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CLINICALTRIALS
SECONDEDITION
CLINICALTRIALS
StudyDesign,Endpointsand Biomarkers,DrugSafety, andFDAandICHGuidelines
SECONDEDITION
TomBrody,Ph.D.
AcademicPressisanimprintofElsevier
Acknowledgments
IthankJuliaHaynes,MollyMcLaughlin, KristineJones,andAprilGrahamofElsevier, Inc.,fortheirdevotionandexpertiseinthe editingandproductionphasesofthisbook.
IamindebtedtoDrWaiheiA.Chu, PharmD,forhisguidanceinthefieldofregulatorywriting.Inhisownwords:Ithankthe followingpeopleforansweringspecificquestionsduringthecourseofthisproject.Nearly allofthesepersonsarephysiciansandprincipal investigatorsinclinicaltrialsinoncology,multiplesclerosis,andinfectiousdiseases.Manyof thesepersonsarethought-leadersinthefieldof studydesignoraretenuredprofessorsinmedicalschools.IthankMashaHareli,AmitBar-Or, andOlafSteve,forauthoritativeguidance onmultiplesclerosis.IthankChristinaSlover forguidanceondrug druginteractions.Iam gratefultoPatrickArchdeacon,PatriciaHarley, MichelleEby,andJoetteM.Meyer,allofthe FDA,forinformationonvariousaspectsofthe FDAapprovalprocess.IamgratefultoPeterC. Raichforgrantingpermissiontoreproduce hisconsentforms,andIthankDavidCellafor sendingmetheseforms.IthankMarcBuyse, TomaszBurzykowski,DanielJ.Sargent,Gerold Bepler,SallyStenning,JohnHainsworth, SanjivS.Agarwala,CliffordA.Hudis,Axel Grothey,Wen-JenHwu,KeithWheatley,Joseph A.Sparano,ElizabethA.Eisenhauer,Miguel Martin,andLindaColangelo,fortheirexpert guidanceonendpoints.Iamdeeplygrateful toFrankWordenandBruceE.Johnsonfor
guidanceonrun-inperiods.Iammostgrateful toDavidCella,BarbaraVickrey,Andrea (Andy)Trotti,andJinnyTavee,forhelpon health-relatedquality-of-life(HRQoL)instruments.IthankJeffreyA.Cohenforhisdetailed responsestomyquestionsonmultiplesclerosis. Also,IamgratefultoChing-HonPui,JamesB. Nachman,EricE.Hedrick,StaceyL.Berg,and TanjaHartmannfortheirinsightsregarding theleukemias.IacknowledgeMargaretvon Mehrenforinformationongastrointestinalstromaltumors.IthankBruceA.Roeformodifying mydiagramofthePhiladelphiachromosome, andIthankAdeleK.Fieldingforfurtherguidanceonthischromosome.Iamalsogratefulto JakeLiangandRobertE.Lanfordforexplaining relationsbetweenIFN-alphaandIFN-gamma, astheyapplytohepatitisCvirus.
IthankMartinE.Stryjewski,JonathanS. Berek,JamesCassidy,OlivierLeroy,and MichaelE.Pichichero,forhelponperprotocol analysisandintent-to-treatanalysis.Ithank LawrenceRubinstein,ThomasG.RobertsJr, ThomasJ.Lynch,MurrayD.Norris,Bradley R.Prestidge,andIgorSherman,forinformationonsubgroupsoroninclusion/exclusion criteria.
IamgratefultoPeterJ.Barrett-Leeforinformationondrugsafety.IthankAnthonyViera forinformationonrandomization.Ithank SyedY.ZafarandRichardL.Schilskyfortheir expertiseonbestsupportivecareandpalliative care.IacknowledgeKarenMosherforher
INTENT-TO-TREATANALYSIS ANDPLACEBOS
Second,theauthorsobservedthatother aspectsofclinicaltrialsareinadequately describedintextbooks,forexample,theywere coveredonlybyashortparagraph.These aspectsincludeintent-to-treat(ITT)analysis, modifiedITT(mITT)analysis,andperprotocol (PP)analysis.ITTanalysisisatermthatis almostuniversallyusedinclinicaltrials,but theavailabletextbooksonclinicaltrialdesign typicallyfailtodescribeITTanalysis,mITT analysis,orPPanalysis,andhowtochoose betweenthesethreetypesofdataanalysis. ThisbookcontainsanentirechapteronITT, mITT,andPPanalyses.Itisalsothecasethat mostorallbooksonclinicaltrialsfailto includeanyorganizedaccountofplacebos. Thisbookhasanentirechapteronplacebos.
