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Studying drug induced-disease

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Studying drug induced-disease

  1. 1. Brian L. Strom, M.D., M.P.H. Chair and Professor, Department of Biostatistics and Epidemiology Director, Center for Clinical Epidemiology and Biostatistics George S. Pepper Professor of Public Health and Preventive Medicine Professor of Biostatistics and Epidemiology, Medicine, and Pharmacology Vice Dean for Institutional Affairs University of Pennsylvania School of Medicine Senior Advisor to the Provost for Global Health Initiatives University of Pennsylvania
  2. 2. What Are Your Drugs Really Doing To Your Patients? Epidemiological Approaches To Studying Drug-induced Disease • Introduction • Current System –Premarketing –Postmarketing/ Pharmacoepidemiology • Pharmacoepidemiology and Dermatology CCEB
  3. 3. What Are Your Drugs Really Doing To Your Patients? Epidemiological Approaches To Studying Drug-induced Disease • Introduction • Current System –Premarketing –Postmarketing/ Pharmacoepidemiology • Pharmacoepidemiology and Dermatology CCEB
  4. 4. Conflict of Interest Disclosure • • • • • • Funding from the National Institutes of Health; Agency for Healthcare Research and Quality (including CERT funding, DEcIDE [Developing Evidence to Inform Decisions about Effectiveness] funding, and patient safety funding; Pfizer Pharmaceuticals; and Takeda Pharmaceuticals North America Grants from Alza Corporation, Andrew W. Mellon Foundation, Asia Foundation, Bayer Corporation, Berlex Laboratories, the Burroughs Wellcome Company, Charles A. Dana Foundation, Ciba-Geigy Corporation, Health Information Designs, Inc., Hoechst-Roussel Pharmaceuticals, Hoffman-La Roche, Inc., Integrated Therapeutics, Inc., a subsidiary of Schering-Plough Corporation, International Clinical Epidemiology Network, Inc., International Formula Council, John Wiley & Sons, Ltd., Joint Commission on Prescription Drug Use, Marion Merrell Dow, Inc., McNeil Consumer Products, McNeil Pharmaceuticals, Mead Johnson Pharmaceuticals, Merck and Company, Institute of Medicine of the National Academy of Sciences, Novartis Pharmaceuticals Corp., Pfizer Pharmaceuticals, PharMark Corp, A.H. Robins Company, Rockefeller Foundation, Rowell Laboratories, Sandoz Pharmaceuticals, Schering Corporation, Smith Kline and French Laboratories, Sterling Winthrop Inc., Syntex, Inc., Takeda Pharmaceuticals North America, the Upjohn Company, US Agency for International Development, US Pharmacopeia, US Veterans Administration, Wyeth-Ayerst Research Pharmacoepidemiology training program support has been provided by NIH and from Alza Corporation, Amgen, Inc., Aventis Pharmaceuticals, Inc., Bayer Corporation, Berlex Laboratories, Inc., Ciba-Geigy Corporation, Genentech, Inc., Hoechst-Marion-Roussel, Inc., Integrated Therapeutics Group, Inc., Johnson and Johnson, Merck and Company, Inc., McNeil Consumer Product Company, McNeil Consumer Healthcare, Novartis Pharmaceuticals Corporation, Pfizer, Inc. , SmithKline Beecham Pharmaceuticals, Whitehall-Robins Healthcare, and Wyeth-Ayerst Research US FDA Special Government Employee for serving on FDA advisory committees, and was a member of the FDA Drug Safety and Risk Management Advisory Committee Consultant to: Abbott Laboratories, Aetna, Alza Corporation, Astellas Pharma Europe BV, Astra-Merck, AstraZeneca LP, Aventis Pharmaceuticals, Bayer Corporation, Berlex Laboratories, Blue Cross and Blue Shield, Biogen Idec, Bracco Diagnostics, Inc., Bristol-Myers Squibb Company, Centocor, Inc., Cephalon, Inc., Churchill Communications, Ciba-Geigy, Inc., Connaught Laboratories, CV Therapeutics, Cygnus Corporation, Inc., Daiichi Pharmaceuticals UK, Ltd., Dupont-Merck, Eli Lilly and Company, Ethicon, Forest Research Institute. GlaxoSmithKline, Hoechst-Roussel Pharmaceuticals, Inc., Hoffman LaRoche, IBEX Technologies Corporation, IMS Health, Inflexxion, Inc., Inveresk Research North Carolina, Inc., IOM/National Academies of Science, Janssen Pharmaceuticals, McNeil Consumer Products Company, Javelin Pharmaceuticals, Luitpold Pharmaceuticals, Mediwound, Mikalix and Company, Novartis, Omnicare, Inc., Orchid Bioscience, Inc., Oscient Pharmaceutical