brian l. strom, m.d., m.p.h

Brian L. Strom, M.D., M.P.H.Chair and Professor, Department of Biostatistics and

Epidemiology

Director, Center for Clinical Epidemiologyand Biostatistics

George S. Pepper Professor of Public Health and Preventive Medicine

Professor of Biostatistics and Epidemiology, Medicine, and Pharmacology

Vice Dean for Institutional AffairsUniversity of Pennsylvania School of Medicine

Senior Advisor to the Provost for Global Health Initiatives

University of Pennsylvania

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What Are Your Drugs Really Doing To YourPatients? Epidemiological Approaches

To Studying Drug-induced Disease

• Introduction

• Current System–Premarketing

–Postmarketing/ Pharmacoepidemiology

• Pharmacoepidemiology and Dermatology

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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

• ““A desire to take A desire to take medications is, perhaps, medications is, perhaps, the greatest feature which the greatest feature which distinguishes man from distinguishes man from other animals.”other animals.”

Sir William Osler, 1891Sir William Osler, 1891

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• ““If the whole materia medica, If the whole materia medica, as now used, could be sunk to as now used, could be sunk to the bottom of the sea, it would the bottom of the sea, it would be all the better for mankind , be all the better for mankind , and all the worse for the and 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

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• Introduction




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

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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

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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

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• 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

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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

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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

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• Introduction



• Pharmacoepidemiology and Pediatrics

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“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

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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

Case-Control StudiesCase-Control Studies

DiseaseDisease

Cohort

Stu

die

sC

ohort

Stu

die

s

Fact

or

Fact

or

PresentPresent(cases)(cases)

AbsentAbsent(not exposed)(not exposed)

PresentPresent(exposed)(exposed)

AbsentAbsent(controls)(controls)

AA

DDCC

BB

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Prospective vs. Retrospective Studies

EventsUnder Study

Prospective Study

Time

Retrospective Study

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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

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Pharmacoepidemiology:Unique Characteristics ofMethodologic Importance

• Exposure to drugs is not dichotomous

• Drug exposures have benefit• Unlike most exposures of

interest to epidemiologists, exposure to drugs is deliberate

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Methodologic Issues of Special Concernfor Pharmacoepidemiology

• Measurement of exposure

• Confounding by indication/ channeling

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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

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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

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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

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Spontaneous Reports of Adverse

Reactions: Advantages

• Incorporates all drugs

• Incorporates all prescribers

• Relatively inexpensive

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Spontaneous Reports of Adverse

Reactions: Disadvantages

• Under- or over-ascertainment• Under-reporting• External events can change

ascertainment or reporting• No denominators

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Computerized Collections of Billing Data:Sources of Data

Provider: Hospital Payor

Provider: Physician

Provider: Pharmacy

DataUser

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Use of Pharmacoepito Study Drug Mechanisms

• Risk factors for drug-induced disease

• Pharmacogenetics • Molecular pharmacoepi• Epidemiologic study of drug

interactions

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Evolution of Therapeutics

Empiric Choice of Therapy

Statistical Predictive Models of PatientsLikely to Benefit or Suffer Harm

Personalized Medicine

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Evolution of Therapeutics

Empiric Choice of Therapy

Statistical Predictive Models of PatientsLikely to Benefit or Suffer Harm

Personalized Medicine

RiskMAPS

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• Introduction




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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

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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 dermatology

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Selected Examples of RecentDermatopharmacoepidemiology 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

brian l. strom, m.d., m.p.h

Health & Medicine

therapeutics

ad hoc studies

existing data

based data

spontaneous

spontaneous

data collected

ayerst research