HOWTOCHOOSEENDPOINTS
Third,definitionsofendpointsusedin oncologyclinicaltrialsarefrequentlydisclosed intheavailabletextbooks,butunfortunately, textbooksgenerallyfailtostatetheadvantages ofanygivenendpointoveranother,andfailto statesituationswhereaparticularendpoint givesambiguousinformationorwhereanendpointcannotbeused.Theseoncologyendpointsincludeobjectiveresponserate(ORR), overallsurvival(OS),progression-freesurvival (PFS),timetoprogression(TTP),timetodistantmetastasis(TDM),disease-freesurvival (DFS),6-monthPFS,andhealth-relatedquality oflife(HRQoL).TheFDA’sGuidancefor Industry(2)providesafineintroductionto theseendpoints,butrefrainsfromdetailing, forexample,situationswhereanygivenendpointislikelytobeunreliableorunusable.
Thisbookfulfillsanunmetneedbyproviding amoredetailedaccountonhowtochoosethe mostappropriateoncologyendpoint,andon whentorefrainfromusingagivenendpoint.
DIAGNOSTICTESTS
Fourth,thisbooktakescaretointegrate diagnostictestswitheachdisease.Whatare describedaredisabilitystatusquestionnaires, HRQoLquestionnaires,bloodcounts,flow cytometry,immunoassays,polymerasechain reaction(PCR),microarrays,andmagneticresonanceimaging(MRI).Moreover,thisbook providesanintroductiontotheprocessof FDAapprovalfordiagnosticstests.
MECHANISMOFACTION
Fifth,thebookdescribesthemechanismsof variousdiseasesandthemechanismsofaction ofvariousdrugs.Thesemechanismsareintegratedintothecontextofclinicaltrials,incommentarydemonstratinghowthemechanismof actioncaninfluencetheinclusion/exclusion criteria,warningsonconsentforms,andinformationonpackageinserts.Thisbookalso describeshowthemechanismofactioncan influencestudydesign,thatis,theparticular combinationandtimingofadministereddrugs. Thebookrevealsthataknowledgeofthemechanismofactioncanencourageregulatoryagenciestoallowaclinicaltrialtobeinitiated.
STANDARDS
Sixth,thetextemphasizestheroleofvariousstandardsthatapplytoclinicaltrials. Thesestandardsincludecriteriaformeasuring
2U.S.DepartmentofHealthandHumanServices.FoodandDrugAdministration.Guidanceforindustry.Clinical trialendpointsfortheapprovalofcancerdrugsandbiologicals;2007(19pp.).
AlthoughPublicLawNo.110-85containsa sectionnamed,Section801,thelawonlyhas 88sections.Section801isreproduced,inpart, below(17):
(i)SEARCHABLECATEGORIES.—TheDirector ofNIHshallensurethatthepublicmay,inaddition tokeywordsearching,searchtheentriesintheregistrydatabankby1ormoreofthefollowingcriteria:
(I)Thediseaseorconditionbeingstudiedinthe clinicaltrial,usingMedicalSubjectHeaders(MeSH) descriptors.
(II)Thenameoftheintervention,includingany drugordevicebeingstudiedintheclinicaltrial.
(III)Thelocationoftheclinicaltrial.
(IV)Theagegroupstudiedintheclinicaltrial, includingpediatricsubpopulations.
(V)Thestudyphaseoftheclinicaltrial.
(VI)Thesponsoroftheclinicaltrial,whichmay betheNationalInstitutesofHealthoranother Federalagency,aprivateindustrysource,orauniversityorotherorganization.
