Principles and Practice of Clinical Trials

2573 Pages·2022·39.901 MB·English

by  Steven Piantadosi (editor), Curtis L. Meinert (editor)

Steven Piantadosi
Curtis L. Meinert
Editors
Principles and
Practice of
Clinical Trials
Principles and Practice of Clinical Trials
(cid:129)
Steven Piantadosi Curtis L. Meinert
Editors
Principles and Practice of
Clinical Trials
With241Figuresand191Tables
Editors
StevenPiantadosi CurtisL.Meinert
DepartmentofSurgery DepartmentofEpidemiology
DivisionofSurgicalOncology SchoolofPublicHealth
BrighamandWomen’sHospital JohnsHopkinsUniversity
HarvardMedicalSchool Baltimore,MD,USA
Boston,MA,USA
ISBN978-3-319-52635-5 ISBN978-3-319-52636-2(eBook)
https://doi.org/10.1007/978-3-319-52636-2
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In memory of
Lulu, Champ, and Dudley
A Foreword to the Principles and Practice of
Clinical Trials
Trying to identify the effects of treatments is not new. The Book of Daniel (verses
12–15)describesatestoftheeffectsKingNebuchadnezzar’smeat:
Provethyservants,Ibeseechthee,tendays;andletthemgiveuspulsetoeat,andwaterto
drink.Thenletourcountenancesbelookeduponbeforethee,andthecountenanceofthe
childrenthateatoftheportionoftheKing’smeat:andasthouseest,dealwiththyservants.
Soheconsentedtotheminthismatter,andprovedthemtendays.Andattheendoftendays
theircountenancesappearedfairerandfatterinfleshthanallthechildrenwhichdideatthe
portionoftheKing’smeat.
Therequirementofcomparisoninidentifyingtreatmenteffectswasrecognizedin
thetenthcenturybyAbuBakrMuhammadibnZakariyaal-Razi(Persianphysician):
Whenthedullness(thiqal)andthepainintheheadandneckcontinueforthreeandfourand
fivedaysormore,andthevisionshunslight,andwateringoftheeyesisabundant,yawning
andstretchingaregreat,insomniaissevere,andextremeexhaustionoccurs,thenthepatient
afterthatwillprogresstomeningitis(sirsâm)...Ifthedullnessintheheadisgreaterthanthe
pain,andthereisnoinsomnia,butrathersleep,thenthefeverwillabate,butthethrobbing
willbeimmensebutnotfrequentandhewillprogressintoastupor(lîthûrghas).Sowhenyou
seethesesymptoms,thenproceedwithbloodletting.ForIoncesavedonegroup[ofpatients]
byit,whileIintentionallyneglected[tobleed]anothergroup.Bydoingthat,Iwishedto
reachaconclusion(ra’y).Andsoallofthese[latter]contractedmeningitis.(Tibi2006)
Butitwasnotuntilthebeginningoftheeighteenthcenturybeforetheimportance
oftreatmentcomparisonswasbroadlyacknowledged,forexample,asinchancesof
contracting smallpox among people inoculated with smallpox lymph versus those
whocaughtsmallpoxdiseasenaturally(Bird2018).
By the middle of the eighteenth century there were examples of tests with
comparison groups, for example, as described by James Lind in relation to his
scurvyexperimentonboardtheHMSSalisburyatsea:
Onthe20thofMay1747,Itooktwelvepatientsinthescurvy,onboardtheSalisburyatsea.
TheircaseswereassimilarasIcouldhavethem.Theyallingeneralhadputridgums,the
spotsandlassitude,withweaknessoftheirknees.Theylaytogetherinoneplace,beinga
proper apartment for the sick in the fore-hold; and had one diet common to all, viz.,
watergruelsweetenedwithsugarinthemorning;freshmutton-brothoftentimesfordinner;
vii
viii AForewordtothePrinciplesandPracticeofClinicalTrials
atothertimespuddings,boiledbiscuitwithsugar,etc;andforsupper,barleyandraisins,
riceandcurrants,sagoandwine,orthelike.Twoofthesewereorderedeachaquartof
cydera-day.Twootherstooktwenty-fiveguttsofelixir vitriolthreetimesaday,uponan
emptystomach;usingagarglestronglyacidulatedwithitfortheirmouths.Twootherstook
twospoonfulsofvinegarthreetimesaday,uponanemptystomach;havingtheirgruelsand
theirotherfoodwellacidulatedwithit,asalsothegarglefortheirmouth.Twooftheworst
patients,withthetendonsinthehamrigid,(asymptomnoneoftheresthad),wereputunder
acourseofseawater.Ofthistheydrankhalfapinteveryday,andsometimesmoreorlessas
itoperated,bywayofgentlephysic.Twoothershadeachtwoorangesandonelemongiven
themeveryday.Thesetheyeatwithgreediness,atdifferenttimes,uponanemptystomach.
