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1、Role of FDA in Guiding Drug DevelopmentCarl PeckCenter for Drug Development ScienceUCSF, UC-Washington CenterWashington DC Principles of Clinical PharmacologyPrinciples of Clinical PharmacologyNIH,NIH, April 26, 2007April 26, 2007QQ空间 http:/www.6665.ccUCSF-CDDS 2007?Why FDA ?When does FDA get involv
2、ed ?How does FDA guide drug development?What comprises FDA guidance ?Whats new at FDA ?New !New !UCSF-CDDS 2007Guiding Drug DevelopmentWhy FDA?FD&C Act: history and its supportersresulted from public safety events or public health challenges 1902/6, 1938, 1962, 1972, 1987, 1997, 2004a uniquely Ameri
3、can phenomenonEvolution of Drug Regulation (R. Temple) SAFETY EFFECTIVENESS INDIVIDUALIZATION. PERSONALIZATION SAFETY UCSF-CDDS 2007When does FDA get involved ?Preclinical (voluntary) phaseanimal testingPre-IND guidance:Subpart E, Fast Track, Orphan designationsClinical development phaseINDNDA revie
4、wMarketing phaseADR surveillancenew uses, product changes, withdrawalsUCSF-CDDS 2007FDA Initiative: Innovation vs Stagnation -Challenge & Opportunity on the CriticalPath to New Medical Products, March 2004UCSF-CDDS 2007How does FDA guide drug development?Written guidancesRegulations, guidelines (inc
5、l. ICH), guidances1Regulatory letters(Statute, Congressional Reports)Face-to-face meetingsPre-IND, EOP2a, EOP2, as-neededFDA Advisory Committee meetingsPodium presentations1 Website - www.fda.govUCSF-CDDS 2007What comprises FDA guidance ?Standardschemistry and manufacturing controls (CMC)preclinical
6、 animal toxicology requirementsethics of human clinical trialsdocumentary requirements for INDs, & NDAsElectronic records (21 CFR part 11)Clinical trialssafetyeffectivenesstrial designUCSF-CDDS 2007How Many Guidancesand are they Binding ?GUIDANCES (http:/www.fda.gov/cder/guidance.htm) 344 guidances
7、(final/draft, FDA/ICH), 3/31/00Guidance documents: Cannot legally bind FDA or the publicRecognizes value of consistency & predictabilityBecause a company wants assuranceSo staff will apply statute & regulations consistentlyUCSF-CDDS 2007Planned Guidances (as of 2000)UCSF-CDDS 2007EXAMPLE 1Clinical/P
8、harmacological GuidancesCDER Comprehensive List of Guidance Documents (April 2006; n 500)Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies In Vitro (97); In Vivo (99) Pharmacokinetics in Patients with Impaired Renal Function (98) Population Pharmacokinetics ( 99)Expos
9、ure-Response (02) Exploratory IND Studies (April 2005)UCSF-CDDS 2007EXAMPLE 2Clinical/Pharmacological GuidancesGeneral Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological ProductsPharmacokinetics in Patients With Impaired Hepatic Function: Study Design, Data Analysis, and I
10、mpact on Dosing and LabelingUCSF-CDDS 2007EXAMPLE 3Clinical/Medical GuidancesProviding Clinical Evidence of Effectiveness for Providing Clinical Evidence of Effectiveness for Human Drug and Biological ProductsHuman Drug and Biological Products (98) (98) Study and Evaluation of Gender Differences in
11、the Clinical Evaluation of Drugs (93) Study of Drugs . used in the Elderly (89) Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency ResearchUCSF-CDDS 2007EXAMPLE 4Statutory Guidance: FDA Modernization Act of 1997“
12、FDAMA”Sec. 111. Pediatric studies of drugsPK bridging studiesSec. 115a. Clinical investigations support of one adequate and well-controlled clinical investigation by “confirmatory evidence” comprising PK or PK/PDUCSF-CDDS 2007FDAMA, Sec. 111 Pediatric studies of drugs“(g) Definitions. - the term ped
13、iatric studies or studies means at least one clinical investigation (that . may include pharmacokinetic studies) in pediatric age groups.”UCSF-CDDS 2007Pediatric Labeling Regulations(21 CFR 201.56)(21 CFR 201.56)“FDA may approve a drug for pediatric use based on . studies in adults, with other infor
14、mation supporting pediatric use. additional information supporting pediatric use must ordinarily include data on the pharmacokinetics of the drug in the pediatric population .Other information, such as data on pharmacodynamic studies.”UCSF-CDDS 2007FDAMA, Sec. 115aFDAMA, Sec. 115a Clinical investiga
