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D ictionary for C T linical rials DictionaryforClinicalTrials Author:SimonDay Copyright©1999JohnWiley&SonsLtd ISBNs:0-471-98611-9(Hardback);0-471-98596-1(Paperback); 0-470-84256-3(Electronic) To Nikki, Anya and Huw D ictionary for C T linical rials Simon Day Medical Department, Leo Pharmaceuticals, Princes Risborough, UK JOHN WILEY & SONS, LTD Chichester·NewYork·Weinheim·Brisbane·Singapore·Toronto Copyright©1999byJohnWiley&SonsLtd, BaffinsLane,Chichester, WestSussexPO191UD,England National 01243779777 International ((cid:1)44)1243779777 e-mail(forordersandcustomerserviceenquiries):[email protected] VisitourHomePageonhttp://www.wiley.co.uk orhttp://www.wiley.com Allrightsreserved.Nopartofthispublicationmaybereproduced,storedinaretrievalsystem, ortransmitted,inanyformorbyanymeans,electronic,mechanical,photocopying,recording, scanningorotherwise,exceptunderthetermsoftheCopyright,DesignsandPatentsAct1988 orunderthetermsofalicenceissuedbytheCopyrightLicensingAgency,90TottenhamCourt Road,London,UKW1P9HE,withoutthepermissioninwritingofJohnWiley&SonsLtd, BaffinsLane,Chichester,WestSussex,UKPO191UD. OtherWileyEditorialOffices JohnWiley&Sons,Inc.,605ThirdAvenue, NewYork,NY10158-0012,USA WILEY-VCHVerlagGmbH,Pappelallee3, D-69469Weinheim,Germany JacarandaWileyLtd,33ParkRoad,Milton, Queensland4064,Australia JohnWiley&Sons(Asia)PteLtd,2ClementiLoop(cid:1)02-01, JinXingDistripark,Singapore129809 JohnWiley&Sons(Canada)Ltd,22WorcesterRoad, Rexdale,OntarioM9W1L1,Canada LibraryofCongressCataloging-in-PublicationData Day,Simon. Dictionaryforclinicaltrials/SimonDay. p. cm. Includesbibliographicalreferences. ISBN0-471-98611-9(cased:alk.paper).—ISBN0-471-98596-1(paper:alk.paper) 1.Clinicaltrials—Dictionaries. I.Title. [DNLM:1.ClinicalTrialsdictionaries. QV13D275d1999] R853.C55D39 1999 610(cid:1).7(cid:1)2—dc21 DNLM/DLC forLibraryofCongress 99—11151 CIP BritishLibraryCataloguinginPublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN0-471-98611-9(cased) ISBN0-471-98596-1(paper) Typesetin9/10(cid:2)(cid:3)ptTimesfromtheauthor’sdisksbyVisionTypesetting,Manchester PrintedandboundinGreatBritainbyAntonyRoweLtd.,Chippenham,Wiltshire Thisbookisprintedonacid-freepaperresponsiblymanufacturedfromsustainableforestry, inwhichatleasttwotreesareplantedforeachoneusedforpaperproduction iv P reface ItisnowfiftyyearssincetheBritishMedicalResearchCouncilpublished the results of a trial entitled ‘Streptomycin treatment of pulmonary tuberculosis’(BritishMedicalJournal,30thOctober1948,pages769—782). Thatstudyiswidelyregardedasthefirstrandomisedclinicaltrial.Earlier examplesofnonrandomisedstudiesarecited,notablythatofJLind(A TreatiseontheScurvy,1753).Despitesuchahistoryandtheenormous numbersoftrialsconductedandpublishedinthelasttwentyorsoyears, manypeopledonotconsider‘clinicaltrials’asadisciplineinitsownright and,assuch,thebreadthoftermsthatshouldbecoveredinadictionary of this kind is not well defined. Ultimately, the choice of entries is a personalone,guidedbyexperiencesofwhatIhavehadtolearnandwhat mycolleaguesinvariousspecialitiesoftheclinicaltrialsspectrumhave struggledtounderstand.AdditionallyIhavetrawledclinicaltrialprotocols, reports,regulatoryguidelinesandpublishedmanuscriptstotrytocover the majority of terms that are likely to be encountered. A lot of the terminology of clinical trials is statistical: terms used for the design (blocks, randomisation, stratification) and for the analysis (confidence