthesubdivisionoftrialsrunthroughtheACPandtestingofsamplesby Wilkinson,wastoblameforthefailureoftheperniciousanaemiastudy.Inaswipeat Wilkinson,Prof.RaperatManchesterwastoldbyEdwardMellanbythatinorderreceive

223 continuedfundingtheyshouldseveritsunhealthylinkswithcommercialinterests.
TheMRCincreasinglyrecognisedthedifficultyofperformingstudiesofclinicaleffectsat thebedsidewheretheyhadnomeansofassayingthetherapy.TheMRCstrongholdswere centresofresearchandlaboratoriesperformingbiologicalassaysratherthanthewards. AlthoughtheMRCabandonedthestudyitwassuccessfullyconcluded independently.TheresultsoftheclinicaltrialswerepublishedintheLancetandBritish MedicalJournalinMarch1928,allowingthefirmstodescribethepreparationsasmade byaprocesstestedandfoundefficientbytheMRC,exactlythekindofendorsementthey

224 needed.
TheMRCpromotedliverextractsnotonlyforthetherapeuticeffects,butalsothe methodsusedtoevaluatethem,namelyexperimentsinanimalsfollowedbyevaluationin manandmonitoringofbloodcounts,whichiswhyWilkinsoninManchesterbecame centralashehaddevelopedanextensivebiochemicalandclinicalmedicineservice. ValierarguesthattheMRCregardedthetreatmentasyetanotheropportunitytofurther

225 shapeandrefinerelationshipswithindustry. Tome,thisislessclearasalltheywere
doingwasusingBritishfirmstomanufacturetheextracts,unlesswhatismeantisthat theythenhopedthatpharmaceuticalfirmswouldgoonandidentify,prepareand standardisetheactiveingredient. Thepharmaceuticalfirms,particularlyBoots,werereluctanttogiveuptheirown privatecontactswithdoctorssuchasWilkinson.Ineffectthebattlelinesweredrawn,for

222 223 224
HelenKathrynValier,(UniversityofManchester:PhDthesis,2002):175. C.C.Booth,ClinicalResearchinJ.AustokerandL.Bryder(eds.),(1989):318.
MRCCouncilMinutesIII,(2March1928):23Theworkwascompletedin1928 andpublishedinLiverExtractintheTreatmentofPerniciousAnemiaBritishMedical Journal (10March1928):398399andLiverExtractfortheTreatmentofPernicious Anemia(MRC)TheLancet(10March1928):514.

225
302
303
Fletcherinsistedthatallcontactwithcliniciansshouldbethroughthemselvestocontrol thedirectaccessthatfirmswantedtodoctors,tosavethedoctorsfromtheembarrassment ofdealingwithanyonefirm,butalsonottolimittheirowndirectcontactwithclinicians. Thiswasnotwhatthemanufacturershadinmind:Themanufacturersareanxious.that arrangementsforroutinetestingshouldnotdeprivethemofthecooperationofclinicians

226 inexperimentalworkaimedattheimprovementofthepreparations.
Fletcher,recognisingtheneedforfirmstohavetheirproductstested,feltthatthe Londonfirmsweremoredeservingoftheirhelp,whereasthenorthernfirms(suchas BootswhoextensivelysupportedtheManchesterunit)seemedtohavetheirown

227 arrangements. From1929Allen&HanburysproducedEugastrol,aformof
desiccatedHogstomachfortreatingperniciousanaemia.Between19301931therewere alsoseveralpublishedreportsofsuccessinthetreatmentofperniciousanaemiabyliver
228 extracts,aswellasHogsstomach.
InOctober1929theChemotherapyCommitteeagreedtopromoteclinicaltrialsof aconcentratedpneumococcalserumthathadagainbeenfirstdescribedinAmerica,atthe RoyalInfirmary,Edinburgh,atUCHandwithDr.R.CruickshankinGlasgow,with suppliesfromBurroughsWellcomethoughseveralfurtherbatcheswereobtainedfrom

229 America. CoxMaksimovtookthistrialashermainexampleofatrialbythe
226
HelenKathrynValier,(UniversityofManchester:PhDthesis,2002):181quoted fromClinicaltestingofcommercialpreparationsforthetreatmentofperniciousanaemia. (Agendaforthesecondconference(18January1934),PRO,FD1/2257).

227
228
J.F.Wilkinson,PerniciousAnemia.PreliminaryReportontheResultsObtained withCertainPreparationsoftheStomachBritishMedicalJournal (8February 1930): 3345J.F.Wilkinson,TreatmentofPerniciousAnaemiawithHogsStomach,Reportof 108casesBritishMedicalJournal (17January1931):8591C.S.D.Don,C.E.Jenkins. HogsStomachin PerniciousAnemia(24January1931):1589C.S.D.Don,C.E. Jenkins,OvarianHormoneBritishMedicalJournal (30May1931):940:TheValueof theLiverinTreatmentofAnemiaBritishMedicalJournal (4April1931):5845inwhich Wilkinsonreported140casesincluding108treatedfor6monthsormoreandnosingle casefailedtorespond.
229
MRCMinutesIII,(25October1929):167MRCMinutesIII,(16May1930):94.
303
304
TherapeuticTrialsCommittee,despitethefactthatitwasstartedbeforetheCommittee
230 wasestablishedin1931.
TherewereotherapproachestotheMRCforclinicalstudies,includingone
231 acceptedfromLeverBrotherstohavetheirconcentratedvitaminApreparationtested.
ThiswaspassedontotheMRCsAccessoryFoodFactorsCommittee,butin1929there wasstillapaucityofclinicalresearchers: Therecanneverbeasuccessfulandmaintainedrecruitmentofyoungmenof abilityforclinicalresearchuntilthereisatleastafewstablepositionsinsight, theoccupationofwhichinmiddleagewillprovidereasonableandadequate 232 powerofeducatingafamily.
6.10TheThirdCampaignoftheABCMforClinicalTrials,192731. TheABCMmembersremainedactivetowardstheendofthedecadeintheir campaigntohavetheirdrugstested.Themostimportantpharmaceuticalmembersofthe ABCMduringtheperiod192731wereCharlesA.HillandFrancisH.Carr(ofBDH), DavidLloydHowardofHowards,whobecamevicepresidentin1931,andW.J.U.

233 WoolcockofthePharmaceuticalSociety.
TheABCMproducedanalphabeticallistofover3,000chemicalsandadvisedon theproducersofdrugsnotinthedirectory.In1931theysetupataskforceinorderto putBritishchemicalstandardisationonaproperbasis.Inrecognitionoftheireffortsthe ABCMwereallocated5membersontheprovisionalcouncil,withE.F.Armstrongas Chairman.By1931theABCMnotedtheycanproduceirrefutabledatatoprovethatthe
230
D.CoxMaksimov,TheMakingoftheClinicalTrialinBritain,19101945. Expertise,theStateandthePublic,(Cambridge:PhDthesis,September1997).
231
MRCMinutesIII,(11April1930):51.
232
MRCReport192930BritishMedicalJournal (7March1931):412and(14 March1931):466.

233
ABCM,BritishChemicals:TheirManufacturersandUses(London:ABCM,1927 &1929&1931)inScienceMuseumArchive.
304
305
KeyIndustrydutyhasbeeninstrumentalinpromotingthedevelopmentofthisimportant
234 keyindustry.
ThefinalimpetustoestablishasystemfortheclinicaltestingofBritishdrugscame notjustfrommedicalorscientificneeds,butasaresultofthedeterioratingeconomic climate,whichledtheGovernmentandhencetheMRCtosupportdevelopmentofa strongBritishchemicalindustry.Theeconomicclimateof19301boreseveral similaritiesto19201butinadditiontoGermany,Americahademergedasanimportant economicrivalwithgreateroptimism,standardisation,investmentandplantcapacity in thefieldofchemicalengineering.TheDepressionandthecollapseofinternationaltrade followingtheWallStreetcrashof1929continuedwithrisingunemploymentinBritain

235 andanincreasedstrainupontheHealthInsuranceFund.
ItwasagainstthiseconomicbackgroundthattheABCMtriedforathirdtimeto establishaformalprocessofclinicaltestingbytheMRC.In1930,GeorgePearsonof Wellcomegavespecificexamplesofstudieswhereithadbeendifficulttorecruitpatients: Ourpositionisthatitappearsimpossibletogetanadequateclinicaltestcarriedout followedbyareportinamedicaljournal.Wellcome'shighlypurifiedliverextracthad beensenttotheWPRLforclinicaltestingbuttheyhadreceivedonlyonereportback. Bulbocarpainesaleswereincreasingdespitethefactthatagaintheyhadtriedtohaveit

236 testedbytheWPRLwithoutsuccess. DiginutinclinicaltrialswerearrangedbyHead
OfficeandpartlybytheWPRLandalthoughresultswerefavourabletherewasno
237 publication. Pearsonalsocommentedthat:
theBritishmedicalpractitionerappearedtobereluctanttopublishclinical reportsevenwhenampleclinicalresultswereavailable.However,unlessthe datawaspublisheditcouldnotbequoted,exceptanonymously,whichwas clearlyoflessvalue.AvenylandNeostamweretrialedbytheWPRL (overseas)andNeoInfundin(posteriorpituitarylobeextract)wasundertrial
234
ABCM(London:ABCM,1927,1929,1931). A.J.P.Taylor,EnglishHistory191445(Oxford:ClarendonPress,1988):287297.
235 236
Bulbocarpainewasanisoquinolinealkaloidusedtotreatexcessivemovementsand spasms,T.A.Henry,(1939):17475,304,311.
237
G.E.PearsontoABCM,(24November1930),FileoftheTTC,MRCFile1523/15.
305
306
butattemptstohaveKurchibarkandthealkaloidalconessineorHarmine 238 testedforParkinsonism,rigororparalysisandmalaria,ledtotheirfailure. J.DavidsonPrattwhohadledtheABCMsince1928forwardedtheletterfromPearsonto theMRC.Hewrote: TheABCMis,asyouknow,veryinterestedintheproblemofclinicaltesting ofnewmedicinalproductsandfirstraisedthequestionwithyouin1926(sic) theAssociationsubmittedvariousproposalsonthissubjectandthesewere discussedatyourrequestwiththenewlyformedChemotherapyCommittee whenthemainfeaturesofasuitableschemewereagreed.Thescheme,has not,howeverachievedallthatwasintendedandthedevelopmentofnew medicinalproductsisbeingseriouslyhandicappedbytheinadequacyofthe facilitieswhichareavailableinthiscountryforproperclinicaltests.The Associationfeelsthatthetimeisripeforafurtherefforttodevelopasuitable systemandwouldbegladifthememberswhoarevitallyinterestedinthe subjectcouldhaveanopportunityoffrankdiscussionofthewholeproblem withyourcommitteeinthehopethatbycooperativeactionitmaybepossible todeviseaschemeofclinicaltestingwhichwilleliminatetheobstacles,which areatpresentretardingthedevelopmentofnewmedicinalproductstothe 239 nationaldetriment. Afurtherapproach totheMRCwasrecordedandtherecognitionofthecontinued
240 problemsonbothsidesstimulatedfurtherdiscussions. Prattfollowedupwitha
furtherletterandaformalmeetingbetweentherepresentativesoftheABCMandthe
241 MRCtookplaceon16February1931. TheMRCmemberswereElliott,Fraser,Dale,
Fletcher,andLandsboroughThompson.ThecompanyrepresentativeswereFrancisCarr
238
G.E.PearsontoMRCforwardedbyJ.DavidsonPratt oftheABCMtoW.M. FletcheroftheMRC,TherapeuticTrialsCommittee(24November1930),MRCFile 1523/15Avenyl,Neostam,andNeoinfundinarediscussedfurtherinthechaptersonthe STCandTTC.Kurchibark(sic)wasthebarkofanIndianplantHalarrhena antidysenterica.Conessinewasoneofseveralalkaloidsisolatedfromit,usedfortreating amoebicdysenteryandbothconessineandHarminehadlaboratoryactivityagainst tuberculosis.Harminewasactiveasanantihelminthicanditinhibitedsmoothmuscle contraction,henceitspotentialforParkinsonism.T.A.Henry,(1939):45760,61722.

239
J.DavidsonPratttoWalterMorleyFletcher,(28November1930),MRCFile1092, TTC1523/15.
240 241
ThemeetingwasrecordedintheMRCMinutesIII,(16January1931):4. J.D.PratttoW.M.Fletcher,(26January1931),MRCFile1092.
306
307
242 243 (BDH),Fred.W.Gamble(Allen&Hanburys), LeonardAnderson(Boots) ,DrH.A.

244 245 Mitchell(EvansSonsLescher&Webb) ,MrC.Chapman(GraesserMonsanto) , 246 GeorgeE.PearsonandT.A.Henry(BurroughsWellcome) ,andMrR.W.E.Stickings 247 ofMay&Baker.
WalterFletcherrecalledthattheCouncilhadbeeningeneralagreementabout arrangingstudiesfortheABCMin1927,but"ithadnotbeennecessary,intheabsenceof
242
FrederickWilliamGamble,encounteredbrieflyinchapter2whenhejoinedA&H asapharmacist.SincethenhehadbeeninvolvedincommitteesoftheLondonChemists AssociationandthefirstPharmaceuticalCodex(19031907)andinrevisionsofitin 1911and1923,theyearinwhichhechairedtheBritishPharmaceuticalCongress.Hewas aBoardmemberofAllen&Hanburysfrom1913andhadageniusforfriendlyrelations withthemedicalconsultants.Between192528GamblewasontheCounciloftheSociety oftheChemicalIndustryandin1930waselectedfirstchairmanoftheWholesaleDrug TradeAssociation(theforerunneroftheABPI)Mr.G.E.Pearsonsalesmanagerof BurroughsWellcomeMr.R.W.E.Stickings,WorksmanagerofMay&Baker,J.Slinn, AHistoryofMay&Baker18341984 (Cambridge:HobsonsLtd.,1984):122,125,128, 142,150,156Mr.J.DavidsonPratt,generalmanagersince1928andsecretaryofthe ABCMTherapeuticTrialsCommitteeMRCFile1092.
243
Mr.LeonardAndersonofBootsworkedinthesaccharindepartmentduringthe warandtookcontrolofthealkaloiddepartmentpostwar,W.H.Simsnotes(8 November1963):2.

244
IwasunabletofindanydetailsaboutDr.H.A.MitchellofEvansSons,Lescher& Webbandhedoesnotfeatureanyfurther.
245
GraesserMonsantochemicalproducedphenol,salicylicacidincluding'aspirin' preparations,vanillinandsaccharin.AsforMitchell,Icouldfindnodetailsabout ChapmanandGraesserMonsantoremainedalignedtochemicals,nevergettinginvolved inclinicaltrials.

246
Dr.T.AHenry,BurroughsWellcome,directoroftheWCRL,andin1931 ChairmanoftheLibraryCommitteeoftheSocietyoftheChemicalIndustry,apost,which hehelduntil1935.HewasVicePresidentoftheSocietyoftheChemicalIndustryfrom 192932.T.S.MooreandJ.C.Phillips,TheChemicalSociety18411941.AHistorical Review(London:TheChemicalSociety,1947):143RobertBentley,ATextbookof OrganicMateriaMedica(London:Longmans,Green&Co.,1887). Presentedto ThomasAndersonHenry,JacobBellScholar18934.

247
StickingswastheworksmanageratMay&Baker.Heservedthecompanyfor36 yearsbeforehediedsuddenlyinDecember1955,whenhewasdeputymanagingdirector andDirectorofProduction.J.Slinn,(1984):122,125,128,142,150,156.
307
308
248 requestsfrommanufacturersforclinicaltrialsofnewdrugs". Thiscommentprobably
reflectsthefactthatcompaniesconsideredthattheChemotherapyCommitteewas inappropriate.J. DavidsonPrattemphasised"thatsomeprovisionforefficientclinical

249 trialsofnewremediesinthiscountrywasurgentlyneeded. ReferringtotheABCM:
Itdesiresfullcollaborationwiththemedicalprofessioninsuchmattersand hasforsometimebeenworkinginclosetouchwiththeChemotherapy CommitteeoftheMRCandwiththeColonialResearchCommitteeinthe productionofnewsubstancesrequiredforextensiveclinicaltrials.Itishoped 250 practitionerswillsupportBritishindustry. Inordertobeginthenecessaryarrangementsfortrials,Prof.ThomasElliottenquiredof theABCMwhatthelargestnumberoflikelyrequestswouldbeinthecourseofayear. Hepointedoutthatclinicaltestingofanewremedymustatleasttakeaperiodofweeks ormonths,particularlyasitmightbenecessaryforagivendrugtobetestedbyseveral
251 differentclinicians.
TherenewedcallsforasystemoftestingBritishdrugscameasa'BuyBritish' campaignwasledbytheGovernment,EmpireMarketingBoardandthePrinceofWales: OnNovember16theEmpireMarketingBoardislaunchingacampaign. EveryretailerisaskedtoassisttofurtherBritishtradeandemployment.The CampaignhastheactivesupportoftheAssociationofBritishChambersof Commerce,theConfederation ofBritishIndustriesandseveralotherbodies. 252 ForeignproductsshouldfindnoplaceinBritishmateriamedica. Themedicalprofession,whosuggestedthatdoctorsshouldalsoPrescribeBritishreadily
253 tookupthebait. Aphysiciandescribinghimselfsimplyas'Countryman'wrote:
248
ReportofJointMeetingbetweentheMRCandABCM,(16February1931),MRC File1092oftheTherapeuticTrialsCommittee.
249
ReportofJointMeetingbetweentheMRCandABCM,(16February1931),MRC File1092oftheTherapeuticTrialsCommittee.
250
BritishChemicalsandDrugsBritishMedicalJournal (31January1931):193. T.R.ElliottatmeetingwithABCM,(16February1931),MRCFile1092ofTTC. BuyBritishChemist&Druggist(24October1931):509.
251 252 253
PrescribeBritishbyCountryman BritishMedicalJournal (12December1931): 1120Dr.W.BertramWatsonofHarrogate,BritishDrugsBritishMedicalJournal (3 October1931):638.
308
309
Asaprofessionwehavebeenaskedtoacceptcutsinourfees,andtomanyof ustheincometaxhasbecomeastillmoredreadfulworry.Atpresentthe campaignof'BuyBritish'shouldfindaswholeheartedsupportamongthe 254 professionasitisapparentlydoingamongthegeneralpublic.
6.11FormationoftheTherapeuticTrialsCommitteein1931. TheChemotherapyCommitteefailedtomeettheneedsoftheABCMmembersand focusedtoomuchontropicalmedicinewithstudiesoverseas.TheBritishpharmaceutical firmsstillhadnomeansbywhichtogetcliniciansinBritaintotesttheirnewdrugs.It wasalwaysassumedthatanorganisedsystemoftestingexistedinGermany,thoughthis probablywasnotthecaseandGermancompanieshadtoarrangetheirownstudies. However,astheyhadnodifficultyingettingtrialsperformedbyGermandoctors,this gavethemacompetitiveadvantage.CarrwaslaterabletoprovideevidencethatBayers scientificdirectorDr.Mertensin19235headedagrouporganisingtheirclinicaltrialsin Germanyandanotherforsalespropaganda.Theformerincludedfivephysicianssplit betweengeneralandtropicalmedicine.Trialswerecarriedoutfirstby14external clinicians,andifpromising,theprogramwasbroadenedover34years,thoughlessthan 5%oftheproductsstayedthecoursetobeissued.Applicationwasthenmadetothe
255 Governmentbutpermissionwasusuallygranted. Germandoctorsdidhoweverraise
concernsaboutthesafetyofnewdrugsafterawidelyreportedtragedyoccurredinLbeck in1930,whenmanychildrendiedandwereinjuredafteradministrationofcontaminated
256 BacillusCalmetteGuerin(BCG)vaccinetonewbornbabies.
254
BuyBritishBritishMedicalJournal (19December1931):1160.Dodd complainedaboutthehighpricesforcatgut,rubbergloves,instruments,plasterofParis andbandages.

255
BritishObjectivesSubcommitteePharmaceuticalJournal (2March 1946):137 50 YearsofBayerRemedies18881938.(Leverkusen:Bayer,1938)

256
TheLbeckTragedy BCGBritishMedicalJournal (21February1931):334M. C.G.Israels,A.D.MacDonald,ThePharmacologyofPeracaineBritishMedical Journal (28November1931):986988,TheBCGTragedyatLbeckBritishMedical Journal (28November1931):1016S.R.Rosenthal(ed.),BCGVaccine:Tuberculosis Cancer(Littleton,Mass:PSGPublishing,secondedition1980):358L.BryderinJ. AustokerandL.Bryder(eds.),(1989):1011.
309
310
ThereweresimilarconcernsintheBritishmedicalliteraturein19301when
257 Bayer'sanaesthetic,Avertin,wasassociatedwithtoxicjaundice. Oneofthemain
reasonsforthedelayinestablishingclinicaltestingofnewdrugsinBritainwasthe relativepaucityofnovelchemicalsestimatedtobesixperyearasstillmostofthenew
258 syntheticdrugswerestillfromGermany. SirWilliamWillcox,physiciantoSt.Mary's
andHomeOfficepathologistwrote: Itshowedhownecessaryitwasthat,beforetheywereplacedonthemarket, thesedrugsshouldbesubmittedtocarefultoxicologicalandtherapeutictests onthehumansubjectaswellasonanimalsThechemicalmanufacturing industries(were)...dailylaunchingimperfectlytriedcomplexorganicdrugson themarketandthesystemoftestingdrugswas"unsatisfactory,exposingthe peopleofthiscountrytogreatdangerfromthetakingofnewdrugsadvertised 259 aspossessingwonderfulcurativeproperties". Asaresultofthegrowingconcerns,modificationsweremadetotheTherapeutic SubstancesAct,requiringwithdrawalofallofabatchfromsaleifitfailedtomeet
260 standards,andtheActcameintoforceon25July1931.
6.12Conclusions. TheclearconclusionofthischapteristhatafterthePharmaceuticalindustry willinglysubmittedtohavingtheirSalvarsanpreparationsassayedduringthewar, representativesofthecompaniesapproachedtheMRCseveraltimesintheperiod1922

257
SirWilliamWillcox,"ControlofDrugs:AWarning",BritishMedicalJournal,(4 April1931):597TheChoiceofanAnaesthetic(14February1931):2656Avertin Anaesthesia(21February1931):330AvertininAnaesthesiaBritishMedicalJournal (20June1931):1095F.B.Parsons,AvertinBritishMedicalJournal,(4October1930): 5547F.B.Parsons,AvertinanaesthesiaBritishMedicalJournal (1November1930): 756FrancisE.Shipway,AvertinAnaesthesiaBritishMedicalJournal (8November 1930):799BasilHughes(Bradford),AvertinAnaesthesiaBritishMedicalJournal (22 November1930):887.Over100,000narcoticdoseswereplacedatthedisposalofclinics beforemarketing.
258
PreparationsandAppliancesNembutalBritishMedicalJournal (28February 1931):359Neoinfundin(7March1931):406.

259
"ControlofDrugs:AWarning",SirWilliamWillcox,BritishMedicalJournal (4 th th April 1931):597(inlecturetoRoy.Coll.Phys19 26 March).

260
TherapeuticSubstancesActH.H.DaleArchives93HDBox21.2.129.
310
311
1931,withtheaimofsecuringasystemofclinicaltestingoftheirnoveldrugs,including synthetics.Afterthefirstapproachattheendof1922,theMRCandthecompanies becamepreoccupiedwithinsulinproduction.Quiteapartfromtheapparentclinical efficacyalreadyseeninNorthAmericawithinsulin,theMRCheldthepatentsfortheUK andtheycouldcontrolthedistribution.Asecondapproachwasmadein1926aroundthe timewhentheMRCwasembarkingonthediscussionswiththeDSIR,whichwereto resultintheTherapeuticSubstancesActof1925.AChemotherapyCommitteewas established,reflectingthenewfocusoftheMRCandDSIRfollowingthediscoveryof Bayer205inGermany.Thereremainedaseriesofothercommittees,foranaestheticsand soon.OneofthereasonsforthefailuretoestablishtheTTCearliermayhavebeensimply thatitwasestimatedbytheABCMthattherewouldonlybehalfadozennewproducts eachyear.Studiesofantiseraandantitoxinswerequitedifferentandwererelativelyeasy toorganisethroughtheBoardofTrade. ThischapteralsosawthecontinuedascendancyofFrancisCarr.Hefinishedthe WarwithhonoursandwasgivenaprestigiousjobatBritishDrugHousesandwentonto fameforhissuccesswiththyroxinandinsulinproduction.By192627hewasthe influentialPresidentoftheSocietyfortheChemicalIndustryandcampaignedforbetter trainingofchemistsandasystemofclinicaltrials.TheChemotherapyCommitteeof1927 didnotmeettheManufacturersneedsandtheABCMcampaignedoncemoreforaclinical trialsystemin1930.Theyweresuccessfulthistime,in partduetothetimingoftheir approachinthemidstofharsheconomicconditionsandagainstabackgroundof increasinggovernmentinvolvement.ThefollowingchapterevaluateshowtheBritish companiesusedthenewTherapeuticTrialsCommitteeandattemptsalsotoassess whethertheavailabilityofaclinicaltestingsysteminfluencedtheirstrategyofdrug development.
311
BurroughsWellcomeStrategyintheInterwarPeriod.
312
CHAPTERSEVEN:BurroughsWellcomeStrategyintheInterwarPeriod 7.1Introduction. Aftertheendofhostilities,firmslikeBurroughsWellcomethathadcommittedto producingsyntheticandotherGermandrugs,hadtomakedifficultchoicesaboutdirections oftheirfutureresearch.Havinglostseveralkeymembersofstaffduringthewar, BurroughsWellcomesufferedfurthersignificantstafflossesimmediatelypostwar.Forthe firmthatalreadyproducedantitoxins,vaccines,syntheticdrugsandalkaloidal extracts, thereweresoontobefurtherstrategicchoicesasorganextractsandvitaminscameinto prominence.Wouldtheyreturntoimportingdrugs,ratherthandiscoveringtheirownand wouldaBurroughsWellcomeTabloidbrandofeachnewmedicinebepreparedorwould they specialise? InthissectionIevaluatesomeofthefactors,whichmayhaveshapedtheirpolicy. ThosethatIhaveidentifiedincludethechangingmarketpostwar,thefiscalandregulatory environment,thesizeandscopeoftheirownmanufacturingandtestingfacilities,andthe availabilityofresearcherstoperformclinicaltrialsontheirnewdrugs.Inordertoaddress theseissues,BurroughsWellcomemovedtowardsamoreformalmethodofdefining companystrategy,intheformoftheirScientificandTechnicalCommittee,establishedin 1925:thischapterisbasedaroundtheminutesofthiscommittee. 7.2StaffChangesandFacilities. InthepasttwochaptersIhavehighlightedsomeoftheproblemsfacedby BurroughsWellcomeduetothelossofexperiencedstaff,particularlychemistssuchas Carr,Ewins,Barger,andPower.On22February1919,Pyman,headoftheWCRL, becameProfessorattheCollegeofTechnologyinManchesterandaFellowoftheRoyal
1 Societyin1920. Dr.ThomasAndersonHenry,whotookoverasDirectoroftheWCRL,
hadstudiedthechemistryofalkaloidsatthePharmaceuticalSocietyfrom1893andat
2 ImperialCollegefrom1896.
H.King,FrankLeePymanObituaryNoticesofFellowsoftheRoyalSociety 4 (1944):681697.
2
Dr.ThomasAndersonHenry(18731958)servedontheBritishPharmacopoeia Commission,andthecommitteesoftheBiochemicalSocietyandChemicalSociety,L.G.
312
313
Asdescribedinthelastchapter,inMarch1919HaroldKing,anotherexperienced chemistleftBurroughsWellcometojoinDaleattheNationalInstituteforMedical
3 Research. RobertR.Baxterwhohadsynthesisedpilocarpine,Kharsivan,Salolandvarious
alkaloidsduringthewar,resignedinDecember1919,movingtoManchestertotakeupa commercialposition.Afurtherexperiencedchemist,MarmadukeBarrowcliff,whohadco authoredabookonsyntheticchemicalswithFrancisCarr,tookuparoleinMalayawitha

4 rubberfirm.
AlfredLouisBacharach,aCambridgegraduatefoodchemist,whohadworkedat
5 theWCRLandAnalyticaldepartmentsince1915,departedinJanuary1920. Bacharach
wasintroducedinthelastchapterwhenhejoinedNathans,aforerunnerofGlaxo,because
6 hedislikedhistediousdailyjourneyfromHampsteadtothenewsiteatDartford. Robert
G.Fargher,whohadpreparedarsenicalsincludingKharsivan(Salvarsan),resignedin September1920totakeupapostasheadoftheChemistrySectionoftheShirleyInstitute inDidsbury,Manchester.HerbertW.B.Clewer,whoproducedsyntheticchemicals includingneosalvarsan,salicylicacid,andpyramidine,movedtothefirmofMessrs.Mason &SonsinRotherhamattheendoftheWar,andFrankP.Walton,wenttoImperial Collegein1923.Itwasnoteasytofindsuitablechemiststoreplacelossesas:itmustbe rememberedthattheFoundationcannotobtainstraightfromtheuniversitiesmensuitable forthisworkanditisonlyafterayearortwo'straininginourlaboratorythattheybecome

7 reallyuseful.
Matthews,HistoryofPharmacyinBritain (Edinburgh&London:E.&S.Livingstone, 1962):255256T.A.Henry,F.L.PymaninE.F.Armstrong(ed.),Chemistryinthe TwentiethCenturyanAccountoftheAchievementandthePresentStateofKnowledgein ChemicalScience(London:ErnestBenn,1924)T.A.Henry,ThePlantAlkaloids rd (London:J.&A.Churchill,3 edition1939).

3
WF:YLBox46,WorksHistorySirCharlesHarrington,HaroldKing(18871956) BiographicalMemoirsofFellowsoftheRoyalSociety 3(1956):159.

4
M.Barrowcliff,TheVitamins (KualaLumpur:St.JohnsPress,1923)WF:YLBox 46WorksHistory.

5 6
WF:YLBox46,WorksHistory.
R.P.T.DavenportHines,J.Slinn,Glaxo:AHistoryto1962(Cambridge:Cambridge UniversityPress,1962):47,7172WF:Box25,WorkRecords.
7
FacilitiesforChemicalWork,(23December1926),STCWF:S/G/49.
313
314
TherewerealsofurtherchangesattheWPRL,whichhadalreadylostDale, Laidlaw,Burn,EwinsandBarger.A.F.WatsonsucceededPercivalHartleyasHeadof
8 Biochemistryin1921,asHartleydepartedfortheNIMR. Inordertoreplacesomeofthe
stafflostattheendoftheWar,researcherssuchasJohnW.TrevanandR.A.O'Brien wererecruited.TrevanwasabrilliantmedicalstudentatStBartholomews,thena demonstrator,obtainingaB.Sc.inphysiologybeforeabriefspellintheArmy.Hewas

9 appointedasHeadofPharmacologytotheWPRLatLangleyCourtin1920. R.A.
OBrien,abacteriologistjoinedfromtheListerInstitute,asdidG.S.Walpole,andtheir
10 mainfocuswasonvaccines. OBrienwasresponsibleforthedailyrunningofthe
laboratory,reportingtoCharlesWenyon,whohadbeenaconsultantpathologistduringthe war.WenyonwasanexpertprotozoologistandhewassecretaryoftheRoyalSocietyof TropicalMedicinefor25years.AllnewseniorstaffhadtobeapprovedbyAndrew Balfour,whoaswesawinchapter3wasappointedasheadoftheWBSRin1913,untilhe

11 toodepartedin1923tojointheLondonSchoolofHygieneandTropicalMedicine.
In1920BurroughsWellcomemovedtheWPRLfromBrockwellHall,HerneHillto
12 a108acresiteatLangleyCourt,Beckenhamcosting30,000. Newfacilitieswere
establishedatTempleHill,includingachemicalsection,watertower,boilerhouse,and
SirHenryDale,SirPercivalHartleyBiographicalMemoirsofFellowsoftheRoyal Society (1957)3:81110H.J.Parish,TheWellcomeResearchLabsandImmunology WF:85/20:2Chapter3.

9
J.H.Gaddum,JohnWilliamTrevan18871956BiographicalMemoirsofFellows oftheRoyalSociety 3(1957):272288.TrevanbecameDirectorin1941andResearch Directorin1952A.S.Milton,BurnOxfordforaStartBrit.J.Pharmacology 119 (1996):12939.

10
W.S.Feldberg,H.H.Dale(18751968)BiographicalMemoirsofFellowsofthe RoyalSociety 16(1970):79174.WalpoleleftBurroughsWellcometosetuphisown manufacturingbusiness.OBrien,AustralianbybirthwentontobecomeDirectorofthe WPRLafterDaledepartedin1914H.Chick,TheListerInstituteofPreventative MedicineEndeavour(July1949):106111R.A.OBrien,PharmacologicalActivitiesof theFoundation,WF:S/G/49.

11 12
H.J.Parish,WF:85/20:2,chapter5.
OppositiontoProposedLaboratoryChemist&Druggist94.3(14May1921):35 WPRLChemist&Druggist94.3(11June1921):61.
314
315
materiamedicafarmanewexploratorylaboratorywasopenedinMay1923andchemical
13 manufacturingwasmovedtoTempleHillinJuly1925.
By1926theWCRLbuildingsalsoneededenhancement: WithregardtotheWCRLthepresentpremisesareinadequateand uneconomicalformodernchemicalworksandmorecouldbedonewiththe presentstaffiftheywerehousedinlargerpremisesandwithmodernised 14 equipment. Themanufactureofephedrine,pseudoephedrine,thyroxineandadrenalinhadtobestopped becauseoflackofequipment,andtherewasnoreserveforemergenciesorsudden

15 demands. Theexperimentallaboratorieswererefurbishedattheendof1926,andthe 16 WCRLwasalteredtoallowformorechemiststoberecruited. By1931anobserver
noted: ThefirmatDartford...[had]anewchemicallaboratoryofremarkable beautyandinterest.TheworksatDartfordunderthemanagementof Jowett,isaremarkableworkstovisitandscientificcontrolofthe manufactureandpackingappearstobeascompleteashumaningenuitycan 17 devise. DuringthisperiodHenryWellcomeincreasinglylefttherunningofthebusinesstoGeorge Pearson,whowasrenownedforhisparsimony,exemplifiedbyconstantcomplaintsover salariesandthathestarvedessentialaccountsandequipment.Thestaffwasencouraged

18 toimproviseandnotspend. Pearsonsdefencewasthatheneverreallyknewwhen
Wellcomewoulddemandthousandsofpoundstopayforhisanthropologicalcollections
19 acquiredoverseas.
7.3TheScientificandTechnicalCommittee.
13
G.E.Pearson,AChronologyoftheHistoryofB.W&Co.18781936 WF:88/34: 41d:1314.

14
Memo:FacilitiesforChemicalWork,(23December1926),WF:STCS/G/49. Ibid. STCMeeting,(17December1926),WF:STCS/G/49. BurroughsWellcomeInsulinLedgers(19301):4445,WF:89/24. H.J.Parish,WF:85/20:2Chapter5.
15 16 17
18
315
316
Intheperiodimmediatelyfollowingthewar,BurroughsWellcomeshapedtheir futureaccordingtothedemandsofchangingmarketsandregulatoryconstraintsratherthan bysettingdownaspecificpolicy.AttheendoftheWar,productionofsomeGerman drugssuchasphenacetinceased(inJanuary1921),asGermanpatentswerereinstated. Drugsthathadbeenneededforthewarwererequiredinsmallerquantitiesbutexport marketsthathadbeencompromisedbythewarwerereopened. Aftertradedeterioratedin1921,BurroughsWellcomestruggledtodecidewhether theyshouldreturntotheirroots,ortofollowthesyntheticapproachtakenduringtheWar. However,theywerenotfullypreparedtoinvestinthelongtermresearchasperformedin Germany,andsotheywereleftwiththepickingsfromcopyingdrugsoutofpatent, chemicallymodifyingthosethatremainedpatentprotected,andproducingsemisynthetic versionsofnaturalextracts.Theonly'new'productsmarketedimmediatelypostwarby BurroughsWellcomewereMenthofax(September1920)andMoogrol(July1921),and
20 theseanaleptics(stimulants)wereonlycopiesofdrugsalreadyavailableonthemarket.
Therewas,ofcourse,insulinarisingasanexternalopportunityandthisdominatedefforts intheperiod192325,andasdescribedpreviously. BurroughsWellcomelearnedagreatdealthroughTrevansexplanationsofwhy somebatchestestedbyBurroughsWellcomefailedtestsattheNIMRduetoinherent

21 biologicalvariationwithintheanimalsusedfortesting.
BurroughsWellcomereturnedinparttotheirprewarstrategyofcharacterising drugsextractedfromplants,butdespitethelossofmanyexperiencedchemists,theystill preparedsomeactiveprinciplesandsemisyntheticanaloguesattheWCRL,before exploringtheirpharmacologyandstandardisingthemattheWPRL.RequestsforTabloids camefromallovertheglobe,butparticularlyfromAfricaandIndia.22 Glennyatthe
19
H.J.Parish,WF:85/20:2chapters5,6MinutesoftheWellcomeTrustees(23 April1935).
20 21
A.W.Haggis,TypescriptHistoryoftheWorks,WF:85/20:2.
A.S.Milton,BurnOxfordforaStartBrit.J.Pharmacology 119(1996):12939 onp.1294.

22
R.A.OBrientoG.E.Pearson,(16January1925),WF:S/G/49.ResearchReports, ScientificandTechnicalCommitteeNotesofMinute(s)andCorrespondence,(January
316
317
WPRLcontinuedtoprepareandstandardisediphtheriaantitoxinandevaluatedoptimised dosingregimensandassaysofimmunity.Clinicaltrialsofantiseraandantitoxinswere arrangedviatheseniormedicalofficeroftheMinistryofHealthatschools,navalshipsand trainingschoolsfornurses,butBurroughsWellcomehadlimitedsuccesswithnew vaccines,thoughascarletfevervaccinewasdevelopedandStaphylococcaltoxinswere

23 evaluated.
TheestablishmentoftheScientificandTechnicalCommittee(STC)inJanuary1925 aimedtofurtherimprovethecommunicationbetweenthevariousBurroughsWellcome laboratoriesandtoprovideaformalmeansofreportingtoGeorgePearson,theGeneral

24 Manager. TheSTCmetmonthlytodefinetheResearchstrategyandincludedWenyon
oftheWBSR,Trevan(WPRL),Henry(WCRL),O'Brien,(WPRL),Jowett(Works), TaylorandSmith(Analytical).Althoughnotovertlystated,theestablishmentofthe CommitteemayhavebeenrelatedtotheimminentTherapeuticSubstancesActwhichwas passedin1925,comingintooperationin1927,whichindicatedgreatergovernmentcontrol ofbothsyntheticandbiologicalsubstances,asdescribedinapreviouschapter.OBrien, Glenny,OkellandParrishwereconsultedregardingthedraftingoftheTherapeutic Substancesguidelines,buttheBurroughsWellcomeinputwasonlyregardingcontrolsfor

25 vaccines.
AsastrategiccommitteetheSTCaddressedissuesrangingfromresearch accommodationandfacilitiesforresearch,tointeractionsandcollaborationswithexternal doctorsandorganisationssuchastheDSIR,ABCMandColonialOfficeitalsoreviewed ongoingprojects,makingsurethateverythingwasinplacetoevaluateandintroducenew drugs.Atitsinception,theSTCreviewedprogressoverthepastfewyears.Burroughs WellcomehadbeenslowinshowingtheirinterestininsulinandlostgroundtoAllen&
1925toDecember1934) STCMeeting,(20January1925)LetterfromBombay,(23 February1926),WF:STCS/G/49.

23
H.J.Parrish,ClinicalResearchonDiphtheria(I)(192240),TheWellcome ResearchLabsandImmunology,chapters34,6,WF:85/20/2.
24 25
ThefirstmeetingoftheSTCwason13February1925,WF:STCS/G/49.
H.J.Parrish,TheWellcomeResearchLabsandImmunology,chapter8,WF: 85/20/2.
317
318
HanburysandBritishDrugHousesandtheirfirstcommercialproductionofinsulinwas
26 notachieveduntilSeptember1924.
Whensuppliesofpancreasbecamerestricted,DaleattheNIMRhadsuggestedthat infutureiftherewasaninsufficientsupplyofanyhormonalpreparations,manufacturers shouldcoordinatetheireffortssothateachfirmconcentratedonadifferenthormone. WhereasFrancisCarrofBritishDrugHousesapprovedofthissuggestionandindeedmay havebeenbehindit,BurroughsWellcomewasconcernedthattheywouldbeallocatedthe

27 leavingsafterBDHhavehadtheirpick.
IfsuchapolicyweretowinfavouritwouldruncountertoBurroughsWellcome's policyofpreparingstandard'Tabloid'preparationsofallsubstancesthatwereindemand. Ideasfornewdrugscamefromthemedicalliteratureandattendanceatmeetings,scientific requestsfromphysiciansforaparticularsupply,orfeedbackonunmetclinicalneeds.Ifa drugshowedpromiseBurroughsWellcomewouldalwaysensurethattheyhadaversion

28 available.
Occasionally,physiciansapproachedthefirmwithspecificrequests,suchasone whoaskedforadrugforanaemia,andtheyprovidedferriccacodylateanotherwanteda
29 reallyreliabledrugtoactasasedativeinepilepsy. Theserequestshadtobemanaged
efficiently,sothateffortswerenotwastedpreparingsmallbatches.Theoppositesituation alsooccurredwhenBurroughsWellcomefoundtheymadetoomuchofadrugsuchas
26
Insulin manufacturestartedinMay1923andmovedfromtheExperimentallabtothe WCRLinSeptember1923,thefirststerilebatchofTabloidinsulinhydrochloridebeing readyinSeptember1924:Hogg,TypescriptHistoryoftheWorks,WF:85/20:2

27
H.A.D.JowetttoG.E.Pearson,TheRelationoftheFoundationtoResearch WorkersandClinicians:MemorandumreScientificSocietiesetc.(12October1926):4. WF:BA/S/6/49.

28
SuchwasthecasewhenG.Voegtlinreportedthebenefitsofreducedglutathionefor inhibitingthepoisoningbyorganicarsenicals,STCMeeting,(25January1925),WF:STC S/G/49. JournalofPharmaceuticalandExperimentalTherapeutics(1925):297The synthesishadjustbeenreportedbyStewartandTunnicliff,BiochemicalJournal XIX (1925):207R.A.O'BrientoG.E.Pearson,(28May1925),WF:STCS/G/49However theonlysourcefromGermanywaspoorquality,(21October1925),WF:STCS/G/49.

29
H.A.D.JowetttoG.E.Pearson,(15January1925):Arequestalsocamefor concentratedvitaminA,STCMeeting,(20January1925),WF:STCS/G/49.
318
319
hordenine(anhaline)analkaloidisolatedfrombarleymaltgerms,andcharacterisedby
30 Bargerin1909andsoneededtofindanoutlet. ThephysiologistsattheWPRLwere
taskedwithfindingalternativeuses.Thissubstancehadpsychicandmotorexcitation effectssimilartoephedrinebutathighdosesiscouldcausedeathbyinhibiting
31 respiration.
Thepostwardecadesawanincreasedinterestinhormonalpreparations.Organ extracts,ororganotherapieswerevariableinstrengthandinorderforBurroughs Wellcometoinvestigateandpreparenewhormonals,O'BriensuggestedtoPearsonthat physiologistsandorganochemistsshouldworkinadjacentlaboratories.Withregardto theWCRLthepresentpremisesareinadequateanduneconomicalformodernchemical worksandmorecouldbedonewiththepresentstaffiftheywerehousedinlargerpremises

32 withmodernizedequipment.
In1925theSTCwereapproachedbytheDSIRwithanoffertocollaborate.In 1920alargegovernmentlaboratoryhadbeenestablishedbytheDSIRatTeddingtonwith theaimofpreparingsomeofthechemicalintermediates,requiredinsmallquantitiesby drugfirms,andwhereitwasnotcosteffectiveforthefirmstopreparethese.Theideawas thattheDSIRcouldpreparetheseinbulkandmakethemavailabletoBritishfirms,tosave themrelyingonoverseassuppliers.Apharmacologybuildingwasaddedin1923,adjoining theNationalPhysicalLaboratoryandthechemistG.T.MorganwasappointedDirectorof

33 theDSIRin1925. MorganbeganhistrainingatFinsburyTechnicalCollege,likeFrancis
Carr.HehadalsobeenaresearchassistanttothechemistWilliamA.TildenattheRoyal CollegeofMinesinLondon.RepresentativesoftheChemicalSocietycontacted
30
31 32 33
H.A.D.JowetttoG.E.Pearson,(15January1925),WF:STCS/G/49. T.A.Henry,(1939):561. FacilitiesforChemicalWork,(23December1926),STCWF:S/G/45.
GilbertThomasMorgan(18701940)wasanassistantatthedyefirmofRead HollidaythenDemonstratorattheRoyalCollegeofScience,firstinDublinin1912,then ProfessorofAppliedChemistryatFinsburyTechnicalCollegefrom1916,andProfof chemistryatBirminghamUniversity191925.In1926hebecametheDirectorofthe ChemicalResearchlaboratoryoftheDSIRatTeddingtonwhereheremaineduntil1939 JamesIrvine,GilbertThomasMorganObituaryNoticesofFellowsoftheRoyalSociety 3,(1941):35462M.R.Fox,DyemakersofGreatBritain18561976(Manchester:I.C.I. plc,1987):91.
319
320
BurroughsWellcome(andotherfirms)earlyinJune1925withanofferfromtheDSIRto collaboratemorecloselyindevelopingnewchemotherapeuticdrugs.Followingthe descriptionofBayer205therewasarenewedinterestinchemotherapyandthegovernment waspreparedtoinvestfurtherresearchmoneyintoasearchfornewchemotherapeutic agents. Dr.HenryrepliedtotheDSIRthattheresearchperformedbyBurroughsWellcome wasquitesatisfactory,andIamemphaticallyoftheopinionthatnosuccesscouldattend anycooperativeefforttoencourageandstimulatescientificresearchandthebestwayisto alloweachfirmtomaketheirownarrangement.HeemphasisedO'Briensearlier considerationthatwhatwasrequiredwasclosecollaborationbetweenchemistsand
34 physiologistsascouldalreadybeachievedatBurroughsWellcome. Thefirmremained
reluctanttosharetheirexpertisewithothers. However,BurroughsWellcomewerequicktosuggestthatifanyproductsarose fromtheDSIR,whichwerelikelytobeofindustrialinterest,thentheexperimental departmentwouldbekeentotakeupthework.HenrycommentedfurtherthattheDSIR planforcollaborativeresearch: doesnotstrikemeasfeasible,partlybecauseofthecomplicationsinvolved bythemedicalsideofthequestionandpartlybecauseofthecircumstances, objectsandoutlookofthecomponentpartsoftheindividualaretoovaried 35 incharactertopermitit. TheDSIRmadeaformalapproachtotheMRCtocollaboratetodevelopnew chemotherapeuticagents,butthesechemistryventureseventuallyfoundered,especiallyas theycouldonlyoffernonexclusivelicensesandbecausetheyreliedonexternal
36 laboratories.Asmoneybecameshort,jointcollaborationswereeventuallyabandoned.
34
T.A.HenrytoA.W.Crossley,(9July1925),WF:STCS/G/49(replytoletterof23 June1925).
35 36
T.A.HenrytoA.W.Crossley,(9July1925),WF:STCS/G/49.
I.Varcoe,Scientists,GovernmentsandOrganisedResearchinGreatBritain19146. TheEarlyHistoryoftheD.S.I.R191416Minerva8(1970):192216R.McLeod,E.K. Andrews,TheOriginsoftheD.S.I.R.ReflectionsonMenandIdeas,19156Public Administration 48(1970):2348E.Hutchinson,ScientistsasanInferiorClass:The EarlyYearsoftheD.S.I.R.Minerva8(1970):396411J.D.Bernal,ScienceinHistory (London:C.A.Watts&Co.,1965)C.E.K.Mees,ThePathofScience(Chichester:
320
321
SincethedepartureofCarrandhiscolleagues,BurroughsWellcomehadadopteda protectiveapproach,limitingstafffrom presentingdataandattendingexternalmeetingsfor fearofevenmorebeingpoached.Theinsularity,whichhadbeenthehallmarkof BurroughsWellcome,alreadyapparentintheirdealingswiththeMRC,begantobe questionedbySTCmembersinmid1926. Theeventwhichseemstohavetriggeredthisreappraisalseemstohavebeenthe inauguralpresidentialaddress:ThePositionandProspectsoftheOrganicChemical IndustryinthisCountrybyFrancisCarrtotheSocietyoftheChemicalIndustryatits ManchestermeetinginJuly1926.Hecalledforgreateremphasisonsyntheticdrugsrather thanthebiologicalsandthestandardpreparationsuponwhichBurroughsWellcomehad
37 chosentoconcentrate. JowettreferredtoFrancisCarr'snewpositionasPresidentofthe
SCIinalettertoPearson:Mr.C's(sic)newpositionwillimprovehisopportunitiesof gettingintouchwithuniversitiesandkindredinstitutions.Jowettwasconcernedabout theincreasingtendencytopatentdiscoveries,primarilyofsyntheticdrugs,andhe suggestedthataspecialagendashouldbeaddressedatthenextmeetingoftheSTC:To considerthebestmeansofgettingintotouchwithworkersinuniversitiesandkindred institutionssothatthecompanymayhavetheirpropershareofthecommercialexploitation

38 ofanydiscoveries. JowettreferredtoapreviousreporttoPearsoninwhichhefirst 39 raisedtheseconcerns.
JohnWiley,1946)J.Jewkes,D.Sawers,R.Stillerman,TheSourcesofInvention (London:MacMillan,1955)A.C.Seward(ed.),ScienceandtheNation (Cambridge: CambridgeUniversityPress,1971)A.Marwick,TheDeluge,BritishSocietyandtheFirst WorldWar(Boston:LittleBrown,1965)especiallychapter7.