(VII)Therecruitmentstatusoftheclinicaltrial.
(VIII)TheNationalClinicalTrialnumberor otherstudyidentificationfortheclinicaltrial.
TheInternationalCommitteeofMedical JournalEditors(ICMJE)adoptedthepolicy thatclinicaltrialsberegisteredattheonsetof
patientenrollment,asaconditionforpublication(18).Inobservingthattrialregistrationis largelyvoluntary,andthatregistriescontain onlyasmallproportionoftrials,theICMJE proposedthattrialregistrationbeasolution totheproblemofselectiveawareness,andset forththegoalthatICMJEmemberjournals require(asaconditionofconsiderationfor publication)registrationinapublictrialsregistry(19,20).Trialsmustregisteratorbefore theonsetofpatientenrollment.Hirsch(21) andothers(22,23)providecommentsonthis policy.Inasurveyofeditorialpoliciesof165 medicaljournals,Hopewelletal.(24),found that44speciallyrequirethattheclinicaltrial beregisteredbeforesubmittingthemanuscript tothejournal.
AccordingtotheFDA’sGuidancefor Industrydocumentongoodpharmacovigilance practices,asponsormayestablishorcreatea newregistry,forexample,forthegoalsof evaluatingsafetysignalsidentifiedfromspontaneouscasereportsorfromliteraturereports, andforevaluatingfactorsthataffecttherisk ofadverseoutcomes,suchasdose,timingof exposure,orpatientcharacteristics(25).
17PublicLaw110-85.110thCongress.September27,2007.FoodandDrugAdministrationAmendmentsof2007.
18FooteM.Clinicaltrialregistriesandpublicationofresults—aprimer.In:FooteM,editor.Clinicaltrialregistries apracticalguideforsponsorsandresearchersofmedicinalproducts.Basel,Switzerland:BirkhauserVerlag;2006. pp.1 12.
19DeAngelisCD,DrazenJM,FrizelleFA,etal.Isthisclinicaltrialfullyregistered?—Astatementfromthe InternationalCommitteeofMedicalJournalEditors.NewEngl.J.Med.2005;352:2436 8.
20DeAngelisCD,DrazenJM,FrizelleFA,etal.Clinicaltrialregistration:astatementfromtheInternational CommitteeofMedicalJournalEditors.J.Am.Med.Assoc.2004;292:1363 4.
21HirschL.Trialregistrationandresultsdisclosure:impactofUSlegislationonsponsors,investigators,and medicaljournaleditors.Curr.Med.Res.Opin.2008;24:1683 9.
22BonatiM,PandolfiniC.Trialregistration,theICMJEstatement,andpaediatricjournals.Arch.Dis.Child 2006;91:93.
23SekeresM,GoldJL,ChanAW,etal.Poorreportingofscientificleadershipinformationinclinicaltrialregisters. PLoSOne2008;3:e1610.
24HopewellS,AltmanDG,MoherD,SchulzKF.EndorsementoftheCONSORTStatementbyhighimpactfactor medicaljournals:asurveyofjournaleditorsandjournal‘InstructionstoAuthors’.Trials2008;9:20.
25U.S.DepartmentofHealthandHumanServices.FoodandDrugAdministration.Guidanceforindustry.Good pharmacovigilancepracticesandpharmacoepidemiologicassessment;March2005(20pp.).
I.GOODCLINICALPRACTICE
Clinicaltrialsintendedforregulatory approvalshouldconformtoasetofguidelines knownas,GoodClinicalPractice(GCP). AccordingtotheICHGuidelines:
GoodClinicalPracticeisaninternationalethical andscientificqualitystandardfordesigning,conducting,recordingandreportingtrialsthatinvolve theparticipationofhumansubjects.Compliance withthisstandardprovidespublicassurancethat therights,safetyandwell-beingoftrialsubjectsare protected,consistentwiththeprinciplesthathave theiroriginintheDeclarationofHelsinki,andthat theclinicaltrialdataarecredible 1 .