interval, P-value, survival analysis, t test, to list but a few). I make no apologyforthehighproportionofstatisticalterms:thoseareusuallythe onesthatareleastwellunderstood.Overallthough,thecontentisbroad anditisverydifficulttosummarisewhatiscovered. Itisalmostasdifficulttosummarisewhatisn’tcovered.Thisisnota dictionaryofmedicalterms,ofstatisticalterms,ofepidemiological,ethical ordatamanagementterms.Itdoes,however,containelementsofallthose disciplines,thefirstthreeinparticular.Manyoftheepidemiologicalterms included would not ordinarily be found in a clinical trial protocol or report;however,inthediscussionofwhetheraclinicaltrialisappropriate for answering a particular medical question, or in discussion of trial resultsalongsideothersourcesofevidence,theissueofotherapproaches suchascase-controlstudiesandcohortstudiesarelikelytobediscussed.I havenotincludedspecificdiseases(amedicaldictionarywouldbemore appropriate) or names of clinical rating scales but I have included a variety of medicalterms that are frequentlyassumed to be understood DictionaryforClinicalTrials Author:SimonDay Copyright©1999JohnWiley&SonsLtd ISBNs:0-471-98611-9(Hardback);0-471-98596-1(Paperback); 0-470-84256-3(Electronic) Preface (termssuchasacute,chronic,subcutaneous,etc.)Abbreviationsarenot included,exceptinthefewinstanceswhereatermisbetterknownbyits acronymthan by its full name (COSTARTand MedDRA are obvious examples).Norarethenamesofprofessionalorscientificsocieties,research institutionsorregulatoryauthoritiesincluded. The intended readership for this dictionaryare all those peoplewho workwithclinicaltrialprotocolsandreportsorwhootherwiseneedto understandtheuseoflanguageinthisspecialistarea.Suchareadership includesclinicaltrialists(thosepeoplewhoactuallycarryoutthevarious administrative, clerical and scientific aspects), those who sit on ethics committees,thosewhoworkinregulatorydepartmentsorgrantawarding bodies,doctors, nurses,pharmacists(and patients)readingclinicaltrial reports,andsoon.Trialssponsoredbythepharmaceuticalindustry,as wellas thoseconductedbyacademicinstitutionsor bysmallgroupsof enthusiasts,allfallwithinthescopeofthisworkasdocommunity-based interventionstudies,vaccinetrials,studiesofmedicalpracticeandmedical devices.Necessarily,manyentrieswillbemorerelevanttosometypesof trialsandtrialiststhantoothers.Ihopethecoverageisadequatewithout beingtoocumbersome. Thestyleofexplanationsanddefinitionsisaimedatbeingpragmatic andreadableratherthanpurist.Pre-existingdefinitions(ofteninregulatory guidelines)havenotnecessarilybeenfaithfullyreproduced,althoughcare hasbeentakentoincorporatetheessentialmeaningfromrelevantguidelines. As an example, the term ‘adverse event’ has a very specific definition within the International Conference on Harmonisation although the explanationgivenhereisalittlemorebrief.Furtherexamplesofpragmatism aboundintheexplanationsofsomestatisticalterms.Manystatisticians maychallengethecorrectnessofmyexplanationsofanalysisofcovariance, BayesianstatisticsorP-value,forexample:Iapologisetotheminadvance buthopethattheexplanationsIhavegivenwillhelpthosereaderswho understandlittle or nothingof such termstoat least gain arough and readygraspoftheirmeaning.Similarly,‘ethics’iscoveredinameretwo lines: there are other related entries but the aim is to get the essential meaningacross.Fullandcompleteexplanationsofallthetermsincluded wouldmeanthisworktakingonthescaleofaseriesoftextbooksandthat isnot theintention.I hopethattheexplanationsgivenhere,putinthe