37
LecturenotesofS.C.I.meeting,(July1926).B.CARR.publications,F.H.Carr, ArchivesF.H.Carr,TheCommercialProductionofHormonesChemist&Druggist 105.1(24July1926):181.

38
H.A.D.JowetttoG.E.Pearson,Cooperation,STCMeeting,(24July1926), WF:STCS/G/49.
39
TheletteroutlinedtheformationoftheSTC,whenitfirstmeton16January1925 todiscussthepharmacologicalactivitiesoftheFoundation.R.OBrientoG.Pearson,(16 January1925),WF:STCS/G/49.
321
322
Thedebateaboutthefirmsrelationshipwithacademicsandclinicianswasevidently
40 difficulttoarrange,duetoPearsongoingaway. FortunatelythisledtobothO'Brienand 41 JowettsettingoutpositionpaperstoPearsononexternalrelations. Jowettdescribedhow
priortoandattheoutbreakoftheWar,itwasonlynaturalfortheGovernmenttoconsult BurroughsWellcomeonmattersofpolicyrelatingtodrugs,asthefirmwasheldinhigh regardforitsresearchwork.Herecalledhowthisreputationwasfurtherenhancedbythe workonSalvarsan.However,itappearsthatBurroughsWellcome,afterthelossofCarr andthepostwarexodusbecameverycautiousaboutallowingtheirtrainedstaffto

42 establishlinkswithoutsideprofessionalbodies.
From1926theSTCallowedincreasingcontactwithexternalinvestigatorsand begantoallowthereleaseoffreesamplesof newdrugsfortesting.Whenthispolicywas reviewedsomeyearslatertheSTCnotedthat:insendingpreparationsfortrialoutsidethe WellcomeResearchInstitutethereisacertainriskofprematuredisclosureofresults,arisk

43 whichmust,however,underthepresentcircumstancesbetaken. Itwas,however,a
matterofpolicytohaveclinicaltestsperformedonallnewbiologicalproducts.44 Jowettcouldonlyspeakforthepolicyregardingtheworksstaff,butthatwasthe department,whichCarrhadleftin1914.Thepolicythereafterwas:Thatitwas inadvisableformembersofthestafftotakeupworkeitherinlocalortechnicalaffairsasit wouldabsorbtheirenergies,whichwouldmoreprofitablybeconservedintheinterestof

45 thefirm.
Jowetthadexperiencedrefusalsanddiscouragementregardingattendanceat externalmeetings,thoughhefeltthatafter30yearsatthefirmhismotivesforattending
40 41
R.A.O'BrientoG.E.Pearson,(28October1926),WF:STCS/G/49.
H.A.D.JowetttoG.E.Pearson,(12October1926):4,WF:STCS/G/49 MinutesofResearchConference,1.RawMaterialtoResearchers,(29October1926).
42
H.A.D.JowetttoG.E.Pearson,TheRelationoftheFoundationtoResearch WorkersandCliniciansMemorandumreScientificSocietiesetc,(12October1926),WF: BA/S/6/49.

43 44 45
STCMeeting,(28February1930),WF:STCS/G/49. STCMeeting,(24October1930),WF:STCS/G/49. MemoH.A.D.JowetttoG.E.Pearson,(12October1926),WF:STCS/G/49.
322
323
couldnotbequestioned.Hestatedthat:Ihaveonlytheinterestsofthefirmatheartand
46 donotinanywayseekpersonaladvancementor'kudos'outsidethefirm. Therewere
exceptionstotherules,forJowettwasassociatedwiththeDartfordAssociationandthe Localemploymentcommittee,attendedsomescientificconferencesandperformededitorial work,butherarelygotinvolvedinpharmaceutical,chemicalandanalyticalsocietiesinthe samewayasCarr,GambleandHill. However,JowettclearlyimpliedthatCarr,whohadpreviouslyreportedtohim,had nowgainedanupperhandbecauseoftherestrictivepoliciesatBurroughsWellcome. Duringthewar,LordMoulton,Prof.JocelynFieldThorpe,ofLeedsUniversity,(authorof DictionaryofAppliedChemistryandTheSyntheticDyestuffsindustryand

47 Intermediates) andotherGovernmentofficials,consultedJowettuntilCarrcameonto
thescene.BothCarrandJowettwereaskedtoserveoncommitteessuchasthePoisonous GasesCommittee,butwhereasBootfullysupportedCarr,Jowetthadtodeclinetheoffers. JowettreferredtotwootherimportantfactorsthathadbeeninCarrsfavour:One wastheinfluenceBoothadwithLloydGeorgeandDr.Addison(MinisterofHealth),and theotherwasCarr'sfriendshipwithCol.E.F.HarrisonoftheRAMCandwithDr.Henry

48 DaleattheNIMR. JowettcontinuedtoexplainthatCarrsmanufactureofboth
saccharinandgasgranules,brought'kudos'toBootsandhewaspersonallyrewardedwith theC.B.E.whileBootreceivedtheO.B.E.andM.B.E.buttheonlyBurroughsWellcome membersimilarlyrecognisedwasO'Brien.CarrwasalsochosentotakepartintheABCM

49 missiontoGermanyin1919alongwithGeneralHartleyandHerbertLevinstein.
Asaconsequenceoftheirlackofinvolvementinexternalactivities,Jowettfeltthat BurroughsWellcomenolongeroccupiedaprivilegedpositioninBritain.Thesewere
46 47 48
H.A.D.JowetttoG.E.Pearson,(12October1926),WF:STCS/G/49. JocelynFieldThorpe,ObituaryJ.Chem.Soc.(1941):444.
CarrwasanintimatepersonalfriendofEdwardFrankHarrisonandhedeliveredthe Harrisonlecturein1919,PharmaceuticalJournal 124(1930):45.

49
AssociationofBritishChemicalManufacturers,(ABCM)ReportoftheBritish ChemicalMissionontheChemicalFactoriesintheOccupiedAreaofGermany.(London: H.M.S.O.,1919).
323
324
50 yearsofconsolidation. BurroughsWellcomehadbeeninitiallycautiousintheir
assessmentofinsulinwhereasJowettstated:BritishDrugHousesstakedeverythingon it.Jowettrealisedthat:CarrandBDHarenowalwaysassociatedwithinsulin,and
51 BurroughsWellcomeandmyselfarewithoutrecognition. Heregrettedthatinregard
totheirpresentpositioninthepharmaceuticalandchemicalworld,BDHarelookedupon asthemostprogressiveofthefinechemicalmanufacturers(includingmedicinal chemicals).Alsofromverymanyhintsgiventome,frompersonalacquaintancesmost favourablyinclinedtothefirm,IshouldsaythatBDHlead,withBoot'srunningBurroughs

52 Wellcome&Co.aclosesecond. BurroughsWellcomehadlostgroundtoBDHon
borocaine,hexylresorcinolandthyroxin,aswellasinsulin.Inordertoavoidlagging behindinthefuture,BurroughsWellcomehadtothinknotonlyofexploitingtheirown discoveries,butalsothosemadeexternally,andinordertoachievethisclosercontactwas requiredwithexternalestablishmentsandwithclinicians. Itwillberecalledalsothat1926sawmajorupheavalsintheindustrywiththe establishmentofIGFarbenandImperialChemicalIndustries.WhenBritishDrugHouses wasestablishedasapubliclimitedcompanyinFebruary1926,theyemployed30trained chemistsandaround40pharmacistswithapayrollofover1,200andanauthorisedcapital of642,000.Thefirmproduced1millionpillsperday,threequartersofatonof ointmentsandover1,000gallonsof3,500chemicalsmonthly. BurroughsWellcomehadnotcapitalisedonitsearlylinkswithgovernmentandits uniquepositionasthefirstholderofaHomeOfficelicensetoperformbiological standardisationtests.Increasingly,thestaffoftheMRCandthePharmaceuticalSociety tookacentralroleandyettheyhadallgainedtheirexperienceatBurroughsWellcome:
53 Dale,Laidlaw,HartleyandBurn. Jowettsconcernwasthat:
50
HenrySolomonWellcomeinD.J.Jeremyetal,DictionaryofBusinessBiography V(London:Butterworths,1986).
51
H.A.D.JowetttoG.E.Pearson,Memorandumre.ScientificSocieties(12 October1926),WF:BA/S/6/49.
52
53
Ibid.
J.H.Burn,MethodsofBiologicalStandardisation (Oxford:OxfordUniversityPress, 1937).
324
325
GovernmentdepartmentsandInstitutionsarenowtakingpartwhichis likelytoextendinthecontrolofdrugsbothasregardsconditionsof manufactureandstandardsofpurityetc.andBDHaremoreintouchwith thesedepartmentsthanBurroughsWellcome&Co.54 Indeed,itwasnotonlyCarr,asF.W.GambleofAllen&Hanburyswasthefirstchairman

55 oftheWholesaleDrugTradeAssociationandwasalsowellconnected.
PostwarBurroughsWellcomelackedscientificdirectionwithHenryWellcome increasinglypreoccupiedwithcollectingartifactsinAfricaandPearson,theGeneral managerwasrenownedforpennypinching,andinthelaboratoriestheymissedthedrive ofPowerandPyman. TheSTCthereforeproposedareturntothepolicyintroducedbySilasBurroughsin

56 thefinaldecadeofthenineteenthcentury,tograntgratismaterialstoresearchers. The
directoroftheInstituteandworksmanagerwerethereforeencouragedtostimulate contactswithmedicalandalliedresearchersbyattendanceatmeetings,acceptanceof honorarydutieswithscientificsocieties,andbyprovisionofmaterialsattheirdiscretion.It washopedthatsuchapolicywouldencouragepublicationofdata,giving acknowledgementtotheWellcomeResearchInstitute,ortoBurroughsWellcomeas opposedtotheindividual.Expensestosupportthesenewactivitieswereplacedina

57 specialaccount. Insucceedingyearstheydistributedsamplesgratisof78bottlesof25
Tabloidsand22bottlesof100Tabloids.Whilstliberaldistributionalongthelinesadopted bycertaincompetitorsisnottoberecommendedwemightgivesamplesalittlemorefreely inthosecaseswherewearesatisfiedthatasubstantialdemandforthesubstancereally

58 exists.
54
H.A.D.JowetttoG.E.Pearson,Memorandumre.ScientificSocieties,(12 October1926):3.WF:BA/S/6/49.
55
GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen&Hanburysand theBritishPharmaceuticalIndustry17151990(London:Murray,1990):99,102, 157,174D.ChapmanHuston,andE.C.Cripps,ThroughaCityArchway,theStoryof Allen&Hanburys17151954(London:JohnMurray,1954):212.

56
57 58
STCMeeting,(29October1926).WF:STCS/G/49. STCMeeting,(29October1926),WF:STCS/G/49.
STCMeeting,(24May1937WF:STCS/G/49,MinutesofResearchConference,1. RawMaterialtoResearchers.
325
326
Intermsofnewdrugs,OBriennotedthatthereweretwoalternativeapproaches: thelinethathasbeenparticularlydevelopedinGermanymaybefollowed....Synthetic chemotherapyortheycouldcontinuetheirprimarilyphysiologicalapproach,itmayseem

59 wisetodeveloponeorotherorboth. InofferingthesealternativesheremindedPearson
thatinGermany: Hundredsofchemistsandphysiologicalassistantsareemployedworking underthecentraldirectionofthepharmacologist.Avastorganisationis necessary,thecastislargeandresultscannotbeexpectedwithoutyearsof work.HundredsofcompoundsweresynthesisedbeforeSalvarsanwas discovered.IrecentlysawrecordsatFrankfurtshowingthatM(eister), Lucius,Brninghadsynthesisedandtestedover2,000separatesubstances upto1924.Iwastoldthatthepharmacologistessentiallyresponsibleforthe discoveryofBayer205hadworkedfor15yearsdirectingabandofseveral 60 hundredphysiologistsandchemistsbeforethisonesuccesswasachieved. [Thus]Thereisanaturaltemptationtoinvestigatecompoundsmadebyotherchemical firmsandtotrybysubstitutiontoimproveonthem.Probablyitwillbeimpossibletoavoid
61 this.Herecommendedsyntheticsbutnotasthemaincourse. InfactBurroughs
Wellcomedidnotmaketheswitchtosyntheticsattheexpenseofbiologyandimmunology, andfoundtheyattractedadifferentkindofresearchertojointhefirmhavingthealkaloid expertThomasA.HenryatthehelmoftheWPRLprobablyinfluencedthis. Jowettwasgiventheimportanttasktoformalisetheprocedureofconsideringany newproductforresearch.Heestablishedguidelinesforthesupplyofrawvegetable, animalandmineralmaterials,thepolicyforpurchasingintermediatesormanufactured articlesandwhethersourceswerelimitedortherewereseveralsources.Hewantedto knowiftherewereanypatentsandwhoheldthem,whatwerethepossibleoutlets,disease

62 scopeandgeographicaldistributionandwhatwouldbethecostofthefinalproduct. It
wasimportantthattheseguidelineswereadheredtowhenrequestscameintoprepare smallquantitiesofanunlistedremedysothatthefirmdidnotwastetimepursuing
59
R.A.O'BrientoG.E.Pearson.PharmacologicalActivitiesoftheFoundation,(16 January1925),WF:STCS/G/49.
60
Ibid.
61
R.A.O'BrientoG.E.Pearson,re.SyntheticChemistry,STCMeeting,(16January 1925),WF:STCS/G/49.
62
STCMeeting,(19May1925),WF:STCS/G/49.
326
327
63 unprofitablelines. JowettsuggestedthattheSTCshouldbeextendedtoinclude
membersoftheworks,thegeneralmanager,publicitydepartment,andrepresentativesof
64 thesalesdepartment. Hewrotethat:
Beforeanynewsubstanceissentoutforclinicaltrialitshouldbeprepared intheExperimentaldepartmentoftheWorkswiththesameapproachto manufacturingconditions.Weshouldbepreparedforasmalldemand,ifthis 65 shouldcomealongsuddenlyasaresultofaclinicaltrial. WhilefollowingtheseprinciplesforstandardtherapiesresearchersattheWPRLcontinued tryingtoidentifynovelactiveprinciplesfromsourcesasdiverseasWandoroboarrow

66 poison.
7.4BurroughsWellcomeandVitamins:IndecisionandDecisions. DuringthenineteenthcenturymuchworkwasdoneinFranceandGermanyto identifytheessentialnutritionalelements:abalanceddietoffat,protein,carbohydrateand certainmineralswasrequired.Inpublicationsbetween1901and1912,GowlandHopkins showedthatadditionalmicroscopicamountsofaccessoryfoodfactorswererequiredand EdwardMellanby collaboratedwithhimtoshowthebenefitsofcertainfoodsinrickets. CasimirFunk,aPolishinvestigatorattheListerInstituteisolatedthecrystallinesubstance protectiveofneuritis(beriberi)andbelievingittobeanamine,coinedthetermvitamine.It wasonlyafterhiscolleagueJackDrummondrecognisedthattheseaccessoryfactorswere notaminesthatthetermwaschangedtovitaminin1920andDrummondproposednaming thevitaminsalphabetically.By1924DrummondwasatUCHandhedevelopedasteam distillationmethodtopreparevitaminAfromcodliveroil,andthefollowingyearheand Rosenheimdevelopedanassayofthevitamin,givingapurplecolourwitharsenic
67 hydrochloride.
63 64 65
66 67
STCMeeting,(3April1925),WF:STCS/G/49. H.A.D.JowetttoG.E.Pearson,(15February1925),WF:STCS/G/49. STCMeeting,(19May1925),WF:STCS/G/49. STCMeeting,(29October1926),WF:STCS/G/49.
WalterSneader,DrugDiscovery:theFoundation ofModernMedicines(London: JohnWiley,1985):227247.
327
328
Earlyin1925BurroughsWellcomebeganextractingvitamins,thoughtheydecided nottodoanyspecificworkonpreparingtheantiscorbitic(vitaminC)andantineuritic (vitaminA)principlesanddidnotseemtohaveaclearstrategy,oftenfollowingtheleadof otherfirmsorexternalinvestigators.TheyassessedDrummondsprocessofpreparing

68 concentratedvitaminAfromirradiatedcholesterol,butwerenotsuccessful. Lees
analysedextracts,whileTrevanarrangedtrials,keepingsamplestoobservehowmuch
69 deterioratedonstorage. BurroughsWellcomerespondedpositivelytoarequestfora
vitaminAconcentratetobeadministeredwithsodiummorrhuatefortreatingtuberculosis, afterresearchersinJapanandAmericahadshownbenefitsofthecombination,andseveral otherfirmswereinterestedin sodiumandethylmorrhuate.BurroughsWellcomethen heardsecondhandthatoneoftheclinicianstestingethylmorrhuateintuberculosishad addedGlaxo'sVitaminAtoproducegoodresults,andwasconsideringapublicationinthe

70 BritishMedicalJournal,sotheypreparedasupplyincaseademandensued.
WhenvitaminAwaspreparedtheywereleftwiththerestofthecodliveroil
71 startingmaterialandsoughtwaysofutilisingthis. BurroughsWellcomenotedthatGlaxo 72 addedvitaminstotheirmilkproducts. TheyanalysedsuppliesofOstelin,producedby
GlaxoforvitaminAandDcontent,sotheycouldchallengetheclaimsmadebyGlaxoand
73 gainacompetitiveadvantage. However,theBurroughsWellcomeextractsalsodidnot 74 containappreciableVitaminA. After1925whenMcCollumshowedthatvitaminD
deficiencywasthecauseofrickets,HarriettChickattheListerInstituteshowedthat
68
SirJackDrummond,ProfessorofBiochemistryatUniversityCollegehospitalwasan expertinthisfieldandbecameScientificadvisortotheMinistryofFoodduringtheSecond War:F.G.Young,JackCecilDrummondObituaryNoticesofFellowsoftheRoyal Society 9(1954):99129J.C.Drummond,A.F.Watson,TheHistoryofFoodstuffs forVitaminsChemist&Druggist95.2(12November1921).

69 70
71 72
STCMeetings,(13February1925and3April1925),WF:STCS/G/49. T.A.Henry,STCMeeting,(8May1925),WF:STCS/G/49. STCMeeting,(20January1925),WF:STCS/G/49.
R.P.T.DavenportHines,andJudySlinn,Glaxo:AHistoryto1962(Cambridge: CambridgeUniversityPress,1992):6897.
73 74
STCMeeting,(21October1925),WF:STCS/G/49. STCMeetings,(2February1926),WF:STCS/G/49.
328
329
childrenwerecuredbyexposuretoultravioletlightanddoctorsinNewYorkfoundthat irradiationoffoodsincreasedvitaminDathousandfold,butbeforetheypublishedtheir findings,HarrySteenbockofWisconsinUniversitytookoutpatentsontheirradiation process,whileBurroughsWellcomecontinuedtousethesteamdistillationprocesson

75 importedScandinavian fishoils. BurroughsWellcomeeventuallyalsodecidedtoprepare
andmarkettwoconcentratedpreparations,RadiomaltandOscodalandmonthly
76 propagandawassenttotherepresentatives. Herringanddugongoilsweretestedas 77 alternativesourcesandfoundtobebetterthanthecodoilsusedforGlaxo'sOstelin.
However,itwasnotlongbeforeBurroughsWellcomedecidedtostopworkon concentratesandturnedtheirattentiontotheirassays.Theyfacedadilemmainmaking concentratedvitaminpreparations:BurroughsWellcomecouldnotwiththeknowledgeat theirdisposal,takepartintheextravagantclaimforconcentratedpreparationsnowbeing

78 madeinvariousquarters. BritishDrugHousesandGlaxohadgreatersuccessthan
BurroughsWellcomewiththeproductionofVitaminDastheytookuplicensestothe
79 Steenbockpatents. BritishDrugHouseswerecompetinginthisareaaswellandtheir
vitaminApreparationwasissuedasavoleumandtheirmaterialwassaidtobefreeof vitaminDasithadbeentestedbyCarrsnewcolorimetrictest,sothatthepreparationwill facilitateclinicalexaminationofthetherapeuticpropertiesofvitaminA.Onceagain BurroughsWellcomeweretwostepsbehind,butin1927thepreirradiationsubstancewas characterisedinGermanyasanalreadyknownproduct,ergosterol. Havingdecidedthatitwasdifficulttomakeconcentratedvitaminpreparations, BurroughsWellcomesoondoubtedthattheyhadmadethecorrectdecisiontheywere certainthatiftheydidnotmarketconcentrates,otherslessscrupulouswoulddoso,despite theirversionscontaininglittleinthewayofvitamins.JowettnotifiedO'BrienoftheBDH interestinaconcentratedpreparationcombiningbothvitaminsAandDnotingthat:there willprobablybearealdemand.TheyhadalsonotedRosenheim'sletterin Natureand
75 76 77
78 79
C.M.WenyontoG.E.Pearson,(17February1926),WF:STCS/G/49. STCMeeting,(25February1926),WF:STCS/G/49. STCMeeting,(29October1926),WF:STCS/G/49. STCMeeting,(25February1926),WF:STCS/G/49. R.P.T.DavenportHinesandJ.Slinn,(1992):6978,240.
329
330
80 attemptedhisextractionofoilfromcowliver. Byearly1928,thedecisionshadbeen
reversedagain.TheSTCdecidedtogoaheadwiththeconcentrationofvitaminsA,Band C.TrevanhadbeenconsultingwidelywithcliniciansinOxfordandwithSirCharlesMartin attheListerInstitute,andsuppliesofvitaminsBandCweretestedinanewanalytical

81 laboratory,organisedbyJowettatDartford. InadditiontheExperimental department 82 begantoinvestigatetheuseofmarmiteoryeastasasourceofvitaminB.
Codliveroilwasadvertisedascontainingnotonlyvitamins,butalso9598%fat, providingnourishment,andasthefatwasmostlyunsaturated,itwasbetterabsorbed. Malt extractwassaidtoprotectagainstoxidationduringextractionandtheproductwas97.7% digestible.Representativesweretoldtomakenoreferencestothegeographicoriginofthe preparations,buttoemphasisethetransparency,lackofodourandtaste.VitaminA concentrateandvitaminD,madeartificiallybyirradiationwereaddedtoarangeof BurroughsWellcomeproductsandthevitamincontentwasguaranteed. Inordertoensurethedemandwasnotseasonal,thestrategywastoemphasisethe needinspringtocounterthelowsunlevels,insummertocounteroverexertion(vitaminB
83 fortifies),inautumntobuilduplevelsandinwintertoprovidetheequivalentofsunshine.
Jowettpreparedamemooutliningthescientificrationalebehindtheworkon
84 vitamins,whichwastobethebasisofasalescampaign. VitaminBwaspreparedfrom
ricepolishingsandvitaminCfromorangejuice.TheoldKeplermaltandoilproducthadits vitaminAcontentincreasedtenfoldasassayedbytheDrummondRosenheimcolourtest anditsvitaminDincreasedbyirradiationofergosterol.Boots,andBDHalsopresented irradiatedvitaminpreparationsRadiostol,RadiostoleumandRadiomaltattheBritish

85 IndustriesFairin1930.
80 81 82
STCMeeting,(11October1927),WF:STCS/G/49. STCMeeting,(8February1928),WF:STCS/G/49.
G.E.PearsontoC.M.Wenyon,(5November1926,20February1928),WF:STC S/G/49.
83
STCMeeting,(31May1928),WF:STCS/G/49. STCMeeting,(6June1928),WF:STCS/G/49. TheBritishIndustriesFairPharmaceuticalJournal 124(22February1930):201.
84
85
330
331
Despitetheexternalsupportfortheproducts,thereremainedafeelingwithin BurroughsWellcomethatvitaminconcentrateswerenotnecessarilybeneficial.VitaminC
86 didnotkeepandtherewasnoreasontoanticipatealargeclinicaldemand.
87 Neverthelesstheconceptofgivingvitaminsfordeficiencydiseaseswaswellestablished.
Theproblemwasthatthepreparationshadlimitedandvariablevitamincontent.Petershad providedamethodologytopreparevitaminB,butBurroughsWellcomefoundthistobe
88 inactive. Inordertoevaluatetheneedforapreparation,travelerswereaskedtofindthe 89 demandfrominstitutesofTropicalMedicineinIndia,AssamandMalay. VitaminB1was
preparedattheTuckahoesiteuntilaBayerprocesspatentwasdescribedforthesynthesis. In1929otherfishliverswerefoundtobebetterthanpreviousversionsandParkeDavis& Co.madeapreparationfromhalibutliver. WorkonvitaminscontinuedthroughouttheinterwarperioduntilVitaminEofa satisfactoryconcentrationwasmadeatDartfordin1939andpassedtotheWorks.The initialaimwasToissuewithnoncommittaladvertisingliteratureastheclinicalvalueof

90 vitaminEconcentratehasnotbeenfinallyestablished. SubsequentlyHoffmannlaRoche
putonthemarketasyntheticproduct,EphynalleavingBurroughsWellcomewiththe dilemmaofwhethertomarkettheconcentrateorarrangeissueofasyntheticversion.The viewoftheSTCwasthatthesyntheticsubstancepossessedsomanyadvantagesoverthe naturalconcentratebuttheylearnedfromRochethatthemanufacturewasstill experimentalinBaselsotheydecidedtoawaitasurplusclinicalsupply.
7.5ClinicalTrialsArrangedbyBurroughsWellcome.
86
87
STCMeeting,(6June1928),WF:STCS/G/49. F.G.Hopkins,Lancet (1March1919):363. STCMeeting,(5October1928),WF:STCS/G/49. STCMeeting,(8February1929),WF:STCS/G/49. STCMeeting,(24March1939),WF:STCS/G/49.
88 89
90
331
332
WorkingwiththeMRConinsulinhadnothelpedfirmstoestablishaclinicaltrial processfortheirnewdrugs,andtheissueseemstohaveresurfacedassoonastheinsulin developmentreacheditsconclusion.ManyoftheBurroughsWellcomeapproaches producednovelchemicalsnotpreviouslygiventopatients,soakeyproblemwashowto getthemtestedinclinicaltrials.Theyarrangedtheirownclinicaltrialswheneverpossible, suchaswiththearsenical,Stovarsol.Dr.Lees,attheWPRL,performedstudiesofa

91 combinationofbismuthandanarsenicalinpreparationforclinicaltrials. However,when
theWPRLstafftriedtoarrangeclinicaltestsofpromisingnewagentswithexternal physicians,theymetwithmanydifficulties. TheysetuptrialsofIodicinwithDr.CohenofLiverpoolUniversity(thefuture

92 LordCohenofBirkenhead) :butitistoomuchtoexpectthathewillspendmuchtime
uponit.Wecollectinthecourseoftime,andbypainfullyslowdegreesclinicalevidenceof
93 thevalueofIodicin. Andyetwhenarepresentativewasaskedaboutalternativemeans
ofadministeringIodicinandwhetheritwasfoundsubsequentlyintheurine,afurtherstudy
94 wasarrangedwithCohen,asthereseemedtobenoalternativetrialists. Thebestchance
ofhavingclinicaltrialsdonewasasaresultofanongoingcollaborationinbasicresearch. Dr.E.CharlesDoddshadalreadyparticipatedintrialsofinsulin.In1925hedescribednew methodsofstudyingtheeffectsofBurroughsWellcomeshormonalextractsdirectlyon uterinecells.At25,hewastheyoungestProfessorinLondon,attheMiddlesexHospital

95 andwewillseefurthercollaborationswithhiminchapter8.
91
92
STCMeetings,(21October1925and29October1926),WF:STCS/G/49.
G.Ansell,Obituary,LordCohenofBirkenheadClin.Radiology (July1978)29(4): 370N.Poynter,LordCohenofBirkenhead(19001977)Med.Hist.22(1)(January 1978):901 J.AmericanMedicalAssoc.238(10October1977):1672 BritishMedical Journal (20August1977):525 Lancet(20August1977):4134TheLiverpoolof HygieneanditsPhysiciansMedHist.(16October1972):31020.
93
CY(arepresentative)toBurroughsWellcome,(15July1925),discussedatSTC meetingon23February1926,WF:STCS/G/49.
94 95
STCMeeting,(23February1926),WF:STCS/G/49.
R.O'BrientoG.Pearson,(24June1925),WF:STCS/G/49F.Dickens,Edward CharlesDoddsBiographicalMemoirsofFellowsoftheRoyalSociety 21(1975):227 267.
332
333
ByNovember1926thesameproducts,producedbyU.S.firmsappeared.Trevan analysedtheSwiss(CIBA)andAmericanversionsofovarianextractsattheWPRL. Becausetheformerwasinactive,BurroughsWellcomeplannedtocontacttheMRCto

96 complainthattheoriginalpatenteecouldnotmakeit. TrevanfoundfromDoddsthatthe
activeprinciple,Oestrone,whichhehadisolated,hadfirstbeendescribedinGermanyin 1915. HealsodiscoveredthatotherLondonfirmshadalreadybegunworkingonthis problem.OBrientoldPearsonthatheintendedtovisitseveralmedicalconferencesin Londonwiththeaimofdiscussingovarianandparathyroidhormonepreparationsandthe newmethodsoftestingthem.WhenTrevanandJowettnextmetwithDodds,herequested hundredweightquantitiesofthehormonalpreparation,whichhethentestedforBurroughs Wellcomeinpatients.Howeverinthiscase,BurroughsWellcomewasslowindeveloping thepreparationwhentheyhadanofferofclinicaltrials. BurroughsWellcomemanagedtogetanalgesicsandantisepticstestedbyDr.E.A.
97 McMahanattheRoyalInfirmaryinEdinburgh. YetwhenTrevanarrangedastudyof
benzoylephedrineasalocalanaestheticatGuy'sHospital,hefailedtoreceiveasingle
98 report. Somesmallstudiesgaveresultsthatdidnotsupporttheintendeduseofnovel
medicines.HenryarrangedastudyofascaridoleinchildreninDarlingtonbutitwas
99 unsuccessfuldespitetheparentchenopodiumoil(oilofAmericanwormseed) beingused
successfullyinGermanyandtheUnitedStates,andappearingtoworkwellinanimal experimentsperformedbyDr.LaidlawatMillHill.Furtherstudiesindogswereplanned
100 byOBrienatBeckenhamtoresolvethisandthedatawaseventuallypublished. When
plansfortheTherapeuticTrialsCommitteewerefinallyannounced,membersoftheSTC metanddiscussedwhichoftheirproductswouldbeforwardedandtheoutcomeofthese deliberationswill bediscussedinthenextchapter.Itwasrecommendedthatthe
96 97 98
99
R.O'BrientoH.A.D.Jowett,(26May1925),WF:STCS/G/49. STCMeeting,(28October1926),WF:STCS/G/49. STCMeeting,(5November1926),WF:STCS/G/49.
ChenopodiumoilaslistedintheB.P.of1948wasanoildistillate,whichhadto containatleast65%w/vofascaridole,BritishPharmacopoeia(London:Constable,1948): 3723.

100
ChemistryandIndustry (29October1926):803.
333
334
ChemotherapyCommittee(sic)beaskedtoundertakeaclinicalcomparisonofthevarious puredigitalisglycosidesavailableatDartford,andTrevanwantedtoinvestigatetheuseof ascaridoleasageneralantihelminticinchildren.Theyweretobealsoofferedsuppliesof harmineforpostencephalitis.TheSTCsuggestedthatinfuturefurthersubstancesmight besentfortrialsuchasouabainandconcentratedoilyorestersolutionsofavenyl orneo avenyl,bothantisyphilitics.Fullreportsofergotoxineethanesulphonate,digoxinand

101 digitalinumverumweresenttotheABCMfortheTTC. Thustheproposed
establishmentoftheTTCofferedthechanceforBurroughsWellcometoreevaluatetheir policiesofcollaboratingwithexternalagencies.Indoingsotheywereclearthatthiswas onlyappropriateinordertosecureclinicaltrials,whichhadbeentheirmajorfailingsince 1921. 7.6TropicalDiseasesaCaseStudyfromLaboratorytoClinic. TheMRCandBurroughsWellcomehadacommoninterestinthesupportof TropicalMedicine.HenryWellcomehadestablishedTheWellcomeTropicalLaboratories inSudanin1902,whiletheMRCsupportedresearchintropicalmedicineatLiverpooland

102 attheLondonSchoolofTropicalMedicine. Theselinkswerecementedfurtherwhen
SirAndrewBalfourleftBurroughsWellcomein1923tobecomeDirectoroftheLondon SchoolofHygieneandTropicalMedicinewhenitwasformallyestablishedthefollowing
103 year. In 1924themuchtraveledCharlesMorleyWenyonsucceededBalfourasDirector
inChiefoftheWBSRandcontinuedtoreceivevisitorsfromallovertheworldashe maintainedanindependentresearchphilosophywithouttheencroachmentofbusiness interests. WenyonservedonvariouscommitteesincludingtheRoyalSocietyandthe TropicalResearchCommitteeoftheMRCandtheColonialMedicineResearchCommittee
101 102
STCMeeting,(27March1931),WF:STCS/G/49.
E.B.Worthington,ScienceinAfrica:aReviewofScientificResearchRelatingto TropicalandSouthernAfrica(London:OxfordUniversityPress,1938):4639M. Worboys,ScienceandBritishColonialImperialism,18951940(UniversityofSussex, D.Philthesis,1979)D.Fisher,RockefellerPhilanthropyandtheBritishEmpireandthe CreationoftheLSHTMHistoryofEducation 7(1978):129143.

103
A.Balfour,ObituaryBritishMedicalJournal (7February1931):2456H.Parrish, TheWellcomeResearchLabsandImmunology,WF:85:20/2LondonSchoolof HygieneandTropicalMedicine:aChildofmyParentsMed.Hist.35(91)385408.
334
335
thatwassetupin1926betweentheMRCandColonialOffice,immediatelyfollowingthe
104 ImperialConference.
OneoftheconcernsoftheColonialOfficewasthereemergenceofGermanyasa forceinpharmaceuticals,andaspecialconcernwastheprogressmadebyGermanyin developingdrugsfortropicalinfectiousdiseases.Bayer205ortryparsamidewasaspecific therapyfortreatingtrypanosomalinfections.JustasBritainhadreliedonGermanyfor antiseptics,anaesthetics,painkillersandSalvarsaninthe1914,apotentialconcernwasthe reliancenowonGermanyforantimalarialsshouldsuchapoliticalsituationariseagain. WhentheSTCwasestablishedin1925therewerealreadysomeTropical Medicinesonclinicaltrial,mostlyoverseas.HenrypointedouttotheDSIRthat BurroughsWellcomewasalreadycollaboratingwiththeschoolsofTropicalMedicinein EnglandandIndia,withthemedicaldepartmentofBristolUniversity,andwithother
105 medicinalinstitutesinBritain,China,BrazilandFormosa. Theworkonantimalarial
drugsisagoodexampleofthecommitmentofBurroughsWellcometoproducenovel chemicals,toevaluatethemextensivelyinanimaltestsandtotesttheminclinicaltrials, beingpreparedtomodifytheproductsifresultswerenotasdesired.Fortwoyears stibamineglucoside,(Stibosan)anorganicantimonialunderwentclinical trialswithvery successfulresultsinkalaazar,acommonformofleishmaniasis,adiseasewhichaffects millionsofchildren,whichpreviouslyhadamortalityof70%.Beforeitwasgivento patients,thedrugwastestedfor6monthsinhamstersinfectedwithkalaazar.

106 Neverthelesssomebatchesstillfailedfurthertoxicitytestsinmice. Theresultsof
treatingkalaazarwithStibosanwerecomparedagainstthoseofNeostam(stibamine
107 glucoside). BurroughsWellcomeremainedcautiouswhiletheystillregardedthedrug
104
C.A.Hoare,CharlesMorleyWenyonObituaryNoticesofFellowsoftheRoyal Society 6(1949):62742.

105
106
T.A.HenrytoA.W.Crossley,(7July1925),WF:STCS/G/49.
STCMeetings,(13February1925,21October192525February192623March 1928)WF:STCS/G/49.
107
IndustrialJournalofMedicalResearch 14(1926):263(21October1925,and5 November1926),WF:STCS/G/49.
335
336
108 asundertrial. Beforeitsreleaseitwastestedinthousandsofmiceandbatcheswere
onlyreleasediftheypassedtestsonatleast120mice.Wenyonestablishedfurthertrialsof stibamineglucosidefortreatingworminfestationsandlymphogranulomatousdiseaseand forsleepingsicknessinCairoandNatal,severalcentresinIndiaandintheBelgianCongo

109 butthetolerateddosenobetterthantheoldtartaremetic. Anotherantimonialreferred
toasSb150/136wassenttothesameclinicinNatalandtotwofurthercentresinSouth
112 110 111 Africatotreatbilharzias. NeilHamiltonFairley testeditinschistosomiasis, and
113 Wenyondiscussedtheresultsofanimaltestswithafurtherstibonatederivative. Dr.G.
CarmichaelLowofUniversityCollegeHospital,Londonpublishedafavourableaccountof stibamineandasaresultBurroughsWellcomebeganadvertisingandmadestrenuous
114 effortstogetaproductoflowtoxicity.
Neostamwasdifficulttomanufacture,butJowettmadeenoughtosupplyDr.
115 EdwardHindleofthekalaazarcommittee. By1928thereweresufficientstocksto 116 advertisetheproduct. Still,therewereoccasionalunexpectedfailuresofabatchin 117 toxicitytests. Eventuallytheproblemsbecametoomuchanditwasdecidednotto
renewthepatentofNeostam.ThoughthereremainedademandfromIndiaandChina,
108
Leonard.G.Goodwin,Pentostam(sodiumstibogluconate)a50YearPersonal ReminiscenceTrans.Soc.Trop.Med.Hyg.89.3(MayJune1995):33941.Goodwin joinedtheWellcomelaboratoriesin1939andbecameDirectoroftheTropicalLaboratory from195863.

109
Tartaremeticorantimonypotassiumtartratehadbeenusedsince1906.Itwasvery effectivewhengivenintravenouslybutcouldalsobehighlytoxic.STCMeetings,(2 February1926),(28October1926),(24May1934)and(7October19),WF:STC S/G/49.

110 111
STCMeeting,(25May1934),WF:STCS/G/49.
SirJohnBoyd,NeilHamiltonFairleyBiographicalMemoirsofFellowsofthe RoyalSociety 12(1966):123145.

112
113
STCMeeting,(21October1925and29October1926)WF:STCS/G/49. STCMeetings,(12July1935and13March1936),WF:STCS/G/49. STCMeeting,(25February1926),WF:STCS/G/49. STCMeeting,(31May1927),WF:STCS/G/49. STCMeeting,(20February1928),WF:STCS/G/49. STCMeeting,(23March1928),WF:STCS/G/49.
114 115 116 117
336
337
salesweresmalldespitesomefavourableclinicalreports.Initsplacethefirmbegantotest
118 Brahmachari'sureastibamine andvonHeydensneostibosanfrom India,neitherofwhich
119 wereavailableinEurope.
Despiteitsproblems,TrevanwasstilltestingNeostamin1936whenheevaluated
120 itsstabilityinsolution. Itwasthentestedinanewform,forlightandtemperature 121 stabilityandsamplesweresenttoChinaforevaluation. Neostamformulatedwith
glucosewaslesstoxic,butthenBurroughsWellcomebecameawareofanewGerman
122 preparation,Bayer561thatthreatenedtocompete. Muchoftherenewedinterestin
tropicalmedicinecamefrom theGermandemonstrationoftheactivityofBayer205in trypanosomalinfectionsWenyonarrangedfortryparsamideorBayer205tobetested

123 withinBurroughsWellcome. MorganattheDSIRevaluatedarylthioarsinitesand
alliedarsenocompoundsfortrypanosomiasisattheChemicalResearchLaboratoriesanda seriesofarsonicacidswereevaluatedincollaborationwithWarringtonYorkeinLiverpool andwithProf.RobertRobinson.In1937Trevanreexaminedsomearylguanidinesfor trypanocidalactivity,havingpreviouslyevaluatedthemin19267.Smithmetwith

124 representativesoftheABCMtoarrangeforatrial.
Becausedrugsbaseduponantimonywereeffective,aDrMuiralsoevaluatedtwo
125 newdrugsbasedonmercuryforleprosyinCalcutta,India. Havingcompletedone
leprosystudy,MuiraskedBurroughsWellcomeforasupplyofDr.BlairBellslead
118
U.N.BrahmachariChemotherapyofAntimonialCompoundsinKalaazar InfectionpartIVFurtherObservationsontheTherapeuticValuesofUreaStibamine (1922),IndianJMedRes.(January1989)89:393404STCMeeting,(2February1926) WF:STCS/G/49.

119
120 121 122 123
STCMeeting,(8May1929),WF:STCS/G/49. STCMeeting,(29May1936),WF:STCS/G/49. STCMeeting,(22January1937),WF:STCS/G/49. STCMeeting,(19November1937),WF:STCS/G/49.
C.M.WenyontoG.E.Pearson,(17February1926),WF:STCS/G/49Dr.Dressel andBayer205,LaboratoryNotesetc.19141923,WellcomeInstitute,GC/62 British MedicalJournal (16July1923):87TryparsamidewasavailablefromtheRockefeller Instituteforlicensing,WF:STCS/G/49,(23February1926).

