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OverviewsonFDAHistory>FDAandClinicalDrugTrials:AShortHistory

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AboutFDA
FDAandClinicalDrugTrials:AShortHistory
SuzanneWhiteJunod,Ph.D.1
Thefunctionofthecontrolledclinicaltrialisnotthe"discovery"ofanewdrugortherapy.Discoveriesare
madeintheanimallaboratory,bychanceobservation,oratthebedsidebyanacuteclinician.The
functionoftheformalcontrolledclinicaltrialistoseparatetherelativehandfulofdiscoverieswhichprove
tobetrueadvancesintherapyfromalegionoffalseleadsandunverifiableclinicalimpressions,andto
delineateinascientificwaytheextentofandthelimitationswhichattendtheeffectivenessofdrugs.
WilliamThomasBeaver2
Overview
TheU.S.FoodandDrugAdministrationhasevolvedasoneoftheworld'sforemostinstitutionalauthorities
forconductingandevaluatingcontrolledclinicaldrugtrials.
Ancientcivilizationsreliedonmedicalobservationtoidentifyherbs,drugsandtherapiesthatworked,and
thosethatdidnot.Beginningintheearlytwentiethcentury,therapeuticreformersintheUnitedStates
andinotherplacesbegantodeveloptheconceptofthe"wellcontrolled"therapeuticdrugtrial.This
concept,included,forexample,laboratoryanalysisfollowedbyclinicalstudy.Asmedicalhistorianshave
pointedout,however,theseearlyreformers'therapeuticvisionoftenfarexceededtheirclinicaland
experimentalgrasp.3In1938,anewlyenactedU.S.Food,Drug,andCosmeticActsubjectednewdrugs
topremarketsafetyevaluationforthefirsttime.ThisrequiredFDAregulatorstoreviewbothpreclinical
andclinicaltestresultsfornewdrugs.Althoughthelawdidnotspecifythekindsofteststhatwere
requiredforapproval,thenewauthorityalloweddrugofficialstoblockthemarketingofanewdrug
formallyordelayitbyrequiringadditionaldata.Theactalsogaveregulatorslimitedpowersof
negotiationoverscientificstudyandapprovalrequirementswiththepharmaceuticalindustryandthe
medicalprofession.Aworldwidedrugdisasterin1961resultedintheenactmentofthe1962Drug
Amendments,whichexplicitlystatedthattheFDAwouldrelyonscientifictestingandthatnewdrug
approvalswouldbebasednotonlyuponproofofsafety,butalsoon"substantialevidence"ofadrug's
efficacy[i.e.theimpactofadruginaclinicaltrialsetting].Increasingly,responsibilityfortesting
standardspreviouslyestablishedasvoluntarybytheAmericanMedicalAssociation's(AMA)Councilon
Drugs,theU.S.PharmacopeiaandtheNationalFormularyweretakenupbytheFDA.Since1962,FDAhas
overseensubstantialrefinementstothebroadlegalrequirementthatpost1962newdrugsbeapprovedon
thebasisof"adequateandwellcontrolled"studies.4
MedicalObservationAsPrecursortoClinicalTrials
Clinicaltrialsareprospective,organized,systematicexposuresofpatientstoaninterventionofsomekind
(drug,surgicalprocedure,dietarychange).Theearliestrecordedtherapeuticinvestigations,however,
lackedtherigorofamodernclinicaltrial.Basedlargelyonobservationsandtestedthroughtimebytrial
anderror,ancientmedicinesuchasthatpracticedbytheEgyptians,Babylonians,andHebrewswas
closelyalliedwithreligion.Nonetheless,someoftheseearlymedicalinvestigationsdidyieldsome
importantsuccessesinfieldssuchasminorsurgeryandorthopedics.TheHebrews,inparticular,excelled
inpublichygiene,buteventheirpublichealthstrictures,soeffectiveinpreventingepidemicdisease,were
observationalandexperientialratherthanexperimental.5
TheBabyloniansreportedlyexhibitedtheirsickinapublicplacesothatonlookerscouldfreelyoffertheir
therapeuticadvicebasedonpreviousandpersonalexperience.6Thefirstmentionofapaid
experimentalsubjectcamefromDiaristSamuelPepyswhodocumentedanexperimentinvolvingapaid
subjectinadiaryentryforNovember21,1667.Henotedthatthelocalcollegehadhireda"poorand
debauchedman"tohavesomesheepblood"letintohisbody."Althoughtherehadbeenplentyof
consternationbeforehand,themanapparentlysufferednoilleffects.
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Oneofthemostmemorablesuccessesfromanearlybutearnestclinicaltrialwasactuallymoreofan
anomalyratherthanaharbingerofgreatprogressinmedicalexperimentation.Britishnavalsurgeon
JamesLind(17161794),whohadlearnedofthedeathofthreequartersofaships'crewduringalong
voyagearoundtheworld,plannedacomparativetrialofseveralpopularlysuggested"cures"forthe
scurvyonhisnextvoyage.Twelvemenwithsimilarcasesofscurvyateacommondietandslept
together.Sixpairs,however,weregivendifferent"treatments"fortheirmalady.Twoweregivena
quartofciderdailytwoan"elixir"twoseawatertwoaremedysuggestedbytheship'ssurgeon
(horseradish,mustardandgarlic)twovinegarandthefinaltwoweregiven"orangesandlemons"
daily.Onemanwhoreceivedtheorangesandlemonsrecoveredwithinsixdays,whiletheother
recoveredsufficientlythathe"wasappointednursetotherestofthesick."AtfirstLindquestionedhis
ownexperimentalresults,butbythetimehepublishedthem(1753and1757)theywererecognizedas
important.Nonetheless,theBritishNavydidnotsupplycitrustoitsshipsuntil1795.7
Althoughsimpleobservationmayprovideastartingpointformedicalstudy,however,experiencehas
shownthatitisrarelyefficientatadvancingmedicalknowledge.Asoneearlyproponentofplanned
experimentationintheformofclinicaltrialsremarked,"whenwearereducedto[mere]observation,
sciencecrawls."8Amoderndrugregulatorismoreexplicit,acknowledgingthatmodernretrospective
[studies],epidemiologicanalyses,andastuteobservationsareallinstructive.Althoughclinicaltrialsare
nottheonlywaytofindthingsout,theclinicaltrialisunique."Itisundertheinvestigator'scontrol,
subjectnottodataavailabilityorchancebuttohisabilitytoaskgoodquestionsanddesignmeansof
answeringthem."9
EvolutionofClinicalTrialConceptinAmerica
AccordingtomedicalhistorianHarryMarks,themoderncontrolledclinicaltrialislargelyanAmerican
inventionasstatisticallybasedclinicaltrialsbecameacriticallyimportantpartofevidencebased
medicineintheU.S.followingWWII.10Certainlyclinicaltrialsinthiscountryhaveevolvedinpursuitof
alargertherapeuticgoaltoseethatthephysiciansusethebestpossibletherapiesavailable.Itis
interestingtonotethatinthelate19thcentury,U.S.antivivisectionistsprotestedagainsttheuseof
humanbeingsassubjectsinmedicalexperiments.Intheirquesttoprotectanimals,theyviewedboth
animalsandhumanbeingsasequallyvulnerable,andfearedthatthereplacementofthefamilyphysician
bya"scientistatthebedside"wouldinspirenontherapeuticexperimentation.Itwastheantivivisectionist
andplaywrightGeorgeBernardShaw,infact,whofirstusedtheterm"humanguineapig."11
Nonetheless,asearlyasthelatenineteenthandearlytwentiethcentury,interestinclinicalobjectivity
grew,spurredonnotonlybyastoundingsuccessesinlaboratoryscienceandclinicalmedicineabroad(e.g.
discoveryofmicrobes,pasteurizationofmilk,developmentofanthraxandrabiesvaccines)butbecauseof
thesorrystateoftherapeuticsatthetimeinAmerica.In1880,patentmedicinesamisnomerbecause
nothingbutthelabelandthebottlewereactuallypatentedortrademarkedconstituted28%ofmarketed
drugs.By1900,however,theyrepresented72%ofdrugsalesandproductswithinertingredientswere
promotedasvigorously,ifnotmoreso,thandrugswithactiveingredients.Itwaspopulartoblameboth
thegulliblephysicianandtheignorantlaymenforbeingequallytakeninbytheadvertisingexcessesof
theera.12
TheAmericanMedicalAssociation(AMA)begantopushforfederalevaluationofnewmedicalproducts
hopingtomakeadentinthepatentmedicineindustry,butitwasunsuccessful.In1905,theAMAformed
itsownCouncilonPharmacyandChemistrywhichleviedafeeonmanufacturerstoevaluatetheirdrugs
forquality(ingredienttesting)andsafety.DrugsacceptedbytheCouncilcouldcarrytheAMA'sSealof
AcceptanceandonlyproductswiththesealhadaccesstotheadvertisingpagesoftheJournalofthe
AmericanMedicalAssociation(JAMA).TheAMA'sChemicalLaboratorytestedcommercialstatements
aboutthecompositionandpurityofdrugsintheirlabs,whiletheCouncilonPharmacyandChemistry
followedupwithsafetyevaluationsandrudimentaryefficacyevaluationsdesignedtoeliminate
exaggeratedormisleadingtherapeuticclaims.13AlthoughtheCouncileagerlysoughtevidencethatdrugs
hadaneffectonthecauseorcourseofadisease,theSealwasawardedtodrugsthatmerelyprovided
symptomaticrelief.AlthoughtheCouncilwouldhavelikedtorelyuponclinicalstudiestosupplement
laboratorystudiessubmittedbydrugmanufacturers,theylackedthenecessaryfundingtosupportsuch
studiesandtheAMAdidnotauthorizetheCounciltorequirethem.Insteadofrelyingontheanecdotal
informationprovidedbyprivatepractitioners,however,theCouncilreliedheavilyontheopinionsand
recommendationsofCouncilmemberswhowerewellrespectedmedicalspecialistsandscientists,a
progressivepracticefortheera.OncetheirevaluationsbecamearegularfeatureintheJournalofthe
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AmericanMedicalAssociation(JAMA)theCouncilbegantomakeinroadsagainstthecommercialismthat
physicianshadfeltwere"debauching"medicaljournalsand"tainting"medicaltextbooks.TheAMA'sdrug
certificationprogramremainedinplaceuntil1955.
