Brian L. Strom, M.D., M.P.H.

1,226 views

Published on

Published in: Health & Medicine, Business
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
1,226
On SlideShare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
36
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide
  • First, the obligatory coi disclosure. It is also a test of your distance vision!
    I could read it all too you, but there would be no more time for the rest of the talk. However, [by category]
  • To quote Sir William Osler
  • Reading the newspaper nowadays makes one think of this quote from Sir Oliver Wendell Holmes.
    While perhaps overly pessimistic, it has certainly fed the development of pharmacoepidemiology


  • •problems--significant piece is statistical

  • • Usually ONLY 500-3000 patients studied before marketing
    • In the wake of the drug crises of the past year or so, phase 3 is being prolonged, and drug approval delayed
  • Inevitably leaves questions to be answered
  • These are successes, not failures--the issue is to detect them earlier.
  • • Includes clinical decisions
  • • Bridging field
    • In many ways, it is also the application of clinical pharmacology to public health
  • PS and IV
  • I had the honor of, and suffered the turmoil from, being one of the first academics to try to use such techniques, in the early 1980s. At that point it was very controversial. Now it is considered second nature as a or the central tool of pharmacoepidemiologists.
  • • Risk factors for drug-induced disease
    --Lesson for my trainees
    --Interventions to prevent use in those at high risk
    --Ex. sulfa study--is a prior sulfa AB allergy a RF for reactions to non-Ab sulfa exposures
    • Pharmacogenetics
    --Bench findings are leading to follow-up epi studies, eg nsaids and MI (Steve)
    --In the future, genetics can be applied as risk factor in DUR
    • Molecular pharmacoepi
    -- using molecular measures as risk factor in epi studies,
    -- eg WISE
    • Epidemiologic study of drug interactions
    --cisapride, terfenadine, ceruvastatin all led to epi studies
    --epi studies of antipsychotics and sudden death/VT, based on QT prolongation
    --beginning use of epi to examine interactions earlier, eg Worth using GRPD to study interactions between warfarin and antibiotics
  • • Common definitions
    • In some ways, the therapeutic use of these terms is similar
  • Tailoring therapy by population averages
    Tailoring therapy by individual


  • •problems--significant piece is statistical

  • Accutane: Studies of birth defects, using epi to change rxing, and then use of epi methods to evaluate
    Acne drugs: does use of Ab cause drug resistance?
    Immunosuppressives used for psoriasis: ?incidence of lymphoma and other serious ADRs?
    SJS: Multi-center and multi-national SCAR case-control study
    Wound healing: predictors and new treatments
    Genetic mechanisms for these effects
  • Brian L. Strom, M.D., M.P.H.

    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. CCEB 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
    3. 3. CCEB 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
    4. 4. CCEB 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, Sanofi- Aventis, 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. • No support was provided for this talk
    5. 5. • ““A desire to takeA desire to take medications is, perhaps,medications is, perhaps, the greatest feature whichthe greatest feature which distinguishes man fromdistinguishes man from other animals.”other animals.” Sir William Osler, 1891Sir William Osler, 1891 CCEB
    6. 6. • ““If the whole materia medica,If the whole materia medica, as now used, could be sunk toas now used, could be sunk to the bottom of the sea, it wouldthe bottom of the sea, it would be all the better for mankind ,be all the better for mankind , and all the worse for theand all the worse for the fishes.”fishes.” Oliver Wendell HolmesOliver Wendell Holmes Medical Essays, “Comments and Counter”Medical Essays, “Comments and Counter” Currents in Medical ScienceCurrents in Medical Science CCEB
    7. 7. CCEB 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
    8. 8. Phases of Drug Development 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 Drug Approval 4PC 1 2 3 CCEB
    9. 9. CCEB 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
    10. 10. CCEB  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 Limitations of Pre-marketing Trials-2
    11. 11. CCEB
    12. 12. CCEB • 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 Resulting Opportunities
    13. 13. CCEB Other Issues in Current System • No incentive for sponsor to complete promised post- marketing safety studies • DTC ads lead to over-use of the drug by patients for whom use of the drug is not compelling
    14. 14. CCEB 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
    15. 15. CCEB
    16. 16. CCEB 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
    17. 17. CCEB “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
    18. 18. CCEB Options in Research Design • Analytic Studies –Experimental Study –Prospective Cohort Study –Retrospective Cohort Study –Case-Control Study • Descriptive Studies –Analyses of Secular Trends –Case Series –Case Reports
    19. 19. Case-Control StudiesCase-Control Studies DiseaseDisease CohortStudiesCohortStudies FactorFactor PresentPresent (cases)(cases) AbsentAbsent (not exposed)(not exposed) PresentPresent (exposed)(exposed) AbsentAbsent (controls)(controls) AA DDCC BB
    20. 20. CCEB Prospective vs. Retrospective Studies Events Under Study Prospective Study Time Retrospective Study
    21. 21. CCEB 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
    22. 22. CCEB Pharmacoepidemiology: Unique Characteristics of Methodologic Importance • Exposure to drugs is not dichotomous • Drug exposures have benefit • Unlike most exposures of interest to epidemiologists, exposure to drugs is deliberate
    23. 23. CCEB Methodologic Issues of Special Concern for Pharmacoepidemiology • Measurement of exposure • Confounding by indication/ channeling
    24. 24. CCEB 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
    25. 25. CCEB 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
    26. 26. CCEB 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
    27. 27. CCEB Spontaneous Reports of Adverse Reactions: Advantages • Incorporates all drugs • Incorporates all prescribers • Relatively inexpensive
    28. 28. CCEB Spontaneous Reports of Adverse Reactions: Disadvantages • Under- or over-ascertainment • Under-reporting • External events can change ascertainment or reporting • No denominators
    29. 29. CCEB 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
    30. 30. CCEB Computerized Collections of Billing Data: Sources of Data Provider: Hospital Payor Provider: Physician Provider: Pharmacy Data User
    31. 31. CCEB 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
    32. 32. CCEB Use of Pharmacoepi to Study Drug Mechanisms • Risk factors for drug- induced disease • Pharmacogenetics • Molecular pharmacoepi • Epidemiologic study of drug interactions
    33. 33. CCEB
    34. 34. CCEB Evolution of Therapeutics Empiric Choice of Therapy Statistical Predictive Models of Patients Likely to Benefit or Suffer Harm Personalized Medicine
    35. 35. CCEB Evolution of Therapeutics Empiric Choice of Therapy Statistical Predictive Models of Patients Likely to Benefit or Suffer Harm Personalized Medicine RiskMAPS
    36. 36. CCEB 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
    37. 37. CCEB 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 pharmacoepidemiology techniques
    38. 38. CCEB Pharmacoepidemiology and Dermatology: Issues • There are few trained pharmaco- epidemiologists 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 dermatology
    39. 39. CCEB 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

    ×