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1、UCSF-CDDS 2007,Role of FDA in Guiding Drug Development,Carl PeckCenter for Drug Development ScienceUCSF,UC-Washington CenterWashington DC,Principles of Clinical PharmacologyNIH,April 26,2007,QQ空间 http:/www.6665.cc,UCSF-CDDS 2007,?,Why FDA?When does FDA get involved?How does FDA guide drug developmen
2、t?What comprises FDA guidance?Whats new at FDA?,New!,New!,UCSF-CDDS 2007,Guiding 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 American phenomenonEvolution of Drug Regulation(R
3、.Temple),SAFETY EFFECTIVENESS INDIVIDUALIZATION.PERSONALIZATION SAFETY,UCSF-CDDS 2007,When does FDA get involved?,Preclinical(voluntary)phaseanimal testingPre-IND guidance:Subpart E,Fast Track,Orphan designationsClinical development phaseINDNDA reviewMarketing phaseADR surveillancenew uses,product c
4、hanges,withdrawals,UCSF-CDDS 2007,FDA Initiative:Innovation vs Stagnation-Challenge&Opportunity on the CriticalPath to New Medical Products,March 2004,UCSF-CDDS 2007,How does FDA guide drug development?,Written guidancesRegulations,guidelines(incl.ICH),guidances1Regulatory letters(Statute,Congressio
5、nal Reports)Face-to-face meetingsPre-IND,EOP2a,EOP2,as-neededFDA Advisory Committee meetingsPodium presentations,1 Website-www.fda.gov,UCSF-CDDS 2007,What comprises FDA guidance?,Standardschemistry and manufacturing controls(CMC)preclinical animal toxicology requirementsethics of human clinical tria
6、lsdocumentary requirements for INDs,&NDAsElectronic records(21 CFR part 11)Clinical trialssafetyeffectivenesstrial design,UCSF-CDDS 2007,How Many Guidancesand are they Binding?,GUIDANCES(http:/www.fda.gov/cder/guidance.htm)344 guidances(final/draft,FDA/ICH),3/31/00Guidance documents:Cannot legally b
7、ind FDA or the publicRecognizes value of consistency&predictabilityBecause a company wants assuranceSo staff will apply statute®ulations consistently,UCSF-CDDS 2007,Planned Guidances(as of 2000),UCSF-CDDS 2007,EXAMPLE 1Clinical/Pharmacological Guidances,CDER Comprehensive List of Guidance Documen
8、ts(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)Exposure-Response(02)Exploratory IND Studies(April 2005),UCSF-CDDS 2007,EXAMPLE 2Cl
9、inical/Pharmacological Guidances,General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological ProductsPharmacokinetics in Patients With Impaired Hepatic Function:Study Design,Data Analysis,and Impact on Dosing and Labeling,UCSF-CDDS 2007,EXAMPLE 3Clinical/Medical Guidances,P
10、roviding Clinical Evidence of Effectiveness for Human Drug and Biological Products(98)Study and Evaluation of Gender Differences in 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 In
11、formed Consent Requirements for Emergency Research,UCSF-CDDS 2007,EXAMPLE 4Statutory Guidance:FDA Modernization Act of 1997“FDAMA”,Sec.111.Pediatric studies of drugsPK bridging studiesSec.115a.Clinical investigations support of one adequate and well-controlled clinical investigation by“confirmatory
12、evidence”comprising PK or PK/PD,UCSF-CDDS 2007,FDAMA,Sec.111 Pediatric studies of drugs,“(g)Definitions.-the term pediatric studies or studies means at least one clinical investigation(that.may include pharmacokinetic studies)in pediatric age groups.”,UCSF-CDDS 2007,Pediatric Labeling Regulations(21
13、 CFR 201.56),“FDA may approve a drug for pediatric use based on.studies in adults,with other information 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 dat
14、a on pharmacodynamic studies.”,UCSF-CDDS 2007,FDAMA,Sec.115a Clinical investigations,“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 con
15、sider such data and evidence to constitute substantial evidence.”,UCSF-CDDS 2007,FDAMA,Sec.115aClinical investigations CONGRESSIONAL COMMITTEE REPORTS1,“confirmatory evidence”=“scientifically sound data from any investigation in the NDA that provides substantiation as to the safety and effectiveness
16、 of the new drug”confirmatory evidence=“consisting of earlier clinical trials,pharmacokinetic data,or other appropriate scientific studies”1 House Commerce Committee,10/7/97,and Committee of Conference on Disagreeing votes of the two Houses,11/9/97,UCSF-CDDS 2007,New Formulations and Doses of Alread