GCPencompassestherequirementthatthe clinicalstudybeapprovedbyanindependent ethicsboard,suchasanInstitutionalReview Board(IRB),priortoinitiatingtheclinical study.GCPalsoencompassestherequirements thatstudysubjectsgiveinformedconsentprior toenteringthestudy,thatrecordsofstudy subjectsbekeptconfidential,thatinvestigators beproperlyqualifiedbyeducationandtraining, thatadequatemedicalcarebegiventoany studysubjectswhosufferfromstudy-related adverseevents,thatseriousadverseevents beimmediatelyreportedtothesponsor,and thatstudydrugsandplacebo(ifany)bemanufacturedaccordingtoGoodManufacturing Practices(GMP).
TheICHGuidelineforGoodClinical PracticealsoprovidestheorganizationandcontentoftheClinicalStudyProtocol.TheClinical StudyProtocolis,inessence,theinstruction manualusedbypersonsinvolvedinconductingthetrial.Additionally,theICHGuideline forGoodClinicalPracticedetailstheorganizationandcontentoftheInvestigator’sBrochure (IB),adocumentthatcompilesrelevantclinical
dataandnon-clinicaldata.Thesedatainclude thosearisingapartfromthestudy,forexample, fromreportsfromanimalstudiesandfromclinicaltrialsconductedbyotherinvestigators,as wellasdatafromhumansubjectsarisingfrom thestudyitself.Mostoftheinformationset forthinthistextbookcanbeviewedinthecontextofGoodClinicalPractice.
TheICHGoodClinicalPracticeGuidelines setsforthinternationalstandardsforthequality,safety,andefficacyofdevelopmental-stage pharmaceuticalproducts.TheICHGood ClinicalPracticeGuidelinesweremadebinding bytheEUClinicalTrialsDirectivein2004.2 Theyrequirethesponsortoverifythequalificationsoftheinvestigators,obtaininformed consentbeforeeachsubject’sparticipationin thetrial,ensurethetrialsareadequatelymonitored,andthattheinstitutionalreviewboard (IRB)reviewsandapprovestheClinicalStudy Protocol,andoverseethetrial.
ThistextbookfrequentlyreferstotheICH GuidelinesandtheFDA’sGuidancefor Industrydocuments,andusesthesedocuments asanchorpointsforthevariousnarratives.
II.FDA’SDECISION-MAKING PROCESSINGRANTING APPROVALTOADRUG
Thistextbookisuniqueinitsextensiveuse ofdocumentspublishedbytheFDAatthe timetheFDAgrantsapprovaltoadrug.These documentarepublishedbytheFDA,inits responsetoanNDAorBLAsubmittedbya Sponsor.Thedecision-makingprocessesleadingtoregulatoryapprovalofvariousdrugsare available,inpart,onthewebsiteoftheFDA. Theavailabledocuments,whicharepublished
1ICHHarmonisedTripartiteGuidelines.GuidelineforGoodClinicalPracticeE6(R1).Step4version,June1996. 2HathawayCR,MantheiJR,HaasJB,SchererCA.Lookingabroad:clinicaldrugtrials.FoodandDrugLaw Journal.2008;63:673 681.
atthetimethattheFDAgrantsapprovaltoa drug,include:
• ApprovalLetter
• PackageInsert
• MedicalRevieworClinicalReview
• PharmacologyReview
• StatisticalReview
• PackageInsert
• AdministrativeDocumentsand Correspondence.
