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Docket 2005N-0285 Division of Dockets Managernent (IIFA-34S) Food and Drug Administration 5`630 Fishers Lane, ltrrt . 1061 Rvckviile, NZD 20852 Re :

phase 1 irivcstigationaJ drugs and FDA's direct final rule/proposed rule to exempt ;GMP) regulation ing praci.ice (C biologics from the current, good r:tanufactui

Drug Administration . Dear Mernbers of the U .S . Food and _

agency's direct final rule/proposed rule Thank you for the opportunity to comment on the . 7_ am opposed and biologics from the CGIAP regulation to, exempt phase 1 investigatiiznal drugs should not be document, which is not legally binding, to this rule, and believe that a guidance safe provides the minimurn requirements for 'he used to replace an existing regulation that place patients in beings, 1 believe that tills rule may manufacture cat drugs or biologics for human phase 1 in jeopardy . Puts patients at risk, and is not legally binding

. They also binding, and no at-it: is required to iollowiht;m Guidance documents are not legally made per for use u1 human beir! ~S should be cannot be enforced- Drugs or biologics made . safely In legal requirements tonYake them CGMI' regulation, which provides the miniiYium, investigate or will make it very difficult lo addition to putting patients at risk., this approach good manufacturing p3actYcc°' is . This prosecute serious cases, and to prove what "current testing, or would keep proper records, perform necessary approach assutnes that new sponsors and or that they would lake the time to learn keep retention samples for later investigations, incriminate requiring thenl to do so (why would they follow CCiMP if there were no regulation CGMPs for [n-'es:tigational drugs (Preamble, thernselves'l) . FDA had always considered proposing Packing orE't-actcce in Manitjaeturing, F`Yoeessirlg, Final Rule, Current Good MuratrJactur- :ng guidance may direct final rulelp~opos~d r~ale ana dra:t Holrlifzg, 1978) . Comments received on tlae biologics. r01e on CGMI's for imvtisttgational drugs and be incorporated instead into a proposed Unethical

for 1 rnaterial being made for the first time and 1n the proposed rule, rDA states that phase be made (1ND) has been submitted to FDA may which an Investigational New Drug application already the CGMP regtilatie7tl), bua if th : .r.aterial is using the guidance docutttent (rather ',han would commercially available, the phase 1 material available in phase 2 or 3 clinical trials, or be would mean that some Phase l material would have to be made per CC'xMI'regulatton . This 1 are not. Patients or healthy volunteers in pliase made per CGiVIP regulation ., and some may humans to o," any participants bcaau: e they are flit, first already shouldering the biggest burden many of them are', chIonrcally i17, receive the compound . Of the patients who participate, they recei=.~e Introducing the possibilit~y t'zat the Yriaterial tenninally ill, or immunoconnproinised . material not inanutactt.rec pe .= the : ame standard as may be contaminated or strpe:cpotent, and



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an pharmacy-compounded products have included the death of one. Other deadly recalls of Scr-raliu liyuelaciens, which as you contaminated with albuterol inhaler for asthmatics that was recently blinded in infections, sepsis, or death- One patient was also know may cause rrspiratory not sterile . a pharmacy that were one eye due to using eyedrops prepared by of deadly recalls . In the medical device industry . the number Medical Device Experience of FDA war-ning letters for single largest ~,~r'oup has increased more than 300°X. since 15W 'Che large percentage issued to mediGai device firms, including a ' `noncompliance are currently being boards involved in device and institutional review going to sponsors, clinical investigators, manufacturing part of CGMP that must be followed when human clinical trials . The only design c:-ontzols (which CCiMP concerning investigational devices is that portion of device product development, reviews at the end of each design phase during requires formal, documented those review:,, ctc .) ~LontYibuting during having an uninterested party pre.s-r.nt and actively what is causing the yet done a root cause analysis tc$ cic,t.errri :rte Questions: Ilas the agency the device sector? Wl-ly .; and compliance problem, in ` deadly proc .uct recalls, warning letters, :or rnvest .gational this sector (in reducing CGNIP requirements ` would the agency want to emulate probie-rns ~x7 the device sector? what is causing the drug,-, or biologics) without first understanding and lacks understanding of QC unit role Violates U .S . and European Union CGNII's, allow-, the same person who manufactured The draft guidance published with the proposed rule . a non-QC unit employee to release material the material to release it to the clinic, and allows requires that a manufacturing practice, which This is a clear violation of U.S . current good violation of the (QC unit) release product, It is also a clear member of the Quality Control unit by training and Qualified Person (qualified European Union CGiV1Ps, which require that a learn that and conlinercial material. Even phar-inuc ~s¢s experience) release investigatiorlal nccPssaz-y checks and they must incorporate that Arhen compounding sterile or aseptic product, balances . importance of having an experienced This approach does not appear to recognize the manufacture the materials safcly, The; agency is and knowledgeable QC unit (or pei son) to responsible for ensuririg organizations that ;s undermining the QC unit, lz-1c one group inside . requirements If a quality assurance urn ~s required for patient safety and enforcing CGIv1Y one is riot needed to release investigationat animal testing, why would the agency propose that time'? material being used in human beings for the first Off Mission

Docket 2005N-0285 Page 3 of 7

mandated by Congress in The The tnissic7n of the L7 .S . Food and Drug Administration, states, that the Food and Drug Food, Drug and Cosmetic Act (Sect. 903, U.S .C . 393) tly health by promptly and efficiently reviewing. Administration shall "promote the public a on the marketing oz regulated products in clinical research and taking appropnati: action ensuring protect the public health by timely manner" and "with respect to such products, and effective ." The direct final rule states that that . . . human and veterinary drugs are safe and prornote the drag dcVeloPnitnt the agency is making this proposal "to streamline agency's mission . this is outside, th~ scone of the. proces : ." If my understanding is correct, protection agency, and 3 check and a The FDA was established to serve as a consumer mandatC includes promptly and balance c.n regulated industry . The Cungczssiona1 appropriate action on the rnarketi.ng of efficiently reviewing clinical research and takingdrug develoPrneiit organization_ reg:tilat.ed products in a timely manner . not becoming a

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Docket 2005N-0285 Page 4 of 7 Insufficient itesting requirements
proposed rule strongly recorrFinends performing The guidance, document issucd with the it . This pharmaceutical ingredient,;, but it does not requlre confirmatoty identity testing on active the sulfanilamide tragedy manufacturing practice . As you recall, in is a violation of current, good antifreeze) States, diethylene glycol (the equivalent o` that occurrec in the 1930s in the Un] Led testing or controls, and without sufficient was used in manufacturing an "elixir" of sulfanilamide, document patients, many of them children . The guidance resulting in the death of more than 100 products be done for biological/biotecluxrzlagy reeornmen.ds hut does not require that testing of viral biobuuden, detoxification of bacterial toxins, safety-rclated purposes such as -viral loads, r-ecominend_s but antibiotics . The guidance documc-nt clearance or inactivation, and clearance at performed "as ipvestigational product be does not require that laboratozy testing oi' tbc This is clearl_y potency, purity, and quality attribictcs ." appropriate to evaluate identity, strength, insufficient . Insufficient aseptic or sterile information

existing CGMP proposal, would be used to replace the The guidance, which if under the current more than one page on phase I materials, contains little regulation for the manufacture of some makes no reference to, media fills. Manufacturing manufacturing sterile or aseptic products, and level of skill and judgment, The, agency's sterile or aseptic dosage forms requires a higher contains by .,Iseptic F'rocessin,- is very detailed and guidance on Sterile Drug Products Produced inforrraation on regulation dot-,s not contain detailed 63 pages . Even though the current CG111P assume that a drug manufacturer, rnanufacturing sterile or aseptic product, it is illagical to the. first time laboratory making clinical material for chenucal manufacturer or (medical research) It is illogical to sterile or aseptic material saicly_ would be aole to follow this guidance arid make take the with other FDA guidance documents or assume that they would read or become familiar to do so per a C¬'sM4' regulation, time to learn or follow C~C'TMP without having Insufficient employee training requirements

entities would the agency does not lcrow how rnariy The direct final rule states that even though have that "all of the e.ntitics aFfec:ted by this rule be affected by the rule, that they believe ." requirements This is illog~~cal, The amount of personnel with skills necessary to comply with substantial, and not yet well described in the training required for aseptic technique alone is ,guidance, ; assumptions no data provided :Based on

rule, how many entities may be affected by this The FDA aclcnowiedges that they do not Icnow performs by this rule . Since FDA only and that they do not keep a database of firms affected (such as "for cause" or during treatment limited inspections of phase 3 material manufacturers "for position? What arc; the results cri the agency's [NDs), what data do FDA have to support their reported during phase l? adverse drug event,; ' cause" in~ipccfions, treatment-IND inspections, or information to be T] taking rl7is proposal'? What do the data show? Does the agency have enough What data are FDA using to support their position? Good A7aria .rf~ctzrg-irzg Practice fo-r Active Proponents of this approach state that ICH Q711, guidance, has been successfully used Pharrnac~=utical Ingredients, an internationally harmonized




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Docket 2005N-0285 Page 5 of 7 pages, and is used to without the need for a regulation . ICH Q7A also has 57 detailed delivered to patients . '1 he draft manufacture material that will be further processed before being for drugs and phase 1 guicaance is currently 17 pages long and provides recontmendalian,s patient injury or death if biologics that may be delivered by injection, or inhalation, resulting .n least inspccts AN the material is improperly prepared or contaminated . FDA also at 1 unless for cause rnanufacturers, although again, the agency does not routinely inspect in phase (or in certain specified circurnstances, such as for "Treatment INDs) . Too risky for estimated benefits o?hea' "i'ed-Lsced" The proposed savings of $1,440 per IND in documentation, training, and industry two-day requirements (or the equivalent of paying tuition to send one person so an adclitiOn, the potential seminar) is not justified by the additional risk to patients in phase 1 . 7n and Ia~burat.ories which costs (estimated a! an additional $g 14 per INi) for chemical manufacturers how much it will cost to have never {nade these materials before) is a gross underestimation of guidance doer ~~sat yet discuss manufacturc sterile or aseptic product for the first time . The draft cabinets, isolators required equipment or facilities far these i)rpes of products, such as biosafety the human colony to and other equipment . Nor does it limit niovernent from an animal this (which is required in the European Union CGMPs ; not iitnitiYig manufacturing environment . "humans .) movement has caused contamination in facilities manuf:ictuYing material for year, using the As far as how many people may be affected by the proposed rule each trial, would mean patients pcr agency's estimate of 255 LNDs per year, and estimating tip to 80 number ;400 -patiQnts and volunteers Nvould be affected . This is a substaritlal that approximately 20 of people who would be exposed to more risk . Confusing portions of the regulation When the 2.geney takes an existing regulation, and attempts to negate (but not a11), the agency using guidance documents, 01- issuing a rule that affects part of the rule one email message from a causes a great deli of confusion in industry . I have already received to use non-CifV1P regulatory affairs executive who stated that from nou- can, when they plan their chemistry, manufacturing material in a phase 1 trial, they will provide more data for FDA in and controls (C1VIC) sectan ofthe dND .

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S eri es

A Brief History of the GN1Ps

The Power of Storytelling

vr (fever ~Ise u ;~i~e dri,-~r Hit tfle point 011c,-' "I f you hc~vc lm irnpor tarit poirlt to n1alee, dor~'t tr~ robe subt(r Wins to I I cluir"Jij I I a o'cole rt CIO us V) h Thoi came back and hit it aguin. Tllier2 hit it a ih I r4 tbnc with
provide are false or riiislc~dingas weii as to the failure to required information ill labeling (2) . Over tic years, th e Wo rd "adulterated" has )een expanded to include prudacts fnunufactureEi withoui 1oJ[owin,. GMPs . Before the publication of The Jur7gle~, II nrvuy ti' iie,y tiand others had been pressing, forn ~uch a law for 25 years . The Act created one of the first government regutatory agencies, 11ow kziowri as ~'A, and it also allowed Cut the seizure of illegal foods, and drugs (3) . Wiley iater became

our ittdusuy Should know the story of how the good manufacturing pract ;ces (GMPs) have corne to be . To obtain and inaintain G?v1P compliance, every manager and supc:rvisur should provide FreGuer.t, meaningful GMP reminders, train arid dcvelap all training em p loyees , and i`ullN/ participate in fot~nial, ongoing nianagenLent must state publicly and . programs Senior '

in F living, you can endure any how ." Everyone

riedich Nietzcheorice siild,"IT you lLnow the whv for

make it clear through their actions that following GMf's is
the only way their company does business .

enforce chief chemist cfthe bureau given authority to

of that act (the Iiuteau of c~hemistry, U .S . Department FDA (4) . AgricuVLUre), a 1'orerunner of

THE 1900s

Early in this cuuntn~'s history, travelin~ medicine show,-; , sold bottles of ointment or "miracle elixir " irom the backs

before 71« Jungle, whe,n at Ieasc ;Z children died fruii i a i :iphthei ia ailiicexin thii was contaminated ~vith live. inspections of 3nan~~f~i~~ :-~lrers and seliers of biological products and testing c+t such products for purity wid

Biologic products acre first regulated a few yeact;

olsvagons . Such u,r,dication was said w be oond for aches and pains : for catanh, rheuruatisnt, and gout - of course

tetariu= bacilli (3). Conj , r~~ss responded to that tra,Tedy by required passing the Biologics ~_onircsl Act of 1902, which strength (5)~

it completely cured cancer - and it worked on horses, too . Luckily, those days are long gone . 1n 1905, a boo}: called The Jvrrgle helped catalyzc public opmion for change . "Muclcraker"social reformer Upton Sinclair ~,vrotc about the Chicago ineat pack i n~j in d us t rv - tile uasanitar y conditions in which animals were slaughtered and processed and the practice of selling ruU.en or diseased meat to the public- 'He also reported that ground nieat sonietimes contained remains of' poisoned rats arid even unfortunate workers who iell into the tnachii7eiy . Sinclair's main incecest was in bringing

THE 19305 medicai A 1933 FDA exhibit oi dangerous food, medicines, illustrated the shortconung, of ' t},e devices, and c;osrneL ;c.5 a 1906 law . "America's Chamber of Horrors, " nicluCfed urc;r (also used as a contraceptive) that could womb su pp puncture the utertis if insertLd inConcctiy; a Weight-11D66

attention to the miserable working conditions and the p1ight
pt_Che Impoverished factory workers, inany of whorn were ,
IIt11111g,7~aI1t5 (1 ) .