ClinicalTrialsandthe1906PureFoodandDrugsAct
WhiletheAMACouncilonPharmacyandChemistryheldoutacarrotofcertificationtoethicaldrug
productsthatmettheirstandards,thefirstfederalfoodanddrugstatute,the1906PureFoodandDrugs
Act,wieldedlittleinthewayofastick.TheAMAhadbeenunsuccessfulingettinganykindofdrugreview
inthenewlawandthestatutemerelyprovidedalegaldefinitionfortheterms"adulterated"and
"misbranded"astheyrelatedtobothfoodanddrugproductsandprescribedlegalpenaltiesforeach
offense.ThelawdidempowertheBureauofChemistry(forerunneroftheU.S.FoodandDrug
Administration)toseizeadulteratedandmisbrandedproductsthatmovedininterstatecommerce,butit
simplyadoptedthedrugstandardsaspublishedintheU.S.PharmacopeiaandtheNationalFormulary.
Thelawalsoprohibited"falseandmisleading"statementsonproductlabels.Inthecaseofdrugs,the
lawlistedelevensocalled"dangerousingredients"includingopium(anditsderivatives)andalcohol
which,iftheywerepresentintheproduct,hadtobelistedonthedruglabel.Thislistingrequirement
aloneinspiredmanymanufacturerstoabandonuseofmanydangerousingredientsfollowingpassageof
the1906Act.Buteffortstoprohibitfalsetherapeuticclaimsondruglabelsweredefeatedbothbythe
SupremeCourtandtheU.S.Congress.
Duringthe1920's,30'sand40'smedicalresearchersbegantoconduct"cooperativeinvestigations"
designedtoovercomeerrorsattributedtoindividualobserversworkinginrelativeisolationandreplace
themwithstandardizedevaluationsoftherapeuticresearchinhundredsofpatients.14Therapeutic
experimentation,however,didnotbegintogainatruefootholdinmodernmedicineuntiltheU.S.legal
systemstoppedequatingexperimentationwithmedicalmalpractice.Aslateas1934,statecourtsseemed
toupholdtraditionalviewsthatthedoctorwasboundtoactwithinacceptedmethodsofclinicalpractice
andthatpatientshadnotconsentedfortheirphysiciantodeviatefromthesemethods.15Inalandmark
stateSupremeCourtdecisionin1935,however,thestateofMichiganseemedtorecognizeandauthorize
controlledclinicalinvestigationsasapartofmedicalpracticewithoutsubjectingtheresearchertostrict
liability(withoutfault)foranyinjurysolongasthepatientconsentedtotheexperimentanditdidnot
"varytooradically"fromacceptedmethodsofprocedure.16Inparticular,theMichiganSupremeCourt
acceptedthatexperimentationwasnecessarynotjusttotreattheindividual,butalsotohelpmedicine
progress."Werecognize,"notedtheCourt,"thefactthatifthegeneralpracticeofmedicineandsurgery
istoprogress,theremustbeacertainamountofexperimentationcarriedon."
By1937,ithadbecomecleartoregulatorsandtoanincreasingnumberofoutsideorganizations,including
theAMA,thattheoriginal1906"Wiley"Acthadbecomeoutdated.Breakthroughdrugssuchasthefirst
sulfadrug,sulfanilamide,newdrugsincludingamphetaminesandbarbiturates,andbiologicssuchas
insulinwerecomingontothemarketandbeginningtotransformmedicineentirely.Clinicaltrialsand
humanexperimentationwerebecomingincreasinglymoreimportantinmedicalresearch.Moreover,turn
ofthecenturypatentmedicineswithinertingredientsandquirkybutquaintlabelswerebecomingatrue
publichealthdangerwhenpatientsreliedonthemratherthanseekingouteffectivenewtherapies.The
caseofBanbar,inparticular,convincedregulatorsearlyinthe1930'sthatthe1906law'srecognitionof
therightsofproprietorswasbecominganincreasingimpedimenttoeffortstoinsuredrugsafety.
Soonafterthe1906Acthadbeenenacted,adisputearoseoverthemeaningandenforcementofthedrug
labelingprovisionsofthelaw.TheSupremeCourtruledinU.S.v.Johnsonin1911,thatthenewlawdid
notprohibitfalsetherapeuticclaimstheproductinvolvedwaslabeledDr.Johnson'sCureforCancerit
justprohibited"falseandmisleading"labelclaimsregardingtheingredientsoridentityofthedrug.In
1912,CongressquicklyenactedtheSherleyAmendment,acompromisethatmerelyprohibitedfalse
therapeuticclaims"intendedtodefraud"theconsumer.Provingthataproprietorknewthathisdrugwas
worthlessinordertodemonstratefraudunderthestatute,however,couldbeadauntingtask.Tocitea
singleexample:anoldpatentmedicinemakercreateda"cure"fordiabeteswhichhemarketedas
Banbar.Itsactiveingredientsincludedmilksugarandequisetum(horsetail).Theproductwas
particularlydangeroussincediabeticswererejectinginsulininjectionsinfavorofBanbar(thehormone
insulinhadbeenisolatedin1922andwasalifesavingtherapyfordiabetics).FDAseizedtheproductin
themid1930s,chargingtheproprietorwithfraudundertheSherleyAmendment.Inhisdefense,the
proprietorsubmittedtestimonialletterswrittentohimthankinghimfortheproduct.Hislawyerargued
thatitwasobvious,sincethesesincerepeopletookthetroubletowritehimandthankhim,thathehadno
ideathattheproductmightnotbeeffectivemuchlessdangerous.Governmentofficialsselecteda
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representativegroupoftestimoniallettersandmatchedthemsidebysidewithdeathcertificatesfromthe
sameindividualsindicatingthattheyhaddiedfromdiabetes.Althoughthepublichealththreatwas
obvious,thecourtruledthattheproprietorhadnotintendedtodefraudhiscustomersandtheproduct
remainedonthemarketuntilCongressenactedanewfoodanddrugstatutewithoutthissocalled"fraud
joker"in1938.Banbar,inparticular,gavedrugregulatorstheirfirstdirectexperienceinterpretingdrug
dataobtainednotfromdirectclinicaltrials,butfrombothuncontrolledtrialsand"historical"data,oneof
threetypesofclinicaltrialdataeventuallyrecognizedasacceptableunderlawin1970.17
MostconsumerswereunawareofBanbar,butin1937,abroaderdrugdisasterdidcapturepublicattention
andfirstdrewthefederalgovernmentintoplayingalimited,butsoongrowingroleintheevaluationof
newdrugs,includingtheconductofclinicaltrialsfornewdrugs.In1937adrugcompanydevelopeda
liquidpreparationofthefirst"wonderdrug"sulfanilamide,usedtofightstreptococcalinfections(i.e.strep
throat).Theproductwasnottestedinanimalsorhumanspriortomarketing.Thesolventusedto
suspendtheactivedrug,diethyleneglycol,wasapoison(chemicallyrelatedtoantifreeze).Itrequired
theentirefieldforceoftheFDAtoretrieveallavailablebottlesofElixirSulfanilamidewhenthecompany's
ownrecalleffortsprovedinadequatetothetask.FDAofficialssoondiscoveredthatadequaterecordshad
notbeenkeptbyeitherphysiciansorpharmacistsdocumentingprescriptionswrittenandfilledforthe
poisonousproduct.FDA,however,wasonlyempoweredtoactagainstthedeadlyproductbecauseitwas
misbrandeditcontainednoalcoholwhereastheterm"elixir"impliedthatitdidcontainalcohol.
ClinicalTrialsandthe1938Food,Drug,andCosmeticAct
Congressreactedtothetragedy,whichkilledover100people,byenactinganewfederalfoodanddrug
statute,the1938Food,Drug,andCosmeticAct.Anewprovisionintheactrequiringdrugsponsorsto
submitsafetydatatoFDAofficialsforevaluationpriortomarketingappearedwithrelativelylittle
discussionfollowingontheheelsoftheElixirSulfanilamidedisaster."Insteadofgoingtomarketbasedon
theirownassessmentofthedrug,sponsorshadtonotifytheFDAoftheirintenttomarketthedrugby
submittinganNDA(NewDrugApplication),"explainsDr.RobertTemple,currentlyheadofFDA'sOfficeof
MedicalPolicy.Althoughthenewlawdidnotspecifyanyparticulartestingmethod(s),thelawdidrequire
thatdrugsbestudiedby"adequatetestsbyallmethodsreasonablyapplicabletoshowwhetherornotthe
drugissafe."SponsorswererequiredtodemonstratetoFDAthattheyhadcarriedoutallreasonably
applicablestudiestodemonstratesafetyandthatthedrugwas"safeforuseundertheconditions
prescribed,recommendedorsuggestedintheproposedlabelingthereof."18Inthefuture,FDAcoulduse
thesenewtoolsnotonlytobanBanbar,buttotryandpreventdrugdisastersratherthanmerelyreactto
them.