Theycontinuedbutsixdaysunderthiscourse,havingconsumedthequantitythatcouldbe
spared.Thetworemainingpatients,tookthebignessofanutmegthreetimesa-day,ofan
electuaryrecommendedbyanhospitalsurgeon,madeofgarlic,mustard-seed,radraphan,
balsamofPeru,andgummyrrh;usingforcommondrink,barley-waterwellacidulatedwith
tamarinds; by a decoction of which, with the addition of cremor tartar, they were gently
purgedthreeorfourtimesduringthecourse.
***
Theconsequencewas,thatthemostsuddenandvisiblegoodeffectswereperceivedfrom
theuseoftheorangesandlemons;oneofthosewhohadtakenthem,beingattheendofsix
daysfitforduty.(Lind1753)
Linddidnotmakeclearhowhis12sailorswereassignedtothetreatmentsinhis
experiment.Duringthelatenineteenthandearlytwentiethcentury,alternation(and
sometimes randomization) became used to create study comparison groups that
differedonlybychance(Chalmersetal.2011).
In1937assignmentwasdiscussedinHill’sbook,PrinciplesofMedicalStatistics,
inwhichheemphasizedtheimportanceofstrictlyobservingtheallocationschedule.
Implementation of this principle was reflected in concealment of allocation sched-
ulesintwoimportantclinicaltrialsdesignedfortheUKMedicalResearchCouncil
in the 1940s (Medical Research Council 1944; 1948). Sir Austin Bradford Hill’s
1937bookwentinto12editions,andhisotherwritings,suchasStatisticalMethods
in Clinical and Preventive Medicine, helped propel the upward methodological
progression.
The United States Congress passed the Kefauver-Harris Amendments to the
Food, Drug, and Cosmetic Act of 1938 in 1962. The amendments revolutionized
drugdevelopmentbyrequiringdrugmanufacturerstoprovethatadrugwassafeand
effective. A feature of the amendments was language spelling out the nature of
scientificevidencerequiredforadrugtobeapproved:
Theterm“substantialevidence”meansevidenceconsistingofadequateandwell-controlled
investigations, including clinical investigations, by experts qualified by scientifictraining
andexperiencetoevaluatetheeffectivenessofthedruginvolved,onthebasisofwhichit
couldfairlyandresponsiblybeconcludedbysuchexpertsthatthedrugwillhavetheeffectit
purportsorisrepresentedtohaveundertheconditionsofitsuseprescribed,recommended,
orsuggestedinthelabelingorproposedlabelingthereof.(UnitedStatesCongress1962)
Post World War II prosperity brought sizeable increases in government funding
for training and research. The National Institutes of Health played a major role in
trainingbiostatisticiansinthe1960sand1970swithitsfellowshipprograms.Bythe
AForewordtothePrinciplesandPracticeofClinicalTrials ix
1980sclinicaltrialcoursesstartedshowingupinsyllabiofacademicinstitutions.By
the1990sacademicinstitutionsstartedofferingPhDsfocusedondesignandconduct
oftrialswithafewnowofferingPhDtraininginclinicaltrials.
The clinical trial enterprise is huge. There were over 25,000 trials registered on
CT.gov starting in 2019. That number, assuming CT.gov registrations account for
70% of all registered trials, translates to 38,000 trials. That amounts to 2.3 million
people studied when those trials are finished assuming a median sample size of
60pertrial.
Lind did his trial before IRBs and consents, before requirements for written
protocols, before investigator certifications, before theHealth InsurancePortability
and Accountability Act (HIPAA), before data sharing, before data monitoring
committees, before site visiting, and before requirements for posting results within
1 year of completion. Trials moved from the backroom of obscurity to front and
centerwithtrialsseenasformsofpublictrust.
Theactoftryingprogressedfromeffortsinvolvingasingleinvestigatortoefforts
involvingcadresofinvestigatorswithtraininginmedicine,biostatistics,epidemiol-
ogy,programming,dataprocessing,andinregulationsandethicsunderlyingtrials.
Thesizeoftheresearchteamincreaseswiththesizeandcomplexitiesofthetrials.
Multicentertrialsmayinvolveinvestigatorshipsnumberinginthehundreds.
Entertrialists–personswithtrainingandexperienceinthedesign,organization,
conduct, and analysis of trials. Presently trialists are scattered, located in various
departments in medical schools and schools of public health. They have no
academichome.
Thescatteringworkstothedisadvantageoftheartandscienceoftrialsinthatit
stymiescommunicationsanddevelopmentofcurricularelevanttotrials.Oneofour
motivations in undertaking this work is hope of speeding development of such
homes.
Theblessingofonlinepublicationsisthatworkscanbeupdatedatwill.Thecurse
isthattheworkisneverdone.Wehopetoadvancethescienceoftrialsbyproviding
the trials world with a comprehensive work from leaders in the field covering the
waterfrontofclinicaltrialsservingasareferenceresourcefornovicesandexpertsin
trialsforuseindesigning,conducting,andanalyzingthem.
13May2020 StevenPiantadosiandCurtisL.Meinert
Editors
Postscript
Whenwestartedthiseffort,therewasnoCOVID-19.Nowwearelivingthrougha
pandemic caused by the virus leading us to proclaim in regard to trials, as Charles
DickensdidinhisATaleofTwoCitiesinadifferentcontext,“thebestoftimes,the
worstoftimes.”