FortheReviews,itisthecasethatFDA reviewersreproducesomeofthedatathathad beensubmittedbytheSponsor,re-analyzethe results,andcometotheirownconclusions.The Reviewsincludeclearlylabeledcommentsfrom thereviewers.Thesecommentsprovideinvaluableguidancefromtheultimateauthorityon thetypesofstudydesignanddatathatare neededtoinfluencetheFDAtograntapproval. Thesecommentssometimestaketheformof complaints,however,sincetheReviewsare publishedatthetimeofFDAapproval,it isgenerallynotthecasethatthecomplaints areharshenoughtobringahalttothedrugapprovalprocess.Onoccasion,partsofthe FDA’sReviewsthatcorrespondtoanearlier phaseofthedrug-approvalprocesswillreveal
harshcomplaints,suchasthoseinvolvinga ClinicalHold ora RefusetoFile notice,andwhere thesecomplaintswereeventuallyovercomeby theSponsor.Moreover,becausetheReviews arepublishedatthetimeofFDAapproval,itis thecasethattheseReviewsoftenemphasize postmarketingrequirementsthatwereimposed bytheFDA,forexample,therequirementto conductconfirmatoryclinicaltrials,inthecase ofatrialthathadreceivedanaccelerated approval,ortherequirementtoincludean REMSinthepostmarketingsituation.
III.DISCLAIMER
Thefollowingisadisclaimer.Thepresent writingdoesnotconstitutelegaladvice,andit doesnotestablishanyrelationshipbetween thereaderandtheauthors.Agoalofthepresentwritingistofacilitatecommunication betweeninvestigatorsinpharmaceuticalcompaniesandtheirattorneys,inmatterslimited toconsentforms,packageinserts,andpatents. Theopinionssetforthhereindonotnecessarilyreflecttheopinionsoftheauthors’past, present,orfutureemployers.
AbbreviationsandDefinitions
ADCC antibody-dependentcellcytotoxicity
ADME absorption,distribution,metabolism,andexcretion
ADR adversedrugreaction
AE adverseevent
ALL acutelymphocyticleukemia;acutelymphoblastic leukemia
AML acutemyeloidleukemia;acutemyelogenousleukemia
APC antigenpresentingcell.APCsincludecellsofthe immunesystem,forexample,dendriticcellsandmacrophages.Antigens,whichtaketheformofpeptidesand oligopeptides,arenoncovalentlyboundtoMHC,and arepresentedtoTcellsbywayoftheMHC,wherepresentationoccursinanimmunesynapsethatinvolves theAPCandaTcell
ASCO AmericanSocietyofClinicalOncology
AUC areaunderthecurveofconcentration,inserumor plasma,overtime.TheAUCrepresentstheoverall impactofadrug,overthecourseoftime,toorgans, tissues,andcells,inthephysiologicalmilieu
bid “bidindie,”whichisLatinfortwiceaday
Cmax maximumconcentrationinplasmaorserum. Plasmareferstobloodcontainingananticoagulant, withbloodcellsremoved.Serumpreparedbyallowing bloodnaturallytoclot,followedbydiscardingtheclot andthebloodcells
Cmin minimumconcentrationinplasmaorserum
CBER CenterforBiologicsEvaluationandResearch
CD clusterofdifferentiation.TheCDnomenclaturerefers tocell-surfaceproteinsofimmunecells,andisusedto identifyimmunecells
CDER CenterforDrugEvaluationandResearch
CFR;C.F.R. CodeofFederalRegulations
CI confidenceinterval
CIOMS CouncilforInternationalOrganizationsof MedicalSciences
CLL chroniclymphocyticleukemia;chroniclymphoblasticleukemia
CMI ConsumerMedicationInformation
CML chronicmyeloidleukemia;chronicmyelogenous leukemia
CONSORT ConsolidatedStatementofReportingTrials
COPD chronicobstructivepulmonarydisease
CR completeresponse.Completeresponseisatypeof objectiveresponse.“Objectiveresponse”meansassessingtumorsizeandnumber,asdescribedbythe RECISTcriteria.CRisalsousedtorefertoatotally differentparameter,completeremission
CRF CaseReportForm