17、y 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 between blood concentration and response,.,it may be possible to conc
18、lude.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-CDDS 2007,UCSF-CDDS 2007,FDA whats new?,LeadershipCommissioner Eschenbach,(
19、Henney),(McClellan)(Crawford)Deputy Commissioner(Woodcock)Initiatives Improving drug development FDA leadership to improve drug development(2003)Critical Path Initiative(2004)End-of-Phase 2a(EOP2a)meeting(04)Model-based Drug Development(05)Critical Path Opportunities List(06)SafetyDrug withdrawals(V
20、ioxx et al)(04)Safety Oversight Board(05)CBER CDER:protein therapeutics,UCSF-CDDS 2007,McClellan Initiative(2003):FDA leadership to improve drug development,Aims to achieve predictable,1-cycle NDA/BLA reviewsRoot cause analysisIntensified FDA-industry communicationsContinuous marketing application p
21、rojectReviewers and ReviewsTrainingReview standardsPeer reviewQuality Systems review improvements,UCSF-CDDS 2007,“Academics”MeetingApril 5,2003,UCSF-CDDS 2007,How can academics help?,Investigate root causes of inefficient drug developmentShare findings and innovative solutions with FDACauses and rem
22、edies 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 approachIntegration of i
23、ntensified early clinical pharmacologyPharmacometrics-population PK/PD,modeling&simulation of clinical trialsPharmacogenetic guided developmentEffective use of biomarkers and Surrogate Endpoints,UCSF-CDDS 2007,Academics to CDER,History of academic sabbaticalsLudden,Weintraub,Amidon,Derendort et alCu
24、rrently-Don Stanski,Bob Powell,Felix FruehWoodcocks Academics to CDER coursesPK/PD(x2),pharmacogenomics,QT,safety,scientific basis of drug development,UCSF-CDDS 2007,UCSF-CDDS 2007,US Pharmaceutical R&D,Total NIH Budget,10 year Trend in Biomedical R&D Spending,Adapted from J.Cossman:“The Critical Pa
25、th Institute”2007&FDA Critical Path Initiative 2004,UCSF-CDDS 2007,New Drug Applications,New Biological Applications,10 year Trend in New Applications to FDA,Adapted from J.Cossman:“The Critical Path Institute”2007&FDA Critical Path Initiative 2004,UCSF-CDDS 2007,Stagnation,PrototypeDesign orDiscove
26、ry,Clinical Development,BasicResearch,FDA Filing/Approval&Launch,PreclinicalDevelopment,MarketApplication,Approval,CRITICAL PATH,Adapted from S.Buckman:“Biomarkers 101”,RAPS,2006,UCSF-CDDS 2007,Coordinate collaborative efforts among government,academia,industry&patient groupsEncourage“toolkits”for b
27、etter product development,safety,medical utility&manufacturingBuild support for academic science bases in relevant disciplinesBuild opportunities to share existing knowledge&databasesDevelop enabling standards,Guiding Principles of Critical Path Initiative,Adapted from S.Murphy:“FDA Update on Critic
28、al Path Initiative”,RAPS 2006,&FDA Critical Path Initiative 2004,UCSF-CDDS 2007,Organization of Critical Path Initiative within FDA,Commissioners Office:Office of Critical Path ProgramsCritical Path Steering CommitteeCDER:Office of Translational SciencesClinical PharmacologyBiostatisticsCritical Pat
29、h InitiativesIntramural Research,UCSF-CDDS 2007,http:/www.fda.gov/oc/initiatives/criticalpath/,UCSF-CDDS 2007,UCSF-CDDS 2007,Executive Summary Six Priority Public Health Challenges,Biomarker developmentStreamlining clinical trialsBioinformaticsEfficient,quality manufacturing antibiotics and counterm
30、easures to combat emerging infections and bioterrorismDeveloping therapies for children and adolescents,UCSF-CDDS 2007,UCSF-CDDS 2007,UCSF-CDDS 2007,UCSF-CDDS 2007,UCSF-CDDS 2007,http:/www.fda.gov/oc/initiatives/criticalpath/opportunities06.html,UCSF-CDDS 2007,Critical Path Collaborations with NIH,J
31、oint workshops with FDAGenetic basis of Adverse Events December 11&12,2006 Imaging in Alzheimers DiseaseDrug development education for NIHNIAIDNational Institute on AgingIndividual Scientist Assistance,UCSF-CDDS 2007,Public/Private Partnerships-I,Predictive Safety Testing ConsortiumCDER-OCP,CPath In
32、stitute,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/FDA ECG Col
33、laboration,“American Course on Drug Development and Regulatory Science”Website:http:/acdrs.ucsf.edu,Ellen G.Feigal,M.D.Course DirectorUniversity of California,San FranciscoDepartment of Biopharmaceutical Sciences/CDDS,Public/Private Partnerships-II,“ACDRS”Vision and Mission,Modernization of developm
