ppt课件-clinicaltrialtimelines（临床试验的时间）.ppt

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1、Clinical Trial TimelinesCornelia Kamp,MBA Executive Director Strategic InitiativesClinical Materials Services Unit(CMSU)Clinical Trials Coordination Center(CTCC)University of RAgendanDrug Development Timeline OverviewnLifecycle of a Clinical TrialSample Timeline HandoutnKey Timeline Milestones in th

2、e various phase of the lifecycle nKeys to staying on TimeDrug Development Timeline OverviewDrug Development Process/Overall TimelineDrug Development ProcessnIt costs about$802 million*(in year 2000 dollars)over 12 years to bring one medicine from discovery in a laboratory to the patient.nFor everyon

3、e one medicine that reaches the marketable stage,between 10,000-30,000 compounds must be screened.*Ref:DiMasiJA,HansenRW,GrabowskiHG.Thepriceofinnovation;newestimatesofdrugdevelopmentcosts.JHealthEcon2003;22:151-85.A Median Phase III studynIncludes 800 subjectsn50 investigator sitesn700 days(2 years

4、)from First Subject First Visit(FSFV)to Last Subject Last Visit(LSLV)nCosts$25 million(including per subject fees,drug supply,laboratory,Project and Data management fees)or$36,000/day Ref:Li,Gen:SiteActivation,TheKeytomoreEfficientClinicalTrials;2008AdvanstarCommunicationsInc.GenLi:formerheadofR&DOp

5、erationsforPharmacia&PfizerLifecycle of a Clinical TrialLife Cycle of a Clinical TrialProtocol Synopsis finalizedSchedule of Activities finalizedProtocol finalizedModel ICF finalizedSites selectedOperations Manual/MOP completedCRFs finalizedIRB approvals obtainedSite subcontracts/payment schedule in

6、 placeFinalize Contracts with third party vendors(labs,ECGs etc.)DSMB establishedBuild databaseFinalize Study drug packaging/labeling*Enroll subjects*Distribution of study drug to sitesAnswer Protocol/CRF questionsTake incident callsSAEsDosage AdjustmentsPremature WithdrawalsDrug DisclosureData quer

7、y processClean/Close databaseTransfer database to BiostatisticsPerform primary/secondary analysisSubmit abstractSubmit manuscriptSubmit CTRPost results on www.clinicaltrials.gov Post-hoc analysisOrientation or Initiation MeetingDatabase LockedAnalysisCONCEPTUALPHASEPLANNING PHASEIMPLEMENTATION PHASE

8、ANALYSIS/PUBLICATION PHASEGrant Award and/or Parent contract establishedThe Process of Conducting Clinical Trials:nFully understand the full lifecycle of any clinical trial,regardless of the phase(I-IV)or indicationnThe process stays the samenLove the process,not the compound under studyCompounds ar

9、e a“dime a dozen”and come and go.(Quote from:Michael Poole,MD Vice President,Wyeth)nThe process is here to stayKeys to Staying on SchedulenAre developed in the conceptual and planning phase.nDevelop a REALISTIC timeline and workscope in the planning phase of a studynKeep It Simple Stupid!whenever po

10、ssibleTimeline and Work Scope nCreate a scope of work document clearly delineating who is responsible for what:sponsor,SC,Project Team,External Vendors,Sites,MonitorsnCreate a detailed timeline of all activities that need to complete in each phase of the Project LifecycleBoth documents will provide

11、the roadmap for the overall projectTools for timeline development:nExcelnMicrosoft ProjectnSmartDrawnLiquid Plannernhttp:/ Development Project Management Tools(Erbian Research Inc.)Copyright2009ClinicalTrialsCoordinationCenter/UniversityofRochester:AllRightsReserved To Ensure Adherence to the Timeli

12、nenHIRE a GOOD Project ManagerIs highly organizedIs remarkably flexible Has planned and executed a large birthday party(Ira Shoulson,MD),Bar-mitzah/Bat-mitzah or a large weddingHas Anal Retentive tendencies(OCD).a good thing in this industryCan still see the forest through the treesHas excellent ora

13、l and written communication skillsCan build strong relationships with all kinds of staff both internal and external to the institutionCan influence people without a direct reporting relationshipIs not afraid to raise issues early on and work on finding solutionsWilling to put in long hoursIs always

14、planning at least 6 months aheadIt Takes a Small Army to Run a Study:with Excellent CommunicationnSteering CommitteenSponsornOperational TeamProject ManagerDatabase ManagerInformation AnalystAdministrative SupportBiostatisticanProgrammerMeeting PlannerMonitorsnEnrolling Site TeamnData Safety Monitor

15、ing BoardnVendor TeamsConceptual Phase Timeline MilestonesFormalize the idea/obtain fundingnDevelop a Protocol Synopsis and Schedule of Activities(2-3 months)nDevelop full research plan following requirement for potential funding source(e.g.NIH,FDA,DOD,Pharmaceutical unrestricted educational grant,F