CRP C-reactiveprotein
CTCAE CommonTerminologyCriteriaforAdverse Events
DC dendriticcell
DFS disease-freesurvival
DMC DataMonitoringCommittee
DNA deoxyribonucleicacid
DSMC DataandSafetyMonitoringCommittee
ECG electrocardiogram
ECOG EasternCooperativeOncologyGroup
ECRIN EuropeanClinicalInfrastructureNetwork
EGF epidermalgrowthfactor
EMA;EMEA EuropeanMedicinesAgency.EMEAwas theformerlyusedabbreviation,butinDec.2009the abbreviationwaschangedtoEMA
FDA USFoodandDrugAdministration
FDAForm356h theformusedtosubmitanNDAorBLA
FDAForm483 Form483issometimesissuedduringthe timeofanFDAinspectionofaclinicalormanufacturing facility.Iftheproblemsarenotcorrectedinduecourse, FDAmayfollow-upbyissuingaWarningLetter
FDAForm1571 theformusedtosubmitanIND
FOLFIRI anticancertherapyusingfolinicacid,fluorouracil,andirinotecan.Folinicacid,alsoknownasleucovorin,isatrivialnamefor5-formyl-tetrahydrofolicacid
FPI FullPrescribingInformation.FPIistheUSFoodand DrugAdministration’snameforpartofthepackageinsert 5-FU 5-fluorouracil
GCP GoodClinicalPractices
GLP GoodLaboratoryPractices
Gy Gray(1gray 5 1J/kgandalsoequals100rad).The grayisaunitofabsorbedenergypermassoftissue
HCV hepatitisCvirus
HERGgene humanether-relateda-go-gogene
Biographies
TheauthorreceivedhisPhDfromthe UniversityofCaliforniaatBerkeleyin1980, andconductedpostdoctoralresearchat UniversityofWisconsin-Madisonandalsoat U.C.Berkeley.Mostofhis20researchpublicationsconcerntheenzymology,metabolism, andpharmacokineticsoffolatesandrelated aminoacids(1,2,3,4).Also,hecloned, sequenced,andexpressedanoncogene(XPE gene)(5,6,7).Later,heperformedresearchon thestructureofanantibody(natalizumab) usedfortreatingmultiplesclerosis(8).The authorhas15yearsofpharmaceuticalindustry experience,acquiredatSchering-Plough,Cerus Corporation,andAthenaNeurosciences(Elan Pharmaceuticals),andhascontributedtoFDAsubmissionsfortheindicationsofmultiple
sclerosis,melanoma,headandneckcancer, livercancer,pancreaticcancer,andhepatitis C.Atanearliertime,hewrotetwoeditions of NutritionalBiochemistry,publishedby Elsevier,Inc.(9). NutritionalBiochemistry describestheclinicalfeatures,diagnosis, treatment,andmechanismsofactionof40 drugs,relatingtothemetabolicdiseases. Morerecently,theauthoracquired3years ofexperienceinFDAregulations,asappliedto packageinserts,aswellasfurtherexperience inmedicalwritinginoncology,immunedisorders,andinfections,atBakerHostetler,LLP, CostaMesa,CA.Theauthorhas16yearsof trainingandexperienceintheCodeofFederal regulations,asitappliestopharmaceuticals andclinicaltrialdesign.
1BrodyT,StokstadELR.Folateoligoglutamate:aminoacidtranspeptidase.J.Biol.Chem.1982;257:14271 9.
2BrodyT,WatsonJE,StokstadELR.Folatepentaglutamateandfolatehexaglutamatemediatedone-carbon metabolism.Biochemistry1982;21:276 82.
3BrodyT,StokstadELR.Nitrousoxideprovokeschangesinfolylpenta-andhexaglutamates.J.Nutr. 1990;120:71 80.
4BrodyT,StokstadELR.Incorporationofthe2-ringcarbonofhistidineintofolylpolyglutamatecoenzymes.J.Nutr. Biochem.1991;2:492 8.
5BrodyT,KeeneyS,LinnS.Humandamage-specificDNAbindingproteinp48subunitmRNA,GenBank, Accession#U18299;1995.
6KeeneyS,EkerAP,BrodyT,etal.CorrectionoftheDNArepairdefectinxerodermapigmentosumgroupEby injectionofaDNAdamage-bindingprotein.Proc.NatlAcad.Sci.1994;91:4053 6.
7DualanR,BrodyT,KeeneyS,etal.ChromosomallocalizationandcDNAcloningofthegenes(DDB1andDDB2) forthep127andp48subunitsofahumandamage-specificDNAbindingprotein.Genomics1995;29:62 9.