Underthelaw,therewasnotruerequirementforFDA"approval"or"clearance"ofanewdrug.Rather,it
waspresumedthatmostdrugswouldbemarketedandthereforethedefaultpositionwas"approval."19
Underthe1938Act,thegovernmenthadsixtydays(couldbeextendedto180days)tocompleteitssafety
evaluation.Form356,theNewDrugApplication(NDA),requiredinformationaboutallclinical
investigations,afulllistofthedrug'scomponentsandcomposition,methodsofmanufactureincluding
facilitiesandcontrols,andcopiesofboththepackagingandlabelingofthenewdrug.Ifacompanyhad
notreceivedaregulatoryresponseattheendof60daysitcouldproceedwithmarketingitsnewdrug.
Regulatorsadoptedmanyofthestandardsandrulesofevidencefirstadvocatedbyturnofthecentury
therapeuticreformers.20LaboratoryanalysisakintothatoriginallyconductedbytheAMA'sChemical
Laboratoryinitiallyscreenedmostnewdrugs,companieswererequiredtoconductsafetystudies,andan
increasingnumberofdrugswouldsoonbestudiedinthekindofclinical(cooperative)drugtrialsthatthe
AMA'sCouncilonPharmacyandChemistryhadadvocated,butnotconducted,earlierinthecentury.21
Animalstudieswerenotrequiredunderthe1938Acttoprecedehumandrugtrials,butsuchstudies,
includinganimalautopsies,couldberequestedbyregulatorsaspartoftheagency'sdrugsafetyreview.
FDAalsobegantoemploythepractice,similartothatoftheCouncil,ofconsultingexpertacademic
specialists,oftenbeforemakingafinaldecisionondrugapprovals.22
FDA'sstatutoryauthorityoverproductsincreasedasaresultofegregiouspublichealthdisasters,butthe
associatedscientificmethodologytoevaluatesafetyandefficacydidnotaccelerateintandem.
RegulatoryworkunderthenewdrugsafetyprovisionsoftheActwasfairlylimited,althoughthenewlaw
didsanctionfactoryinspectionsforthefirsttimeandofficialswereabletoeliminatemanyworthless
productssubmittedforapprovaltotreatseriousdiseases(i.e.canceranddiabetes)byholdingthemtobe
"unsafe"underthestatute.23Regulatorscoulddenyanapplicationifthesponsor'sdrugapplicationdid
notinclude"adequatetestsbyallmethodsreasonablyapplicabletoshowwhetherornotsuchdrugissafe
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foruseundertheconditionsprescribed,recommendedorsuggestedintheproposedlabelingthereof."24
Occasionally,ininterpretingthisprovision,agencyofficialsrecommendedlabelingchanges,including
warnings,tosponsorsandtotheU.S.P.,butFDAitselflackedauthorityunderthe1938Acttodetermine
thetextandlayoutofdruglabels.25Largereffortstoimprovedrugtesting,prescribingpatterns,and
patientuseandcompliance,however,werelefttothepracticeofmedicineandmedicine'sscientificand
professionalauthorities.
AlthoughFDAhadauthorityunderthe1938Acttoestablishrulesgoverningtheuseofinvestigational
drugs,FDAdidnotemploythisauthoritytoregulateclinicaltrialsandclinicaltrialmethodologyuntil1961.
26EventhoughphysiciansateliteuniversityclinicsandmembersfromtheAMACouncilonPharmacy

andChemistryallagreedontheimportanceofstandardizeddrugtestingthroughclinicaltrials,FDAdid
nothavetheauthoritytorequirethemunderthe1938statute.27FDAscientists,however,didbeginto
exertsomeinfluenceontheconductofclinicaltrialsandmoveinthedirectionofstandardizationonthe
eveofWWII,whentheypublishedanarticleinJAMAonexperimentaldesign,properclinicaltrial
methods,andmethodsofdataanalysis.28Theirarticle,however,waspublishedasaReportunderthe
auspicesoftheAMA'sCouncilonPharmacyandChemistryandwasaccompaniedbyadisclaimertothe
effectthatthe"outline"presentedinthereportwas"offeredasanobjective,apattern,andnota
regulation."DuringWWII,theagencyactivelypromoteddrugtestingstandardsinthefaceofincreased
wartimeexpendituresfordrugtrialsdesignedtoanswerimportantquestionsaboutthesafetyanduseof
manynewdrugsforthewareffort.29Animportantbreakthroughinclinicaltrialdesignfollowedfrom
theshortagesofanewdrug,streptomycin,shortlyafterthewar.
Followingwartrialsofpenicillin,Britishepidemiologistandbiostatistician,A.BradfordHill,wasfacedwith
thetaskoftestingapromisingantibiotic,streptomycin,againsttuberculosis.ResearchersintheUnited
Statesstudyingthesamedrughadamplesuppliesandledtomoreeffectivetreatmentforpatientsubjects
butproducedlessconclusiveclinicaltrialdata.30Hillandhiscolleagues,however,werefacedwitha
severeshortageofthestreptomycindrugtheywerestudying.InpostwarBritain,thecentralgovernment
couldnotaffordtopurchasemoreofthedrug.Scarcityandexpense,therefore,justifiedtheirdecisionto
formallybutrandomlyassignpatientstocontrolgroupsandtreatmentgroups.Thiseliminatedawell
knownformoftreatment"bias"inwhichphysiciansareknowntoselecttheirhealthierpatientsfor
experimentaltreatmentleavingsickerpatientsinthecontrolgroup.Hill'sstudywasatruerandomized
study.Itwasnot,however,"doubleblinded"anotherwayofinsuringtheobjectivityofatrialby
neutralizingthepowerof"suggestion."
Inadoubleblindclinicaldrugstudy,trialsaredesignedinsuchawaythatneitherthepatientnorthe
researcherknowswhoisreceivingthetreatmentdrug.31InHill'sstudy,streptomycinrequired
injection,andtheresearchersdidnotwishtouseinertinjections.Howeverthelackoftruedouble
blindinghadlittleimpactontheresults,sinceHillwasabletoshowconclusivelythatstreptomycincould
curetuberculosis.Whentheresultsofhisstudywerepublishedin1948,Hill'suseofconcurrentcontrols
(randomized,controlled)waspraisedashavingusheredin"aneweraofmedicine."32
HillandhisNorthAmericancolleagues,includingHarryGoldattheCornellMedicalSchool,begantomap
outgeneralcriteriafordrugtestingandspecifystagesthroughwhichdrugdevelopmentshouldproceed.
