08/14/2015 Introduction to the Process of Drug

07:30 – 09:30 Development

YL6: 01.12.02 Principles and Perspectives
Cecilia A. Jimeno, M.D.

OUTLINE !! Poorly!served!disease!(Treatments$are$not$yet$
I.! Introduction! A.! Targets!and!Leads! available.$Drugs$only$alleviate$symptoms)!
A.! Why!Are!New! B.! Drugs!and!Products! −! e.g:!Alzheimer’s,!motor!neuron!disease!(ALS)!
Drugs!Needed?! III.! The!Process!of!Drug! !! Trends/Needs:!e.g.!antibiotic!resistance,!prevention!
B.! How!To!Determine! Development! by!immunotherapy/vaccines!(HIV,!dengue,!Type!1!
What!Drug!To! A.! PreGClinical! DM)!
Develop! Research! →!Commercial!potential!!
C.! Background!of!Drug! B.! Clinical!Studies! !! Pfizer$developed$a$powdered$form$of$insulin$that$was$
Development! C.! Other!Steps!or! meant$to$be$inhaled$but$it$was$eventually$phased$out$
D.! Approaches!to!Drug! Mechanisms!for! due$to$the$inconveniently$sized$inhaler$(the$size$of$a$
Discovery! Developing!Drugs! small$umbrella)$which$proved$to$be$unpopular$in$the$
E.! Overview!of!the! D.! Life!Cycle! market$and$unprofitable$for$Pfizer$
Drug!Discovery!and! Management! →!Patient/Public!demands!
Development! Review!Questions! !! Patients$would$rather$have$drugs$to$take$rather$than$
Process! Freedom!Space! change$their$behavior$
II.! Modern!Drug!Discovery! References! !! e.g.$Rather$than$diet$or$exercise,$people$would$opt$to$
and!Development! Appendix! take$drugs$to$cure$lifestyle$diseases$
Process! !
! C. BACKGROUND OF DRUG DEVELOPMENT
I. INTRODUCTION !
! The Changed Context of Drug Discovery and
A. WHY ARE NEW DRUGS NEEDED? Development
! !
•! Unmet!medical!needs! Table!1.!Differences!of!Drug!Discovery!and!Development!in!the!last!
→!New!diseases!(e.g.!Alzheimer’s,!H1N1,!and!obesity)! two!centuries!
!! e.g.$Obesity$is$not$a$new$disease$but$is$not$easily$ The!1800s! The!1990s!
treated.$Liraglutide,$an$analogue$of$GLP81$and$is$ •! Natural!sources! •! Synthetic!source!
originally$intended$for$diabetics,$can$help$one$lose$ •! Limited!possibilities! •! Unlimited!possibilities!
weight$if$it$is$given$at$higher$doses$ •! Prepared!by!individuals! •! Prepared!by!companies!
→!Low!efficacy!(e.g.!dementia!and!cancer)! •! Small!scale! •! Massive!scale!
!! e.g.$Breast/lung$cancer$drugs$are$being$developed$ •! Not!purified,! •! Highly!purified,!
to$improve$efficacy$and$extend$life$expectancy! standardized!or!tested! standardized!and!tested!
→!Side!effects!(e.g.!antidepressants,!antipsychotics,!and! •! Limited!administration! •! WorldGwide!
cancer)! •! No!controls! administration!
!! e.g.$One$cycle$of$chemotherapy$can$lead$to$a$total$ •! No!idea!on!mechanism! •! Tight!legislative!control!
loss$of$hairB$Antipsychotics$can$cause$metabolic$ of!action!of!the!drugs! •! Mechanisms!of!action!
problems$like$diabetes$and$obesity$ •! e.g.$penicillin,$metformin! partly!or!wholly!
!! There$is$still$a$need$to$find$safer$drugs$with$minimal$ understood!
side$effects$ !
→!Downstream!health!costs!(e.g.!Alzheimer’s,!spinal! Sources of Drugs
injury,!and!Parkinson’s)! •! Animal!
!! Because$people$live$longer,$the$cost$for$paying$for$ →!Insulin!(pig,!cow)!
health$increases$(i.e.$these$diseases$lead$to$ !! Discovered$by$Dr.$Frederick$Banting$and$Charles$
disability$which$is$costlier$considering$rehab$and$ Best$
therapy).The$cost$of$maintaining$health$is$higher$
→!Growth!hormone!(man)!
than$curing$the$disease$
•! Plant!
→!Cost$of$therapy$(e.g.$Viagra$and$interleukins)$
→!Digitalis!(Digitalis$purpurea$/!foxglove)!
!! Many$of$the$new$drugs$are$expensive$so$there$is$a$
need$to$improve$cost8effectiveness$ →!Morphine!(Papaver$somniferum$/!opium!poppy)!
→!Costs$to$individual/country!(e.g.!depression)! →!Does!not!isolate!the!active!principleV!crude!extract!
!! e.g.$In$the$workplace,$employees$won’t$be$efficient$if$ •! Inorganic!
they$are$depressed$which$adds$to$cost$for$the$ →!Gold!(used!for!rheumatologic!diseases)!
company$ →!Lithium!(used!for!bipolar!disorders)!
•! To!sustain!industrial!activity!(e.g.!pharmaceutical!industry! •! Synthetic!
employs!thousands!and!makes!a!massive!contribution!to! →!Chemical!(propranolol)!
overseas!earningsV!patent!expiry)! →!Biological!(penicillin)!
! →!Biotechnology!(human!insulin)!
B. HOW TO DETERMINE WHAT DRUG TO !! Insulin$is$no$longer$produced$from$animal$sources$
DEVELOP with$the$advent$of$human$recombinant$technology$
!
•! Therapeutic!needs!are!determined!by:! D. APPROACHES TO DRUG DISCOVERY
→!Existing!therapies:! !
!! WellGserved!diseases!(but!room!for!improvement)! Traditional
−! e.g.:!Heart!failure,!hypertension,!asthma! •! Trial!and!error!