This znricle wa,-wrimn hy Barbara Inuy,eI, prv~~tdcne of t,mz,et ;`1 h`  . t"o1°ri" 1a`"LT .`°`Ii``R`t<.,ndustctty .

Food and Drug Act in 1906, arid for the first time it becan~e or meat . Also , illegal to sell contaminated (adulleruied) fooci b for the first time, labelin v had t o be truthful -- n0 (On TeC
. . `.L;OLI~i~ 811y017C promise On ~l ~i1b01

i ure itnpact oil the American public . Congress passed the

major The Pure Food and Drug Act. 7°he Jungle had a , ~

in . Kesourcca Lt_C, t c~,a~sulii,~g nnJ publishing firtn,pLfdalizi«g .rmaccuncd, :Lncc~, quality a~sti.:~nce, and n~ :~inui~+ for thr rhx cE~mpL
.id~ns; I~.ciLat :iisthccdtr~~r it,-chief ;,Icf,<" '~unelRcr :rr,a~ticwslc~eerrpro

. Shc~ ~Edvite and guid, :nce for i11 insgcrs ir+ MA-tegulatc<? industrieswhere
"v1agu,itec s also or. tha~ Fdiuoriul A,I~~i,ory R,;ird of liioP6uim

die h.t5 ~vavcd a., th,~ir (IMP iind lur;utacory compl,ai«< c,'lu°uqlsc
2nd DLRTt« )Il~ t7 ;! 1'F. ~

adults ofte.n coritained alcohol, opium, o~ moi~t~ine,

Syrup to calm "colicky" babies and "tonics" for

"i}"le moon atand tt7c stars . 

I, rnwr i .nr :: ; l cn , c ~ ~s ;, since !Y96 }ler articles i) ivc also ;yppe ;ered in 1 .~nel aaea~coi~~rli,:~~ P~, ;n,ncr .e reai I~:c inL~caCi : ~)Pr, !~i~~P,,jrc,sincrro,u!i~,nr,i, u( !ii Pli'a nr (}rSfiin :~l) tLu ; uiticlr ap~7 :~rcct i :i ehr .At~qusc 2000 issue !lie Hu,i".urir 6ui:ic Mana:.ine, and in the i~cr~~cinbe, 2002 su~~plement,


which aCldtcteci mariy people who used T~fatn . SO the

1906 Act also required selected dangerous in~rzdi~~lts to be labeled on all drugs. Inaccurate or false labeling was

rnGr",1%lhs oly. Itc~~nne }«~~n~ssian wn ; gr:~nted

by ch~ publtyh~-r, .~~dvan,t:.r C~,liun~~rucqti~n~, r"gnz, Oregon .

called misbrandinL~, and that became Illegal . "Misbranded" applies to statements, designs, or pictures ill (abetitl~, that
MCguurccs L LC ;

1y aw . . .

: &. cli ) i-2( .1 , ntmV

y pr~.~ tn;i tc lru.7Sri:1sS'tctl`. 7, makneUC 6r e rci7onic nr_aI7S slncl epro(tIwho:l, p1aLUCtspytng,slalcnecor




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drug that caused death ; a hair remover .hat caused baldness, even if not used on the head ; lotions and creams that could

cause me-rcury Poisoning : hair dyes that could cause lead pui ;oninp, and an eyefasli dye that blinded wornc;n (3) . Eleanor Roosevelt cook that exhibit to the White House, asking Americans to campaign for stronger consumer protections . .4 traLedy was ~{-aiting around the corner thaY would make her case for her . Sulfa drugs were introduced in 1935 . Many manufacturers began making the new Anti-infectives . One company used d_iethytetle, glycol, a poisonous solvent and chemical analog of anti-freeze, in ari oral "elixir of ." sulfanilamide Before the problem was discovered, 107 people died, many of them children (3) . In response, Congress passed the Federal t o .xl, Drug Cosmetic (PD&C) Act of 1938 . For the. fi rst t i me and companies were required to prove that tlie.irproducts were safe before marketing thLnm (3) . Still the major act coverim; oversight our subject n)atter On ihe books, it extended FDA -

teratogenic : it caused serious deformities in developing f:etLsses . e'hiiclren whose mothers took thalidomide in the

severely deformed anns and first trimester were horn with legs . Att estimated t0,000 cases of infant deformities in EUrOpe Were linked to thalidomide use (3) . I'hv product was not allowed on the market in the United States . The drug reviewer responsible for the tlialidosnidr application in i~~,, United States was Frances Kelsey, tn 1962 l'resident Kennedy awarded lier the President's Distinguished Federal Civilian Service Award,

the highest honor a oovenmrnent employee may earn as a

explicitly au?hori«d to Cosmetics and therapeutic devices, prosecutions (6) .

civilian (3) Thalidotnide, calvani, ed public oDutirnt lNV o IegssLator,, ri.cfaciver and Harris, pushed inore strin~ent lcy ;islaeion through Congress that required comuzuues to Yrst not only to etlsuce that products wefe safe . 'Out that they were efficacious fur their ii :tencied uscs, Regulating clinical n -ials, thc a ;nendttis.iits reqtcired ciru,t;s tu be tested in animals belfor;,' people . The) rnade investigators responsib!e

factory inspections, required standards for foods, arid added injunctions to previous penalties of seizures and a sminal

foi supervising dru~~s under study . Manufacturers Were

expected to inform partimp<tstis ii ~j drug, was being used for irSVCStigational purposes and to obtain their consent be fore t es t i n g it on therin . Drugs had to be shown it) work before going t3n the iriarket . Manufacturers were required to

THE 1940s AND 19505

report unexpected fiari2t (adverse events) . FDA was givcn

jured In 1941 nearly 300 ~people were killed or injured by one , ole tablets, a sulfa drub tainted with company's sultiathiaz the sedative, phenobarbit<il . That incident caused FDA to revise rn~unutacturinG and quality control requireirrents, leading to what would later be called GNIF's (ti) . The Public Health Services (YH5) Act passed in 1944 covc;r<tl n l,roau spectrum of concerns including regulation of biological

authority to regula~e advertising of prescription drugs (3) . And in 1963 , th :, GESt, Civ7Ps tar tmishcd pharmaceuticals Nvcre :nacfe filial (14) . THE 19705 The 1 970s were a watershG d ior product regulation . In 1979, good manufaciurir±~ practices fer dru~s (21 CFft

products and control of communicable diseases (?j.

Also dnrin- the ~1"Nll era, batch certification by FDA became a requirement for Certain drugs . It requirec{ companies to submit samples from each lot to FDA for testing . and the agency Would give permission for t h e i r . release That practice, t~egun in 1941 for insulin and 1945 for penicillin, was later expanded lo include all antibiotics . BY 1983, the requirement for batch certification of drugs was dropped (7) . In 1955, Jonas Sail< discovered a way to vaccinate against polio (8)- Many manufacturers began making It is polio vaccine . One conipany failed to inactivate the vieUs completely in a single lot . About 60 individuals inoculated developed polio, and another 89 ofthcir family mvinbe2s

Parts zlU and 211 ) were e.reatly expanded anti inedical

devic~2s (2l L;FR p2i)) arid Gkti1F's were, for the first time, made fina! . Tlley were intended to help ensure the safety and efficacy of a11 products : Thc regulatioDs . . . curitam the minimum current good m :mtitacturma practice; ',or methods to be used in, and the facilities or controls cu be used for, the manufacture, processing, packing, or holding of a drug, to assure that such drug meets the requii2m+:°tits of tfie act as to safety, and has the identity arid strength and meets dhe yuiAlity and purity chaiacceeistics that it purports or ie. represented to possess . (11}

grandparents) niothers, fathers, brotPiers, sisters, and contracted polio iroin them (9) . We vaccinate out children

controls govern the methods used in and the facilities and

<=ui'requirenlents for devices ~,+,~rc: intended "to

to p rcvei t thein from -ettirtg a disease and also as a public t . ~ 11ea1Th measure to protect sociery froir, tlic~ spread of disease,

THE 1960s

`r~ialtaoa, rd~ was marketed oa,rd~

in Eu r ope as a slee p ing pih and gul ator Y 7 toi treat morning sickness . When regulatory agencies gave ~~eriilission to sell the drug, for that indication, t1~ey had no

used for the desigqi, manu(acture, pacf :at~ing, labeling, storage, installation, arid servicing of ail finished .medica l devices intended ior human use,' as deseribcd in the most recent revision (12)Good Labcratury i'ractec-es (6 l _ .Ps) were made final in : 1979 They define "laboratory pra~:?ices ior conducting nonclinicai good i~aboratary studies rh~tc support or are intended to ~1~P3~ort a~plicatsc~ns lot research ur ~naiketing

knoixleclge of its serious side effects. It turned out, to be

pennits for products iep lated by the Food and Drug

transmissfon 6y magncticnr electronic me-,ins stri,:tly prohfbilcd by law 772001- 2004, Immci T'~c .ocr :,es L1 .C', Repmdueuon . Eihatncopyi7 .510 :qe or










P .11

t  . . Biologics, and Devices " ; important Definitions Drugs, , _ - --The following definitions describing the major differences between drugs, bioiogicals, and devices, are abstracted from Enforced by the the Requirements o f L a ws and Regulations and Drug Administration (2) . U .S- Food

if improperly nreparec ~Y their nature atEntially dangerous wishing ;o ship or t es te d . Under the PHS Act , manufacturers or biological products in interstate commerce or for import appropriate U .S . license(s) . P re vious obtain the
Biologics recently been sti'eamlineci into the single (BLA; . Application

export. must an Establishment and a liCa .^sing requirernerits caI'ei1 for both

i, Drugs Act defines drugs a5 ' The Food , Drug & Cosmetic (FD &C) cure, mitigation, r "articles intended for use in the diagnosis, animals" . or prevention of disease in mar Or other treatment, intended to affect tire structure and "aiticles (other than food) of the body of man or other animals . " It is

be flied . That has Product License Applicatian (ELA, and PLA) to Licensiny

or any function something is a ~ the intended use that determines whether subject to the drug drug . Thus, foods and cosmetics may be them requirements of the law if therapeutic claims are made for

Devices health products from Medical devices include several 4housand

depressors, and simple items such as thermometers, tongue dialysis s t o iUDs , heart pacemakers, and kianey heating pad

fall FDA before they go tu market, Drug applications typically New - into three catego ries : a New Drug Application (NDA), a Drug Animal Drug Application (NADA), or an Abbreviated New Application l,ANDA ; for generic products,

misbranding cf any dnig The FD&C Ac, prohibits adulteration or approved by requires that `new drugs" be reviewed and and

device is defined as "auy machines . Under the FL78G Act, a principal inte~ded care pro duct that does not achieve its health action in or on the body or by being purposes by chemical metabolized_ " P roci uo t s t!-at work by cheimcai or metabolic,

r Biofogieals as ~ The Public Health Services Act defines a biological product

includes action are regulated as drugs . The !ar!rt devices" also accessories 3f med i ca l d e vices , Components, Parts, o!diagnostic aids such as reagents, antibiotic sensitivity disks diagnosis of diseas~s and test kits for 1n vitro (outside the body) and other conditions . Three classes of medical device exist
manufacturers ° Class i, General Controls (reaisfration of requirements, compliance with record keeping and !abei+ng

antitoxin, vaccine, blood, E 'any virus, therapeutic serum, toxin, product, or analogous ~ blood component or derivative, allergenic cure of applicable to the prevention, treatment, or product . , Biologics +rtcVude such vitally ~ diseases or injuries o' man_ . ." diphtheria important products as polio and measles vaccines, and s!<in test substances as well as i and tetanus toxoids, transfusions Biological whole blood and blood components for subject to all the adulteration, misbranding, _ products are of the FDBG Act . Because mos t

and registrations provisions they are biological products are derived from living organisms, Administration, including food and color additives  aiiunal food aciditives, human and animal drugs, nicdical devic~s for hUnnan use, biological prc~dL4cts, and electronic products . Coniplianice with this part tl~c ;s intended to assure [he quality and inte~;rit~~ of

oerforrnance Class 11, Spee ;ial Con:ro,s (including registries) standard s, post marker surveillance , and patient Approval (;Implanted and life° Glass II{, Pre market Devices 'subs'.antially support i ng or life-sustainiric devices), others ma/ be filed using a 510(K) equivalent" to athers , and aI : Class III devices, require filing app li ca ti on ; a ll market approval application (PMA), a pre


safety data filed . (l2)

THE 1980s AND 1990s Act t,~~~i~1~ [n 1980 : Con~tress paascu t(se Isifant Formula .7lority to ere2rl~~ a>>d enforce standards and s1'ieeify FDA au~ formulas . mitriti<xnai reuuirert~ents for camiaiercial infant mvrc than 100 intau :s were "~11at followeri 1979 rLports ihat ill two soy-h<iscd ma d e ser ious ;v ill by a lack of chloride

A few yeaes earlier, tile Medical i~evicc Amendments to {signed as law in 197G) strengthened FDA's aull~urity

cc, f~nnulati (15 ). ~`lan~fa °turer~ arc now~ requited to anal~
s ;~fety each batch of fc~rntula l"or nutrient tcvcls and make stauil-ty 2cst5, code eacli container with checks . cc~nduct

oversee lnedieai devices . The law was precipitated b~~

associated with a high 'the market in 1975 b"Buse it was

incidents involvin, a ct~ncracepuve tntraut~f'iua device (IUD) that about two million women were using . Many off users \Arere seriously injured (3) . The product was taken incidence of pelvic infections, infertility, and sorn~ deaths

~ ~o~ number, lteep d~t'~i ;ed records of production and

Part analysis, and so on (16) . The food C;MPs (21 CFR for iniant formulas, I 10j, which include specie.! provisions we-re finalized in the 1481)~ . her an extrati:at S1112 felt'if:e_ she h~+d a cold . They gave

told her parents In 1982, t2_y,oar-old Macv Kellernian

( i,; j .

The Medical Device Ai~~endmenis rc.q~tired manufacturers of most medical devices (particularly moderate- or hi-risk devices) to provide FDA with safety and effectiveness data bcforc rnarketrng klicin .

screogtli'l~yleriol acet<nnnincphc :n capsule, and witl~.ii~ a few

Furthermore, the law provided for a syscenl of pre- ;ind

iRicidcnt, hours shc: ditd . Six other people died in tln, iragic (two brothers and including three membcrs froin one family birfh to one of their wives) jud a woman who had just giyeii her fourth child (17) . investigation revealed . -) i wil'tion bottle nf "C'ylenol_ l~heir (bund oi that a criruinal tampevtn (who has ncver been capsule : %+itl~ prosecuted) had opened u~~ and laced soine million bot!:les of cyanide . The campanv destroyed all 31 ovcr-the-counter medicine in [tic country the lar;ect-setlin ;
y aH'-

to ensure po ;ti»arket oversight including FDA inspections GMPs, keep appropriate rccords o« that couipanies follow the clesign and mt+nufacLure of their products, aucl rilairttaitt systems for Lt,andling complaints (14)

Johnson k, Johnson announced a

nationwide recall of

l _ 24, in,ne! r,

777 ~ ,C ; r~3ro ucti~~n.