8BrodyT.Multistepdenaturationandhierarchyofdisulfidebondcleavageofamonoclonalantibody.Analytical Biochem.1997;247:247 56.
9BrodyT.Nutritionalbiochemistry.2nded.SanDiego,CA:AcademicPress;1999.
is,wherethedrugsareanalogsofthesechemicals.Theseincludeanalogsofintermediatesor finalproductsofbiosyntheticpathways.Drugs thatareanalogsofchemicalsinbiosynthetic pathwaysincludemethotrexate,cladribine,and ribavirin.
Stillotherdrugsoriginatedbyfirstidentifying atargetcell,ortargetprotein,andthenby preparingantibodiesthatbindtothattarget. Vaccineshaveasimilarorigin.Onceatarget proteinisidentified,thistargetprotein(ora derivativeofit)canbeformulatedasavaccine. Typically,vaccinestaketheformofthetarget proteinderivative,calledan“antigen,”incombinationwithasecondcompoundthatisan immuneadjuvant.
Drugsarealsoderivedusingascreening assayandbytestinghundredsorthousands ofpurifiedcandidatecompoundsusingthat assay.Wherethescreeningmethodisautomated,themethodiscalledhigh-throughput screening.Thescreeningassaymayconsistof tumorcellsthatareculturedinvitro,wherea robotdeterminesifthecandidatedruginhibits aparticularenzymeinthetumorcellorif thecandidatedrugkillsthetumorcell.
II.STRUCTURESOFDRUGS
Aknowledgeofthestructureofadrugto beusedinaclinicaltrialisneededforthe followingreasons.First,theissueofwhether adrugishydrophobicorhydrophilicwill dictatethenatureoftheexcipient.Ifadrugis notwater-soluble,thentheexcipientmight needtoincludeasolubilizingagent,suchasa solvent.Second,thestructurecanalsoprovide anideaofstabilityduringlong-termstorage andthusinneedofprotectionfromlightorin needofcoldstorage.Third,thestructurecan dictatetherouteofadministration,andenable
apredictionofpharmacokineticsofthedrug andpathwaysofmetabolism,transport,and excretion.Fourth,thestructureofthedrug canhelptheinvestigatorpredictadverse eventsthatmightbeexpectedfromthedrug. Forexample,ifthedrugbelongstoaclassof compoundsthatactivatescytochromeP450, someoftheadverseeventscanbepredicted. Fifth,regulatorysubmissionstotheUSFood andDrugAdministration(FDA),suchasthe InvestigationalNewDrug(IND),Investigator’s Brochure,andthepackageinsert,typicallycontainadrawingofthedrugstructure.
a.OriginofWarfarin
Warfarinisadrugthatiswidelyusedto preventbloodclotting,forexample,inpeople atriskofheartattacksorstrokes(10).Anaturalproductproducedduringthespoilingof sweetcloverinspiredwarfarin’sdesign.The drugwasnotnamedafteranykindofwarfare, eventhoughitisusedinwarfareagainstmice andrats;itwasnamedafterthe Wisconsin AlumniResearchFoundation.
Spoiledsweetclovercontainscoumarin,a compoundthatinhibitsanenzymeinthe liver,wheretheend-resultisimpairedblood clotting.Bloodclottingfactorsarebiosynthesizedintheliver,andthenreleasedinto thebloodstream.Farmersinthemid-West foundthatcattlebledtodeathduringthe processofde-horning,wherethecattlehad eatenspoiledsweetclover.Eventually,one particularfarmerinWisconsintookabucketof unclottedbloodtoresearchersattheUniversity ofWisconsin.Theresearchersexaminedthe blood,aswellassamplesofspoiledsweet clover,anddiscoveredthattheculpritwas dicoumarol,adegradativeproductofcoumarin.Researcherssynthesizedandtestedabout 50analogsofthiscompound.Theanalogswere
10 YehCH,etal.Evolvinguseofneworalanticoagulantsfortreatmentofvenousthromboembolism.Blood 124:1020 8.
testedinrabbits.Itwasdiscoveredthatthe bestanalogwaswarfarin(11).Warfarinisalso theactiveingredientinrodentpoison.