YL6: 01.12.02 Group 1: Abacan, Aldea, Bermudez, Chua A, Chua K , Lanip, Song, Vargas, Yacob, Zafra 1 of 9!
 →!Ethnopharmacology:$involves$testing$the$efficacy$of$ •! After,$you$test$it$on$animals$for$safety$and$toxicity$$
different$medicinal$plants$discovered$in$different$ •! Then$you$test$it$on$recruited$human$volunteers$
races/locations! •! $Afterwards,$you$submit$a$drug$dossier$to$regulatory$
!! e.g.$Diverse!cultures!and!systems!of!medicinesV! agenciesB$subject$for$approval$
Drugs!discovered!from!various!herbal!and!botanical!
sources:!morphine,!quinine,!ephedrine,!artemisinin!
•! Once$it$is$registered$and$approved,$you$market$it.$Even$
after$marketing,$you$still$do$monitoring$even$after$human$
(an$anti8malarial$drug$discovered$in$China),!aspirin,!
sennosides!(a$laxative)! testing$to$test$it$on$a$larger$population$and$see$the$full$
! drug$profile$(post$registration$/$Phase$IV$monitoring)$
Empirical •! Depending$on$feedback,$you$may$have$to$re8develop$or$
tweak$the$drug.$
•! Builds!on!understanding!of!relevant!physiological!process!
!
→!Develop!drugs!which!have!the!same!structure!and!
II. MODERN DRUG DISCOVERY AND
activity!as!the!existing!molecules!
DEVELOPMENT PROCESS
→!e.g.!GLPG1!
!
!! Causes$the$incretin$effect:$important$for$insulin$
release$during$post8prandial$periodB$inhibits$glucagon$$
!! Broken$down$by$dipeptidyl8peptidase$4$(DPP84)B$by$
inhibiting$DPP84,$this$will$increase$the$bioavailable$
GLP81$in$the$body$
•! Use!of!naturallyGoccurring!lead!molecule!!
→!e.g.!propranolol!and!other!β!Gadrenoceptor!antagonists,!
H2Gantagonists!!
!
Molecular
•! Most!drug!discovery!is!based!on!this!approach!
•! Molecular!biological!techniques!
→!Advances!in!genomics!(e.g.!Human!Genome!Project)!
! Figure!2.!Modern!Drug!Development!and!Development!Process:!A!
Other Approaches Progression!from!Targets!and!Leads!to!Products.!
!
•! Historical:!cinchona!(quinine)!and!willow!barks!(aspirin)V! •! From$a$huge$range$of$targets,$they$identify$a$lead$agent$or$
Chinese!medicine!currently!
product$(molecule,$protein$or$drug)$
•! Study!disease!process:!breast!cancer!(tamoxifen)V!
•! The$lead$agent$or$product$is$then$a$candidate$for$first$trials$
Parkinson’s!disease!(LGDopa)!
in$humans$(FTIH)$
•! Study!biochemical!/physiological!pathway:!reninG
•! Clinical$testing$is$done$to$establish$proof$of$concept$(PoC)$
angiotensin!system! –$Phase$I$to$III$
•! Develop!SAR!(structure!and!activity!relation)!to!natural!
•! If$it$is$proven$to$be$safe$and$effective,$it$is$filed$to$different$
compound:!β!Gadrenoceptors!(propranolol),!H2!receptors! regulatory$agencies$and$launched$to$the$market$
(cimetidine)!
•! After$launch,$there$is$life$cycle$management$
•! Design!to!fit!known!structurally!identified!biological!site!
→!Much$like$any$product$it$should$be$taken$care$of$and$
(e.g.!angiotensinGconverting!enzyme!inhibitors)!
improved$if$necessary$
•! By!chance!(serendipity)V!random!screening!(e.g.!penicillin!
•! By$the$time$the$drug$is$finished,$it$would$have$cost$billions$
and!dimenhydramate)!
to$market$the$product$
•! Genomics!(e.g.!identification!of!receptorsV!gene!therapyV! $
recombinant!materials)!
A. TARGETS AND LEADS
•! Driver!is!unmet!medical!need!in!a!viable!market!! !
!
E. OVERVIEW OF THE DRUG DISCOVERY
AND DEVELOPMENT PROCESS
!

! !
Figure!1.!Drug!Discovery!and!Development!Process$ Figure!3.!Overview!of!Target!to!Drug!Process!
$ !
•! Discovery! Target Selection
→!Find!new!active!structures! •! Start$by$looking$at$targets$
•! Development! →!Proteins$expressed$from$the$gene$that$is$relevant$to$the$
→!Convert!the!identified!active!structure!to!a!useful!drug! drug$or$disease$of$interest$(Figure$4).$
form! →!With$modern$technology,$targets$can$also$be$identified$
•! Initially,$there$are$pre8clinical$processes$where$you$ from$specific$genes/proteins$of$interest$(Figure$4).$
discover,$refine,$and$characterize$the$drug$$

YL6: 01.12.02 Introduction to the Process of Drug Development: Principles and Perspectives 2 of 9!
 !! e.g.$Targets$identified$by$knowing$MAPK$Signalling$ III. THE PROCESS OF DRUG DEVELOPMENT
Pathway$
•! Identify$one$or$more$of$the$protein$targets$
•! Look$at$structure/activity$relationships$
!

!
Figure!4.!Flowchart!of!How!Targets!are!Identified!
!
Target Validation: Linking Targets to Diseases
and Treatments
•! Target!Validation! Figure!5.!Drug!Development!Diagram!(See!Appendix)!
→!Series!of!activities,!which!aim!to!build!confidence!that!a! !
drug!which!acts!by!modifying!the!function!of!the!target! I.! PreGclinical!Research!
will!deliver!the!efficacy!and!safety!required! A.!Synthesis!and!Purification!