124
STCMeeting,(13May1938),WF:STCS/G/49. STCMeeting,(2February1926),WF:STCS/G/49.
125
337
338
preparationorcolloidalleadwiththeunderstandingthattheriskoftakingitwastobehis ownresponsibility,andtheSTCsuggestedthathebeofferedsomeofthegoldcompound, sanochrysinfortrial,andlatercopperderivativesincludingcopperglycine,sodiumcopper

126 127 citrate,potassiumcoppercyanide,neoavenyland theraremetal,Tellurium. Having
foundawillingtrialistBurroughsWellcomewereclearlykeentouseMuirtothefull.The newbenzoylatedcocaineanaestheticderivativesandorganicmercurialsweretestedin
128 syphilis,tuberculosisandleprosy. AttheSTCmeetingon12July1935Henryraisedthe
questionoftestingmethyleneblueandalsovitaminproductsforleprosy. Drugsprovidedforuseintropicalclimatesweretestedforstabilityatahigher
129 temperature,aswhenTrevansentephedrinetoIndiaandBaghdad. Trevanalsotested
theeffectsofkeepingneoavenyloveralongperiod.TheWCRLalsoevaluatedmaterials sentbackfromtheTropicssuchasAlstoniacongensisbarkreceivedfromtheGovernment ofUgandathroughtheImperialInstituteformalaria.Thereweresomanypossibilitiesthat BurroughsWellcomedidnothaveenoughfacilitiestoperformchemistryworkonthe

130 antimalarialstheywishedtotest. However,throughtheirendeavoursintropical
medicine,BurroughsWellcomecircumventedmanyoftheproblemsofhavingdrugstested clinicallyinBritain. ThefirmshowedparticularinterestinantimalarialsfollowingthesuccessthatBayer hadwithAtebrin(mepacrine)discoveredin1930.Previouslytherehadbeenlimited successwithantimalarials,theonlysyntheticstoshowpromisebeingmethyleneblueand arsphenamine,neitherofwhichwereasactiveasnaturalquinine.WilliamRoehlofBayer developedtechniquesfortestingpotentialdrugsincanariesandininsanepatients. Promisingleadswerechemicallymodifieduntilaftertestingseveralhundredcompounds, plasmoquinewastestedclinicallyandmarketed,whenitwasshownthatitactedina differentwaytoquinineandimprovedtheefficacyofthelatterwhengivenin
126
127 128
STCMeeting,(5November1926),WF:STCS/G/49. STCMeeting,(18February1938),WF:STCS/G/49. STCMeeting,(20January1925),WF:STCS/G/49. STCMeeting,(29October1926),WF:STCS/G/49. STCMeeting,(5November1926),WF:STCS/G/49.
129
130
338
339
131 combination. Dr.GreenofMalayasuggestedthatBurroughsWellcomeshouldpreparea 132 TabloidformofBayers(IGFarben)promisingAtebrin.
TheMRCandDSIRbeganresearchonantimalarialsin1929andBargerin EdinburghandRobertRobinsonatUCHelucidatedthestructureofPlasmoquinebeforeIG Farbenpublishedit.Robinsonhadalreadysynthesizedharminein1927.Nothingcame directlyfromtheearlyantimalarialworkin1929despitethesynthesisof120compounds, andindeeditwasBayerwhodiscoveredfurtherantimalarials,themostactiveofwhichwas mepacrineorAtebrin,onwhichpublicationsappearedfrom1931.TheSecretaryofthe ChemotherapyCommitteetoldThomasHenrythattheMRCproposedconcentratingthe testingofantimalarialsinCambridgewithDr.Keilin,theDavidQuickProfessorofBiology

133 attheMoltenoInstituteinCambridge. WenyondiscussedclinicaltestswithCol.James,
whohadfirsttestedharmineandharmalineandfoundthemuselesshethenevaluated
134 hydroquinine.
From1931newmedicinessuitablefortestingwithinBritainwerediscussedwiththe TTC,althoughonlytropicalmedicines,beyond1931havebeendescribedinthissection. ThemostimportantchemotherapeuticsdevelopedinBritainwerethesulphonamides thesearediscussedinthenextchapter. OverthenextseveralyearsBurroughsWellcomecollaboratedwithseveralexternal scientiststotrytodevelopantimalarialsandothertropicalmedicinestoavoidfurther relianceonGermany.HoweverinMay1934theyresolvednottodoanyfurtherworkon

135 alreadypatentedcompoundssuchasAtebrin andPlasmoquin. AttheNIMR,Harold
Kingperformedteststoestablishchemicallywhyquinineandothercinchonaalkaloidswere
131 132 133
W.Sneader,(1985):26875. STCMeeting,(14Feb1934),WF:STCS/G/49.
MarkW.Weatherall,Gentlemen,Scientists,andDoctors:MedicineatCambridge 18001940(Cambridge:BoydellPress,2000).
134
135
STCMeeting,(28March1930),WF:STCS/G/49. STCMeeting,(19May1934),WF:STCS/G/49.
339
340
136 antimalarial. Ethylapoquinineandapoquinineandchinchonaalkaloidswereexaminedat 137 theWCRLandWPRLandinclinicaltrials.
IodoBismutideofquininewasconsideredforAustraliawheredemandforbismuth metalpreparationswasdecreasing.Thisnewproductcouldbegivenlongtermwithout
138 stomatitisandtheWassermanntestwasnegativeearlier. HenryaskedTrevanfor
referencesontheactionofdihydroquinine,dihydroquinidine,andepiquinineinorderto contacttheTherapeuticTrialsCommitteeabouttrials.Prof.RobertRobinsonmovedtothe DysonPerrinslaboratoryinOxfordin1930andpreparedfurtheranaloguesofPlasmoquine andAtebrin.C.H.BrowningandcolleaguesinGlasgowandDrE.E.TurneratBedford CollegeforWomenpreparedfurtherantimalarials. BothquinidinesulphateanddihydroquinidinesulphateweresenttoDrWaynein SheffieldfortestingaDutchgrouphadshownthatitwasimpuritiesofthelatterthatwere active.HenryfeltthatDutchevidenceshouldprovideasufficientfoundationinthiscase

139 forBurroughsWellcometoproceedwithoutwaitingfortrialsbytheTTC.
Itshouldbeclearfromthepreviousaccountthatfromtheendoftheinsulinwork untiltheoutbreakoftheSecondWar,BurroughsWellcomehadawiderangeofproducts indevelopment.TheSTCcontinuedtodebatewhethertoremainaUniversalprovider, orwhethertoconcentrateonsynthetics,biologicals,vitaminsortropicalmedicine. Probablythescaleoftheirdevelopmentworkhasbeenpreviouslyunderestimated becausemanyoftheirdrugswereaimedattropicalmedicine,orwerehormonalorvitamin preparationsthathavesincebeenreplaced.Ihavetriedtoshowhowtheclinicians,Trevan andWenyontookaleadroleinestablishingclinicaltests,thoughwithlimitedsuccessinthe UKuntiltheTTCwasestablished.CollaborationswiththeChemotherapyCommitteewere moresuccessfulbutprimarilyregardingoverseasstudiesintropicaldiseases.
136 137
SirCharlesHarrington,HaroldKing(1956):161.
J.A.Goodson,T.A.Henry,J.W.S.MacFie,TheActionoftheChinchonaand CertainOtherAlkaloidsinBirdMalariaBiochemicalJournal (1930):87490STC Meeting,(13March1936),WF:STCS/G/49.

138 139
STCMeeting,(28May1936),WF:STCS/G/49. STCMeeting,(19November1937),WF:STCS/G/49.
340
341
BurroughsWellcomecontinuedtoreleaseastreamofnewproductsfromthe establishmentoftheSTCuntiltheoutbreakofWorldWarTwo.Atotalof62separate productlaunchestookplaceintheperiod1925to1939thoughfewofthesewere synthetics.Theseincludedvariousformulationsofinsulin,hormoneextracts,purified vitamins,andinorganicpreparations,togetherwithpurifiedalkaloids Atthestartof1937therewasanimportantrequesttoBurroughsWellcomefrom theWarOfficeforalistofpossibleBritishsubstitutesforforeignsyntheticdrugs.The Governmenthadclearlylearnedalessonfromtheproblemsfacedattheoutbreakofthe FirstWorldWarandweremakingearlypreparationsincaseoffurtherhostilities. BurroughsWellcomereviewedthelistattheSTCof22January1937andbrokethelist
140 intoclassesofdrugsandtheequivalentthatBurroughsWellcomecouldoffer.
ThegovernmentwasinterestedinanalepticsofwhichBurroughsWellcomecould supplyCoramineandIcoralLocalanaesthetics(Percaine):Pyelographicsubstances(Per abrodiHypnotics(EvipanNa,Avertin,PentothalNa)Antimalarials(Atebrinand Plasmoquine).Researchwasongoingfornewanaleptics,hypnoticsandantimalarials thoughitwasnotpossibletosaythattheycouldpreparecommerciallypracticable substitutes.Theycommentedthat:alldrugsinthelistarepatentedandmanufacturewould nodoubtbetakenupiflicensestomanufacturecouldbesecuredbynegotiation,withthe patenteesorifpatenteeswerecompelledbyappropriatelegislationtograntlicenses.Sucha procedurewouldprobablybetooslowtobeuseful.Theymadeitclearhoweverthatitwas mostdesirablethatintheeventofWar,manufacturersshouldhavehadexperienceinthe productionofessentialdrugs,whichareatpresentimported.ItseemedclearthattheWar OfficewouldprefertodealwithasingleorganisationinthismatterandtheCommittee (STC)areoftheopinionthatMessrs.B.Wellcome&Co.mightsuggestthattheWar OfficeshouldprovideatonceashadowfactoryatDartfordwithasmallstaffofchemists toworkoutalltheprocessesforthemanufacture.BurroughsWellcomefurthersuggested thatifthiswasnotacceptable,theNationalChemicalLaboratoryatTeddingtonengagedin longtermresearch,wasthereforetechnicallycapableandcouldbeplacedatthedisposalof manufacturersthroughtheABCM.Thiswasadevelopmentofaprocedurealreadyputin operationforanentirelynewdrugrecentlydiscovered.Eitherwouldbequickerthanathird
140
STCMeeting,(22January1937),WF:STCS/G/49.
341
342
alternativewhichwouldbemorecomprehensive.Severalofficialorganisationsarealready concernedwiththismatterviz.theMRC,theTTC,theChemotherapysectionofthe NationalChemicalLaboratoryatTeddington.Thesethreebodiesmightinconsultation decidewhatimporteddrugsarereallyessential,notonlyfortheWarOffice,butforthe countryasawhole.Whenthispreliminaryworkhasbeendoneconsultationsmightbe extendedtotheABCMtodecidehowmanufactureoftheseessentialdrugscouldbestbe

141 undertaken. TheWarOfficerepliedthatPentothalcouldprobablybesuppliedbyBDH.
AttheSTCof29September1939,theSTCconsideredthelistof40Germandrugs
142 anddecidedwhichtoconcentrateonwithaviewtomanufactureoverthenext3months. 143 Therewerealsosomethatwerenotconsideredworthmanufacturing.
Regardingantimalarials,AtebrinwastobelefttoICIbutPlasmoquinetocouldbemadeif suppliesof8aminoquinolinewereavailableandsomedrugswouldonlybeattemptedif rawmaterialscouldbeobtained.Ephedrinecouldbemadesyntheticallyifthenaturalbase wasobtainableoritcouldbefermentedwithexternalhelp.Phenothiazinecouldbemadeif supplieswereavailablefromICI.PhaodormandUroselectanneededfurtherworkatthe WCRLandBurroughsWellcomeplannedtospeaktoCoreyMannregardingpreparation ofSolganolB. Robinsoncollaboratedwithseveralpharmaceuticalfirms,havingjoinedtheICI

144 researchcouncilasearlyas1927. HeworkedonantimalarialswithPymanofBootsin
theleaduptotheWarandcollaboratedwithHoffmanlaRocheandSandoz,andwith
141
C.M.WenyontoAMD3,WarOffice,STCMeeting,(9February1937),WF:STC S/G/49.
142
Thesewereadrenaline,arecoline,Atebrin,Avertin,cardiazole,Doryl (carbaminoylcholinechlorideorintermediatestoprepareit),Epanutin,Ephedrine synthetic,Eumydrine,Evipan,Fouadin,Hepaprin,Neostibosan,Pantocaine(Decicaine), Phanodorm,phenobarbitone,phenothiazine,Plasmoquine,progesterone,Prominal, Solganol,SolganolB,Solustibosan,Tutocaine,Uroselectan,STCMeeting,(29September 1939),WF:STCS/G/49.

143
Adalin(carbromaliumBP),ascorbicacid,Butolan,Icoral,Lopion,Moogroliodinised, Oestrodiol,Oestrone,Pentothal(Abbott),Perabrodil,Rivanol,Surfen,Zephiran,ibid.
144
TrevorIWilliams,RobertRobinson,ChemistExtraordinary (Oxford:Clarendon Press,1990):956,1045.RobinsoncontinuedtoconsultforI.C.I.untilheretiredin1955.
342
343
KemballBishopofBromleyfrom1938tomakecitricacidandtartaricacidby fermentation. 7.7Conclusions. BurroughsWellcomeunderwentprofoundchangesintheinterwarperiodandlostground onitsmajorcompetitorsinBritain,particularlyBritishDrugHouses.Thiswasbecauseof thesignificantstafflosses,partlyduetoapolicyoffollowingmedicaladvancesratherthan focusingontheirownresearch,andpartlyduetotheirinsularity.HenryWellcomes focusedmoreonhistravelsandcollectingmedicalartifacts.HoweverbothHenry

145 WellcomeandH.A.D.Jowettdiedin1936. Morale,likewageswaslowandthis 146 worsenedafterthecripplingdutiespayableafterWellcomesdeathin1936. George
Pearson,whohadbeenGeneralManagersince1905,andAssistantGoverningDirector from1924,tookoverasGoverningDirectorhisirondisciplineandunimaginativeand overcautiousnatureprevailed,althoughhewasaverydistinguishedmemberofthe (Pharmaceutical)SocietyandwasalsoanactivememberoftheSocietyoftheChemical

147 Industry. Heretiredin1940after45yearsserviceandin1941Trevanbecameheadof
theWPRLsucceedingR.A.OBrien,andA.C.Whitetookoverhisroleasheadofthe
148 pharmacologydepartment.
DalelaterwrotetoElliott:Thereisstillmuchtobedonetomakegoodthelong yearsofneglectbyWellcomeandbywhomheappointedandleftinchargeandtocatchup
149 withmissedopportunities. ProfessorElliottthoughtthecompanyoughttobe
emphasisingresearch.In1938hewrote:specialmenandespecially(Sir)Andrew BalfourwerealwayseagertokeepthemselvesandtheirBureau(ofScientificResearch)
145
G.H.Lyall,H.H.Dale,L.C.Bullock,M.Prince,T.R.Elliott,TheWilloftheLate SirHenryWellcomeTheLancet(1937):289.
146
A.R.Hall,B.A.Bembridge,PhysicandPhilanthropy:theWellcomeTrust193686 (Cambridge:CambridgeUniversity Press,1986).

147
Obituary,G.E.PearsonChemist&Druggist155.2(7April1951):433Extracts fromapharmacyjournalinWF:E2PFObituaryTheTimes(31March1951Obituary PharmaceuticalJournal 166(7April1951):2728.

148 149
J.H.Gaddum,JohnWilliamTrevan(1957):275.
H.H.DaletoT.R.Elliott,(10December1957),inH.DaleArchivesattheRoyal SocietyMemoirs,HD36/4.26.
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344
dissociatedinthepubliceyefromthecommercialsideThesewereundistinguished
150 years. Howeveritwasnotallbleakandsomeprogresswasmade.Ihavedemonstrated
thesignificanteffortsthatwentintodevelopingsyntheticdrugs.BurroughsWellcomes approachcouldbeclassedasafastfollower.Theykeptaclosewatchonthemedical literatureandsoughtfeedbackfromthemedicalprofessionandimproveduponGerman drugs,particularlyifavalidpatentwasnotinplace.Thedrugsproducedweremoreactive, moresoluble,withlesssideeffectsorwereeasiertoadminister.Themodifieddrugswere patentedwherepossible,themanufactureofsomeweresimplycopiedandproducedunder license.Theadvancesintheirchemicalunderstandingtoachievethisshouldnotbe underestimated,butBurroughsWellcomeneverthreatenedtoestablishempiricresearchon theGermanscale.Bypreparingaseriesofsimilardrugs,observationsweremadeon structurefunctionactivities.Clinicaltrialswereestablished,thoughitwasmoredifficultin theBritainthaninthetropics,andmanyadvanceswereaimedatTropicalMedicine,always aninterestofWellcomeandWenyon,andofincreasingstrategicimportanceastheSecond WorldWarthreatened.Bytheendofthisperiodchemicallaboratoryfacilitieshad expandedsignificantlyandsotohadthemanufacturingcapacityoffirmssuchasBurroughs Wellcome,Boots,Glaxo,Allen&HanburysandBritishDrugHouses.
150
D.J.Jeremy(ed.),H.S.WellcomeDictionaryofBusinessBiography 6(London: Butterworths,1986):36.
344
TheTherapeuticTrialsCommitteeoftheMRC
345
CHAPTEREIGHT:TheTherapeuticTrialsCommitteeoftheMRC. 8.1Introduction. InpreviouschaptersIhaveshownthatasignificantproblemfortheBritish pharmaceuticalfirmshadinhavingtheirnoveldrugstestedclinically.Chapter6emphasised repeatedABCMcampaignstotheMRCfrom1922to1930forameansofperforming clinicaltrialsofpharmaceuticalfirmsdrugs,whiletheMRCtestedinsulinandotherdrugs fromabroad.TheMRCtesteddrugsduringtheGreatWar(chapter4)andthen coordinatedbiologicalstandardisationofdrugs(chapter5).Chapter7exemplifiedthe difficultiesthatBurroughsWellcomeencounteredinhavingnewdrugstestedinBritain, mostoftheirsuccessfulclinicalstudiesbeingintropicalmedicinecentresoverseas. TheMRChaddifficultiesincollatingclinicalresponsestoSalvarsan,duetothe variabilityofthedrugsupplied,andthecircumstancesofwartimerecordkeeping.Inthe secondSalvarsanCommitteefrom1918,theMRCclearlydefendedBritishpreparationsin comparisonwithGermancompetitors,toensureBritishproductionofSalvarsan.Itwasthe samewithinsulin,excludingcompetitivethreatsfromEliLillyofAmericaandLeoof Denmark.StimulationoftheBritishethicalpharmaceuticalindustrywenthandinhand withtheMRCaimofregulatingdrugqualityandevolvingasystemofclinicalresearchin Britain.Theyweremorecomfortablewhenadrugsuchasinsulinwasstandardisedand evaluatedinthelaboratory,andglucoselevelsweremeasuredasasignalofefficacyin clinicalstudiesintheirownresearchcentres. Liebenauarguedthatthedevelopmentofinsulinwassymbolicofthechanging industrygovernmentrelationsandpartofanMRCaimtoregulatetheBritish
1 pharmaceuticalindustry. Valieralsoreferredtothisassymbolicofthechanging
relationshipbetweengovernmentandindustryandsuggestedthatitwasthewartime shortagesofdrugsandtheuniqueopportunityofinsulinthatledtheMRCtoabandonits noninterventionistpositionwithrespecttoindustry,andtakeonaregulatoryand

2 supportiverole. However,sheremarksthatthisnewethosofinterventionismwasfirst
JonathanLiebenau,TheMRCandthePharmaceuticalIndustry:TheModelofInsulin inJoanAustokerandLindaBryder(eds.),HistoricalPerspectivesontheRoleoftheMRC (Oxford:OxfordUniversityPress,1989):16380. 2 HelenK.Valier.ThePoliticsofScientificMedicineinManchesterc19001960: 148(UniversityofManchester:PhD.Thesis,2002).
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346
employedinrelationtoinsulin,whereasIwouldemphasisefurtherthatthishadalready begunindepthwithSalvarsanandwaspartofamoregeneralcampaigntoensurethatonly scientificallyprovendrugsweremarketed. WhereasinsulinmayhaveprovidedagoodmodelforfurtherMRCledstudies,it didnotprovideagoodmodelforBritishpharmaceuticalfirmstogettheirownnovel, sometimessyntheticproductstested.IndeedinsulinpreoccupiedboththeBritish pharmaceuticalindustryandtheMRCforseveralyears,andseemstohaveinhibitedthe testingofotherdrugs.Moreover,theMRCandindustryapproachedclinicaltestingfrom differentperspectives.TheMRCfeltthattheircontroloftheinsulinpatentsprevented

3 commercialisationofinsulin. TheBritishfirmsontheotherhandwantedtheirdrugs
testedsotheycouldcommercialisethem. Britishcompaniesclearlyhaddifficultyinarrangingclinicaltrialsoftheirown products,aspreviouslyhighlightedbyGeorgePearsonofBurroughsWellcomein1922. TheestablishmentoftheMRCChemotherapyCommitteein1927didnothelpthe pharmaceuticalfirmsasitfocusedoncollaborationwiththeDSIRandontropical medicines,whichwereamongthefewdrugsthatBurroughsWellcomemanagedtoget testedinthecoloniesasdescribedinchapter7.4 Inthe1920s,Britishfirmsthatcouldnot gettheirnewproductsclinicallytested,dependedonwhateveraffidavitstheycouldget. Thefollowingexampleoftrichlorophenylmethyliodosalicyl(morewidelyknownasthe antisepticT.C.P)fromBritishAlkaloidsLimitedwastypical: Thepreparationistestifiedtobymanymembersofthemedicalprofession asbeingnontoxicandanalgesicandausefulapplicationasagargleorspray inaffectionsofthenoseorthroatandasalotioninwoundsandscaldsas 5 wellasineczema,chilblainsandhaemorrhoids. Thisabovecaseishowever,unusual,asthedrugsucceededduetoadvertisingtothe public,whereasadrugmarketedtophysicianswouldhavefailedwithoutsupporting publications.
3 4
PatentsandDesignsBillBritishMedicalJournal (11June1931):1107. TheChemotherapyCommittee,establishedjointlywiththeDSIRincludedThomas HenryofBurroughsWellcome,FrankPymanofBootsandJ.DavidsonPratt,thesecretary oftheABCM:JoanAustokerandLindaBryder,TheNationalInstituteforMedical ResearchinJoanAustokerandLindaBryder(eds.),(1989):45. 5 TCPLancet (11January1930):114.
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347
ThischapterexplorestheexperiencesoftheTherapeuticTrialsCommittee(TTC) fromitsestablishmentin1931,bothfromtheMRCperspective,andfromtheviewpointof thepharmaceuticalfirms,andespeciallyBurroughsWellcome.Ithasbeenpossibletogain anunderstandingofthefunctioningoftheTherapeuticTrialsCommitteefromTTC Minutes,MRCMinutes,thepersonalcorrespondenceofthecommitteemembers,Elliott,

6 Dale,andGreen, TTCfilesonindividualdrugs,publishedreports,theBritish
Pharmacopoeia,companyhistoriesandprimarysourcesatBurroughsWellcome, particularlytheScientific&TechnicalCommittee(STC)minutes.Asynthesisofthese diversesourcesallowedmetofollowtheprogressofmostdrugsexamined,bothfromthe TTCperspectiveandthatofthecompanyprovidingthedrug,andtherebygivinganinsight intothestateofBritishdrugdevelopment,whereaspreviousresearchhasfocussedonlyon themajordrugs. Thischapterexaminesthetypesofcompoundsputforward,andassesseswhich BritishandforeignfirmsweremostactiveinprovidingdrugsfortheTTC.Itgivesan insightintohowtheTTCselecteddrugsforclinicaltrialandhowtheyorganisedthetrials. Threethemesemerge,thedifferingemphasisplacedonsyntheticchemistrybetweenfirms thecontinuityoftestingwithingiventherapeuticfields,bothintermsoftheclinical investigatorsandtheevaluationsperformedandthefailureofahighproportionofthe TTCstudies.TheexampleoforganotherapyshowshowtheTTCpursuedtheMRC interestinthistherapeuticapproach,whichinitiallyreliedonbiologicalstandardisationof thedrugs,butsubsequentlyextractswerereplacedbysyntheticversions.Notablealsowas thechangearound1935,asaresultoftheBayersdiscoveryofProntosil,whenthe realisationthattheactiveingredientwasnotpatentprotectedledtomorefirmsadopting syntheticdrugsandalsototheirincreasedacceptancebyphysicians,keentoobtainsamples ofthesepowerfulnewtherapies. ThepressurefromtheABCMfortheproposedTherapeuticTrialsCommitteepaid off in1931atatimeofincreasingGovernmentreceptivenesstotheneedtoexclude ineffectivemedicines,andtogiveprecedencetothescientificallyvalidateddrugsofethical
F.H.K.GreenwastheSecretaryoftheTTC.FrancisHenryK.Green,19001977 ObituaryLancet (19November1977):1067.
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348
7 pharmaceuticalmanufacturers. Attemptstocontroloftheclaimsmadebymanufacturers,
seenfirstinthecampaignsagainstpatentmedicinemanufacturers,andcapturedinthe TherapeuticSubstancesActsof1925and1927,continuedthetrendofGovernment intervention,requiringstandardisationofthepotencyofaneweraofbiological drugs, includingvitamins,organotherapyextracts,hormones,antitoxinsandvaccines.Thishadthe impactofdrivingevermorecomplexmethodsofmanufactureandcontrol. TheTTCwasestablishedatatimeofincreasingdruglegislation,inthesameweek asthefirstdraftofafurtherrevisionoftheTherapeuticSubstancesRegulationswas

8 published. The'ProprietaryMedicinesBill'inMay1931continuedthefightagainstfalse 9 testimonialsbypatentmedicinemanufacturers. TheConsumersCouncilBill relatingto
thepricingofdrugs,andespeciallyimports,wasalsobeforeParliament,andthePharmacy andPoisonsBill(concerninglicensingofpharmacists)wasinthecommitteestageinthe
10 Lords,havingbeenintroducedon17December1930.
TheTTCwasalsoestablishedduringaperiodofpoortradebalances, unemployment,increasednationalismandthreatsoftariffs.By19September1931foreign
11 creditswereexhaustedandthegoldstandardwasabandoned. Inthemidstofthe
economicuncertainty,with thepounduncompetitiveforexports,theGovernmentfell.The resultingdevaluationandhighfixedexchangerateledtolowerexportprices,andraisedthe priceofimports.ThemedicalliteraturecalledforastrongBritishPharmaceuticalIndustry andsomepapersweresimplysigned'Antiforeign.J.DavidsonPrattoftheABCM

7
TheMRCannouncedameetingwithrepresentativesoftheABCM:(16January 1931),MRCMinutes1523/15:4. 8 TheTherapeuticSubstancesRegulationswereissuedon25July1931andpresentedto theHouseofCommonson14SeptemberNationalEconomyBillBritishMedicalJournal (19September1931):551.

9
TheWarpostponedlegislationfromtheSelectCommitteereportof1914anda ProprietaryMedicinesBillintroducedin1920waswithdrawnintheHouseofLords: MedicalNotesinParliament(ProprietaryMedicinesBill)BritishMedicalJournal (25 July1931):168NationalHealthInsuranceBritishMedicalJournal (28November 1931):1016T.Hynes,ThePatentMedicineStampDutyitsOriginandHistoryBritish MedicalJournal (9January1932):3233.

10
ConsumersCouncilBillBritishMedicalJournal (4April1931):607Poisonsand PharmacyBillBritishMedicalJournal (4April1931):607.
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consideredthatitwasthemostdifficultperiodeverfaced,withatradedeficitof9m.He calledforfurtherprotectionforfinechemicals,asgivenbytheDyestuffsActforthe23
12 millionofdyesimportedintotheEmpire. ThePureFoodCouncil,BritishMedical
Association,PharmaceuticalSocietyandProprietaryMedicinesManufacturersmetto
13 discusstheneedforaregistryofproprietarydrugs,medicines,andmethodsoftreatment.
However,inthegrowingeconomicgloom,thepossibilityofenforcedregulationofdrugs wasdroppedtoallowthewholesessionofParliamenttobedevotedtotheNational
14 EconomyBill. Thus,thecollaborationofrepresentativesoftheindustryandtheMRC
waspartofmuchbroaderencouragementoftheinfantBritishIndustryandmorefollowed
15 suchastheImportDutiesBillintroducedbyChamberlaininFebruary1932.
Incontrasttoincreasinggovernmentinfluenceontheclaims,strengthandvariability ofmedicines,someinfluentialclinicianssuchasLordDawson,PresidentoftheRoyal CollegeofPhysicians,stronglyadvocatedthatWhitehallshouldplaynopartindrug regulations,leavingdoctorstoprescribe,astheywanted.ThequarrelsthatLordDawson andLordMoynihan,PresidentsoftheRoyalCollegeofPhysiciansandofSurgeons respectively,hadwiththeMRCweredocumentedpreviously.Moynihandidnotthink MRCresearchershadenoughclinicaljudgmentskills.However,FletcherattheMRC insistedthattheTTCdidnotaimtotelldoctorswhichtherapiestouse,onlytotestnovel drugstoseeiftheyhadclinicalutilityandthattheyweresafetoprescribe.Whetherthey werethenprescribedwasamatterforthedoctorsthemselvesandthefirmspromotingthe
11
TheDyestuffsActChemist&Druggist113.2(18October1930):475ABCM: DyesandTextiles(18October1930):486 A.J.P.Taylor,EnglishHistory19141945 (Oxford:ClarendonPress,1988):28397. 12 J.DavidsonPratt,Chemist&Druggist114.2(31October1931):551 Chemist& Druggist 114.2(26December1931):757.ThegrowthinChemicalindustriessincethe WarwasintheratioU.S.6.3,Germany5.2,andFrance4.8comparedwithBritain2.1and worldtraderosefrom11.5min1913to23min1928L.F.Haber,TheChemical Industry19001930:InternationalGrowthandTechnologicalChange(Oxford: ClarendonPress,1971):1,7.
13
ABCM:BritishChemicals:theirManufacturersandUses(London:ABCM,1927, 1929,1931).
14
15
A.J.P.Taylor,(1988):32150. A.J.P.Taylor,(1988):330.
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products.InanattempttobringtheRoyalCollegesclosertotheirlineofthinking,Fletcher cooptedLordDawsonofPennontothemaincommitteeoftheMedicalResearchCouncil. 8.2TheTherapeuticTrialsCommittee19311939. TheTherapeuticTrialsCommitteehasreceivedlimitedattentionpreviously. Whetherthisisduetothenumberandcomplexityofdrugstestedorthestateofthefilesis

16 notclear. TheTTCcomprisedmostlydoctorsthathadbeensupportedbytheMRC
throughoutthe1920s.TheChairmanwasProfessorThomasRentonElliottofUniversity CollegeHospital,London.Hisclosefriend,HenryDale,theDirectoroftheNational InstituteofMedicalResearch,representedtheChemotherapyCommitteeandprovidedan excellentlinkbetweentheMRCandtheindustry,afterworkingatBurroughsWellcome andcollaboratingwithindustryonthestandardisationofSalvarsanandotherdrugs ProfessorF.R.Fraser(laterSirFrancis)oftheClinicalMedicinelaboratoriesatSt.

17 Bartholomew'sHospital,LondonandFellowoftheRoyalCollegeofPhysicians had
collaboratedwithbothDaleandElliottonacommitteearrangingtrialsinpernicious
18 anaemia.Fraserwasanexpertinthestructureactivityrelationshipsofalkaloids. He
wasamemberofthePharmacopoeiaCommissionfrom1928,remainingamemberuntil
19 October1944. FrankH.K.Green,previouslyarecipientofanMRCgrantforresearchat
St.BartholomewshadbeenamemberoftheMRCsince1929.Hewouldhavebeena
20 consultantbutforhisbronchiticasthma,soadeskjobasSecretaryoftheTTCwasideal.
Thesefourchosetheremainderofthecommittee,whichincludedprominentfiguresfrom manyfieldsofmedicine:ProfessorArthurW.M.EllisoftheLondonHospitalDrJohnA. Ryle,whohadaprivateclinicinWimpoleStreet(laterSirJohnRyle,RegiusProfessorof PhysicatCambridgeandOxford)21SirJohnW.ThomsonWalker,animportantHarley
16
IreviewedthefilesattheMRCbuildingsjustbeforethemovetothePROandata timewhenmanyfileswerebeingshredded. 17 Retrospecton40yearsofPractice:BMAPresidentialAddress,BritishMedical Journal (29July1939):209. 18 MRCMinutesII,(16July1920):114MRCMinutesII,(15July1927):156. 19 BritishPharmacopoeia (London:GeneralMedicalCouncil,1948):viii ix. 20 MaisieFletcher,TheBrightCountenance:aPersonalBiographyofWalterMorley Fletcher(Hodder&Stoughton,1957):323F.H.K.Green,ClinicalEvaluationof RemediesinBritain,Brit.Med.Bulletin 2(1944):5860. 21 JoanAustokerandLindaBryder(eds.),(1989):76,214,224M.W.Weatherall, Gentlemen,ScientistsandDoctors:MedicineatCambridge18001940(Cambridge: BoydellPress,2000):2778.
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StreetfigureandaseniorurologistatKingsCollegeandsurgeonatSt.PetersHospital,
22 London. SirEdwardFarquharBuzzard,aneurologistandsuccessortoWilliamOsleras
RegiusProfessorofMedicineatOxfordProfessorD.P.D.Wilkie,ageneralsurgeonand urologistfromEdinburghSirThomasLewis,theeminentcardiologistofUniversity CollegeHospital,LondonSirJohnH.ParsonsCBE,PresidentofOphthalmologyatthe BMAinLondonandlaterinBirminghamandMrWilfredTrotter,aprominentHarley

23 StreetandUCHsurgeon. Overthenextyearsfurtherexperiencedresearchdoctorswere 24 addedasothersretired. EdwardMellanbyofSheffieldjoinedandwastobecomethenew 25 SecretaryoftheMRC, andThomasWattsEdenwasoneoftheforemostgynaecologists
inLondonandhadhelpedtofoundtheBritish(laterRoyal)CollegeofObstetriciansand
26 Gynaecologistsin1929,andin1930hewasPresidentoftheRoyalSociety.
TheTTCmetforthefirsttimeon6March1931andsentoutnotestopharmaceutical firmsandotherinterestedpartiesentitledConditionsunderwhichtheTTCmaybe preparedtoundertakeclinicaltrialsofnewremediesofBritishorforeignorigin,submitted

27 bythemanufacturers.
22
MRCMinutes,(13March1931):33J.W.ThompsonWalker,ThePartofthe PractitionerintheTreatmentofthePreOperativeStageofEnlargedProstate,British MedicalJournal (15January1921):71.

23
TrotterwasapupilofSirVictorHorsley.HewasasurgeonatUCHfromitsopening in1906:W.R.Merrington,UCHanditsMedicalSchool (London:Heinemann,1976): 47,102:MRCFile1523/1J.H.Gaddum,WilfredBattenLewisTrotter.Biographical MemoirsofFellowsoftheRoyalSociety 3(1957):27388. 24 FromJanuary1934FredMenzies,MedicalOfficerofHealth,LondonCounty Council,andDr.ThomasCarnwath,aseniormedicalofficerintheMinistryofHealthwere added.LindaBryder,PublicHealthResearchandtheMRCinJoanAustokerandLinda Bryder(eds.),(1989):5982FromJune1934,ProfessorA.J.Clarkwasadded:D.H. Clark,AlfredJosephClark18851941,aMemoir(Glastonbury:C.&J.Clark,1985) MRCMinutesII,(29October1931):128HelenK.Valier,(UniversityofManchester: PhDthesis,2002). 25 SirHenryDale,EdwardMellanby.ObituaryNoticesofFellowsoftheRoyalSociety 1(1955):193222. 26 ObituaryofThomasWattsEden(8May186422September1946BritishMedical Journal (5October1946):517. 27 TheTherapeuticTrialsCommittee.FacilitiesfortheClinicalTestingofNew Remedies,(6March1931),MRCFile1523/1(TTC).
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352
Thenewcommitteewouldbeempoweredtoassignthesubmittedremedies fortrialbyapprovedworkersintheclinicalfieldandwouldreceiveand 28 publishtheirreportsinsuitablemedicaljournals.

29 Noticesalsoappearedin 'TheTelegraph'. 'TheTimes'recordedthat:
TheMRCannouncethattheyhaveappointedaTherapeuticTrials Committee,asfollows,toadviseandassisttheminarrangingforproperly controlledtrialsofnewproductsthatseemlikelyonexperimentalgroundsto 30 havevalueinthetreatmentofdiseases.
OneweeklateralongarticleappearedintheBritishMedicalJournalreinforcingnotonly thefunctionsbutalsotheneedforthenewlyconstitutedcommittee. AsignofthetimesisthesettingupoftheTherapeuticTrialsCommittee. Untilnowithasbeenlefttothemanufacturerstoarrangeastheythoughtfit forclinicaltrials,withtheattendantdifficultyofnotalwaysbeingableto ensurethenecessarytestsbeingconductedinasufficientnumberofcases.As aruleIbelieveitisthecustomforfreesamplestobesuppliedtosuchprivate practitionersasarewillingtoacceptthem,andtorelyuponthose practitionerstomakeuseofthemincasesthoughttobesuitable.Butwhat happensIimagineisthatinmanyinstancesthesamplesareonlytriedbyway ofexperiment,whentheordinaryremedieshavefailedinparticularcases. Evidenceofthissortofthingcanbefurnishedbymanychemistswhocarry onbusinessindistrictswheredoctorsfondoftryingnewproductsallegedto possessremedialpropertiesareinpractice.Sometimesgoodluck attendstheempiricaltrials,butmorefrequentlyitdoesnot,andanelementof uncertaintyseemstoattachitselftotheresultsobtainedbysuchhappygo luckyclinicaltrialssocalled.Moresystematicmethodsdoubtless characterisetheprocedureadoptedbysomemanufacturersofnewproducts offeredforthetreatmentofdisease,butitseemsalltothegoodthat opportunityshouldnowbeprovidedforarrangingproperlycontrolled clinicaltests.Thenewcommitteeisastrongone,includingindividualsofthe highestreputesandbothmedicineandpharmacyoughttobenefitbyits 31 existence. ThisdefinitionoftheTTCwasbroaderthanthatinterpretedbyValierwhowrotethatit
32 wassetuptoensurethatpotentiallyuseful syntheticproductswerequicklyrecognised.
28 29 30 31 32
ClinicalTrialsofNewRemediesLancet(8August1931):304. Telegraph (31July1931).CuttinginMRCFile1523/1(TTC). Times(31July1931).CopyinMRCFile1523/1(TTC). ClinicalTrialsofNewRemediesBritishMedicalJournal (8August1931):2512. HelenK.Valier.(UniversityofManchester:PhDthesis,2002):168.
352
353
Iwillshowthatalthoughsomedrugsweresynthetic,andsomewerenovelinotherways, thetherapiestestedwereoftennotnew,somedatingbacktothepreviouscentury,and neitherweretheyasopentoforeigndrugsassuggestedabove,atleastinitially.Manyof thedrugstestedwereBritishversionsofforeigndrugs.Infacttheclearphrasingoftheir remitimmediatelyplacedtheTTCinadilemma.Theirveryexistencewasduetopressure fromtheABCMtoassistBritishfirms,andyetjustbeforetheTTCwasformed,oneofthe

33 membersoftheChemotherapyCommittee,C.H.Andrewes(laterSirChristopher)
receivedarequestfromtheGermanfirm,Scheringforhelpinarrangingtestsofanewdrug
34 called'SolganolB'oraurothioglucose,agoldbaseddrug.
Inthebeliefthatgoldhadanantisepticandantitubercularactivity,Solganolhad beengivento39Germanpatientswithunderlyingcomplaintsattributedtoinfections. However,becauseseveralwhoalsohadrheumatoidarthritisexperiencedareliefof joint

35 pain,Scheringdecidedtoexplorethisfurther.
ScheringhadindependentlyapproachedaDr.WilliamRobertsonSnodgrassat GlasgowRoyalInfirmary,whoagreedtotreat30casesforthem.Onhearingofthis,the
36 ProfessorofBacteriology,C.H.Browning attheUniversityofGlasgowsuggestedthat
SnodgrassmightbeinvitedtosubmithisrequestinsteadtotheTTC,butsecretaryF.H.K.
37 Green considered:itwashardlyfairtotheABCMthatthefirstactivityofthenew 38 committeeshouldbetheacceptanceofareportontheGermandrug. Dalecommented:
33
ChristopherAndreweswasthesonofSirFrederickAndrewes,andperformedcancer researchunderWilliamGyeattheNIMR.Afterworkingondogdistempervirus,hewas oneofagroupthatisolatedtheinfluenzavirusin1933:JoanAustoker,LindaBryderin JoanAustokerandLindaBryder(eds.),(1989):4144. 34 C.H.BrowningtoF.H.K.Green,(27February1931)MRCFile1523/1(TTC). Scheringhadalreadytestedanantibacterial,NeotropinWalterSneader,DrugDiscovery: theEvolutionofModernMedicines(Chichester&London:JohnWiley,1985):90.

35 36
W.Sneader,(1985):90. C.L.Oakley,CarlHamiltonBrowning,(18811972)BiographicalMemoirsof FellowsoftheRoyalSociety 19(1973):173215.CyrilL.Oakley,aphysicianfromUCH, whereBurroughsWellcomehaddrugstested,joinedtheWPRLin1934toworkasan experimentalpathologistunderGlenny.

37 38
F.H.K.GreentoC.H.Browning,(3March1931)MRCFile1523/1(TTC).
F.H.K.GreentoH.H.Dale,(3March1931),ThomasRentonElliottFiles, TherapeuticTrialsCommittee(TTC)193343,WellcomeInstitute,WI:GC/42,13/1.
353
354
itwasofcourseverystupidofBrowningtobringthatsuggestiontousviathefirmin
39 question.
GiventheinauspiciousstartwithSnodgrass,theTherapeuticTrialsCommitteeset downoperationalrulesonhowtheyproposedtowork.Dalepointedoutthatthe committeewaslikelytobeaskedtoarrangetrialsofmanydrugswhichweremerely modificationsofexistingremedies,solelyinorderthattheirreportsmightbequotedas propaganda,andhefelttheTTCshouldonlyselectnewremedieslikely(onthebasisof

40 experiments)toadvancetherapeutics. Thiswoulddiscouragespeculativeapproaches
suchasbytheResearchAssociationofBritishRubberManufacturersinMalaya,tohave Querbrachitoltested,whenintheabsenceofdataItoccurredthatthisproductmight
41 possesssomepropertiesofuseitwasrejected.
Ellissuggestedthatinordertoavoidfuturecontroversy,studiesshouldbe performedatmorethanonecentrethosewheretheMRCalreadyfundedworkandwhere
42 theyhadtrainedstaffinplace. TheTTCinsistedthatthemanufacturingfirmprovidedall
availableinformationonanewdrugonaconfidentialbasis,andtheyprovidedastandard formtocollectthis.Theyalsoinsistedthattheyweresolelyresponsibleforstudiesandthat thecompanycouldnotattempttosetuptheirownstudiesinparallel.InreturntheTTC offeredtimelycompletionofthestudy,whichifsuccessful,wouldbepublishedina reputablejournalasasealofapproval.
8.3ClinicalTrialsEstablishedbytheTherapeuticTrialsCommittee. TheTTCmetformallyononlytenoccasionsbetween1931and1939,which perhapshighlightsboththescarcityofsignificantclinicaldevelopmentsduringtheperiod, butalsotheimportanceoftheinterveningminutesandcorrespondenceonwhichIbasemy

39 40 41
H.H.DaletoF.H.K.Green,(27February1931),MRCFile1523/1(TTC). FirstmeetingoftheTTC,(8July1931),MRCFile1523/15(TTC).
Querbrachitol,(1methylinositol),MRCFile1523/15correspondencesfrom17 March1932to26October1933. 42 ThisisclearfromacomparisonofthefilesoftheTTCandtheMRCMinutesfromthe previousyears.MRCFiles1523/1and1523/15.
354
355
assessments.Betweenmeetings,progresswascoordinatedbetweenmembersbythe secretaryGreen,whoalsocorrespondedwithindividualfirms.Aftertheinitialdecisionnot toarrangeastudyonbehalfofSchering,thereappearstohavebeenaclearpolicyof preferentialtreatmentforBritishfirms.Thefirsttwelvesubstancesinvestigatedwereall

43 Britishandonlytwoofthefirst26testedwereGerman. In1934GreenwrotetoElliott:
Althoughitmightperhapsbethoughtdesirabletoexplorethesupposed actionofbeevenomin'rheumatic'conditions,IimaginethattheCommittee wouldhardlywanttoarrangefortestsofthebeevenomintheformof a Germanointment? HewascorrectforElliottreplied:

44 Sorry,youcan'tstingmeintoanyenthusiasmforthisquest!
ThemajorBritishfirmsallturnedimmediatelytotheTTCfortestingoftheirdrugs.Ten drugswereputforwardtothefirstmeetingoftheTTCinJuly1931,andincludedfour fromBoots,threefromBurroughsWellcomeandtwofromMay&Bakerwhoalongwith

45 Allen&HanburyswerefourofthefiveprincipalBritishfirms. Theothermajorfirm,
BritishDrugHouses,submittedtheirOestrinpreparationandfollowedwiththreedrugsfor
46 thenextmeetingoftheTTCinJanuary1932.
Thecommitteeaccepted8,butrejected2oftheinitialtendrugsasbeingunworthy oftesting.ThesuccessfulagentsincludedtwosyntheticantisepticsfromBoots,butthe otherswereallderivativesofnaturalproducts.NoreasonsweregivenforrejectingPropyl guiacolfromBootsandParosanfromMay&Baker,althoughtheformerrepresenteda newsyntheticversionofacompoundfirstdescribedin1887,whenitwasisolatedfrom

47 beechwoodtar. ParosanisnotmentionedinSlinnsbookonMay&Bakerorinthe
BritishPharmacopoeiaof1948,soitappearsnottohavebeendeveloped.Ofthedrugs offeredtotheCommittee,itappearsthattheygaveprioritytothosethatcouldbeassayed
43
TheTTCexamined59remediesbetween19319TTCMinutes110,MRCFile 1523/15.Furthercompoundswereforwardedbutnotdiscussedatthemainmeetings.
44
F.H.K.GreentoT.R.Elliott(25June1934)T.R.ElliotttoF.H.K.Green(27June 1934),T.R.ElliottFilesTTC193334WIGC/42.
45 46 47
TTCMinutes1,(8July1931),MRCFile1523/15. TTCMinutes2,(15January1932),MRCFile1523/15.
NeitherofthesedrugsappearsintheBritishPharmacopoeiaof1948andtheywere presumablynotmarketed.(London:BritishPharmacopoeia,1948).
355
356
biologicallyandforuseinindicationsinwhichtheyhadexpertise,suchasorganotherapies asdescribedbelow.Anotherreasonforselectingorganotherapies,asacasestudyisthat workinparallelsuggestedthat,oncetheactivehormonewasidentified,itcouldbe synthesisedandtherebyofferapureversionofthehumanhormone,ratherthanrelyingon extractsfromtonsofanimalorgans,andthesedevelopmentsinturnstimulateddrug synthesisinBritishpharmaceuticalfirms. 8.4CollaborationinOrganotherapyandVitaminsLeadstoIncreasedCapacity.

48 Severalauthorshaveaddressedthedevelopmentoforganotherapy. Theterm
appliedtotheuseofextractsfromvariousanimaltissuesandglandsthatweregivento replacedeficienciesindietormetabolism,anditwasanalogoustotheextractionof alkaloidsfromplants.Organotherapybecamepopularattheendofthenineteenthcentury withextractsoftestes,adrenalglands,pancreaticglands,andovaries,followingthe discoveryofthebenefitsofthyroidextractsin1874.49 Naturalthyroidhormonedeficiency andtheproblemsseenafterthyroidectomycouldbedistinguished,andthepotentialbenefits ofiodinewerenoted,wellbeforeKendalldescribedthyroxinin1915,andbefore

50 Harringtonsynthesisedthehormonein1926.
AmericanpharmaceuticalfirmssuchasArmouradvertisedanextensiverangeof
51 organotherapiesin1918. Areportin1919hadindicatedthepotentialroleofpituitary 52 extractsfortreatingmenstrualmigraines,andyetpreparationswereofvariablestrength.
Organotherapywasstimulatedfurtherbythediscoveryandsuccessofthepancreatic hormoneinsulin,bythedemonstrationthatcodliveroilpreventedthebonedisorderrickets, andtheuseofliverextractsforperniciousanaemia,allofwhichwereinvestigatedbythe

48
M.Borrell,OrganotherapyandtheEmergenceofReproductiveEndocrinologyJ. Hist.Biol.(1985)18:130M.Borrell,Organotherapy,BritishPhysiology,andDiscovery oftheInternalSecretionsJ.Hist.Biol.(1976)9:23568 BritishMedicalJournal (6 February,1915):243247E.C.Dodds,TheHormonesandtheirChemicalRelations Lancet(19May1934):104854SirHumphreyRolleston,TheHistoryof OrganotherapyBritishMedicalJournal (15May1937):103336SirW.LangdonBrown, RecentAdvancesinOrganotherapyPharmaceuticalJournal 141(30July1938):93. 49 W.Sneader,(1985):192. 50 C.Harrington,G.Barger,ChemistryofThyroxine.(III)ConstitutionandSynthesis ofThyroxineBiochemicalJournal 21(1927):169. 51 Thesubstancesandglandpreparationsincludedbronchial,cardin,cerebrenin,corpus luteum,duodenal,lymphatic,mammary,orchitic,ovarian,pancreas,parotidandpineal Chemist&Druggist(6July1918)suppl.V.
356
357
53 MRC. Eachnewhormonewasexaminedinasimilarfashion.Firstlyextractsweremade
ofvariablequality,andthenimprovedmethodsofextractionwereidentified,thesubstance wascrystallisedifpossibleandinthecourseofadecade,syntheticdrugsweremade, rapidlysupersedingtheextractionoftensofthousandsoftissuesamplestoproduceasingle

54 gramofmaterial.
WalterM.FletchersetupaSexHormonesCommitteewithintheChemotherapy
55 Committeein1930,includingDale,WattsEdenandEllis. Organotherapywaswithinthe
comfortzoneoftheMRC,becausetheorganextractshadtoundergobiological standardisationintheirlaboratories.HaroldKingattheNIMRinvestigatedthechemical
56 structureofthehormones,justasGeorgeBargerhadwiththyroxinein1927. Because
theMRCalreadysupportedresearchinorganotherapy,theTTChadnodifficultyin arrangingstudies. OneoftheoriginaldepartmentsoftheNIMR,theDepartmentofApplied PhysiologyandEndocrinologyheadedbySirLeonardHillhadceasedtoexistwhenhe

57 retiredin1930. FromJuly1932asubdepartmentstudyingthePhysiologyofSex
HormoneswasestablishedunderAlanParkes(laterSirAlan),whohadpreviously
58 collaboratedwithGuyMarrianatUCH andalsowithProfessorE.C.(LaterSirCharles) 59 Doddsonhormones.
52 53
W.Sneader,(1985):96,166,334. J.Barnes,M.J.Brady,G.M.James,TheComparativeValueofIrradiated ErgosterolandCodLiverOilasaProphylacticAntirachiticAgentwhenGivenin EquivalentDosageAccordingtoRatUnitsofVitaminDAmericanJournalofDiseasesof Childhood(1930)xxiv45.A.WalterSneader,(1985):193.