. ecUUnii mepns stnclty pro u bi ;e otocu~~y,Rg, stnragC or Yfansnus5tor. iy magneUr or e





01 :313p

I mme l





p .12

A GMP Timeline
1902 Biologics Control Act y Trag ed y At least 12 children die of tetanus contiaeted from " Contaminated diphtheria vaccine . Result Requires inspections
facilities and products and testing of biologics ma~ufacturers' Pure Food and Drug Act agencies (now °. Creates one of the first government regulatory FDA) ; the culmination of 25 years of lobbying, this '~ known as or act m akes it illeg al to sell "adulterated" or "misbranded" food

15f>3 GP~A!'s for Drugs (2fi FR 6395) . Good manufacturing practices far manufacturing . processing packing, or holding finished pharrnaceubcals were fir s ',
published Final Rule 1975 9975 GCMPs for Blood and Blood Components good manufacturing practices for Establishes er,inlmum current compatibility b l oo d es tablishments in the collecting , processing, and distributing of blood and blood components ; . testing, storing, 1976 Medical Device Amendments injures many patients . Tragedy the Dalkon 5bie[d IUD seriously Res p onse : New law strengthens FDA authori'.y to oversee medical devices. 210-2'P1 and 197B CGMPs for Drugs and Devices (21 CFR ffZD) for medical A -najor rewrite for the drug GNAPs and GMPs mimmum devices were published . These regulations establish manufacturing, current good manufacturing practices For


'' Tragedy : Sulfanilamide made with poisonous solvent causes safety 10? deaths . Result: Requires manufacturers to prove the

1938 Federal Food, Drug and Cosmetic (FD&C) Act

` ot products before marketing

1941 Two Unrelated Events I nsu li n Amendment requires FDA to test and certify purity and fran; potency of insulin- Tragedy: nearly 300 deaths and injuries of suiPathiazole, tablets tainted with pheno b arbita l . : distribution controls , Result FDA revises manufacturing and quality

` drastically, the beginning of what will later be called GMPs

processing, packing, or holding drug products and medical oevices .

1944 Public Health Services Act communicable Re g ulates biological products and control of diseases

1979 GLPs (21 CFR 58) Finafl Rule conducting ronclinical Establishes good laboratory practices for support applications for rese arch or laboratory studies that

1962 Kefauver-Harris Drug Amendments

Trayedy Thalidomide causes birth detects in thousands of efficacy of European babies . Result h~lanufacYUrers must prove

marketing permits for :iuma :i and animal drugs, medical devices !or iiuman use, and bioloyiuai products

prod,icts before marketing them and ensure stricter control over drug testirg FDA issued tamper-resistant packaging regulations for all over-the-counter human drug products arid incorporate.d them into the G'MF's- Coni.~ress passed the Federal Anticrime to tamper with Taniper .iug A c t i n 1983 , makin g it a consumer products (IS) . The ace(auninaphen packaged tragedy had a major impacl on the industry 'Vuc only do we need to provide onL; ;oui- GMP training to all at oW emP, making sure thcy are adequately and Yhorouglrly l~~y`ces , trained and supervised, but now we worry about how murderers could usc our products to harm the public . Guidance d ocuments . In the 1990s , PDA be-an picbdishing a series of g;uidance documents that have 'bad a major effect on cm interpretation ofcurrent good manufacturing practice_ One such documenr was tile "Guide io Inspection ofCoMputerized SVsteIr3s in 'Drug Processing' published in 1983, which gave early ex Pect~iiiuns for tile funccLonin~ of computer systetns and perhaps signaled the bt~ginnin?; nf' computer validation (19) ~ Of course , the very famous "Guideline on General ' Principles of Process Validation" ill 1987 outlined currert

1980 infant Formula Act .nously ill linked to lack of Tra g ecl y 1OD children reported s:

thinking or expectations nfprncess validation for drugs anci devices (20) Sucli docutneuts, including the Points in reflect current agency thinking and expectations .
C '2(Y)1-207 . mme

chloride in soy-based formulas . Result : Congress gives FDA . authority to set and enforce nitritional and quality standards The h°rininology recently changed eo reflect the faut that some active ingredients are ma d e us ing biolo-ical rather than chenticai processes The. tert}z "new che-nicai entity" Molecular (NCE) is also no", oflen relerrecl lo as a "ilew entity'"( _Nr\4F,) for the snmu rea~~nn 'l he naturally cu,cucxi :i~ amiiio acid_ l,-tr_yptophan, mid used :o be widely Promoted Js a di tary supplemellt ('or insoinnia, depression, obesity, and was used as an zuci an '_or children with attention deficit disorder . Ill t9b9, nic of eosino p hilia-E,iyalgia syndrnirie (EMS) was ep id ei linked to dietary suppleansncs containing ( .-tryptophtuZ . The Centers fas Diseas° CuntroL (C :DG) identified more deaths, th at than 1,500 cases of EMS, including at least 38 in cesu run hy both wc~~e assncieteci svith L-trypiophan FDA and the Mayu Clinic, ifflpLtritir;s were confirmed in some L,-cryptc}ph~in products on tlie marl<el . One unpurity Although its sigiiificac~ce rcm~i i i~~ was called Peak unlaiown , Peak X was found in one case of EMS associated with L-fryptophan in 1y91 . Unfortunately, the exact cause of the 1939 epidcnnic and of the EMS associated with 5H'1`P continue to rL+ unclcar. in part because 5}iTF' is

synthesized from L-tryptupitan ;n the body . Research has sonle other racxoi°s (21) .

Caa .~ider, provide guidance only on prilf~i~~lcs and practices that are not legal reclu reinents_ However, typically they L-tryptophan . Active pharmaceutical ingredients (APIs') u ; ;cd to be called bulk pharmaceutical chemicals (SPCsj .

not _yet conclusivs;ly resolved wheiher I~MS was caused by by ; L-tryptop f 3itn, by 5F3"l C bv one ce more i?npurities, or Some 70-80 °'o (if i,nnrc of tLlc APIs used to
~y e4v.

ntag~~~t .' o: e c:r_troqie: ineans s~nct y rro i ttec '~suurces LT-C, heprt~ uL.ion, !7 otucbpYut~, storagc or l :ailsmission >y





01 :37p

I mme 1




i 81 a

p. 13

A GMP Timeline (continued)
s 1882 Tamper-Resistant Packaging Regulations Issued for ' OTC Products Tragedy . Acetaminophen-capsule poisoning 'r.y cyanide causes
7 deaths Result : Rev.sion of Gf41Ps to require tamper-resistant .

1997 CGNIPs for Medical Devices (Quality System Regulation) FBnat Rule Major revision to current good manufacturing practices !or
!es( of rule June 1997}-

packaging .

controls in medical aevices becnm~_-s effective, with desigr,

R&D the major change (design controls effective June 1990, 1597 Electronic Records Final Rule (21 CFR 11) Requires controls that cnsure security and integrity of all electronic date '8998 Draft Guidances
"Manufacturing, Pro=ssing, or Hold ;ng Active Pharmaceutical

9983 Two Unrelated Regulatory Events The "Guide to the Inspection of Computerized Systems in Drug ' Processing" initiates tighter controls on computers and computer validation Federal Anti-Tampering Act makes it a federal crme to
tamper with packaged consumer products 1987 Guideline on General Principles of Process Validation ~. are outlined

Agency expectations regarding the need for process validation 1990 Safe Medical Devices Act

Ingredients" and "investiyating Out-of-Specification (G0 :7)
Test Results for Pharmaceutical Production .

' Tragedy . Shiley heart valves and other incidents, Result FDA

1999 G2S1T Inspection Handbook tracking

given authority to adc preproduction design controls and gains ability to order device recalls

New FDA technique for inspecting device companies focuses

of critical or impfantable devices to CGMPs; requires notification of serious device problems by user facilities to FDA. The agency

on four major subsystems management controls, design

control5, prAuctinn and process controls, and corrective arid preventive action_

a 1992 Generic Drug Enforcement Act

r Precipitated by illegal acts involving abbreviated new drug

2009 ICk-! Q7A API Guidance Manufcturing Practice Guidance for-Active ICH's "Good States, Europe, and Japan, and becomes the de facto
manufacturincz standard forAPls .

applications . Result . Creates debarment penalty.
1996 Two Unrelated Events

Pharmaceutical Ingredients (APIs)" is adopted by the United

Proposed revision to U .S . CGh?Ps for Drugs arrd Biologics ' (21 CFR 210-211) adds detail for val[daton, blend uniformity, '; prevention of cross-contamination, and handling out-o£, specification results . : "iCH Guidance for Industry : E6, Good Clinical Practice Consolidated Guidarce" becomes the de facto standard for conducting human clinical trials . inanufacCure products for the United States coaue frotn sources outside thC country, where manufacturing stardards

2U02 Drug Manufacturing Inspections Compliance Manual

New FDA technique for routine drug manufacturing inspections focuses on ,wa or more systems, with mandatory coverage of the quality system . Other systems are : facilities and equiarnen±, materials, production, packaging and labeling,
and laboratory controls_

. ,

niay not be as slrin;;ent . For this reason, both the European the International Conference on Harmonization (SCE-9 ;, a consortium of individuals from Europe, North Ami:rica, (22) This docunlenS has been published and accepted :ii

of supervised release (`0r Conspirin" to defraud FDA by selling illegal heart call7eters . The company itselfpi+ .d

Union and the United States recently published draft . guidance documents for the n1unuFaclure of APIs Re;cently,

guilty to similar charLes in 1993 and agreed co pay w>61

million for hcalth fraud_ (The U _S . govcrnoient estir:lated that total sates of illegai catheters had amounted to 577

and JUpaHI, published "ICH Q7A on Good N9anufactut,ing Practice Guidance ';or Active Pharmaceutical Ingredients ."

million .) It had been thic. first company to obtain approval ?o market a l;alloUiti angioplast ; c-athetcr in this country. Heart cathetc,rs Are used in angioplasty to clear

and Yi-onz 19$0 to 19135 it w6zs the only distributor oi heart catheters in Kfie United States cto~%ed artei ies . In 1987, the company he,~asi to redesign those already approved by FD/! and sold the ne~v ve;rsion . withuui obCainis-ig approval The redesigned catheters often rnalfiunctiodlod, b :~t the comp :iny iaileci to report chose problEnls to FDA . The company learned during illegal humaa- cli :7ira( trials that the. caflaefer tips broke offin the acteries of two percent of patients, but it kept that information from FDA . The agency approved the ree9eaigntd device in January 1989 . unaware of' ttie tip breakage problem . Within three months, the company received 33 iepo~ts of lip breakage, so it redesigned the catheter again, again Without informing FDA, mid it)
y aw ...

Europc, 7apan, and the United Stoles, aild it is considered the de faclo standard for manufacturing active pltannaceutical ingredients . Illegal catheters . Most of the crises in this i-eprr;seotative history were mistakes and!o1 mysteries, meaning that the individuals or coniaanies involved had no imcntiore o .- desire ' ot haruiing anyouc+ The acctamiclophJn poisoning ca~,e wos clearly criinina : . Let's look at a different kind of criitjirial case . In 1996, three fortrier executivcs of a company that made balloon heart . catheters in the Uuited States each were sentenced to 1$ trionths in prison followed by two yeurs
.~a ) 1-_ ti~,, mme e.3ources L ,c~

eproauctinn, p otocopymg, star<~gc <cr transmusiun y magnetic or c catron~c iu< ens striet y proubite










iViarch began distributing the redesigned catheters . Upon learning of the malfunctions, FDA informed the company chat it` calhelers wcrc illegal and subject June to seizure . In 1989, the company recalled previous versions or models . W11e3i FDA told the cornpariv that its ,acest mudel viulxted Liie law as wCll, it rccalled that model, modified it, renamed it, and continued to distribute it . )Nhen FDA told the company i! needed a preinarkei approval application for the mode' on the inarhcL the c ;c7mpariy discontinued selling it and reintroduced the ori~inal model, which had major problems that had necessitated the redesign in the first Flac-e . Finally, FDA seized all the catheters and witnessed their destruction (23) . !'hose heart catheters were associated with at least one death and with emergency heart surger ., for at least 20 patients (24) . A grand jury handed down a 39-count indictment against the three founer executives and others in 1995 . in sentencing those former executives, die judge emphasized that "-corporate entities do not commie crinies : people do," and that "executives running other companies who might engage in such conduct should bear in mind the prison terms imposed in lhis case" (23) . Defective heart valves . The Bjork-Shilcy {_ onvzxot.ancave mechanical hear[ valve was manufactured and sold between 1979 and 1986, About 86,000 (if those valves are believed to have bee(t 'Implanted in patients worldwide, including 30,000 in the United States . In a small numbey of cases, the valves CxpCi-ience a "strut fracture" failure chat necessitates immediate cardiac surgery, As of November 1998, about 620 fractures had hee :i tepor[ed to Shilcy worldwide_ In roughly two-thirds of' those cases, a patient died following the fracture, The company, which no lancer makes heart valves, has entered into a settlement ~~reei~~ent with the government to p .iy lnr the costs of valve strut failures and replacement SLIVgeriCS, including hospital care, medical supplies, and tile usual fees of physicians . surgeons, and other health care prt7fessiomals . Furthermore, Shiley ano. its parent company will pay ;he costs incurred by each patient from adinission throt;gh d'rscharoe, including emergency services . They will also pay for ally complications dzrectly resulting frorn tile treatment `over a reasonable period thereafter (25), C?rviousfv, that is a very serious case . When we discuss the case in GMI' classes, I often ask, "How many defects do you think that you can have in a heart valve)" y (The answcr, of coL)rsC, is noraer .) Impiantable devices are especially dangerous when something goes 1.vrong . A difficult decision musl hr reached- whetiter it is better for the patient to cow iuue with the device or vvhetltier the risks neceSsicate removal . Patients must be ~well enough

to survive explRnta(iorr, opening them up (literally and figuratively) to infection, possible additional comp)icatsvrbs, another recovery period, and so on, Medical device safety . In response to the Shiley heart valve and other cases, Congress passed the Safe Ibtedical Devices Act of 1990, for the first ti .ine giving FDA authority to go into R&D regular ;y . The act al-ItI10FIzed addition of
mma csuurce.; :L , .