•! A!target!is!never!fully!validated!until!a!drug!acting!on!it! B.!Animal!Testing!
works!in!patients! II.!Clinical!Studies!
! A.!(Phase!0:!NonGclinical)!
B.!Phase!I!
Screening to Generate Hits and Identifying
C.!Phase!II!
Leads D.!Phase!III!
•! Identify$molecules$or$compounds$that$can$“hit”$or$bind$to$ III.!Other!Steps!
the$target$and$initiate$the$outcome$or$product$ A.!Accelerated!Development!Review!
•! Means!of!measuring!“hits”$ B.!Treatment!IND!(Investigational!New!Drugs)!
→!Compound!binds!to!cell!surface!receptor,!which!can!be! C.!!Parallel!Track!
measured!in!a!binding!assay!
→!Binding!can!evoke!a!cellular!response,!which!can!be! A. PRE-CLINICAL RESEARCH
measured!in!a!functional!assay!
•! Leads$are$refined$and$then$tested$on$animals$and$humans$ Purpose
! •! To!develop!adequate!data!to!reach!a!decision!that!it!is!
Summary reasonably!safe!to!proceed!with!human!trials!of!the!drug!
•! The!starting!point!for!modern!drug!discovery!is!picking!the! →!To!develop!a!pharmacologic!profile!of!the!drug!e.g.!
right!target!and!the!right!compound(s)! mechanism!of!action!based!on!inGvitro!&!inGvivo!
→!“Picking!the!winners”! laboratory!animal!testing!
→!It!may!be!12G16!years!and!cost!more!than!£500!M!to! →!To!determine!acute!toxicity!of!the!drug!in!at!least!2!
find!out!you!were!right!! species!of!animals!
•! To!reach!this!point!will!have!taken!3G4!years!and!cost!£!1G →!To!conduct!shortGterm!toxicity!studies!ranging!from!2!
2!M!per!successful!lead! weeks!to!3!months!depending!on!the!proposed!duration!
! of!use!of!the!substance!in!the!proposed!clinical!studies!
B. DRUGS AND PRODUCTS !
! Levels of Testing
How Are Drugs Developed? !
•! Several!stages!from!benchwork!and!virtual!models!to!
animal!models!and!then!to!human!experimentation!
•! Human!subjects!of!drug!investigations!
→!Normal!healthy!subjects!
→!Relatively!healthy!patients!
→!Broader!spectrum!of!patients!of!various!stages!
!
The Process of Drug Development
•! Search!for!new!&!effective!drugs:!complicated,!costly!&!
timeGconsuming! !
•! No!guarantees! Figure!6.!Levels!of!Testing!
•! Pharmaceutical!companies!spend!millions!in!developing!a! !
single!drug! Biochemical Testing
•! Hundreds!&!sometimes!thousands!of!compounds!must!be! •! Chemical!and!Biological!Characterization!
made!&!tested!to!find!one!that!can!achieve!a!desirable! →!Chemical:!structure,!synthesis,!purity,!isomers,!pKa,!
result! stability,!solubility,!salts,!assay!
! →!BiologicalV!acute!pharmacological!profile!G!LD50,!ED50,!
binding!data!for!many!receptors,!doseGeffect!

YL6: 01.12.02 Introduction to the Process of Drug Development: Principles and Perspectives 3 of 9!
 relationships,!open!field!tests,!particular!tests!for!
different!activities!(e.g.!CVS,!CNS,!GI!tract)!
!! LD50:$Median$Lethal$Dose$or$Lethal$Dose$–$dose$that$
1
kills$half$of$the$subjects$or$animals $
!! ED50:$Median$Effective$Dose$or$Effective$Dose$–$
dose$where$half$of$the$response$is$seen$
→!Both!positive!and!negative!information!are!useful!
•! Synthesis!and!Purification!of!Drugs!
→!Initial!research!is!inFvitro:!testGtube!experiments!using!
assays,!compounds!added!one!at!a!time!to!enzymes,!
cell!cultures,!cellular!substances!grown!in!the!
laboratory!
→!Computers:!to!simulate!chemical!compounds!&!design!
chemical!structures!that!might!work!against!theseV!
receptor!sites!&!interactions!
→!Testing!compounds!made!naturally!by!microscopic!
organisms!or!herbs!
•! Isolation!of!Active!Principles!
→!Identification!of!the!active!ingredient(s)!
→!Analysis!of!the!biological!effects!(pharmacodynamics)!
of!individual!ingredients!and!of!their!fate!in!the!body!
(pharmacokinetics)!
→!Ensuring!a!precise!and!constant!dosage!in!the!
therapeutic!use!of!chemically!pure!constituents!
→!The!possibility!of!chemical!synthesis,!which!would!
afford!independence!from!limited!natural!supplies!and!
create!conditions!for!the!analysis!of!structure–activity!
relationships!
•! Formulation!Studies!!
→!Formulation!Considerations!
!! Inclusion!of!additives:!filler,!lubricant,!coating,!
stabilizer,!color,!binder,!disintegrator!
!! Dosage!form:!capsule,!tablet,!injection!
!! Manipulate!duration/profile:!e.g.!sustained!release!or!
immediate!release!
→!Guiding!Principles!
!! Bioequivalence!
!! Bioavailability!
!! Ease!of!use!
!
Bioavailability$means!the!rate!and!extent!to!which!the!active!
ingredient!or!active!moiety!is!absorbed!from!a!drug!product!
4 Acute!toxicity!
and!becomes!available!at!the!site!of!action. !
$
Bioequivalence$means!the!absence!of!a!significant!
difference!in!the!rate!and!extent!to!which!the!active!
ingredient!or!active!moiety!in!pharmaceutical!equivalents!or!
pharmaceutical!alternatives!becomes!available!at!the!site!of!
drug!action!when!administered!at!the!same!molar!dose!
under!similar!conditions!in!an!appropriately!designed!study. !
4 subchronic!
! toxicity!