16、oundation,or approval of internal pharmaceutical company budget etc.)nSubmit for funding and go through the review process(typically max of 2 submissions of the same idea)Can take anywhere from 6-9 month to 4-5 years or longernIn some cases funding does not materialize.Planning Phase Timeline Milest

17、onesKey Planning MilestonesnProtocol Synopsis and Schedule of ActivitiesnProcurement of Drug SupplynSet-up and maintain Trial Master File(TMF)nFinal ProtocolnModel Informed Consent Form(ICF)nDevelop patient recruitment materials:patient brochure;website;newspaper,TV and radio ads;1-800 call center s

18、cripts etc.Regulatory SubmissionsnIND submission(2-4 wks after final protocol available)FDA approval/complete or partial hold status (must wait 30 days before starting the study for FDA to respond)Most IRBs require proof of IND status via written documentation(email/formal letter)from the FDA that t

19、he trial may proceedPros/Cons of submitting Final protocol/model consent to sites prior to IND/protocol approval from FDAnSubmission to other Regulatory authorities as applicable(e.g.Health Canada,European Union etc.)Initiate Site Selection ProcessnSend Confidential Disclosure Agreement(CDA)to possi

20、ble sites(must be returned before site selection materials can be sent)(2 weeks to send and receive)nSite selection questionnaire sent to sites with fully executed CDAs(completed 1 week after final protocol synopsis is available)Select SitesnBased on:Access to patient population/geographic distribut

21、ionPast performance of investigator/coordinator teamProjected number of subjects/anticipated enrollment rateReceipt of FDA 483sLack of competing studiesAbility to attend orientation mtgAvailability of required equipment or specialized staffnNotify selected and back-up sites of statusnNotify sites no

22、t selectedSite Activation Drives EnrollmentnBudget/Contract negotiationnGain Institutional Review Board(IRB)approval in the US or ethics Board approvals in Europe/CanadanCollect other regulatory documents(e.g.FDA form 1572,CVs,financial disclosure etc.)nProvide sites with clinical supplies(e.g.lab k

23、its,drug supply)nPatient Recruitment Begins once above elements are completedSite ActivationnEnrollment cycle time varies by disease state and sponsor,but across disease states site activation accounts for 70%of enrollment cycle timenActivation of a single center on average takes 100 days(3.3 months

24、)n20-50%of studies have rescue missions where new sites are brought in late in the game to enhance enrollmentRef:Li,Gen.SiteActivationtheKeytoMoreEfficientClinicalTrials.PharmaceuticalExecutive,12/12/2008.www.PharmaESite Subcontract Responsiveness-NIH contract July 1997Ref:DatafromA.Shinaman,Clinica

25、lTrialsCoordinationCenter.UnpublisheddataSubcontract Response Rate-Industry Sponsored contract 2000Ref:DatafromA.Shinaman,ClinicalTrialsCoordinationCenter.UnpublisheddataData ManagementnCreation of Case Report Forms(CRFs)/eCRFsFirst draft of full set of forms within 4 weeks of final protocol,final v

26、ersion available 4 weeks after first draftObtain appropriate permissions to use forms,often including purchase of such forms(e.g.,Beck Depression Scale,SF-36)Include appropriate references on published forms(e.g.UPDRS,UHDRS,MMSE,PDQ39 etc.)nDatabase creation/validationCannot begin until final CRFs/e

27、CRFs are availableTakes 6-8 weeks to completeTimeframe varies base on whether a CRF library is already available for most of the CRFs or if all is being created from scratchnCreate/Finalize Data Management Plan(DMP)First draft 4 weeks after final CRFs available,with final DMP 2-3 weeks after first d

28、raftOperations Manual/Manual of Procedures(MOP)nIncludes detailed operational instructions for the site on:SAE reportingDrug packaging,distribution and storage requirementsFull complement of CRFs and instructions for completionMonitoring expectationsProject Team contact listLaboratory proceduresCont

29、ents of Regulatory binderProper procedures for conducting various assessmentsnFirst draft available within 4-6 weeks after final protocolnFinal MOP available for the Orientation mtg/Site initiation mtgnTypically updated throughout the study via Study Newsletters or complete replacement of certain se

30、ctionsSelect and Contract with External VendorsnCentral laboratory for safety labsnPK analysisnCentral ECGsnElectronic diariesnHolter monitoringnManufacturer of study drugnPrimary and secondary drug packager and distributornMonitoringObtain bids from 2-3 vendors to compare prices/services early in p

31、lanningAll vendor contracts should be completed prior to Orientation mtgThe number one rate limiting step in any clinical trial is:nStudy Drug!nStudy Drug!nStudy Drug!ACTIVELY MANAGE ALL ASPECTS OF THE STUDY DRUG AS EARLY AS THE CONCEPTUAL PHASE(INITIAL GRANT SUBMISSION)Drug SupplynItems for conside

32、ration:Purchase active and matching placebo or have donated?How will drug be delivered(e.g.Bulk shipment in drums,unit packaged,all at once,quarterly shipments)Secondary packaging/labeling and distribution requirements?Blindedness testing:Are active and placebo identical in:color,taste,smell,appeara