34、ent and regulation of medical products via Certified,comprehensive instructionIntegration of cutting-edge concepts Best practices in medical product development and regulatory sciences,“ACDRS”Emphases,Three Principles of Optimal DevelopmentLearn-Confirm ApproachRegulatory CollaborationEfficient Prog
35、ram Execution,“ACDRS”Faculty and Teaching Methods,International faculty network from universities,companies,and regulatory authoritiesExperts in regulatory sciences,medical product discovery and development,product evaluation and business practicesTeaching methodsLecturesWorkshopsPanel discussionsTe
36、am-oriented case studiesInteractive learningAccreditation and credit,and certifying examination,The Launch,East and West coastsWashington DC in September 2007CDDS,FDASan Francisco in September 2008UCSF Mission Bay Campus,UCSF-CDDS 2007,Critical Path Initiative Projectsthat impact Exploratory Clinica
37、l Development-two examples,Exploratory INDEnd-of-Phase 2a Meeting,UCSF-CDDS 2007,UCSF-CDDS 2007,Goals of the Exploratory IND,Reduce time&resources on drugs unlikely to succeedSelect most likely to succeed from group of candidate drugsTo learn PK,biodistribution,mechanism of actionReduced preclinical
38、 requirements due to less risk,UCSF-CDDS 2007,Exploratory IND,“Phase 0”studies prior to traditional drug development Phase I trialsMicrodose,sub-pharmacologic or pharmacologic doseSingle dose or limited period of administration,UCSF-CDDS 2007,Types of Exploratory Studies,Single DosePK,ImagingMultipl
39、e DosePharmacological,Pharmacodynamic endpointsCMCGLP(+/-)Summary report,UCSF-CDDS 2007,Requirements,CMCGLP(+/-)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+m
40、ax 1/4 of 2 wk NOAEL)Two species,14 day repeat dose,UCSF-CDDS 2007,UCSF-CDDS 2007,UCSF-CDDS 2007,End of Phase 2a meeting,Two Years Experience Reviewed at FDA Pharmaceutical Sciences AdvisoryCommittee Meeting,November 14,2005http:/www.fda.gov/ohrms/dockets/ac/05/slides/2005-4194S1_Slide-Index.htm,UCS
41、F-CDDS 2007,End of Phase 2a Meetings,Purpose:Late phase clinical trial(2b,3)unnecessary failureFormat:non-binding scientific interchange.Marketing issues should be in the development plan,not at this meetingDeliverables:Perform modeling(relevant phase 1/2a data)&simulation of next trial design emplo
42、ying Mechanistic 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
43、 from FDA work,Sponsor can extend work(EOP2,NDA)Answers to other questions from the clinical and clinical pharmacology development planTime-course:6 weeksKey sponsor&FDA participants:physician,biostatistician,clinical pharmacology(pharmacometrics),project management,Adapted from R.Powell,FDA,UCSF-CD
44、DS 2007,Completed 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 involvement,End of Phase 2a Meetingscurrent status*,*Bob Powell,LBS SymposiumDecember 5,2006,UCSF-
45、CDDS 2007,Of 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 burden of conducting additional trials.,UCSF-CDDS 200
46、7,PM analyses were ranked as important in regulatory decision making in over 85%of the 31 NDAs.,UCSF-CDDS 2007,Model Based Drug DevelopmentWhat is it?,Model:mathematical explanation of relationships thought to explain outcome over time period of interestDrug-Disease Model(empiric&mechanistic)Disease
47、 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)and patient(e.g.,size,age,adherence,dropout)effects and adverse effects to the disease
48、 modelSimulation-TargetClinical trial design-optimalNew designs-enrichment,randomized withdraw,adaptiveDosage regimen(s)selectionGo/No go-Sponsor&/or FDALabeling-Sponsor&/or FDA,R.Powell,FDA,UCSF-CDDS 2007,Model Based Drug Development:Drug,Efficacy(Potency)&Safety Information,Late Discovery,Pre-Clin
49、ical,Phase I,Phase II,Phase III,NDA,IND,a:Proof of Principle,b:Dose Ranging,DESIGN,DECIDE,SELECT,EOP2,EOP2a,Pre-IND,Clinical Development Plan Recommendations Quantitate drug effect&disease progression(biomarker strategy)Define Proof of Concept criteria Phase I-IIa Study Plans Criteria for risk asses
50、sment Data submission format,Provide comments on Phase IIb&III trial designs based on modeling&clinical trial 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&t