Animal Testing
•! Drug!companies!make!every!effort!to!use!as!few!animals!
as!possible!and!ensure!their!human!and!proper!care!
•! Generally,!two!or!more!species!(one!rodent,!one!nonG
rodent)!are!tested!because!a!drug!may!affect!one!species!
differently!from!another!
•! Purpose!
→!To!measure!how!much!of!a!drug!is!absorbed!into!the!
blood!
→!How!is!it!broken!down!chemically!in!the!body!
→!Toxicity!of!a!drug!and!its!metabolites!
→!Kinetics:!How!quickly!the!drug!and!its!metabolites!are!
excreted!from!the!body!
→!Initial!pharmacokinetics!is!performed!in!animals!to!
gain!an!idea!of!how!the!drug!may!be!metabolized!in!
humans!(hypothesis)!
•! Animal!Models!
→!Models!of!Efficacy!
!! Existing!normal!behaviors/effects!(anesthesiaV!
contraceptionV!paralysis)!
YL6: 01.12.02 Introduction to the Process of Drug Development: Principles and Perspectives
−! Affect$normal$behavior$of$animals$
!! Create!behaviors!(fat!ratsV!hypertensive!ratsV!anxious!
ratsV!epileptic!rats)!
−! Create$models$of$animals$that$have$been$
genetically$modified$to$express$specific$
behaviors/characteristics$
!! Find!unrelated!behavior!affected!by!existing!drugs!
(Learned!helplessness!for!antidepressants)!
−! Elicit$behaviors$that$are$not$the$intended$effect$
→!Advantages!
!! Predictive!for!efficacy!and!toxicity!
→!Disadvantages!
!! Expensive,!timeGconsuming,!variable,!uncertain,!
troublesome,!ethical!questions,!skilled!workers!
needed!
→!Subjected!to!legislative!control!!
!
Safety Assessment
•! Are!the!toxicology!species!good!models!for!humans!in!
terms!of:!
→!Systemic!exposure!to!the!drug?!
→!Routes!of!metabolism?!
→!Systemic!exposure!to!metabolites?!
•! Safety!and!Toxicity!in!Animals!
→!Acute!toxicity!profile!
!! For$assessment$of$short8term$safety!
→!Chronic!toxicity!profile!
!! For$assessment$of$long8term$safety!
!! 14Gday!toxicity!test!in!one!rodent!and!one!nonGrodent!
species!before!use!in!man!
!! 3Gmonth!study!read!out!at!28!days!
!! Longer!studies!(12!&!24!month)!
→!Three!dose!levels!(below,!about,!well!above!human!
dose)!
→!It!is!insufficient!to!use!doses!that!are!not!toxicV!the!
doses!producing!toxic!effects!and!the!nature!of!these!
effects!MUST!be!established!
!
Table!2.!Definitions!of!Safety!Tests !
1
Safety!Tests!
Type!of!Test! Approach!and!Goals!
Usually!two!species,!two!routes.!
Determine!the!noGeffect!dose!and!the!
maximum!tolerated!dose.!In!some!
cases,!determine!the!acute!dose!that!
is!lethal!in!approximately!50%!of!
animals!
Subacute!or! Three!doses,!two!species.!Two!
weeks!to!3!months!of!testing!may!be!
required!before!clinical!trials.!The!
longer!the!duration!of!expected!
clinical!use,!the!longer!the!subacute!
test.!Determine!biochemical,!
physiologic!effects!
Chronic!toxicity! Rodent!and!at!least!one!nonrodent!
species!for!≥!6!months.!Required!
when!drug!is!intended!to!be!used!in!
humans!for!prolonged!periods.!
Usually!run!concurrently!with!clinical!
trials.!Determine!same!end!points!as!
subacute!toxicity!tests!
Effect!on! Two!species,!usually!one!rodent!and!
reproductive! rabbits.!Test!effects!on!animal!mating!
performance! behavior,!reproduction,!parturition,!
progeny,!birth!defects,!postnatal!
development!
Carcinogenic! Two!years,!two!species.!Required!
potential! when!drug!is!intended!to!be!used!in!
humans!for!prolonged!periods.!
Determine!gross!and!histologic!
pathology!
4 of 9!
 Mutagenic! Test!effects!on!genetic!stability!and! →!Guarantee!safety!in!humans!
potential! mutations!in!bacteria!(Ames!test)!or! →!Predict!the!human!response!
mammalian!cells!in!cultureV!dominant! →!Define!a!mechanism!for!the!changes!
!
lethal!test!and!clastogenicity!in!mice!! !
! B. CLINICAL STUDIES
!
Clinical Trials/Testing
•! An!investigational!drug!is!administered!to!humans!&!is!
evaluated!for!its!safety!&!effectiveness!in!treating,!
preventing!or!diagnosing!a!specific!disease!or!condition!
•! Four!phases:!
→!Phase!I!(volunteers)!
→!Phase!II!(patients)!
→!Phase!III!(large!scale!multiGcentre)!
→!Phase!IV!(post!registration!monitoring)!
!! Phases!can!also!be!defined!by!the!information!you!
! are!trying!to!get!out!of!the!testing!
Figure!7.!Aspects!of!A!Safety!Assessment! •! Human!Testing:!Key!Messages!
$ →!Entry!into!man!is!a!major!milestone:!major!ethical!and!
•! Determine$whether$the$drug$would$be$given$at$a$one8time$ safety!reviews!before!approval!
dose$or$as$a$maintenance$drug$ →!No!absolutes!in!designing!a!clinical!plan!–!but!subject!
•! This$may$have$acute$or$chronic$responses$based$on$the$ safety!is!always!paramount!
dose$and$timing$ !! Drugs!can!be!pulled!out!at!any!point!in!the!trials,!
•! Even$a$single$dose$can$cause$genetic$damage$ even!Phase!I!
