1. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. U.S. Food and Drug Administration Practices, People, Politics and Prescriptions

2. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Mission http://www.fda.gov/opacom/morechoices/mission.html

3. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Overview Development & Evolution of the FDA Limitations of the FDA Regulatory System Contemporary Challenges Facing the FDA

4. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Development & Evolution Cycle Crisis – Public health disaster Legislation – Congressional response Adaptation – Steps FDA took to implement the new law

5. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Early Medicines Buyer beware Boastful and extravagant claims Alcohol as the main ingredient Addictive and dangerous ingredients

6. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Significant Milestones in Drug Law Biologic Control Act 1902 Pure Food and Drugs Act of 1906 Federal Food, Drug and Cosmetic Act of 1938 Durham-Humphrey Amendment of 1951 Kefauver-Harris Drug Amendments of 1962 http://www.fda.gov/opacom/backgrounders/miles.html

7. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. A Public Outcry for a New Law Upton Sinclair’s book, The Jungle, drew attention to adulterated meat (Meat sales dropped by 1/3) Roosevelt was persuaded to sign Pure Food and Drugs Act on June 30, 1906 along with the Meat Inspection Act 1906 Act transformed a scientific bureau into a regulatory agency that would become FDA

8. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. 1906 Pure Food and Drugs Act “Adulteration” and “Misbranding Prohibited interstate transport of unlawful products New labels Sanctioned drug standards

9. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Limitations of the 1906 Act Crazy Crystals Radio/Print Advertising…

10. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. A Turning Point Elixir Sulfanilamide –First wonder drug –Used untested “solvent” DEG –Proved deadly –Legal Implication…

11. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Federal Food, Drug, and Cosmetic Act 1938 Pre-market safety approval of all new drugs Prohibited false therapeutic claims for drugs Drugs labeled with adequate directions for safe use Food standards “in the interests of consumers” Cosmetics and medical devices under FDA’s jurisdiction

12. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. A Disaster Averted Thalidomide Sedative sold over-the-counter in Europe –Treated morning sickness during pregnancy –Produced birth defects in European babies FDA received application for marketing in the US –Reviewer Frances Kelsey had concerns –Delay in approval prevented its being sold in US

13. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Amendments – 1960-80s Kefauver-Harris Amendments - the most significant changes in the Food, Drug and Cosmetic Act –Pre-market efficacy and safety –Good manufacturing practices –Prescription drug advertising

14. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Drug Regulation Changes New drug approvals based on safety AND efficacy Required GMPs and later GLPs New controls over Rx advertising New patient protection policies

15. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Significant Milestones in Drug Law Tamper-Resistant Packaging Regulations of 1982 Orphan Drug Act of 1983 Drug Price Competition & Patent Term Restoration Act of 1984 Prescription Drug Marketing Act of 1987 Medicare Prescription Drug Improvement & Modernization Act of 1997 Prescription Drug User Fee Act (PDUFA) of 1992, 1997, 2002, 2007 http://www.fda.gov/opacom/backgrounders/miles.html

16. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Critical Thinking Questions Given the history of the U.S. Food and Drug Administration (FDA) as a regulatory agency constantly reacting to a series of “crisis---legislative---adaptation cycles: 1.What do you think the U.S. medication system would be like if these regulations were not in place? 2.Do you think the U.S. is on the verge of another “crisis”--legislative—adaptation cycle?

17. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Overview Development & Evolution of the FDA Limitations of the FDA Regulatory System Contemporary Challenges Facing the FDA

18. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Mission http://www.fda.gov/opacom/morechoices/ mission.htmlhttp://www.fda.gov/opacom/morechoices/ mission.html

19. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Modern FDA

20. 20 (Borchers AT, et al. The history and contemporary challenges of the US Food and Drug Administration. Clin Ther 2007;29:1-16)

21. NCTR CBER CDRH CFSANCVM Food and Drug Administration Center for Drug Evaluation and Research CDER ORA

22. http://www.gpoaccess.gov/cfr/index.html Industry Guidance Industry Guidance

23. PRE-CLINICAL RESEARCH FDA & INDUSTRY TIME FDA TIME INDUSTRY TIME SPONSOR/FDA MEETINGS ENCOURAGED DISCOVERY/SCREENING SYNTHESIS AND PURIFICATION

24. DISCOVERY/SCREENING PRE-CLINICAL RESEARCH SYNTHESIS AND PURIFICATION ANIMAL TESTING SHORT-TERM LONG-TERM IND CLINICAL STUDIES NDA FDA & INDUSTRY TIME INDUSTRY TIME SPONSOR/FDA MEETINGS ENCOURAGED FDA TIME

25. DISCOVERY/SCREENING PRE-CLINICAL RESEARCH SYNTHESIS AND PURIFICATION ANIMAL TESTING CLINICAL STUDIES PHASE 3 PHASE 1 PHASE 2 FDA REVIEW SHORT-TERM LONG-TERM INDNDA/ BLA FDA & INDUSTRY TIME INDUSTRY TIME SPONSOR/FDA MEETINGS ENCOURAGED FDA TIME FDA ACTION

26. 26 PHASE 1PHASE 2PHASE 3 CLINICAL STUDIES

27. DISCOVERY/SCREENING PRE-CLINICAL RESEARCH SYNTHESIS AND PURIFICATION ANIMAL TESTING PHASE 3 PHASE 1 PHASE 2 PHASE 4 CLINICAL STUDIES ADVERSE REACTION SURVEILLANCE PRODUCT DEFECT REPORTING POST MARKETING SURVEYS/ SAMPLING TESTING POST APPROVAL INSPECTIONS SHORT-TERM LONG-TERM FDA REVIEW PARALLEL TRACK TREATMENT USE ACCELERATED APPROVAL ACCELERATED REVIEW: SUBPART E ACCELERATED REVIEW E EXPANDED ACCESS: PARALLEL TRACK TREATMENT USE IND NDA/BLA FDA ACTION FDA & INDUSTRY TIME INDUSTRY TIME SPONSOR/FDA MEETINGS ENCOURAGED FDA TIME

28. New Drug Application (NDA) or Biologic License Application (BLA) contains the following: Pre-clinical studies Human clinical studies Manufacturing details Labeling – Indication(s) Additional information

29. ODE IODE IIODE IIIODE IVODE V Neuro- pharmacological Oncology Cardio-Renal Metabolic and Endocrine Pulmonary Gastrointestinal and Coagulation Anesthetic, Critical Care, and Addiction Medical Imaging and Radiopharmaceuticals Anti-Viral Anti-Infective Special Pathogen and Immunologic Anti- Inflammatory, Analgesic and Ophthalmologic Dermatologic and Dental Over-the- Counter Reproductive and Urologic ODEVI Therapeutic Biological Oncology Therapeutic Biological Internal Medicine Review Management & Policy DRUG PRODUCT DIVISIONS

30. Review Team Project Manager Medical Officer Chemist Microbiologist Statistician Pharmacologist Establishment/Facility Reviewer Support Personnel

31. Panel of OUTSIDE experts Provide advice and opinions to the FDA drug review team FDA advisory committee information, 1-800-741-8138 or 301-443-0572 ADVISORY COMMITTEE http://www.fda.gov/oc/advisory/default

32. Prescription Drug User Fee Act (PDUFA) http://www.fda.gov/oc/pdufa/default.htm Permits CDER/CBER to charge pharmaceutical manufacturers a fee to review drug applications These fees provide appropriate resources to accelerate the review of applications Not the only source of funds for CDER/CBER Funds go directly to CDER/CBER, not individuals