Corp., Pfizer, Inc., PharMark Corporation, Quintiles Strategic Research and Safety/The Lewin Group, Inc, Rhone Poulenc Rorer Pharmaceuticals, Inc., Roche Laboratories, Inc., RW Johnson Pharmaceutical Research Institute, SanofiAventis, Sanofi Pasteur, Inc., Schering-Plough Research Institute, Science, Toxicology, and Technology Consultants, Searle, Shire Pharmaceuticals, Syntex,USA, Inc., Takeda Pharmaceuticals North America, TAP Pharmaceuticals, Teva Neuroscience, Inc., Value Health Sciences, Warner Lambert, Wyeth Consumer Healthcare Division, and numerous law firms Former Member of the Board of Directors of Medco Health Solutions, Inc. • CCEB No support was provided for this talk
  5. 5. • “A desire to take medications is, perhaps, the greatest feature which distinguishes man from other animals.” Sir William Osler, 1891 CCEB
  6. 6. • “If the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind , and all the worse for the fishes.” Oliver Wendell Holmes Medical Essays, “Comments and Counter” Currents in Medical Science CCEB
  7. 7. What Are Your Drugs Really Doing To Your Patients? Epidemiological Approaches To Studying Drug-induced Disease • Introduction • Current System –Premarketing –Postmarketing/ Pharmacoepidemiology • Pharmacoepidemiology and Dermatology CCEB
  8. 8. Phases of Drug Development PC 1 2 3 4 Drug Approval PC: Preclinical studies 1: Dose escalation in normals 2: Dose ranging, first time in patients 3: Pivotal trials for registration 4: Post-marketing, not always required CCEB
  9. 9. Limitations of Pre-marketing Trials-1 • Carefully selected subjects may not reflect real-life patients in whom drug will be used • Study subjects may receive better care than real-life patients • Short duration of treatment • No info on comparative effectiveness CCEB
  10. 10. Limitations of Pre-marketing Trials-2  development costs lead to  need for immediate huge sales (“blockbuster drugs”), and aggressive marketing practices • Yet, development programs with 3000 patients cannot reliably detect adverse events with an incidence of < 1 per 1000, even if severe CCEB
  11. 11. CCEB
  12. 12. Resulting Opportunities • 51% of drugs have label changes due to major safety issues discovered after marketing • 20% of drugs get new “black box” warnings after marketing • 4% of drugs are ultimately withdrawn for safety reasons CCEB
  13. 13. Other Issues in Current System • No incentive for sponsor to complete promised postmarketing safety studies • DTC ads lead to over-use of the drug by patients for whom use of the drug is not compelling CCEB
  14. 14. Net Effect • Public misunderstands “safety”: post-marketing discovery of a drug ADR means someone “messed up” • Increasing concern about the safety of our drugs • Over-reaction leads to increased pre-marketing requirements with delayed access and drugs dropped from development CCEB
  15. 15. CCEB
  16. 16. What Are Your Drugs Really Doing To Your Patients? Epidemiological Approaches To Studying Drug-induced Disease • Introduction • Current System –Premarketing –Postmarketing/ Pharmacoepidemiology • Pharmacoepidemiology and Pediatrics CCEB
  17. 17. “Traditional” Pharmacoepidemiology: Definition • The study of the use and effects of drugs in populations • Applies the methods of Epidemiology to the content area of Clinical Pharmacology CCEB
  18. 18. Options in Research Design • Analytic Studies – Experimental Study – Prospective Cohort Study – Retrospective Cohort Study – Case-Control Study • Descriptive Studies CCEB – Analyses of Secular Trends – Case Series – Case Reports
  19. 19. Case-Control Studies Disease Absent (controls) Present (exposed) A B Absent (not exposed) C D Factor Cohort Studies Present (cases)
  20. 20. Prospective vs. Retrospective Studies Events Under Study Prospective Study Retrospective Study Time CCEB
  21. 21. Pharmacoepidemiology: Unique Setting • A large population needs to be studied • Randomized clinical trials are less likely to be productive • Answers often must be obtained very quickly CCEB
  22. 22. Pharmacoepidemiology: Unique Characteristics of Methodologic Importance • • • CCEB Exposure to drugs is not dichotomous Drug exposures have benefit Unlike most exposures of interest to epidemiologists, exposure to drugs is deliberate
