1. A History of Stats at the FDA Mary A. Foulkes, Ph.D. U.S. Food And Drug Administration Office of Biostatistics and Epidemiology Center for Biologics Evaluation and Research 2006 FDA/Industry Statistics Workshop

2. The views presented are my own and do not represent the official view of the U.S. Food and Drug Administration

3. FDA Centers Center for Biological Evaluation and Research (CBER)Center for Biological Evaluation and Research (CBER) Center for Drug Evaluation and Research (CDER)Center for Drug Evaluation and Research (CDER) enter for Device and Radiological Health (CDRH)Center for Device and Radiological Health (CDRH) Center for Food Safety and Applied Nutrition (CFSAN)Center for Food Safety and Applied Nutrition (CFSAN) Center for Veterinary Medicine (CVM)Center for Veterinary Medicine (CVM) National Center for Toxicological Research (NCTR)National Center for Toxicological Research (NCTR)

4. OUTLINE Early years Kefauver-Harris Amendments Grandfather Women, Kids and Animals Globalization Critical Path and Beyond

7. A Public Outcry for a New Law Upton Sinclairs 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. Pre-1962 Safety Advertising

9. Wax, P. M. Ann Intern Med 1995;122:456-461 An original 1-gallon bottle of Elixir Sulfanilamide

10. Public Health Reports, January/February 2000, Volume 115

12. Pre-1962 Safety Advertising Elixir Sulfanilamide LD 50 Bioassay

13. Kefauver-Harris Amendments Evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. FD & C Act Section 505(d)

14. Kefauver-Harris Amendments Evidence consisting of and investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. FD & C Act Section 505(d) adequatewell-controlled

15. 1962 and Beyond DESI (1938 – 1962) drugs – Grandfathered Fed Reg 1970 – appropriate statistical methods Orphan Drug Act 1983 1990s – Expanding demographics (Age, Gender) FDAMA 1997

16. FDA Biometry and Epidemiology Methodology Advisory Committee

17. The American Statistician, 1968

18. Treatment of insomnia - triazolam Re-analysis of 25 plcbo-contr trials Mixed-effects regression models – using all available data Diff btw trials and spontaneous reports – Recommend: longer term, high dose studies JASA, 1999

19. A priori Analysis Plan Still, it is an error to argue in front of your data. You find yourself insensibly twisting them around to fit your theory. Sherlock Holmes in The Adventure of Wisteria Lodge

20. Control of Type I error Primary and secondary outcomes Composite endpoints Power Essential Multiplicity Implications for design

21. Age enrollment to match indication Gender Demographics Pediatric Rule Subgroups

22. Other Issues Active/placebo/historical controls Adaptive trials Combination products Adverse Events/MedDRA/Data Mining Multiplicity Endpoints QA/QC

23. Group Sequential Boundaries

24. Interim Monitoring Outcome trials Serious morbidity/mortality Minimize risks Futility Regulatory implications

25. Large Safety Studies IbuprofenN = 84,192(1995) CLASSN = 8059(2000) VIGORN = 8076(2000) RotavirusN = 68,038(2006) SMARTN = 26,355(2006)

26. Counterterrorism Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies are not Ethical or Feasible Animal Rule

27. Counterterrorism Anthrax Botulism Plague Smallpox Tularemia Viral hemorrhagic fevers Under Animal Rule, use data from two species to predict human responses:

28. ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Regions: EU, Japan, US Observers: WHO, others Co-sponsors: EC, UFPIA, MHW, JPMA, FDA, PhRMA

29. Intl Conf on Harmonisation E-3 Clinical Study Reports E-5 Acceptance of foreign data E-6 Good Clinical Practice E-8 Genl Consids for Clinical Trials E-9 Statistical Principles E-10 Choice of control groups

30. Critical Path and Beyond Design efficiency Conduct efficiency Targetted therapies Imputation Simulation Extrapolation

31. Basic Research Prototype Design or Discovery Preclinical Development Clinical Development FDA Filing/Approval & Launch Preparation Market Application Approval Critical Path Critical Path and Beyond

32. Improved trial efficiency Better prospective planning Use of prior information Handling of missing data Analysis of multiple endpoints Addressing non-inferiority

33. Random Sample of recent FDA Statisticians

34. Celebrating 100 Years of Public Service

35. Pace of Statistical Contributions Year of Statistical Contributions 1900 1938 1950 1962 1980 20002010

36. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

37. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

38. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

39. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

40. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

41. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

42. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

43. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

44. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

45. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

46. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

47. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

48. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

49. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

50. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

51. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions

52. 1900 1938 1950 1962 1980 20002010 Pace of Statistical Contributions Year of Statistical Contributions The Sky is the Limit