Patientsweretobeselectedthroughformalcriteriaandthenrandomlyseparatedintotreatmentand
controlgroupstrialsweretobedoubleblindedandemployobjectivediagnostictechnologiesanddrug
dosesweretobeadministeredaccordingtoafixedschedule,whilepatientobservationsweretobe
chartedatuniformintervals.Theirsuccesssetthestageforthesubsequentdevelopmentofmore
sophisticatedclinicaltrialdesignswhileprofessionalcollaborationsallowedstatisticianstoincreasingly
dominatetheconductofclinicaltrialsintheU.S.33Nonetheless,oneexpertestimatedin1951that
45%ofclinicaltrialshadnocontrolgroups.34
AfterWWII,medicalresearchincreasedexponentiallyintheUnitedStates.In1950,fundingformedical
andscientificresearchwas$161milliondollars.By1968,thisfigurehadgrowntoover$2.5billion.35
TheNationalInstitutesofHealth(NIH)openeditsClinicalCenterinBethesda,MDasaresearchhospitalin
1952,andNIH'sextramural,peerreviewedresearchgrantsystemsoonsupportedbiomedicalandclinical
researchprojectsatinstitutionsaroundthecountry.Centrallyplannedclinicalresearchprojects,
includingcooperativetrials,weresooneclipsedasgrantssupportedtheworkofindividualmedical
investigators,manyofwhomdesignedandconductedtheirownclinicaltrialsincollaborationwithother
colleagues.Ethicalconcernsabouttheprotectionofresearchsubjectsfurthercomplicatedclinicaltrial
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design,postwar,particularlyfollowingreportsofthegrossmedicalabusescarriedoutonNaziprisoners
ofwar.36Ethicaldebatesovermethodologyoftencenteredaroundquestionsconcerningwhenitwas
appropriatetouseplacebocontrolledtrialsandwhenitwaspreferabletocompareactivetreatmentsin
evaluatingnewtherapies.TheNIHClinicalCenteradoptedapolicythatplacedmuchoftheresponsibility
forsafeguardinghumansubjectsofbiomedicalresearchwithprincipalinvestigators.Researchinvolving
normalhumanvolunteerswastobeformallyreviewedbypanelsofscientists,buttherewasvirtuallyno
discussionaboutanypotentialroleforthefederalgovernmentinregulatingmedicalresearch.Meanwhile,
bothNIHandFDAgaveclinicalinvestigatorswidelatitudeinthepursuitoftheirresearchobjectives.37
Sulfadrugsandantibiotics,amongothertherapiesforacutediseases,hadprovidedimportantexperience
inevaluatingnewdrugs,butincreasinglyafterWWII,investigatorsandregulatoryofficialsbegantorely
onincreasinglysophisticatedtrialdesignstostudyeffectivenessinwholenewclassesofdrugsforchronic,
ratherthanacuteconditions.Bloodpressureandantiarrhythmicdrugs(1950s/60s),drugsfor
tuberculosis,cancer,heartdisease,andtheoralcontraceptives(1960)wereallapprovedusingnewand
increasinglyadvancedtrialmethodologyinvolvingassessmentofdatafromsometimestensofthousands
ofpatients.Statisticiansinsistedonuniformselectioncriteriaforpatientsinclinicaltrials,separate
treatmentandcontrolgroups,uniformdosingregimens,andutilizedobjectiveevidencefromlaboratory
testssuchasbloodandurinetestsmadebothbeforeandaftertreatment.Withtheaidofanewscience
ofbiostatistics,bothregulatorsandregulatedindustrybegantounderstand,appreciate,andinterpret
manynuancedcomponentsoftrialdesignandtheireffectontheinterpretationofdata.38Although
severalkindsofrandomizedcontrolledtrialmethodologiescanbeusefultoresearchersandregulators,
ultimately,itwastherandomized,doubleblinded,placebocontrolledexperimentwhichbecamethe
standardbywhichmostotherexperimentalmethodswerejudged,andithasoftensubsequentlybeen
referredtoasthe"gold"standardforclinicaltrialmethodology.Insituationsinwhichusingaplacebo
seemedunethical,positive(treatment)groupsratherthanplacebogroupswereemployedandregulators
hadtolearnhowtointerpretthedatastemmingfromthesetrialsaswell,aformidableprobleminmany
cases.39
TheKefauverHearingsandDrugCritics
Intheearly1950stheAMAdiscontinuedmanyofitsdrugstudyactivities.Itcloseditsmicrobiological
laboratoryusedtotestnewdrugs(successortotheChemicalLaboratory)anddiscontinueditsSealof
Acceptanceprogram.SinceonlydrugsthathadtheSealcouldadvertiseinthepagesofAMAperiodicals,
thediscontinuationofthisprogramopenedthedoorforanexplosionofadvertising(andadvertising
revenue)inJAMAandotherAMApublications.AMAdiscontinueditsinspectionofdrugplants,itsefforts
toexertsomecontrolovergenericdrugnames,andevenacampaignithadinstitutedtoexplainand
encouragephysicianstoprescribeusinggenericnamesratherthanbrandnames.40Intheirplace,the
AMAinitiatedaregistryforreportingadversedrugreactions,althoughithadnomechanismtoenforce
datacollection.41
Beginningin1958,hearingsonthedrugindustryheldbySenatorEstesKefauver(DTennessee)focused
unanticipatedattentiononthequalityofdrugcompanysponsoredclinicaldrugresearch.Inparticular,the
hearingsdrewattentiontothepoorstateofclinicaltrialresearchasithadbeenconducted(orfailedtobe
conducted)underthe1938statute.Kefauverannouncedhishearingsonthedrugindustryitsproducts
anditsprofitabilityafterheandhisstaffhadobtainedevidencedocumentingthehighmarkupsand
exorbitantprofitmarginsthathadbecomeevidentonprescriptiondrugs,beginningwithantibiotics.Yet
thehearingssoonturnedtoothertopicsastheindustrytriedtodefenditsprofitsbyassertingthehigh
costofresearch,includingthecostsofconductingclinicaltrials.Aspopularwithconsumersasthey
provedunpopularwiththepharmaceuticalindustry,thesehearingsgeneratedimportantevidence
documentingthefrequentlysorrystateofdrugtestingandadvertisingaswellasthecompetitive
pressureswithintheindustrywhichsupportedsuchpractices.Abletestimonywasoffereddocumenting
manypoorclinicalstudiesdoneinsupportofthemarketingofmanymediocredrugs.Dr.LouisLasagna,
anexpertinclinicalpharmacology,testifiedthatitwas"shockingthatexperimentaldrugsaresubjectto
noFDAregulationofanysortbeforepatientsreceivethemItisreprehensibleformantobethefirst
experimentalanimalonwhichtoxicitytestsaredone,simplybecausebypassingtoxicitytestsin
laboratoryanimalssavestimeandmoney."42Atonepointinthehearingsaformermedicaldirectorat
Squibbtestifiedthattheindustrywasalwayspointingoutthehighcostsofresearchandthefactthatso
manyproductsfailedinthecourseofresearchtojustifyitsmarkupsandprofitmargins."This,"he
agreed,"wastrue,sinceitistheveryessenceofresearch."Theproblem,hequipped,layinthefactthat
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"theymarketsomanyoftheirfailures."43Mostnewdrugproducts,expertstestified,werenot
improvementsoveroldones,andmostweremarketedbeforeclinicalstudieswerepublished.Manynew
drugs,infact,werecombinationsofolderdrugs,withorwithoutmodification,whichgainedextended
patentlife(andprofitability)incombination.Adequatelycontrolledcomparisonsofdrugs,Lasagna
testified,were"almostimpossibletofind."44
Yearslater,FDA'sChiefCounselWilliamGoodrichrecalledthatduringtheKefauverhearingsthe
pharmaceuticalindustry"steppedrightintothebeartrap"whenittriedtodefenditselfbytoutingthehigh
costsofresearchanddevelopmentfornewdrugs.
Thatjustfocusedattentiononthesevariousphasesofnewdrugdevelopmentandpromotionfirstofall,
wasitreallyallthatexpensive?Weretheyreallydoingallthatkindofresearch?Andanyonewhohad
lookedatanyoftheNewDrugApplicationsknew,asIknew,thatthatwasallbaloney,andwhatthey
weresayingtousinthoseearlydayswasessentiallyabunchoftestimonials.Thewaydrugswere
investigatedaphysicianfromthecompanywouldgooutinthecommunitywithsomesamplesandsayto
thedoctor,"I'vegotthisnewdrugforsoandso.Here'ssomesamples.Tryitoutandletusknowhow
youlikeit."Andtheywouldgetbackaletterfromhim:"Itrieditoutoneightpatientsandtheyallgot
alongfine."That'sthekindofstuffthatwascominginforthescience.Ofcourse,thatwascompletely
unsatisfactory,andassoonaspeoplefocusedonthat,thatraisedtheproblem.45
Bythe1960s,followinganotherdrugcrisisin1962,therewasagrowingrecognitionoftheimportanceof
clinicaltrialsinnewdrugdevelopmentaswellasinclinicalmedicine.Pharmacologistsandmedical
researchersaswellasofficialsatgovernmentagenciessuchastheVeteran'sAdministrationandthe
NationalInstitutesofHealthknewmoreabouttheconductofgoodclinicaltrialsthandidtheFDAatthat
time.Thischangedrapidly,however,beginningwithadrugcrisisin1962.Followingapatternfirstseen
intheelixirsulfanilamidecrisiswhichledtochangesinU.S.drugregulationin1938,asimilarcrisisin
1962spurredevenmorewidespreadchanges,bothintheU.S.andaroundtheworld.In1961,apopular
druginEurope,ahypnoticknownasthalidomide,wasdiscoveredtocauseseverebirthdefectsandeven
deathinbabieswhentheirmotherstookthedrugearlyintheirpregnancies.Becauseoftheconcernsof
FDAdrugreviewerDr.FrancesKelsey,thedrugwasneverapprovedforsaleintheU.S.Nonetheless,the
drugsponsorhadsentsamplesofthedrugtothousandsofU.S.doctorswhogavethesamplestotheir
patientswithouttellingthemthatthedrugwasanexperimentalone,makingtheirpatientstheunwitting
subjectsofhumandrugexperimentation.Itisbelievedthatthereweremorethanadozenthalidomide
babiesbornintheUnitedStatesasaresultofthisunauthorized"sample"program.Asaresultofthe
worldwidethalidomidedisaster,countriesaroundtheworld,includingtheUnitedStates,updatedtheir
drugregulatorysystemsandstatutes."Innexttonotime,"recalledFrancesKelsey,"thefightingover
thenewdruglawsthathadbeengoingonforfiveorsixyearssuddenlymeltedaway,andthe1962
amendmentswerepassedalmostimmediatelyandunanimously."46
TheINDProcessandClinicalTrialRegulation
Priortothelaw'sfinalpassage,regulationsbegantoaddressknownproblemsintheuseofclinicaltrials
bythedrugindustry,indicatingthatFDAfeltmoreconfidentinitsauthoritytoregulatethem,evenunder
theold1938statute.47Newregulationsprohibitedtestingadruginhumansuntilpreclinicalstudies
couldpredictthatthedrugcouldbegivensafelytopeople.48The1962[KefauverHarris]Drug
Amendmentsandthe1963investigationaldrugregulationsthemselvesintroducedmanynewprocedures
thatstrengthenedcontroloverinvestigationalnewdrugsintheUnitedStates.49Oneofthemost
significantwasasystemofpreclinicaltrialnotificationandapprovaldesignedtoprovideenough
informationtoregulatorstodemonstratethatitwassafetoconductclinicaltrials.Underthisnew
system,companydrugsponsorswererequiredtofilea"noticeofclaimedinvestigationalexemptionfora
newdrug."The"notice"wasactuallyapackageofmaterialsthatacompanysubmittedtoFDAfor
approvalpriortostartinghumantrials.TheacronymIND(InvestigationalNewDrug)wascoinedto
paralleltheacronymNDA(NewDrugApplication).50Technically,anINDisanexemptionfromthe
normalpremarketingrequirementsforanewdrugnamely,thesubmissionandapprovalofanNDA.