preproduction design cL)ntro .s to the CC;MP regulations, when FDA analyzed dr vice recalls over a six-year period, it found that about 44 `10 of qu :ility problems leading to recalls were attributed to errors or deficiencies designed into those devices . When the at~ency analyzed software-s-elated recalls, it found thaC oycr 90 `F~ nf a11 sof'tware-rclated device, failures were design :elated, particularly the failure lo validate software before. ) outine production (12) . )n the 1990 Ac(, Congcc+s authorized FDA to make its medical device regulations ricre thorou-Ii and consistent with otliei world standards, ,uch is ISO 0000 . The act rcyuirecJ nursing tiorries, hospitals, a :id uilier facilili .--s usin ;~ medical devices to repoirt to FDA all incidents in wiiich a medical device; probably "wsed or contributed lo a death or serious Hijury . h1anufaLrt : :-ess are rc:quired to conduct postmarkeC surveillance on permanently implanted device ;, whose failt;re tnight cause s~2rious harm or dea[h and to e;stabli,h ttlethods for tracirlg and locat-ing patients having those devices . The Act also iwchorized ! DA to order device product recalls (7) . During the 1990s, the medical device regulations wet1t through a ntajor revision, with one major chanl-e being in design control, or the need to formally review and document product desigei at predetermined stages . The final rule became effective in June 199? ; the design control portion of the regulations became effective a yCar later in 3urie i99$_ In the late 1990s, FIaA turned to a more directed ii7spectianal approach to mUdicai devices called the Quality System Lnspection Technique !QSl f) . I'hat approach calls for focusing on several key systeins, including inanagement ;, ciintroi .S, design control proc7uctinn and process controls . and corrective auid pre-venUve actions (1Z6) . Also in the 1990s, proposed revisions to the GMYs for dnigs nnd biologics were issiied . Alt-hough those revisions were not vet final when this a.rticlc went to press, they do :lectr0nic Records represLnt FD/0's cuirent thinlting . The l Final Rule (? 1 CFR Pas-C t i ), requires control, that ensure the secui ity and accuracy of all ciata and computer systeois used . Part I ( will have sweeping ralnliications on the industry for _years to corTte, ;,.rid is perhaps the biggest change in o~~ir industry suice CXiMPs were first published . International harmony. Besides producing the AN guide, ICFi hits been working on a ni1r1lber of c~uaiity, satiety, and e9Tectiveness documents . As these doc.Uineslts are adopted or madle tmal by 1CH, they ho-come "iizdustty practice" in all participating countries The 1996 ICI-i Eb guidance on good clinical practices has t:lccom . the de facto standard on Perforni :ng lrutnan cliniCal trials (27)_ A number of other FDA guidance documents, including a draft guidance on handling out-of=spe :;i ;ic:awon results, recently became available (ZS) . Even though guidelines and draft guidanees are not legally binding, they represent current thinking on their subject matte, and tend 'to 1}e. ac?opted rapidly and/or viewed as "current industry practice " Generic drug scandal . Congress passed the Generic Drug Enfc,ce ¬ mewE Act f:;t' 1992 to isnpose cfebannent and other penalties for illegal acts involving abbreviated drur

epra uctzun . p77oc.opying, stc+rage o, transmiss.on by mugnetic arr elec(so!uc inetins su ¢ctly prohur ;ted by law



01 :39p







applications (6) . The 1992 Act resulted from a bribery and fraud case in Which executives Of one or more generic companies bribed FDA reviewers (one for as little as . ;) $1,000 in gift. certificates Rather than testing its own version of a drug, the company tested the brand ~ieneric name version instead and Sent those resitlts with a generic

Brave New World? I u a recent cunseizt decree, one of tile world's largest d iage7ostic,~ companies agreed to stop manc3i'actu~-irYg 3r1~ 3 distributing many of its i.^. vitro diaanoseic teAS until it corrects manufacturing problervs The company inm~ecii~ icely paid ~3 $I00 million civil

applic~ltiuti . Although typically executives (presidents, vice presidents, chairmen, and so oil) are indicted in fraud or other cases, the lowest-ranking employees successfully prosecuted in the generics companies falsified Certificates of Analysis ; destroyed samples, directed others to chat3ge manufacturing procedures, and falsified records to hide or conceal ma nufactu~-in~ chai~gcs (29,30) . Be Sure to train ail employees in yoUnr coiiipany to record data thoroughly and ~~ ~ accurately . lcacl} tli~,n : t 1 ta t ma k ind a fa'se evltrv fal5ify~ing. signing for someone else ; making up dates or backdating,

data, and signing for something they did not do is fraud,
arid (he consequcnces call be severe .

Individuals found guilty in the generic drug scaxtdal were "debarred" tioin working in the industry . The narnes job candidates are not on that list before YOU ttlal;e a job
of all such individuals can be found along with many of their stories oil tile FDA web site . Check that potential

offer. Whcn you submic any marketing i+pplication to 1"DA (whether an NDA, ANC7A, BLA, 510(K), or PMA) you inust certify in writing that no otle who has been debarred
WU.CkCIl on the product.

6%, inc~ney penalty :and ~~z eed to pay the U .S . Treasiu-y '~ rnrdically necessary devices (tile of the gross sales of af ( confirming thak []lose co~l~pany"s eutire ~;rc~fi t portion) utltil aareeci to pvoclucts are produced irv GtvVs . (n addition, it pay $ 15 ;000 per day P er process on medically necessai:y product,; until each pr( )cess is validated and S 15,000 per . day of ope.ratio~1 ui~l :i it is Gi4SP compliant (34) consent decree to date, a nnajor In. the maSt enpu :l :qive ph~irmaceutica3 and oN ;er-tile-counter (OTC) eoilipariy agreed to pay a record S~u0 anilLiou dollars to the US, Treasury, to disgorge , Drofits :r_ade by the compally on ;d over the past three years that were drug products j ;t1ML'a . Tile company also agreed made i7a viulazi ynti~'.nts Of Up to $ I75 million dollars To future 11?onE onal pl-ofit.s should it fail to mee4 the and to disgoi-ai e_ The actioei follows Li inspecrsons at tinielines of th. ucito Rico plants since 1998 in which four East Coas t r'i0lattons oj CGN!iP reguiatiorls . FDA found sit( 5 Li ;Ferent Prescription and OTC The decree aft ~5;c facilities . As part of ehe consent d ;ugs produce agreeo~ to suspend it ianufacO ring decree, the coi

of i i Other prr LOOKING TCJ are all respon~


clleclc their backgrounds to ensure that they are not
disyuelified ." Di : ;qualification can occur if a»

Similarly, before hiring any clinical trial investigators,

As we vii

invesYiKator repeatedly or deliberately fails to compLy with rc:.gulacory requirerrients, or if he or sl~,e has subinitted false
information tu a study sponsor. Studies from individuals

work Uiat othb faster than soi
always ask pe

who beconle disqualified will be unde:r great scr«tiny and may be disallowed (31 ) . With the recent death of a young nlan participating in a t;ene therapy trial, clinical trials
uttdoubtedly will '0e under increased scrutiuy (3 :-) Change (St : PAC) .iocunients presented oil the FDA web

1.111111 impartat companies, oi Our indu
find c :unes for

Making better changes. 'The Scale-Up and Post-Approval

of the tcagedi
regulations ai

`'approved drug applications can be made . The dc;cutnenCs

site provide "uidance on what is needed before changes to required itemize the types of information or studies
based upon [he magnitude or risk of proposed changes . For biological products, companies are now preparing -comparability protocols' to address proposed changes, Abbreviated, routine drug Inspections . In ?OU2, FDA went

balances on i

samilar, froal e

efE::ctivc proi

Z f .tit ceni.urj~, let's renicrilber that we Ie w ill see things iii our daV-t0-ciay ilnt, or we inay reach a conclusion el s e, in all tlie classes 1 teach, 1 spca ;c lip -and cOntinuc: to do so s arc addressed_ Otherwise patients, ~ykzts tnay sutfer . .St,,, to relieve suffering or pain, Lind to cs . It also is hig.ltljy regulated . Because havL occurred, rriost people see Jle cl regulatary agencies as checks arid , believing as 1 do that we a11 have a n0n -- to bring innovative, sate, and ~ nlarket .


ACKN()WLE , ~E'tGiii than!

to a new, abbreviated inspection technique, focusing on

cxeuut've wi

two or iilore systems, including mandatory ccsvcra~e c~1' the quality systcin, ;n routine drug manufac:luriag iispcctions . The other systtom0 Facilities and equipnlent, materials, production, packaging and labeling, and laboratory controls . FDA has said publicly that they consider a
company t0 be "out of control if d1lV Sy5tei71 is out Of
COf1tC01 .~~ 3 . . . ..

excellent tall this article, z

NTa 3ne Brooks-Sinith, a compLtance Bfosciences (San Jose, CA) for an

years ago dlat was the impetus for clr~ Swann, FDA historian 0\oclcviile . ~ and contributions .

(1) .SFnark Cililtb


nn,ry oi he Jung1e by Iipto.j Sinclair," elin := Snedc Giride' ( 1 heSpark .eom inc>., A, ?99)l.

:oo by magnctie inmcl ~.esuurceti ~, .L, epre>c ucUOn, p ~c~lncupytng, atoraee nr lranwmiss

u~ic rncans sCncl!v Prolubitea try :a"






707 7'76


P .16

. (Z) Key«ire)nt-nr.r r?/ l nw< nnd Idegitlatiorzs EnJurcrc; y tile U, S.
(21) C'enter for Food 5sfety and Applir:d Nutrition_ FDA Milk 1'cr~er- Ir;tptt+'iriss Canatr,ijed ill Irierr~ry Srt~plcutcr~,t 5If~~rlrcr_3y-1 .-li;ig~toplrurl (l L},4,V.'ashington, DC . 31 ""ugusc i~J9k~ ;. . fur (22) Eriternationai Con£erencc on 13acrnoiSi-talinn . "C ;uidance :try : Q7l1, Good MmnuEaclziring f'racticc i;uiduncca fia lnuu,

:Ivi19e AD . rcvisc;d Food and Drugildmf;ai.etratinn (FDA, Roc l9)7), ~~_`v~v .f ta . o~l c~~oilt,%ut<~rrchuicesh_nt a~ ~Lsiness/ l2lubook-hliiioffice of Women's Il2allh, VUM b-f7lestvrieN in N Looking Back as We Mnve into :ht' New ~LPi(iOM Rockvillc. NIL), 21)(1(1), ~~~v~~; id:1 .2~?W v 1LtiJL9117~

' (i)

men's Kealllc


FU-4 flisrary . FU4 C mrimissioncrs aud Their P. ~CCP55(IVS I), rev. 6 U's, Food and DrugAdministrntimi, 1tucE:vi(le, April 2000- r~,nc~~ fci ,i ,o ~iu~acum?mu rcc }oicu . 1-r 1-111 .TAW-1 I~ . Ro6erLs, tialel) .4s,cssineisl in Pediatrics,' < ntcrfor Drug F.v"Iluiitic>n Ono Research, l_LS . Food and Drug E inmi :tratic,n, S .Iti :y 1999, ~N"rte tJu u4!cdei ~i'~ritlda- !~!)~a, ~-clLy91
If1C1CS .f1i111

~_si,zv ,llu,,l

~n (FDA,

Active rt,ati,},l"t«L31 inzizaicnt :," (FDA . Rockvi!io, MD,
A .U$US( L00l),

;" L" liA (23) }' . Kuri-I.Nci1,'"Lx-Aarci 1-.,~ec .itives 5c°r,lenced to Prison i~Jdc ~ii«_ Coiesrrmer 30( 10) (Dc cc nibcr 19')G) ~,v~\%v .fi n Q-9p- ir~i h tml . Contwusv(,,t}erul Pnud and Diugs. H~tst n~ (Zd) D . A . Lcclu'r~ (Vva ;hington, M '. aG Decelnl) .r [993j, ~~~~~t~°l la ~  v; . ?5 ; S. Sciacca, "Sl:'tlr.y Arui,A,i1 LtuspfLal Administrator 1_ .eller, Heart Valvt Prograeii" (?' ire.r Inc_ . Vcw York . l_)eccmber 1999), Qaalitr (7,G) Office ul lZegulutury All .ius, Grimlc if) InopecNoms v,i _ .Sr.,7ern,s (FDA Peockviile, Nit), Au_aust1999}, %t~t~~J~JdTuv orc~;
(27) i ntumat on~! (~ :~n . eience oil I~e711101115iitlUi1 . ~r71lLt~C fiOr lf7uilSIY)~'
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lenlar lo :- Dill-, l ;vali.aC[bt7 and Rescarch, 7ime C'hrunw/o~zv ol Urnt~ RegaLarion in (he United 5 : \'\l _ Ruukv i lie, RID) \\ 'i .1dil . elrt'/-'C~CC%211)OuU : 1i ;tU_ 'Milestones ~n U .S . : ood and Drug Law Histor 13ackgroruxler Ciu rm[ ~7rtd Use/id l~!l~rrn!i~ion and Urrrff .-lrzrnirti .ctrwiuri (FDA . Rockvillc, Mr -,i ., t~~_~rn)il~.,s_b ;.B "Iunas 5alk. Nil) --13iography" (An-iesican Ac Ac}ucvanent, ZU00), ww~v.~chievqmc: t.orzau I .R . Slehlin, Asscssing Risks with Polio VacCi C'onsumer 29(li)) iDecenzher 4995), w_ww .4tj 9j

me' ~c..,,- (Fll .A, ' f7» oil? ihc how'
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emy ul


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Guiclcnrr (: eneva . S~vit,ctrlan~}, .kpril 1996 . PuhGshctl it :

the Psdera! Rcgistm 62(90) 9 May 149?, PP . 2 5691-2)709 .
(Z3) Drcrft G+rirlancz ; for lnrtrr irv (OOS) 7est Resrills for /'harmwcFteticrzl Production, (H)A, Rocks"ilte . N1L31, 5eptember 1998 , 1212Li f i~1_!:. t7: l~c~bnrr~~en~ (29) Ofjtcc ofRefiulatoryAJ1oirz Corr7f lc -ic~: Rtf ~e~,ce : J ct. ~1~1.7~1 . I~>>ckvilic Lift , ) ~t h,ar'~c tu~,S~t~_l DA : BarcinK People 1roni the Drub (30) 7 ra, ~qui ~Gun~:c .suuM31(2)_ eti ~~ ~r I~~dustry, ~ F1J;a Cnr f :i~)
.itnrir>,? /131A~PJj Uisnuaii~ecl~h<+ .crridrc~'-I csf~rc~rc~" L :sr,~;w A9or


