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A History of Stats at the FDA

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.

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A History of Stats at the FDA

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  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 Drug Evaluation and Research (CDER) • Center for Device and Radiological Health (CDRH) • Center for Food Safety and Applied Nutrition (CFSAN) • Center for Veterinary Medicine (CVM) • National Center for Toxicological Research (NCTR)

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

  5. A Public Outcry for a New Law • Upton Sinclair’s book, TheJungle, 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

  6. Pre-1962 • Safety • Advertising

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

  8. PublicHealth Reports, January/February 2000, Volume 115

  9. Pre-1962 • Safety • Advertising • Elixir Sulfanilamide • LD 50 • Bioassay

  10. 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)

  11. Kefauver-Harris Amendments Evidence consisting of andinvestigations, 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. adequate well-controlled FD & C Act Section 505(d)

  12. 1962 and Beyond • DESI (1938 – 1962) drugs – Grandfathered • Fed Reg 1970 – “appropriate statistical methods” • Orphan Drug Act 1983 • 1990’s – Expanding demographics (Age, Gender) • FDAMA 1997

  13. FDA Biometry and Epidemiology Methodology Advisory Committee

  14. The American Statistician, 1968

  15. JASA, 1999 • 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

  16. 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

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

  18. Subgroups • Age enrollment to match indication • Gender • Demographics • Pediatric Rule

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

  20. Group Sequential Boundaries

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

  22. Large Safety Studies • Ibuprofen N = 84,192 (1995) • CLASS N = 8059 (2000) • VIGOR N = 8076 (2000) • Rotavirus N = 68,038 (2006) • SMART N = 26,355 (2006)

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

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

  25. 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

  26. Int’l Conf on Harmonisation • E-3 Clinical Study Reports • E-5 Acceptance of foreign data • E-6 Good Clinical Practice • E-8 Gen’l Consid’s for Clinical Trials • E-9 Statistical Principles • E-10 Choice of control groups

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

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

  29. Critical Path and Beyond • Improved trial efficiency • Better prospective planning • Use of prior information • Handling of missing data • Analysis of multiple endpoints • Addressing non-inferiority

  30. “Random Sample” of recent FDA Statisticians

  31. Celebrating 100 Years of Public Service

  32. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  33. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  34. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  35. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  36. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  37. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  38. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  39. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  40. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  41. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  42. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  43. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  44. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  45. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  46. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

  47. Pace of Statistical Contributions 1900 1950 2000 2010 1980 1938 1962 Year of Statistical Contributions

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