→!e.g.$Thalidomide$(used$then$by$pregnant$women$to$ →!Initial!studies!usually!undertaken!with!healthy!male!
cure$nausea):$some$took$it$at$a$single$dose$and$had$ volunteers!at!very!low!doses,!with!intensive!monitoring!!
caused$shortness$of$limbs$in$their$babies$due$to$ !! Most!health!females!are!of!reproductive!age,!to!
genotoxicity$ prevent!generational!adverse!effects,!males!are!
•! In$the$long$term,$it$may$also$have$carcinogenic$effects$ selected!instead.!
$ →!Surrogate!or!clinical!markers!are!used!
Table!3.!List!of!Toxicology!experiments!and!what!it!should!examine! →!Initial!goal:!to!establish!safety!and!tolerability!in!
Experiments! Endpoints! human!
Safety!Pharmacology!! Behavior,!function,! !
(in!vitro,!rodent,!nonGrodent)! physiology! Clinical Research
General!Toxicology!! Behavior,!function,!
•! Under!US!FDA!requirements,!a!drug!sponsor!must!first!
(rodent,!nonGrodent)! physiology,!clinical!
submit!data!showing!that!a!drug!is!reasonably!safe!for!use!
biochemistry,!pathology!
in!initial,!smallGscale!clinical!studies!
Genetic!Toxicology!! Mutation,!chromosomal!
•! Options!to!fulfill!this!requirement:!
(in!vitro,!in!vivo)! changes!
Carcinogenicity!! NonGgenotoxic!carcinogens! →!Compile!existing!nonGclinical!data!from!past!inGvitro!
(rodents)! laboratory!or!animal!studies!on!the!compound!
Reproductive!and! Fertility,!pregnancy,!fetal!and! →!Compile!data!from!previous!clinical!testing!or!marketing!
Development!Toxicology! periG/postGnatal!development! of!the!drug!in!the!country!or!another!country!whose!
population!is!relevant!or!similar!
!
→!Undertake!new!preclinical!studies!designed!to!provide!
→!Tests!more!than!the!active!drug!substance!
evidence!to!support!safety!of!administering!the!
!! All!medicines!contain!more!than!the!active!drug!
compound!to!humans!
!! Also!tests:!related!substances,!solvents,!degradation!
!
products,!excipients,!other!active!materials,!
extractives! Phase I Clinical Studies
!! e.g.!Erythropoietin$caused$pure$red$cell$aplasia$ •! Definition/!Characteristics:!
which$was$caused$by$a$substance$in$the$syringe$ →!Initial!introduction!of!an!investigational!new!drug!into!
rubber$stopper$$ humans!
! →!Closely!monitored!
Summary •! Purpose!
•! What!data!can!it!provide?! →!Main!purpose!is!to!determine!safety!for!human!use!
→!DoseGselection!for!initial!clinical!studies! →!To!obtain!sufficient!information!about!the!drug’s!
→!Suggest!‘markers’!to!monitor!safety!in!humans! pharmacokinetics!and!pharmacologic!effects!thus,!
→!Drug!absorption,!metabolism!and!toxicity!of!the!drug’s! permitting!the!design!of!wellGcontrolled,!scientifically!
metabolites! valid!Phase!II!studies!
→!Speed!with!which!the!drug!and!its!metabolites!are! •! Objectives!
excreted!from!the!body! →!Determine!metabolic!and!excretory!pathways!(impinges!
•! Preclinical!safety!studies!will! on!toxicity!testing!in!animals)!
→!Explore!the!response!at!up!to!maximum!achievable! →!Determine!variability!between!individualsV!effect!of!
doses! routeV!bioavailability!
→!Detect!potential!hazards! →!Establish!tolerate!dose!range!
!! Toxic!and!pharmacologic!effects!of!a!drug! →!Determine!side!effects,!especially!doseGrelated!
!! Genotoxicity!screening!results! →!Obtain!early!evidence!of!effectiveness!
→!Generate!data!to!enable!a!risk!assessment!to!be! •! Subjects!
made! →!Usually!20G80!healthy!volunteers!
•! Preclinical!safety!studies!cannot!necessarily! •! Components!

YL6: 01.12.02 Introduction to the Process of Drug Development: Principles and Perspectives 5 of 9!
 →!Pharmacologists!&!employees!(15G30!in!number),! •! Subjects:!!
ethical!approval,!healthy!volunteers,!informed!consent,! →!1500G3500!ill!patients!
full!resuscitation,!medical!backup,!monitor,!single!and! →!In$another$slide:$Include!several!hundred!to!several!
repeat!doses,!increase!dose!levels! thousands!of!people!
•! Note:! !
→!Doctors!do!not!have!to!be!the!ones!to!administer!the! Drug Actions Depends On:
tests.!They!just!need!to!be!there!to!monitor!and! •! Pharmacodynamics!
resuscitate! •! Pharmacokinetics!and!dose!regimen!
→!The!regulatory!agency!can!impose!a!clinical!hold!OR! •! Drug!interactions!
prohibit!a!study!from!proceeding!for!reasons!of!safety,! •! Receptor!sensitivity!of!patient!
or!due!to!failure!of!sponsor!to!disclose!the!risk!of!study!
•! Mood/personality!of!patient!&!doctor!
to!investigators!
•! Patients!expectations!and!past!experience!
→!In$the$Philippines$this$is$not$a$common$study$being$
•! Social!environment!of!patient!
done$because$of$the$complexity$of$the$set8up$and$
manpower$required$for$the$experiment! •! Clinical!state!of!patient!
! •! Clinical!trial!controls!these!variables!and!examines!
Phase II Clinical Studies action!of!drug!in!defined!set!of!circumstances!
!
•! Definition/!Characteristics:!
Pivotal Phase III Studies
→!Early!controlled!clinical!studies!conducted!to!obtain!
some!preliminary!data!on!the!effectiveness!of!the!drug! •! Why!
for!a!particular!indication/s!in!patients!with!the!disease! →!Determine!safety!and!efficacy!in!target!indication!to!