; , (,10) Federal Regi.cter, "Drugs Current 6u<xl Manu cutrinb " Praclicc in MnnufaCtw'e, Processing . Packing c Holdiny ('art 133, 23 FR 6385, Tune 20, 1963
arid I}ricg:; (1l) Code of FedeiuJ Xe ;,rrlaliuris, Food Good ManufEcturing Pi tc:ticc in ib1aniifacturiit Packine, or 1-IoId'ine n(' TJnigc .- r(:viscd AUtiI 2

~'ru cc~sut 6>... . . ) 0, 'TiUe ?, l Dc), Pzi1 210--211 (U_S . Printing Officc,"Washingto Cocie nJ! edera? Kugrilat :ons, Fond areu' i.)rugs ~ledicnl (1?) lleviccs- ("tin-cm Good M;jnuiecturing 6'tactia (CCwP) Fin-al Rtilc," revi,;e~ ,4pril 1999, ?itle 2.1 P~irl F )~U .S_ Printing Olhce, \4'ashingfon, DC) . (1i) (~nde o1 Federal Re.grelntivns, Food and Drupt 'GeneraL Good Laboratory P~aciice for NoncHnicsll Lah Studies,' revised n-,iri{ 2000, Titic 21 Nar~ ~K ( S. Primtt7e
(14) 'l_ Nurdenhzq~,'''l~rcilecling,Againsl Unwanted Guide co Conu ;ice,r,liNe Cliciiccs ' FU.4 C_'un,su [)97), ~~~a~t t d_i . ~rs .- t ~n ~~ L~tlut~c,-19 9?/397 1


Compliarrcrhcl"rnce Iinrv~eardr

Cliirical hrvr :rtigutors, (FDA , IYocl<ville. MD),

Ofliee, Washington . DC).

rv 31(3) (April r ; tmi . (l5) l . Nurdeubvig. FI)n and Medical llevic<:,' A ti ?_D Years, a Look Back, a Look Ahead,' FDA Consaurter 3 lU) (1lcccuibcr 199fi) . ~ti~~~s Ic7d _~~~ ~ ~I .dao/leat u~'e cl096 i n~Jcy_ 1162 Drug lltueu3menti,- VIM Cofrsunver (Ji. : ~981 J . Ill : ( I(i) jlG1 "The Story (if the Laws i3ehind the Labels', Pn Office Of SpQciaf NuQ-itionnis. OVel-VieW Of Iii, a( Forrrrrrlaa (FDA . C'atlcr Cor i ood Sulely and Appiu:d N, itioia, Washington DC . August 1997) { 1 ; 1 Collier lor Food Sa14ly tind Applied Nun;uun, Spcciul NulriCioitals . "Overview oi~lnlanl For (FDA,Washingtnrl DC .,4ugust l99 IN) T Kapl .+n_ . .lhc l"y;enoi Crisis Haw G19c;.Uv : Saved Johnson & iohnsnn° {Penn Mate Univ~ Web Pages, PA ; 199A). >;~«}~~ ersc~ual_~~au .~-du Oleo of

runanc,Y= n

(32) _'tii:w Initiatives to Prot~cC f'*.rcicipanes in Gcne Therapy Trials," f-IIAS Press Release, CBCR (FDA . Ituckvilie, i~i t,7), 7 Niaruh 200G,.v~, u,fd~i~ov ~bhe; cc~oicslNk~;W~1 '~LLi_'(ZIi71 .`~tmL }Wk Sta?T (33) "Lc;mpiianco Yrugrsin (~uidancc Mnnua' iiOr Lispzclions Prueraoi ?356 .U02" (1- DA, Drug R2 ;mutacturin2 Ftockville . iv91). Febmnry 2002 . Nk ~c" .lil :~ k n!cdc :-dntll4 i
k3A) C . I eWiti, "IYSVCsU6ilIOlS .


Cost Ahboli Kewrd-t3rc~i!cing P:syincnCS, FDA Con umer ;4(1) (May_)tinr 2U4)(>)_ Availah,e Lit ~%w%vlciti_, (L\ltd ,, l,t ~~1 de~t~ ~t~(1~E( ~JU ~r~ (?5) F'1) :1'Vmti: "Rcitering-i'touLh Signs Cuscnt Decree with 17 ., FDA, Agrees to Piiy 4;3E1U Million" !FDA 1'eod~villc, Pvif:,,
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~_v\ k' I Git\ lcnI I'u~s S. 't-;it1, 1J9) National Center for Drugs and L3iaiugi(~~~, "Gi of Computerized ~ ysicuis in Drog Processing Rockvillc, A1U) .Febiv,in 1983, ~~tic~v .t ~t .~ ~ i~" cSd .Litm ! .
(20) Ccntc;r 1or Drug Lvaluution and IZcsearch, "C General Principle : of T'irocecs Vilidation" (1-'I MD) . May 1987, )w ~v.id :~ .~ uvl ct~ri ~ ic ~~

lc to lnspec[iou (FDA, p-~,'ins~cct relr

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, . Undestsrtding FDd's Fropassl tr. £kempt l,IctenallEv Phase ~ ' Nmco! Triah ~mm GY:MO neptjrAnanc, arn7 nsw draft Guidance
- -- ~ Prepared for Participants of the

Chipping Away at the Gi~lPs :


I' ' '

'J~h3t rDA i~ proposing , Ftnpq ed ui a w 1e'i r'nni ri,le a FDA.'s rcissio+i and history 

_ ~raY guiti :rr e m mplace cCnir %gjlAnon everis



-I J -'L

by Barbara tmmel, Presrdent, Immel Resources LLC, and Editor, Immel Report T"

30'~'Annua! International GMP Cortferente, University of Georgia, March 2006


0 'f+i~r ~~~K ~~,ay ~ flaw~a . vVh3[ your Ott3dnfzaUan =an do

. Pedfnt dest'n ; r ?ha" 1 c.i21s , aPwm,acy -p,unding expe .ierxe o Madical devic'.eea~e-rle~~c~ D~ttgulcarr;12 .

e Questions )Pd ans~e~s





FDA is



, DisGlaimer -- ---

. The foflowing are opinions of Immel

Resources LLC only . This presentation is not experienced quality assurance or regulatory compliance professional . Please ensure that

a On January 17, 2006, FFDA published a

intended to replace the advice of an

proposed rule ano a direct final rule i« the

Fadera! Register to amend current good

you ar :- following al! applicable regulations and consult with an experienced quality assurance or regulatory cornpAance professional regarding any questions that you may have .

manufacturing practice (CGMP) regulations

for human drugs, liocluding biological products, to exempt most investlgational "phase 1" drugs from complying with the
CCNIP regulation ;2J CFR Z10/21.1),

What FDA is Proposing

7 ..n xdM J+~m.14:aw .+estxr_U .~ 55947 . iGYUy~

., .x.

FDA's Phase 1 Proposals
April 3, o Written c.~mments or, the rule(S) are due Dy 20UE . .'-QOG , and for [he draft gu :dance by March 20, received, " If timely significant adverse camments are adverse the agency will publlsb a r7o:ice of significant

.~ At the same time, FDA published l draft gU1d~3f1Ce entitled IIV~S - Approaches t0 CoRlplylrl~ with CGMP DtJI7f79 Phase

1 "tC provide guidance (to replace the existing regulation) to provide "recommendations on approaches to statutory compliance" to manufacture
Phase 1 material .

comment ;n the Federai Register withdrawing the

commennu,, " It FDA receives no s+gntilcart a d vers ethe agency wdl M^:thfn ;he specified ramment peYiod, the

direc: final -utc .


confirm me elfectNe dace of (he ~~~a~ vuie in
)une 1, 2006 .

FeJera! Register, and ehe flnal rule wild go into place





01 :41p






P .18

~ant Significant Adverse Comment
.u .v. . . ., .v4 .u . .r .,F .~P~FOU. ..c, .el

9ecn~!nmfleo:wf .Ui~'7 :.W.ac

< CW« ?'~ . N0 iH .b. CW

~ "This action is




:aro~+.u~ ..~. onncl: . .rc4v

. Explains why rule would he inappropriate m includes challenges to -ule' s underlying prom ise or

unaccepCabie without the change . Ts serious enough to warrant a -substantive response
A comment recommending a rule change in addition to the rWe is not a siynirican', adverse cornmenC unless the cemment also states why this rule would be ineffective wlthout the a dditiona l ch ange . Cem ments that are frivolous, insubstantial or outside .

approach Explains why rule wvulc be ineffective or

intended to stream line and promote the drug development investigationai drug products, those
intended for use in Phase 1. clinical trials , " ONW '

in notice and comment process

process while 2r`SUCifIg the Sdfety and quality Of the earliest stage

the scope of the rule will not be considered significant


. ' ~._

N, .




._,. . . .~... ~ ,~~~...~..~,.,~~.. .rt . :.m,
_. . . .

. "The Food and Drug Administration (has) announced steps to advance the earliest

. .. .. . ~` , ; "The probiem is that ;e ..earchers conducting very , early studies were required to follow the same

Rationale T.~.~...:w~.

21YAYn91trc_ - 


of innovative medical treatments . FDA's g(-,al is to improve the process for bringing safe and effective drugs for potentially seriuus and life-threatening diseases, such as cancer, 9Ical heart disease and neurological disonders, to the market ." ,
W ~ ^a~=~~ «

phases of clinical research in the development

manuFaciuring procedures as those companies that

i ~

mass produce products far broad scale distribution,"

said )anek Woodcock, MD, FDA Deputy Commissioner for operations "These requiremcr,~ti are so burdensome for early phase i studies that many leading medical research institutions have not'aeen able to conduct these. studies of discoveries made in
their laboratories. Too,,y, for the first time, mEdical


researchers ore getting specific advice from the FDA studies." . s,~r, .,a»~ .a . .

about how tn sa'cly pi eparz products far exploratory


Rationale ~ ~ ~n~~ ~ .,_ . . .. . . . _ . v_. .~. . ~rv
commitment to modernize existing CGMP regulations to streamline clinical

Proposed C hange. . a .~ .

.M .

_ . "The documents released ., are part of FDA's development . These efforts are P art of the Agency's Critical Path Initiative, launched ~n March 2004 . The goal of the Critical Path

drug for use in a Phase 1 study, as . An J defined in Sec. 312.Z1(a) of this chapter, is sub eC. to t he sta tu tory requi rements set forth at Zi U . S . C . ssi(a)Sz)(a~. The production of sucn dtuq Is exemiiPc from compliance vilth the regulations in part 211 0 this chapter. Novvever, this exemption does not apply to an invesClgational drug far use in a Phase 1 stud once the invastigasaanal drug h as b een made avai~ar~le
for use by or for the spansor in a Phase 2 or Phase 3 study, as cterineG in Sec. 312 .23(b) and (c ) of this ch ap te r, or the drug has heen lawfully marketed . If the investlgationsi druhas been made available in a


InICI2tIVe is to reduce the time and resources expended on cand i d a te pro d ucts th a t ire

unlikely to succeed, by creating new tools to distinguish earlier ir, the process those car+ did ares th a t h o ld pro mise . "

phase 2 or 3 study or t~r!e drug has beer lawf~,~ily marketed, the drug for use in the Phase 1 study must corni piy with p are 211 .

, F1pr



01 :42p







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- specifics
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Sodec DI af~

Yu o O .R 6F . K~n v . . ~q ~av .e xeq : . . ec l . .verJ~stlv . .i rb... w.. hVD :1.~vwK,IL111f Niaa'oYNf1L'4AG 547., Cn ~



. Phase 1 studies are designed to establish
basic safety of the compound, and to determi~se the metabolism arid pharmacologic actions of [he drug in humans , . Number of subjects is limited to no More than $0 patlents per phase 1 tria l .

Phase 1 studies are the first introduction of an ime5tigational new drug into h umans . I ~

. Phases Z and 3 er~roll larger numbers of
subject;, with the aim ho test the effectiveness of the product .

FDA is proposing re uiating phase 3 material by oN means oth~r than CWMr re g ulations . How it'; & i) By Federal fooC Drugma Co,met:c Ac: that deern= nufadunng Coes not a druq aduiteratld it conform to CGF1Ps (sta :utary requiremen[), new drug (It~d) submissions of 2) 5y invesCigaUOr,al sponsors, which inci i,Ce a c h emistry, manu factur i ng, and controls (CMC) section . FDA states that it: may place an IND on clinical hold ;F study Subjects are exposed to unreasonable and si rificant risk , or if 9N3 does not contain suffcient . in~ormat :on to essess -1sks to subject, FDA states that IC may also term .r,ateate an C~Nb if i . discovers that the manufacturing of rhe investigaticnaf material is Inadequate .

~ '^'1"'

.i - ~

. t . cv~r.t u,Ui r~n ian .


.a ,v .. rwuv.a ..~m .

i Specifics ..~ so.,K~r u<. ,w cv

F . 34i161lB17r JYnP 9L, irto .94GY8t'9mp~v7a1~ . __-

.n~~v vR~~ xn

. e, ..m, 

. e. o2z,,

e Although unstated, FDA currently does not commonly insoect during phase 1 studies unless for cause. . FDA says that ft believes the change is appropriate because many issues presented by production of i nveskiga ti onal drugs i n tend ed f use in relativel y or small phase 1 dlnical trials are dIfferent from issues commerci a l mar ke t r . ; .q . FDA is considering additional guidance and regulations to clarify agency's expectations re : CGh1P requirements far phase 2 and 3 studies.
prescrrtF;d by production of drug products for use in ' arger Ph ase 2 and Phase 3 cli ni ca l tria l s or for


FDA adds many requi ;~ments in 21 CFR Z11 do not apply to fimked production of investlqationai drugs for p hase 1 , for exam p le , fully validated

. 'fns rule, G approved, would apply to inves'igationa . biological products kha : are sub)ecC N CGMP requirements , including recombinaet and nonrecombinant therapeunc products, vaccine oraduas,

manufacturing processes, roCaton of stock for drug pro3utt containers repackaging and relabeling of dru prod u cts , ant~ se parate p aciaglng and pro~uceion areas,

allergenic products, :n vivo diag rosti:s, plasma derivative products, blood ar~d loci products, gene trierapy praducrts, ano sernatic cellular therapy products (including x2natransplan.aYlon products).