51AnapprovedINDapplicationallowsinvestigatorstoproceedwithnewdrugtrialsforadrugunder

development.TheinformationcollectedunderanINDmaylaterbecomeapartofanNDAsubmissionif
thesystematicdrugtestssetuptotestthedrugaresuccessful.IND'sarealsorequiredwhenasponsor
wishestorestudyapreviouslyapproveddruginordertogatherdatainsupportofsignificantlabeling
changes,advertisingchanges,changesinrouteofadministrationordose,oranyotherchangethatmight
altertherisk/benefitequationuponwhichtheoriginalapprovalwasbased.TheINDregulationsalsoled
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FDAtodefinemoreclearlythroughregulationthe"phase"processofdrugtestinginvolvedinthe
regulatoryapprovalofanewdruginthe1963regulations.52
AnINDsubmission1)alertsregulatorstoasponsor'sintenttobeginclinicalstudiesintheUnitedStates
2)providesthepreliminaryanimaltoxicitydataindicatingitisreasonablysafetoadministerthedrugto
humans3)providesinformationaboutthemanufacturingprocessforthenewdrug4)provideschemistry
backgroundmaterial5)describestheinitialclinicalstudybeingproposed,focusingonitssafetymeasures
(whoisconductingthetrials,theirqualificationsandfacilitiesandthetypeofstudypopulationinvolved
volunteers,sickpatients,prisoners,women,men,children,etc.)and6)providesassurancethananIRB
(InstitutionalReviewBoard)willapprovethestudyprotocolbeforethestudybegins.Inadditiontothe
INDsubmissionitself,everyinvestigatorparticipatinginthestudymustsignaform,maintainedbythe
sponsor,indicatingtheirqualifications,thelocationoftheresearchfacilitywherethestudywillbe
conducted,andthenameoftheIRBresponsibleforreviewingandapprovingthestudyprotocol.
Investigatorsmustsigncommitmentsto
1.conducttheclinicalstudyinaccordancewiththeIRBapprovedprotocol
2.personallyconductorsupervisetheconductoftheinvestigation
3.informpotentialsubjectsthatthedrugsarebeingusedforinvestigationalpurposesand
4.reporttothesponsoradverseeventsthatoccurinthecourseoftheinvestigation.
EfficacyUnderthe1962DrugAmendments
Anewandkeyprovisioninthe1962amendmentswastherequirementthat,inadditiontothepremarket
demonstrationsofsafetyalreadyrequiredunderthe1938Act,futurenewdrugswouldalsohavetobe
demonstrated"efficacious"priortomarketing.Thisprovisionrequiredcontrolledtrialsthatcouldindeed
supportclaimsofefficacy.The60dayapproval"default"underthe1938Actwasremoved.Newdrugs
hadtohavepositiveandspecific,andincreasinglydetailedapprovalfromFDAtogotomarketandFDA
wasgiventheauthoritytosetstandardsforeverystageofdrugtestingfromlaboratorytoclinic.In
addition,FDAcouldrequiremarketwithdrawalsforthefirsttimeandestablish"GoodManufacturing
Practices(GMP's)"togoverndrugmanufacturing.Inordertopreventanother"thalidomidedisaster,"
Congressinsertedlanguageinthe1962DrugAmendmentsrequiringthatinvestigatorsmaintainpersonal
supervisionoverclinicalinvestigationsandagreenottogivethedrugtootherinvestigators.Senator
JacobJavits(DNewYork)wasparticularlyconcernedaboutthefactthatsomanypeoplehadtaken
thalidomidewithoutknowingthatitwasanexperimentaldrug.EvenmanydoctorsthatFDAhadsurveyed
hadbeenconfusedastothestatusofthedrugatthetimetheygaveittotheirpatients.53Javits
sponsoredwhatbecameaveryimportantprovisionofthelawitself:therequirementthatinformed
consentbeobtainedfromallresearchstudysubjectssothatpatientswouldhavetobespecifically
informedifadrugtheywerebeinggivenorprescribedwas"experimental,"somethingthathadnot
happenedinthecaseofthalidomide.
Thelegallanguageemployedinthestatute,whichlaidoutthecriteriathatwouldbeusedinassessing
efficacyinsupportofanewdrugapproval,wasnotparticularlystringent.Thelawrequiredthattherebe
"substantialevidence"thatthedrug"willhavetheeffectitpurportsorisrepresentedtohaveunderthe
conditionsofuseprescribed,recommended,orsuggestedintheproposedlabeling."Lawyershave
concludedthatCongresscouldhaveestablishedamorestringentdrugapprovalprocesssimplybyusing
strongerlegalterminology.Thefactthattermssuchas"preponderanceofevidence"or"evidencebeyond
areasonabledoubt"werenotusedindicatesthatCongressdidnotintendtosetthebarforefficaciousnew
drugapprovalstoohigh.54Newdrugsdidnothavetobesuperiortootherdrugsonthemarketnordid
"substantialevidence"meanevidence"sostrongastoconvinceeveryone."55
Thestrengthinthestatutorylanguage,however,camenotfromtheevidentiaryrequirementsbutfroma
lastminutecompromiseoverstudymethods.56Sponsorswereonlyrequiredtoprovide"substantial
evidence"ofeffectiveness,butthatevidencehadtobebasedon"adequateandwellcontrolledstudies,"
i.e.clinicaltrials.Withoutdefiningeither"adequate"or"wellcontrolled,"thelawpavedthewayfor
expertsinthefieldtoestablishthecriteriathatwoulddefinebothtermsunderthenewstatute.Although
thelawdidnotdefineawellcontrolledstudy,testimonybeforeCongressmadeitclearthatitincluded,as
aminimum,theuseofcontrolgroups,randomallocationofpatientstocontrolandtherapeuticgroups,
andtechniquestominimizebiasincludingstandardizedcriteriaforjudgingeffectiveness.57Apoorly
designedtrial,itwasargued,notonlywastedresources,butitunnecessarilyputpatientsatrisk.
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ClinicalTrialRegulationsof1970andtheDESIProcess
OverthenexteightyearsFDAworkeddiligentlytoimplementthe1962drugamendments.Intheearly
yearsafterpassageofthe1962amendments,sponsorsweremoreorless"ontheirown"withlittle
guidancefromFDAaboutwhatwouldbeacceptableexceptintheformofanNDAnonapprovalletter
whichdidexplainwhythesponsors'submissionwasconsideredinadequate.ConcernsthatFDAmight
becomeoverly"vested"inthedevelopmentofacommercialdrugproductledtoanabundanceofcaution
inagency/sponsorinteractions.Accordingtooneofficial,"Therewas,infact,explicitconcernthattoo
muchparticipationbyFDAstaffinthedevelopmentprocesswouldleavetheAgencyunabletobeproperly
neutralandanalyticalwhentheresultingdataweresubmittedaspartofanNDA."58Overtheyears,
however,asRobertTemplenotes,FDAhasbecomeincreasinglyinvolvedinthedevelopmentofspecific
drugproductsincludingthedesignofclinicaltrials,"reflectingtheviewthatthepublic,theindustry,and
theFDAarepoorlyservedbydrugdevelopmenteffortsthatarepoorlydesignedorinadequateandthat
thereforewasteresourcesanddelayavailabilityoftherapy."59Inthelatetwentiethcentury,Congress
itselfhasevenbegunmandatingmeetingsbetweenregulatorsandindustryconcerningthedesignand
conductofclinicaltrialsdeemedparticularlyimportantforanyofanumberofreasons.60
Regulatoryofficialssoonbegantoreceiveaninvaluableeducationintheconductofclinicaltrialsasa
resultoftheagency'sDrugEfficacyStudy(DES).The1962DrugAmendmentsrequiredFDAtorereview
alldrugsthathadbeenapprovedunderthe1938Food,Drug,andCosmeticAct(19381962)onthebasis
ofsafetyalone,thistimelookingforevidenceofefficacy.Examiningallpre1962NDA'sposedadaunting
taskforFDAsoin1966,FDAcontractedwiththeNationalResearchCounciloftheNationalAcademyof
Sciencestoperformthereview.61Thirtypanelsofexpertsreviewedspecificdrugcategoriesusing
evidenceobtainedfromFDA,thedrug'smanufacturer,scientificliterature,andthepersonalexpertiseof
thepanelmembersthemselves.Theirratingsoneachclaimforadrugfellintosixcategories:effective
probablyeffectivepossiblyeffective,ineffective,effectivebut,andineffectiveasafixedcombination
(combinationdrugsforwhichtherewasnosubstantialreasontobelievethateachingredientaddstothe
effectivenessofthecombination.).62
FDAwaschallengedtodeviseamethodbywhichthosedrugsruledineffectivecouldbelegallyremoved
fromthemarketalongwithother"metoo"drugsdrugswiththesameessentialingredientprofile.