“The best of times” because never before has there been more interest and
attention directed to trials, even from the President. Everybody wants to know
whentherewillbeavaccinetoprotectusfromCOVID-19.
x AForewordtothePrinciplesandPracticeofClinicalTrials
“Theworstoftimes”becauseofthechaoscausedbythepandemicinmounting
anddoingtrialsandtheimpactof“socialdistancing”onthewaytrialsaredonenow.
Itisagiventhatthepandemicwillchangehowwedotrials,butwhateverthose
changes will be, trials will remain humankind’s best and most enduring answer to
addressingtheconditionsandmaladiesthataffectus.
Acknowledgment
Weareindebted toSir Iain Chalmers for his review andcritical input inreviewing
this piece. Dr.Chalmers isfounder of theCochrane Collaborationand first coordi-
natoroftheJamesLindLibrary.
EventsintheDevelopmentofClinicalTrials
Date Author/source Event
1747 Lind Experimentwithuntreatedcontrolgroup(Lind1953)
1799 Haygarth Useofshamprocedure(Haggard1932)
1800 Waterhouse Smallpoxtrial(Waterhouse1802,1800)
1863 Gull Useofplacebotreatment(Sutton1865)
1918 Firstdepartmentofbiostatistics;JohnsHopkins
University,https://www.jhsph.edu/departments/
biostatistics/about-us/history/
1923 Fisher Applicationofrandomizationtoexperimentation
(FisherandMacKenzie1923)
1931 CommitteeonclinicaltrialscreatedbytheMedical
ResearchCouncilofGreatBritain(MedicalResearch
Council1931)
1931 Amberson Randomassignmentoftreatmenttogroupsofpatients
(Ambersonetal.1931)
1937 NIH StartofNIHgrantsupportwithcreationofthe
NationalCancerInstitute(NationalInstitutesofHealth
1981)
1944 Publicationofmulticentertrialontreatmentfor
commoncold(PatulinClinicalTrialsCommittee
1944)
1946 NürembergCodeforHumanExperimentation(Curran
andShapiro1970)https://history.nih.gov/research/
downloads/nuremberg.pdf
1948 MRC StreptomycinTBmulticentertrialpublished;BMJ:
30Oct,1948(MedicalResearchCouncil1948)
1962 Hill Book:StatisticalMethodsinClinicalandPreventive
Medicine(Hill1962)
1962 Kefauver, AmendmentstotheFood,Drug,andCosmeticActof
Harris 1938(UnitedStatesCongress1962)
AForewordtothePrinciplesandPracticeofClinicalTrials xi
Date Author/source Event
1964 NLM MEDLARS®(MEDicalLiteratureAnalysisand
RetrievalSystem)oftheNationalLibraryofMedicine
initiated
1966; USPHS MemofromSurgeonGeneralofUSPHSinforming
8Feb recipientsofNIHfundingofrequirementforinformed
consentasconditionforfundinghenceforth(Stewart
1966),https://history.nih.gov/research/downloads/
surgeongeneraldirective1966.pdf
1966 Levine PublicationofU.S.PublicHealthServiceregulations
leadingtocreationofInstitutionalReviewBoardsfor
researchinvolvinghumans(Levine1988)
1966; USgovt FreedomofInformationAct(FOIA)signedintolaw
6Sep byLyndonJohnson6September1966(PublicLaw
89-554,80Statue383);ActspecifiesUS
GovernmentalAgenciesrecordssubjecttodisclosure
undertheAct;amendedandextendedin1996,2002,
and2007,https://www.justice.gov/oip/foia_guide09/
foia-final.pdf;5September2009
1967 Tom Structureforseparatingthetreatmentmonitoringand
Chalmers treatmentadministrationprocess(CoronaryDrug
ProjectResearchGroup:1973)
1974; USgovt CreationofU.S.NationalCommissionforthe
12July ProtectionofHumanSubjectsofBiomedicaland
BehavioralResearch;partoftheNationalResearch
Act(PublicLawNo.93-348,§202,88Stat.342)
1974 USgovt USCodeofFederalRegulationspromulgated
establishingInstitutionalReviewBoards,https://www.
hhs.gov/ohrp/humansubjects/guidance/45cfr46
1979 OPRR BelmontReport(EthicalPrinciplesandGuidelinesfor
theProtectionofHumanSubjectsofResearch);
productoftheNationalCommissionfortheProtection
ofHumanSubjectsofBiomedicalandBehavioral
Research(OfficeforProtectionfromResearchRisks
BelmontReport1979)
1979 Gorden NIHClinicalTrialsCommittee(chairedbyRobert
Gorden)recommendsthat“everyclinicaltrialshould
haveprovisionsfordataandsafetymonitoring”
(NationalInstitutesofHealth1979)
1979 SocietyforClinicalTrialsestablished
1980 FirstissueofControlledClinicalTrials(Meinertand
Tonascia1998)
1981 Friedman Book:FundamentalsofClinicalTrials(Friedman
etal.1981)