→!WellGcontrolled! provide!data!for!regulatory!approval!
→!Closely!monitored! •! What!
→!Relatively!small!number!of!patients,!usually!several! →!Two!adequate,!wellGcontrolled,!doubleGblind!clinical!
hundred!people! trials!
•! Purpose! →!Compare!with!gold!standard,!placebo!or!supportive!
care!
→!To!obtain!some!preliminary!data!on!the!effectiveness!of!
a!drug!for!a!claimed!indication!in!patients!with!the! •! How!
disease!or!condition! →!Participants:!600G3000!patients!
→!To!help!determine!the!common!shortGterm!side!effects! →!Duration:!1.5G5!years!
and!risks!associated!with!the!drug! →!Cost:!£4G50!M!per!trial!
→!Establish!appropriate!dose!and!regimen!for!Phase!III! →!Location:!Multiple!sites!and!countries!
clinical!trials! !
2
•! Objectives! Pivotal!Phase!III!Study !
→!Indication!for!use! “A!trial!designed!and!executed!to!get!statistically!significant!
→!Type!of!patient! evidence!of!efficacy!and!safety!as!required!by!HAs!for!NDA/!
sNDA!approval.!It!also!includes!studies!with!the!aim!to!
→!Severity!of!disease!
include!claims!into!the!label!as!well!as!postmarketing!
→!Dose!range!
commitments”!
→!Schedule!and!increment!
!
→!Pharmacokinetic!studies!in!ill!people!
Regulation
→!Nature!of!side!effects!and!severity!
→!Effects!in!special!groups! •! Regulatory!Authorities!
•! Subjects! →!International!Conference!on!Harmonisation!
!! (US)!Food!and!Drug!Administration!
→!150G350!ill!patients!
!! (Japan)!Ministry!of!Health!Labour!and!Welfare!
•! Components:!
!! (EU)!European!Medicines!Agency!
→!Performed!by!practicing!licensed!doctors!(not!simply!for!
→!(UK)!Therapeutic!Goods!Administration!
life!support!and!monitoring),!informed!consent,!
→!(Canada)!Health!Canada!
maximum!monitoring,!full!resuscitation!
→!There!are!over!120!‘international’!markets!
•! Note:!
•! Regulatory!Process!
→!Clinical!hold!can!be!issued!if!a!study!is!unsafe!
→!Differs!from!country!to!country!
!
→!Demands!safety!and!quality!of!product!
Phase III Clinical Studies
→!Encourages!efficacy!and!need!for!product!
•! Definition/!Characteristics!
→!Grants!clinical!trials!certificate!if!volunteer!and!animal!
→!Expanded!controlled!&!uncontrolled!trials! data!OK!
→!May!be!conducted!as!a!multiGcenter!trial!! →!Approves!protocols!and!examines!data!
→!Interactions!between!drugs!start!to!become!measurable! →!Original!data!available!
in!the!larger!population!
→!Two!way!processV!authority!and!company!trying!to!
!! SubGgroups!start!to!be!established!
produce!a!safe!effective!product!
!! Special!features!and!problems!show!up!
→!Release!for!a!specific!purpose!and!use!
•! Purpose!
•! Registering!in!Asia!
→!Used!to!gather!information!about!effectiveness!&!safety!
→!Controlling!for!pharmacogenetics!
that!is!needed!to!evaluate!the!overall!benefitGrisk!
→!Local!studies!need!to!be!done!
relationship!of!the!drug!
→!Provide!an!adequate!basis!for!extrapolating!the!results! →!Ensure!that!dosing!is!appropriate!
!
to!the!general!population!&!transmitting!that!information!
in!the!physician!labeling! Phase IV Post-Marketing Studies
→!Observe!effect!of!drug!disease!with!accompanying!coG •! Done!by!physicians!in!actual!practice!
morbidities! •! Main!Objective:!Safety/Pharmacovigilance!
•! Objectives! →!It!will!be!used!by!more!patients!that!previously!tested!
→!More!certain!data!for!the!objectives!of!phase!II!studies! →!Involves!real!world!problems!of!misreading!labels!by!

YL6: 01.12.02 Introduction to the Process of Drug Development: Principles and Perspectives 6 of 9!
 patients!and!doctors!
→!Involves!collecting!reports!of!adverse!drug!reactions!or!
adverse!events!to!ensure!that!newly!marketed!drugs!
are!safe!(and!not!just!effective)!
→!Problems!are!reported!back!to!the!developer!
→!Sometimes$instead$of$being$a$formal$study$it$becomes$
a$seeding!venture$because$doctors$are$paid$by$the$
pharmaceuticals$as$long!as$they$answer$the$
feedback/evaluation$form!
! prevent!them!from!participating!in!controlled!clinical!trials!
C. OTHER STEPS OR MECHANISMS FOR
DEVELOPING DRUGS
!
Accelerated Development Review (ADR)
•! A!highly!specialized!mechanism!for!speeding!the!
development!of!drugs!that!promise!significant!benefit!over!
existing!therapy!for!serious!or!lifeGthreatening!illnesses!for!
which!no!therapy!exists!
•! Incorporates!checks!to!ensure!that!rapid!development!and!
review!is!balanced!by!safeguards!to!protect!both!the!
patients!&!the!integrity!of!the!regulatory!process!
•! ADR!can!be!used!in!these!2!circumstances:!
→!When!approval!is!based!on!evidence!of!the!product’s!
effect!on!a!“surrogate!endpoint”!
→!When!the!FDA!determines!that!safe!use!of!the!drug!
depends!on!restricting!its!distribution!or!use!
•! Manufacturers!must!continue!testing!after!approval!to!
demonstrate!that!the!drug!indeed!provides!therapeutic!
benefit!to!the!patient!
•! If!not,!product!can!be!withdrawn!more!easily!than!usual!
! •! Information!on!new!drug!