54
H.E.Dale,TheChemistryofSexHormonesPharmaceuticalJournal (27April 19139):43234. 55 TTCMinutes2(18January1932)MRCMinutesII,(16May1930):87.DrF.H.A. Marshallwaschairman,withDr.V.KorenchevskyandDrA.J.Parkes.MRCMinutesII, (20June1930):112and(4June1931):91. 56 WalterSneader,(1985):209.

57 58
JoanAustoker,LindaBryderin JoanAustokerandLindaBryder(eds.),(1989):489.
A.J.Parkes,TheRiseofReproductiveEndocrinology192640Journalof Endocrinology 34(1966)xxxxxiiH.H.Dale,NIMRinDaleArchives,RoyalSociety, HD47.13.144.

59
DoddswasProfoftheUniversityofLondon:MRCMinutesII,(30April1926):74: E.C.Dodds,SyntheticOestrogensEndeavour(1947):1457E.C.Dodds,L.
357
358
BurroughsWellcometookanearlyinterestinorganotherapyandwas,likemany firmsinvolvedintheinsulinstudies.Theyhadalreadyplacedtheirthyroxinepreparationon
60 themarketinSeptember1926. BurroughsWellcomesanteriorpituitarylobepreparation,
neoInfundin,wasmarketedin1931andwasclaimedtobefreefromthepressorprinciples
61 associatedwithearlierextracts. ThefirsthormonesubmittedtotheTTCbyBurroughs
WellcomewasProgesterone,whichhadbeenisolatedin1929. TheNewYorkhouseofBurroughsWellcomeatTuckahoe,establishedin1906, preparedafurtherextractfromthebrainsanteriorpituitarylobeforDr.Leestotestatthe

62 WPRL. By1933severalcompaniessoldpreparationsofanteriorpituitarylobeextract.
Becauseoftherapiddevelopmentsinorganotherapy,asectionofhormonephysiologywas createdattheBurroughsWellcomesiteatBeckenhamandfurtherorganextractswere made.JowettpreparedaduodenalextractusingaprocessdevisedbyTrevan.63 Prof.C. C.Lambie,bynowattheUniversityofSydneywasinvitedtotheWPRLtodescribehis

64 workonthyrotropichormone.
8.4.1Oestrin AtthefirstmeetingoftheTTCitwasproposedtoevaluateOestrinfromBritish DrugHouses,incollaborationwithmembersoftheSexHormonesCommittee,includingT. WattsEden.Oestrinwasanovarianfollicularhormoneextract,firstdescribedinAmerica

65 in1923byEdgarV.AllenofColoradoandEdwardAdelbertDoisy. ParkeDavis
supportedDoisy,andheisolatedthecrystallinehormonein1924.TheMRChadsupported ovarianhormoneresearchsincetheearly1920s,culminatinginthedetectionofovarian
Goldberg,W.Lawson,R.Robinson,OestrogenicActivityofCertainSynthetic CompoundsNature(1938)141:247.
60 61
Mr.Hogg,HistoryoftheWorks(1907)III,WF:S/G/145. Preparations&Appliances:NeoinfantineBritishMedicalJournal (7March1931): STCMeetings,(12July1935)and(19November1937),WF:STCS/G/49.
406.
62 63 64
STCMeeting,(29May1936),WF:STCS/G/49. STCMeeting,(24May1937),WF:STCS/G/49. 65 E.V.Allen,E.A.DoisyAnOvarianHormone:PreliminaryReportofits Localization,ExtractionandPartialPurificationandActioninTestAnimalsJ.American MedicalAssociation 81(1923):81921E.V.Allen,E.A.Doisy,IsolationoftheActive PrincipleoftheOvarianHormone(Oestrin)J.BiologicalChemistry 61(1924):711723.
358
359
66 hormonesintheurineofpregnantwomenbyGuyMarrianatUniversityCollegeHospital.
CharlesDoddsoftheCourtauldInstituteofBiochemistryattheMiddlesexHospitalin London,whohadbeeninvolvedintheearlyproductionofinsulinandalsohadcollaborated withtheBurroughsWellcomeSTCregardingOestrin(chapter7),showedthatoestruswas causedbySecretin,extractablefromovariantissue,whichifinjectedintoovariectomised animalscausedanartificialoestrus.Forawhiletheurineofpregnantwomenandmareswas thechiefsourceofSecretin,allowingcommercialproductionofcrystallineextracts,which wereusedtotreatovariandysfunctionssuchasmenopausaldisorders,amenorrhoea,and menstrualheadaches.TheDutchfirmOrganonpublishedthefirstpatentsformethodsof extractionon28May1927,followedinNovemberbySocietiChemicalIndustrieofBasle

67 (CIBA)withParkeDavis,ScheringKahlbaumandIGFarbensooncompeting.
Becauseobservationsoftheclinicalutilityoforganextractswerepublishedopenly, anyfirmwithappropriatefacilitiescouldattemptproductionalthougheachwouldguard themethodsofextraction.Thisledtoasituationwherebytheseveralextractsappeared simultaneously,thatcouldonlybedifferentiatedbiologicallyintermsofratunits,defining

68 theamountofanextractbringingaboutoestrusorabortion. From1931,boththe
AmericanfirmofParkeDavisandtheGermanfirm,Scheringcommerciallyproduced
69 oestroneandrelatedhormones. Oestrinwasshowntohelp23outof25womenwith 70 menstrualmigraineinanindependentclinicalstudyin1932. Dr.JohnChassarMoir,who
hadbeenfundedbytheMRCandcollaboratedwithDaleinrefiningergot,tookupthe TTCworkonOestrinandotherorganextracts.MoirhadtrainedinVienna,Berlinand JohnsHopkinsintheUSA,andperformedresearchinEdinburghbeforetakingapostat

71 UCHin1930.
TheMRCSexHormonescommitteerecommendedtotheTTCthatstandards shouldbedefinedandthatclinicaltrialsbearrangedforOestrinandforsomeBritishfirm
66
J.K.Grant,GuyFrederickMarrian(190481)BiographicalMemoirsofFellowsof theRoyalSociety 28(1982):34778.

67 68 69 70
STCMeeting,(19May1933),WF:STCS/G/49. ClinicalEffectsofOvarianHormoneLancet (15March1930):586.
W.Sneader,(1985):1934. A.P.Thompson,AContributiontotheStudyofIntermittentHeadacheLancet (30 July1932):229235. 71 Obituary.JohnChassarMoirLancet(10December1977):1240.
359
360
72 toundertakeitsproductionandBDHsubmittedtheirversion. Doddsreported
favourableclinicaloutcomesinhisstudies,whichencouragedhimtoattemptthe
73 identificationandsynthesisofOestrin. Inthesummerof1932,theMRCcollaborated
withtheLeagueofNationstoestablishInternationalStandardsUnitsforoestrogenic hormonesandAlanParkesdepartmentperformedmanystudiesofsexhormones
74 preventingfertility. Withabiologicaltestinplacetomeasuretheoverallactivity,therace 75 begantodefinetheactivesubstancewithintheextracts.
Havingfollowedthedevelopmentofthyroxine,BurroughsWellcomedecidedto
76 keepawatchonthepossibilitiesofsyntheticoestrogeniccompoundsofthistype. In
1932RosenheimandKingproposedthatoestrogenshadastructuresimilartoergosterol, andDoddsestablishedtherelationshipbetweentheessentialpartsofthechemicalstructure andoestrogenicactivity,findingpotentactivityinanol,which wascheaplypreparedfrom naturaloils.BurroughsWellcomesSTCsupportedtheproductionofextractsofOestrinat

77 Dartford,wherethefirstexperimentalbatchwasproducedinDecember1934. Oestrin
givenorallywasasuccessfulproductforBurroughsWellcomeandotherfirms,butthey
78 alsoprovidedDoddswithlargequantitiesofmaterialtotrytosynthesiseit.
By1937aseriesoffirmsweresellingoestrogenichormonesbasedoneither ketohydroxyoestrinsuchasScheringsProgynonandParkeDavisTheelinandOestroform fromBDH,orpreparationsbasedonoestadiolbenzoateinwhichcasetheletterBwas addedbyBDHandOrganonproducedOestroformB.BootsproducedOvostaband Ovostal. DoddsthencollaboratedwithSirRobertRobinson,theWaynfleteProfessorof ChemistryinOxfordandadvisortoindustry,whosuggestedthatstilbenes,23timesmore potentthanoestronewereformedbythecondensationoftwoanolmoleculesandthusthe

72 73
MRCMinutesIII,(13March1931):39. E.C.Dodds,F.Dickens,S.Wright,ObservationsuponthePreparationofthe OvarianHormoneBiochemicalJournal 19(1925):85359E.C.Dodds,J.D.Robertson, ClinicalExperimentswithOestrinLancet I(1930):13902. 74 J.Austoker,L.Bryder,in JoanAustokerandLindaBryder(eds.),(1989):49. 75 Oestrinisstillusedinitsmodernformasoestrogen,R.E.Jowett,SomeUnusual ExperienceswithOestrinTherapyJ.Laryngol.Otol.82(1)(1968):6971. 76 STCMeeting,(19May1933),WF:STCS/G/49. 77 STCMeeting,(14December1934),WF:STCS/G/49MRCMinutesII,(26June 1931):91.
360
361
syntheticsubstitutesstilboestrol,hexoestrolanddienoestrol,werepreparedinJanuary
79 1938.
WithinweeksofDoddsdiscovery,BurroughsWellcomesynthesised diethylstilboestrolonacommercialscale,andBootsandBDHsoonalsoprepareditand bothoftheirpreparationswereacceptedfortrialbytheTTCinJuly1938atUCH,the PostgraduateMedicalSchoolandGuysinLondonandtheRoyalMaternityHospitalin

80 Edinburgh. Dr.P.M.F.BishopatGuysHospitalwasalecturerinchemicalphysiology,
MurielBoycottatUCHhadbeenaBDHsponsoredresearchfellowsinceOctober1937, andS.ZuckermanwasfromtheDepartmentofPathologyinOxford.Theirmulticentre clinicalstudydemonstratedthatstilboestroldiproprionate(BDH&Boots)andhexoestrol (Boots)werebothhighlyactive,withstilboestrolbeingmostactive,althoughhexoestrol

81 wasgivenatalowdoseinaseriesof152cases. TheearlysuccessofOestrinextractsin
TTCtrialsclearlyencouragedattemptstosynthesisthehormoneandtheearlyavailability ofsyntheticversionsstimulatedtheTTCtoexamineseveralfurtherpreparations,thistime showingclearbenefitsandaclearcaseofsuccessfulindustrycollaborationwithacademia andtheTTC.TheTTChelpedtoorganisethetrialsbutalsoendorsedtheproducts.The syntheticpreparationscouldbegivenbyinjectionandtheirdecreasedcostcomparedto
78 79
R.A.OBrientoH.A.D.Jowett,(26May1925),WF:STCS/G/49. S.A.B.Kipping,ChemistryandIndustry (25February1963):304W.Sneader, (1985):196,201,336,340LordTodd,J.W.Cornforth,RobertRobinsonBiographical MemoirsofFellowsoftheRoyalSociety 22(1976)415527STCMeeting,(31January 1939),WF:STCS/G/49E.C.Dodds,W.Lawson,ASimpleAromaticAgentwithan ActivityofthesameOrderasthatofOestroneNature139(1937):627E.C.Dodds,L. Goldberg,W.Lawson,R.Robinson,OestrogenicActivityofCertainSynthetic CompoundsNature141(1938):24748. 80 TTCMinute9,(14July1938),MRCFile1523/15W.R.Winterton,T.N. MacGregor,ClinicalObservationswithStilboestrol(Diethylstilboestrol)BritishMedical Journal (7January1939):1012ANewSyntheticOestrogenBritishMedicalJournal (7 January1939)2334AlfredA.Loewer,TherapeuticTrialsofDiethylstilboestrolBritish MedicalJournal (7January1939):13. 81 P.M.F.Bishop,M.Boycott,S.Zuckermann,TheOestrogenicPropertiesof Stilboestrol(diethylstilboestrol)Lancet(7January1939):5P.M.F.Bishop,R.K. Bowes,M.Boycott,R.Kellar,T.N.MacGregor,B.C.Markers,OestrogenicProperties ofStilboestroldiproprionateandHexoestrolLancet(6April1940):629633Synthetic oestrogensBritishMedicalJournal (25February1939):351.
361
362
extracts,promisedearlysuccessanditwasnotlongbeforeBoots,BDHandOxojoined
82 BurroughsWellcomeinmanufacturingstilboestrolampoulesandtablets.
8.4.2SuprarenalCorticalExtract(Cortin). AdrenocorticalsteroidshadbeenfirstdescribedinAmericain1927,buttheclinical potentialonlybecameevidentafterstrongerpreparationswereextractedusingbenzeneand

83 ParkeDaviswasfirsttoprepareacommercialversion. Towardstheendof1933,
OrganonofOssinHollandapproachedtheTTCtoperformthefirstUKtrialsofsuprarenal corticalextractonpatientswithAddisonsdisease,adeficiencydiseasefirstdescribedby
84 ThomasAddisonin1855. TheTTCwereconcernedthatsuprarenalcorticalextracts
calledEucortone(Allen&Hanburys)andEschatin(ParkeDavis)werealreadyonthe
85 marketandbothwereexpensive. Organonsversionwasanunpatentedpreparationwith
animprovedbiologicalstandardisation.Inthiscase,ratherthanpromotetheBritishfirmas theysooftendid,theCommitteetooktheviewthatitwouldbeadvantageoustoeveryone ifacheaperversionwereallowedonthemarket.TheCommitteearrangedfortrialsofthe OrganonextractstobeperformedattheRoyalFreeHospitalinLondon,andinAberdeen

86 andManchester. DespitealloftheconcernsthattheMRChadwithManchester,itwas 87 Wilkinsonwith8casesthatcontributedthemostpatients. AlthoughOrganonsCortin
wascheaper,thecommitteewereconcernedaboutstartingapatientoffonCortininatrial, andthenhavingtoswitchtomoreexpensivemarketedpreparations: Ifwestartapatientsuccessfullywithourfreeextract,atwhatcostwill maintenancetreatmentbeprovided?Wecan'tdragapatientfromthepitand
82
SexHormones:StandardisedCommercialPreparations,PharmaceuticalJournal 142 (27April1939)436442. 83 W.Sneader,(1985):221. 84 th SirJohnConybeare(ed.),ATextbookofMedicine(Edinburgh,E.S.Livingstone,9 edition1949):2578. 85 T.R.ElliottFile,WIGC/42Eucortone,Corton(A&H):extractofadrenalcortexfor thetreatmentofAddisonsdiseaseandotherconditionshighlyactive,highlypurified (London:Allen&Hanburys,1938)advertisementatWellcomeInstituteQV26 1938A42e. 86 TTCMinutes5,(5March1934),MRCFile1523/15. 87 F.H.K.GreentoT.R.Elliott,(20December1933),T.R.ElliottFiles,WIGC/42 TTC193334TTCMinutes5,(5March1934),MRCFile1523/15.
362
363
thenleavehimtoslideback.Yetthehospitalmightnotrelishthisaftermathof 88 theinvestigation.
InFebruary1934aconferencewasheldtodiscusstheclinicaltrialsofsuprarenalcortex extractsandtheCommitteedecidedtodowhattheMRCdidbest,toperformcomparative
89 laboratorytestsofpotencyonthethreeavailablepreparations. Whiletheintentionof
providingacheaperproductwaslaudable,thestudystruggledtorecruitsufficientpatients
90 withonly14casestreatedfrom12differentLondonhospitalsduringthewholeof1933.
Inordertofindfurtherclinicalcasestotreat,advertisementswereplacedintheLancet, BritishMedicalJournal,ClinicalJournalandPractitioner.Datawerecollectedondose, pigmentation,muscularweakness,digestivesymptoms,historyofcases,lossofweightand

91 specifiedclinicalandpathologicaltests. EdwardMellanbychairedasecondconferenceon
theroleofCortininAddisonsdiseaseinJuly1936,butthestudywasstillafailurewith only20casestreated.MurrayLyon,whohadtreated4casesconcluded:theresultsasfar astheygodonotseemtobeencouragingbuttheydonotgofarandElliottwhohadonly

92 onecasecommentedtamely:hisresultsdonotshowthatCortinisuseless. TheCortin
studiescanthereforeatbestbeclassedasinconclusive,andtheperformanceoftheTTCin
93 recruitingcaseswaspoorandalthoughfurthertrialistswerecontacted,itwastoolate.
PerhapstheMRCfeltanobligationtostudytheOrganondrug,havingrefusedanimport
88
T.R.ElliotttoF.H.K.Green(21December1933),T.R.ElliottFiles,WIGC/42TTC 193334.
89
ClinicalTrialsofExtractsofSuprarenalCortex(6February1934),T.R.Elliott Files,WIGC/42,TTC193334,13/1.
90
F.Menzies(LondonCountyCouncil)toT.R.Elliot(23March1934),TRElliott Files,WIGC/42,13/1TTC193334Clinicaltrialsofextractsofsuprarenalcortex, conferenceSimpsonhadalreadypublishedexperimentalstudiesusingrats:S.Levy Simpson,A.KohnSpeyer,V.Korenchevsky,TheAdrenalCortexandSexLancet(25 November1933):1194.

91
MRCClinicalTrialsofCortin,firstconference(6February1934),T.R.ElliottFiles, WIContemporaryarchive,13/1TTCcorrespondence. 92 ThequoteisfromT.R.ElliotttoF.H.K.Green,12March1936)TTCMeeting7, (11February1937),MRCFile1523/15Elliotttreated1,LevySimpson6,MurrayLyon4, Wilkinson9,T.R.ElliottFiles,WIGC/42TTC193334 SocietyofTherapyand Pharmacology (1937):11411145.

93
F.H.K.GreentoT.R.Elliott,(30April1934):T.R.ElliottFiles,WIGC/42,TTC 193334.
363
364
94 licenseofthatfirmsinsulininOctober1923. Thefailureofthestudymaybeascribedto
therelativerarityofthetypesofpatientsrequired,buttheresultsthatwereavailablewere notstunningandthisalmostcertainlyreflectedthequalityoftheextractsprovided.Itwould beafurther20yearsbeforethecomplexchemistryoftheadrenocorticalsteroidswasfully resolved. 8.4.3ProgestationalAgents. OrganonapproachedthecommitteetostudyitsProgestinextract,trademarked 'Hombreol',havingalreadyindependentlyapproachedasurgeon,Mr.VictorDixatthe

95 LondonHospital,toperformastudyinprostaticcases. TheTTCarrangedfurtherstudies
throughitssubcommitteemembersA.S.ParkesandChassarMoir,butitwasdifficultto
96 collectadequatedata.HombreolwasalsostudiedatGuysHospital, andSt.
BartholomewsinLondon,Edinburgh,Manchester,inpatientssufferingrepeatedabortion,
97 98 prostaticcases,andchronicinterstitialmastitis. Oncemoreoverallresults were
inconclusive,buttheEdinburghdatawasatleastsubmittedtotheBritishMedical
99 Journal. By1934theactiveprincipleprogesteronehadbeenisolated,butithadtobe
injectedinlargequantitiestobeactiveanditwasseveralmoreyearsbeforeasynthetic routewasderived. Meanwhile,bythetimeoftheseventhTTCmeetingon11February1937,amore purifiedSwissversionoftesticularhormonewasavailableasCIBA2020,anditwas decidedtoabandonOrganonsHombreolinfavourofthis.CIBAhadbeeninthe

100 hormonefieldsince1913,whentheyfirstpreparedovarianextracts. Therewerealready
atleast4preparationsonthemarket(ProlutonfromSchering,ProgestinfromOrganonand BDH,andLutrenfromBayer).NeverthelessOrganonstillsoldNeohombreol,fromMay 1942.CIBA2020wasforwardedtotheLondonHospital,St.Bartholomews,andto

94
JonathanLiebenau,MedicalScienceandMedicalIndustry.TheFormationofthe AmericanPharmaceuticalIndustry (Basingstoke:MacMillan,1987):1767MRCFile, 1092/35Organon.

95 96
TTCMinutes6,(28February1936),MRCFile1523/15. TTCMinutes8,(7February1938),MRCFile1523/15. 97 MissA.N.MacBethtoF.H.K.Green(29July1938),T.R.ElliottFiles,WIGC/42 TTC193542TTCMinutes6,(28February1936)MRCFile1523/15. 98 TTCMinutes5,(5March1934),MRCFile1523/15. 99 TTCMinutes6,(28February1936),MRCFile1523/15. 100 W.Sneader,(1985):193.
364
365
OxfordwhereProf.J.A.Gunnperformedphysiologyexperimentstoconfirmitspowerful
101 pressoreffectandfoundadrenalinlikeeffectsontheintestineandrabbituterus.
Publicationofhisstudywasheldupattheendof1937untilCIBAmadedecisionsona nameforthedrug,andwhethertheywouldmarketit,astherehadbeensomeminorsafety
102 issues. Bythefollowingyearastudyof150patientshadbeencompletedinLondon 103 confirmingthesharprisesofbloodpressureandalsoutilityinasthmapatients. Schering
Kahlbaum,attheforefrontofattemptstosynthesisethehormone,senttotheTTCtheir malehormoneextract,Proviron,forthetreatmentofbilateralorchidectomy,premature senility,andimpotence.Howeveroveraperiodof2years,onlyonecasewassecuredfrom 2centresandalthoughtwofurthercentreswereaddedeventuallythisstudywasalso

104 abandoned.
Inconclusion,despitetheTTChavingamajorinterestinorganotherapy,theyfailed toestablishsuccessfulclinicaltrialswithseveralorganextracts.Allpreparationssentto themwereacceptedforevaluation,evenwhenalternativeversionswerealreadyavailable commercially.TheTTCdidnotadheretotheirpromisetoexamineonlynovelagentsand onseveraloccasionstestedpreparationssimplytoensurethataBritishversionwas available,whileallowingtestingofforeignpreparationsfromOrganonoftheNetherlands andCIBAofSwitzerlandwhentheythoughtthiswouldreduceprices.TheTTC recognisedtheproblemswithearlyextractsbeingofvariableandoftenweakpotencyand theywereflexibleintheirapproachtoevaluatingnewextractsthatofferedgreaterpotency. Theironlyrealsuccesswaswithoestrone,andthiscorrelatedwiththeparalleldevelopment oftheunderstandingoftheactiveingredientsandultimatelywiththeirsynthesisand manufacturebypharmaceuticalfirms. 8.4.4PerniciousAnaemia.
101
TTCMinutes9,(14July1938),MRCFile1523/15Gunnwasstilltestingitin1939, TTCMinutes10,(28March1939). 102 F.H.K.GreentoT.R.Elliott,(13October1937)andT.R.ElliotttoF.H.K.Green (15October1937),T.R.ElliottFiles,WIGC/42TTC193542. 103 Thecontinueduseofthecodenamewasunderstandableinthelightofthechemical nametrimethoxybenzyldihydroimidoazolhydrochloride.Preparation2020forraising BloodPressure,PharmaceuticalJournal 140(26February1938):211. 104 TTCMinutes4,(undated,1933)TTCMinutes5,(5March1934)TTCMinutes6, (28February1936),MRCFile1523/15.
365
366
In1926twoAmericanscientistsdiscoveredthatinperniciousanaemia,rawliver couldcureapreviouslyfataldisease,andwhileitwasundesirabletogivethelarge quantitiesofliverextractrequired,thiswasattemptedwhiletheactiveprinciplewas sought.GlaxolicensedanextractionprocessdevelopedinNorwayin1936,resultinginthe

105 marketingofExamen. BurroughsWellcomemadeliverextractscommerciallyfrom
December1927,andbeingunabletodecideuponclinicalteststheycontactedthe ChemotherapyCommittee,andthendirectlyapproachedtheAssociationofClinical Pharmacologists.Asaresult,andasdescribedinthepreviouschapter,theMRCbecame involvedinstudyingliverextractsforperniciousanaemiain1928.BurroughsWellcome producedamoreconcentratedforminMay1932andtookpartintheirfirstPernicious

th AnaemiaConferenceon5 January1934,involvingAllen&Hanburys,Boots,British
DrugHouses,BurroughsWellcome,OxoandGlaxo.Giventhepreviousconflictsonthis project,theTTCmaintainedthatdoctorspreferredtoreceivesamplesviatheMRC,rather
106 thandealingdirectlywithafirm. Despitethis,WilkinsoninManchestercontinuedto
testbothstomachandliverpreparationsbydealingdirectlywithBoots.Meanwhile,the AssociationofClinicalPathologists,thathadtriedtocollaboratewiththeMRCbecame frustratedwiththem,andturnedtousingwhattheyregardedasasuperiorGerman preparation.Anumberofcommercialliverpreparationswereavailableuptotheoutbreak

107 oftheSecondWorldWarinamarketdominatedbyBritishandAmericanfirms.
8.4.5Vitamins. WhileGlaxoembracedvitaminsimmediately,itwillberecalledthatBurroughsWellcome wasmorecircumspectuntiltheymanufacturedCalciferol fromSeptember1932.Manyof

108 theearlypreparationsusedfishliversasthesourceofvitamins. Bytheearly1930s
interestwasrekindledafteraseriesofstudiesledtothediscoveryofthechemicalstructure ofvitaminCasascorbicacid,allowingsynthesisandtherebyavoidingthevariablenatureof extracts.YetwhencommercialproductionofsyntheticvitaminCwasachievedby

109 HoffmanlaRocheofSwitzerland, andtheyapproachedtheTTCin1934,Elliottargued
105
R.P.T.DavenportHines,JudySlinn,Glaxo:AHistoryto1962(Cambridge: CambridgeUniversityPress,1992):176. 106 HelenKathrynValier,(UniversityofManchester:PhDthesis.2002):180.

107 108 109
CommercialLiverPreparationsPharmaceuticalJournal 142(11March1939):169. TheCodLiverIndustryPharmaceuticalJournal 141(19November1938):529. WalterSneader,(1985):234.
366
367
thatascorbicacid,intheformoffruit,hadbeenusedforyearsandhedidnotconsiderthat thesyntheticagentwasanydifferentsotheTTCdidnotpursueanystudies.Yet,when GreenlaterreceivedacasereportofthefirstpatienttreatedintheUK,hewasatleastin

110 favourofpublicationifonlyforitshistoricinterestandsotoo,wasMellanby. Elliott
arguedthatCalciferol,(vitaminD2)couldalsobeconsideredsynthetic,thoughitdidnot originatefromelementarysubstances.Meanwhile,BurroughsWellcomedecidedto
111 manufacturethesyntheticvitaminandissuedsuppliesinSeptember1934. Thenitwas 112 recognisedthatirradiatedmilkofferedthebestadministrationofvitaminD. Szent 113 GyorgysvitaminP(citrin)wasalsoprepared andsenttoDr.MacFarlaneandDr. 114 SylvesterZilvaattheListerInstituteforexperimentalwork. Prof.NoahNorris
comparedvitaminD3 andcalciferolinhumanricketswithoutshowinganydifferences, althoughasDaleshowedtheformerappearedahundredfoldmoreactiveinlaboratory

115 tests.
By1939Britishfirmsweremanufacturingthewholerangeofvitaminsinavariety ofpresentations.VitaminAwasproducedascapsules,tabletsandinaparenteralform. BurroughsWellcomemadevitaminsA,B1,B2,C,andD.BritishDrugHousesmadeA, B1,B2,C,D,Eandcombinations.Allen&HanburysmadevitaminsA,B1,B2,C,D,and combinations,andGlaxomadethewholerangeandalsovitaminP.MayandBakermade

116 onlyvitaminA.
8.5Prontosil:aNewEraofChemotherapy. In1935Dr.GerhardDomagk,directoroftheBayerResearchlaboratoriesin Elberfeld,reportedthediscoveryofthefirsteffectivesulphonamideantibacterial,with
110
F.H.KGreentoT.R.Elliott(19February1935),T.R.ElliottFiles,WIGC/42 TTC193542.
111 112
STCMeeting,(19May1933),WF:STCS/G/49. DosageofVitaminDBritishMedicalJournal (17November1934):907. 113 STCMeeting,WCRLReport,(22January1937),WF:STCS/G/50. 114 STCMeeting,(22January1937),WF:STCS/G/50F.H.K.GreentoT.R.Elliott, (19February1935),T.R.ElliottFiles,WIGC/42TTC193542. 115 H.H.DaletoF.H.K.Green(8July1938),T.R.ElliottFiles,WIGC/42TTC 193542
116
TheVitamins(VI):thePotencyofCommercialPreparationsPharmaceutical Journal 142(21January1939):5459.
367
368
117 promisingactivityagainststreptococcalinfections. HenryDalewasprobablythefirst
personfromthiscountrytomeetDomagkatBayer,andtosharehisfindingbefore
118 publication,whichwasdelayedforayear. AftertheTTChadfocussedforfouryears
onBritishdrugs,thescientificandmedicalpromiseofProntosiloutweigheditsGerman origins,buttheCommitteestilldebatedwhoshouldtestit. Accordingtotheirrecords,the TherapeuticTrialsCommitteewereapproachedbyColebrookfromQueenCharlottes HospitalinLondon,whowantedtobethefirstandonlypersonintheUKtoworkon

119 Prontosil. InanotherversionDale:
SucceededinpersuadingthehighlyscepticalColebrooktoundertakesucha controlledtrialofitsactiononpatientsinhisPuerperalFeverUnit,aswould convincinglydeterminewhetherthesubstancewasclinicallyeffective,and finallyhavinghadthechance,Colebrookconfesseditwasratherbetterthan 120 anythingthathetried.
Dalewasastoundedtohearthestorythathe(Colebrook)hadtakentheinitiativeand
121 goneovertoElberfeldandcorroboratedhisversionwithFrankGreen. Nevertheless,
theCommitteeagreedtoallowColebrooktoinvestigateProntosileventhoughElliott remarked:wewillnevergetconvincingclinicalevidencewhenareportismadebyonly
122 oneman. 123 Prof.CharlesCyrilOkell, ProfessorofBacteriologyatUCHsince1930,having
workedinthelaboratoriesofBurroughsWellcome,notedthatHopefulresultson
117
Domagk(18951964)qualifiedinmedicinein1921andtrainedasabacteriologist. HewasappointedasDirectorofResearchatIGFarbenin1927:R.A.Kyle,M.A. Shampo,GerhardDomagkJAMA 247(14May1982):2581. 118 H.H.DaletoA.LandsboroughThompson,(17February1967),93HD47.5.151. 119 F.H.K.Green,G.Covell,MedicalResearch,chapter7inA.S.MacNalty(ed.), HistoryoftheSecondWorldWar(London:HMSO,1953):258271E.J.Lowbury, LeonardColebrook(18831967)BritishMedicalJournal 287(1983):19813J.L.Turk, LeonardColebrook:theChemotherapyandControlofStreptococcalInfectionsJ.Roy. Soc.Med87(December1994):72728.
120
H.H.DaletoA.LandsboroughThompson,(17February1967),DaleArchives,Royal Society,93HD47.5.151. 121 H.H.DaletoA.LandsboroughThompson,(17February1967),DaleArchives, RoyalSociety,93HD47.5.151. 122 T.R.ElliotttoF.H.K.Green,(8May1935),T.R.ElliottFiles,WIGC/42TTC 193542.

123
CharlesCyrilOkell,ObituaryBritishMedicalJournal (18February1939):362.
368
369
124 ProntosilhadbeenreportedfromGermany. HeexplainedtoGreenthattheGerman 125 workwasnotasuddenskyrocketbuthadbeenburningsteadilyforsometime. Early
in1935,BayertoldDalethattheywerereadytosupplyProntosiltotheMRCandhad Okellnotfallenill,hewouldprobablyhavebeentestingProntosilaheadofColebrook. HavingestablishedtheinitialmainstudywithColebrook,theCommitteewas inundatedwithrequestsforProntosil,andtheyacceptedthemallexceptonefromaDr.A. H.Douthwaite,ofHarleyStreetwhowishedtoperformaclinicalstudyofstreptococcal arthritisafterhearingalectureonProntosilbyProf.HeinrichHrlein,theHeadofBayer

126 Pharmaceuticals. ElliottrecommendedthatDouthwaiteshouldnotbesupplied:Heisa
manwithbrainsandperhapsacriticaljudgementbuthasbeenspoiledbysuccessin practice.Hewritestoopubliclyeverythingthathetouchesistherightthingbecausethe
127 kinghastouchedit. Prof.C.H.BrowninginGlasgowinvestigatedProntosil,andDr.
AlexanderJoeattheNorthWestFeverHospital(inEdinburgh,)treatedcasesoferysipelas andscarletfever,thoughwithdiscouragingresults.Londonstwofeverhospitalstreated
128 casesofgonorrhoeawithBayersUleronformulationofProntosil. InMarchof1936, 129 GreencontactedW.R.SnodgrassinGlasgow, andhetreated60erysipelascases,while 130 Prof.Ellisagreedtotreatcasesofarthritis. Wilkieshowedremarkablygoodresultsin 131 somecases.
124
Prof.Okelldrewattentiontoapaperin DeutscheMed.Woch:T.R.ElliotttoF.H. K.Green,(8May1935),T.R.ElliottFiles,WI:GC/42193343.

125
T.R.ElliotttoF.H.K.Green,(8May1935),T.R.ElliottFiles,WIGC/42TTC 193542.
126
F.H.K.GreentoT.R.Elliott,(7October1935),T.R.ElliottFiles,WIGC/42 TTC193542.HrleintookchargeofBayerspharmaceuticaldepartmentin1910andhe hadengagedthescientistsRoehlandDomagkwhocontinuedBayerstraditionof discovery.FromGermanintoAcylureidopenicillin (Leverkusen:Bayer,1980):1332.

127
T.R.ElliotttoF.H.K.Green,(10October1935),T.R.ElliottFiles,WIGC/42 TTC193542. 128 TTCMinutes8,(7February1938),MRCFile1523/15TreatmentofSyphilis Lancet(25September1937):75960. 129 F.H.K.GreentoT.R.Elliott,(9March1936),T.R.ElliottFiles,WIGC/42,TTC 193542.

130 131
TTCMinutes6,(28February1936),MRCFile1523/15. TTCMinutes7,(11February1937),MRCFile1523/15.
369
370
ThomasHenrymadeProntosilattheWCRLfortrialatWPRL,andapatentsearch
132 wassetunderwaytoseewhetheritwasprotected. Althoughitwasasimplederivative
ofadyeintermediate:evenifitprovedtobeunprotectedBurroughsWellcomedoubted whetheritcouldbemanufacturedsuccessfullyincompetitionwithadyeworks,andthere
133 wasevidencealreadyofRochepatentactivity. However,J.TrfoulatthePasteur
Instituteshowedthatthecolourlessparaaminobenzenesulphonamidewastheactivepartof
134 Prontosil,andasithadbeendescribedin1908,itwasunprotectedbypatents. Alarge
batchofthisbasecompoundwasmadeatDartfordbyaprocesssuppliedbytheWCRL, fortestsonlargeranimals,forclinicaltrials,andasastartingpointforpreparingfurther
135 similarsyntheticderivatives. Thefirstofthesetobeofferedfortestingwas 136 diaminodiphenylsulphone. BurroughsWellcomeofferedBritishmadeProntosiltothe
TTCasthematterwasurgent,inviewofpossiblesimilaractionbyanotherfirmTrevan suggestedthatifthetrialwereagreed,fulldetailsofthepharmacologicalresultsatthe
137 WPRLwouldbesupplied. On1October1935,theyheardthattheTTCwerealready
examiningmaterialfromanothersource(Bayer).G.A.H.Buttle,whoworkedunder TrevanattheWPRL,sentalettertotheSecretaryoftheTTCregardingpreliminary
138 experimentswithProntosilinmeningococcalbacteria(acauseofmeningitis). Burroughs
WellcomeadvertisedthattheyhadpreparedProntosil,andcontrarytotheirusual experiencesofdifficultiesinarrangingtrials,theysetupapolicyfordealingwithan anticipatedrushofexternalrequests: a) ThosecomingfromGPsandmenofnooutstandingimportancealetterwouldbe sentadvisingthatthepreparationwasunderclinicaltrialbytheTTCandwouldnot bemadeavailableuntiltheirreportispublished.
132 133
STCMeeting,(12July1935),WF:STCS/G/50. IGpatent430,580waspossiblyanticipatedbyRo149,428,STCMeeting,(15 November1935),WF:STCS/G/49. 134 M.Weatherall,InSearchofaCure:aHistoryofPharmaceuticalDiscovery (Oxford:OxfordUniversityPress,1990):150153. 135 STCMeeting,(13March1936),WF:STCS/G/50. 136 ReportofWCRL,(January1937),WF:STCS/G/50. 137 STCMeeting,(29May1936),WF:STCS/G/50. 138 G.A.H.Buttle,R.A.Q.OMeara,TheModeofActionof betaaminobenzenesulphonamideandProntosilinhaemolyticStreptococcalInfections Lancet(5December1936):132326.
370
371
b) MenconsideredbytheDirectoroftheWPRLtobeofsufficientimportancewereto receivespecimenswithintroductionregardingdosageetc.directfromtheWPRL whoweretomaintainalistofthosesupplied. GiventheintenseinterestinProntosil,itwasfrustratingfortheTTCtowaitsolongforthe resultsfromColebrook.Dr.R.M.FrywhocollaboratedwithColebrooksentinasummary reportofthefirst36casesofhaemolyticstreptococcalinfection.FewpatientsonProntosil diedoftheirinfections,butinlargedosesitwasassociatedwithsomeadverseeffects,and asaresulttheTTCadvisednottouseProntosilprophylactically.Almostayearafter beginninghisstudiesonProntosil,Colebrooksentinthereport,whichwouldeventually

139 heraldthedawnofthenewchemotherapeuticera. However,theinitialpaperwasnot
wellwrittenandprovokedsignificantdebateattheTTC,incurringfurtherdelays.
140 DalediscussedthepaperwithAndrewesandKingandresolvedseveralerrors.
Elliottwrote:Idon'tfindthewholepaperwellwrittenanddonotthinkitwilldomuch morethanincitesomeotherinvestigatortotrythesubstance,andyethesupported publicationinthehopethatfurtherevidencewouldconfirmthatthesubstanceis

141 unquestionablyuseful. AfurtherdraftofColebrookspaperwasforwardedfromElliott 142 toGreenandwasdiscussedatameetingoftheTTCinDecember1936. Elliotthad
alreadysenthiscommentsdirectlytoGreen: SinceMellanbyissatisfiedwiththispaperIagreetoitsimmediate publication.Iwasn'tmuchimpressedbythefirstpaper,andIregrettedthe outburstofexcitementinthepublicpressaboutthediscovery,whichwas onlyanextensionoftheGermanwork.Someofthecasesinthesecond paperareindeedcertainlymoststriking.But,thewriting,withitsitalicsand excitedadjectives,remindsmeofQueenVictoria's'Leavesfromahighland diary' afterwhichpage10dragsonedownwithasadbathus.(Sic).This page10mustberewritten.Iremainalittlesceptical,andIwonderwhether
139
140
F.H.K.GreentoT.R.Elliott,(22May1936),T.R.ElliottFiles,WIGC/42TTC 193542.
141
142
L.ColebrooktoF.H.K.Green,(29October1936),F.H.K.GreentoT.R.Elliott, (29October1936),T.R.ElliottFiles,WIGC/42,TTC193542.
371
372
thetreatmentisanybetterthanthatbyGlycerinewhichDr.Colebrook,I 143 think,formerlyadvocated.
Thepartinglinemadeitclearthat,despitehavinganewsubstancewithunparalleledactivity inthelaboratory,anddespitethedelayandmultipleeffortstowritethepaper,ithadbeen impossibletodesignandperformaclinicaltrial,whichconclusivelyshowedthebenefitof Prontosil.Colebrook'strialwasfinallypublished,andsoonotherProntosilreports appeared.144 Graduallyapositiveconsensusofitsremarkableactivityemerged,opening thewayforseveralfirmstoproducesulphonamidevariantsbychemicalmodification, includingAmericanCyanamid,Sharp&DohmeandMerck.Colebrooktestedthe

145 sulphanilicacid4acetanilide(Ilivin)ofE.Merck,whichwasmeanttobelesstoxic.
EvansSons,Lescher&WebbandBurroughsWellcomealsoforwardedpreparationstothe
146 TTC.
Greenmetinvestigatorswhonotedthealarmingadverseeffectsofcyanosisand thoughtthedrugmightbeaffectingthepatientsheart.Itbecameapparentthatthenew agentsthoughofferinggreatpotential,werenottheEhrlichs'magicbullet'fortheyhad newandhithertounseendangersanditwasessentialthatthesewereobjectivelyassessed. Colebrookinvestigatedallnewsulphonamidesandproducedabetterreportofhis

147 experienceofsulphanilamideforpuerperalfever. ThepromiseshownbyProntosil
encouragedtheGovernmenttoinvest30,000in1936inthepreparationofchemically
143
T.R.ElliotttoF.H.K.Green,(28October1936),T.R.ElliottFiles,WIGC/42, TTC193542.
144
T.R.ElliotttoF.H.K.Green,(12February1937),T.R.ElliottFiles,WIGC/42, TTC193542.L.Colebrook,M.Kenny,TreatmentofHumanPuerperalInfectionandof ExperimentalInfectionsinMicewithProntosilLancet (6June1936):279Treatment withProntosilofPuerperalInfectionsduetoHaemolyticStreptococci,Lancet (5 December1936):131922.

145 146
TTCMinute9,(14July1938),MRCFile1523/15. TTCMinutes8,(7February1938),MRCFile1523/15. 147 F.H.K.GreentoT.R.Elliott,(18October1937),T.R.ElliottFiles,WIGC/42, TTC193542.
372
373
148 uniquesulphonamides,andresearchinchemotherapywasexpandedattheNIMR. The
MRCconclusionswerethat: Resultsofpracticalvaluehadsofarbeenmeagrewhencomparedwiththe workdoneinGermanyonalargescaleoveralongerperiodeffective cooperationwasnotobtainableinthiscountry.Variousproposalsfor expansionoftheschemewerementionedandparticularlyoneforacentral labforcombinedchemicalandbiologicalinvestigationssupplementedby 149 grantsinaidofworkatacademiccentres.
IhavedescribedhowBurroughsWellcomebeganpreparingProntosilasearlyas 1936.Nopatentcouldbetracedforthewatersolublesulphonamide,whichBurroughs
150 WellcomealsopreparedasSoluseptasinein1936. Thisandsimilarproductsappeared
inpublicationsasMay&BakeralsopreparedanintramuscularformofSoluseptasineand
151 anoralform,proseptasine.
ItistheexperienceofourrepsinthiscountryandthatinmanyInstitutesthat ProntosilandProntosilalbumhavegainedaverystrongholdandthatinmany Institutessuppliessufficientfor1yearhavebeendonated.Wehearfromour Egyptiandepotthatsolusephasineisbeingdistributedliberallyinordertofully establishitinthatterritory.Thecompetitionismakingconsiderableprogressas 152 aresultoftheirextendedclaims. ThefirstBritishfirmtomarketasulphonamidewasMay&Baker,whereGeorge

153 Newberry, agraduateoftheRoyalCollegeofSciencewhohadjoinedin1918prepared
ProntosilasM&B576inJanuary1936.ByMay1937BurroughsWellcomesSulphP, versionofProntosilwasbeingusedforotitismedia,mastoiditis,rheumaticfever,
148
MRCAnnualReport19367,(1937):915referstoNIMR588/6memoThePresent PositionandFutureDevelopmentofBritishResearchWorkinChemotherapy(17March 1936). 149 MRCMinutesIII,(20March1936):47. 150 G.M.Roberts,SoluseptasineandSulphapyridineinMeningitisDuetoPfeiffer BacillusBritishMedicalJournal (25November1939):1041ATableof Sulphonamides,Chemist&Druggist146.1(14September1946):33637Soluseptasine andProsephasineBritishMedicalJournal (27March1937):666. 151 STCMeeting,(19November1937),WF:STCS/G/50. 152 STCMeeting,(7May1937)WF:STCS/G/50. 153 J.Slinn,AHistoryofMay&Baker18341984(Cambridge:HobsonsLtd., 1984):100,124.
373
374
meningococcalmeningitis,puerperalsepsisandthesofttissueinfection,erysipelaswith
154 greatsuccess.
ArthurJ.Ewinsandhisteamsynthesisedthesulphonamideanalogue,M&B693in November1937andsentasampletoDrLionelWhitby,pathologistattheMiddlesex Hospital,andAssistantPathologistattheBlandSuttonInstituteandhehelpedthemto

155 selectthisastheirmostpromisingderivative. SampleswerealsosenttoDr.R.Wienat
thepharmacologicallaboratoriesofthePharmaceuticalSocietyfortestinginmice,andit
156 wasmadegenerallyavailableinSeptember1938assulphapyridine. Therewassome
adversecriticismofM&B693bytheAmericans,butColebrookresolutelydefendedthe
157 sulphonamides.
AsregardsthetestingofBayerProntosil,GreenrecordedintheminutesoftheTTC meetingin1938that: Thedrugswerenowbeingtestedsoextensivelyinvariousdiseasesby independentworkersthroughouttheworldthattheirvalueandlimitations werelikelytobedeterminedwithouttheCommitteetakingfurtherinitiatives, unlesssomenewandparticularlypromisingvariantofsulphanilamidewerein 158 duecourseoffered. Snodgrasshadextendedhisexperiencetoinclude360casesofScarletfevertreatedwith

159 sulphanilamide. FundamentaldetailsrelatingtothedosagewereunclearandColebrook
hadnoexactinformationontheincidenceoftoxiceffectsthoughhehadseentwocases
160 ofagranulocytosis,ordepletionofthewhitebloodcells. Therelationofdosageto
154 155
STCMeeting,(24May1937),WF:STCS/G/50. H.H.DaleArthurJamesEwins,BiographicalMemoirsofFellowsoftheRoyal Society 4(1958):8191L.E.H.Whitby,Lancet(26May1938). 156 J.Slinn,(1984):122125H.J.Barber,HistoricalAspectsofChemotherapy:Six Essays(May&Baker,1978):27. 157 P.H.LonginIagoGaldston,BehindtheSulfaDrugs.AShortHistoryof Chemotherapy (NewYork:AppletonCentury,1943)P.H.Long,E.A.Bliss,The ClinicalandExperimentaluseofSulfanilamide,Sulfapyridine,andAlliedCompounds(New York:MacMillan,1939)
158 159
TTCMinutes8,(7February1938),MRCFile1523/15. W.R.Snodgrass,SulphanilamideinChemotherapyBritishMedicalJournal (1939):297. 160 T.T.C.Minutes10,(28March1939),MRCFile1523/15.
374
375
toxicitycertainlyneedstobecarefullystudied.Itisalittledifficultinourcasesassomany
161 ofthemhavehadacertainamountofsulphanilamidebeforeadmission.
ReferencewasmadetoBDHandtheircompressingoftablets: Thelongerwemaintainourstrictlyconservativeattitude,themoredifficultit becomestoestablishtheproductofthefirmandinviewoftheresearchwork doneintheInstituteoftheFoundationitisonlyreasonablethatBW&Co 162 shouldreapthefullestcommercialreward.