~w ,

e - . rra~m~m.m~.ax(mmrt~LWasSer~vdna .r.m



u .n F .

'nm ..nm+Y .m~


cM .zmel~z_v~ xo,

is proposing that production of an investcgafional new drug for use! In a phase 1 study

conduc:ej under an IND when drug has not yet been or !snot being, manufactured for use in phase Z or 3 stcdies or For an already approved Use, is not . Once an !nvee'tigaNonal drug product has a.ready been manufactured and is available for use in phase
Z or 3 studies or for an already apprnved use, invescigakional drug product used ;n any subsequent p h ase 1 st u d y ro u st com pl y with 21 CFR 221 . . "The ac' Jon taken should be noncontroverial, and the aoenry does not anticipate receiving any s:gniffcant adverse comment on this rule." subject to requirements in 21 CF~i 211 .

would affect drug marwfdr_turers, chemical manufa :;tvrers, and labaratores t7a: mar1ufacture  The agency stakes tnat they believe that for drug

drugs nn a small scala for use in phase 1 clinical trf~~.s.

manufacturers that product Phase 1 material in house and approved drug products, this rule wilt redurv the amount of c'acumentatron they pruGUCe arid maintain when they manufacture a phase 1
drug . In some cases, it should also reduce the

amount ofcvrnpnrent and pindud testing.

---_ 1



Rpr,, 03


01 :42p3

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a, . . ,~.a n.w ~ n a~w-.Ma+ :'s~'mm.was

r .ro .x.auMOw o .~v~nm : a~ >w . e~~mm.m~

_ . .r

, Specoflcs o n,x ~ cm
:~ m, .a

, .a :in.. o .

~ unwu>: . ~ sx,s rnunn .v r r~~taxc~u. .osas~.em

,..w .n,~. .


. FDA states cn ac

cost saviigs . Some examples where substantial savlnys nay be realized are the level oftesting and analyzlngCOmpon2ntsandin-processmeterials. These ccsts typical',y range from $SO to $1,200 pe-



data to ~st.imate the ex:enc c~¬

~ For chemical manufacturers and labs,
f0!' deVLl0p1ng SoPS for quality,

requirement rp3y increase time required process, and procedural controls . May be in incremental increase +n training
costs to educate

. The extent of the need for SOPs and methods

comoonenrtesced .

vallUatlo,r may also he g ;Eally reduced . FDA estZates that large drug manufacturers that praJuce phase I drugs in-hou&e rould pctentia!ly Save Z4-40

CGMPS. We estimate additional i2 t0 24
!1vU75 may be I'FQUI!"C_(j depending 011

ympfoyees an the

hours per IND (of lead some large firms to product phase 7 material m house, rather than contracting

the worw out) .

experience ~f Firm and its employees ~~ CGMPs .


3 " wi ._ 7m, ,



. Agency notes that they do not: keep a database of facilities manu actunng phase 1 materials, so do not . [n 2003, FDA received 350 research and 500 commercial INDs. Not all affected by this rule since the maiorii~ are for aru~ products that a',ready have approval s. +nce a bou t U% of INDs are for new . Slnce companies produce multiple drug product, f~sr phase 1 tr'als in given year, and use dlFferent Companies to produce them, FDA does not know hew many entities would be affected each year .
. Estimated patient impact : Z55 INDs per year X 80 patients -- 20,400 patitints affe&ed molecular entitles each year agency es:irn~tes tha' the rule would affect about ~255 INDs per year, have a number affected by rule .

1% 1a wM inmu w~~p P,eM:s N.eO~.mn uM meN'Mllc.a . Xm :N+O . I . P1L'ilmm 17 " oL+l~^nVC~scn~IIQm~1JA?

' : t'~ ~ .

Ae .o, C Qu" d u .e. .4 Pq9s " . .^G Same . . .-r ~a ..~ n ~ .~al . . Y.'R :'ilrim'.d~ .¢vx.ac~'a.,cwtifYINU2l:15) b


.e vuN

eq, ;M Orte+.

e FDA estimates that 65"/u Of entities

submitting fVDAs jnci E'slAs to FDA are 5ma!f

entities, The Small Business Administration defines biologic product manufacturers as small if they ~R~p l oy fewer th an 50Q p eo p le, ~ FDA believes that all of the entities affeCtec ~ by this rUIP have personnel with skills .
necessary to compy with requirernerilts and drug Mai7lJiaCturer5 as 5m01! if they e!'rlpioy fewer tha~ 750 people .

A oricy adds that does not ~now experiencc levzis X cl:Lci ent i ties .

SPecific. S ,
a FDA states that tncy do not know the number

Estima'-e savings to iarge manufacturers trom reduced SOP and vabdahorr requirements- 'or phase i
dru p,cotxt,on in-house, assuming time savings of 32 U rs q5 I anct TOer 2.PlIcation, fully loaofed wage ra t ebef IN p er year (351/. d 255) would o ~ 1,410 per IND .

and sizc distribution of entities affected by this rule, they believe the impact on them will
be negligible and should "actually reduce the compliance burden for some," "To clarify the

. For chemical manufacturers and laboratories, assum!ng ali would Incur costs and assuming average of 18 hours per appHcation for writing 50Ps and
trainina a fully loaded wage rate of $'~5 and 165 1NDs (6~5% of 255) would be $810 per 1FJD .

requirements far ;he manufacture of drugs for ph :~se I trials, we have prepared a draft guidance dncurnerit with recommendations for COmp~ianC~ ."



Rpr ;03








p .21


------- ----

I Guidance
. . . . . .


nn r,


Ra ti ona l e
. In 1t5 draft guidance., "FDA OUtII~iBS a suggested approac h t0 comp lying witfl

.Draft qtnQance appl:es m investlgdhonal new human dnig and 6io!ogIcal products (uicluding finished dasa~Je (orms used LS pIacebas ; Interided for human use ciuNnq pha x 7 d eve.opmertt, Examples of invesBgational biological products covered 6y this guklance Irrhuie Investiqaqnnal remmb~,nan[ and nonrn._umClnant

therapeutic Products, vaccine products, allerpr~ilc pr~iucs, in viva dagnos8cs, plasma derlvaCveproducL , blood and b;ood r.omP~ nenLS, gene therap y proCUCts,, and wmat(c cellular thernjri pnoU~xrs ( mduding xenotransplantation p\oduRs) that aresublKt a to the CG MP requirernents of 501(a)(2)(b, of the FO&C Ad . The quldarce applies to IItveStl ationai products wheFher tliey are produced in smaP- or Ia rge ~ seaPe env ironmenCs b ecause such ~ (~p rally deslgneC to assess to'erablilry or reisi~ucy for Fuiher deve ~opment of a specific drug or biological product. , Guidance does rwt a pp l y to human ceii or ti ssue prod ucts ; d ill trials for products ula',ed as devices, or alrnady b proved e~ cts t re b ~ng used durn9 Dhase 1 sNdie~P(e .9 . . for a pe~ ~C t ao n)

Current good manufacturing practice (CGMP) requirements for dfl :gS intended POf U5e so l el y i n gh ase 1 stu d ies. With C~115 llew p '' .

8f1C~ arid an accompanying fe9Ul8tIDn, ~(7A fOrit1811y recognizes specific standards for the manufacture fJf small amounts of drug

product for phase 1 studies and formulating
an approach to CGMP COfflplfaflCe that i5 appropri ate f or t h e ;~at"~ICUIa~ yG.9gE Of dRtg (~eyElo p mert . ~~


' .

eew, ,v.n z. ___ ._ GCCJaemi' .ro~.yvrr .M IuCI:udidytNPS'1f .. .._ ~ ~ S


Concerns re : Draft Guidance
.u.pxoL 6 MSJ " :+s+.tJe~n(t4n!~fW.Wylsar¢.cd1 . .


. .

4'-a .





._ . .


-he Craft quidance describe-5 FDA s current thinkif1p rec,arding 4Df1In15 for SPBCidi p10dUCtlOf1 situations (e .f~ B I,a~~81Gry xlting c tp iorato -y stvdics, mi dV-pruduc[ ar,d mu l li-Uel d i ,



. -

testinq5 and speclflc product ~,ypes .(e g., tbiological/bioterhnology asepticaiYy processed products) or 1N D p vducts rr:anufbctured fvr usc during ph_ise 1 cli;uuil trials as ,escrit~rd ~n the scope sectlon o, the guidance . As the new ru+e Will cpecify if tinallZed, the particular requirements m part 171 "em rmt b~ met for most explo; atory products mane facturatl

~~uuld 6 e usr~~ ( pcr curren t pr~pasel s) ta Cl e.rci>Gny an regWation for phase 1 material . A s current l y written, appear ; i,suFficienl to protect patients , As turrer',Iy tvrl eppea- ; insufficient to manufacture


p~ovic~s recnrnrrir_nclations; not leqally bindirig

. .
. .


for use during phase : clinical trials.

~ .

ml cena . saiely p~ not harmonite with eU r~Giirements ;hat Ouaiifierl Pe:son
reiea,e lrtvestigBtlone~ ma!e~iat Assumption that sponsors or ottiers would read or follow f : ;or learn er,ough about CGh!F;. aseptic procecsinp, etc) without a regulation requiring them, fa do so Assumption that a reader would be a6T to l 17-page a d ocumen t and manufacture. material ,AFely per basic GMP principles, particulady for nlolesyic products, or aseptic/sterii2

When finalized, this guidance will replace the 1991 "GuideGne on the areparation of lnvestlgaNanal New Drug Products (Human e nd An i m.a l~" for the production of iND products for phase 1 eli~ca! trials described in the scope secbor. of the guidance, Phase 2 and 3 t ri a l s will conti nue to tie sUbIect in those portions of parts 27 :7 and 21 1 that are applicable,

dosage forms

sow.e . .']


Concerns Re : Draft Guidance
I 'ma° CO ~NKGAUre L D.a(~ l[tarNCai u~ilVmo at .:

.mc'.~-S . Fo~d Me WYO

'1 ._

~ p l~Y .w

Concerns Re: Draft Guidance
5 WnJniio ' 9:AVE MW l4 Km 1~~ o Jrp,~A1 :LDU~ .r ~ :6 Does /14t




~ . ' .

. . .



cwarl used !o ueri'ize;ion re cuaGfed

All. .. n0, Q(. Ufl'I (flpp QA) pe7sOMLI to fQIN35Q product; 31o " S "(TIC N ;IN7!vH'JJd who pEffo,fItCd production to also ILiEdSC 0r fN)pC1 batch Ill'.UII (.lC1Ilt72` Null f7S . arc CnVll'Of f'iC!lf3i coon DI5 rUr dSCGiK t .:, Ie~IC o~ hlbl0y1C71 ~7ro(1I)~,t5 ~~ OIt1~Ulal Iy I~l~,`CIdI :IC « irifi~nlN Frud~[ti./ AliowsGMP v,hrF; and researci, W be done m samc nrea ; ,2earnrnend ttiat s ~


11'Ji!Wfl G'WU'=hM 3,PA

e1, <YPa(,ng- to di54us5 0' ~rtrit R10VE71len( train 8n1,TLl COIOny b


OOCs f;p( vet 'JISGti>S routine P~YI' .~ic 2Ufllt'~!1^ (one OI R105C IrpOfCdl1 : C,UdQC( Sti'S1CT5) 315t1 iEGIJIR Ca ~~'t~l SE'I~C(101 Of (Ot~(2 :COr5


. Appears to allow reduced CestinSi ~ For exam lc, veron9,Y ~mmenAS for perfo .mi~r c~nifUnialorv 1D te_,Ym7 for RP157  .ovPl Of PrO~XYCd Chdn9es ;,uC ~cru:~7 and q1--e ;~~~~n-app onalc
" .

L~cuff en~ treln~ng reQWremenGS (very dlRcu?C tc Gven or lewn aseFtechnryue, even fw experie^ .ce,i laboratory

Does not seem to yr.kiw`vledge :he .kllis and er:pedtnce needal of l il QA

. ~

Re,7o~nrnr~(lg kCC 4~rr a t~-~~d { s .,ch as s I W hooki cn~talnin Q reievant . ~ .J ~n omatiol corx,timin g a ll cvmF:~ ats; let:nmmend^. f:tab45hi'ig .

a:cevW+~e cr!terin tv spe~ilN~ a .r butes of each cnr .i~z:nen;. ~ ~crvn,merw~vthnf bG ccstir.g uf L wva,qqnUubi p~orluu pe perlvnPCc as ee ~A'late to cval,b ;e ufent-;y, ytreflG;fi, poCen. PJf:Y, and 4~el~Y "Y~ '
(or -wn snlRly" mlettd Co r.ns, spedGco4ons etwulU G`C 1!tit$CIlGh~'_d dllf) InCI . (JpeC not Si'CiT LO itCk!1 ;NlICoi Illf Y[?3fC (7( halo! -k J'Id e('fOrt ,r Q2CII,l9 . R60 qroups n0 r . .ompanles, unncrcitiec m con-,ply (or thaL o ya ~ah az


. .






Ocxs nn,' an7ieAr to rEqulre rl valid36on ;reEOtnmend, teStc be d,+i? l :r.dP, CV'1:'OIIel~ COrCk'\0,5, 'oI~OW WfIRCP SOP,) REC2:~~~lA:(!d$ LI1C USC Q1 dSGa:iC Ct![I1f1iG~$ t0 pIYVPfI; fllCfO~l]I dllj ert~otoxln contdm nhthn it yo_arc raanutvdurin~ asr .plicalty N rcunr x iw ;h.aC trsbng o! 6ia1 ~g keIJbICOechnolog~cal prod=s for safety-


related pa posee; such as viral laads, 6ioG~uYdcn, detoK flceVon of bacterial t oxins, v i ra l c.eardnce or Ina_t(va[Im, and cleararce of annhlntics ee AGne

~+ith share~ :Pail uwally navz ::antuctinr~ pr:unqes, 4irrkul,y~ !o;lowvm n quiremen[5} "




01 :43p






p .22



Exploratory Studies Guidance
ei .. . mErx,i7lA'7e ' .1 wr7ep6_n~ :/1~+',o .:ollc0flf9u'77~CU19UHn'V~


W+on EV'+~nmYlnUilWti. r~ervMe~.T .tY1Mmi:Kmv 'malOVk~x(l1SBGOlWI

Exploratory Studies Guidance

, This guidance darifles what precl?nicai and clinical issues V (Including chemistry, manufacturing, and controls Issues)

'Exis;inw ~reauwtfons

should be considered when planning exploratory studies . Once finalized, it will represent- FDA ' s thinking or this topic. . The phrase exploratory IND study is intended to describe a clinical trial that is conducted early In phase 1, invo l ves ,,cry limited human exposure, and has no therapeutic or

diagnostic intent (such as screening stzjdies, microdose studies) . . Such exploratory IND studies are conducted prior to the
duration of dosing In an exploratc~y IND study is elliceLted ~o trc! 1IT-ited ~e .g ., 7 days) . .

allow : great deal of flexibility in terms o~ ltie ariount of da :a chat iieed to be submitted with any IND ap,p~ icatian dependin g nn the goals of the proposed inVest;gBGon , the Spea6c hUman testing proposed , and tri e expected risks . The Agency believes that sponsors have not taken !`ul', advantage of that flexibility . As a resu l t, li m ; Yed , ear iy p~iase 1 st udies, suc h as th ose i described in this guidance, are often supported by a more


extensive precliriical database than Is required by the regulations. "

traditional dos? escalation, safeh'~ and tolerance studies _

"Because explaraharytA'L>s1t~d~espre .sent fewerpafential doseri~ks than do tr~dltforial phasa l studies that look fordase-

that ofdriarily initiate a clinical drug development program.