33. DISCOVERY/SCREENING PRE-CLINICAL RESEARCH SYNTHESIS AND PURIFICATION ANIMAL TESTING PHASE 3 PHASE 1 PHASE 2 PHASE 4 CLINICAL STUDIES ADVERSE REACTION SURVEILLANCE PRODUCT DEFECT REPORTING POST MARKETING SURVEYS/ SAMPLING TESTING POST APPROVAL INSPECTIONS SHORT-TERM LONG-TERM FDA REVIEW IND NDA BLA ACTION FDA & INDUSTRY TIME INDUSTRY TIME SPONSOR/FDA MEETINGS ENCOURAGED FDA TIME PARALLEL TRACK TREATMENT USE ACCELERATED APPROVAL

34. Post-market Surveillance

35. Potential Regulatory Action for Postmarketing Safety Issues Labeling Change Scientific publication "Dear Doctor" letter (for specific warnings) Restricted use Restricted distribution Patient Medication guide Product withdrawal

36. 36 Office of Drug Safety Division of Drug Risk Evaluation Division of Medication Errors and Technical Support, Division of Surveillance, Research, and Communication Support

37. 37 MedWatch Website Safety Information Retrieval Adverse Event Reporting for Drugs,Devices, Biologics and Dietary Supplements www.fda.gov/medwatch

38. Database Internationally compatible Adverse Event Reporting System (AERS) Office of Drug Safety (ODS) uses AERS to: triage review assess risk

39. 39 DDMAC (Division of Drug Marketing Advertising and Communications) Promotional Materials Review Guidance and policy development Research Surveillance and enforcement

40. CDER’s Office of Compliance Sets labeling, manufacturing, and testing standards Monitors the quality of marketed drugs Evaluates, classifies, and recommends human drug recalls

41. Can We Improve the Current FDA System

42. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Overview Development & Evolution of the FDA Limitations of the FDA Regulatory System Contemporary Challenges Facing the FDA

43. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Problems With the Current System? 1.Initial review for approval often fails to detect serious ADR’s 2.FDA’s surveillance system is plagued with underreporting 3.Threshold for action in response to ADR reports is subjective

44. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Problems With the Current System? 4.Performance of post-marketing surveillance studies is out of FDA controls 5.FDA lacks direct legal authority to hold accountable drug companies that violate its recommendations 6.FDAs intrinsic structure is viewed as presenting a potential conflict of interest

45. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Problems With the Current System? 7.FDA is highly dependent on user fees 8.Shortage of FDA expertise in drug safety and public health

46. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Vision for the Next Century Critical Path Initiative –Transform medical product development –Keep pace with expected medical advances http://www.fda.gov/oc/initia tives/criticalpath/whitepape r.html

47. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Debate on Current FDA Issues Independent Agency –Transperent –Accountable Science-based –Enhanced Predictive Tools –Allow for Disagreement Increased Legal Authority –Enforcement/Oversight –Minimize Conflict of Interest Culture of Safety –Enhanced Communication

48. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®.

49. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Perspective Practices, People and Politics

50. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Classroom Activities Post-Marketing (Phase IV) studies Medicare Prescription Drug Improvement & Modernization Act of 1997 Prescription Drug User Fees Act (PDUFA) of 1992, 1997, 2002, 2007

51. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Classroom Discussion Post-Marketing (Phase IV) studies Medicare Prescription Drug Improvement & Modernization Act of 1997

52. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Classroom Discussion Prescription Drug User Fees Act (PDUFA) of 1992, 1997, 2002, 2007

53. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Perspective Practices, People and Politics Protecting the Health of the Public http://content.nejm.org/cgi/content/full/355/17/1753/DC1

54. This work was made possible by a grant from the state Attorney General Consumer & Prescriber Education Grant Program which is funded by the multi-state settlement of consumer fraud claims regarding the marketing of the prescription drug Neurontin®. Perspective Put this information in the context of your: Group assigned medication exercise Classroom learning Direct-patient care activities next year Professional practice “Be a part of the DEBATE”

55. Challenges Are We Headed for Another Public Health Crisis?