163 BDHhadasulphonamideavailablein1937. Meanwhile,BurroughsWellcomeprepareda 164 seriesofsulphonamidederivatives,includinganewheterocyclicsulphonamide, and
ButtleandTrevanworkedonadiacetyldiaminodiphenylsulphonederivative,whichwas
165 senttoProf.GarrodatSt.Bartholomews, whileclinicaltrialsofsulphonamide
glucosideandalsoadiadipylderivativewereproposed,iflaboratorytestswerepromising. Inshort,theexcitementcreatedbyProntosilandthelackofpatentprotectionofthe originalbasestimulatedBurroughsWellcomeandotherBritishfirmstoproduceaseriesof

166 sulphonamidesfortesting. C.J.HewlettandSons,May&Baker,EvansSons,E.R.
SquibbandBurroughsWellcomepatentedvarioussulphonamidesin1937,andTrevan arrangedclinicaltrialsofSulphonamidePin1938.TheTTCfoundthatSolusalvarsan waslesseffective,andwasmoretoxicthanneoarsphenamine.Therehadbeeneightcases ofarsenicaldermatitis,includingonewithjaundice,outofonly20casestreated.Itlacked theadvantagesclaimedandgavegeneraltoxicsymptomsorlocalpainonlyInthiscase theTTCdecidedthattheresultswouldnotbepublishedunlessthecompanywithdrewthe
161
L.ColebrooktoF.H.K.Green,(11May1939),T.R.ElliottFiles,WIGC/42, TTC193542.
162 163
STCMeeting,(24May1937),WF:STCS/G/50. SulphonamideBDH,PharmaceuticalJournal (13February1937):187 Sulphonamidecompounds:aSummaryofRecentReports,PharmaceuticalJournal (25June 1938):66566. 164 STCMeeting,(31January1939),WF:STCS/G/50. 165 J.H.Gaddum,JohnWilliamTrevanBiographicalMemoirsofFellowsofthe RoyalSociety 3(1957):275. 166 C.L.Oakley,NoteonProntosilPoisoninginMiceBiochemicalJournal 31 (1937):729730AnOutlineofChemotherapySulphonamidesPharmaceuticalJournal 142(29April1939):44344.
375
376
167 productandtheydecidedtoadvisetowithdrawapplicationtotheMinistryofHealth.
Atthe1939BritishPharmaceuticalConference,chairmanJ.RutherfordHill calledfor
168 clinicalexperiencetestspriortodefiniteauthoritativerecognition. Hisconcernwas
thatBritainwasstillfightingabattleagainstpatentmedicinesandcarelessmanufacturers recallingthatthishadbeenongoingsincetheearlyeffortsofProfA.J.Clarkandthatthe 1914SelectCommitteehadwarned: Britishlawispowerlesstopreventanypersonfromprocuringanydrug,or makinganymixture,whetherpotentorwithouttherapeuticactivitywhatever (aslongasitdoesnotcontainascheduledpoison),advertisingitinany decenttermasacureforanydiseaseorailment,recommendingitbybogus testimonialsandtheunwantedopinionsandfacsimilesignaturesoffictitious physicians,andsendingitunderanynamehechooses,onthepaymentofa 169 smallstampduty,foranypricehecanpersuadeacredulouspublictopay. TheVenerealDiseasesActof1917representedtheonlyrealprogressthathadbeenmade againstsuchremedies. BecauseofthepublicitygeneratedbyProntosil,British firmsfoundreadytakersfor theirnewsulphonamidesanddidnotneedtoevaluatethemthroughtheTTC.Thiswasan importantmilestoneinthedevelopmentandtestingofthesyntheticBritish pharmaceuticals.Whenphysicianswereconvincedoftheactivityofinsulin,synthetic oestroneandsulphonamides,theywerekeentoparticipateinclinicaltrials.
8.6ClinicalTrialsofOtherAntisyphiliticsIncreasedSyntheticActivity. AlthoughSalvarsanhadbeenavailableandhadbeenstudiedextensivelyfor25 years,researchwasstillbeingperformedonorganicarsenicalsatBurroughsWellcomeand severalotherBritishfirmsin193437.EwinsofMay&Bakerregisteredpatentsfor
167
T.T.C.Minutes6,(28February1936)andT.T.C.Minutes10(28March1939), MRCFile1523/15.
168
J.RutherfordHill,PublicHealthinRelationtoRecognition,definition, standardisationandControlledsupplyofMedicinesPharmaceuticalJournal (22July 1939):85. 169 Ibid.
376
377
170 organicarsenicalsin19356. However,despitetheestablishmentofproceduresfor
testingnovelagentsbythesecondSalvarsanCommitteefrom1918,ColonelHarrison commentedontheunsatisfactorystateofthepresentarrangementsfortestingnew antisyphiliticremediesonbehalfoftheTTC...(itwas)unfairtothemanufacturertoexpect

171 onemantoassessanewremedy. HiscommentsreferbacktoBayersSolusalvarsan
inJuly1936,importedundertheTherapeuticSubstancesAct,whichHarrisonexaminedat St.ThomasHospital,buthisstudiesdraggedonforeighteenmonthsandwerestill
172 inconclusive.
GreenaskedHarrisontonominateasmalladhocconferenceofvenerologiststomeet attheMinistryofHealthtoundertakeclinicaltrialsofanypromisingnewantisyphilitics submittedtotheTTC.ThoseinvitedtoparticipatewereT.AnwylDavies,andV.E.Lloyd

173 ofGuys'Hospital,G.L.M.McElligott,andMrs.M.RorkeoftheRoyalFreeHospital 174 175 andThomasCarnwath ,aseniormedicalofficerintheMinistryofHealth. Firstlythey
discussedongoingtrialsofEustab(Boots),Bismutrat(distributedbyWilcox,Jozeau&Co. onbehalfofaNordmarkWerkeofHamburg),Solusalvarsan(Bayer),andMapharsan (ParkeDavis).Theunusualstepwastakenofinvitinganoverseasinvestigator,Prof.H.

176 HaxthausenofCopenhagentoparticipateintestsofEustab. However,Bootseventually
agreednottomarketEustabandin1938Bismutratwasalsogiventheverdictof unpromising177 Afterthepatentsofthetwoprincipaldrugsfortreatingsleepingsickness (tryparsamideandBayer205orGermanin),lapsedinNovember1935,Burroughs WellcomeannouncedthatTryparsonewouldbeavailableondemandasaspecial,following

170
D.M.Joliffe,AHistoryoftheUseofArsenicalsinManJ.RoyalSoc.Med.86 (May1993):28789. 171 F.H.K.GreentoH.H.Dale(9January1936):T.R.ElliottFiles,WIGC/42.TTC 193542ColonelL.W.Harrison,wasaspecialistinsyphilogy,whowasinvolvedin the InternationalStandardscommitteeMRCMinutes,(20January1922):190.

172
F.H.K.GreentoH.H.Dale,(9January1936)TTC.Minutes5,(5March1934) MRCFile1523/15.
173 174
TTCMinutes6,(28February1936),MRCFile1523/15. L.BryderinJ.AustokerandL.Bryder(eds.),(1989):69. 175 TTCMinutes6,(28February1936),MRCFile1523/15. 176 T.R.ElliotttoF.H.K.Green,(10January1936),T.R.ElliottFiles,WIGC/42, TTC193542.
377
378
theintroductionofNeocryl.MostoftheSTCmembersfelttherewouldbeconsiderable
178 demandthoughJowettfeltsaleswouldbeunremarkableattheprice. Burroughs
WellcomesNeocryl,(Crylarsan)wastestedinabout100casesofneurosyphilis,butno clinicianstreatedmorethanahandfulofcasesandasaresultnonehadsufficientcasesfora
179 publication. TheTTCwereconvincedthatthedrugwaslessactivethanTryparsamide,
andwhentheynotifiedthistotheManufacturersAssociation,theCompanydecidednotto markettheproductinBritain.Prof.WarringtonYorkeattheLiverpoolSchoolofTropical Medicinearrangedforhiscolleague,Dr.IanS.AcrestostudyNeocrylforAfricansleeping

180 sicknessintheBelgianCongoanditwasactive,butonlyinthefirststageofdisease.
FurtherconfirmationcamefromanotherofYorkesformercolleagues,Dr.F.Murgatroyd
181 intheGambia. InviewoftherenewedinterestinNeocrylandthecompetitiveprices,the 182 BurroughsWellcomestrategywasthatitwasonlytobesoldondemand. However,
thedecisionwasshortlivedasin1938theydecidednottodoanyfurtherclinicalworkon
183 Neocrylbecauseofsafetyissues. Incomparisontothesulphonamide,thearsenicals
werenowapooralternative.
8.7NovelCompoundsPutForwardforTestingbyBritishFirms19311939. IhaveoutlinedhowtheTTCextendedtheinterestsoftheMRCinorganotherapy, anareainwhichtheyfelttheycouldexertcontrolovermanufacturersbybiological standardisationandbrieflydescribedtheirstudiesofvitaminsandantibacterials.Theaimof thissectionistoevaluatewhichfirmsutilisedtheservicesoftheTTCandforwhich additionalproducts.ItgivesaninsightintothestateoftheBritishpharmaceuticalindustry

177 178
TTCMinutes8,(7February1938),MRCFile1523/15. STCMeetings,(19May1933),WF:STCS/G/49(15November1935),(13March 1936),WF:STCS/G/50. 179 TTCMinutes10,(28March1939),MRCFile1523/15.

180
W.YorketoF.H.K.Green,(15June1937),T.R.ElliottFiles,WIGC/42,TTC 193542.
181
Dr.F.MurgatroydhadtrainedinLiverpoolunderWarringtonYorkeandhad receivedagrantfromtheMRC:MRCMinutesII,(11November1927):190. 182 STCMeeting,(28May1936),WF:STCS/G/49. 183 STCMeeting,(18February1938),WF:STCS/G/49.
378
379
from1931to1939andallowsanassessmentofhowmanyproductsweresynthetic,or otherwisenoveldrugsandhowmanywerecopiesofdrugsdiscoveredelsewhere.The generalgrowthofBritishpharmaceuticalmanufacturingbetween1919and1931was describedinchapter5. Inthe10yearsthattheTTCwasinexistenceatotalof59productswereacceptedfor testingasnotedintheformalminutesoftheirmeetings.Therewerethreeoccasionswhen twocompaniessubmittedidenticaldrugs,makingatotalof62drugstested.Thesewere providedasfollowsBoots9,BurroughsWellcome8,BritishDrugHouses7,CIBA (Switzerland)4,May&Baker3,E.Merck(Germany)3,Organon(Netherlands)3, HoffmannlaRoche(Switzerland)3,Bayer(Germany)3,Napp(UK)2,ImperialChemical Industries(UK)2,ParkeDavis(USA)2,WilcoxJozeau1,ABCM1,EliLilly(USA)1, Beiersdorf(Germany)1,Glaxo1,Merck(USA:NewJersey)1,Chase(France)1,Cilag (Switzerland)1,BoakeRoberts(UK)1,Schering(Germany)1,UpsterSmith(USA)1, independent1,SmithKlineFrench(USA)1.TheEdinburghbasedcompaniesdidnotuse theTTCandtheirmaininteractionwaswiththeResearchlaboratoryoftheRoyalCollege
184 ofPhysiciansinEdinburgh.
TheprincipalBritishcompaniesinvolvedwiththeTTCwereasfollows: 8.7.1BootsPureDrugCompany. TheimmediatepostwardevelopmentsatBootsweredescribedinChapter5,upto theappointmentofPymanin1927.IhavealreadydescribedhowBootspropylguiacol

185 antisepticwasrejectedatthefirstmeetingoftheTTC, thoughtheChemotherapy 186 CommitteethenarrangedtrialsofitasanamoebicideinKualaLumpur. JesseBootdied
inJuly1931,buthissonboughtanewsiteatBulwellontheoutskirtsofNottinghamand
187 returnedBootstoBritishcontrolagainin1933. Thefirmhadeffectivelybeenin
Americanhandssince1920whenJesseBootacceptedanofferof2.25milliontosellthe
184
EdinburghManufacturingHousesPharmaceuticalJournal 141(20August1938): 1634. 185 TTCMinutes5,MRCFile1523/15,(5March1934). 186 TTCMinutes1,MRCFile1523/15,(8July1931). 187 ChristopherWeir,JesseBootofNottingham.FounderoftheBootsCompany (Nottingham:TheBootsCompany,1994):601R.P.T.DavenportHines,J.Slinn. (1992):97.
379
380
188 businesstotheUnitedDrugCompany. Bootshadboastedbeingthelargestauthorised
manufacturersofinsulinandhadanunrivalledanalyticaldepartmentwithinaplantof14
189 acresandmorethanamillionfeetoffloorspace. TheBootsPureDrugCompanyhad8
drugsacceptedbytheTTC,though4ofthesewerevariantsofHarmol,asaltofthe alkaloidharmine,testedasapotentialvasodilatorforcoronarydiseaseandthealternative nonylHarmol.Harmolcouldbeusedtocutshortheartattacks,toforestallindividual attacksandtopreventattacks.ItwastestedinonlyonecaseattheTropicalLaboratories inLondon,andwasthensenttotheLondonHospital,toGuysHospital,theNationalEye Hospital,LondonandManchester,andalthoughstillonlytestedinalimitednumberof cases,describedasoflittlevalueyetitreceivedmuchpraiseintheNationalpress. BramwellinManchesterinvestigatedHarmolin41cases,butonly7respondedandthe

190 moreactive,butalsomoretoxicpropylHarmolin20cases. Someinvestigatorsfound
Harmolusefulforangina,whengivensubcutaneouslybutitcausedirritationandhadlittle
191 effectwhengivenorally,andlargerdosescausedcolic. ThiswasthereasonthatBoots
offeredamoresolubleversiontoFraserandRyleandsubsequentlytoawiderrangeof investigators,whileG.CarmichaelLowandN.HamiltonFairleyevaluatednonylHarmolas anamoebicideinthetropics.ItwasveryactiveagainstEntamoebabutunfortunatelyitdid

192 notsurvivetheacidtestofclinicaltrial. Theanalogyisinterestingastheacidtest
presumablyreferstotheuseoflitmuspapertogiveaclearunambiguousresult.Boots releasedacirculatorystimulantcalledPhrenazolontothemarketin1939andalsomarketed preparationsofHogsstomachforperniciousanaemiaandAnthostat,agonadotrophin hormoneextractbuttheycamelatetohormonalextractsandconcentratedfromthestart onsyntheticsincludingdiethylstilboestrol.
188
BootsDrugsBusiness.ReasonsfortheAmericanAmalgamationTheTimes(5 July1920):25. 189 JonathanLiebenau,TheMRCandthePharmaceuticalIndustryinJoanAustoker andLindaBryder(eds.),(1989):179. 190 TTCMinutes3,(8July1932),MRCFile1523/15J.C.Bramwell,J.M.H. Campbell,W.Evans,HarmolHClandonPropylharmolLactateinAnginaPectoris Lancet(8July1933):69G.K.Elphick,J.A.Gunn,Quart.J.Pharmacology (1932):37.
191 192
TTCMinutes2,(15January1932),MRCFile1523/15. H.King,FrankLeePymanObituaryNoticesofFellowsoftheRoyalSociety 4 (1944):681697.
380
381
193 Bootshadanearlierintestinalandurinaryantisepticcalledhexylresorcinol andamyl
metacresol,asyntheticderivativewasfoundbyPymantobe280foldmoreactivethan phenolonthebasisoflaboratorytests.Itwasputupforclinicaltrialin19312atSt. PetersHospitalandQueenCharlottesHospitalinLondon,butwasfoundtobeineffective

194 andnopublicationwasissued. FurtherBootsantisepticswerestudiedatStBarts,St
ThomasandQueenCharlottesinLondonandTheLondonHospital,theNationalHeart
195 HospitalandinEdinburgh,CambridgeandManchesterbutwithoutrealsuccess. Onthe
basisoftheTTCfindings,Bootsfeltthatthelackofactivitywasduetopoorsolubility, hencethereasonforpreparingmoresolublesaltswerepreparedbuteventuallyBoots agreednottoissuethesubstance. Prof.J.B.CoheninLeedswasamemberoftheMRCCommitteeonResearchin

196 ChemotherapyandtherecipientofanMRCgrantforbiologicalwork. Heprepared
Quinadil,andhadalongterm interestintopicalantisepticsandhadproducedvarious chloramineswithDakinduringtheFirstWorldWar.BootshadalreadysentQuinadiltothe ChemotherapyCommitteeandbothBootsandBDHsubmittedtheirversionsofittothe TTC,anditwasthenpromptlysentitbacktoProf.Cohenforevaluation,butithadno

197 specialadvantagesinsurgeryanditwasdecidednottopublishtheresults. W.A.Broom
andE.M.BavinofBootsperformedpotencytestsontheirheparinpreparationand
198 collaboratedwith theNIMR,butitwasnotsenttotheTTC.
Insummary,Bootsachievedfewtrulynovelcompoundsinthe1920sandearly 1930s,whentheycontinuedtheirwartimeinterestinantiseptics.Theymarketedanew formofBurnolacriflavinecreamin1934.Theymusthavebeendisappointedthattheir interactionswiththeTTCasantisepticsandHarmolderivativesthattheythoughtwere usefulwereshowntohavelimitedvalueinsmallstudies.TheproblemfortheMRCwas thatlaboratorytestingofantisepticsdidnotreflecttheirpotentialactivitywhengiven

193 194
Chemist&Druggist103.3(12December1925)xiadvert C.H.Hampshirein WhatIndustryOwestoChemicalScienceRichardB.Pilcher,F. ButlerJones,(eds.),(Cambridge:W.Heffer,3rdedition,1945):6874TTCMinutes3,(8 July1932)TTCMinutes4,(unknown,1933),MRCFile1523/15S.A.B.Kipping. ChemistryandIndustry (25February1963):304.

195 196 197 198
TTCMinutes1,(8July1931),MRCFile1523/15. MRCMinutesII(15July1927):127. TTCMeeting3,(8July1932)TTCMeeting4,(undated),MRCFile1523/15. TheBiologicalStandardisationofHeparin,DaleArchive93HD38.16.3
381
382
systemically.Bootseventuallygaveuptheireffortsonantisepticsandtheytooprepared
199 sulphonamideantibioticderivativesafterthediscoveryofProntosil, patentinga
sulphonamideantibacterialwithincreasedstability,Psulphonoamidobenzamine,whichwas shownbytheNIMRtobethefirstagenttocuremiceinfectedwith Salmonellatyphi. UnderPymansdirectionaseriesofglycerophosphatessalts,histidinepreparations, glyoxalines,isoquinolines,arsenicderivativesandavarietyofamidinesweresynthesised andhisteamevaluatedlocalanaesthetics,antiseptics,pressordrugs,antimalarials, hypoglycaemics,purgatives,acridinesandorganicsaltsofbismuth200 Pymangavean insightintoBootsresearchinhispapertotheSCIon13May1935.Heexplainedthe chemistrybehindHarmolandthepreparationofbismuthinoilandtheimproveddrugsthat
201 werenowavailabletoreplaceSalvarsan,suchasStabilarsan,amorestableform.
8.7.2May&Baker. Ewinsbuiltupasmallbutstrongchemicalandmanufacturingteam.Inadditionto Newberry,theytookonCapt.R.W.E.Stickings,agraduateofKingsCollege.Theirwork focusedonarsenicalsfromRhnePoulencandthenfrom1925theypreparedtryparsamide underlicensefromtheRockefellerInstitute.FrankPaxonjoinedasachemist,thenmoved totheworksandwasreplacedbyDr.H.J.BarberfromKingsCollegein1927sotheyhad

202 4chemists,2pharmacistsand6assistants. FollowingBayersdemonstrationofthe
potentialoforganicarsenicals,May&Bakerbeganproducingthesechemicalsbychemical modificationfromSeptember1926,achievingthesynthesisofsomecompoundswith moderateactivityagainsttrypanosomes.Oneofthesyntheticserieswastestedinthe laboratorybyWarringtonYorkeinLiverpool,butdidnotprogresstotrials.May& BakersHalarsolwasevaluatedbytheTTCandfoundtobeusefulforsyphilisbuthad severesideeffectsandwasconsideredunsuitablethoughgoodresultswereobtainedin treatingyaws,atropicaldisease,causedbyasimilarspirochetebacteriatothatcausing
199
S.A.B.Kipping,(1963):302310.Bootsproducedpatentsonsulphonamide derivativesin1940and1942,H.King,(1944):681697. 200 H.King,FrankLeePymanObituaryNoticesofFellowsoftheRoyalSociety 4 (1944):681697. 201 F.L.Pyman,PharmaceuticalJournal (25May1935):619. 202 J.Slinn(1984):1001.
382
383
203 syphilis. TheTTCarrangedforcentresinCardiffandGlasgowtoevaluateamoredilute 204 solutionofHalarsol. ParosanwasrejectedbytheTTC,thoughnoreasonwasrecorded.
NeitherHalarsolnorParosanwerementionedinSlinnsHistoryofMay&Baker,norin the1948BritishPharmacopoeia,indicatingtheywereprobablydroppedthoughPyman
205 referredtoHalarsolin1935.
May&BakerhadonlylimitedinteractionwiththeTTC:ofthe3productsthattheyput forwardonewasrejectedandtheotherswereoflimitedvalue.Itisperhapssurprisingthat withEwinsinchargeMay&Bakermadesuchlittleprogress,butinthepastEwinshad beenpartofanexperiencedteamwithphysiologists,bothatBurroughsWellcomeandthe MRC.Inthe36yearsafterleavingDaleheputhisnametoonly6furtherpublications.He wasnotoneforinnovativework,butquicklybuiltuponthefindingsofothers.However oneofhiscolleagues,H.J.BarberatM&Bexplainedthathehadplayedasignificantrolein buildingtheirresearchcapacityatM&B.DrR.Wien,(whojoinedthefirmasaresultof theircollaborationwiththePharmaceuticalSociety),J.G.EverandMrE.J.Baineswere

206 colleaguesinthechemistrysection. May&Bakerfelttheyneededacliniciantohelp
themtomaximisethenewopportunityofferedbyM&B693.ThisisthefirstcaseIhave foundofaBritishpharmaceuticalfirmrecruitingaphysicianspecificallytoperformclinical trials.May&BakerputtheirrequesttotheABCMforadoctoraged30to35years: whocouldputinahalftothreequartersofhistimeattheworksofthe firm,andtherestofthetimedoinghospitalwork.Thelatterwouldhaveto bedonesomewhereeastwardsofLondoninorderthatthedoctorwouldnot havetospendtoomuchtimetravelling.Theworkwouldberelatedto venerealdiseasetreatmentanditwouldbethereforebeadvantageousifthe 207 hospitalworkcouldsimilarlybesorelated. Althoughnobodywasimmediatelycametomind,LandsboroughThompsonwrotetoPratt oftheABCMthat: thefactthatatleasthalfthemanstimewillbetakenupsuggeststhatheis todosomethingmorethanadviseonclinicalquestionsanddealwith
203 204 205 206
TTCMinutes4,(datenotrecorded,1933),File1523/15. TTCMinutes2,(15January1932),File1523/15. J.Slinn,(1984).
H.J.Barber,ArthurJ.Ewins,ObituaryChemistry&Industry (22February 1958). 207 May&BakertoABCM,(18September1935),ABCMMRCFile1523.
383
384
professionalinquiries,butifheistotakeanygreaterpartintheproductionor testingoftherapeuticpreparations,thenspecialqualificationswouldbe 208 required.
However,withinfourdaysacandidatecalledRobertForganwasidentified.Hewasalittle differenttotherequirementashewasnearly44yearsoldandhadbeensowinghis politicalwildoatsbeforereturningtogeneralpractice.HehadspecialisedinVenereal Diseasesformanyyears.Furthermorehehadexperienceofthecommercialsidehaving actedforatimeinanadvisorycapacitywithBDHLtd.Hewasdescribedasamanof

209 energyandideas,withaleaningtowardsworkofanadministrativekind.
IntheirnextroundofcommunicationwiththeABCM,May&Bakerindicatedthat theirrequirementswerewiderthanfirstindicated: 1.Amedicalmantodofulltimeworkonliteratureetc.insidetheoffice. 2.Connectionswithamedicalmanstillinpracticewhocouldgiveusadviceandassistance inlaunchingnewproducts,especiallyinmattersofdosageetc. 3.Oneortwomedicalmenwhowillactforusasanoutsiderepresentatives. Inthecaseofthelattertheywantedayoungmanotherwisetheywouldprobably

210 wanttoomuchremunerationorbenogood. Theaimwasclearlytomakethemostof
theirbreakthroughproductM&B693andtheemploymentofForgantogetherwiththe collaborationwithWhitbypointedtoagreaterindependenceinclinicaltesting.Itwas relativelyeasytoarrangestudiesofM&B693.Alargestudyof102casesreportedin December1938wasindebtedtoM&BforsuppliesofthedrugandtoDr.RobertForgan

211 212 foradviceandliterature. Forganhelpedtoproduceapamphletaboutthedrug.
208
A.LandsboroughThompsontoJ.D.Pratt,(20September1935),ABCMMRC File1523.
209
A.LandsboroughThompsontoJ.D.Pratt,(24September1935),ABCMMRC File1523.
210
J.D.PratttoA.LandsboroughThompson,(27September1935)ABCMMRC File1523.
211
R.C.L.Batchelor,R.Lees,M.Murrel(EdinburghRI),G.J.H.Braine(Colonial MedicalService),BritishMedicalJournal (3December1938):11425. 212 M&B693BritishMedicalJournal (12November1938):1028.
384
385
Thereafter,themostsignificantcontributionsofM&Bwereaseriesofdiamines,prepared fromDecember1937(M&B720).SeveralweretestedbytheTTCandsomefoundusein tropicaldiseases:M&B736orphenamineforbovineandcaninebabesiasisandM&B744or stibamineforkalaazar,whileM&B782andM&B800wereusedintrypanosomal infections.Probablythemostusefulwaspentamidine.
8.7.3.BurroughsWellcome. GeorgePearsonofBurroughsWellcomehadbeenoneofthemaindrivingforces requestingassistancefromtheMRCinsettingupclinicalstudies.Frustratedbythe difficultyofgettingdrugstestedinBritain,PearsonhadaskedThomasHenryoftheWPRL atthestartof1931todiscusswiththefirmsGermanoffice,thepossibilityofperforming clinicaltrialsofergotoxineinGermany,asithadneverbeenthesubjectofathorough

213 clinicaltrialonthecontinent.
TheBurroughsWellcomeSTCrecommendedthataclinicaltrialofergotoxineshould bemadebothinEnglandandinGermany,andDalewascontactedinformallytoestablish whethertheChemotherapyCommitteewouldraiseanydifficultyaboutdoingatrialwith theTTCifonehadalreadystartedinGermany.Dalesreply,inlinewiththeproposed guidelineswasthatatrialofergotoxineshouldbeperformed,butthattheTTCwereonly

214 preparedtodothisworkifnotrialsweredoneinGermany. Inviewoftheestablishment
oftheTTC,theSTCreviewedalloftheirproductssinceneoavenylin1925todecide
215 whichtosubmitfortrials.
213
CommunicatedfromH.A.D.JowetttoG.Pearson,(25February1931)andG. PearsontoC.M.Wenyon,(25March1931),WF:STCS/G/49.
214 215
STCMeeting,(21October1925),WF:STCS/G/49. ThedrugsconsideredforsubmissiontotheT.T.C.wereAscaridole(chenopodium oil),glutathione,ergotoxine,ovarianhormone,hirudin,adenosine,Kharophen,carotene, ventriculin,vitaminB,(neo)infundin,harmine,bulbocarpine,dhyoscyamine,diginutin,and Collipsplacentalextract,bismuthcacodylateincombinationwithStovarsol,reduced glutathione,digitalisglucosides,ouabain(extractedfromseedsfromNigeria),thyroxine, andsoloidironalum,liverextract,irradiatedergosterol,quinoxyl,hypnocampusoil, quinine/urethane,andCarofax.STCMeeting,(27March1931),WF:STCS/G/49.
385
386
AllofthethreecardiovascularproductsthatBurroughsWellcomesubmittedtothe
216 firstTTCmeetingwereacceptedfortrials.Inadditiontoergotoxineethanesulphate, 217 theseweredigoxinanddigitalinumverum(diginutin),discoveredinAugust1929. There 218 werenewderivativesofDigitalis,whichhadbeenusedasanextractforcenturies.
However,withimprovedcontrolofitsactivity,firstbybiologicalstandardisationandthen bypurificationoftheactiveglycosides,digitoxinanddigitalinthatweredescribedin1928 9,many companiesweredevelopingnewformulations.In1930Dr.SydneySmithatthe WPRLisolateddigoxinfromfoxgloves(Digitalislanata)andtheTTCproposedtocontact Prof.LewisatUniversityCollegetoevaluatethenewpurifiedglycosidefortreatingheart

219 pains(angina). TheTTCwasverysatisfiedwiththestudyperformedandsuggesteda
220 publicationbyEdwardJ.WayneofUCH(laterProfessorofMedicineinGlasgow) in 221 ClinicalScience(previouslyHeart),theBritishMedicalJournalandNature.
Similargradualadvanceshadtakenplaceinunderstandingtherolesofthevarious activeingredientsofergot.JoshuaBurnatthePharmaceuticalSocietyexaminedergotoxine forBurroughsWellcomeandfoundthattheirpreparationErnutinwasbetterthanother biologicalandcalorimetricstandards.However,onlyergotoxinewasassayedandtheynow recognisedtheneedtoreporttheamountofergotaminepresent.BurroughsWellcomehad patentedtheirergotoxinepreparationandifergotaminealsoturnedouttobevaluablethey plannedtoapplyforasubsidiarypatent.Thesimilaritybetweenergotoxineandergotamine ledclinicianstoquestion,whichwasbest.MeanwhiletheWCRLexaminedStollsnew

222 ergotalkaloidergocristine,toevaluatewhetherthatfurtherconfusedthesituation.
216
ThispreparationhadtheadvantageofstabilityoverpreviousversionsJ.Chassar Moir,ClinicalComparisonofErgotoxineandErgotamine:reporttotheTTCofthe MRCBritishMedicalJournal (4June1932)10224TTCMinutes3,(8July1932),MRC File1523/15.

217
E.J.Wayne,ClinicalObservationofTwoPureGlucosidesofDigitalis:Digoxinand DigitalinumverumClinicalScience1(1933):63. 218 WalterSneader,(1985):13638. 219 STCMeeting,(23January1931),WF:STCS/G/49.

220 221
Lancet(13October1990):932. TTCMinutes3,(8July1932),MRCFile1523/15STCMeeting,(19May1933), WF:STCS/G/49. 222 STCMeeting,(2April1938),WF:STCS/G/49WalterSneader,(1985):107.
386
387
TheTTCinvitedF.J.BrowneofUCHtocomparethedrugsclinicallyandoneof hisassistants,JohnChassarMoir,devisedasensitivemethodofdetectingtheireffectsby insertingaballoonintotheuterusofpatientsundergoingpelvicexamination,aweekafter givingbirth.Usingtheballoontomeasureuterinepressurecharges,Moirshowedthat neitheroftherecognisedalkaloids,ergotoxineandergometrinehadaneffectontheuterus butthattheliquidextractpreviouslythoughttocontainlittleergotgaveunprecedented

223 activity,andDudleylateridentifiedthisin1935tobeduetoergometrine. Within3
weeksWenyonarrangedpreparationofcommercialsuppliesofergometrineatBurroughs
224 225 Wellcome. Afavourablereportledtocautiousreferenceinthecompanyliterature. 226 BothAllen&HanburysandBDHsoonfollowed. ChassarMoirperformedfurther 227 clinicaltestsonergometrineandconfirmeditsactivity. SomeyearslaterMoirrecalled
hisresearch: asarecentcomertothehospitalIhadsensedtheneedforcautionin conductingresearch.IknewthatIhadthesupportofmychiefandother membersofstaff,butinsomequarterstherewasundoubtedlyanatmosphere 228 ofsuspicionwhichsometimesevenapproachedhostility. ThenextdrugthatBurroughsWellcomeapproachedtheTTCwithwasProstigmine. ThomasFraserinEdinburghhadextractedtheactiveingredient,physostigminefrom
223
C.Moir,H.H.Dale,TheActionofErgotPreparationsonthePuerperalUterus:a ClinicalInvestigationwithSpecialReferencetoanActiveConstituentofErgotasyet UnidentifiedBritishMedicalJournal (18June1932):1119 H.Dudley,J.C.Moir,The SubstanceResponsiblefortheTraditionalClinicalEffectofErgotBritishMedicalJournal (16March1935):52023,53233J.C.Moir'IntrinsicDysmenorrhoeaProceedingsof theRoyalSocietyofMedicine29(1936):950P.M.Dunn,JohnChassarMoir(1900 1977)andtheDiscoveryofErgometrine Arch.Dis.Child (FetalNeonatalEdition)87.2 (2002):F1524In1935MoirmovedtotheHammersmithhospitalandin1937became thefirstNuffieldProfessorofObstetricsandGynaecologyinOxfordandamemberofthe MRCCommittee.
224
STCMinutes,(12July1935),WF:STCS/G/49ErgometrineBritishMedical Journal (4May1935):929. 225 STCMinutes,(7October1936),WF:STCS/G/49WalterSneader:(1985):108 110. 226 ErgometrineBritishMedicalJournal (25May1935):1075. 227 C.Moir,ClinicalexperienceswiththenewalkaloidergometrineBritishMedical Journal (24October1936):799801E.M.Tansey,Ergottoergometrine:anobstetric renaissance?ClioMed.61(2001):195215. 228 J.C.Moir,TheObstetricianbids,andtheuteruscontractsBritishMedicalJournal (1964)ii:10259,quotedinP.M.Dunn,JohnChassarMoir(19001977)andthe discoveryofergometrineArch.Dis.ChildFetalNeonatalEd(September2002):F15254.
387
388
Calabarbeans,anditcouldpreventblindnesscausedbyglaucoma,butphysostigminewas readilybrokendowninthebodybyhydrolysis.TheformerBurroughsWellcome researchersEdgarStedmanandGeorgeBarger,inEdinburghdiscoveredthestructureof physostigminein1925andproducedstableanaloguesincludingmiotine,whichwastested intheclinicin1931.Severalpharmaceuticalfirmspreparedfurtherstableformsandthe TTCwasalreadytestingProstigmineforHoffmannlaRoche,whichwasfoundtobeof valuebyFraser,CarmichaelandWilkie.AseriesoffactorsledBurroughsWellcometo evaluateProstigmineandotherurethanesattheWPRL.In1932Stedmanshowedthat theseanaloguesblockedthecholinesteraseenzyme,whichdestroysacetylcholineinthe

229 body,therebystoppingnervetransmissions. Urethaneshadbeenexaminedpreviouslyin
Germany,bythepharmacologist,SchmiedebergandBayerhadevaluatedacompound calledHedonalin1899,butfoundsomeminortoxicityissuesandtheirpatentsexpiredin
230 1913. In1934aBritishcliniciannotedthesimilaritiesbetweenthesymptomsoftherare
paralyticdisordermyastheniagravisandthepoisoningbycurare,forwhichphysostigmine wasanantidote,soshetrieditonapatientwiththediseaseandachievedexcellent
231 results. AlthoughtheBurroughsWellcomeversionwasinitiallyreportedby Trevanto 232 233 beunsatisfactoryinthelaboratory,itwasbeneficialinmyastheniagravis. Ryle in
Cambridgeagreed,butthoughttherewaslittleadvantageoverpituitaryextract
234 235 (pituitrin): FrancisFraser,atSt.BartholomewsandE.ArnoldCarmichael atthe
NationalHospitalinQueenStreet,Londonreportedamulticentrestudythatshowed Prostigminewashelpfulforpostoperativeatonyoftheintestine,causingcontractions, withoutthecardiovasculareffectscausedbyphysostigmine.Prostigminewasalso evaluatedinasthma,bronchialasthma,myastheniagravisandenuresis,andforraising

229 230
WalterSneader,(1985):11617. STCMeetings,(5April1935)and(12July1935),WF:STCS/G/49Walter Sneader,(1985),27,337338. 231 WalterSneader(1985),118. 232 STCMeeting,(7October1936),WF:STCS/G/49. 233 D.Porter,ChangingDisciplines:JohnRyleandtheMakingofSocialMedicinein Britaininthe1940s,Hist.Sci.30(1992):13764Hewasinchargeofthelabsetup undertheEPHLS,theemergencyPublichealthservice:GeoffreyTweedale,AttheSignof thePlough:275YearsofAllen&HanburysandtheBritishPharmaceuticalIndustry1715 1990(London:Murray,1990):36. 234 J.RyletoF.H.K.Green,(30May,1933),MRCFile1523/21. 235 E.A.CarmichaelhadreceivedanM.R.C.grantin1926forresearchoncerebral glioma,M.R.C.MinutesII,(22October1926):16,181.
388
389
236 bloodpressurefollowinganaesthesia. Infact,overallthestudiesonProstigminewere
probablyamongthemostsuccessfulbytheTTCintermsofgeneratingdataand
237 publications.
BurroughsWellcomealsosentpreparationsofIndianephedrineand pseudoephedrinetotheTTCforevaluation.G.W.BrayandL.J.Witts,NuffieldProfessor
238 ofMedicineinOxford treated52coursesin18patientswithephedrineand49coursesin 239 20controlpatients. Wilkiereportedthatingeneral,pseudoephedrinewasnotasgoodas
ephedrineinraisingbloodpressureinanaestheticshock.Theseagentswerealsoevaluated inasthmaclinicsatGuysHospitalandatGreatOrmondStreet,240 andinthereliefofpost

241 operativedistensionandparalyticileus. InthiscasetheTTCwereabletotake
advantageofemergingpharmacologyandfullyevaluatetheBurroughsWellcomeand Rochepreparations. BurroughsWellcomewasalwaysonthelookoutforotherpotentialnewdrugsin themedicalliterature,suchasanextractfrom Potentillaanserma,andanextractoflarvae of Luciliacericorta.242 Whenferrousironpreparationsforanaemiaweredescribedin

236
E.H.Carmichael,S.R.Fraser,D.McKelvey,D.P.D.Wilkie,Lancet(5March1934): 342.
237
J.E.Monro,EphedrineandPseudoephedrineinSpinalAnaesthesiaQuarterly JournalofPharmacyandPharmacology 7(1934):32G.Barger,FromPhysostigmineto ProstigminPharmaceuticalJournal 141(29October1938):43738.

238
J.AustokerandL.Bryder(eds.),(1989):214,220,2234,236.RylenotedWitts whenhewasayoungclinicianatGuyshospital.In1934hereceivedMRCsupportforhis researchonsplenicanaemia.HebecamethefirstNuffieldProfessorinOxfordandlater editedoneoftheearliestbooksonclinicaltrials,L.J.Witts(ed.),MedicalSurveysand ClinicalTrials:SomeMethodsandApplicationsofGroupResearchinMedicine(London: OxfordUniversityPress,1959). 239 TTCMinutes2,(15January1932),TTCMinutes3,(8July1932),MRCFile 1523/15G.W.Bray,L.J.Witts,PseudoephedrineinAsthmaLancet(14April1934): 788790. 240 TTCMinutes2,(15January1932),MRCFile1523/15. 241 T.R.ElliotttoF.H.K.Green,(9February1934)andF.H.K.GreentoT.R. Elliott,(21February1934),T.R.ElliottFiles,WIGC/42TTC193334J.B. Christophersen,M.Broadbent,EphedrineandPseudoephedrineinAsthma,Bronchial AsthmaandEnuresis,BritishMedicalJournal (2June1934):97879S.B.Dimson,The PressorActionsofEphedrineandPseudoephedrineinManQuarterlyJournalofPharmacy andPharmacology 7(1934):23J.E.Monro,EphedrineandPseudoephedrineinSpinal Anaesthesia,QuartJ.Pharm.7(1934):32.
242
STCMeeting,(1October1936),WF:STCS/G/50.
389
390
LancetandBritishMedicalJournalarticles,BurroughsWellcomepreparedpropagandaon Blaudspills,whichtheyalreadysold,asastableferrouspreparation,whichinthepresence
243 ofgastricjuiceproducedferricchloride. EvenbeforeTrevanarrangedclinicaltrialson
histidinehydrochlorideforthetreatmentofduodenalulcersitwassuggestedtoreleaseit
244 onthebasisofpublicationselsewhere. Onasimilarbasistheymarketedarylestersof
hydnocarpusoilacid,andCarbasone.ThelatterhadnoUKpatentnorhadatradename
245 registered. Theyfelttherewassufficientevidencefortannicacidjellytojustifyplacingit
onthemarketinCanada.TheseproductswerenotsenttotheTTCastheywereprepared inresponsetoaperceivedclinicalneed,andcouldbesoldonthebasisofgeneral publications. On19May1933theABCMwrotetoBurroughsWellcomeagainaskingaboutthe possibilityofcollaborationwiththeDSIR.246 BurroughsWellcomefeltthat:while progressindevelopmentofbiologicaldrugs(hormones,vitaminsandplantconstituents)is satisfactory,thediscoveryofnewsyntheticdrugsstilllagsbehindtheachievementsof foreigncountriesandisalmostwhollydependentuponforeigninitiativetheCommittee areoftheopinionthatifChemotherapyinthiscountryistoholditsownincompetition withforeigndevelopment,amoredefiniteorganisationthanthatindicatedintheABCM letterisrequired.Thisquestionshouldbeconsideredfromthepointofviewof 1. Thepossibilityofcooperationamongindividualfirmsandifpossible,thenatureof thiscooperationanditsrelationshiptotheDSIR. 2. TheparttobetakenbyGovernmentDepartmentsand
247 3. Thekindofresearchtobeundertaken.
TheDSIRoutlinedtheirongoingresearchandthesepointswerediscussedatthe STCmeetingon14July1933.Oneofthemainareasofcollaborativeworkproposedwas
243
TheAssimilationofIronLancet(4September1937):588TheActionofIron BritishMedicalJournal (13November1937):970971 Proc.Roy.Soc.Med. (March 1933):607STCMeetings,(19May1933)and(1October1936),WF:STCS/G/4950. 244 STCMeetings,(5April1935),(12July1935)and(1October1936),WF:STC S/G/4950. 245 STCMeetings,(19March1933),(24May1934),STCMeeting,(1October1936), WF:STCS/G/4950. 246 14July1933,WF:STCS/G/49. 247 14July1933,WF:STCS/G/49.
390
391
inthefieldofmalariaandtheproposedcollaborationtooktheformofbothresearchand clinicalcooperation.However,itisclearthatBurroughsWellcomewasnotfocusedon syntheticdrugs. Twosadeffectshitthefirmin1936.ThemostlastingwasthedeathofHenryasit alteredthestatusofthefirmtothecharitableWellcomeFoundation.Inhislastwillof1932 HenryWellcomehadarrangedforallmoneymadeoutofthecompanysoperationsinthe reliefofsufferinganddiseaseshallbeusedfurthertofurtherthereliefofsufferingand

248 disease. ThentheSTCof7October1936reportedthesuddendeathofJowett:
themembersoftheCommitteedesiretoplaceonrecordtheirsenseofthe greatlosstheCommitteehavesustainedbythedeathoftheiresteemed colleagueDrJowettwhoseripeexperienceandsoundjudgementwere 249 alwaysofthegreatestvalueintheirdeliberations. IntheWCRLreportofJanuary1937,Wenyondescribedextensiveresearchon virusdiseases,thedevelopmentofparasites,generalpathology,bacteriologyand parasitology,antileproticoils,antimalarials,streptococcalandmercurycompounds.The discoveryofsulphonamideshadrestimulatedinterestinthetherapyofallinfectious diseases. Avenylcreamwasamercurialpreparation,whichhadbeenusedinleprosyfor
250 years. Earlierin1931,BurroughsWellcomesentittoleprologistsinSudan,Korea,Cape
Province,SouthAfrica,andChinaandreceivedfullreports.Henry,SmithandTrevan summariseditspropertiesandthesupportingdataincludingstabilityattropical
251 temperatures. AvenylwasthensubmittedtotheTTCafterevaluationattheWPRLasa 252 possibleantisyphilitic. Afteraconsiderabledelay,theTTCagreedtoarrangestudiesof
Avenyl,andsuppliesweremadeatBurroughsWellcome.253 AttheSTCmeetingof25 May1934itwasstatedthatresultscannotbeexpectedforsometimeyet.By28 September1934,DrHenrywasdissatisfiedwiththemannerinwhichthishasbeen
248
G.MacDonald,InPursuitofExcellence:OneHundredYearsWellcome1880 1980.(London:WellcomeFoundationLtd.,1980):35SirHenryWellcomesWill, Lancet(30January1937):275. 249 STCMeeting,(7October1936),WF:STCS/G/49.