33、nce,shape,size?Stability testing:ambient and accelerated:how many lots of each or is it even required?Expiry/retest issues?Storage requirements:ambient,refrigerated,light sensitive,moisture sensitive?Drug Accountability centrally and at site levelSite SOPs to address all aspects of study drug receip

34、t,dispensing,return etc.(overall accountability)Sources for Drug Supply DelaysnLack of sufficient animal toxicology datanHeld up in manufacturing:impurities found,long queue,API not available,stability issuesnProblems matching active with placebo suppliesnFailure to place order with enough lead time

35、nCustom delays(e.g.shipment exported/imported from other countries)Cosmetic Bottling(paneling)ProblemPaneling caused a 4 month delay in study start due to inspection time,Corrective Action Plan,and requirement for resupplyEstablish Data Safety Monitoring Board(DSMB)and CharternSelect DSMB membersTyp

36、ically 3-5 independent scientists with no conflicts-of-interest and no other role in the study(should include:a biostatistican,disease expert,expert on drug under study,expert in body system with AE profile of greatest concern,ideally most have prior clinical trials experience)nCreate/Finalize DSMB

37、charterSpecifies exactly what the DSMB is charged to monitor,stopping rules for efficacy/safety,major areas of concern(e.g.renal,hepatic etc.)nDMSB members and final charter should be in-place prior to FPFVRegister Trial with www.clinicaltrials.gov Before FPFVnFood and Drug Administration Amendments

38、 Act of 2007 or FDAAA),Title VIII,Section 801 mandates that a responsible party(i.e.,the sponsor or designated principal investigator)register and report results of certain applicable clinical trials:Trials of Drugs and Biologics:Controlled,clinical investigations,other than Phase I investigations,o

39、f a product subject to FDA regulation;Trials of Devices:Controlled trials with health outcomes of a product subject to FDA regulation(other than small feasibility studies)and pediatric postmarket surveillance studies.nApplicable clinical trials generally include interventional studies(with one or mo

40、re arms)of drugs,biological products,or devices that are subject to FDA regulation,meaning that the trial has one or more sites in the U.S,involves a drug,biologic,or device that is manufactured in the US(or its territories),or is conducted under an investigational new drug application(IND).Orientat

41、ion Meeting or Site Initiation MeetingnDepending on size of the study“training”of investigators,coordinators and other site staff can be accomplished via either mechanismnMaterials to be created include:AgendaPresentations to include:Study overview,review of inclusion/exclusion criteria,drug/device

42、under study,GCPs,adverse event reporting,eCRF/CRF completion,use of eDC system,laboratory requirements,unique safety assessments,primary outcome measure,diaries etc.Orientation MtgnSecure meeting space and lodging 3-6 months prior to the planned mtgnTiming of the mtg should be such that at least hal

43、f of the sites have IRB approval and subcontracts in placenMeetings held too soon are wasteful given staff turn-over,people forget etc.Typically requires additional training mtgs when sites are actually ready to goInitiation MeetingnDirectly at the participating site;conducted by the lead monitor,pr

44、oject manager,and the PI or their designee nNot conducted until individual site has IRB approval,subcontract in place and has received drug supplynAllows for complete training of ALL staff at the site that have been delegated responsibilities per the“Delegation of Authority Log”nSites should be read

45、y to start screening/enrolling subjects immediately following this trainingnFormat usually used for smaller studies(1-7 sites);phase I-IInMost phase III studies use the Orientation mtg format where all investigators/coordinators attend the mtg and hear the same informationnSome pharmaceutical sponso

46、r may have both a Orientation Mtg and a Site Initiation MeetingAt the Starting Line(6-9 months later)Implementation Phase Timeline MilestonesKey Implementation MilestonesnDrug Supply available at the site (within days of the orientation mtg or at the initiation visit)nFPFV=First Patient First Visit(

47、typically a screening visit;within days of the orientation mtg)nFPI=First Patient In(randomized)-(within days of the orientation mtg)nSubmit Press Release announcing study startnFPLV=First Patient Last Visit-(determined by duration of treatment)nLPI=Last Patient In(randomized)based on planned enroll

48、ment period.(#Subjects Enrolled/Site/Month)nLPLV=Last Patient,Last VisitnDatabase Lock (eDC:1-2 weeks following LPLV;paper:6-8 weeks following LPLV)Implementation Timeline KillerENROLLMENT DELAYSn86%:Percentage of studies in which enrollment is delayed 1 to 8 monthsn14%:Percentage of studies in whic

49、h enrollment is completed on timenSignificant effort should be spent on identifying appropriate sites and setting up realistic enrollment expectations.Always have a back-up planBe sure to train any back-up sites brought on board after study start and any new site staff at existing sitesRef:http:/www

50、.ciscrp.org/information/documents/101FactsaboutClinicalResearch.pdfOther Implementation MilestonesnContinuous management of drug supply from FPFV to LPLVnDevelop Statistical Analysis Plan(SAP):Created within 4 weeks of a complete Data Management Plan(DMP)being finalizedMust be finalized BEFORE datab