15、tions“If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence . are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence.”UCSF-CDDS
16、2007FDAMA, Sec. 115aFDAMA, Sec. 115aClinical investigations Clinical investigations CONGRESSIONAL COMMITTEE REPORTS1 “ “confirmatory confirmatory evidenceevidence” ” = “scientifically “scientifically sound sound data data from from any any investigationinvestigation in the NDA that provides substant
17、iation as to the safety and effectiveness of the new drug” confirmatory evidence = “consisting of earlier clinical trials, pharmacokineticpharmacokinetic data, or other appropriate scientific studies”1 House Commerce Committee, 10/7/97, and Committee of Conference on Disagreeing votes of the two Hou
18、ses, 11/9/97UCSF-CDDS 2007New Formulations and Doses of Already Approved Drugs*Where blood levels . are not very different, it may be possible to conclude . is effective on the basis of pharmacokinetic data alone. Even if blood levels are quite different, if there is a well-understood relationship b
19、etween blood concentration and response, ., it may be possible to conclude . is effective on the basis of pharmacokinetic data without an additional clinical efficacy trial. * Guidance for Industry “Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products”, May 1998 UCSF-
20、CDDS 2007UCSF-CDDS 2007FDA whats new?LeadershipCommissioner Eschenbach, (Henney), (McClellan) (Crawford) Deputy Commissioner (Woodcock) Initiatives Improving drug development FDA leadership to improve drug development (2003)FDA leadership to improve drug development (2003) Critical Path Initiative (
21、2004)Critical Path Initiative (2004) End-of-Phase 2a (EOP2a) meeting (04)End-of-Phase 2a (EOP2a) meeting (04) Model-based Drug Development (05)Model-based Drug Development (05) Critical Path Opportunities List (06)Critical Path Opportunities List (06)SafetyDrug withdrawals (Vioxx et al) (04) Safety
22、Oversight Board (05)Safety Oversight Board (05)CBER CDER: protein therapeuticsUCSF-CDDS 2007McClellan Initiative (2003): FDA leadership to improve drug developmentAims to achieve predictable, 1-cycle NDA/BLA reviewsRoot cause analysisIntensified FDA-industry communicationsContinuous marketing applic
23、ation projectReviewers and ReviewsTrainingReview standardsPeer reviewQuality Systems review improvements UCSF-CDDS 2007“Academics” MeetingApril 5, 2003UCSF-CDDS 2007How can academics help?Investigate root causes of inefficient drug developmentShare findings and innovative solutions with FDACauses an
24、d remedies for failed phase 3 trialsRationale and examples to motivate abandonment of inefficient, costly, empirical traditional drug development, replacing with a quantitative, causal-model and simulation approachAdvance methods for optimization of clinical drug testingLearn-confirm approachIntegra
25、tion of intensified early clinical pharmacologyPharmacometrics - population PK/PD , modeling & simulation of clinical trialsPharmacogenetic guided developmentEffective use of biomarkers and Surrogate EndpointsUCSF-CDDS 2007Academics to CDERHistory of academic sabbaticalsLudden, Weintraub, Amidon, De
26、rendort et alCurrently - Don Stanski, Bob Powell, Felix FruehWoodcocks Academics to CDER coursesPK/PD (x2), pharmacogenomics, QT , safety, scientific basis of drug developmentUCSF-CDDS 2007UCSF-CDDS 2007US Pharmaceutical R&DTotal NIH Budget10 year Trend in Biomedical R&D SpendingAdapted from J. Coss
27、man: “The Critical Path Institute” 2007 & FDA Critical Path Initiative 2004UCSF-CDDS 2007New Drug ApplicationsNew Biological Applications10 year Trend in New Applications to FDAAdapted from J. Cossman: “The Critical Path Institute” 2007 & FDA Critical Path Initiative 2004UCSF-CDDS 2007PrototypeDesig
28、n orDiscoveryClinical DevelopmentBasicResearchFDA Filing/Approval &LaunchPreclinicalDevelopmentMarketApplicationApprovalCRITICAL PATHAdapted from S. Buckman: “Biomarkers 101”, RAPS, 2006UCSF-CDDS 2007Coordinate collaborative efforts among government, academia, industry & patient groupsEncourage “too
