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 Resources
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) Grouped Based on Clinical Expertise Clinicians, pharm/tox, microbiologists Office of Pharmcoepidemiology and Statistical Sciences (OpaSS) Biostatistics and Drug Safety including post-marketing Office of Pharmaceutical Sciences (OPS) Chemistry, clinical pharmacology & biopharmaceutics, generic drugs, testing & research
5	FDA CDER Mission CDER assures that safe and effective drugs are available to the American people
6	FDA History How Has Our Mission Changed Over Time?
7	FDA EVOLUTION Safety alone Safety & Efficacy Safety & Efficacy & Expanded Access (1938) Food, Drug & Cosmetic Act (1962) Kefauver-Harris Amendment (1983) Orphan Drug Act (1984) Generics (Waxman-Hatch) Accelerated Approval (late 1980s, AIDS and other life threatening) Pediatric Initiatives (mid-90’s) Institute Review Timelines (mid-90’s: PDUFA, FDAMA)
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9	Investigational New Drug Application (IND) IND is not a marketing application IND 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-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 earlier notification by the FDA that studies may begin.
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 marketed drug
13	Drug Review Is a Team Effort Clinicians Statisticians Clinical Pharmacologists Chemists Pharmacologists /Toxicologists Microbiologists Project Managers
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15	Components of Clinical Review Efficacy Appropriate Route? Schedule? Dose(s)? Onset-of-Action and Duration Endpoints (1^oand 2^o) Populations (geriatric, gender, pediatric, etc.) Safety Major toxicities identified? AE profile Risk/Benefit determines Approval
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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 deficiencies, 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 document 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 FDA’s Adverse Events Reporting System (AERS) Adverse events may also be reported directly to FDA’s 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 modes 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 European 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-30’s), female, and otherwise healthy 1989--Contribution of co-administered 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 AE’s 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
25	Summary of SELDANE Experience Is there something to be learned? Avoidable risk and unavoidable risk Scientific advances over time can lead to safer and more efficacious drugs BUT--Limitations of pre-approval studies of drugs make post-marketing surveillance important. For reasons of public health: Medical professionals should read the label Medical professionals should report problems to FDA and/or manufacturer Risk/Benefit balance
26	HOW TO CONTACT FDA General Web Address: www.fda.gov Approved Human Drug Information: www.fda.gov/cder/index Biologics/Vaccines: www.fda.gov/cber/index Adverse Event Reporting: www.fda.gov/medwatch