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1、1,Food and Drug Administration, Center for Drug Evaluation and Research: Regulatory Review of New Drugs,2,GOALS and OUTLINE of TALK,History Overview of Drug Development Applications: IND: Investigational New Drug (Application) NDA: New Drug Application Example of Post-marketing Action FDA/CDER Web R
2、esources,3,WHO ARE WE in FDA?,6 CENTERS CDER: Center for DRUGS CBER: Center for BIOLOGICS CDRH: Center for DEVICES CVM: Center for VETERINARY Medicine CFSAN: Center for FOODS NCTR: National Center of Toxicology Research “Headquarters” and Field Offices,4,WHO WE ARE in CDER,Office of New Drugs (OND)
3、Grouped Based on Clinical Expertise Clinicians, pharm/tox, microbiologistsOffice of Pharmcoepidemiology and Statistical Sciences (OpaSS) Biostatistics and Drug Safety including post-marketing Office of Pharmaceutical Sciences (OPS) Chemistry, clinical pharmacology & biopharmaceutics, generic drugs,
4、testing & research,5,FDA CDER Mission,CDER assures that safe and effective drugs are available to the American people,FDA History,How Has Our Mission Changed Over Time?,7,FDA EVOLUTION,Safety aloneSafety & EfficacySafety & Efficacy & Expanded Access,(1938) Food, Drug & Cosmetic Act(1962) Kefauver-Ha
5、rris Amendment(1983) Orphan Drug Act (1984) Generics (Waxman-Hatch) Accelerated Approval (late 1980s, AIDS and other life threatening) Pediatric Initiatives (mid-90s) Institute Review Timelines (mid-90s: PDUFA, FDAMA),8,9,Investigational New Drug Application (IND),IND is not a marketing applicationI
6、ND is a request for exemption from the federal statute which prohibits transport of unapproved drugs in interstate commerce,10,IND APPLICATION PROCESS,IND contains: sufficient Chemistry, Manufacturing, and Control pre-clinical safety information and describes the proposed human trial (Phase 1) Multi
7、-disciplinary Review Team 30-Day Deadline for Decision Team Decision Yes? “Okay to Proceed” No? Clinical HOLD Communication to sponsor: What work must sponsor do to get HOLD lifted?,11,Studies shall not be initiated until 30 days after the date of receipt of the IND by the FDA unless you receive ear
8、lier notification by the FDA that studies may begin.,30-Day Safety,12,New Drug Application (NDA),NDA is an application for marketing NDAs are submitted for: New molecular entity New formulation of previously approved drug New combination of two or more drugs New indication (claim) for already market
9、ed drug,13,Drug Review Is a Team Effort,Clinicians Statisticians Clinical Pharmacologists Chemists Pharmacologists /Toxicologists Microbiologists Project Managers,14,15,Components of Clinical Review,Efficacy Appropriate Route? Schedule? Dose(s)? Onset-of-Action and Duration Endpoints (1o and 2o) Pop
10、ulations (geriatric, gender, pediatric, etc.) Safety Major toxicities identified? AE profile Risk/Benefit determines Approval,16,17,NDA Actions,Approval Letter: States that the drug is approved and includes the label Approvable Letter: Signals that the drug can be approved, after correction of defic
11、iencies, sometimes limited to labeling Not Approvable Letter: Lists the deficiencies and explains reasons for non-approval,18,Labeling: Package Insert,Communicates to the physician the information learned during drug development Proposed by sponsor, reviewed and amended as necessary by FDA Dynamic d
12、ocument Sponsor may decide to include label in PDR,19,Postmarketing Surveillance - I,Clinical trial safety database too small to detect rare events ( 1 : 1,000) Sponsors are required to report postmarketing adverse events to FDAs Adverse Events Reporting System (AERS) Adverse events may also be repo
13、rted directly to FDAs Medwatch program by health care professionals or consumers,20,Postmarketing Surveillance - II,Safety evaluators and epidemiologists in OPaSS monitor AERS for signals of AEs not identified during clinical trials Drug reviewing divisions may institute labeling changes and other m
14、odes of risk communication Dear Health Professional Letter Medguides,21,An Example of Post-Marketing Action,Terfenadine (SELDANE) Antihistamine “NME” or New Molecular Entity US Approval (1985) Safety and efficacy data from clinical trials including several thousand patients Supported by 4 yrs Europe
15、an experience 2nd generation: “Nonsedating” claim was novel,22,SIGNALS,1983-First non-US cases of cardiac rhythm disturbances reported 1987-First US cases reported Rhythm “torsades-de-pointes” was unusual “Typical” patient was young (mid-30s), female, and otherwise healthy 1989-Contribution of co-ad
16、ministered drugs (drug-drug interactions),23,ACTIONS - I,1987 Label changed to include cardiac arrhythmia (irregular heart beat), syncope (loss of consciousness), and hypotension (low blood pressure) under AEs 1989 More label changes to include potential drug interactions under Warnings 1990 & 1996 Manufacturer required to send “Dear Doctor” letter to all potential prescribers 1992 “Black Box” Warning added to label,24,ACTIONS - II,1996-Survey commissioned by Agency showed continued co-prescription of contra-indicated medications 1998-Seldane voluntarily withdrawn from the Market,