contextwherethewordorexpressionhasarisen,willallowmostreaders tounravelmostuncertainties. vi Preface InmydefenceoveraccuracyandqualitycontrolIcanclaimthatevery singleentryhasbeenreviewedbyavarietyofmycolleagues;andintheir defenceIacknowledgethateverysingleerror,discrepancyandinconsistency remainsmyresponsibility. vii T G R he round ules Thefollowingisabriefguidetowhat’sinandwhat’snotin,andrulesfor cross-referencingrelatedor alternativeterms. Ingeneral,studyisusedratherthantrialexceptwherethedistinctionis helpful(strictlyspeaking,studyencompassestrialbutmanytypesofstudy will not be trials). Similarly, trial is taken to mean clinical trial. For example,acutestudyislisted,butnotacutetrialor acuteclinicaltrial. Phrases may sometimes be abbreviated but, I hope, without causing any difficulty in finding them. For example, adaptive design should be takentoencompassadaptivetrialdesignandadaptiveclinicaltrialdesign. WherealternativetermsmaybeusedinterchangeablyIhavetriedto pickthemostcommontermtodefineanditssynonymswillsimplydirect (cid:2) you there with the symbol . For example, alpha error simply says (cid:2) ‘ type I error’ (where an explanation is given). The most important termsusedwithinthedefinitionsofothertermsareemboldened,asare referencestocontrastingterms(Û...)andrelatedterms((cid:1)...).Ihope thatsometimesgivingindicationofcontrastingorrelatedtermsmayhelp understanding. It is inevitable, however, that some definitions will be circular:activecontrolcontrastswith(Û)placebocontrol;placebocontrol contrastswith(Û)activecontrol.Ultimately,justaswithalldictionaries, alldefinitionsmustusethetermshereintoexplainothertermsandthe circularitybecomesinevitable. DictionaryforClinicalTrials Author:SimonDay Copyright©1999JohnWiley&SonsLtd ISBNs:0-471-98611-9(Hardback);0-471-98596-1(Paperback); 0-470-84256-3(Electronic) B ibliography Thereisavarietyofbookswrittenaboutclinicaltrialsandseveralother dictionariesandglossariesthatmayprovehelpfulindefiningtermsand clarifyingtheiruse.Thefollowingtitleshaveprovedparticularlyhelpful incompilingthisdictionaryandmayserveasusefuladditionalsourcesof reference: AppliedClinicalTrials(variousissues) Churchill’s Illustrated Medical Dictionary (1989) New York: Churchill Livingstone. Boyd KM, Higgs R and Pinching AJ (1997) The New Dictionary of MedicalEthics.London:BritishMedicalJournal. Bull K and Spiegelhalter DJ (1997) Survival analysis in observational studies.StatisticsinMedicine16:1041—74. DuncanAS,DunstanGRandWelbournRB(1981)DictionaryofMedical Ethics,revisededition.London:Darton,LongmanandTodd. DupayratJ(1990)DictionaryofBiomedicalAcronymsandAbbreviations, 2ndedition.Chichester:JohnWiley& Sons. EverittBS(1995)The CambridgeDictionary ofStatistics in theMedical Sciences.Cambridge:CambridgeUniversityPress. Friedman LM, Furberg CD and DeMets DL (1985) Fundamentals of ClinicalTrials,2ndedition.Littleton:PSGPublishingCompany. GrieveAP(1998)FAQsofStatisticsinClinicalTrials.Richmond:Brook- woodMedicalPublications. HeisterR(1989)DictionaryofAbbreviationsinMedicalSciences.Berlin: Springer-Verlag. JadadA (1998)RandomisedControlledTrials. London:BritishMedical Journal. Johnson FN and Johnson S (1977) Clinical Trials. Oxford: Blackwell ScientificPublications. Last JM (1995) A Dictionary of Epidemiology, 3rd edition. New York: OxfordUniversityPress. DictionaryforClinicalTrials Author:SimonDay Copyright©1999JohnWiley&SonsLtd ISBNs:0-471-98611-9(Hardback);0-471-98596-1(Paperback); 0-470-84256-3(Electronic)