Pharmacoepidemiology: Goals and Methods Sean Hennessy, PharmD, PhD Assistant Professor of Epidemiology & Pharmacology Center for Clinical Epidemiology and Biostatistics University of Pennsylvania School of Medicine CCEB

“The study of the use and effects of medications in large numbers of people” Strom

“The application of epidemiologic knowledge, methods, and reasoning to the study of the effects (beneficial and adverse) and use of drugs in human populations.” Porta and Hartzema

“The study of drugs as determinants of health and disease in the general unselected population.” Spitzer

Pharmacoepidemiology Clinical pharmacology Epidemiology Strom

Pharmacoepidemiology Pharmacology Epidemiology Therapeutics Statistics Spitzer

Health services research Clinical epidemiology Health economics Outcomes research Pharmaco- Epidemiology Economics Conceptualization by Harry Guess

Animal studies Phase 1 Phase 2 Phase 3 Drug approval Phase 4 Human subjects Not always required

Pre-marketing Post-marketing Pre-de-marketing

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

Study size –Studies with 3000 patients cannot reliably detect adverse events with an incidence of < 1 per 1000, even if severe –Studies with 500 patients cannot reliably detect adverse events with an incidence of < 1 per 166, even if severe Limitations of pre-marketing trials-2

About 20% of drugs get new “black box” warnings after marketing About 4% of drugs are ultimately withdrawn for safety reasons Consequences of Limitations of Pre-marketing Trials

Hypothesis generating Hypothesis strengthening Hypothesis testing

Case Reports & Case Series Cerivastatin (Baycol), an effective and inexpensive lipid lowering drug, was introduced in It was removed from the market in 2001 because of reports of fatal cases muscle breakdown (rhabdomyolysis).

Ecologic studies Obtain group-level exposure information and disease prevalence at the same point in time.

Ecologic Studies: Breast Cancer Incidence by National Fat Intake Japan Romania Yugoslavia Hong Kong Israel Italy Hungary Poland Spain Sweden UK N Zealand France Switzerland USA

Randomized Trial Random process Treated Untreated Observation Period = Study outcome Study population

Rate Ratio = Events / person-time in exposed Events / person-time in unexposed

Cohort study Non- Random process Treated Untreated Observation Period = Study outcome Study population

Rate Ratio = Events / person-time in exposed Events / person-time in unexposed A RCT is just a special case of a cohort study

Case-control study* Non- Random process Treated Untreated Observation Period = Study outcome Study population Controls sampled (*using “risk-set sampling”)

Cohort vs. Case-Control Advantages of cohort studies -Can calculate incidence -Can directly calculate relative risk -Less measurement error? -Can study multiple outcomes of single exposure Advantages of case-control studies -Need exposure and confounder info on fewer subjects -Often quicker, less expensive -Can study multiple causes of a single disease

Data sources Spontaneous reporting systems Ad-hoc studies Health Care data –Medicaid –General Practice Research Database –Tayside Medicines Monitoring Unit –Group Health Cooperative of Puget Sound –United Health –Etc.