250 251 252 253
STCMeeting,(14February1934),WF:STCS/G/49. STCMeeting,(13March1936),WF:STCS/G/49. STCMeeting,(24November1933),WF:STCS/G/49. STCMeeting,(9Feb1934)and(19May1934),WF:STCS/G/49.
391
392
handledbytheTTC,andfinallyinDecembertheSTCon14Dec1934theTTCreporton
254 Avenylwasdiscussed. TheTTCquestionedwhethermercurialsofthistypewereeven
necessaryasBritishmedicalmanpreferredbismuthandarsenicalpreparationssono progresshadbeenmade.Asaresult,BurroughsWellcomedecidedtoproceedwitha furthertrialofAvenylwithadoctorinSalfordwhohadpreviouslydonetrialsforthemon

255 bismuthoxychloride. Theyprovidedhimwiththetwoconflictingpreclinicalreports
fromCalcuttaandfromtheTTC.IntheformerstudytheWassermannreactiontestsfor syphilisbecamenegativein10casesafter15dosesof0.025grammes,whereastheTTC reportshowednoeffectontheWassermannreactionafterbiweeklydosesfor6months. TheSTCdecidedtoawaittheoutcomeoftheSalfordstudybeforeproceedingwithfurther

256 trialswithaDrLeonardintheUSA.
SnodgrasseventuallyperformedtheTTCstudyinGlasgowandshowedthat Avenylwasbetterthancalomelbuthedidnottopublishthedata,andasaresult
257 BurroughsWellcomedecidednottoadvertiseitforuncomplicatedsyphilis. Their
Tuckahoesitepreparedandpatentedaseriesofnovelorganicmercuriatedaromaticamines coupledtopolyphenols,asnovelgermicides.However,onlyonecompoundhadan unassailablepatentpositionandmercurochromewasconsideredunlikelytoraise sufficientdemandtojustifymanufacturing.258 Inadditiontoreviewingpatentsforanyopportunitiesarisinginthemedical literature,BurroughsWellcomelookedfortheexpiryofotherfirmspatents,butthey foundthatsomedrugsthattheywishedtomarketwerestillprotected.From1933they decidedtodonofurtherinvestigationsonpatentedcompounds,buttotaketheopportunity

259 ofproducingtheirownlineifanyshouldcomeoutofpatent. Theyappointedthree
juniorchemicalassistants,twoattheexperimentaldepartmentatDartfordandoneatthe WCRLwhohelpedtosearchthechemicalandpatentliterature,freeingthechemiststo
254 255
STCMeeting,(14December1934),WF:STCS/G/49. STCMeeting,(25May1934)and(28September1934)and(14December1934), WF:STCS/G/49. 256 STCMeeting,(5April1935),WF:STCS/G/49.

257
TTCMinutes5,(5March1934)TTCMinutes6,(28February1936),MRCFile 1523/15. 258 STCMeeting,(25May1934),WF:STCS/G/49. 259 STCMeeting,(19May1933),WF:STCS/G/49.
392
393
260 concentrateonresearch. Ifcompetitorcompoundswerealreadypatentedthefirmcould
261 trytonegotiateasaleslicense.
In1936Benzedrineandotherephedrinederivativeswereevaluatedasanaleptics
262 (stimulants). Smith,Kline&Frenchhadmarketedtheseinaninhalerin1932foruseas
nasaldecongestants,andTrevansummarisedtheireffectinshorteningtheawakeningtime
263 ofanaesthetisedmice. BurroughsWellcomepreparedmodifiedversions,including
methylanddimethylBenzedrine,norephedrine,norpseudoephedrine,ephedrine, pseudoephedrine,methylephedrineandmethylpseudoephedrine.Foreachcompound,one oftheisomerswasmoreactivethantheother,sothemostactiveisomerwasprepared. Dextroopticalisomerswerethemostactiveofthebenzedrinesandlaevoformswerethe mostactiveephedrines.Overall,themostactiveandleasttoxicoftheseamphetaminelike

264 substanceswasmethylisomyn(methylBenzedrine), sothiswassubmittedtoGreenof 265 theTTC, who,inturnsubmittedittotheMaudsleyHospital,whereitspropertieswere
confirmed,incomparisonwithisomyn(Benzedrine)266,whichhadbeenevaluatedby BargerandDalein1910.Severalfirmsexaminedthesesympathomimeticaminesinthe
267 early1930s.
OverallitseemsthatBurroughsWellcomebenefitedfromtheirinteractionwiththe TTC,getting8productsevaluated.Theygotusefulfeedbackontheircardiacproductsand thoughAvenylwasadisappointment,theygotaquickandcleardecisionaboutit,andthe manypublicationsonProstigminehelpedtheirmarketingofthedrug.Despitetheir successfulcollaborationwiththeTTC,BurroughsWellcomecontinuedtoarrangesomeof theirownstudies.Theyperformedtheirownevaluationofinsulincombinedwith
260
261
262 263 264 265 266 267
STCMeeting,(14December1934),WF:STCS/G/49. STCMeeting,(25February1926),WF:STCS/G/49. STCMeeting,(7October1936),report(January1937)WCRL,WF:STCS/G/50. STCMeeting,(7May1937),WF:STCS/G/50. STCMeeting,(7May1937),WF:STCS/G/50. STCMeetings,(19November1937)(18February1938),WF:STCS/G/50. STCMeetings,(24March1939)(29September1939),WF:STCS/G/50.
TTCMinute8,(7February1938),TTCMinute9,(14July1938),MRCFile 1523/15TheActionofBenzedrinePharmaceuticalJournal 141(5November1938): 469.
393
394
antisepticsaftermouldswerefoundgrowinginpreparations.268 Trevanprepared
269 crystallineinsulinandsentanoteonthistoNatureandthePharmaceuticalJournal.
SamplesweresenttoHarrington,presumablyforhimtotrytosolvethestructureofinsulin
270 andsynthesiseitashehadwiththyroxine. Theydevelopedfurtherinsulinformulations, 271 havingLocalinsulintestedatGlasgowRoyalInfirmary. Everybatchofprotamine
insulinproducedwastestedinrabbitsattheWPRL,butnothavingsuccessinmakingthe insolublederivativeofProtamineinsulinate,itwassuggestedthiscouldbelicensedfrom
272 anotherfirm.
8.7.4.Glaxo. InthePostwarchapterIdescribedhowGlaxoevolvedfromNathansby incorporatingscientificconceptsintotheirfoodbusiness.After1931Glaxocontinuedto evaluatevitaminstoaddtotheirmilkproducts.Calciferolwasisolatedinpurecrystalline formin1932,allowingGlaxotoproduceevermoreconcentratedformsofOstelin,that couldbemorereadilystandardisedandwhichweremorestable.VitaminAwasfoundin milkfatandGlaxodevelopedaseriesofproductsrichinvitaminAincludingtheAdexolin lines,OstomaltandMaltoline.Theyalsoproducedvitamin enhancedfoodstuffsincluding Farexin1932.BacharachandJephcottfoundtheyneededtoeducateignorantdoctorsas
273 theytriedtomarketproductsthroughethicalchannels. However,whentheir
intramuscularcombinationformulationofvitaminsAandDwassubmittedtotheTTCin June1933,itwasinitiallyrejected,asGlaxogavenoclearindicationthatitwouldbebetter
274 thantheoralform. AnM.D.thesisprovidedbyGlaxowassaidbyEdwardMellanbyto 275 beabsoluterubbish. Dawsonstated:theconcentrateofvitaminsAandDfor 276 intramuscularusedoesnotimpressmemuch, andT.WattsEdenwasalso
268
STCMeeting,(27March1931):G.E.PearsontoC.M.Wenyon,(8June1931), WF:STCS/G/49. 269 STCMeeting,(19May1933),WF:STCS/G/49. 270 STCMeeting,(8May1929),WF:STCS/G/49. 271 STCMeeting,(18February1938),WF:STCS/G/50. 272 STCMeeting,(29May1936),WF:STCS/G/50.
273 274 275 276
R.P.T.DavenportHines,J.Slinn,(1992):8083. F.H.K.GreentoGlaxo,(28June1933),TTCFile1523/22. E.MellanbytoF.H.K.Green(12June1933),TTCFile1523/22. TTC1523/21(10June1933).
394
395
277 doubtful. FurthercliniciansinLondon,Glasgow,andEdinburghwereinvitedtotest
vitaminsAandDandMellanby,TWattsEdenandProf.Wilkiediscussedthecombination compound.Themainproblemwasthatthecommitteecouldnotthinkofawayinwhichit couldbetestedexcept,perhapsinrickets,whichwouldonlyevaluatethevitaminD

278 component. AnotherpossiblereasonfortherejectionwasthattheMRCPatentsub
committee,whichranfrom 1929,disapprovedoftheSteenbockpatentstakenoutby
279 Glaxo. TheyfeltthatSteenbock,basedinWisconsinwasprofitingfromawidepatentin
astateofuncertainknowledgebasedonearlierBritishwork.FrankRobinsonjoinedthe
280 researchteamasachemistin1933.
GlaxoremainedprimarilyanutritionalproduceruntiltheestablishmentofGlaxo LaboratoriesinMarch1935,whenworkbeganonanewsitefor250staffinGreenford,
281 Middlesex. BythistimeJeffcottwasManagingDirectorandFarmerwasprogressingto
seniormanagement.Glaxoestablishedlaboratoriesforbacteriologyandforanalyticalwork, biochemistryandorganicchemistry,whichwerecompletedinSeptember1936and
282 occupiedtheupperfloor. Theyalsohadanampouleunitandtheirownuniqueglass
blowingfacilities.AmongthefastsellinginorganicproductstheypreparedwereFersolate tabletsofferroussulphate,andExamen,thepreviouslydescribedinjectionofliverextract forperniciousanaemia,likethatpreparedatBurroughsWellcome,butnosynthetic productswereproducedintheinterwarperiod.TheTTCwasclearlynotinfluentialinthe developmentofGlaxo,astheysubmittedonlyonevitamincombinationproductandthat wasrejected. ItisinterestingtonotethereforethatGlaxowentdownthesamepathasMay& Bakerandappointedtheirownphysiciantotakechargeofexternalinteractionsand arrangingclinicalstudies.HectorWalkerwasayoungpractisingphysicianinHarrow

277 278
TTC1523/22,(4June1933). TWattsEden,TTCFile1523/22,(4June1933). 279 R.P.T.DavenportHines(ed.),History,BagmenandMarkets:Studiesinthe HistoryofMarketingandBritishIndustrialPerformance18301939 (Aldershot:Gower, 1986):787993HD47.9.1MRCPatentsSubcommittee192945,MRCMinutesII,(29 November1929):205.

280 281 282
R.P.T.DavenportHines,J.Slinn,(1992):136. C.Turner(ed.),(1985):3242. C.Turner(ed.),(1985):3537.
395
396
whenhispatientHarryJephcott,bynowtheManagingDirectorbeganaskinghisopinion aboutmedicalproductsandseekinghisguidanceonwritingfordoctorsfrom1935whenhe wasemployed.MuchoftheirexternalresearchwasdoneincollaborationwiththeLister InstituteandNIMR.In19378theycreatedaconsultativecommitteeofexternalscientific advisorsdirectedtowardsproblemsuponwhichweareworkingbutalsohadsubstantial

283 andusefulcooperationfromtheprincipaluniversitiesinthecountry. Researchwas
beingperformedonthesynthesisofvitaminAandaseriesofiodinecompounds,anew acridinecompoundandtheisolationofbacterialantigensandpituitaryhormonesandliver extracts.Glaxoalreadysoldaliverextract,whichtheylicensedfromaNorwegiancompany in1936,andinthelatterpartofthedecadepharmaceuticalswerecontributinggreater profitsfromamuchsmallerturnoverthenthefoodproducts.284 TheGlaxostaffat Greenfordroseto600by1939,andthefirmwerespending5,000p.a.onresearchin

285 1938. Theadditionofscientificproductssuchasvitaminstotheirmilkstuffsrange
helpedtoextendtheirproductlines,leadingtoanincreaseinmanufacturingcapacity,and bringingJ.F.Nathan(Glaxo)intopharmaceuticals,althoughover50%ofsaleswerefrom justoneproductGlucodin(glucoseandvitaminD).AttheoutbreakofthewarDr.Joseph Ungar,aCzechrefugeejoinedthebacteriologydepartmentandbecameinvolvedinstudies

286 onantibiotics.
8.7.5.BritishDrugHouses. Asdescribedinearlierchapters,BritishDrugHouseswereprobablythemost progressiveBritishfirmimmediatelyfollowingtheGreatWar,afterchairmanCharlesHill securedthechemicalengineerFrancisCarrandhiscolleagues,andtheysuccessfully manufacturedthyroxinandinsulin. Overtheperiod19311939,BDHsubmitted7compoundstotheTTC.Oneofthe firstagentswasPerparine,thelatestinalonglineofanticholinergicdrugssimilarto atropine.Germanfirms,particularlyMerckhadimprovedupontheoriginalnaturalproduct,

283 284 285 286
R.P.T.DavenportHines,JSlinn,(1992):86. R.P.T.DavenportHines,JSlinn,(1992):86C.Turner(ed.),(1985):63. C.Turner(ed.),(1985): 38,106R.P.T.DavenportHines(ed.),(1986):62. R.P.T.DavenportHines,JSlinn,(1992):136.
396
397
firstsplittingitintotwoopticalisomersandthenrecognisingactivitycouldbemaintained bygivingonlythetropeinepart.Furthersyntheticmodificationimprovedthetherapeutic margin,thedifferencebetweenthedosesgivingactivityagainstthosegivingsideeffects.A HungarianfirmhadalreadypreparedPerparinein1930,beforeBDHmadeitsown

287 preparation. OneconcernthattheTTChadwasinpersuadingBritishdoctorstouse 288 perparine,aspapaverinehadalmostbeenabandonedinfavourofatropineandmorphine. 289 DespitethisJohnBell&Co.putforwardpapaverineforclinicaltrials. Furtherstudiesof
Perparineweredelayedfor6months,pendingresultsfromcontinentalworkersanditwas neveractuallytestedinBritain.Amongtheotheragentssubmittedfortestingjustbefore
290 theSecondWorldWarwasEupaverin, asyntheticpapaverinederivativefromMerck,
claimedtobelesstoxic.Merckhadfirstdiscoveredthisalkaloidfromopiumplantsin1848
291 aftermorphineandcodeinehadbeenremoved. AlthoughasGreenwrotetoElliott:
IhardlyimaginethattheCommitteewillfeelabletoacceptthis,asyouwill rememberthattheyrecentlydeclinedanapplicationIrespectofasimilar productfromaBritishfirm.Headded,IunderstandfromTrevan,ofthe th WellcomelabsthatBWarelikelytosubmitanewapplicationbeforethe7 . (ThedateofthenextTTC)Thereisalsointheoffinganapplicationfrom 292 ParkeDavis&Co.
BothEupaverinandPerparinewentontobewidelyusedasantispasmolyticsinthe 1930s. BDHproducedanaloguesofcocaineincludingBoracaine,alocalanaestheticin severalsaltforms.TheyalsopreparedCaprorol(hexylresorcinol),Intamine,(diorthodi aminothiobenzene),andContamine(diethylammoniumdiethyldithiocarbamate).293
287 288
WalterSneader,(1985):1206. TTCMinutes4(undated,1933),MRCFile1523/15. 289 JohnBell&CroydonwereadirectdescendentofthefirmofJohnBell&Co. foundedin1798.Theymadesurgicalinstruments,travelmedicinesandimportedand exporteddrugs.Theystilltradeunderthesamenametodaybutwouldbeconsideredas retailersratherthanpharmaceuticalmanufacturers:MRCFile1523/15T.A.Henry, (1939):1812,18591.

290 291
WalterSneader,(1985):1256. T.A.Henry,(1939):185 292 F.H.K.GreentoT.R.Elliott(1February1938),T.R.ElliottFiles,WIGC/42TTC 193542.

293
BritishChemicals:TheirManufacturersandTheirUses(London:ABCM,1927)
397
398
BritishDrugHousesmademoresyntheticdrugsthanotherfirms,probablyreflectingthe influenceofFrancisCarr,andtheywerealsooneofthefirstfirmstoproducesteroid hormonesfrom dehydroepiandrosterone,obtainedfromcholesterolbyirradiationofsterols

294
AfterthediscoveryofcalciferolanditspreparationbyGlaxo,BDHsenttheirversion,
RadiostoltotheTTCfortestinginSheffield,London,andNewcastleinstudiescontrolled byXrays.MellanbyfounditsatisfactorybutwonderedhowitcomparedwithAmerican
295 irradiatedergosterol. BDHalsoaddedconcentratedvitaminstotheirmaltproductssuch
asRadiomalt,whichincludedstandardisedvitaminsA,B1,B2,andD.Carrdevelopedthe techniqueofmoleculardistillationin1932,makingitpossibletoseparateoutthevitamins A,DandEfromoilsandpreventthedestructionofvitaminAthatoccurredbyheatingwith

296 vacuumdistillation. Anothersynthetic,acetyl 6naphthoicacid(producedbyBDH.
andICI)wasputtotheTTCfortestingasananalgesicininoperablecancer.Studieswere performedbyCuthbertWallaceattheMiddlesexHospital,Prof.T.R.ElliottandSir FarquharBuzzard,buttheTTCwereunabletorecommenditasitledtoheadachesand

297 highbloodpressureanditwasnotissued.
TheresultsoftheBDHinteractionwiththeTTCaredifficulttointerpret.Inonecase BDHwerelateincopyingaGermandruganditwasdifficulttosetupastudybecause Britishworkersnolongerusedthattypeofdrug,andintwocasestheygotclearfeedback whenproductswereeitheroflimitedvalueorledtosideeffects.Themajorityofthe studiesweresimplyinconclusive.Itappearsthattheearlysuccesseswiththyroxinand insulinwerenotbuiltupon.Aseriesofsyntheticdrugswereproduced,butoftenonly minorvariationsonexistingproductsandwithlittleobviousadditionalclinicalbenefit.It seemsthattheskillsthatCarrbroughtwereintermsoflargescalemanufacturingrather thaninnovation.However,theadvancesinmanufacturingcapacityallowedBDHto capitaliseonexternaladvancesastheyhadwithinsulinandtheirpreparationofsteroidsat inthe1930s.TheBDHannualmeetingin1935reportedthatnearly35,000hadbeen spentonanewfactorybuildingtoproducefinechemicalsandanewbiologylaboratoryand
294
V.Petrow,SirF.Hartley,TheRiseandFalloftheBritishDrugHouses,Steroids, 61:476482. 295 TTCMeeting2(13January1932)and4(undated1933)1523/15. 296 F.H.Carr,MolecularDistillationPharmaceuticalJournal 141(12November 1938):498. 297 TTCMeeting2,(13January1932)TTCMeeting3,(8July1932),MRCFile 1523/15.
398
399
298 sportsgroundhadbeendeveloped. ThesefoundationshelpedBDHbecametheleading 299 producerofsteroidsinthenextdecades.
8.7.6Allen&Hanburys. Allen&HanburyspreparedinnovativeproductssuchasaHaliborange,which maskedthetasteofhalibutliveroilandincorporatedvitaminsA,C,andD.Intheearly 1930stheirgrowthcontrollinghormoneoftheparathyroidglandwastestedattheRoyal CollegeofSurgeonsandattheKingsCollegeforlimitingthespreadofcancerandan adrenalcorticalextract,EucortonewaspreparedforthetreatmentofAddisonsdisease. Inreviewingthestateoftheindustryin1935,Gambledescribedthestrategywithin Allen&Hanburys,withnewscientificproductswerebeingpreparedalongsidethe centuriesoldremedies: Whenwesurveytheprogressthathasoccurredinthisperiod,weseethatit is due to the introduction of new types of pharmaceutical products, which have required improvements of methods and plants. These have grown up alongsideoldproducts,whichhavecontinuedtobemanufacturedbytheold 300 methods,thoughoftenimprovedindetail.
OneofthesurprisesofmyanalysisisthataftertheinvolvementofGambleincampaigning fortheTTC,Allen&Hanburysdidnotputforwardasingledrugtothemfortesting.They haddevelopedtheirownreputationthroughtheworkoninsulinandwiththeincreaseof productsandclinicaltrialactivity,Allen&Hanburystookonaladydoctortoarrange clinicswithnursesandmothersandaspeciallyqualifiedmedicalmanwas(also)hiredto

301 bringthemeritsoftheinfantfoodstopaediatriciansandotherspecialists.
8.7.7ImperialChemicalIndustriesandOtherBritishFirms. ImperialChemicalIndustries(ICI)wasfoundedin1926astheBritishconglomerate tocompetewithIGFarbeninchemicalsanddyes.Thecompanytraceditsrootstothe earlierformationofBritishDyestuffsCorporationwithunitsinBlackleyunderA.G.Green

298 299 300
BritishDrugHouses,PharmaceuticalJournal (20April1935):471. W.Sneader,(1985):203.
F.W.Gamble,N.Evers,AdvancesintheManufactureofPharmaceuticalProducts, 19101935PharmaceuticalJournal 134(1935):541543.

301
GeoffreyTweedale,(1990):151.
399
400
andinHuddersfieldunderRobertRobinson.Adyestuffsresearchconsultativegroupwas establishedin1929,andafterthediscoveryofsulphonamideantibioticsintheperiodfrom 1935,andtherealisationthattheywerestructurallyrelatedtodyestuffs,thatamedicinal chemistrysectionwasestablishedandICIembarkedonpharmaceuticalresearch,initially

302 303 onalimitedbasis,stilldirectedbyRobinson. Oneofthesevenfoundingchemists
FrancisLeslieRose,whohadtrainedunderKippinginNottingham,joinedBlackleyin 1932,aftertrainingatUniversityCollege,Nottingham,includingaPhDpartsponsoredby
304 ICI. TheresearchmanageratICIwasMarmadukeBarrowcliff,alsoaNottingham
graduatewhovisitedfrequentlyalongwithhisAcademicRelationsOfficer.We encounteredBarrowcliffearlieratBurroughsWellcomeandBootshehadalsospentsome
305 timeinMalayainresearchonrubber. AlthoughICIdyestuffsputinrequeststotheTTC
fortestingacetyl6oxynaphthoicacidandquinadil,previouslyreferredtoassubmitted jointlywithBDH,theyalsoputforwardtheirownquindolinemethochlorideasan
306 antiseptic,butdecidedafterdiscussionswiththeTTCtowithdrawtheapplication. The
TTChadpreviouslyshownthatoftenantisepticsthatshowedpromiseinthelaboratorydid notfulfilthatpromiseinpatientsandtheyshowedthatquinadilhadinadequateactivity.In 1937ICIbegantoappointPhDpharmacologistsincludingC.M.Scott,W.Lees,A.R. Martin,A.L.WalpoleandJ.R.Raventosbuttheyalsoworkedwithexternalssuchas GunninOxford,WarringtonYorkeinLiverpoolfortropicaldiseasesandClarkein

307 Edinburgh. In1938LordMacGowan,thechairmanconfirmedthatICIwereworking
onspecialisedpharmaceuticalandmedicalproducts,whichwereexpectedtobecomean importantpartofthedyestuffsgroupactivitiesandwerecollaboratingwiththeLSHTMin
302
RobinsonhadmovedfromManchestertotakeupthechairatUniversityCollegein London.LordToddandJ.W.Cornforth,RobertRobinsonBiographicalMemoirsof FellowsoftheRoyalSociety 22(1976)415527. 303 PharmaceuticalResearchinICI193657(Macclesfield:ImperialChemicalIndustries Ltd.,1957):12.TheotherswereF.H.S.Curd,W.R.Boon,J.C.Lumsden,D.J. BranscombeandH.C.CarringtonandSamEllingworthledtheteam. 304 Obituary,FrankL.Rose,TheTimes,(5March1988)C.W.Suckling,Francis LeslieRose27June19173March1988BiographicalMemoirsofFellowsoftheRoyal Society 36(1990):491524. 305 ThelibrariansatAstraZenecaassistedmeinidentifyingthepatentstakenoutby Barrowcliff.Hisfirsthadbeenontrypanarsinitesin1908andhisfirstforICIwasin1934 (UKpatent408258). 306 TTCMinutes7,(11February1937),MRCFile1523/15. 307 C.W.Suckling,B.W.Langley,FrancisLeslieRose27June19093March1988 BiographicalMemoirsofFellowsoftheRoyalSociety36(1990):490524.
400
401
abasicstudyofimmunisationThecompanyhadestablishedaresearchcounciland researchcommitteeswereintouchwiththeleadingscientistsinthecountry,including
308 chemistssuchasRobertRobinson,IanHeilbronandJocelynThorpe. Thefirst
sulphonamideantibioticmadebyICIchemists,Sulphathiazolewastoolatetoclaimpatent priority.Anotherderivative,sulphadiazinewasmadeinAmerica,butICIdevelopedan easiertomakederivative,sulphamezaphine,whichbecamethefirstdrugmanufacturedby ICI.atthestartoftheSecondWorldWar.ThisworkledthemtoevaluateGerman antimalarialsinpreparationforWorldWarTwo.ICIdidnotestablishaformal pharmaceuticaldepartmentuntil1954,andopenedanewresearchsiteatAlderleyPark,

309 Cheshirein1957.
Oneofthefastestgrowingproprietarymedicinemanufacturersinthe1930swas Beechamswhoreportedsalesof500,000in1936buttheydidnotproduceethical
310 productsofinteresttotheTTCwithsalesofthatmagnitudetheydidnotneedto. A. 311 BoakeRoberts&Co.ofLondon submittedjustoneproducttotheTTC,anamyl
salicylate(Abracide),whichwasanewphenolderivative,evaluatedbyWilkiesgroupin Edinburgh,whoshoweditseemedtorelievepainatonceanddecreasedsepsisinburns
312 patientsandhepreparedapaperfortheBritishJournalofSurgery. TheCommitteedid
notseemtomindthatWilkiesreportgaveratherapufftotheproprietaryantisepticas thecompanydeserveditforitwastheonlyantisepticwhichblendedwellwithamyl
313 salicylate. TheactualresultsweresecondarytowhattheCommitteethoughtofthe
compoundandinthiscasealettertotheBritishMedicalJournalwassuggested.
308
CommercialFirmsandResearch,PharmaceuticalJournal 140(30April1938):
460.
309 310
PharmaceuticalResearchinI.C.I.193657(1957). Michael Robson,ThePharmaceuticalIndustryin BritainandFrance19191939. (London:PhD,June1989):38 R.P.T.DavenportHines,JSlinn,(1992):86.

311
Foundedin1869theyproducedbrewingchemicals,flavouringessencesandessential oils.TheymergedwithothersmallLondonfirmsStaffordAllen&SonsandW.J.Bush& Co.tobecomeBush,BoakeAllenLtd.in1966andthisfirmwasacquiredbyInternational FlavorsandFragrancesInc.tobecometheworldslargestflavoursandfragrancecompany. www.IFF.co.us

312
TTCMinute2,(15January1932)TTCMinute6,(28February1936),MRCFile 1523/15. 313 F.H.K.GreentoT.R.Elliott,(16November1936):T.R.ElliottFiles,WIGC/42 TTC193542.
401
402
ArequestbyNappofCambridgetohaveHepamult(liverextract)andProfundol (Progestin)testedwasdeclined,buttheformerwasstillmarketedasadrycalfliver
314 315 extract. Nappalsoproducedsanocrysin,whichhadbeentestedearlierbytheMRC.
Nevertheless,theircollaborationwiththeTTCwasfruitfulandledtofurthersignificant
316 interactionsfrom194248.
Evans,Lescher&Webbcontinuedtoproducevaccinesandantitoxinsbuthadno interactionstheTTCregardingnewdrugs.Bythemid1930stheywereoperatingatrading
317 profitof45,111. Theyoperatedquiteindependently,mostoftheirinteractionsbeing
withtheEvansBiologicalInstituteatRuncorn.In1935theypublishedpapersshowingthat
318 theyhadworkeduponthestorageofergotandthestandardisationofthyroidextracts.
ConsiderableextensionsweremadetotheEvansBiologicalInstitutein1937asthe companyproducedvaccinesforcholera,plagueandsmallpox,butalsotuberculins,heparin andhyaluronidaseandthesyntheticStreptocidesulphonamide. DuringthisperiodBritishfirmsattemptedforthefirsttimetoproducenoveldrugs, butdidsobyfollowingseveralparallelstrategies,eachfirmplayingtotheirownparticular strengths.BurroughsWellcomecontinuedtofavourphysiologyandalkaloidalextracts, manyfirmspurifiedandstandardisedhormonesandtookasimilarpathwithvitamins. Althoughtheybasicallyproducedthesameproducts,hormoneandvitamintherapywasan areawhereBritainwasaheadofGermany.Somefirms,andparticularlyBootsfrom1927, May&BakerandmostofallBritishDrugHousesemphasisedsyntheticdrugs. Howeveritmustberecognisedthatthenumberofnovelchemicalssynthesisedwas farbelowGermaneffortsandthemainemphasiswasonmarginalimprovements preparationofsynthetichormones,thyroxineanddiethylstilboestrol,oropticalisomers withenhancedactivityorbettertoleratedormoresoluble,evenlongerlastingsaltsof availabletherapies.Theseledtomarginalimprovementsbutafrustrationforthefirmswas thatitwasdifficulttoarrangestudieswiththeTTCtoshowthesebenefits,orperhapsthey
314
TTCMinutes5,(5March1934),MRCFile1523/15Preparations&Appliances BritishMedicalJournal (5May1934):950. 315 GoldPreparation Sanochrysin,BritishMedicalJournal (4May1935):927. 316 ThetwomaincollaborationsconcernedParpanit,MRCFile1523/71andIrgamid, MRCFile1523/66. 317 EvansSons,Lescher&Webb,PharmaceuticalJournal 134(9March1935):282.
402
403
werejustinsufficient.Asaresultcompaniescontinuedtodevelopdrugsforthetropical marketandbegantoemploytheirownphysiciansasGlaxo,Allen&HanburysandMay& Bakerdid. Animportantconclusionalsoisthattheprocessesdevelopedforlargescale manufacture,forcrystallisations,enhancingpurity,developingbettersaltsandfor molecularmanipulationweretheskillsthatbenefitedBritishindustrywhensulphonamide antibacterialswerediscoveredandmanyBritishfirmswererapidlyabletodevelopbetter alternativestoProntosil.Whenevertherewasastepchangeinactivityaswithinsulinand Prontosiltherewasareadystreamofphysicianswillingtotestthem. 8.7.8.ForeignFirms. AswellastheeverpresentthreatoftheGermanfirms,theinterwarperiodwas markedbytheestablishmentofUSfirmsinBritain,thoughinitiallytheirinteractionswith theTTCwerelimited.Theyactedprimarilyassalesunitsforproductsdevelopedin America.KhellaviswasanewdrugsaidbyEgyptianworkerstoassistinremoving
319 calculi. UpsterSmith&Co.werebasedinMinneapolisandtheirversionofKhellavis
wassenttoWilkieinEdinburghin1933,whotreated3casesofuretericcalculi,oneof
320 whompassedastonebuttheothershadnobenefitandsufferedfromsevereflatulence. 321 Anothertrialistaskedtoparticipatefoundnocases. Eventuallyitwasconcludedthatit 322 wasnogood.
Smith,Kline,Frenchtriedtoestablishstudiesofpentanucleotidefrom1933through theirU.K.subsidiaryMenleyJames.TheTTCsentthedrugto6centresandDawson
323 treated3cases,showingitincreasedtheleucocytes Wilkieinvestigateditsrolein
increasingleucocytespriortosurgery,inmalignantneutropeniaandotherconditions
324 associatedwithneutropenia. GarrodatSt.Bartholomews,KnottatGuys,Wilkinsonin
ManchesterandWittsinOxfordwereinvolvedandpresentedcasestotheRoyalSocietyof
318
R.F.Corran,ThyroidstandardisationandStorageandEvansBiologicalInstitute, RuncornPharmaceuticalJournal(29June1935)78183. 319 TTCMinutes6,(28February1936),MRCFile1523/15. 320 TTCMinute4,(undated1933),MRCFile1523/15 321 TTCMinutes5,(5March1934),MRCFile1523/15. 322 TTCMinutes7,(11February1937),MRCFile1523/15. 323 TTCMinute4,(undated1933)TTCMinute5,(5March1934),MRCFile1523/15.
403
404
325 Medicine. ByTTCstandardsthisdrugwassuccessfulandthecompanybenefitedfrom
thepublicitygenerated. Towardstheendoftheperiodunderreviewanincreasingnumberofforeignfirms drugswereevaluatedbytheTTC,andmanyweredescribedunderthesectionon

326 organotherapy.ArequestfromE.MerckfortestingofEpivarintestedwasdeclined.
AdovernfromRocheandTussipectfromBeiersdorfwerealsoturneddownwithnoreason recordedandHelborsidfromRochewasconsidered,butthecommitteedecidedtowaitfor
327 6monthsforresultsfromelsewhere,presumablyoverseas.
CIBAofferedcompound2834/35,thehydrochlorideofquinoline8oxyacetn dibutylamidine,whichwasmeanttohaveergotaminelikeproperties.TheTTCwere onlyinterestedifChassarMoirexaminedit,anditwasdroppedafterhepostedpreliminary

328 unsatisfactoryresults. AfurtherCIBAcompound,3259orbenzyldihyhdroimidazolin
hydrochloride,wassenttoW.R.TrotteratUCHandalthoughheshowedavasodilator effectontheconjunctiva,thecompoundhadnegligibleeffectsonbloodpressureanditalso
329 hadunpleasanteffects,andthereforewasnotdeveloped.
BayersubmittedavitaminD3/calciferol(vitaminD2)combinationpreparedby synthesisofirradiated7dehydrocholesterol,andsaidtobeidenticaltothenaturalvitamin Dofcodliveroil.Unlikecalciferolitwaseffectiveinchickens.TheinitialTTCappraisal wasthatitwasverydoubtfulwhethercertainGermanclaimsthatitwasmoreactivethan

330 calciferolinhumanricketscouldbesubstantiated. Prof.NoahMorrisofGlasgowand
J.C.SpenceofNewcastlecomparedthetwoforms,treatingfourcasesoneachtreatment withlittledifferencebetweenthem.ThiswasthenearestthattheTTCgottoacontrolled
324
TTCMinute6,(28February1936),MRCFile1523/15G.StewartSmith,ACase ofAgranulocytosisTreatedwithPentanucleotideLancet(16March1935):607. 325 L.J.WittsAgranulocytosisProc.RoyalSocietyofMedicine29(1936):671. 326 TTCMinutes5,(5March1934)File1523/15. 327 TTCMinutes7,(11February1937)File1523/15. 328 TTCMinute9,(14July1938),MRCFile1523/15. 329 TTCMinutes8,(7February1938)TTCMinutes9,(14July1938),MRCFile 1523/15. 330 TTCMinutes8,(7February1938),MRCFile1523/15.
404
405
331 trial BayerwasbasedatSt.DunstansHillinLondonandtheyemployedGeorgeH. 332 Morrison:amedicaladvisor
HoffmannlaRocheputforwardtheirSyntropanoramprotropine,introducedin 1933.Thechemicalstructurewasprovidedalongwithdetailsofpreliminarylaboratory
333 andoverseasclinicalstudies. Thiswasthefirstofseveralatropinelikemoleculeswhere
anattempthadbeenmadetoseparateoutthebeneficialpharmacologicaleffectsofthedrug
334 fromitssideeffects,suchascausingadrymouth. Thereferencesprovidedbythefirm 335 werehighlyeulogistic,suchasthebrilliantresultsofthisantispasmolyticin15cases.
TheTTCstudiesfoundSyntropantobesimilarto,butweakerthanatropineinits spasmolyticactivityonthegut.Itwasofvalue,particularlyincasesofbladderpainand acutecystitiswithdysuriaandfoundittobefreeoftheunpleasantsideeffectsof

336 atropine. TheuseofSyntropaninseasicknesswasreportedintheLancetof21January
1936.Itshowedgreatpromiseasabetterantispasmodicthanatropineandwitha
337 weakermydriaticeffect,lesseningtheproblemofdryeyes. BurroughsWellcome
consideredpreparationofSyntropan,buttheirstafftraceditspatentsothiswasnot
338 pursued. Mr.Ian LawsonDickofthepathologylaboratoriesinEdinburghfirstshowed
thatSyntropanwaspharmacologicallylessactivethanatropine:myclinicalobservations arenotextensiveenough itworksinmildcoliconly,butProf.AlfredJosephClark,339 ProfessorofMateriaMedicaandPharmacologyinEdinburgh,thoughttherewasacasefor
331 332
TTCMinutes9,(14July1938),MRCFile1523/15. LetterfromGeorgeH.MorrisontoTTC(21September1931)regardingtheirliver preparation,Campoloon,MRCFile1523/15. 333 SummaryonSyntropan,(dated18January1934),T.R.ElliottFiles,WI:GC/42 193343.

334 335
WalterSneader,(1985):123. F.H.K.GreentoT.R.Elliott,(10June1936),T.R.ElliottFiles,WIGC/42TTC 193542K.Fromherz,TheModeofActionofSyntropaninAnimalExperiments QuarterlyJ.PharmandPharmacology IX(1936)16.

336
TTCMinutes5,(5March1934)TTCMinutes6,(28February1936)TTCMinutes 7,(11February1937),MRCFile1523/15. 337 STCMeeting,(28May1936),WF:STCS/G/50. 338 STCMeeting,(7October1936),WF:STCS/G/50. 339 E.B.Verney,AlfredJosephClarkObituaryNoticesofFellowsoftheRoyal Society 3(1941):969984.
405
406
340 furtherstudies. SirDavidWilkieandMajorMcKelveywereinvitedtoperformfurther
testsonSyntropan.TheurologistC.J.Bondhadalreadyperformedsomestudiesin dysuria.F.J.Barrington,anotherurologysurgeon,examinedthedrugintubercularcystitis,
341 asdidR.OgierWard,GeoffreyParker,JamesCarverandVictorDix.
In1938ParkeDaviswantedtheirsodiumthioethamyltestedandsubmitteditfirstto theanaestheticscommittee,whoinaccordancewithpolicypasseditontotheTTC. However,onlylimiteddatawasprovidedandthecompoundwasreturnedtothe anaestheticscommitteesfortesting,andeventuallyC.LangtonHewar,anaesthetistatSt

342 BartholomewsandtheBromptonpublishedthedata. MerckandMay&Bakerboth
providedTrichloroethanolbutthiswasalsopassedtotheAnaestheticscommitteefor evaluation. Dr.G.H.A.ClowesatLillyinIndianapolis,whohadarrangedinsulinstudies, providedasurgicalantiseptic,Merthiolate.Ithadbeenpraisedinthe19334MRCreport foritsbenefitsintuberculosisbyCapt.D.P.LambertinIndia,whoalsopublisheddatain theLancet,butwhenProf.S.L.CumminsinCardifffurthertestedit,hefoundittobeof

343 novalueintuberculosis.
MercksubmittedanapplicationforDoryl,anextremelystablecarbamicacidesterof choline,whichwassenttoChassarMoirattheBritishPostgraduateMedicalSchool,who founditusefulfor(urinary)retention.ItwasalsoevaluatedinWilkiesdepartmentin
340
F.H.K.GreentoT.R.Elliott,(26February1936),V.DixtoF.H.K.Green,(8 January1936),andF.H.K.GreentoT.R.Elliott(14March1936),T.R.ElliottFiles,WI GC/42TTC193542.

341
C.J.Bond,OntheInfluenceofAntisepticsontheActivitiesofLeucocytesBritish MedicalJournal (1916):77782 BritishMedicalJournal (1917):164C.J.Bond, th ConsultantSurgeonatLeicesterRoyalInfirmary,joinedtheMRCon10 April1920:510 11F.H.K.GreentoT.R.Elliott,(26February1936),T.R.ElliottFiles,WIGC/42TTC 193542.

342
TTCMinutes8,(7February1938),MRCFile1523/15C.LangtonHewer,Sodium thioethamylBritishMedicalJournal (21January1939):109. 343 F.H.K.GreentoT.R.Elliott,(18December1937),T.R.ElliottFiles,WIGC/42 TTC193542TTCMinutes7,(11February1937),MRCFile1523/15Merthiolateisstill inuseasthiomersol,(sodiumethylmercurithiosalicylate),apreservativeinvaccinesdespite controversyoveritssafety.www.Ansme.com
406
407
Edinburgh.Thiswasastimulantwiththesameactionasacetylcholineanditwasmarketed
344 345 inMay1935. BurroughsWellcomeproducedaversionofDorylinNovember1939.
Itisclearthatapartfromtheirinterestinhormonalextracts,foreigndrugsreceived limitedsupportfromtheTTC,untilthediscoveryofProntosilopenedthewayformore GermanandSwissdrugs,thoughseveralwereturneddown.Ironically,thedevelopmentof severalfurthersulphonamidesstimulatedfirmstohiretheirownmedicalstafftoestablish clinicaltrialsandthisnewpolicyledtophysiciansbeingtakenonbyAllen&Hanburys, GlaxoandMay&Baker,toarrangetheirownclinicaltrials. Howeverlackofclinicaltrialsdidnotalwaysstopforeigncompaniesfromreleasing theirproductshere,especiallyiftheyfellintothecategoryofvitaminsororganotherapies whentherewassufficientdataavailable.ForexampleMerckmarketedaliverextract Oroheptalin1937andHoffmannlaRochemarketedahistidinepreparationLorostidinfor ulcers. 8.8MRCStudiesofAntisera:LargeCooperativeTrialsandStatistics. WhilethepreviousaccountregardingnoveldrugsshowsthattheTTCseemedtobe satisfiedwithtestingafewpatients,theyalsoperformedstudieswithantisera,whichuntil 1935theTTCbelievedofferedbetterhopesofcombatinginfections.Twoexamplesare givenheretoshowthescopeofthestudies.Dr.MurrayLyoninEdinburgh,Prof. DavidsoninAberdeenandR.CruickshankandCowaninGlasgow,performedatrialof specificseraforpneumoniabetween1929and1934,whichLilienfeldascribedasthefirst collaborativestudy.346
344
TTCMinutes6,(28February1936)1523/15J.ChassarMoir,TheUseofDorylin PostOperativeandPostPartumRetentionofUrineLancet(30January1937):26163 J.S.Maxwell,TheTreatmentofPostOperativeRetentionofUrinewithDorylLancet (30January1937):26364Doryl(Merck)BritishMedicalJournal (11May1935):980 R.OgierWard,AcuteRetentionofUrineBritishMedicalJournal (21January1939): 12123SurgicalProcedureinGeneralPractice:ChronicRetentionofUrine British MedicalJournal (28January1939):17778. 345 STCMeeting,(29November1939),WF:STCS/G/50. 346 MRC1487,TTCTheSerumTreatmentofLobarPneumoniaBritishMedical Journal (10February1934):2415.TheSerumTreatmentofLobarPneumonia.AReport oftheTTCoftheMedicalResearchCouncilLancet(10February1934):29095A.M. Lilienfeld,CeterisParibustheEvolutionoftheClinicalTrialsBulletinoftheHistoryof Medicine56(1982):118 G.F.Petrie,andR.A.O'Brien.(twoletters)Treatmentof LobarPneumoniainAdultsBritishMedicalJournal (28March,1931):5578.
407
408
However,fortheirownlargerserumstudies,theMRCadoptedadifferentapproach
347 tothatoftheTTC,andincludedinputfromthemedicalstatisticians,MajorGreenwood 348 andAustinBradfordHill. GreenwoodwasDirectoroftheMRCStatisticalUnitand
chairmanoftheNutritionAdvisoryCommittee.BradfordHilleventuallytookoveras DirectorofthestatisticalunitwhenGreenwoodretiredin1945.Inthepneumococcal serumstudytheMRCestablishedseveralcentres,includingFraser,Ellis,andR. CruickshankandCowanfromGlasgowtogetherwithCecilandProf.Dochezfrom Americawhosharedtheirexperience,withRyleofSt.Bartholomewschairingtheirinitial

349 meeting.
TheoneotheroccasionwhentheTTCestablishedalargetrialprogramwasagain forserumtherapy,whenBurroughsWellcomeandtheListerInstitutesubmitted staphylococcusantitoxinfortestingin1934.Itunderwentvigoroustestsin15London

350 centres. Thecriteriaforentryofpatientsintothestudywerespeltoutclearly.The
antitoxincouldonlybeusedinacuteosteomyelitis,staphylococcalsepticaemiaand pyaemia,chronicskininfectionsincludingboilsandsycosis,allwithprovenbacteriology, butexcludingringworm.Thebloodwastobemeasuredpreandposttreatmentforthe developmentofantihaemolysinforrabbitcorpuscles.Whenaconferencewasarrangedto discussthefindingsDr.PetrieoftheListerInstitute,Dr.O'BrienofBurroughsWellcome andDr.PercivalHartleyoftheNationalInstitutewereinvitedtoattend.Themeetingwas chairedbyDr.S.C.Dyke,secretaryoftheAssociationofClinicalPathologists,whohad collaboratedwiththeMRCinarrangingstudiesonperniciousanaemiastudiesat

351 Wilkinsonscentre,andbyEdwardMellanbyasheadofthetoxoidcommittee.
347
M.Greenwood,EpidemiologyanditsLessonsLancet (27January1934):201. GreenwoodwasanofficeroftheMinistryofHealthfrom1920,MRCMinutesII,(7July 1920):111. 348 BradfordHillwasonlyappointedtotheTTCatmeeting9on(14July1938),MRC File1523/15P.Armitage,BradfordHillandtheRandomizedControlledTrial, PharmaceuticalMedicine6(1992):2337R.Doll,SirAustinBradfordHillandthe ProgressofMedicalScienceBritishMedicalJournal 305(1926December1992):1521 6. 349 Theconferencetobeheldon27July1932wasreportedinTTCMinutes3,(8July 1932),MRCFile1523/15. 350 TTCMinutes5,(5March1934),MRCFile1523/15. 351 TTCMinutes5,(5March1934),MRCFile1523/15.
408
409
O'BrienindependentlyarrangedforDrRichardArmstrong,abacteriologistat
352 CharingCrossHospital toteststaphylococcustoxoidincasesofbreastabscess,causing
confusionwhenArmstrongsenthisdataonincreasedantibodylevelstotheMRCand
353 askedforasmallgrant. IndoingthisOBrienupsettheMRCrulesonsoletesting
rights. FollowingthesecondconferenceonstaphylococcaltoxoidattheendofJuly1935, areportwaspreparedbyDr.D.S.MurrayofRichmondandwascirculatedtoTTC

354 membersandtoDaleandHartley. Becauseofconflictingresultsintheindependent 355 studiesfurtherdiscussionsbetweenthegroupsweresuggested aconferenceconcluded:
thestaphylococcaltoxoidsatpresentavailableinGreatBritainmaybeusefulforthe treatmentofboilsandstiesbuthavelittle,ifanyvalueforthetreatmentofsycosis
356 (follicularpustules,duetoinfectionbystaphylococcus). Therewasadifferenceof
opinionbetweenpathologistsanddermatologists,regardingfurunculosis(amoredeep
357 seatedinfectionofthehairfollicle). Theoverallconclusionwasthatthetoxoidhelpedin
treatingsuperficialskinlesions,butwasoflimitedvalueformoredeepseatedinfections, whichwerepronetorelapse.Asaresult,differentreportswererequestedforcarbuncles
358 whereitwaspromisingandfortoxaemia, whereasagroupofsixsurgeonsfoundit 359 notencouraging. Theseapparentlydiscrepantfindingswerediscussed,andthen
352
RichardRobinsArmstrong18851975,ObituaryBritishMedicalJournal (5April 1975):44. 353 TTCMinutes5,(5March1934),MRCFile1523/15.

354
TTCMinutes6,(28February1936)D.S.Murray,StaphylococcalToxoid,a ClinicalTrialLancet(9February1935)L.Forman,OntheTreatmentofSycosiswith StaphylococcalToxoidProc.IXthInt.CongDermatology,Budapest(1935). 355 F.H.K.GreentoT.R.Elliott,(12May1935),T.R.ElliottFiles,WIGC/42,TTC 193542.