b.OriginsofMethotrexate and5-Fluorouracil
Thenaturalsubstrateofoneparticular enzyme,dihydrofolatereductase,inspiredthe designofmethotrexate.Thisnaturalsubstrate is dihydrofolicacid (12).Dihydrofolicacidisthe end-productofthebiosyntheticpathwayof folates(13).Anticancerdrugsthatinhibitdihydrofolatereductaseweredesignedbysynthesizingandscreeningchemicalsthatresembled dihydrofolate(14,15,16).Methotrexate,which isananalogofdihydrofolicacid,andalsoan
analogoffolicacid,inhibitsdihydrofolicacid reductase.Anotherantifolatedrugusedin oncologyis5-fluorouracil.Fluorouracilwas inventedbyCharlesHeidelberger(17,18).The drugwasdevelopedonthebasisoffindings inthe1950sthatcancercellsincorporated alargeramountoftheuracilbaseintothe DNAthannormalcells.Intestinganumber ofhalogen-substituteduracilcompounds,5fluorouracilappearedtobethemostactive andpromisingdrug.Fluorouracilisa suicide inhibitor ofthymidylatesynthase.Thismeans thattheenzyme’sowncatalyticactivity resultsintheactivationofthedrug,where thisactivationcausesthedrugtoreactcovalentlywiththeenzyme,therebydestroying theenzyme’scatalyticactivity.
11LinkKP.Thediscoveryofdicumarolanditssequels.Circulation1959;19:97 107.
12Folicacidisusedasavitaminsupplementandforenzymaticstudiesofdihydrofolicacidreductase.Butfolic acidisnotanaturallyoccurringchemical.Folicacidisformedduringthebreakdownofdihydrofolicacid,upon exposuretooxygen.Dihydrofolicacidisanaturalproductmadebymicroorganismsandplants.
13BrownGM,WilliamsonJM.Biosynthesisofriboflavin,folicacid,thiamine,andpantothenicacid.Adv.Enzymol. Relat.AreasMol.Biol.1982;53:345 81.
14FriedkinM.Enzymaticaspectsoffolicacid.Annu.Rev.Biochem.1963;32:185 214.
15BertinoJR.Themechanismofactionoffolateantagonistsinman.CancerRes.1963;23:1286 306.
16BrodyT.Folicacid.In:MachlinLJ,editor.Handbookofvitamins.NewYork:MarcelDekker,Inc.;1990.p.453 89.
17MuggiaFM,PetersGJ,LandolphJrJR.XIIIInternationalCharlesHeidelbergerSymposiumand50yearsof fluoropyrimidinesincancertherapyheldonSeptember6to8,2007atNewYorkUniversityCancerInstitute, SmilowConferenceCenter.Mol.CancerTher.2009;8:992 9.
18HeidelbergerC.Ontherationaldevelopmentofanewdrug:theexampleofthefluorinatedpyrimidines.Cancer Treat.Rep.1981;65(Suppl.3):3 9.
c.OriginofRibavirin
Ribavirinwasdiscoveredbysynthesizing analogsofacompoundparticipatinginthe pathwaysofnucleotidebiosynthesis.Indesigning,synthesizing,andtestingavarietyofanalogsofintermediatesinnucleotidebiosynthetic pathways,theresultwasthediscoveryof ribavirin,alsoknownasvirazole(19,20).
Ribavirin,incombinationwithoneor moredrugs,isusedtotreatHCVinfections (21,22,23,24,25,26,27,28,29).Theotherdrugsin thiscombinationincludesofosbuvir,dasabuvir, andpegylatedinterferon-alfa.Ribavirinalone hasbeenusedtotreathepatitisEvirus(30).
19WitkowskiJT,RobinsRK,SidwellRW,SimonLN.Design,synthesis,andbroadspectrumantiviralactivityof 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamideandrelatednucleosides.J.Med.Chem.1972;15:1150 4.
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