Accelerated!Development!Review!is!a!process!that!
incorporates!several!novel!elements!aimed!at!making!sure!
that!rapid!development!and!safeguards!to!protect!both!the!
patients!and!the!integrity!of!the!regulatory!process!balance!
4
review. !
! Seeding!Trial !!
A!surrogate!endpoint!is!a!laboratory!finding!or!physical!sign!
that!may!not!be!a!direct!measurement!of!how!a!patient!feels,!
functions,!or!survives,!but!is!still!considered!likely!to!predict!
4
therapeutic!benefit!for!the!patient. !E.g.!For!instance,!
smoking!is!known!to!cause!lung!cancer,!and!a!trial!of!the!
benefit!of!education!in!preventing!lung!cancer!might!use!
smoking!as!a!surrogate!endpoint!rather!than!the!occurrence!
5
of!the!cancer!itself. !
! medically!useful!knowledge,!and!deceive!researchers,!
Treatment IND
•! Treatment!investigational!new!drugs!are!used!to!make!
promising!new!drugs!available!to!desperately!ill!
patients!as!early!in!the!drug!development!process!as!
possible!
•! Allowed!if!there!is!preliminary!evidence!of!drug!efficacy!
and!the!drug!is!intended!to!treat!a!serious!lifeGthreatening!
disease!or!if!there!is!no!comparable!alternative!drug!or!
therapy!available!
•! Drugs!at!this!stage!need!to!complete!or!be!nearly!
complete!with!Phase!II!trials!
•! Could!be!applied!to!Ebola!virus!disease!management!plan!
! →!New!formulations!to!improve!access/ease!of!use!
The!Treatment!IND!is!a!mechanism!for!providing!eligible!
subjects!with!investigational!drugs!for!the!treatment!of!
serious!and!lifethreatening!illnesses!for!which!there!are!no!
4
satisfactory!alternative!treatments. !
! !
It!may!be!granted!after!sufficient!data!have!been!collected!to!
show!that!the!drug!"may!be!effective"!and!does!not!have!
unreasonable!risks.!Because!data!related!to!safety!and!side!
effects!are!collected,!treatment!INDs!also!serve!to!expand!
4
the!body!of!knowledge!about!the!drug. !
! administered!by!physicians!with!proper!disclose!of!risks!
! b.!Phase!III!trial!with!a!trial!population!of!1,551!patients!
Parallel Track
•! Similar!to!Treatment!IND!but!do!not!necessarily!involve!
dying!patients!
→!Drugs!become!available!after!only!just!finishing!Phase!
II!
•! Allows!wider!availability!of!drugs!even!those!which!are!still!
undergoing!testing!
•! Permitted!in!the!US!in!response!to!AIDS!
•! Under!this!policy,!patients!with!AIDS!whose!condition!
can!receive!investigational!drugs!shown!in!preliminary!
studies!to!be!promising!
The!purpose!of!the!parallel!track!policy!was!to!expand!the!
availability!of!promising!investigational!drugs!to!those!
persons!with!AIDS!and!HIVGrelated!diseases!who!are!without!
satisfactory!alternative!therapy!and!who!cannot!participate!in!
4
controlled!clinical!trials. !
!
The!policy!differs!from!the!Treatment!IND!primarily!in!that!it!
applies!only!to!AIDS!and!HIVGrelated!diseases,!and!that!
investigational!drugs!could!be!made!available!earlier!in!the!
4
development!process. !!
!
Stavudine!(d4T)!is!the!only!drug!that!was!submitted!for!
4
consideration!under!the!parallel!track!policy. !
Marketing
•! Getting!the!product!right!(packagingV!formulation)!
•! Right!therapeutic!slot!
•! Information!for!honest!comparison!
•! Reporting!problems!
•! Reporting!new!indications!
•! Therapeutic!trends!
!
3
“Seeding!trials!are!clinical!studies!primarily!intended!to!
promote!use!of!the!study!drug!by!physicians!and/or!to!
convert!physicians,!especially!opinion!leaders!—!and!study!
subjects!—!into!advocates!for!the!study!drug.!Seeding!trials!
seed!the!market!with!product!samples.!The!sponsor!hopes!
that!physicians!and!patients!will!continue!using!the!drug!after!
the!trial.!Seeding!trials!are!unethical!because!they!exploit!
study!subjects!for!commercial!purposes,!create!little!or!no!
subjects!and!IRBs.”!!
!
D. LIFE CYCLE MANAGEMENT
!
•! Product!Line!Extensions!
→!New!indications!to!expand!claims!
!! e.g.!GLP81$originally$meant$for$Diabetes$as$a$
treatment$for$obesity!
→!New!target!patient!populations!to!expand!patient!base!
→!New!administration!routes!
!! e.g.!Insulin$from$an$injectable$to$an$inhaled$powder$
or$orally$administered!
!! e.g.!Insulin$reformulations$to$improve$length$of$effect$
and$lessen$injection$times!
→!Combination!therapies!to!simplify!therapy,!improve!
compliance!
REVIEW QUESTIONS
!
1.! Which!of!the!following!instances!is!a!clinical!hold!
possible?!
a.!Phase!II!trial!with!a!population!of!300!participants,!

YL6: 01.12.02 Introduction to the Process of Drug Development: Principles and Perspectives 7 of 9!
 c.!Phase!I!trial!with!a!population!of!20!participants!where!
drug!development!is!approved!
d.!Phase!II!trial!with!a!population!of!300!participants,!
administered!by!any!drug!manufacturing!team!with!
proper!disclosure!of!risks!
2.! Which!of!the!following!is!false?!
a.!Accelerated!Development!Review!is!applicable!for!
serious/lifeGthreatening!wherein!the!drugs!are!available!
even!after!phase!I!
b.!Treatment!IND!are!for!serious/lifeGthreatening!patients!
wherein!the!drugs!are!available!even!after!phase!I!
c.!The!parallel!track!policy!allows!for!a!wider!availability!
drugs!even!if!testing!is!still!ongoing!
d.!The!parallel!track!policy!attended!to!the!burgeoning!
demand!for!HIV/AIDS!medication!in!the!United!States.!