356 357
TTCMinutes6,(28February1936),MRCFile1523/15. L.E.H.Whitby,TheTreatmentofStaphylococcalSkinLesionswithToxoid Lancet(27June1936):145456R.Klaber,SpecificandNonspecificTreatmentofBoils, withSpecialReferencetotheResultsofTreatmentbyStaphylococcalToxoidLancet(3 October1936)78486R.S.Wale,K.Maddis,StaphylococcalToxoidintheTreatment ofDiabetesBritishJournalofComparativePathology 17(1936):279. 358 WilkiewasamemberofthecommitteeoftheMRC.In1938aUnitforClinical ResearchwasestablishedinEdinburghTTCMinutes6,(28February1936),MRCFile 1523/15. 359 TTCMinutes6,(28February1936),MRCFile1523/15F.H.K.GreentoT.R. Elliott,(28December1934),T.R.ElliottFiles,WIGC/42,TTC193334.
409
410
relayedtoO'BrienofBurroughsWellcomesothattheycoulddefinewhichpatientswere mostlikelytobenefit.LionelWhitbyoftheMiddlesexHospitalpublishedafurtherstudyin staphylococcalskinlesionsinwhichhetestedtwointramuscularpreparationsfrom BurroughsWellcomeandonefromtheListerInstitute.Heevaluatedalmost200casesand achievedgoodoutcomesinboils,stiesandcataractswith6588%respondingbutonlyone

360 of8casesofsycosisresponded,andthatonelaterrelapsed.
FollowingarecommendationfromDaleandwiththebackingofboththe ChemotherapyandAnaestheticsCommitteesitwasdecidedtotestMercksbasalhypnotic,
361 trichloroethanol. Thishadbeenfoundtobedangerouslytoxicinastudyperformedat 362 St.GeorgesandatthePrinceofWalesHospital inTottenham. Dr.C.LangtonHewer,
anaesthetistatSt.Georges,LondonhadstudiedParkeDavis'Sodiumthioethanylshowing itwasalmostidenticaltoPentothal. TheTTCdidnotfollowupontheclaimsofacompanycalledCausythLtd.from ItalythattheirsubstanceCausythwasdefinitelysuperiortothesulphanilamide

363 antibiotics.Theysimplydidnotbelieveit.
ChaseLaboratoriesofNewark,NewJerseyappliedtohaveclinicaltestsperformed ofaFrenchneuroleptic,Cyclamide(morpholinenicotinamide),buttheyprovidedverylittle pharmacologydatasoitwassenttoProf.ClarkinEdinburghforpharmacologicaltestsand hefoundthatinsteadofhavingthesameactivityasCoraminewithlesstoxicityaswas claimed,ithadonefifthoftheactivity.HeshowedthatalthoughitsactionontheC.N.S. waslowithadnotoxiceffects.Clarkconcluded:Isupposefromthepointofviewofthe

364 TTCtheabsenceoftoxicityisthemostimportantfeature.Howeveritwasdropped. It
wassuggestedthatWilliamEvansattheLondonHospitalcouldperformclinicalwork,as hehadrecentlydoneindependentworkonCoramineandothercardiacorrespiratory
360
L.E.H.Whitby,TheTreatmentofStaphylococcalSkinLesionswithToxoid,Lancet (27June1936):145456. 361 SodiumThiethamylBritishMedicalJournal (21January1939):109.

362
C.LangtonHewer,DouglasBelfrage,TrichloroethanolonTrialLancet(3 December1938)12901.
363
F.H.K.GreentoT.R.Elliott,(18March1938),T.R.ElliottFiles,WIGC/42TTC 193542.Thissubstance,prophenazoneisstillproducedbyCausythandusedasananti inflammatoryandanalgesic(BiamaccessedApril2003).

364
TTCMinute9,(14July1938),MRCFile1523/15.
410
411
365 366 stimulants. OtherssuggestedwereFraser,GunnandL.J.Witts. Elliottreplied:I
supposethatforinternationalreasonsweshouldseektosupporttheFrenchCyclamideas againstCoramine.ButIamnoteagertodomuchforthesecontinentalfirmsunlessthey
367 haveverypromisingsubstancestooffer.
ThemeetingoftheTTCinMarch1939wasthetenthandlastmeetingofthe Committeebeforethewar.SirDavidWilkieofEdinburghhadjustdiedsoareplacement surgeonwasrequired,whileProf.(Sir)JohnW.McNeewasattendingforthefirsttime. McNeehadbeenthefirsttodemonstratetheinfectivenatureoftrenchfeverbackin1915.

368 HeworkedunderElliottatUCHbeforebecomingProfessorofMedicineinGlasgow.
TheCommitteediscussedcompoundsfromOrganon,ParkeDavis,Merck, BurroughsWellcome,BDHandBoots,MayandBakerandCilag) 8.9ConclusionsRegardingtheTherapeuticTrialsCommittee. TheTTCwasestablishedagainstabackgroundofincreasinggovernment interventionindrugproductionandawaveofprotectionismbroughtaboutbytheharsh economicclimate.Bytheendof1939theTTChadperformedstudiesonover60drugs.I haveattemptedtogiveaflavouroftheoverallstudiesandalthoughIrecognisethatthisis inevitablyincomplete,theimportantpointistogetanoverallimpressionofthetypeand scopeofstudiesperformed.Thestudiesshouldbejudgedonthemeritsoftheresearchat thetime,notaccordingtowhichdrugsgavethelastingbenefits:insulin,sulphonamidesand steroids.Itwasacomplexprocesstounravelthetestingofallofthedrugsandfurther supportivedatacouldbefound,buttheworkdonesofargavemeaninsightintothe researchandstrategiesofBritishpharmaceuticalmanufacturersintheinterwarperiod.
365
Coramine,ornicethiamideisastimulantstillproducedinGermanyforthetreatment ofcardiacinsufficiency. www.ansme.com 366 F.H.K.GreentoT.R.Elliott,(25June1938),T.R.ElliottFiles,WIGC/42TTC 193542

367
T.R.ElliotttoF.H.K.Green(29June1938):T.R.ElliottfilesWIGC/42,TTC 193542.
368
Thecommitteeattheendof1939wasProf.Elliott,Col.Harrison,Dr.Carnwath,Dr. BradfordHill,Prof.Clark,Prof.J.W.McNee,SirHenryDale,SirEdwardMellanby,Lord Dawson,Prof.JohnRyle,RegiusProfessorofPhysicatUniversityofCambridge.Dr. WattsEden,Dr.Herald(actingsecretary),Prof.Fraser,Prof.GunnJohnMcNeeJ. AustokerandL.Bryder(eds.),(1989):66,212.
411
412
Certainoveralltrendsarediscernable.Firstly,severalBritishfirmshadabacklogof compoundsreadytobeassessedin1931whentheTTCwasestablished.TheTTCclearly setouttheirstallnottoevaluateGermandrugsandtoassistBritishmanufacturers whereverpossible,andthemajorityofdrugstestedupto1935wereBritishuntilProntosil changedthewholeapproach.Ontheotherhand,organotherapiesfrombothSwitzerland andHollandwereevaluatedinthehopeofbringingsomeordertotheveryvaried preparationsonsale.Butonseveraloccasionswhenorganotherapieswereavailablefrom foreignmanufacturers,theTTCstillwentaheadtotestandencouragethereleaseofa Britishversion.TheMRCperformedclinicaltrials,primarilyinthosecentreswherethey hadalreadyfundedresearch.Thismeantthatalargeproportionofstudieswereperformed atUCH,St.BartsandGuysinLondon,butalsoinEdinburgh,Glasgow,Manchester, SheffieldandOxford,withthesametrialistsnamesappearingseveraltimes. TheformersecretaryoftheTTC,F.H.K.Greennicelysummarisedthe requirementsandtheachievementsoftheTTCintwopapers.Inonepaperheconfirmed thedifficultiesfacedbyBritishmanufacturersowingtoacertainreluctanceofmany Britishdoctorstocarryoutclinicaltrialsatthedirectrequestofcommercialfirms,and especiallytoallowtheirnamestobequotedastheauthorsofsuchtestsandthisplaced BritishmanufacturersatadisadvantagecomparedwithsomeoftheirEuropean
369 competitors.
Certaintrendsalsoappearinthetypesofdrugassessed,withaprolongedfocuson organotherapy.TheneedsoftheTTCandthecompanieswerecomplementary,becauseof thecloseinvolvementoftheMRCinbiologicalstandardisation.Asaresult,theweaker biologicalswereweededout,andthemoreconcentratedversionsallowedMRCstaffand universitychemiststoelaboratethestructuresandtosynthesisetheactiveingredients, whichcouldinturnbestandardised.Aconsequencewithlonglastingconsequencesforthe pharmaceuticalindustryisthatmanycompaniessimultaneouslyjumpedontothe bandwagonandpreparedsyntheticderivativesofeachnewdrug.Nowherewasthis clearerthanintheexamplegivenoforganotherapy,whentherewereseveralpreparations ofOestrinandProgestinandsuprarenalcorticalextract.In1935,justfiveyearslaterthe samesituationarosewhensulphonamideswerediscoveredinGermany,butFrench workersshowedthatthepatentswereinvalid,astheactiveingredienthadbeenidentified
412
413
severalyearsearlier.Againthisallowedawiderangeof companiestosimultaneously preparesyntheticderivativesofthesulphanilamidebase.Thisprocesswasrepeatedover andover,andmultiplefirmspreparedinsulinandvitamins,andthevarious organotherapiesthismorethananything,keptthepharmaceuticalindustryasadiverse, poorlyconcentratedindustry.
By1934collaborationswereincreasinglycommonbuttherelationshipofscientists anddoctorstocommercewasproblematical.Dale,inhisRoyalSocietyrolereceiveda letterfromElliottdiscussingaProf.(Kapitza)whoaskedtoreceivefeesforsecretwork withbusinessfirms.Elliottraisedthepossibilityofdeflectiontoshorttermaimsandasked Dalethetheoreticalquestion: WouldyouallowLaidlawtotakecomfortablefeesfromWellcomeforadvice onpreparationofdistempervirus?WhynothaveMellanbyhavegivenhis adviceandevenhispowerfulnametoGlaxoLtd.inthepreparationoftheir 370 patentcoveredvitamineDandbeensuitablyrecompensated.
ElliottreferredtotheAlistofRoyalSocietymenandexpressedconcernattheimpartial
371 positionoftheSocietyinitsincreasingrolewithindustry. AccordingtoGreentheTTC
weremeanttoevaluateonlyentirelynewremedies,minormodificationsandimprovements ofknownremediesbeingexcludedandmixtureswerealsoexcluded.Theyhadtobe submittedtotheCommitteebeforetheywereplacedonthemarket,sothatthe manufacturermightbesavedembarrassmentiftheresultsofthetestswere

372 unfavourable. TheMRClegitimiseddrugsnotdoctorsorindividualscientists.The
advantageofthearrangementwasprimarilythattheviewoftheMRCwasseenas independent. Regardingthetestingofnewdrugs,aneditorialin1935statedthat:theuseofany newcompoundisnotjustifieduntilextensivelaboratoryinvestigationhasrevealeditstype andmodeofaction,itsprobabletoxicityanditssuperiorityoverotherdrugshavingthe

369 370
F.H.K.Green,Brit.Med.Bull (1944)2:5860. T.R.ElliotttoH.H.Dale,(19February1934)DaleArchives,HD36.4.4. 371 H.H.Dalelettersto/fromT.R.ElliottT.R.ElliottoH.H.Dale,(19February 1934)inDaleArchives,HD36.4.6. 372 F.H.K.Green,Brit.Med.Bull (1944)2:5860.
413
414
373 sameorsimilaraction. Notallcompanieswenttothesamelengthstoevaluatetheir
drugsanditwassuggestedthatacentrallaboratorywouldbeuseful:Fewlaboratoriesare equippedadequatelyfortheproperpharmacologicalevaluationofnewdrugsandalthough arrangementscanbemadebycommercialhousesfortheclinicaltrialofnewdrugsthrough theTTCoftheMRC,thereisanobviousneedforacentrallaboratory,suchasthatcarried onbythe(Pharmaceutical)Society,wherethepharmacologicaltestingofdrugscanbe undertaken.Manyofthesyntheticchemicalsemployedaschemotherapeuticagentsare tributestotheenterpriseofourlargepharmaceuticalmanufacturers,whotakeconsiderable financialriskinthedevelopmentofnewremedies.Often,howeverenthusiasmhasbeen allowedtooverridecaution,andmanycompoundshavebeenplacedonthemarketwith

374 insufficientpreliminarylaboratoryandclinicaltesting. Thereasonforinsistingthatthe
MRCwerethesoleagentsperformingstudieswasostensiblytopreventtheappearanceof conflictingandconfusingreportsupontheproduct,duetotheprematurepublicationby independentworkersofreportsonitstrialininadequateseriesofcases,beforetheofficial

375 investigation. Theyrecognisedthatthiseffectivelyexcludedanyproductalreadyonthe
marketinBritainorabroad.Greenlistedthemostimportantagentslaunchedbythe
376 committeeascalciferol,digoxin,Prontosil,stilboestrolandSulphanilamide.
TheMRCweretogetaroundtheproblemfordoctorsbypublishingstudiesasa reporttotheTTCoftheMRC,thusexoneratingclinicians,keepingthemfreefrom commerce.AccordingtoGreenover40compoundsweretestedandinhiswordssome oftheinvestigationshavebeenonastatisticalbasis,andthesehavebeenplannedand

377 assessedwiththeadvicefromthestatisticsstaffoftheCouncil. Inaseparateaccount
hewrotethat:itwasearlyrealisedthatthemedicalstatisticianisavaluablememberofthe planningteam,evenwhenthenatureoftheinvestigationisnotsuchastorequirelarge
373 374
TheInvestigationofNewDrugs,PharmaceuticalJournal (1June1935):653. ACentralLaboratory,PharmaceuticalJournal (1June1935):653. 375 F.H.K.Green,ClinicalEvaluationofRemediesinBritain,Brit.Med.Bull.2 (1944):5860. 376 F.H.K.Green,TheClinicalEvaluationofRemediesTheLancet(27November 1954):10851091.F.H.K.Green,Brit.Med.Bull (1944)2:5860L.Colebrook,A.W. Purdie,Lancet(1937):1237,1291W.R.Snodgrass,T.Anderson,BritishMedicalJournal (11December1937)II:1156. 377 F.H.K.Green,ClinicalEvaluationofRemediesinBritain,Brit.Med.Bull.2 (1944):5860.
414
415
378 numbersofsubjects. Hereferstothenotoriousdifficultyofsecuringcontrolleddata
andhowthiswasovercomebytheorganisationofblindedtestsandtheuseofinert substances.Unfortunatelythereisnodatainthefilesorpublicationstosupportsuch statements.ThestudiesarrangedbytheTTC,generallyemployedseveralcentres,but recruitedrelativelyfewpatients.Thedesignofthestudiesallowedthemtoreadilyidentify overtlytoxicdrugsordrugsthatsimplydidnotworkorwerepoorlytolerated.Wherethey struggledwaswiththemanydrugsbeingproducedbydifferentfirmsthatwerevariantsor marginalimprovementsonathemethosethatwerebetterextractsorsyntheticversions orimprovedsalts.Thiswasparticularlyproblematicwhenthedrugwastestedinan unusualandrarediseasesuchasmyastheniagravis.Despitetheclaimsoftheroleof statisticians,Ifoundnoevidenceandthenumbersrequiredwerenotplanned,ratherthe TTCarrangedforasmanypatientstobetreatedascouldbemustered. Theimpressionisgiventhattheevaluationofmedicineswasbasedona combinationofthescientificrationale,thedatapresentedfromanimalstudies,thepurity ofthedrugsandfreedomfromothercontaminantsandfinallytheclinicalefficacyand toleranceinclinicaltrials.InadditionfactorssuchastheavailabilityofaBritishversionand tosomeextentcostswerealsotakenintoconsideration.
Whataboutfromthemanufacturerspointofview.Asidefromthedisappointmentof theslowprogressofsomestudies,firmswerefrustratedbythelackofcontrolovertheir productsdestiny,andtheirlackofaccesstocliniciansbutasRutherfordHillpointedout therewasnothingtostopthemplacingproductsonthemarket.Attheendof1937J.W. TrevangaveanoutspokenPresidentialaddressonthissubjecttotheSectionof TherapeuticsandPharmacologyoftheRoyalSocietyofMedicine.Herecalledhowthe spateofsyntheticdrugshadbeguninthe1880s.Heannouncedthatsomeresponseshad beenlessdramaticthanhopedfor.Hereasonedthat: Ifaphysicianispreparedtotaketheriskofadministeringanewproductto aseriesofpatientsheshouldbepreparedtotaketheriskofwithholdingthe
378
F.H.K.GreenTheClinicalEvaluationofRemediesLancet(27November1954):
1088.
415
416
remedyinthecaseofsomepatientsuntilacertainprobabilitywas 379 established,greaterthansaytentoone,thatthematerialwasactive. HegaveexamplessuchastheuseofvitaminAforinfectionsandvitaminBfor constipationbasedonlittleevidence.Hereferredtothefactthatduetothehappyhunting groundofthesyntheticchemist,chemotherapywasnowoneofthechiefgrowingpointsof therapeuticsandmedicalmenmightlookforwardtoaconsiderablyenlargeddailypost. Hecomplainedaboutthereprehensiblepracticeofmakingstatements,whichwere demonstrablyuntrue,althoughmadewithapparentscientificassuranceandhethoughtthe rubbishoutweighedthegoodandhewaspessimisticaboutheadingtowardsatherapeutic darkage.Themoneyspentwasenormous,soclearlytheadvertisementshadsomeeffect. Trevanhadreviewed43recentcasesandfoundthatevenbylenientstandardsonly27 claimedfoundationinthelaboratoryorclinicandthat13weremisleadingorsimplysilly. HefeltthatonesolutionwouldbetohaveanindependentlaboratoryattheLondonSchool ofHygieneandTropicalMedicineoratthePharmaceuticalSociety.Oneoftheproblemsof competitionwasthemultiplicationofsimilarproductsbycompetingmanufacturersandthis couldnotbeavoidedaslongasproductionwasinprivatehands. HedidcommentoftheTTCthattheywere:doingextremelyvaluableworkandofwhich hewishedthemanufacturerswouldmakemoreuse.Coulditbehopedthatnonewremedy
380 wouldbeintroduceduntilithadbeenpassedbysuchacommittee.
AttheendoftheperiodunderreviewandwiththeoutbreakofWar,afurtherseries ofmorespecialisedcommittees,includingoneonpenicillin,andanotheronantimalarials wereestablishedallowingmanufacturerstomaintaincloserconductwiththeclinicians makingtheteststhan hashithertobeenpermittedinpeacetimeinlinewithadesiretosee

381 fasterreportingofresults.
CoxMaksimov,inherevaluationofclinicaltrialsmethodologiescoveredthesame periodthatIdo,butfromquiteadifferentperspective.SherecognisedtheTTCas assessingtherapeuticauthority.Hermainthesiscontrastedtheinteractionsbetween mainstreammedicalresearchersledbyFletcherattheMRCwiththefraudstersand charlatansthatpeddledtheirpatentmedicines,andchallengedthemedicalestablishment.In

379 380
J.W.Trevan,PharmaceuticalJournal 140(1January1938):3. Ibid.
416
417
dramaticstyleshewrotethat:Whatwasatstakewastheveryfutureofthenation.This wasacontestbetweenthepursuitofsecretremedieswithunfoundedclaimsagainstthe rigorouslytested,scientificallyvalidatedmethodsoftheestablishmentinvolving disclosure,integrityandcharactertogetherwithstandards,fairnessandstatistics.Butit

382 wasjustasmuchaboutmaintainingthesocialorderofBritain.
Oneshouldbecarefulofgeneralisationshere.CoxMaksimovfocussedon theTTC studyofconcentratedpneumococcalserumattheRoyalInfirmary,EdinburghandUCH: butthiswasnotatallrepresentativeofthemainworkoftheTTC,noritsstatedobjectives. ItwasnotaBritishpreparation,itwascertainlynotfromindustryanditsstudyhadalready beenplannedin1929,twoyearsaheadoftheTTC.Itwasanexpensivepreparationthat

383 PaneldoctorscouldnotaffordanditwasinitiallyimportedfromAmerica. Cox 384 Maksimovwentontoexaminethemulticentrestudyofpatulin forthecommoncold.
Patulinwasanaturalextractderivedafungusthatgrewonapples.Thislatterstudywasthe brainchildofPhillipDArcyHart,DirectoroftuberculosisworkfortheMRC,whowasto
385 beintimatelyinvolvedinthe1946,randomisedcontrolledstudyofstreptomycin. Cox 386 MaksimovsummarisedherinterpretationthattheTTCbecamearegularmachine. She
focusedonstatisticalmethodology,arguingthatthefirstrecognisedrandomisedcontrolled trialonstreptomycinorganisedbyAustin BradfordHill,theMRCstatisticianin1946

387 1948 wasbasedonalineofdescentfromthestatisticalconceptsofrandomisation 388 evolvedbyRonaldFisherinagriculturein1935. AustokerandBryderfoundnoevidence
381
SirArthurS.MacNalty,HistoryoftheSecondWorldWar:MedicalResearchF.H. K.Green.G.Covelleds.(London:HMSO,1953). 382 D.CoxMaksimov,(1997):185.

383
MRCMinutesIII,(25October1929):167(16May1930):84(28November 1930):175(23October1931):127(21October1932):171. 384 H.Raistrick,PatulinintheCommonCold:CollaborativeResearchonaDerivative ofPenicilliumpatulumbainierLancet(20November1943):625. 385 P.DArcyHart,AChangeinScientificApproach:fromAlternationtoRandomized AllocationinClinicalTrialsinthe1940sBritishMedicalJournal (28August1999):319 386 D.CoxMaksimov,TheMakingoftheClinicalTrialinBritain,19101945. Expertise,theStateandthePublic(Cambridge:PhDthesis,September1997):185.
387
J.FisherBox,R.A.FisherandtheDesignofExperiments,19221926The AmericanStatistician 34(February1980):17. 388 R.A.Fisher,TheDesignofExperiments(Edinburgh:OliverandBoyd,1935).
417
418
ofFisherinteractingwiththeTTCandthismeantthathisexpertisewasnotutilisedin
389 ordertotranslatehispowerfulideasonexperimentaldesignintoaclinicalcontext.
BradfordHillwascertainlyawareofFishersworkbuttherandomscatteringofseeds infieldswasadifferentmattertophysiciansadoptingthenullhypothesisandadmittingto themselvesandtotheirpatientsthattheyreallydidnotknowwhichoftwotreatmentswas bestandthattheycouldfacetheethicalissuesofrandomlyassigningpatientstooneoftwo

390 therapies. Thiscontrastedwiththephysiciansart,whichwasincarefullydiagnosingan
individualpatientandcarefullychoosingthemostappropriatetherapyforthatpatientand themethodsofclinicalstudythatIhavedescribedintheremainingTTCstudiesinthe 1930s.BradfordHillquestionedthemethodsofallocationtotreatment,criticisingthat greatereffortshouldbetakenthatthedivisionofcasesreallydidensurearandom

391 selection. TheseconceptswereembodiedinaseriesofarticlespublishedintheLancet 392 atthestartof1937andsummarisedinabookinthesameyear. AccordingtoBradford
Hillandothers,Fisherplayednopartinthedesignofclinicaltrials. Theinterwarperiodshowsanincreasingsophisticationof drugsandthemeansof assessingthem.Liebenauagreedthat: Asdrugcompaniesrequiredincreasinglytechnicallyadvancedpeoplefor researchanddevelopment,andasmedicalscientistswereincreasingly availableforindustrialemploymentduringtheinterwarperiod,theuseof 393 newsciencebecamethecentralelementofcompetition. ThereluctanceoftheBritishmedicalprofessiontocollaboratewithindustryintestingtheir newdrugsstifledBritishresearchinsyntheticdrugsuntiltheMRCassistedattherequest ofindustryinestablishingtheTherapeuticTrialsCommitteein1931.Ihaveexaminedthe successorotherwiseofthisventure.ItwashelpfulinthoseareasintheMRCcomfortzone wheretheycouldassistingettingaBritishversionofadrugonthemarket.Theyhad greatersuccessintestingsomebutnotallorganotherapiesandotherdrugsthatcouldalso betestedbybiologicalstandardisationorthesuccessofwhichcouldbefollowedinthe
389 390
J.AustokerandL.Bryder,inJ.AustokerandL.Bryder(eds.),(1989):47. PersonalcorrespondencebyletterwithSirAustinBradfordHill.(6October1988) andtelephonediscussion(1January1989). 391 A.B.Hill,SerumTreatmentofPneumonia(22December1933),MRCFile1487. 392 A.B.Hill,PrinciplesofMedicalStatisticsseriesofarticlesTheLancet(1937) 393 J.Liebenau,ResearchandDevelopmentinPharmaceuticalFirmsintheEarly TwentiethCenturyBusinessHistory 26(1984):329346.
418
419
laboratory.Thesyntheticdrugstudieswerefarlesssuccessful,partlybecauseofthe reluctancesmentionedabove,butalsobecauseindividualdoctorssawonlylimitedcases. Apartfromvaccineandtoxoidstudies,theTTCstudiesweregenerallysmallandoften inconclusive,exceptwhereevenasmallstudyshowedsomesafetyproblems.Synthetic drugsbroughtnewissues,notleastregardingpatentsbutbothHarryJephcottofGlaxoand Prof.H.HrleinofBayerdefendedpatentingasameansofprotectinginvestmentsand

394 allowingareturntoinvestinfurtherresearch.
Anotherreasonforinsulinnotbeingagoodmodelforclinicaltrialswasthatthe firmshadtointeractwithphysiciansthroughtheMRCandwerenotallowedindependent studies.ItwasonlyafterthediscoveryofProntosil,andthepreparationofsulphonamides bymanyBritishfirmsthattheirsyntheticdrugswereindemand. TheTTCdealtwithabacklogofdrugsthathadnotbeentested,givingclear prioritytoBritishdrugs.Ithelpedtoestablishanetworkofclinicalresearchcentresand contributedtowardsthestandardisationofdrugs.Italsoofferedanindependentbodyof opiniononnoveldrugsandmethodsoftreatment,keepingdoctorsfreeofdirect collaborationwithindustry.TheTTCwasmostsuccessfulindealingwithbiologicaldrugs, largelybecausethatwasanareawheretheMRCwerecomfortableandhadconsiderable expertise. ThisthesisdoesnotextendintoandbeyondtheSecondWar.Howeveritisclear thatBritishfirmscameoutevenstrongerhavingbeeninvolvedinthedevelopmentofboth penicillinandtheantimalarials.Theformerwasagainunpatentedandofferedfurtherscope forchemicalmanipulation.SuchwerethebenefitsofantibioticsthatthelargerBritishfirms didnotseetheneedtocollaboratewiththeTTCpostwaralthoughthesmallerfirmNapp did.Indeedironically,givenitsinitialraisondtreoftheTTCitbecameameansfor foreigncompaniesespeciallyfromHollandandSwitzerlandtohavetheirdrugstested. Britishfirmsinsteadbegantoestablishtheirownstudies.Thistrendhadbegunin1936 whenMay&BakerappointedthephysicianRobertForgantoestablishclinicaltrialsof M&B693andtoanswermedicalqueries.GlaxohadtheirownphysicianinDrHector
394
MedicalPatentsrepliesbyH.JephcottandbyH.Hrlein,PharmaceuticalJournal 140(15January1938):50.Thiswasinreplytoaneditorialin PharmaceuticalJournal 139 (4December1937):589andtosimilarpointsraisedinAmericaDr.Fishbein,Journalof AmericanMedicalAssoc.109(1937):153943.
419
420
WalkerandAllen&Hanburystookontwofemaledoctorstoselltheirvitaminproducts andBayerhadaphysicianevenearlier.ThusthemajorBritishfirmsbegantoestablishtheir ownMedicaldepartmentsandtookcontroloftheprocessofclinicaltestingofdrugs.Sir EricScowenwasinvolvedin studieswithM&BandbeforetheSecondWorldWaronthe antiseptic,pentamidineandworkeddirectlywithICIonsulphadimidineafter1936. M&BscompoundwasevaluatedinEdinburghinstudiessetupbyacompanymancalled

395 HarryThrower.
395
EricScowenvisitedICIinJune1990.Personalcommunication.Healsoevaluated Progestininpatientswithchronicinterstitialmastitis,TTCMinutes7(11February1937): 5.
420
ConcludingComments CHAPTER9:ConcludingComments.
421
Thischapteraimstobringtogetherasummaryoftheresearchperformed,thebroad trendsdiscoveredandsomeprovisionalconclusions.Italsoidentifiesareaswherefuture researchersmayprofitablyextendthisstudy. FollowingtheintroductorychapterinwhichIexaminedthehistoriographyofthe pharmaceuticalindustryandclinicaltrials,IdemonstratedinChapter2,theextentofthe relianceonGermanyforsyntheticdrugsandchemicalintermediates,andthesmall capacityofBritishpharmaceuticalfirmsincomparison.Britishpharmaceuticalfirms facedaparticularshortageofchemistswithpracticalskillsofchemicalengineeringand drugproduction.ThegovernmenthadfailedtosupportthecompetitivenessofBritish industryinitspatentlaws,andwithitshighdutyonalcohol,andfocussedinsteadonthe battleagainstpatentmedicines.IncontrasttotheesteeminwhichtheGermanindustry washeld,thatinBritainhadapoorimage,contributingtothedifficultyingettingdrugs testedinBritainincontrasttotheclosecollaborationsbetweenindustryandacademiain Germany.TheimpressioninBritainwasthatitwaseasyforGermanfirmstogettheir newdrugstested. IntheremainderofthethesisIhaveaddressedthesepoints,firstlytoexplainhow Britishfirmswereabletomakesyntheticdrugsandthenhowtheyremainedcompetitive. InChapter3,IdemonstratedhowBurroughsWellcomebecameaninnovativecompany, continuallystrivingtoproducedifferentiateddrugs,takingideasfromotherinnovators suchasParkeDavisandGermanfirms.BurroughsWellcomecuttheirtieswithWyethto establishtheirownmanufacturingfacilities,andemployedGermanengineerstobuildand runtheirchemicalmanufacturingsite.HenryWellcomeestablishedChemicaland PhysiologicalLaboratoriesthatcollaboratedclosely.Theirstrategywassetoutearly, combiningadvancedAmericantablettingtechnologywithnoveldrugsfromGermanyand combiningGermanstylepatentingandtradenameswithAmericanstyleselling techniquesemployingsalesrepresentatives. HenryWellcomeemployedthemostpromisingresearchersoftheera,throughhis contactsinCambridgeandLondon.TheappointmentsofBarger,DaleandGlennywere inspiredchoicesthathavebeenwelldocumented,butIhaveemphasisedtheimportanceof chemistssuchasFrederickPower,whohadauniquecombinationofexperienceresulting fromworkinpharmacies,trainingatthePhiladelphiaCollegeofPharmacy,andresearch atimportantGermanandSwisslaboratories.Ialsoemphasisethebenefitsoftheclose 421
ConcludingComments collaborationwiththealkaloidexpertWilliamDunstan,attheImperialInstitutein London,whichresultedintherecruitmentofJowett,Carr,ThompsonandReynolds.
422
Thephysiologicalresearchperformedinthelaboratoriesunderanimallicensesis wellknownthankstoTansey,butIhaveshownthatsyntheticchemistrywasafarmore importantandearlierfeaturethanhaspreviouslybeendescribed,beginningsoonafterthe arrivalofPowerandJowettin1896. TheTabloidnameatBurroughsWellcomesignifiedknownpurityandstrength, achievedbyemployingexpertbotanistsandchemiststodefinethespeciesofplants,to standardiseextracts,andtodeterminethechemicalstructuresofpurifiedalkaloidsand glycosides,whichwerethenassayedphysiologicallyagainstpuresynthesisedchemical standards.Someactiveingredientswerechemicallymodifiedtoevaluatetherelationship ofchemicalstructuretobiologicalfunction.Potencywasmeasuredbythecontentof specificalkaloids,ratherthantotalalkaloids,andthisgavecompetitiveadvantagesover firmswithoutlaboratories.Syntheticchemistryalsocontributedtothepreparationofsalts ofnaturalproductstomakethem moresolubleorstable.Furtherdifferentiationwas achievedbyincorporatingGermansyntheticdrugsintoTabloids,andfrom1906by incorporatingopticalisomersofsomedrugs,suchastropeinesandhyoscyamine, increasingpotencydramatically.Somenaturalmoleculeshadchemicalstructuresthat
1 existedinamixtureintwoormoremirrorimageforms(oneforeachchiral centreintheir
chemicalstructure)Jowettandhisteamdiscoveredhowtoseparatethese,andhowto preparechemicalsinonlythebiologicallyactiveform. PowercontributedtothePharmacopoeiaandCodex,andensuredthatthehighest possiblestandardswereset,sothatfewerfirmscouldachievethosetargetsandtherefore fewcouldcompete.BurroughsWellcomesoldafewsyntheticdrugsincludingthe arsenical,Kharsin,someisoquinolinesandsyntheticSuprarenin,butthesewereminor comparedtotheirthrivingTabloidalkaloidbusiness.Theydidnoteventrytocompete withGermanyinpreparingthepopularsalicylatesorothersyntheticdrugsevenwhenthey werebeyondtheperiodofpatentprotection.Theimportanceofsyntheticchemistryat BurroughsWellcomefrom1896,andtheparalleldevelopmentofanunderstandingof chemicalengineeringprinciplesattheWorks,helpstoexplainhowBurroughsWellcome
1
Achiralcentreisacarboninthechemicalstructurewithdifferentgroupsattached. Theyrotatelightdifferentlyaccordingtowhichgroup isontherightandwhichontheleft. Theimportantfeatureisthatoneformmightbealmostinactiveandtheotherhighly active. 422
ConcludingComments wereinapositiontopreparecomplexGermansyntheticdrugswithinweeksofthe
2 outbreakoftheFirstWorldWar.
423
Chapter4assessedthegeneralimpactoftheFirstWorldWarontheBritish
3 PharmaceuticalIndustry. AlthoughtheextentofthedependenceonGermanywaswell
recognised,thespecificquantitiesofeachdrugandchemicalintermediatesrequiredwere verypoorlyunderstoodattheoutbreakofthewar,asBoardofTradefigureswerenot specificordetailedenough.Thesituationwascomplicatedbytheneedforchemical intermediatesandespeciallyasthesameintermediateswererequiredfortheproductionof dyesandexplosives,socentralcoordinationwasessential,andaMinistryofSupplieswas created. Idemonstratedhowvariouscommitteeswereestablishedtodecidewhichdrugs wereessentialtoassesswhichcompaniesmadeorcouldmakethem,wheretheshortages were,andwhatwasneededtopreparetheGermandrugs.Furthercommitteesorganised suppliesofessentialchemicalintermediates.Pharmaceuticalmanufacturerswere representedonallofthesecommittees,includingtheindividualsHoward,Tyrer,Hill, Morson,Lescher,WebbandJowett. Immediatelegislationpreventedtheexportofessentialmaterials,whileGerman patentsofsyntheticdrugswereabrogatedalongwiththeirTradeMarkstoencourage manufactureinBritain.Severalcompanieseventuallyproducedthelesscomplexsynthetic drugs,buttheysoughtassurancesthattheireffortswouldberewardedbyprotection againstGermancompetitionpostwar,beforetheyinvestedheavilyinmanufacturing facilities,whichformedthebasisofastrongerindustrypostwar. Beforethewar,GermanSalvarsanhadbeenstandardisedandtestedforpurityby EhrlichinFrankfurt,sotheMRCtookoverthisroleinBritainduringthewar.Ihave demonstratedbyreferencetotheSalvarsancommitteehowthepreviousBurroughs Wellcomeworkonbiologicalstandardisationwasinfluential.DaleandEwinsanda stringofexBurroughsWellcomestaffsupportedtheirformercolleagues,andlaterMay& Baker,bydemonstratingthatBritishSalvarsanwasasgoodandsafeastheGerman version,bycollatingdatafromhospitalsathomeandinFrance.However,theirexternal
2
F.H.Carr.SyntheticOrganicDrugstheirManufactureasAffectedbytheWar Chemist&Druggist88.4(29July1916):7789. 3 M.Robson,in TheChallengeofNewTechnology J.Liebenau(ed.),(Aldershot: Gower,1988):82105.
423
ConcludingComments supportforBritishdrugsmaskedpoorlyrecordeddatathattheyhadlittlecontrolover.
424
TheyfailedtoconvincesomeBritishphysicians,whohadextensivefirsthandexperience ofthevariousproducts.OneinparticularcampaignedthatBritishSalvarsancouldnotbe asgoodastheGermanversionsanexampleofthelackoffaithinBritishchemistry,and oftheconservativenatureofBritishphysicians.Asaresultofongoingconcernsover jaundiceandsomeraredeaths,asecondSalvarsancommitteewasestablishedin1918, specificallytocompareclinicaldataontheuseofvariousSalvarsanderivatives.The SalvarsanworkwasimportantinestablishingacentralroleoftheMRCasanarbiterof biologicalstandardsandthenoftheclinicalefficacyofnewdrugs.Bytheendofthe periodunderreviewtheMRCwerecoordinatingInternationaleffortsonstandardsand

4 thisbecameacentralfeatureoftheirwork.
Duringthewinterof191415,afterPowerleftBurroughsWellcometoreturnto America,FrancisCarrledafurtherexodusofstafftojoinrivalsBoots,wherehe establishedsyntheticdrugmanufacture,extendedtheirlaboratories,andprepared salicylates,anaestheticsandantiseptics,butalsoabsorbentmaterialsforgasmasks.The governmentencouragedthesupplyofchemicalintermediatestocompaniesin1915by establishingBritishDyestuffs,andthemergerofseveralfirmstoformDistillersprovided plentifulalcohol.TheestablishmentoftheDepartmentofScientificandIndustrial Researchin1915providedfurtherchemicalintermediatesandencouragedcollaboration withindustry.Carrandotherpharmaceuticalmanufacturerstookanactiveroleinthe establishmentoftheAssociationofBritishManufacturersin1916,whichledtoabetter bargainingpositionforBritishPharmaceuticalmanufacturersinthecampaignforlonger termprotectionhewasamemberoftheirfinechemicalcommitteealongwithHilland Howard. IemphasisedthegrowingimportanceofFrancisCarr,whowasrewardedwitha CBEforhiswartimedrugmanufacturingatBoots,andwaschosentorepresenthis country,alongwithIvanLevinstein,onABCMvisitstotheGermanfactorieswithinthe occupiedterritories.FrancisCarrwasthenheadhuntedtojoinCharlesHillatBritish DrugHousesin1920,withthepromiseofmajorfundingtocreateanextensive manufacturingbusinessandhisloyalteamfollowedhim.Ishowedhowattheendofthe warBurroughsWellcomelostseveralfurtherexperiencedstaff,includingFrankTutinand HaroldKing,whojoinedDaleattheMRC.FrankPymanleftforManchesterUniversity,
4
P.Hartley,InternationalBiologicalStandards:ProspectandRetrospect Proc.Royal
424
ConcludingComments
425
beingreplacedbyThomasHenry,whospecialisedinalkaloids.Thesestafflossesmay haveinfluencedsomeoftheirpolicydecisionsregardingwhethertofocusonsyntheticsor traditionaldrugs. Theperiodfrom1919to1931wasdealtwithin3parallelchapters(57),dealing withpostwarmarkets,howeachfirmrespondedandnewlegislationondrugs,howthe ABCMcampaignedtotheMRCforasystemofclinicaltrials,andthestrategiesfor productdevelopment,describedbytheBurroughsWelcomeScientificandTechnical Committee.Muchofthisrelatedtotherecognitionthatastrongindustrywasneededin BritainforstrategicreasonsandrequirednurturingandIdemonstratedseveralwaysin whichprotectionfortheBritishpharmaceuticalindustrywasachieved.TheTradingwith theEnemyActandtariffsondyeimportswereextendedtopharmaceuticalsinFebruary 1919.Withexportmarketsreopened,therewasahoneymoonperiodoftrading,butthe SankeyjudgementinDecember1919ledtoafloodingofthemarketwithGerman products.TogetherwithGermanreparations,andadownturnintheeconomy,thisledto overcapacityonceagaintheindustrywasunderthreat.Carrcampaignedforfurther protectionandresearchtoprotectthecountryagainstfutureattack,whilePearsonof BurroughsWellcomepromisedthatasyntheticdrugindustrycouldbedevelopedin Britain iffirmswereallowedaperiodofprotection. Idemonstratedthatin1922theABCM,representingthepharmaceuticalindustry, approachedtheMRCforasystemwherebynoveldrugscouldbeevaluatedinclinical trials.Previoushistoricalwork,originatingfromLiebenau,suggeststhattheMRC imposedamethodoftestingofnewdrugs.All Britishfirmshaddifficultyarranging studiesofnovelproducts,andBurroughsWellcomeonlyhadsuccessfulclinicaltrialswith theirtropicalmedicines,evaluatedoverseas.TheTrialsCommitteedidnotmaterialise immediately,astheMRCbecameengrossedwithinsulin,collaboratingwithseveral Britishfirmstoprepareinsulinonalargescale,andtoorganiseclinicalstudiesofinsulin. However,followingexploratorystudiesbytheMRC,itwasFrancisCarratBDHwho perfectedtheproductionofinsulin,suchthatwithinayearBDHproduced95%ofthe materialrequiredforBritishuse,thusmakingtheclinicaltrialspossible.Productionof insulinwasahighlytechnicallargescaleoperationthatrequiredsignificantmodification ofexistingmanufacturingplant.In1924Carrachievedsimilarsuccessinthelargescale productionofthepreviouslyprohibitivelyexpensivehormone,thyroxineandBritainheld
Coll.Med.38(1945):45. 425
ConcludingComments
426
aleadingpositioninproductionofthenewhormones.In1925theTherapeuticSubstances Actwaspassed,makingitcompulsorytohavebiologicalsevaluatedbeforesale,and formalisingtheMRCroleinbiologicalstandardisation aroleitwillberecalledthatwas initiallydevelopedwithinBurroughsWellcome.Asaresultsomeforeigndrugswere excludedfromtheBritishmarket.TheABCMapproachedtheMRCagainin1926fora systemofclinicaltesting,buttheMRCinsteadestablishedaChemotherapyCommittee, whichaimedtoevaluatenovelchemotherapeuticagents,baseduponthesuccessofanew Germandrugactiveagainsttrypanosomalinfections,Bayer205.TheDSIRweremeantto developnovelchemotherapeuticagents,andweregranted30,000toassistthisprocess andtheyapproachedBurroughsWellcomewithanofferofcollaborationbutthefirms ScientificandTechnicalCommittee(STC)dismissedtherequest,insistingthatthemain collaborationneededwasinestablishingclinicaltrialsoftheirnewowndrugs. JowettsetdownguidelinesfortestingofnovelproductsatBurroughsWellcome, andthecriteriaforbringingthemtomarket.HebemoanedthefactthatBurroughs WellcomehadfallenbehindbothBootsandBritishDrugHouses,andheputtheblame firmlyontheshouldersofFrancisCarrandhisexternalpoliticalinfluence.Burroughs Wellcomewasinsularbycontrast,andhavinglostsomanystaff,theyrarelyallowed employeestoattendexternalmeetings,forfearofmorepoaching.Idemonstratedhow Carrestablishedhimselfasadrivingforceforchemicalengineering,buthealsowas PresidentoftheSocietyoftheChemicalIndustry19267,givinghimtheplatformto describehisvisionofthefuturesyntheticpharmaceuticalindustry,andtheneedforan organisedsystemofclinicaltrialsfordrugsproducedbyindustry. TheMRCfinallygotthemessageandcreatedtheTherapeuticTrialsCommittee (TTC)in1931,afterafurtherpushfromtheABCMinvolvingHill,Carr,Pearsonand Gamble.Britishdoctorsremainedreluctanttocollaboratewithpharmaceuticalfirms despitetheirgrowingcommitmenttolaboratoryscience,andthefewwhodidworkwere notpreparedtoputtheirnamestopublicationssupportingnewdrugs.ThisplacedBritish firmsatacompetitivedisadvantage.WhereasdoctorsinGermanywereusedtotesting noveldrugs,thiswasnotthecaseinBritain.PrevioushistoricalresearchonSalvarsanand insulinhasnotaddressedthisissueasthesedrugswerealreadyrecognisedassignificant advancesfollowingstudiesoverseas,anddoctorswerekeentoobtainsupplies.Thequite differentchallengeforBritishfirmswastosecureclinicaltestingoftheirownnoveldrugs, especiallytheirearlyattemptsatmakingsyntheticdrugs.
426
ConcludingComments
427
AlthoughtheTTCproposedrestrictingtheirservicetonoveldrugs,theyoftentook theopportunitytotrialan Englishversion,eveniftherewasalreadyaforeignversionof adrugonthemarket.TheygavepreferencetoBritishdrugsandturnedawayseveral foreigndrugsuntilonecamealongthatwastoogoodtoignore ProntosilfromBayer. TheTTCwasmostsuccessfulintheirareasofspecialinterestsuchasorganotherapy,and IagreewiththeconclusionofValier,whoexaminedstudiesoflivertherapyinpernicious anaemia,thattheMRCweremostcomfortablefollowingprogressinthelaboratoryrather thanatthebedside.Severaloftheirstudieswerefailures,notonlybecauseofpoorresults, butoftensimplyduetopoorrecruitmentofpatients.Theanalysisofallofthestudiesleft mewithquiteadifferentimpressioncomparedtothereflectionsoftheTTCsSecretary,
5 FrankGreen,whosummarisedthemajorstudies. HefocusedontheTTCsuccesses,most
ofwhichoccurredinthelateryears,andoftenasaresultofimprovedformulationsof extractsandtheprovisionofsynthetichormonesandvitamins. IhaveexaminedtheTTCfromtheperspectiveofthepharmaceuticalfirmsaswell asfromtheMRCside.TheMRCrepackagedtheTTCasbeingtheirowncreationanda focusfordevelopingnoveldrugs,andyetIhaveshownthatitwasonlyestablishedafter repeatedattemptsbytheABCMin1922,1926and19301,anddidnotonlyexamine noveldrugs.ThemostfrustratingaspectforBritishpharmaceuticalfirmswasthatfirms werenotallowedtocontactcliniciansdirectly.ValierdescribedhowtheMRCfrowned uponJohnWilkinsonofManchesterintheperniciousanaemiastudy,whenhe collaborateddirectlywithBoots.InotedsimilarexampleswhenOBrienofBurroughs Wellcomeestablishedhisowntrials,andwhenBurroughsWellcomewasaskednotto establishparalleltrialsofergotoxineinGermany.Idiscoveredthatseveralfirmsgot aroundthisinthelater1930sbyemployingtheirownphysicianstoliaisewithdoctors, oncetheyhadestablishedasuccessfulproduct.Glaxo,Allen&HanburysandMay& Bakerallemployedtheirownphysicianstoanswermedicalqueries,butalsotoestablish clinicaltrials.Thistrendcontinuedintothepostwarperiod,untilinthemid1950sthere wereenoughphysiciansworkinginindustrytocreatetheirownAssociationofMedical
F.H.K.Green,ClinicalEvaluationofRemediesinBritain. Brit.Med.Bulletin 2 (1944):5860F.H.K.Green,TheClinicalEvaluationofRemediesLancet(27 November1954):108590.
427
ConcludingComments AdvisorsinthePharmaceuticalIndustry(AMAPI)in1957.6 Iinterviewedmany physiciansinvolvedinpharmaceuticaltrialsintheearly1950s,butonaccountofthe
428
materialIhadalready,IconcludedthisthesisattheoutbreakoftheSecondWorldWar. Anextensionofthisworkintothepostwarperiodwillfollow. WemaynotethatBritainonlygainedaninsightintotheclinicaltrialsoperationsof GermanfirmsaftertheSecondWorldWar,andafurthervisittoGermanfactories,this timebytheCombinedIntelligenceObjectivesSubcommittee.Ithadbeenwrongly assumedthatsomesortofcentralisedclinicaltestingprocedureexisted.Representatives ofthemaincompaniesincludingMay&Baker,BurroughsWellcome,GlaxoandICI foundthatBayerhadaScientificDirectorofPublicityintheperiod192335,witha departmentsplitintotwosectionsforarrangingclinicaltrialsandforsalespropaganda.In thefirstsectiontherewere5physicianscoveringbothgeneralandtropicalmedicine. FirmshadtoorganisetheirowntestsandIGFarbenweregiven34yearsbeforedrugs wereputonthemarket.Initialtrialswerefirstcarriedoutby14clinicians,andthenwere broadenediftheproductlookedpromising.Lessthan5%ofdrugstestedstayedthecourse andwereissuedcommercially,followinganapplicationtothegovernment.Inthesales departmentatBayertherewere70doctorsqualifiedinbiology,pharmacologyand chemistryandtheyweredividedtocovertheregionsofGermany.Therapeutische Berichte(TherapeuticReports)wassentoutmonthlyto70,000doctors,andaphysicians
7 yearbookwasalsoprovided.
UnlikeseveralprevioushistoriansIchosenottofocusonasinglechosenexample ofadrugorastudy,butIhavetriedtogetundertheskinof theproblembytryingto understandsomeunderlyingfundamentals.IndoingsoIevaluatedawiderangeofthe drugsproducedbyBritishPharmaceuticalIndustry,coveringtheperiodupto1931in chapters5andfrom193139inchapter8.InevitablyIhavenotdonejusticetoany