G:mlhhg taxicities, such frm!td explonatury XD #7vesh,gatinns in humans can be Initiated with less, cr ~ ...!All) >tudies. "

alftemnt, prtclirical suppor, thafi s requifouf ~oi tracyltzorial

c ,T* : F-Y r.,rorc ino stuc . ~arv~vv ~c_anoz:i(GVrn.f9a .u~JSds.ltw!7ar:i~'zu~iL.^ ..^,' : :t is a[ all preclinicalsafety studies supporting the safety af ar, exploratotY IND appJcation will be perPornted in a manner censfstent with q,7od Iaboralory praRlces (Gi Ps). . CLP provisions 3ppi y to a troad vartely of gludies, test articles, and test systems . Sponsors are encouraged to discuss any need for an exemption from GLP provisions with the FDA prior to conducting s5fety related studies. for example, duiing :i pre~TNl) meeting . 5ponsars must Iustify any, noneonformanrn with GLP provisions (11 CFR 3:2,23 (a)(8}(II:} ." "The common theme_ throughout this guidance is that, dependlnS7 or) the study, the pnecuekai testing programs for exptaratary JND stud(es can be less extensive than for traditional 1ND studies, This I5 because , thr aOProachesdiscusseci in this guidance, wFdth involve admfmsteriPg

Concerns re : Guidance

FDA Mission
o :~ ; r tma .

.~. ~. . c . ,i.

(a) IN~GENERAL. Th2rE I.5 established in C'te pepartmenc of Health and Human Services the Food
, (p ; MISSION, - The AdrnSNStration shall 1 P " ° t_~ promote [he {~ ublic health Fa Y promptly and e171C~ 2r. d y r 'BY i ( l nq c1iN Ca l research a nd ta kin g :W Gppropriat~ a~ion o~ marketing of regulated products ; r: a timel y m anner . (i) tuRh respect to such products, protect the publlc on(~ Drug Admfni5i'.ratlOn thCrCinaftCr in this Section fEf2i'red t4 as the "AdmifiI5tr2ti0r °




. . . .

. .. . . . .

sub-pharmacologic doses of a candidate product or products, tne potential risks to human subjects are less than fora traditional phase t


"Tiiis guidair~e dunSbeS some e~cploratrny appr0achrs . . .thnt will eoable sponsors to move ahead more efficiendy with the development of promislncandidate products while maintaining needed human sthhject protections' -

d (A) foods are safe, wholesome, sanitary, and

health ~Y ~nSU°in 5 that -

properly labeled ; " ({ 8 )y hUrT73n and veYQt'~t~a" drugs are safe and effective ;


FDA Mission
~h:L :L=tm. r+ ._ ~lu

Tragedy and Responsa°_ :
~;~ . . pdJ1vM' a'~:u~ C_ . ..

i o. u. 7dcuNMUl9.Sw " -, ac ~ . . . .-_ . ._

A Brief History of Regulation in the U . S .
~ in,~~4Mer~ Sm9 .r 'y ; ehrp ~v 0 .4m M .ovc ~

.ur . . . , eatrv te ~~JiI


. (C` :here Is reasonable assuranLe of the sa`ety and . (O) cosmetics are safe and properly labeled ; and . (E) public hea!th and safety are protected front .

eRectiveness of devices Intended for human use; electronic product, radiation ;

k.,i . . 1902

(mprimeria vacav,e) Zrevu ns ~nsuea .ons and t~'-vcor sinda+r5 e ~ury~e) (he«i W

Dio;oghcs Control Act

. i D o ,


u,s:iou or oiolcyc cradecc ; ror pur,ry rnd rmnqmu Pure Fool and Drug Act r)a urAM~eisei rrwtera:ca or m sn~~~eEa ~""° °` dryg "~°""~ "'`°'a~e Food, Drug, and Cosmetic Act ~,utan :ismi~e> ;s~rvry; r,umonzecf inspeca-> ; F:~rug A .nen ;!manrs of 1962 (2hn`IAOmlde ~ ~ eIikacy, r~~in~:1 dru q s to M tested


(3) paRic!pate throuq'n appropriate processes with rep~esentatives of other countries to reduce the burden of regu'iation, harmonize regulatory rcqulrements and achleve appropriate reciprocal arrangements ; an~ (4) as deten^".Ined to be app, opriatc by the Secretary, carry out paragraphs (1) throjqh (3) In consultation with experts in science, medlcine, and public health, and in cooperation with consumers, users , manufacturers, importers, packers, distributors, and retailers of

1938 ;g62 1963

;) in arimais teru~, ;xY.2nnxme: con,elc, au=
First GMPS published

regulated products,

a 1979

Current GM Pspubiished


, Flpr- 03


01 :44p

I mme l


?0 7




Tragedy and Response : A Brief His,ory of Regulation in the U .S,
. .. pAliinevl ns 7M NoM .vrr . .. . . ~ ~ 1980 _,.
Swrt^ ~9nNi0cfoyln GM3,

The B~.'li"i'lfltlt Report
ell .4v nnKarPm,n~

de m GnrP ki~nn t~v N. Irtr~r . . . .. . . __ . .

771c HrHad5t7MLry, IImnkNeseutietUl

r1o.aTJie' MOl

tl'~1GmeaJ! .G ~:MuUV Jed
._ ~



r .

_ .

sv~~uNeaew .e,k,v~u,~+'


Infant Formula Act (sodium cFdoride)

. .



7rimperReSfstant Packaging (aretominophen)



"Guide to Ins ecCion of Computerized
"Guide to Inspection of Bulk Drug Manufacture (L-Tryptophan)


Sr1ejtiVC 'e:nran:h has prpduccd sub5tantJal s~x7a~ xnefits I. has aso pq6Ed z ritE [rw61fn1 ethical pue5k`~r~s, CubGc tt'ent'.a3 w3 davm [o tne~e yrestiwu d~; reporte4 abuse> or human si bla-Ss',n bl« ~t~:cai ~x ;,HC,mente, espr.~cally during ttse5ecwid 'No kl War. During th~ Nu .~embey wae Crime Traas', 0i, Nun:mtrerg code was draRd as a sec ot st3n~arc7s tor J~x}gl~g pTysh .an5 atb sc~eoUsls w!m tuq mrMuCed b;omcsSfca l ~peN n, :nU on n~nccn,r aocn cam p F Qer . 1h's -de aecznehe prom :~,usor many lacer rours ln e(,ec~J to assure that icsauicn -nvoNir,g . ~man suo~ect would t,e ,rt~ed a~tin a e[h:r.al
. 7hrYe',l,lyv- prhUa '.r . ., dmofig t'iGSe dlera04 arCPptcq In OUrcVitufai tTndi:ton, arc aenc~ianr rde+a-c m f~,e ctn;c or reseircn involving hUmrn atbjeet th e pr4r~c i~ ~ es o f reipecZ for pe rsvns, be neficence , anG s JVy7." C . ..

. .

Marn r





. . 1990



Safe Medical Devices Act


19905 on

( hear t va lv e) Uudated, Revised Regulations

nespa-t tar per--n, incorporale at lea';two eth~,al cmm-tbns ; RrsG rc~ 'ccvnd. cha: mauaua s s~-wd ne aeacrd s au:nrwrran e e .e that p , non5 with dimn hea auto .om~ are e~iue~to o~= ~iotecti~n .,_-

7wo genual ru!es ave Gekn Fc mjIateJ as .oviiDIemencery expres5l s nf bnnefren rt;nn 4n Ws sena_ (1) do no hai7n and f2 ; marimize possVc vrnen ts,9rct n i r, iml zr vot.i ole nari,s . : .

The Belmont Report
. ' An Ln]ustice a;curs when some Wnefit to which a person 15 entitled is denied without good reason or when some burden is Imposetl un0i.ly . RnoYier way Vf coiKeiviny Uie plinciple VF

, The Declaration of Helsinki
, . Ccvlcem'br the nFere,u of We SJhject must alway~ prevail m ove^ the Interests of susnce aiW souery._ ^Pnysirt~n. shnuk7abstAln fronn enga9lny tn resrarch Proje~~t~ . .

. .

Justice is trial For informed subjects that "in balancing n tI,F, s o a b

equals ought to be treated equally, =sent, "there (should be) no undisclosed risks to are more than minimal . . . . these different elements, the risks and berielits ch , 1 . 1 0 "' n s"""le"t n have been prutecteG, Beneflc~.nce ttws ie~u Ires f the

~nvbivktg human subjects unless they are satisfied that the hazards Inwlvzro are believed to be preci dable. . . .

.J1QS, each po[endal suDject must "[n any researLfi .Un hJRldil !K' be adequately informed o r tne arms, method s, anti cipa te d


l~yL n I ._ ' 'is nn ' IV

befipflts and Wential hazards or the study and the discomfort It may "Ihe 0 pdatenltial Ixmk,fiti,,, liazards and risceoifbr~ of a rew meth shoi,,W be wei ghed agains, the advantages of the best ,
ciPreM oiagnosUC ant] awrapeuoc mNttr;xfs . .. . being of the SUtrject,"


' I

that we pru:ect against [he rIrisk h hartn occa'he ' o( subiects and also th.+E we be w "n~ehI ~ ed ae oes n andns b'e"'to 0 'ne' benefits" -1 once e aboutO`he Ioss O be substant~sl "'e-sethat Me ed the fe ec" v` o "na"'mcan , l1e -se 0
iniyht te gained from research ."

" 7n research on man, the interest of science and wciety shuuld never take precedr .^e over miuideratiois rrlatecl to ; h e we l .n.





Recent, pertinent events
. Patien' : deaths in phase 1 trials
. Johns Fiupkln5 . Uri(vr I'Siiy of Pennsylvania

Johns Hrapkicos `
~ WR l ~'itJtw

" . o

Healthy volunteer Urn Roche, 19 years old, died as

result or uamcipat;ng in a phase. i salecy trial in zooi
Physician conductirsg trial, Dr . Alkis Toqias, restricted by FDA for 3 years, FDA issued warninlett°r 21 months after Ellen's deact,, and offered-restricted agreement

o Pharmacy compoundlng experience
a Medical device experience

o Within five days of inhi;ling expanmenta! compound, Ellen was admitted to intensive can wlth respiratory distress. Sf~e died within a month of lui)g failure, . Qr, 7ogias had sti!bmittPd ;At, [ND to FDA years earlier 1997) to study capsaii.in in lungs; FDA prohibited k im from initiating that 5tu6y




01 :44F)









Johns Hapkirs


ro~ W.min9 :. .r,e., htm 4MVnN4 ¢n1uV IR&n1t7~9.~. w m.1 .5r. . sar}sttrahnv.u,sv:n o- uV. wJn," , ke ' w' ~a.,o.ruvam n.onnroewe~~.rv ma~ ':m'o a  wiWC. r . uLywcyutt~amaM.,,etniro^

University of Pennsylvania

.4c~dm4Rfo.ed Mu M X~~i, .a ~, ~ :. .r ,.Emw~s Y.H .~W imim~i-_K  hy,ov.~~~~, n w xat7'ah~n n ', d >h



' .

. Violations . Did m)t submit iND application for use or unapproved new drug . Informed consent failed to disclose inhalation of nexanethonfum bromide experimental use of drug
a [n,`ormed consen : failed to disclose material with labeling, stating :

1999 curing a phase 1 gene therapy trial . . Clir,ical investigators : James Wilson, Mark 8atshaw, and Steven Raper, navc all been -estricted, with restrictions more severe for cril investigator
. Tnal investigating use of y2neUcally enyineered

)esse Gelsnger, an 18-year-old teenager, died :r


chemical grade, labeled for laboratory use only,

be harmFui if inhaled " . Consent farm not updated lo Include unexpected adverse events experienced by first two subjects in i:rlal (persistent cough/shortness of breath)

Do not breathe dust ; may

adel to ameliorate an enryme deficiency,
om(thine transcarbamy!ase deficiency (OTCF~)

. Some irdivitiuals are born with 01 -l which is a deficiency In an essaneial enzyme needed to form urea, corna and deatn can occur with l;7CD

University of Pennsylvania
. .
i .y :.+wvcL~ aH N 1~+Lt,m . .vJ Te.s,rr M vE .1 . .e ~a ~voJf~lanLwn'vv " Wn .v

Pharmary Compounding Experience
~~ ." " ~'~ W ~y.,y1a~o 1~~~i a4RVfIJ Ihvrt ~Y1PIl7 .H t~ y~ . lN:h~J4r. ~f .51u>M v4~.a¢lY7> . .-_ . ._ . .SCrJ .I . . . . A~l +he ~_-

o_ . .,.






.r .