FDA'sinitiallegaleffortstoremovebioflavonoiddrugsandanUpJohnfixedcombinationdrugcalled
Panalbawereenjoinedbythecourts.63Facedwiththeprospectofconductingformaladministrative
hearingsoneverydrugitproposedtohaveremovedfromthemarket,theagencychangeditsapproach,
ledbyFDA'sDirectoroftheBureauofMedicine(andlaterCommissioner)Dr.HerbertLey.Ley
supportedthedrafting,publicationandimplementationofregulationsdefining"substantialevidence"
leadingtoashowingofeffectivenessunderthe1962Amendments.These"evidencerules"hadtwo
separatecomponentsbutcompanieswishinganadministrativehearingontheproposedwithdrawalof
theirpre1962drugwouldhavetomeetbothcriteria.1)Thefirstformallyspecifiedthescientificcontent
of"adequateandwellcontrolledclinicalinvestigations,includingclinicalinvestigations,byexperts
qualifiedbyscientifictrainingandexperiencetoevaluatetheeffectivenessofthedruginvolved,"under
the1962statute.Wellcontrolledtrialsdidnothavetobeplacebocontrolledtheycouldhaveactive
controls,orevenhistoricalcontrolsbuttheregulationsstatedclearlythat"uncontrolledstudiesarenot
acceptableevidencetosupportclaimsofeffectiveness."64Nohearingwouldbegrantedunlesstherewas
a"reasonablelikelihood"thatsuchevidencewouldbeforthcoming.652)Thesecondrequiredthe
submissionofpositiveresultsfromatleasttwoclinicalstudiesinordertoescapeanautomaticwithdrawal
ofapprovalforthedrugwithoutahearing.66Thecourtsupheldtheagency'snewapproachand
accordingtoPeterBartonHutt,FDA'sChiefCounselfrom19711975,nohearingsweredeemednecessary.
Bytheendof1971,FDAhaddisposedofdozensofrequestsforhearingsontherevocationofNDA's.In
noinstancehaditdeterminedthatamanufacturer'ssupportingdataweresufficienttojustifyahearing.
Oneexplanationofthisstrikingconsistencyisthattheagency'ssubstantialevidenceregulationsembodied
requirementsforclinicalinvestigationsthatfewpre1962studiescouldmeet.Thedrugsitinitially
selectedforwithdrawal,thoseevaluatedbytheNASNRCas"ineffective"alsopresentedtheeasiest
targets.Butitwasbecomingobviousthatamanufacturerwouldhavetomakeanoverwhelmingshowing
topersuadeFDAtoexpendthetimeandresourcesthatevenonehearingwouldrequire.67
TheresultsoftheDESstudyledtorecommendationssoonimplementedthroughtheDrugEfficacyStudy
Implementation(DESI),whichremovedover1000ineffectivedrugsanddrugcombinationsfromthe
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marketplace.Aspartofthisprocess,FDAdrugreviewersthemselvespublishedhundredsofcritiquesof
theclinicalstudiesthathadbeensubmittedforapprovednewdrugsinsupportofthesafetyrequirements
mandatedinthe1938statute.Mostoftheseoldstudies,recalledRobertTemple,whobeganworkatFDA
in1972,were"inadequatebeyondbelief."Aslateasthe1960sandearly1970shenotes,"Youwouldbe
horrified[attheclinicaltrialdata]submittedtotheagency.Therewasoftennoprotocolatall.There
wasalmostneverastatisticalplan.Sequentialanalyseswereunheardof.Itwasaverydifferentworld."
68

Positivechangesinclinicaltrialmethodology,however,soonbegantobeevidentinnewNDAandANDA
submissions."Everyone,"notesTemple,"cametobelievethattrialsshouldhaveaprospectivelydefined
andidentifiedendpoint,arealhypothesisandanactualanalyticalplan."Aninternational,professional
organization,theSocietyforClinicalTrials,wasorganizedin1978andbegantodevelopanddiscuss
clinicaltrialdesignandtheanalysisofclinicaltrialsingovernmentaswellasindustrysponsoredclinical
trialresearch.FDAassistedthedrugindustryduringthelate1970s,bycollaboratingwithexternal
advisorycommitteesandconductingFDAindustryworkshopsinsupportofthedevelopmentofnearly30
drugclassclinicalguidelineswhichdescribedindetailthestudydesignsandexpecteddatarequiredfor
particulartherapeuticclassessuchasdrugsforulcerdisease,depression,orangina.
DuringtheAIDSepidemicofthe1980s,regulatorswereagainpushedtoconsidertheessential
requirementsofameaningfulclinicaltrial.FDAhadcreatedaspecialclassofinvestigationsknownas
the"TreatmentIND"in1987inwhichpatientscouldreceiveaninvestigationaldrugoutsidethenormal
"blinded"researchsetting.69Althoughdatafrompatientsunderthisprotocolwasstillcollected,the
programwasnotespeciallyconducivetothetreatmentoflargenumbersofpatients,especiallythose
desperatelysickpatientswhopushedforaccesstodrugsattheirearlieststagesofdevelopment.70
In1985regulationsrecognizedwhathadalreadybecomeacentraltenetofmoderndrugevaluationby
formalizingtherequirementthatapprovalsbebasedonan"integratedsummaryofallavailable
informationaboutthesafetyofadrugproduct."71Congressitselfmandatedin1988thateachAIDS
drugINDmustbepubliclydisclosedinacomputeraccessibledatabasetofacilitateaccessbypatients
withAIDS,andformallyrecognizedtheimportanceofFDA'sTreatmentINDprograminsupportofAIDS
patients.72AlthoughsomeAIDSorganizationsrequestedagencysupportof"openclinicals"inwhicha
drugsponsorcouldallowanypatientaccesstoongoingtrialswiththesupportoftheirphysicians,FDA
refusedtoallowsucheasyaccess."Themoreopenendedthedesignofaclinicaltrial,"notedagency
officials,"thelesslikelythechancethetrialwillprovideanswers."73Between1990and1992guidelines
wereproposedandnegotiated,andregulationsfinallyapprovedbyFDAestablishinga"paralleltrack
approval"processinwhichspecialcategoriesofdrugswouldbeexpeditedduringthereviewprocessanda
widergroupofpatientswouldhaveaccesstothedrugthanundernormalprocedures.74
Beginninginthemid1980s,FDAhasfocusedonimprovingtheanalysisofdatafromclinicaltrials.One
lessonlearnedfromtheAIDSepidemicandtheconcomitantdevelopmentofclinicaltrialsnecessaryto
testdrugproductsforitstreatmentisthescientificutilityofsurrogateendpointsincertaincircumstances.
Someofthisdataanalysishasbeenmotivatedbysponsors'interestinpresentingevidenceofclinical
effectivenessthroughmeasurementsofbiomarkersandevaluationof"surrogateendpoints."Surrogate
endpointsmeasureoutcomesthatarenotclinicallyvaluablebythemselves(loweredcholesterol,blood
pressure,elevatedtcellcounts)butarethoughttocorrespondwithimprovedclinicaloutcomes
(decreasedheartdiseaseorstroke,feweropportunisticinfectionsforAIDSpatients).FDAapprovedthe
firststatindrug,forexample,in1987,basedonthesurrogateofloweringbloodcholesterol.75FDAis
cautious,however,inacceptingsurrogatesandusuallyrequirescontinuedpostmarketstudytoverifyand
describecontinuedclinicalbenefits.In1992,newregulationsfortheacceleratedapprovalofnewdrugs
gavetheagencyexplicitauthoritytorelyonasurrogatemarker.76
In1994,FDAmadechangesinitspoliciesdesignedtofacilitatewomen'sparticipationintheearliest
phasesofclinicaldrugtrials.77Mostrecently,FDAhasissuedguidelinespromotinggreaterstudyand
betteranalysisofpatientsubgroupsincludingdrugsintheelderly,separateanalysisoftrialdataforboth
genders,andpediatricstudiesaswellasdoseresponseinformation.78

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TheFuture
Inanerainwhichhealthcarecostsarerisingatratesfarhigherthantherateofinflationandthenation
facesthechallengeofpromotingthehealthofthe"boomer"generationduringitsretirementyears,there
havebeencriesformorecomparativedrugstudies,inparttohelpcontaindrugcosts.Greater
knowledgeofgeneticscienceandtheabilitytoconductmorenuancedanalysesofdrugtrialdata,
includingretrospectivemetaanalyses,havealsohelpedfueloptimismoverthefutureofpersonalized
medicine.Inthepastthedrugindustryhasconcentratedondevelopingsocalled"blockbuster"drugs.
Thelargescale,randomizedclinicaltrialhasbeencriticalindemonstratingthesafetyandefficacyof
thesedrugs.Many,however,arepredictingthatthefutureofmedicinepointstowarddevelopingdrugs
anddiagnosticstotreatsubsetsofpatientswhomayrespondtoonetreatmentbutnotanotherbecause
ofgeneticandotherfactors.Thishasledmanytospeculateonthefutureofrandomizedtrials."The
randomizedclinicaltrialisexcellentmethodologyifyouwanttounderstand,onaverage,whetherone
treatmentisbetterthananothertreatment,"notesJohnBridges,assistantprofessoratJohnsHopkins
SchoolofPublicHealth,"butifwethinkaboutadistributionofoutcomes,nosinglepersoninthehealth
caresystemistheaverage."43Personalizedmedicinepresentschallengesofitsown,includingincreased
costsforresearcherstestingdrugsandpatientstakingthem.Itseemsmorelikelythatbetteranalysisof
clinicaltrialdata,alreadybeingencouragedbytheFDA,andpursuedbybothresearchersanddrug
sponsorsasthefirststeptowardsamorepersonalizedperspectiveondrugdevelopment,willbean
integralpartoftheevolutionofpersonalizedmedicine,whilecontinuingtoaddtoouroverallknowledgeof
thesafetyandeffectivenessprofilesofmedicinesandtherapeuticsalreadyonthemarket.The
randomizedclinicaltrialisunlikely,ineitherscenario,togothewayofthedinosaur.
Originallypublishedas"FDAandClinicalDrugTrials:AShortHistory,"inAQuickGuidetoClinicalTrials,
MadhuDaviesandFaizKerimani,eds.(Washington:Bioplan,Inc.:2008),pp.2555.