6
ThisbecametheBritishAssociationofPharmaceuticalPhysicians,andin1976,The SocietyforPharmaceuticalMedicinetoreflecttheexpansionoftherole.AFacultyof PharmaceuticalMedicine,affiliatedtotheRoyalSocietyofMedicinewasestablishedin October1989T.B.Binns,WhatdoPharmaceuticalPhysiciansActuallyDo? PharmaceuticalMedicine1(1986):213219P.D.Stonier,DiscoveringNewMedicines: CareersinPharmaceuticalResearchandDevelopment(Chichester:J.Wiley,1994)D.M. Burley,T.B.Binns(eds.)withaforewordbySirAbrahamGoldberg,Pharmaceutical Medicine(London:EdwardArnold,1995)F.J.Gabbay,A.J.Salter,TheSocietyof PharmaceuticalMedicineDevelopmentoftheDiscipline,J.Pharm.Med.1(1991):53 60. 7 IGFarben:ThePropagandaDepartmentPharmaceuticalJournal (2March 1946): 137. 428
ConcludingComments
429
specificdrugbutthatwasnottheintention.InsteadIaimedtoexaminepatternsofchange andgeneraltrendsandtotrytounderstandwhyfirmschoseaparticularstrategic direction.MyconclusionsdifferfromRobsonwhowrote:thepharmaceuticalindustryin realityhadlearntlittlefromthewarwithfewnotableexceptionsresearchand

8 developmentwerenotamajorfeatureoftheindustryduringtheinterwarperiod.
Mygeneralconclusionisofgradualprogressbeingmadeby Britishpharmaceutical firms.TheyhadendedtheFirstWorldWarcallingforprotectionsothattheycould establishasyntheticdrugindustrytocompetewithGermany.Thiswasalwaysgoingto taketime,sotheyevaluatedthemanyotheropportunitiesthatcametheirway,andwere successfulinproducingenoughinsulin,thyroxinandvariousorganotherapypreparations andvitamins,whichsatisfiedthehomemarketandalsogeneratedexportsales.Whereas previousauthorshavetakeninsulinasamodelforthedevelopmentofclinicaltrials,little attentionhasbeengiventothecomplexitiesofmanufacture.Ihavepointedoutthescaling upofplantrequired,thenewcentrifugalfiltrationprocedures,therefrigerationofthe variousprocessesandtheneedforcarefulcontrolofacidconcentration.Therewere similarproblemsintheproductionofotherhormonesandtechniqueshadtobedeveloped forcontinuouslowtemperatureevaporationsandforretrievingthevastquantitiesof
9 alcoholusedasasolvent. ThesamewastrueforvitaminsandFrancisCarrovercame
manyofthesedifficultiesatBDH,includingthecomplexsterilemanufactureplacinghis firminagoodpositionforsimilarworkonfurtherhormones,vitamins,andultimately
10 antibacterials. HaditnotbeenforthesedevelopmentsBritishfirmswouldnothavebeen
abletoreactquicklytosupplysulphonamideantibacterials.Carrrecognisedthat:once weunderstandthechemicalnatureofinsulinitisnottoomuchtoexpectthatthehistory ofadrenalinandthyroxinewillberepeated,andinsulin,likethetwolatter,willbe
M.RobsonTheBritishPharmaceuticalIndustryintheFirstWorldWarinJ. Liebenau(ed.),(1988):82105.
9
F.H.Carr,TheCommercialProductionofHormones,SCI,Chemist&Druggist 105.1(1926):181. 10 F.H.Carr,Howinsulinisisolated,Chemist&Druggist106.1(26February 1927):263F.H.Carr,TheVitaminsintheirRelationtoMedicalSupplies PharmaceuticalJournal 117(1926)729,739.F.H.Carr,VitaminsintheirRelationshipto MedicalSupplies,Chemist&Druggist105.2(18December1926):89799. 429
ConcludingComments
430
11 manufacturedartificially. Inorderwords,thepatternheforesawwasagradualswitch
fromnaturalextractstopuresyntheticdrugs. LiebenauconcludedthatAllen&Hanburys,Morson,Whiffens,Howardsand May&BakerhadanaversiontoinnovateandMay&Bakerhadnoimportant

12 productsuntil1937. HisassessmentofBritishDrugHouseswasthattherewasalso
littleemphasisonR&D.Hewrote:toproduceinsulintheyhiredCarr,whereasI clearlyshowedthatBDHhiredCarrin1920,andwerepreparedtoinvest250,000before insulinwasevendiscovered.LiebenauwrotethatBootshadanalystsonly,butthiswas notthecaseitseemsthathemeasuredBritishfirmsonlyagainsttheGermanmodelofa largelaboratorystaff,searchingformanyyearsfornoveldrugssuchasSalvarsanora Bayer205.GermanfirmssuchasHoechstandBayercouldaffordtoindulgethismodel astheyhadtheinfrastructure,includingsuppliesofintermediatesandprofitsfromthedye businessandalsobenefitedfromhighsalesofmanyoftheearlysyntheticdrugssuchas phenacetinandaspirin.TheBritishindustryincontrastwasopportunisticintheinterwar period,butitcouldbearguedthatthiswasanefficientuseofthelimitedresources, tailoringtheireffortstoidentifyopportunitiesthathadalreadycomeoutofpatent modifyingpatenteddrugsandcollaboratingwithexternalinventors,asGlaxodidwith Steenbock. Suchhistoricaljudgementsbegthequestion,whatisresearchanddevelopment? Doesresearchnotalsoincludefindingbetterdrugs,purerdrugs,preparingthosewith greatersolubilityandlowersideeffects,andparticularlywastheworkdonebyBurroughs Wellcometoidentifyandstandardisetheactiveingredientsoftheirdrugsnotresearch?It certainlyledtotheidentificationofnovelactivedrugs.Developmentincludesidentifying methodstoassessthesafetyofdrugsinpreclinicalmodelsandimprovingtheproduction andreliabilityofthemanufacturing,asCarrsooftendid.Myargumentisthatbythese standardsofresearchanddevelopmenttheBritishindustrywassuccessfulintheinterwar period,andfurthermoreexpandedthecollaborationsdevelopedintheFirstWar,to provideabetterinfrastructureforthebiologicalandclinicaltestingofnewdrugs.
11
F.H.Carr,InsulinanditsManufacturePharmaceuticalJournal (5March1927): 24445.Infactthisneverhappenedasinsulinturnedouttobeacomplexprotein,and humaninsulinhasonlyrecentlybeenpreparedbycloningthegeneinbacteria.

12
J.LiebenauPatentsandtheChemicalIndustry:ToolsofBusinessStrategyinJ. Liebenau(ed.),(1988):13550.
430
ConcludingComments
431
Thesignificantadvancesmadeinmanufacturingduringtheinterwarperiodwere summarisedbyFrederickGambleandNormanEvers.Theextractionofhormonesbore littleresemblancetotheearlierextractionofalkaloids.Manufactureoftheseproducts requiredadelicacyofcontrolbeyondanywhichhadpreviouslybeenavailable:infactit wouldhavebeenimpossibletomakeinsulinonalargescaleafewyearsbeforeits discovery.Thecontrolofhydrogenionconcentrationswasessentialandhugeamountsof alcoholandothersolventswereneededandmethodshadtobedevelopedtorecoverthese. Evaporatingplantwasrequiredtoresistbreakdownbytheacidsusedandinthisrespect thereplacementofcoppervesselswithstainlesssteelhadbeenvital.Oldmethodsof filteringwerealsoinadequateandhighspeedcentrifugaldeviceshadbeeninstalled. Sterilisationtechnologyalsohadtobedevelopedsothatlargevolumescouldbesterilised withouttheuseofheat,andthiswasdoneusingasbestosbasedSeitzfilters,which allowedrefrigeration.Specialirradiationtechniqueshadtobedevelopedtoprepare
13 vitaminDandnewtechniqueshadbeendevelopedforpreparingemulsions.
Throughtheworkonstandardisationofdrugs,BritishscientistssuchasTrevan, GaddumandBurnmadeimportantstatisticalcontributionstotheunderstandingof biologicalvariation,andBritishfirmstookadvantageofthis,andtheirstronglinkswith physiologistsandtheexpertiseinalkaloids,toproducenewstandardisedalkaloids,and helptoidentifytheactiveconstituents.Althoughtheactualdiscoveriesmightbecredited toanexternalacademicsuchasChassarMoirwithergometrineorDoddsandRobinson withthesynthesisofstilboestrol,theycollaboratedwithindustryandtheirdiscoveries wereonlymadepossiblebytheprovisionoflargemanufacturedquantitiesoforgan extracts.However,whenitwasdiscoveredthatexistingpatentsdidnotcovertheactive ingredientofProntosil,Britishfirmsrapidlyseizeduponthisopportunityandproduced andpatentedtheirownchemicallydistinctsulphonamides.Thisinvolvedthechemical synthesisofhundredsofderivativesandtheirevaluationinthelaboratoryandwith externalconsultants.May&BakerworkedcloselywithLionelWhitby,apathologistat theMiddlesexHospitalandrapidlymasteredthelargescalemanufacturing. Hillsummarisedtheprogressmadeby1935:thewholefoundationofpharmaceutical manufacturehasbeenundergoingachange,atfirstgradualbutinthelateryears increasinglyrapid.
13
F.W.Gamble,N.Evers,AdvancesintheManufactureofPharmaceuticalProducts, PharmaceuticalJournal,(4May1935):5413. 431
ConcludingComments Hecontinued:
432
themanufactureoforganotherapeuticproductshasbecomeahighly organisedsectionofthefinechemicalindustry.Itinvolvesthesynthesisof complexsubstances,andalsotheseparationandpurificationofnatural principlesfromanimalsourceschallengingthesupremacyofsynthetic 14 organicchemicalswhichhaveheldswayforseveralgenerations. Althoughtheproductionofdrugshadincreasedsignificantlytherewerestill concernsattheMRCthatBritainwascopyingratherthandiscoveringdrugsandthatthis stillplacedthecountryatrisk.TheMRCreportof1936hadkickedoffthiscontroversy, hotlydisputedby Britishpharmaceuticalfirmsbywriting:thediscoveryandproduction ofchemicalcompoundsofvalueinchemotherapyhasdependedalmostentirelyon Germanscienceandindustryandstillsodepends,asituationwhichintheeventofwar couldbefraughtwithgravedanger.TheABCMcountered:duringthelast20yearsthe BritishChemicalIndustry,withthestimulusoftheKeyIndustrydutieshasmadesuch greatstridesthatthepositionwasvastlydifferentfromwhatitwasin1914.Mostofthe syntheticproductswhichareessentialtothehealthservicesoftheEmpirearenow manufacturedinthiscountryinadequatequantities.Patentsprotectedafewbutitwas feltthattheycouldbemadeunderlicense.TheMRChadinvested30,000fornew researchin chemotherapybutmostofthecostsweretakenupbyspendingonnew
15 buildingsfortheNIMRatMillHill.
ThomasEdwardLescherofEvans,Lescher&Webb,chairoftheBritish PharmaceuticalCongress193637recalledinJuly1937that:thewarexperiencegave Britishchemiststheiropportunityandthemanufactureoffinechemicalsandbiologicals todayisonascalesufficienttomeettherequirementsofourtrade,bothathomeand

16 overseas.
Increasednumbersofsyntheticdrugs,butalsootherformsofsophisticated medicationshadledtoincreasedmanufacturingcapacity,whichtogetherwithabetter infrastructureofchemicalintermediatesandasystemoftestingdrugs,ledtoBritainbeing inastrongpositionattheoutbreakoftheSecondWar.CharlesHillandothersclearlyfelt thatthiswasduetotheKeyIndustryActs.Notonlywerenewsyntheticspreparedsuchas procaine,benzocaine,orthocaineandamylocaine,butalsochemicalssuchas

14
C.A.Hill,TheChangingFoundationsofPharmaceuticalManufacturers, PharmaceuticalJournal (4May1935) 15 ChemotherapyandtheBritishChemicalIndustry,PharmaceuticalJournal 140(26 March1938):353.
432
ConcludingComments
433
phenolphthaleinwereproducedinsuchquantitiesthatsomecouldbeexported.Hillwrote: Thenewdrugsincludedpalatablefishoilsassourcesofvitamins,purifiedhormones suchasthyroxin,insulinandoestroneandisolatedalkaloidssuchasergometrine. VitaminsB,CandDhadbeenisolatedinpurecrystallineformandvitaminChadbeen

17 synthesised.
Mr.DavidAdams,LabourM.P.forConsett,askedthePresidentoftheBoardof
th TradeaquestioninParliamenton20 May1938abouthowsuccessfulBritainhadbeenin
replacingGermanimports.Thelatestdata(from1935)showedthatoutputofSalvarsan likecompoundsinBritainwas7,900lbs.(equivalentto107,000).Adamshad specificallyaskedaboutthelevelofimportsofthekeyGermanantiinfectiveproducts Salvarsan,Neosalvarsan,Bayer205,tryparsamide,Atebrin,Plasmoquine,trypanblueand Trypaflavin.Thesewerenotseparatelyrecordedbutin1933therewereimportsofonly69 lbs.ofSalvarsan,neosalvarsanandorganicarsenicals.Britainhadclearlyovercomea relianceonGermanyforthisdrug.Themainproblemwithimportswasnotthe2.5mof theNHIdrugbillbuttheUKspendof2028monpatentmedicinesandthisexplainsthe constantfocusofthegovernmentandBMAonthesesecretremedies.FredGamble confirmedthattheuseofsecretandproprietarymedicineshadincreasedandthatpriorto 1932thiscountrywasthedumpinggroundoftheworldandstillistosomeextentin spiteofthefactthat,withtherarestexceptionsBritishpharmaceuticalfirmscan
18 manufactureallthatisrequired.
Ausefulbarometerofthechangesthathadoccurredintheinterwarperiodwasan editorialwritteninApril1939,whichreferredbacktowhathadbeenwritteninthesame journalinMay1918,gavesomepropheticwarningsabouttheneedforBritain tobeself reliantinmedicines: Itisnotsomuchaquestionofprotectingourownmanufacturers,although withineconomicandcertainlimitsthatisessentialenough,asthe imperativenecessityofsettingupandperpetuatingonastableandenduring basisinthiscountryfundamentalindustries,sothatabsitomenshouldthe

16
17
BritishPharmaceuticalCongressChemist&Druggist (31July1937):11819. C.A.Hill,(4May1935) 18 F.W.Gamble,FacingRealities,HarrisonMemorialLecturetothePharmaceutical Society,Pharmaceutical Journal 140(12March1938):26769. 433
ConcludingComments
434
timeeverreturnwhentheBritishEmpirehastofightforitsveryexistence, itwouldbeprovidedwithalltheinternalresourcesrequiredforthe occasion.Thanksinparttotheremovalofsomeunfairtradingconditions, butchieflytotheenterpriseofBritishChemicalmanufacturerswearenow inafardifferentpositionfromthatwhichobtainedin1914,andlittle difficultyshouldbeexperiencedinmeetingalldemands,forallthemilitary 19 andcivilneedofourpeople.
InasimilarrecollectionHerbertLevinsteinrecalledhowunpreparedBritainhadbeenfor warin1914,eventotheextentthatnofirmmadeT.N.T.here.Thereweredeficienciesof chemicalplantandfewwelltrainedengineerscouldbefound.IncontrastinMarch1937 hefeltthat:shouldanotherwarcomethiscountrywillbepreparedforitatleastonthe

20 chemicalside.
InBritainbetween192038,thecapitalemployedinthepharmaceuticalindustry trebled,andthenumberofresearchchemistsandresearchspendingincreased4fold.The weightoffinechemicalsproduced,increased11foldandJ.DavidsonPrattoftheABCM wasabletodescribeacomprehensiveandprogressivesyntheticorganicchemical

21 industry. Intermsofbalanceofpayments,thecountryowedagreatdebttothe
pharmaceuticalindustryintheinterwarperiod.Manyhormonepreparationsweremade, suchthatBritaindidnotrelyonLilly,Organon,ScheringandCIBA,andthesamewas trueofvitaminpreparations.Duringthisperiodgreatemphasiswasplacedongivingthe

22 correctdietandthisledtoastrongfocusonvitaminsupplementation. In1938the
ABCMtookonitsowninitiative,activestepstopromotethemanufactureofthose medicinalchemicalsthenimportedfromGermanyandlikelytobeessentialintheeventof
23 warsotherewouldbenoshortages. 24 By1939allofthemajorBritishfirmsproducedawiderangeofvitaminproducts.
Britishfirmshadnotincreaseddramaticallyinsize,withonlyICIapproachingthesizeof theGermangiants.HoweverfirmssuchasGlaxoandAllen&Hanburyshadbecome
19 20
DrugsinWarTime,PharmaceuticalJournal (22April1918):40304. HerbertLevinstein,ProgressoftheBritishChemicalIndustry,Pharmaceutical Journal (13March1937):264. 21 J.Davidson Pratt,TheEconomicsoftheFineChemicalIndustry,Chemistryand Industry (20January1951):38 22 CeliaPetty,PrimaryResearchandPublicHealth:thePrioritisationofNutrition ResearchinInterwarBritaininJ.AustokerandL.Bryder(1989):83108. 23 ABCMReportontheChemicalIndustry (London:ABCM,1949).
434
ConcludingComments leadingproducersofhormonesandvitamins.Figuresreportedin1939(andtherefore referringto1938)showedthatICImadeaprofitofjustover7m.Boots,whichwas
435
primarilyaretailbusinessmadeprofitsof776,292,J.Nathan(theforerunnerofGlaxo)
25 made90,647,BDHmade49,790andEvansmade39,140. 26 BritainwaswellpreparedfortheSecondWorldWarintermsofdrugsupplies.
TheABCMhadcontinuedtocatalogueessentialdrugsandtheirmanufacturers. BurroughsWellcomereviewedalistof40suchGermandrugsattheirSTCmeetingon29 September1939.Fivewerealreadybeingproduced,andadozenorsowereconsidered notworthmaking,butplansweremadetomanufacturetheremainder,aslongaschemical intermediatescouldbeobtainedfromICI,andmostwereinhandbyNovember.The mergerofmanydyestuffsandalkalifirmstocreateICIhadresolvedmanyofthe problemsof theprovisionofchemicalintermediatesforpharmaceuticalmanufacturers.It wasrecognisedthattherecentGermandrugssuchasAtebrinandPlasmoquinewould havetobereplacedintheeventofwarandthiswasoneofthereasonsbehindthegranting
27 offundsforresearchinchemotherapy.
ThemainchallengetoBritainintheSecondWorldWarwastopreparesynthetic versionsoftheantimalarialsthatBayerhadrecentlydeveloped,andthiswastobea
28 collaborativechallenge,withICIplayingaleadingroleduringthewar. Burroughs
Wellcome,astheyhadintheFirstWorldWardominatedthesupplyofantitoxinsand vaccinessobothGlennyandParishcontributedtothewartimecommittees. WhileitisnotwithinthescopeofthisthesistoexaminetheSecondWorldWar,it isclearthatthemodelsdevelopedintheFirstWorldWarwerebuiltupon.Committees likethoseintheGreatWarwereestablishedin193940,andmanyofthescientiststhatI

24 25
TheVitamins,PharmaceuticalJournal (21January1939):5459. Figuresarequotedfrom PharmaceuticalJournal 143(1939)asfollows:ICI(25 March1939):322Boots(3June1939):884J.Nathan(14January1939):49BDH(8 April1939):377andEvans(11March1939):269. 26 AssociationofBritishChemicalManufacturersPharmaceuticalSpecialities:British nd EquivalentsandAlternativesforForeignProprietaryProducts(London:ABCM,2 edition1940) 27 ParliamentaryNews.ImportsofFineChemicalPharmaceuticalJournal 140(28 May1938):581ThePatentMedicineTrade.ProfA.J.ClarksIndictment, PharmaceuticalJournal 140(14may1938):518. 28 D.Greenwood,ConflictsofInterest:theGenesisofSyntheticAntimalarialAgents inPeaceandWar.J.AntimicrobialChemotherapy 36(1995):85772A.S.MacNalty, HistoryoftheSecondWorldWarMedicalResearch sectioneditedbyF.H.K.Green, G.Covell,(London:HMSO,1953):9,15559. 435
ConcludingComments
436
havedescribedparticipated.AMinistryofFoodwasestablishedandfrom19413Harry Jephcottwasanadvisor.ATherapeuticResearchCorporationwasestablishedin1941 involvingBoots,BurroughsWellcome,BritishDrugHouses,May&BakerandGlaxo,

29 andlaterjoinedbyICI. Collaborationsbetweenfirmscontinued,withDaletakinga
prominentcentralroleasPresidentoftheRoyalSocietyfrom1942. ATherapeuticRequirementsCommittee,chairedbyProfL.J.WittsofOxfordand includingJ.H.Burnwasestablished,togetherwithaseriesofspecialisedsubcommittees andonceagainaMinistryofSupplywasestablished,thistimewithaChemicalFactories MedicalSubCommittee,ChairedbyProf.SirJosephBarcroftandinvolvingProf.J.A.

30 RyleandProf.C.G.Douglas. Manyofthosewhocontributedtoearlierexaminationsof
medicineswereinvitedtoparticipateandtheseincludedE.A.Carmichael,Edward Mellanby,AustinBradfordHill,C.LangtonHewar,LeonardColebrook,E.C.Dodds, LionelWhitby.InadditiontoBurnthere,theformerBurroughsWellcomestaffincluded

31 wereProf.P.A.Buxton,PercivalHartley,HaroldKing,andJ.H.Gaddum.
Liebenauattemptedtoevaluatethesuccessoffirmsinthisperiodandreferstoa surveycarriedoutin1942andcoveringtheperiod193641,whichcoincideswiththe latterperiodcoveredbytheTTC,inwhichheevaluatedthenumberofpatentsand

32 publicationsproducedbyeachfirm.
BritishPatentspublicationsgraduatesdoctorates May&Baker40 BurroughsWellcome Glaxo BDH Boots 115815
62206624 13345 8
7325 101227024
29
R.P.T.DavenportHines,JudySlinn,Glaxo:AHistoryto1962(Cambridge: CambridgeUniversityPress,1992):13841. 30 Ibid:328331. 31 A.S.MacNalty,(1953). 32 J.LiebenauPatentsandtheChemicalIndustry:ToolsofBusinessStrategyinJ. Liebenaued.,(1988):13550. 436
ConcludingComments
437
ItwouldbeusefultogainsomefurtherinsightsintothesefiguresasIbelievethe firmsinvolvedhadquitedifferentapproachestopatentingandpublishingandLiebenau himselfcautionsagainstthis.Becausetheanalysisabovecoverstheperiodfrom1936,I believeitmustbestronglybiasedbythesignificanteffortsthatwentintosulphonamide drugproductionfrom1936. Comparedto1914whenonlyonethirdofthe250activeprinciplesweresynthetic, by1948thishadrisentomorethanhalfof440.TheSecondWorldWarproved abundantlythatthekeyindustrydutyhasbeeninstrumentalinprotectingthecountry againstarecurrenceof1914.By1948theABCMincluded90firmswithacapitalof

33 68m. Insummary,IhaveprovidedarationaleforhowBritainbecameindependentin
regardtoethicaldrugsupplies.Whilethiswasnottherouteofmajordrugdiscoveriesthat othershavesought,itdoesexplainhowandwhyBritainsurvivedthetwoworldwars.For thosewhodetractfromtheachievementsoftheindustry,noexplanationhasbeenoffered astohowtheindustrydidbecomesuccessfulinBritainasitcertainlyis. Regardingclinicaltrials,thesulphonamidesinparticular,andsynthetichormones, wererecognisedasimportantbydoctors,helpingtoovercometheirreluctancetobe involvedinclinicaltestingsoitwasnolongerdifficulttofinddoctorswillingtotestthese excitingnewtherapies.Andheremyworkcanbecomparedwiththatofotherhistorians oftrials.AlanYoshiokiconcentratedhisresearchonthefirstsignificantrandomised controlledclinicaltrials,ofstreptomycin(anotherexternaldiscoveryfromAmerica)
34 organisedbetween1946and1948bytheMRC. Hisresearchtopicrelatestoanother
majordrugboughtfromAmericapostwarwithpreciousdollars.Becausenotenough couldbeboughttotreateverybody,itwasacceptabletoevaluateitincomparisonwithno activetreatmentinthefirstmajorsuccessfulrandomisedplacebocontrolledtrial.The subjectisthereforemoreaboutmethodologyofacentrallycontrolledtrialratherthanthe practicalityofgettingstandardnewdrugstested.CoxMaksimovpointstoaseparate
33 34
J.DavidsonPratt,(1951):38 AlanYoshioka.Streptomycin,1946:BritishCentralAdministrationofSuppliesof aNewDrugofAmericanOriginwithSpecialReferencetoClinicalTrialsinTuberculosis MedicalResearchCouncilStreptomycininTuberculosisTrialsCommittee,(Universityof London:PhDThesis,1998)AlanYoshiokaStreptomycininPostWarBritain:aCultural HistoryofaMiracleDruginDrugsonTrial,ClioMed.(1999):53Streptomycin TreatmentforPulmonaryTuberculosis:aReportoftheStreptomycininTuberculosis TrialsCommitteeBritishMedicalJournal (30October1948):769782. 437
ConcludingComments
438
35 evolutionarypathoftrialsintheUSAasdescribedbyHarryMarks, althoughBradford
Hill,theMRCstatisticianforthestreptomycinwashighlyinfluentialinspreadingthis
36 methodologytotheUSAthroughaseriesoflectures. Thestreptomycinstudystimulated
furthermajorcollaborativestudiesinAmerica,andHarryMarksexaminedthe sociologicalandorganisationalaspectsof collaborativestudiesbyacademictherapeutic reformersratherthanpharmaceuticalcompanies,butagainhefocusedonthemajor

37 38 drugs. LaraMarks addressedgenderissuesintrialsofthecontraceptivepill,and
DavidCantorexaminedstudiesofcortisone,whichaseriesofcompanies,includingBDH andBootsworkedoninthe1950s.Morerecentlyithasbeenlefttoscientiststorecall
39 theirownearlyeffortsinthetestingofnewdrugs. Quirke,SlinnandTweedalealso
offersomefurtherinsightsintolaterdevelopments. AlthoughQuirkeandCoxMaksimovarguedforaprogressionfromtheTTC modelthroughtotherandomisedcontrolledtrials,Iammoresceptical.Iexaminedallof theTTCstudiesandsawhardlyanyevidenceofstatisticalinput,andtheTTCcommittee weresatisfiedtoevaluatethedrugsinasmallseriesofpatientsandproclaimabenefitor not.Inparallel,theMRCwereperformingquitesophisticatedepidemiologicaland vaccinestudies,involvingstatisticians.AsValierargued,theMRChadlesscontrolover thebedsidethanthelaboratory,butIbelievethattherewasamajordifferencebetween offeringavaccineornotforadiseasethatmightoccur,asopposedtoofferingadrugora placeboforanactivediseasethatneededtreating.TheTTCwasnotformally reconstitutedpostwarbutasignificantnumberofmostlyforeigncompanies,especially
35
HarryM.Marks.IdeasasReforms:TherapeuticExperimentsandMedicalPractice, 19001980(MassachusettsInstituteofTechnology,BostonMass:PhDThesis,1983).
36
ReportofaConferenceonthePlaceofStatisticalMethodsinBiologicaland ChemicalExperimentation(2829January1949)Ann.NewYorkAcad.Sci.52(1950): 789D.Maitland,TheClinicalTrial,SomeDifficultiesandSuggestionsJ.Chronic Diseases11(1960):48496. 37 HarryM.Marks,(PhD.thesis,1983)H.M.Marks,NotesfromtheUnderground. TheSocialOrganisationofTherapeuticResearchinD.Long,R.Maulitz(eds.),Grand Rounds:100yearsofInternalMedicine,(Philadelphia:UniversityofPennsylvania,1987) H.M.Marks, TheProgressofExperiment.ScienceandTherapeuticReforminTheUnited States,1900 1990(Cambridge:CambridgeUniversityPress,1997).
38
LaraMarks,SexualChemistry:AHistoryoftheContraceptivePill (Yale:Yale UniversityPress,2001). 39 th CarlDjerassi,ThisMansPill:Reflectionsonthe50 BirthdayofthePill (NewYork, OxfordUniversityPress,2001)JF.Borel,H.Staehelin,CyclosporinATheHistory andSignificanceofitsDiscoverySandoramaII(Basel:Sandoz,1983):559. 438
ConcludingComments CIBA,establishedfurthertrialswiththeTTCasacoordinatingbody.Themajorityof
439
Britishfirmswentontomaketheirownarrangements,exceptforsmallercompaniessuch asNappofCambridge.TheclinicaldevelopmentprocesswasinternalisedinBritainand companiesbuiltuponthesuccessanddemandforantibioticsbyestablishingtheirown studies.
MyhopeisthatIhavenotonlyansweredmyownquestions,buthavealsoraised somefurtherquestionsworthyofmoredetailedstudy.Iwouldliketohavepursuedthe careerofFrancisCarrtocompletehisbiography,andfurtherstudyofhisworkatBoots andBritishDrugHouseswouldbeof value.Ionlyexploredhiscampaignsforchemical engineeringtrainingtoalimiteddegree,anddidnotdivertintohiscommitteeworkon wargasesandonpatents.EquallytherewasagreatdealofdetailonthecareerofFred PowerthatIhadtoomit,andamoredetailedaccountofthescopeofchemistryperformed atBurroughsWellcome18961914wouldbevaluable.Iamcertainthatamoredetailed studyofthecomplexthemesofensuringdrugsuppliesduringtheWorldWarsis warranted,utilisingsourcesatthePROandtheRoyalSociety. Thisthesishasbeenwiderangingbuttherearesomeclearpointstoemerge: SyntheticchemistrybecameimportantfarearlierinBritainthanwas previouslyrecognisedbutitwasinitiallyusedforcheckingthepurityand standardsofextracts. BurroughsWellcomewasanimportantsourceofmanufacturingchemists forothercompaniesFrancisCarrwasanimportantchemicalengineerand playedacentralroleindevelopingthesyntheticdrugindustryinBritain. Britishfirmscampaignedforclinicaltestingoftheirdrugs thiswasnot somethingimposeduponthem.TheMRCledstudiesoftheTTCwerenot basedonstatisticalprinciplesormodeledonearlierinsulinstudies. AseriesoffactorscontributedtothesuccessoftheBritishindustryintheinterwarperiod. ItwasnotjusttariffprotectionorthenewTherapeuticSubstancesActbutalsothe emergenceofnewtypesoforganotherapyandvitamins,whichhelpedthemtomake profitswhilebuildingtheirmanufacturingcapacity.TheimportanceBritishsuppliesof chemicalintermediatesandsolventsshouldnotbeunderestimated.
439
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BRITISHPHARMACEUTICALINDUSTRY, SYNTHETICDRUGMANUFACTUREANDTHE CLINICALTESTINGOFNOVELDRUGS 18951939.

AthesissubmittedtotheUniversityofManchesterfor thedegreeofDoctorofPhilosophyintheFacultyof LifeSciences,2005.

KeithJohnWilliams CentrefortheHistoryofScience,Technologyand Medicine.

Listofcontents,abbreviationsanddeclarations Engineering. 5.8 5.9 PostWarGermanyandOtherForeignCompetition. Conclusions. 249 254

CHAPTERNINE Conclusions. BIBLIOGRAPHY

ABSTRACT BritishPharmaceuticalIndustry,SyntheticDrugManufactureandthe ClinicalTestingofNovelDrugs18951939.

Furtherinformationontheconditionsunderwhichdisclosuresandexploitationmaytake placeisavailablefromtheHeadoftheCentrefortheHistoryofScience,Technologyand Medicine.

W.Ormandy,BritainandGermanyinRelationtotheChemicalTradeinW.M. Gardner,TheBritishCoalTarIndustry,ItsOrigin,DevelopmentandDecline(London: Williams&Norgate,1915):335350.

Insomecases,theymeasuredsuccessbysimplycountingthenumberofpatentsfiledor salesfigures,whichmaybeverymisleading,especiallyifthefirmhadinterestsotherthan justpharmaceuticals,asmanydid,oriftherewereaseriesofsimilarproducts,someof

T.DavenportHines,J.Slinn,Glaxo,AHistoryto1962 (Cambridge:Cambridge UniversityPress,1992)GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen &HanburysandtheBritishPharmaceuticalIndustry (London:JohnMurray,1990)Judy Slinn,AHistoryofMay&Baker18341984(Cambridge:Hobsons,1984).

J.Kemp,PharmaceuticalPatents:InBritain,India,Italy,JapanandtheUSinG. TeelingSmith(ed.),InnovationandtheBalanceofPayments:theExperienceinthe PharmaceuticalIndustry (London:OfficeofHealthEconomics,1967):23J.Liebenau,

G.TeelingSmith,ThePharmaceuticalIndustryandSociety:AStudyoftheChanging EnvironmentandEconomicsoftheInternationalIndustry (London:OfficeofHealth Economics,1972).

VivianeQuirke,ExperimentsinCollaboration:TheChangingRelationshipBetween ScientistsandPharmaceuticalCompaniesinBritainandinFrance,19351965(University ofLondon:PhDthesis,1999).

E.M.Tansey,TheWellcomePhysiologicalResearchLaboratories18941904:the HomeOffice,PharmaceuticalFirmsandResearchExperimentsMedicalHistory 33 (1989):141.

HelenTurner,HenryWellcome,theMan,hisCollectionandhisLegacy (London: Heinemann,1980).

J.B.Blake(ed.),SafeguardingthePublic:HistoricalAspectsofMedicinalDrug Control (Baltimore:JohnsHopkinsUniversityPress,1970):112122,144157.

19 Bumlersaccount,towhichIreferextensivelyinChapter2. Beergivesanexcellent 20 accountof thedevelopmentoflaboratoriesinGermanfirms, whileFox,Haberand 21 Readerprovidebackgroundondyestuffsdevelopments.

J.J.Beer,TheOriginsoftheGermanChemicalIndustry (Urbana:Universityof IllinoisPress,1959)J.J.Beer,CoalTarDyeManufactureandtheOriginsoftheModern IndustrialResearchLaboratoryIsis49(1958)123131.

M.R.Fox,DyemakersofGreatBritain18561976:aHistoryofChemists, Companies,ProductsandChanges(Manchester:I.C.I.plc,1987)W.J.Reader,Imperial ChemicalIndustriesLtd.AHistory:TheForerunners18701926volume1(London: OxfordUniversityPress,1970)L.F.Haber,(1958)and(1971).

JonathanLiebenau,ScientificAmbitions:thePharmaceuticalIndustry,19001920 PharmacyinHistory 27.1(1985):311J.Liebenau,TheRiseoftheBritish PharmaceuticalIndustryBritishMedicalJournal (3October1990):72428.

J.Parascandola,ThePharmaceuticalSciencesinAmerica,18521902J.Am.Pharm. Assoc.40.6(2000):73335J.Parascandola,DrugTherapyinColonialandRevolutionary AmericaAm.J.Hosp.Pharm.5.12(1976):6977.

BurroughsWellcomeandtheproblemsofovercomingtheantivivisectionistmovementin Britain.EvenaftertheformationoflaboratoriesinBritain,andespeciallyafterthe DangerousDrugsActof1923,whenpharmacistshadtobeincharge,QuirkesawBritish andFrenchlaboratories,asdemandpulledratherthanresearchpushed,andthis

Squibb,allofwhichevolvedtobemajorU.S.pharmaceuticalmanufacturers.Swann identifiedthreemaintypesofexternalcollaborator:thegeneralist,thespecialistandthe projectspecificconsultant,andtheywereprimarilypharmacologistsandchemists.Froma

E.M.Tansey,TheWellcomePhysiologicalResearchLaboratories18941904:the HomeOffice,PharmaceuticalFirmsandResearchExperimentsMedicalHistory 33 (1989):141.

GeoffreyTweedale,AttheSignofthePlough:275YearsofAllen&Hanburysand theBritishPharmaceuticalIndustry (London:JohnMurray,1990).

VivianeQuirke,ExperimentsinCollaboration:TheChangingRelationshipBetween ScientistsandPharmaceuticalCompaniesinBritainandinFrance,19351965(University ofLondon:PhDthesis,1999).

FrankL.Rose,OriginandRiseoftheSyntheticDrugsinF.N.L.Poynter(ed.), ChemistryintheServiceofMedicine(London:Pitman,1963):179197.IntheRose accountitsays1954andthemainsiteatAlderleyParkdidnotopenuntil1957.

JohnP.Swann,(1988):34,3334,45,51,6583Richardsperformedresearchwith HenryDaleattheNationalInstituteofMedicalResearchinLondon:C.F.Schmidt,A.N. RichardsBiographicalMemoirsofFellowsoftheRoyalSociety 13(1967):32742.

Traditionaltradersthatimportedrawmaterials,purifiedandprocessed them suchfirmsincludedMorsons,Whiffens,May&Baker,Allen& HanburysandHowards.

M.Robson,TheBritishPharmaceuticalIndustryandtheFirstWorldWarinJ. Liebenau(ed.),TheChallengeofNewTechnology:InnovationinBritishBusinessSince 1850 (Aldershot:Gower,1988):82105.

M.Robson,ThePharmaceuticalIndustryinBritainandFrance19191939(Dept.of EconomicHistory,LondonSchoolofEconomics:PhD.thesis,June1988)J.Sigvard, DrugIndustryinFrance:SomeHistoricalPointsBull.Acad.Natl.Med. 166(June 1982):82934.

ErwinAckerknecht,MedicineattheParisHospital17941848(Baltimore:Johns th Hopkins,1967)J.P.Vandenbrouke,ClinicalInvestigationinthe20 Century:the AscendancyofNumericalReasoningTheLancet(October1998)Sii:1216.

HarryM.Marks,IdeasasSocialReforms:TheLegaciesofRandomizedClinicalTrials (PhDThesis,HarvardMedicalSchool,1983)HarryM.Marks,TheProgressof Experiment:ScienceandTherapeuticReformintheUnitedStates,19001990(Cambridge: UniversityPress,2000).

G.L.Geison,DividedWeStand:PhysiologistsandCliniciansintheAmerican Contextin M.J.VogelandC.E.Rosenberg,TheTherapeuticRevolution:Essaysinthe SocialHistoryofAmericanMedicine(Philadelphia:UniversityofPennsylvaniaPress, 1979).

Theconclusionthatasystemofclinicaltrialswasmodelledonthoseforinsulinand thattheMRCbuiltuponthisinanefforttocontroltheindustryhasnotbeenchallenged sinceLiebenausaccountinwhichhereferredmistakenlytoinsulinasapituitaryhormone.

J.Liebenau,TheMRCandthePharmaceuticalIndustry:theModelofInsulinin JoanAustokerandLindaBryder(eds.),HistoricalPerspectivesontheRoleoftheMRC (OxfordUniversityPress,1989):163180.

H.Raistrick(firstofseveralpresentations),PatulinintheCommonCold. CollaborativeResearchonaDerivativeofPenicilliumpatulumBainierLancet (20 November1943):62534.

J.M.Stansfield,A.E.Francis,C.H.StuartHarris,LaboratoryandClinicalTrialsof Patulin:MedicalResearchCouncil,ClinicalTrialofPatulinintheCommonCold(16 September1944)Lancet:37375.

D.B.E.C.Gill,RandomisedMentalHealthTrialBeganin1935andM.Clarke. QuasirandomAllocationofTreatmentwasReportedin1930,bothin BritishMedical Journal 312(18May1996):1298A.M.Lilienfeld,Ceterisparibis,theEvolutionofthe ClinicalTrial. BulletinoftheHistoryofMedicine56(1982):118.

PietroCorsi,P.Weindling,InformationSourcesintheHistoryofScienceand Medicine(London:Butterworth,1983)P.Weindling,ResearchMethodsandSourcesin E.Clarke(ed.),ModernMethodsintheHistoryofMedicine(London:Athlone,1971): 173.

TheearlypartofthethesisaddressesthedominanceofGermanchemistrywithina researchorientedindustry.Dyestuffsandchemicalintermediateswereprimarilyimported fromGermany.Universitybasedchemists,manyofwhomwereconsultantstoindustrial firms,hadwarnedbeforetheFirstWorldWaraboutthefactorsleadingtothedominance

EricMoonman,ReluctantPartnerships:aCriticalStudyoftheRelationshipBetween GovernmentandIndustry (London:VictorGollanez,1971):17.

JosephBenDavid,TheScientistsRoleinSociety (EnglewoodCliffs:PrenticeHill, 1979):16068.

K.J.Williams,B.Gennery,TheHistoryofthePharmaceuticalIndustryinJ.Lloyd, A.Raven(eds.),HandbookofClinicalResearch (London:Churchill,1994):122K. Williams,ATenthAnniversaryfortheAssociationforClinicalResearchinthe PharmaceuticalIndustry(ACRPi)PharmaceuticalMedicine3(1988):219224.

FrancisJ.Griffin,Obituary,FrancisCarrChemistryandIndustry (15February 1969):196.

Ethicalmanufacturerstookadifferentapproach.Theidentification,extraction,and purificationofmorphineinParisin1803stimulatedtheestablishmentofseveralalkaloid manufacturingfirmsinFrance,followedbyBoehringer,Merck,andScheringin

A.Burman,TheHeroicApproachtoNineteenthCenturyTherapeuticsBulletinof theAmericanSocietyofHospitalPharmacists11(1954):32027DavidL.Dykstra,The MedicalProfessionandPatentandProprietaryMedicinesDuringtheNineteenthCentury BulletinfortheHistoryof Medicine29(1955):40119.

PatentMedicineTaxReceipts18291914Chemist&Druggist85.1(8August 1914):3536T.Hughes,ThePatentMedicineStampDuty:itsOriginandHistory BritishMedicalJournal (9January1932):3233RevenuefromPatentMedicineTax Stamps18001931Chemist&Druggist114(30May1931):639.

5 Germany. Suchmanufacturersdifferentiatedthemselvesfurtherbyproducingthenewly 6 discoveredchemicalelementsbromineandiodine,inrichsupplyinGermany. Luke

WalterSneader,(1985):4142. D.L.Howard, Brit.Col.Pharmacist(August1926):241.

W.Bernsmann,ArzneimittelforschungundEntwicklunginDeutschlandinder ZweitenHlftedes19JahrhundertsPharmazeutischeIndustrie29(1967):6Mark Honigsbaum,TheFeverTrail:TheHuntfortheCureforMalaria(London:MacMillan, 2001).

12 Hanburyswasthefirstpresident. TheSocietywasmodelleduponthePhiladelphia 13 CollegeofPharmacy,foundedinAmericain1821. WhereasFrenchfirmsmade

referencetoexperimentsinanimalsbyphysiologistssuchasFrancoisMagendieand ClaudeBernard,andGermansreferredtoEmil Fischer,HermannKolbeandothers,such assayswerecontinuouslyhamperedinBritainbytheantivivisectionlobbyfromthe1860s andthisinhibitedthedevelopmentofpharmacologyandinteractionsbetweenthe

Germany,whereasAmericanfirmsmadesignificantadvancesinnovelmeansof administeringdrugs.AnappreciationofthecompetitionfacedbyBritishfirmswillenable ustounderstandmuchaboutthewaysinwhichasectionoftheBritishpharmaceutical

JohnBellaComingCentenaryChemist&Druggist52(11June1898):1605S. W.F.Holloway,RoyalPharmaceuticalSocietyofGreatBritain18411991:APolitical andSocialHistory (London:ThePharmaceuticalPress,1991):appendix.

L.G.Matthews,HistoryofPharmacyinBritain (EdinburghandLondon:E.&S. Livingstone,1962):11827L.G.Matthews,AnUnrecordedWilliamAllenCaricature MedicalHistory 15(1971):3056.

J.W.England(ed.), TheFirstCenturyofthePhiladelphiaCollegeofPharmacy 18211921(Philadelphia:PhiladelphiaCollegeofPharmacy,1922).

J.M.D.Olmsted,FrancoisMagendie(NewYork:Schumanns,1944)Claude Bernard,AnIntroductiontotheStudyofExperimentalMedicineTrans.H.C.Greene, (NewYork:Dover,1957)R.D.French,AntiVivisectionandMedicalSciencein VictorianSociety (Princeton:PrincetonUniversityPress,1975).

J.T.Mahoney,Merchantsof Life:AnAccountoftheAmericanPharmaceutical Industry (NewYork:Harper,1959).

termethicalmedicinecameintousein theUSAafterthe1847codeofethicsofthe AmericanMedicalAssociationforbadedoctorsfromprocuringapatentforaremedy,and

ThePharmaceuticalIndustry'tovaryingdegreesincluded'theChemicalandAllied Trades'and'theFineChemicalIndustry':WhatisaFineChemicalChemist&Druggist 85.2(29August1914):51.

L.G.Blochman,DoctorSquibb:TheLifeandTimesofaRuggedIdealist(New York:Simon&Shuster,1958)J.T.Mahoney,Philadelphia,CradleofPharmacy:Smith, Kline&French,WyethandOthers(1959):3041.