  23. 23. Methodologic Issues of Special Concern for Pharmacoepidemiology • Measurement of exposure • Confounding by indication/ channeling CCEB
  24. 24. Pharmacoepidemiology: Other Unique Characteristics • • • • • Some studies can be very expensive Major role played by industry - Premarketing studies - Funding for postmarketing studies - Contract Research Organizations (CROs) Interplay of industry vs. regulators Enormous public interest in drug safety Rife with risk of conflict of interest CCEB
  25. 25. Key Problem of “Historical” Pharmacoepidemiology • Adverse drug events are the most common iatrogenic causes of patient injuries • Most are the result of an exaggerated but otherwise usual pharmacological effect of the drug • Yet, historically these have been ignored by pharmacoepidemiology, as they do not represent a focus of commercial and regulatory interest CCEB
  26. 26. Data Sources for Pharmacoepidemiology Studies • Spontaneous case reports of adverse reactions • Aggregate population-based data sources • Computerized collections of data from organized medical care programs • Data collected for pharmacoepi on an ongoing basis • Existing data collected as part of other ad hoc studies • Data collected de novo CCEB
  27. 27. Spontaneous Reports of Adverse Reactions: Advantages • Incorporates all drugs • Incorporates all prescribers • Relatively inexpensive CCEB
  28. 28. Spontaneous Reports of Adverse Reactions: Disadvantages • Under- or over-ascertainment • Under-reporting • External events can change ascertainment or reporting • No denominators CCEB
  29. 29. Data Sources for Pharmacoepidemiology Studies • Spontaneous case reports of adverse reactions • Aggregate population-based data sources • Computerized collections of data from organized medical care programs • Data collected for pharmacoepi on an ongoing basis • Existing data collected as part of other ad hoc studies • Data collected de novo CCEB
  30. 30. Computerized Collections of Billing Data: Sources of Data Provider: Pharmacy Provider: Hospital Provider: Physician CCEB Payor Data User
  31. 31. Data Sources for Pharmacoepidemiology Studies • Spontaneous case reports of adverse reactions • Aggregate population-based data sources • Computerized collections of data from organized medical care programs • Data collected for pharmacoepi on an ongoing basis • Existing data collected as part of other ad hoc studies • Data collected de novo CCEB
  32. 32. Use of Pharmacoepi to Study Drug Mechanisms • Risk factors for druginduced disease • Pharmacogenetics • Molecular pharmacoepi • Epidemiologic study of drug interactions CCEB
  33. 33. CCEB
  34. 34. Evolution of Therapeutics Empiric Choice of Therapy Statistical Predictive Models of Patients Likely to Benefit or Suffer Harm Personalized Medicine CCEB
  35. 35. Evolution of Therapeutics Empiric Choice of Therapy Statistical Predictive Models of Patients Likely to Benefit or Suffer Harm RiskMAPS Personalized Medicine CCEB
  36. 36. What Are Your Drugs Really Doing To Your Patients? Epidemiological Approaches To Studying Drug-induced Disease • Introduction • Current System –Premarketing –Postmarketing/ Pharmacoepidemiology • Pharmacoepidemiology and Dermatology CCEB
  37. 37. Pharmacoepidemiology and Dermatology: Opportunities • Skin reactions are among the most common types of ADRs • More toxic drugs are now being used in dermatology • That ongoing experience represents an enormous opportunity to learn a huge amount about the effects of drugs on skin, and vice versa, through the use of CCEB pharmacoepidemiology techniques
  38. 38. Pharmacoepidemiology and Dermatology: Issues • There are few trained pharmacoepidemiologists in the world – Only 1 NIH training grant, with only 2 slots – Multiple headhunter calls/week – Under FDAAA, FDA doubling its pharmacoepidemiology group • There are many fewer trained pharmacoepidemiologists in CCEB dermatology
  39. 39. Selected Examples of Recent Dermatopharmacoepidemiology Issues • • • • Accutane: use and effects Acne drugs: side effects Immunosuppressives for psoriasis: ADRs Stevens-Johnson Syndrome and TEN: Drug-induced • Wound healing: predictors and new treatments CCEB

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