1.FDAHistoryOffice,WhiteOakBuilding1,room1204,10903NewHampshireAvenue,SilverSpring,
Maryland20993.Suzanne.Junod@fda.hhs.gov.
2.AffadavitofWilliamThomasBeaver,M.D.inthecaseofPharmaceuticalManufacturersAssociationv.
RobertH.FinchandHerbertLey,CivilActionNo.3797,UnitedStatesDistrictCourtfortheDistrictof.
Dr.BeaverwastheclinicalpharmacologistatGeorgetownUniversitywhoiscreditedwithdraftingthe
initialregulationsdefining"adequateandcontrolled"clinicalstudies.(personalcorrespondence,Peter
BartonHuttEsq.andDr.RobertTemple,FDA,December,2007,FDAHistoryOfficeFiles)
3.HarryMarksTheProgressofExperiment:ScienceandTherapeuticReformintheUnitedStates,1900
1990(Cambridge:CambridgeUniversityPress,1997).HereafterreferredtoasMarks,Progress.
4.The1938ActrecognizedthepuritystandardspublishedbytheU.S.P.andtheNationalFormulary.The
U.S.PunderthenewlawwasresponsibleforallpackagingandlabelingstandardswhileFDAenforced
thesestandards.SeeArthurDaemmrich,"PharmacovigilanceandtheMissingDenominator:The
ChangingContextofPharmaceuticalRiskMitigation,PharmacyinHistory49:2(2007),p.64.
5.JohnP.Bull,"TheHistoricalDevelopmentofClinicalTherapeuticTrials,"JournalofChronicDiseases
10:3(1959),p.219.
6.Ibid.
7.Bull,p.228.
8.GeoffreyEdsall,"APositiveApproachtotheProblemofHumanExperimentation,"inExperimentation,
p.279.
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9.BobTemple,"GovernmentViewpointofClinicalTrials,"DrugInformationJournal82:January/June
(1981),p.10.
10.Marks,Progress,p.12.
11.SusanLederer,SubjectedtoScience:HumanExperimentationinAmericaBeforetheSecondWorld
War(Baltimore:JohnsHopkins,1995),p.xiv.
12.Ibid,p.19.
13.ArthurDaemmrich,"PharmacovigilanceandtheMissingDenominator,"p.64.
14.HarryF.Dowling,"TheEmergenceoftheCooperativeClinicalTrial,"TransactionsandStudiesofthe
CollegeofPhysiciansofPhiladelphia43(1975),pp.2029.Marks,Progress,p.5354.
15.Brownv.Hughes(94Colo.295,30P.2d259(1934).Ironically,atthistime,manyifnotmostof
these"accepted"clinicalpracticeswerenotbaseduponrigorousscientificstudy.
16.Fortnerv.Koch(272Mich.273261NW762(1935)ascommentedonbyWilliamJ.Curran,
"GovernmentalRegulationoftheUseofHumanSubjectsinMedicalResearch:TheApproachofTwo
FederalAgencies,"inExperimentationwithHumanSubjects,ed.PaulA.Freund,pp.402455.Hereafter
citedasExperimentation.
17.35Fed.Reg.7250(May8,1970).The1970regulationsrecognizedcomparativeevidencefromno
treatmentandtreatmentgroups,placebocontrolledtrials,activetreatmenttrials(comparingtreatments),
andhistoricalcontrols.
18.Initialregulationsunderthe1938Act(issuedDecember28,1938),requiredthepersonwhointroduced
aninvestigationalnewdrugintointerstatecommercetoobtainfromtheexpert(qualifiedbyscientific
trainingandexperiencetoinvestigatethesafetyofdrugs,i.e.theclinicalinvestigator)"asigned
statement...thathehasadequatefacilitiesfortheinvestigationtobeconductedbyhimandthatsuch
drugwillbeusedsolelybyhimorunderhisdirectionfortheinvestigation."Thiswas,ofcourse,unlessor
untilanNDAwasapprovedbyFDA.
19.RobertTemple,"DevelopmentofDrugLaw,Regulations,andGuidanceintheU.S,"Principlesof
Pharmacy(1994),p.1643.
20.Marks,Progress,p.72.
21.Dowling,"TheEmergenceoftheCooperativeClinicalTrial,"p.2529.
22.See,forexample,SuzanneJunodandLaraMarks,"Women'sTrials:TheApprovaloftheFirstOral
ContraceptivePillintheUnitedStatesandGreatBritain,"JournaloftheHistoryofMedicineandAllied
Sciences,57:2(April2002),pp.117160.
23.DanCarpenter,draft,ReputationandPower:OrganizationalImageandPharmaceuticalRegulationat
theFDA,p.97andfn.122.RalphSmithinBureauofMedicineduring1950s"Adrugisunsafeifits
potentialforinflictingdeathorphysicalinjuryisnotoffsetbythepossibilityoftherapeuticbenefit."
["safetyimpliesefficacydoctrine"]CitedbyJusticeThurgoodMarshall,U.S.v.Rutherford,No.78695,
442U.S.553,fn.9.
24.52Stat.1040,21U.S.C.June25,1938.
25.ArthurDaemmrich,"PharmacovigilanceandtheMissingDenominator,"p.64.
26.Thereferencetoinvestigationaldrugsundersection355(i)ofthe1938Actwasbrief."TheSecretary
shallpromulgateregulationsforexemptingfromtheoperationofthissectiondrugsintendedsolelyfor
investigationalusebyexpertsqualifiedbyscientifictrainingandexperiencetoinvestigatethesafetyof
drugs."Food,Drug,andCosmeticAct,52Stat.1040(75thCong.3dSess(1938)).
27.ArthurA.Daemmrich,Pharmacopolitics:DrugRegulationintheUnitedStatesandGermany(Chapel
Hill:UniversityofNorthCarolinaPress,2004),p.24.HereaftercitedasDaemmich,DrugRegulation.
28.Winkle,Harwick,Calvery,andSmith,"LaboratoryandClinicalAppraisalofNewDrugs,"JAMA126
(1944),95661.
29.Daemmrich,"Pharmacovigilence"p.51.
30.Dowling,"TheEmergenceoftheCooperativeClinicalTrial,"p.24.
31.Ibid.p.52.
32.SilvermanandChalmers,"SirAustinBradfordHill,"p.102.
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33.Daemmrich,"Pharmacovigilence,"p.52.
34.Ross,"UseofControlsinMedicalResearch,"JAMA145(1951),pp.7275.
35.Curran,Experimentation,p.402.
36.Atthe1946Nurembergtrialof23Nazimedicalprofessionals,onlyahandfulofvictimssurvivedto
confronttheirtorturers,outofhundredsofthousandsofprisoners.Thedefendantswerechargedwith
offensesrangingfromsubjectingtestsubjectstoextremesofaltitudeandtemperaturetousingthemas
humanculturestotestvaccinesfortyphusandmalaria.Inlightofthetestimony,aninternationalcodeof
ethicstoprotectallsubjectsofhumanresearchwaswrittenandadoptedbymostmedicalresearchersin
countriesworldwide.TheNurembergCodeacceptedandcodifiedethicalstandardswhichthe23
defendantshadgrosslyviolated,andthusbecamethefirstinternationallyrecognizedcodeofmedical
researchethics.Itsstatedgoalwasnotmerelyto"preventexperimentalabominationsinthefuturebut
toincreasetheprotectionoftherightsandwelfareofhumansubjectseverywherebyclarifyingthe
standardsofintegritythatconstrainthepursuitofknowledge."ThefirstprincipleoftheNuremberg
Codestressedtheimportanceofobtaining"informedconsent"fromresearchsubjects.Thecodealso
emphasizedthathumanstudiesshouldnotberandomorunnecessary,thatanimalstudiesshouldbe
undertakenbeforehumanstudies,andthatsurveysofthenaturalhistoriesofdiseaseshouldbe
undertakenbeforesubjectinghumansubjectstolaboratoryinduceddisease.
37.Curran,Experimentation,p.508.Researchinvolvingnormalhumanvolunteerswastobeformally
reviewedbypanelsofscientists.
38.BradfordHill,"MedicalEthicsandControlledTrials"BritishMedicalJournal1(April20,1963),pp.
104349.
39.SusanEllenbergandRobertTemple,"PlaceboControlledTrialsandActiveControlTrialsinthe
EvaluationofNewTreatments,"AnnalsofInternalMedicine133:6(Sept.19,2000),pp.455470ICHE
10(ChoiceofControlGroupandRelatedIssuesinClinicalTrials)@http://inside.fda.gov/portal/page?
_pageid=197,726738&_dad=portal&_schema=PORTAL(sitelastvisited10/17/07).
RobertTemple,"GovernmentViewpointofClinicalTrials,DrugInformationJournal82(1981),pp.1017.
40.RichardHarris,TheRealVoice(NewYork:TheMcMillanCompany,1964),p.126.
41.Daemmrich,"PharmacovigilanceandtheMissingDenominator,"p.6465.
42.StatementonS1552"LouisLasagna,DrugIndustryAntiTrustAct,p.1083.
43.Ibid.p.7879.
44.Ibid,testimonyofDr.LouisLasagna,p.8139.
45.OralHistoryInterviewwithWilliamGoodrich,FDAHistorywebsite,
www.fda.gov/oc/history/default.htm1.Lastvisited10/22/07.
46.FrancesKelsey,AutobiographicalReflections,p.71.FDAHistoryOffice.
47.NoticeofProposedRulemaking,27FedReg7990(August10,1962).