3.! Which!of!the!following!is!true?!
a.!A!manufacturing!company!may!skip!preGclinical!testing!
if!the!previous!studies!on!it!have!already!been!
conducted!
b.!Safety!and!toxicity!testing!must!be!conducted!on!ten!
rodent!and!ten!nonGrodent!species!and!must!be!done!
on!three!dose!levels!
c.!Healthy!subjects!between!the!ages!of!20!and!40!years!
old!may!partake!in!phase!I!trials!regardless!of!sex!so!as!
to!be!equitable!to!all!
d.!Pharmacovigilance!is!the!main!purpose!of!phase!IIIV!
thereby,!necessitating!a!larger!population!size!than!the!
initial!phases!
4.! Which!of!the!following!is!false?!
a.! One!of!the!purposes!of!animal!testing!is!to!establish!
toxicity.!To!determine!this,!scientists!introduce!3!doses!
of!the!drug:!below,!about!the!same!and!well!above!
human!levels!of!toxicity.!
b.! Scientists!limit!animal!testing!to!use!as!few!animal!test!
subjects!as!possible.!!
c.! Phase!3!clinical!trials!tests!the!drugs!effect!on!patients!
experiencing!different!coGmorbidities!
d.! LongGterm!chronic!toxicity!studies!performed!on!animal!
subjects!for!≥!6!months!must!be!completed!before!
proceeding!to!human!trials.!
5.! The!empirical!and!molecular!method!of!drug!
development!both!work!on!specific!physiologic!
effects!of!molecules.!They!only!differ!in!that:!
a.! The!molecular!method!attempts!to!mimic!specific!
physiological!functions!of!body!systems!and!the!
structure!of!the!specific!molecules!involved!
b.! The!empirical!method!attempts!to!use!cultural!
knowledge!of!medicinal!plants!through!a!systematic!
process!of!trial!and!error!
c.! The!molecular!method!targets!specific!proteins!linked!
to!the!disease!by!generating!“hits”!from!molecules!that!
affect!the!action!of!these!proteins!
d.! The!empirical!method!does!not!!use!naturally!occurring!
molecules!
!
Answers:!d,!b,!a,!d,!c!
!
!
FREEDOM SPACE
!
QUESTIONS!AFTER!THE!LECTURE!
!
Q:!In!testing!for!safety,!when!do!studies!on!adverse!effects!
for!pregnancy!tested?!
A:!After!marketing!the!drug,!it!is!only!when!safety!concerns!
arise.!
!
Q:!Considering!genetic!differences!due!to!race,!is!the!African!
population!also!tested!for!drug!efficacy!aside!from!
Caucasians!and!Asians?!
YL6: 01.12.02 Introduction to the Process of Drug Development: Principles and Perspectives
A:!A!lot!of!drugs!are!tested!in!Africa!and!Asia,!for!example!
HIV!drugs,!but!in!the!end!the!drugs!are!inaccessible!to!them!
because!it!is!not!marketed!to!them!but!for!Caucasians!
!
Q:!Can!formulations!be!changed!after!the!completion!of!a!
phase!or!after!marketing?!
A:!Yes,!they!can!change!formulation!or!revise!the!product!
insert!for!new!indications.!
!
Q:!If!new!indications!are!found,!can!the!drug!manufacturer!
skip!Phase!I?!
A:!!Yes,!they!can!skip!phase!I!since!the!safety!has!been!
established,!especially!when!the!mechanism!of!action!has!
been!established,!but!they!can!still!conduct!studies.!
!
Supplementary!websites:!
WHO!on!Ebola!Drugs!and!list!of!Ebola!drugs:!
http://www.who.int/medicines/emp_ebola_q_as/en/!
!
Genentech!The$MAPK$Signaling!Pathway:!
https://www.youtube.com/watch?v=oDjDUUhGVsI!
!
FDA!Drug$Development$and$Review$Definitions:$$
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Ho
wDrugsareDevelopedandApproved/ApprovalApplications/Inv
estigationalNewDrugINDApplication/ucm176522.htm!
!
REFERENCES
!
1.!Katzung!B,!Trevor!A.!Basic$and$Clinical$Pharmacology.!
th
13 !ed.!New!York,!NY:!McGrawGHill!EducationV!2015.!
2.!Website:!Bahadur,!N.!(2008).!Overview$of$Drug$
Development$[PDF!document].!Retrieved!from!
http://www.ich.org/fileadmin/Public_Web_Site/Training/GC
G_G
_Endorsed_Training_Events/APEC_LSIF_FDA_prelim_w
orkshop_Bangkok__Thailand_Mar_08/Day_1/Clinical_De
v_Plans_G_Namrata_Bahadur.pdf!
3.!Website:!Hochhauser,!M.!(June!2009).!Is!this!a!Seeding!
Trial?!Journal$of$Clinical$Research$Best$Practices,$Vol.$5,$
No.$6.$$Retrieved!from!
https://firstclinical.com/journal/2009/0906_Seeding.pdf!
4.!Website:!CFR!G!Code!of!Federal!Regulations!Title!21.!
(n.d.).!Retrieved!August!15,!2015.!Retrieved!from!
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfr
search.cfm?cfrpart=320!
5.!Journal!Article:!Aronson,!J.!K.!(2005).!Biomarkers!and!
surrogate!endpoints.!British!Journal!of!Clinical!
Pharmacology,!59(5),!491–494.!doi:10.1111/j.1365G
2125.2005.02435.x!
!
8 of 9!
 APPENDIX
!

!
Figure!1.!Drug!Development!Diagram!
!
!

!
Figure 2. Overview of Steps in Drug Development (note time approximations)

YL6: 01.12.02 Introduction to the Process of Drug Development: Principles and Perspectives 9 of 9!