29、lkits” for better product development, safety, medical utility & manufacturingBuild support for academic science bases in relevant disciplinesBuild opportunities to share existing knowledge & databasesDevelop enabling standardsGuiding Principles of Critical Path InitiativeAdapted from S. Murphy: “FD
30、A Update on Critical Path Initiative”, RAPS 2006, & FDA Critical Path Initiative 2004UCSF-CDDS 2007Organization of Critical Path Initiative within FDACommissioners Office: Office of Critical Path ProgramsCritical Path Steering CommitteeCDER: Office of Translational SciencesClinical PharmacologyBiost
31、atisticsCritical Path InitiativesIntramural ResearchUCSF-CDDS 2007http:/www.fda.gov/oc/initiatives/criticalpath/UCSF-CDDS 2007UCSF-CDDS 2007Executive Summary Six Priority Public Health ChallengesBiomarker developmentStreamlining clinical trialsBioinformaticsEfficient, quality manufacturing antibioti
32、cs and countermeasures to combat emerging infections and bioterrorismDeveloping therapies for children and adolescentsUCSF-CDDS 2007UCSF-CDDS 2007UCSF-CDDS 2007UCSF-CDDS 2007UCSF-CDDS 2007http:/www.fda.gov/oc/initiatives/criticalpath/opportunities06.htmlUCSF-CDDS 2007Critical Path Collaborations wit
33、h NIHJoint workshops with FDAGenetic basis of Adverse Events December 11&12, 2006 Imaging in Alzheimers DiseaseDrug development education for NIHNIAIDNational Institute on AgingIndividual Scientist AssistanceUCSF-CDDS 2007Public/Private Partnerships - IPredictive Safety Testing ConsortiumCDER-OCP, C
34、Path Institute, 15 pharma firmsPre-clinical toxicogenomic biomarkersNephrotoxic biomarkers expected early 07Biomarker Consortium NIH/ PhRMA/ FDA/CMSregulatory pathway for biomarker validationFDG-PET in NHLOncology Biomarker Qualification Initiative FDA, NCI and CMS Microarray Quality ConsortiumDuke/
35、FDA ECG CollaborationUCSF-CDDS 2007“American Course on Drug Development and Regulatory Science” Website: http:Website: http:/acdrs/acdrs. .ucsfucsf. .edueduEllen G. Feigal, M.D.Ellen G. Feigal, M.D.Course DirectorUniversity of California, San FranciscoDepartment of Biopharmaceutical Sciences/CDDSPub
36、lic/Private Partnerships - IIPublic/Private Partnerships - IIUCSF-CDDS 2007“ACDRS” Vision and MissionModernization of development and regulation of medical products via Certified, comprehensive instructionIntegration of cutting-edge concepts Best practices in medical product development and regulato
37、ry sciencesUCSF-CDDS 2007“ACDRS” Emphases Three Principles of Optimal DevelopmentLearn-Confirm ApproachLearn-Confirm ApproachRegulatory CollaborationRegulatory CollaborationEfficient Program ExecutionEfficient Program ExecutionUCSF-CDDS 2007“ACDRS” Faculty and Teaching MethodsInternational faculty n
38、etwork from universities, companies, and regulatory authoritiesExperts in regulatory sciences, medical product discovery and development, product evaluation and business practicesTeaching methodsLecturesWorkshopsPanel discussionsTeam-oriented case studiesInteractive learningAccreditation and credit,
39、 and certifying examinationUCSF-CDDS 2007The Launch East and West coastsWashington DC in September 2007CDDS, FDASan Francisco in September 2008UCSF Mission Bay Campus UCSF-CDDS 2007Critical Path Initiative Projectsthat impact Exploratory Clinical Development - two examplesExploratory INDEnd-of-Phase
40、 2a MeetingUCSF-CDDS 2007UCSF-CDDS 2007Goals of the Exploratory INDReduce time & resources on drugs unlikely to succeedSelect most likely to succeed from group of candidate drugsTo learn PK, biodistribution, mechanism of actionReduced preclinical requirements due to less riskUCSF-CDDS 2007Explorator
41、y IND“Phase 0” studies prior to traditional drug development Phase I trialsMicrodose, sub-pharmacologic or pharmacologic doseSingle dose or limited period of administrationUCSF-CDDS 2007Types of Exploratory StudiesSingle DosePK, ImagingMultiple DosePharmacological, Pharmacodynamic endpointsCMCGLP (+
42、/-)Summary reportUCSF-CDDS 2007RequirementsCMCGLP (+/-)Incomplete impurity profileSummary reportToxicology - depends upon goalSingle Dose - 1/100 est. pharmacological dose or 100 ugSingle species (rodent), 14 day observationMultiple Dose (1/50 NOAEL + max 1/4 of 2 wk NOAEL)Two species, 14 day repeat