48.Specifically,therequirementwasthatbeforeclinicaltestingcouldproceed,drugsponsorshadto
submit"reportsofpreclinicaltests(includingtestsonanimals)ofsuchdrugadequatetojustifyproposed
clinicaltesting."NoticeofProposedRulemaking,27FedReg7990(August10,1962).
49.76Stat.780(October10,1962)PL8778128Fed.Reg.179(January8,1963)28Fed.Reg.5048
(May20,1963)28Fed.Reg.10972(October11,1963).
50.FrancesKelsey,AutobiographicalReflections,p.71.FDAHistoryOffice.
51.RobertTemple,"DevelopmentofDrugLaw,RegulationsandGuidanceintheU.S."chapter113
PrinciplesofPharmacology,pp.16431664(1994),p.1644.
52.28FR179(January8,1963)130.3(a)(10).Seealso,RobertTemple,"Currentdefinitionsofphases
ofinvestigationandtheroleoftheFDAintheconductofclinicaltrials"AmericanHeartJournal139:2000:
S133S135.
Clinicaltrialstodayarereferredtobyregulators,clinicians,andinvestigatorsasbeinginorhaving
completedPhaseI,PhaseII,PhaseIII,andevenPhaseIVtrials(postmarketingstudies).Theremaybe
considerableoverlap,butingeneral,PhaseIstudyprovidesthefirsthumanstudiesofanewdrugeither
inpatientsorinhumanvolunteers.Althoughthenumberofparticipantscanvary,PhaseItrialsusually
involvetwentytoeightypeople.Theseearlytrialscanprovideearlyevidenceofeffectiveness,butthey
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aredesignedtofurnishgreaterunderstandingoftheexperimentaldrug'ssafetyincludingsideeffectsin
relationtodrugdose.Ideally,aPhaseIstudyshouldbedesignedtoprovideenoughinformationabout
thedrugtodesignawellcontrolledPhaseIIstudy.
APhaseIIstudyisthefirstcontrolledclinicalstudytoevaluatetheeffectivenessofadrugforaspecific
therapeuticuseinpatients.Itisawellcontrolled,closelymonitoredstudy,usuallywithnomorethana
fewhundredpatients.Suchstudieslookattheeffectsoftreatmentonsymptomsoronasurrogatefora
clinicaloutcome(i.e.loweredbloodpressure,decreasedviralload,etc.).Ideallysuchstudiesaredouble
blindplacebocontrolledinvestigationsinwhichpatientsarerandomlyassignedtoadrugtreatmentgroup
oraplacebogroupandneitherthepatientnortheinvestigatorknows,untiltheendofthetrial,which
optionthepatientreceived.PhaseIIstudiesarealsothefirsttoconsidertheriskofadrug'ssideeffects.
PhaseIIIdrugtrialsarereservedforexperimentaldrugswhichhaveshownatleastsomeevidenceof
effectivenessinprevioustrials.Theyinvolvelargenumbersofpatients(severalhundredtoseveral
thousand)andaredesignedtogatherenoughinformationonsafetyandeffectivenesstoallowanadequate
assessmentofarisk/benefitratioforthestudydrugaswellasforthepreparationofmaterialfor
physician'slabeling.Theyalsouseabroaderpatientpopulationandcanbedesignedtogatherlonger
termsafetyandeffectivenessdataaswellasdatatoestablishoptimumdrugdosing.PhaseIIItrials
alsotypicallyhaveadatamonitoringcommitteeoverseeingthecollectionofdataduringthetrials.
53.FrancesKelsey,"AutobiographicalReflections,"p.73.FDAHistoryOffice.
54."InAmericanlegalterms,"substantialevidence"isnotahighstandardindeed,ithasbeen
describedbyaformerFDAchiefcounselassomewherebetweena"scintillaandapreponderance."Ibid.
55.RobertTemple,"DevelopmentofDrugLaw,RegulationsandGuidanceintheU.S,"p.1644.
56.Harris,TheRealVoice(NewYork:McMillanPress,1964),pp.204205.Harris'accountofthefinal
negotiationsoverthe1962Amendmentsmakesitclearthatindustrydidnotfullyappreciatethe
significanceofthephrase"adequateandwellcontrolledinvestigations"atthetimeitagreedtoit.
CounselfortheDepartmentofHealth,Education,andWelfareimmediatelygraspedthesignificanceand
remarkedthat[thelanguageadopted]"givesusallkindsofpowerespeciallythewordadequate'to
makesurethatdrugsdowhatisclaimedforthem."
57.Animalstudieswerenotmandatedunderthenewlaw,butwithinafewyearsfollowingpassageofthe
1962amendments,afairlystandardizedsetofanimaltoxicologystudiestoprecedeandsupporthuman
trialswasinplace.Bythe1970sadrugforchronicusewouldgenerallyberequiredtobetestedintwo
animalspeciesforthefulllifetimeoftheanimalatthemaximumtolerateddose.Temple,Principles,p.
1646.NewYorkAcademyofMedicine:CommitteeonPublicHealth,"Theimportanceofclinicaltestingin
determiningtheefficacyandsafetyofdrugs,"Bull.N.Y.Acad.Med.38:415439,1962.
58.RobertTemple,"DevelopmentofDrugLaw,Regulations,andGuidanceintheU.S.,inPrinciplesof
Pharmacology,1994,p.1646.
59.Ibid.,p.1647.
60.Duringthemid1970s,allegationsofa"druglag"intheapprovalofnewdrugsmadeofficialsmore
willingtomeetwithsponsorsattheendofPhase2drugtesting.InCongressenactedtheOrphanDrugs
Acttoencouragethedevelopmentofdrugstotreatrarediseases.Sponsorsoforphandrugswereoffered
therighttoaskforFDAassistanceintheirresearchplanning.In1987,revisedINDregulationsoffered
moremeetingstosponsors,though"primarily"forIND'sinvolvingNME'sormajornewusesofmarketed
drugs.Requestsformeetings,theregulationsstated,wouldbehonored"totheextentthatFDA's
resourcespermit."In1988regulationsdesignedtofacilitatedevelopmentofdrugsforlifethreateningor
debilitatingdiseasesalsoallowedsponsorsofsuchdrugstorequestearliermeetingswithregulators.
61.31Fed.Reg.9425(July9,1966)and31Fed.Reg.13014(October6,1966).
62.RichardA.MerrillandPeterBartonHutt,FoodandDrugLaw:CasebookandMaterials(Mineola:
FoundationPress,1980),p.373.
63.PanalbaestablishedthelegalvalidityunderlyingFDA'scurrentrulesrequiringacombinationdrugto
showthatthecombinationproductismoreeffectivethaneachcomponentusedseparately.
64.34FedReg14596(September19,1969),130.12(a)(5)and(7)(b)(iii).
65.OralHistoryInterview,WilliamGoodrich,FDAHistorywebsite,www.fda.gov/oc/history/default.htm.
"Havingtalkedabouttheadequateandwellcontrolledclinicalstudyregulations,IwanttobesureI
attributetoHerbLeyfullcreditforthatitwasHerbLeywhoreallyputthatthingthroughandgaveit
somescientificstaturethatitotherwisewouldn'thavehad.Paradoxically,Herbwasdoingthis,whichis
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oneofthegreatestthingsthateverhappenedtoFoodandDrug,yetatthesametimehewaslosinghis
jobovercyclamates."
66.34Fed.Reg.14596(September19,1969).
67.MerrillandHutt,Casebook,p.375.
68.RobertTemple,"HowFDACurrentlyMakesDecisionsonClinicalStudies,"ClinicalTrials2(2005),p.
276.
69.RobertTemplemakesthepointthattheimpetusforthedevelopmentoftheTreatmentINDwas
"perceivedasaresponsetoAIDS,butitsoriginsgobacktoaround1980beforeHIVwasidentified."
RobertTemple,"DevelopmentofDrugLaw,RegulationsandGuidanceintheU.S.,"p.1660.
70.JamesT.O'Reilly,FoodandDrugAdministration(NewYork:McGrawHill,1993),p.1387.
71.AccordingtoRobertTemple,"theideathatsafetydatashouldbelookedatalltogether,asopposedto
studybystudy,isarelativelyrecentinsight."Temple,"DrugLawDevelopment,"p.1649.
72.102Stat3066(1988).FrankYoung,"NewInformationAvailableAboutAIDSTreatments,"FDA
Consumer23:6(1989).
73.FDATalkPaperT8874,FDARespondstoACTUPDemands(October5,1988).
74.Comment,"PrescriptionDrugApprovalandTerminalDiseases:DesparateTimesRequireDesparate
Measures,44VanderbiltLawReview(1991),p.925.Kiser,"LegalIssuesRaisedbyExpeditedApprovalof
andExpeditedAccesstoExperimentalAIDSTreatments,Food,Drug,andCosmeticLawJournal45
(1990),p.363.
75.SuzanneJunod,"Statins:ASuccessStoryInvolvingFDA,Academia,andIndustry,"FDLIUpdate
(March/April2007),p.41.
76.Temple,"DrugLawDevelopment,"p.1656.
77.RuthMerkatzandSuzanneJunod,"HistoricalBackgroundofChangesinFDAPolicyontheStudyand
EvaluationofDrugsinWomen,"AcademicMedicine69:9(1994),703707.
78.Temple,"DevelopmentofDrugLaw,RegulationsandGuidanceintheU.S.",p.1646.
"IsComparativeEffectivenessAntitheticaltoPersonalizedMedicine,"RPMReport2:9(September2007).
79."IsComparativeEffectivenessAntitheticaltoPersonalizedMedicine,"RPMReport2:9(September
2007).

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