Principles and Practice of Clinical Trials PDF
Preview Principles and Practice of Clinical Trials
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 ©SpringerNatureSwitzerlandAG2022 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation, broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdeveloped. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant protectivelawsandregulationsandthereforefreeforgeneraluse. Thepublisher,theauthors,andtheeditorsaresafetoassumethattheadviceandinformationinthisbook arebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsorthe editorsgiveawarranty,expressedorimplied,withrespecttothematerialcontainedhereinorforanyerrors oromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictionalclaims inpublishedmapsandinstitutionalaffiliations. ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSwitzerlandAG. Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland 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)
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