43、 dose UCSF-CDDS 2007UCSF-CDDS 2007UCSF-CDDS 2007End of Phase 2a meetingTwo Years Experience Reviewed at FDA Pharmaceutical Sciences AdvisoryCommittee Meeting, November 14, 2005http:/www.fda.gov/ohrms/dockets/ac/05/slides/2005-4194S1_Slide-Index.htmUCSF-CDDS 2007End of Phase 2a Meetings PurposePurpos
44、e: Late phase clinical trial (2b, 3) unnecessary failure FormatFormat: non-binding scientific interchange. Marketing issues should be in the development plan, not at this meeting DeliverablesDeliverables: Perform modeling (relevant phase 1/2a data) & simulation of next trial design employing Mechani
45、stic or empirical drug-disease modelLiterature estimates for comparative drug effects if relevantPlacebo effect (magnitude & time-course)Rates for dropout and compliance. (prior FDA experience)Recommendation on sponsors trial design + alternative including patient selection, dosage regimen,Code from
46、 FDA work, Sponsor can extend work (EOP2, NDA)Answers to other questions from the clinical and clinical pharmacology development plan Time-courseTime-course: 6 weeks Key sponsor & FDA participantsKey sponsor & FDA participants: physician, biostatistician, clinical pharmacology (pharmacometrics), pro
47、ject managementAdapted from R. Powell, FDAUCSF-CDDS 2007Completed 12-15 EOP2a meetingsMixed, mostly positive valueSuspending EOP2a experiment Resource issueFunctional EOP2a meetings permitted as Type CImportant to notify OCPB to ensure FDA clin pharm involvementEnd of Phase 2a Meetingscurrent status
48、* Bob Powell, LBS SymposiumDecember 5, 2006UCSF-CDDS 2007Of about a total of 244 NDAs, 42 included a pharmacometrics component.Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs.Of 14 reviews that were pivotal to approval decisions, 6 reduced the burd
49、en of conducting additional trials.UCSF-CDDS 2007PM analyses were ranked as important in regulatory decision making in over 85% of the 31 NDAs.UCSF-CDDS 2007Model Based Drug DevelopmentWhat is it?ModelModel: mathematical explanation of relationships thought to explain outcome over time period of int
50、erestDrug-Disease ModelDrug-Disease Model (empiric & mechanistic)Disease model: relationship of patient (e.g., gender, age, genotype), biomarker (e.g., biochemical, imaging) relationship to disease morbidity and mortalityDrug-Disease model: addition of drug (dose, concentration, combination, placebo
51、) and patient (e.g., size, age, adherence, dropout) effects and adverse effects to the disease modelSimulationSimulation- TargetClinical trial design- optimalNew designs-enrichment, randomized withdraw, adaptiveDosage regimen(s) selectionGo/No go- Sponsor &/or FDALabeling- Sponsor &/or FDAR. Powell,
52、 FDAUCSF-CDDS 2007Model Based Drug Development : Model Based Drug Development : Drug, Efficacy (Potency) & Safety InformationDrug, Efficacy (Potency) & Safety InformationLate DiscoveryPre-ClinicalPhase IPhase IIPhase IIINDAINDa:Proof of Principleb:Dose RangingDESIGNDECIDESELECTEOP2EOP2aPre-INDPre-IN
53、DClinical Development Plan Recommendations Quantitate drug effect & disease progression (biomarker strategy) Define Proof of Concept criteria Phase I-IIa Study Plans Criteria for risk assessment Data submission format Provide comments on Phase IIb & III trial designs based on modeling & clinical tri
54、al simulation Estimate dose-response Propose bridging strategy for subpopulations Approve Phase III trial design or recommend alternative designs based on modeling including IIb trial results & trial simulationSupport approval decision based on cross-trial efficacy & safety modeling analysis for: Dr
55、ug approval Label dosage regimen & claims Phase IV commitmentsR. Powell, FDAUCSF-CDDS 2007Universities Responses to Critical Path InitiativeUCSF - “JETS”“JETS”“ACDRS”“ACDRS”U Arizona - “ “CPATh CPATh Institute”Institute”SUNY Buffalo - “CE-PK/PD”“CE-PK/PD”U Indiana - “ICIS”“ICIS”UCSF-CDDS 2007SOME FI
56、NAL OBSERVATIONSFDA clinical guidances are increasingly based on principles of clinical pharmacology“guidance” versus “regulation”value added versus barrierFDA guidancenational “treasure” versus “national nuisance” a bargain !Value of FDA guidance is related to the quality of sponsor data and preparationUCSF-CDDS 2007