. .. mao._0 .o . .1v




oea[ns fn monkeys durinq q~edlnical tzes;ioq

. ]esse died wic+rin a Yew day .; o` having mml Irill into
. . '

Jesse', d . : .ease was being well mnValieci by medication his liver U.S . governrticcit prosecut~l InvrStiqatora and thelr :

. 0

P`,armaey eOmpoul law i5 oar- of 199! Food, Drug anC Modernization AcT (FDAMA) 1_ImiCed to Rx rFquesYS ; may no- co-pound large quantities 6f conSmerCfally "vvdIIdhIe drugs ..

crqanizatiors alleging :

. Trial p~:i')cu .cd toxlaties in humans Mat shn~~!d have resuliec In it; lermtnaFOn . but stud)' c.-~nh'~:ea


. Reaons misrNpreserr,cec actual .imicai ~Irvtl sjhrit~~d m FDA, N :~, a-d :nas



l .ein . contend conduct al ail dm- lawful aod appropriate

1nfcr(r cC II en' ?~-"css dl() -t dill .- ~''~ : anJc:pated t-1cYCii.-c . vWiaoo~s oecrvu False Calm, an n 5uo,bml false uaeGP~~u to FDA and Ia6s

o UsY o` acceptable ingredil approved proc'uds, monographs Of USP dtiJC~S . Sell ;,robiems : 3 Infants died of intravenous ~;olutiqn inc orrettly prepared by pharmacy, 1 patient blind in one eye due to pharmacy-prepared eye drops

that veere not sterile

their emplnpen patd Fine ; of §517,495 and $514,622 to settle
the case



Pharmacy Compounding Experience

P ., 



- NVZ'4n . .

uv'~ ""x ~

rin ,

Medical Device Experience

. ~:Mw+XhW' .t91 L

.LI ..VLmt

`C ~ (~

.~ 4'C AM fl7~-Y~LI~~~et'kn'SI+era .rm~n .it5~asw n1l,Y . v




. .

Carneys 'D~ajp Rochester, NH -Fentany k~ttipops (naru,tic analgesic) wtthoutrequlred labeling (safety na7ard for chfidren)
Ur9ent Care Pharmaq, Spartanburg, St=- crntaminated methy lp recinisolrme acetate Injecliai - rare Fungal (wang&lla)

menin9its, six patients affected, one died


. .

Mud-Mart PWrnonary Services, Nnaatn and 8akcrsReld, CA C~ass I recalls of albuterol lnhaler due to ~a631/qUefHCicns

Slnce 1490, FDA ha, found at least 55 quality problems with
campou%ided product5

m Deadly ;:lass i re~:all< have Increased more than 300°io since 1998  Greate5".: nureib~P of warning letters, Yrorn FDA are being issued to medical device firms, with a l arge s; Rufnber to sponsorv, clinical investigators and IRS a For inVe5tlgdtl0fld! 0<vICOS, only part of CGf~'IP ( S~ uallty S ySter :'1 R?g . :IgCiof?) K'f1lClt rT1'~ be fOllowed ,
i5~7c75iJf'i Conkra~s

, i




. .

. .

:n 2001, FDA survey of i9 programs (Including harnonal products aril anesthe ti a, s te.- o~d s, sterile in)ectab'.es, ophthalm~cs ~d asfhma medlcaNone) tound 34Ci~ of tssted products( (aifed one or ml tests, Many were Subpo :ent (59I,
- 89°,b of labeled strell In same opc~otions, large quantities m t-ny made In advance o( receiving prescription, copying approved

(~~~s!ior! : CoUid thcr~ be a link between not Follo~rririr~CGMPs fo~ inw_StIgaCo~al devices, hasty or rushed c,hniCal or product development, and ChB
deadly C2Cal15, warn no letters, and compliance proble




comrnerr.lal drug, subpotent/superl issues






01 :45p






p .25

Why Logic May Be Flawed
' ' . ~

,.,~VUhy Logic May Be Flawed
n Assumph~ r~ ;.cL to marRet (our ex,~e~;mce te~ls ~c [net it may =,_,~~P= m,arKCt : I( n0: reproducibla or su(fidentty CocvmerteG, or I f paYlen6~ ;~;urcd . ~1"35C 2 Is ryR~caIIY "blp ~nxn^ m

. .



. Guidana is not legelly blndlng, nor casily er.fortedMe " Questron: Does agen .ry yet ha~m Cnough er.pedence valfh phasF 1 ur ?arler (~°d~:cal research, etc.) s~~Nxtions to be rr~kinq proposal? Ylhat dine do FDA have that ,upports [N5 p ~ eposal ~ ( dt~.s :n phase t and their root cauoes, corr.riai ins xctlon8i~flndlrt~as durir phase 1 , or treatment INQ NspeCtirn>, s:irvey or aralySis of phase~.
. . 0 :7Bf8CI0n5, &c .) AssumF6on ttiat io ividuals K UI !eam aseptic lecFmi:pu CGhiPS, " .:, withou, regulaU r 4irig llsn~~ W

.s Patent safely [nnce~r . If material o, oing i~1n hurtlans, it Sha.ll, Crt made indnr a m.rxmum, [S;h7F re6wlau~ . PhaSe 1 is fcund9Ua, of trial






E v

small oortqsn~es in Implernenhng aIf CGMp syslems.) FDA hav 6ef,~,leG It fill (Z : CPR 58 . GoW L0h91aWiV Pradic~s) for ~recNnical o- animal tesUe,q, also is still requiring Gy?s for pnax II and 1 :1 -- why drop pmteC.!an d~ermg ~~1wse i? ~~~,,,,,, x°st14n' Are mtK^~~PS o. Lilt aoeY .'y~ Seekfng ln ir~rJemnIiY companles, '

. "

Pssixrp,iun aat ndiwdva's'w~ill be. able

... . . .


especleily asepoc pirxesslng [o ProJu~ ~Ilrlcet rcntena! safdy or r ding n gurlIn  daeument

fez,,, enuugh at":t Gt~'u~ o(
, .

G~rdanm lc curreMly 17 pages tong ; aseptic or stent piviiucLS veh

d mculS to 1 While Anmei R-', s , no ; cor .ce`^md abo-R P ;oneer firms. w? r!m V~ COf1CU11(~ bc;JC If1iri 0< <11CdKt~ rfSGP .fC11 I(15CICUIIt71-IS W!1ch have never made cllckal mater;uls before. ,

~YSICId775, 9f tflfCke', fC5F3fC0 :`. : front eCCP11PCHblIRY In FFH1 :A 1'~ Are hL'pld(~ DB{71gS Whp VolUiCCt' (Q' p118$P l CIInICDI frldl5 fCSS'vdIUdbIN .r than snlmakS? Are pd(terb In phase 1 trials k5, ~alua6k tonr Da6nrs in pha>c 2 or pl ase 3 trals~ Ar~ hu . pr. x,.^ .g w ho ~o lwKCCr l or phorc t h Ts ~xpr .ndebie ,ihce there ~r< Irxer Of Ih~.hr' it m~.tU nothing !or agency to krM.p CG^1P regWatrony o~1 booF.-l QuCSiKn: Is " 'rc n J '¢y Uucw. ny -n tF c taare!' Rec~gniZing M. t lACy d. enforr or rnutinely inspe~.-t In human dinl,4sl h" .e not have the staff Apis currenGY rer,l~lard off i Aft 54aN[orv authority, butS:Fi Q%A `!s7 for API, 5, deta .lao Pagus :






Quesnon: IS this a Itawed use of rlsk manayement cunc~apt? Are the nurr ~vers involv(id more iRlportdnt then the spHCieS Invohl%9C7

. Why Logic May Be Flawed ----

Why Logic May Be Flawed ~~ _ _
" , .
, +

Estimated savings are rrlinlmai (¢1,940 per ING - same cost to send

Has kcenq' Yrt dune a Mot wuse analy5a o'wt,a[ Is causir~ dra-riatc mcrt>ase m inetllcelrJev~ce dl class 1 recall5, and Increa5e6 ru~mbee ,~,,'F, usmk,p iettrrs7 Why en-rate drvice sector wS :Y~,cwt unde.s~ndmg Doe, nut acnnow3edgetile oriu;io~ ;hat is already re>ultinq in so-v, indlvln~nls th.r~.ktr~ thsc m!_y may use no,-GNP material Ir phasc i i-4r,,med cans c[ will ne M t o ch ange to inrnra~ pa[, ncs of char ge m e smr.dard, Increased risk. to pa3.ects :,C fir y

1 person to an industry two-day setl for n5ks invdveC Estimated additional ct,st o( $610per IND fe : chemical prtiduCC~s And laborator ies who have not ye t ma de produc t d oes not yet a ppear to address costs involved ki facility, equipment, or contracting work out,
;ertlcularty for aseOUUsterlle products (unless that is a ¢iven) Question : IS Agency beCUmlriq irlofe of d research-e, tabling 01

riere an: carnpttari i-u;es~


~ .

product marisetny agency rather than a consumer protection agency'
D_ e~~~Y wnnt to write man Y warning Ic :has For vivlative Nrms or 9 or gamzation5? ~~r Issue restricted agreements to clinical inveSCrgatars `

Ethical mn5idler8tiot 5' Per° Pekaont Report, D_~araGon of Heisinki indnvlua) pNCs nqhtS :uiYigh all oer r,gL, are pallei[s sNwld c S flat' Wily should ~ve c-~e aWut G IS? de .rause a!I o' us know (or wil b,uw) v~navne c:, v tmnily ,-,be, -. wit cor,,ldcr pnrtidpotlng


. a
. . ..

or take them to caJrt If there Are more patient deaHis in phase 1?

Agency's missicn : where 6vo standards apply, stMCier should prevail . HisWry has shown that paper reviews do not work (t's why FDA tieas

?granted granted i~spectior,al author!ty) and that nol performlng necessary g can be deadly (5uS!anllemlde, etc.) . _.. . . . . _ . . -._ . . . ._._~J .

I f


In c inkal [dal . From a Qn penpzcGve, cgnnot allow harin LO come to paflenr if hrmw [t

can ee prmentrd . Protec:~ng ~ne P.1,-,,s rumne~ onr_.
._ _



I .

impediment to scientific exploration or i nnovati on ? ~


Y e~'

1 ho;e .mzt the aganowif? rondwithdrawing the airec ; final rile, and keepinq phase 1 na:ensl for homans under the
pmter4oen(theCGMP rc ;fjaNon .


. Are CGMP tequirernents in phase i truly the . Are CGMPs truly that burdensome? . Why ciol ttiis i iew rule apply to phase 1 and
not (JfinaE:eS 2 and 3?
s IS YhC dt efl C}I just seeking to deregulate ] .

n "

one option. wousd be lsswrj Dvposed cMFs for invesriqanonal drugs as FDA had originally cQrsidered . If se hip draft giddAnc-e l could be us"] as . start W those proposed v nans.
Another Option IS that the draft guidance muid be firaGZec1 and teplaCe the! eerller 1991 qt ; dance as planned, but with no exr_oon of phase 1 material from CGMP regWation_ mA

, .

. .

SORlethltlC] (aflVthiSl J) where it may affect the


. Will "GMP Lite" really Improve drtlg
de:vc :lOpfnefit?

fewest people .


A third option would be pr :,~posing and takEnq the phase 1 g uidance thrvu gfi the [CH pracpss.

Your Opinionf ma ditftr . ^h^ hoj~e i5 that ridlvlduels and a"qanlzatlans wirh experience manufaduring clinical and commercial product will tziki Fha. Ume to think about and send in : Nny written comments thnt they may In.3ve IT) the agency .





01 :46E:)






P .26

. . . . . . . , .

Wh at You Can Do

~~ 1~

Rcac Fon proposais and draft guidance, diuus, them ~~i m your yuur uiganizaeon has, if
to, sta!f, and s~end any written mrranents FOA by the commenC due dates . you chowe to do so, Men subn,ittinq comments, please be slPciric .
Ilnal rule, If you are commenting on theproposed or dlrxt state i( you are for or against the rule, and why. r~~son'ng, logic, and qmd sC.ence . Use Attach any references . Include the docket numtrer . E Ensure all curnmencs are mevan t . State why the rule is Inappropriate, stafe. P- ,(de a thalienpe to the rule's Underlysng hremh Lx why 'tie ru~e is Ineffective w unan:epPable wnrrant a sLbstaeitivc issues cho'j1d be serious enough co , reso)nse finm the agency, and should sufilclenl:y challenge [he agency's view that the rule is needed .

ou Can Do 1, at y on the draft guidance, Docket 2OQ5pTo comment
0286 , seixl your com :nent5 6y Marcn ZD; 2U06 . You may send them electronically to : .

. f[ _(1 Y1~~ 5EARCHRF~U JLT~, -~FM. comments tod Dr send two copies of your written


Docket No . 200SD-D28b Division of Dockets Management (HFA-305) Food and Drug Administration
Sb30 Fishers ~,8P1'~' . Rm . lU(~l RoCkvllle, MD 20A52

. ' !




____ _

---- -



'1~ . ,_ ~~.~ . To comment on the proposed o9' direct final rule to exempt phase 1 material from CGMP regulation (these r.~~es are identical ; any comments received wiii be applied to bnth) or Docket 20DSN-0285, send vow comments by April 3 , 2(706 . ..

What You Can Do

. You may send them electronically to :
htto :/lw4vw .a ~ IR ~ .f

mm AF . Or send two copies of your written comments to : Docket 23OSN-0285 Division of Dockets Management (IiFA-305) Food and Drug Administration 5630 Fishers lane Rm, 1061 Rockville, MD 1QAt2

, ~ ~f` Ot5 lp ,j~ oc ~ ~SS. Pv ~ k $S

"~ ~~ .pirect Final Rule, Curtr.nt .Goad Mani(actunnr, Prattf[e ` k~pulatlon and tnvestig .anai New Drugs, I i:v~llyr~vw frfa aovlc~ r n_~~d~kai;/48hiW-353 _2tm ; Rule Currer,t ~A),1 Manu .'aduring Practice Regulation o Propost~ and inver+igatbr,ai Ne-+ Drugs, LtS¢11r4tW-,f_da".44='~~'=~~ ~~"'~rrL26-35~ , hL Phase 1 v iMDS- Approaches to Cflzrp!ying with CGMR During Draft GwGxrce ; Jar~~ry mob, h~t~;Ili~rill.fd~-9s2YL~~"1-~SlQ°txe~`` -4%UI95~Q~~G~d14a41udf
. Expluratc}ry INP Sludies Guidance, January 2005,

Re com mended Reading _--


. .


'~ `Y-, R2view --- What FDA is --- _ pnopasmg .

-~: Thank You `''

;OA's inisven and history

. ~~tix~~ ~~F a~c a ~~: _~-«l-ect~NF

. Charlie Gammill, University of Georgia
~~~ Conference

Thank you a!! for participatir~y `-~'_--


, Mc,k a ,d~;«cxp~r ;en« . Draft 9uidance .lawed . ~Nhy Icgic maY be' . ,,,,flt your orja-,Gun c, do

Recent even'~u . paPan; c7ea:hs in phase : mail .g , Ptnrma~y compoonA~r e~pc:r~cncc

. '~'o all of my C~If.-'TItS and subscribers,



mentors, friends, and current and former members of the agency who have helped me to formulate my
thoughts on this subject t