Pharmacoepidemiology: Goals and Methods Sean Hennessy, PharmD, PhD Assistant Professor of...

Pharmacoepidemiology: Goals and Methods

Sean Hennessy, PharmD, PhDAssistant Professor of Epidemiology & Pharmacology

Center for Clinical Epidemiology and BiostatisticsUniversity 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 servicesresearch

Clin

ical

ep

idem

iolo

gy

Health economicsOutcomes

research

Pharmaco-Epidemiology

EpidemiologyEconomics

Conceptualization by Harry Guess

Animal studies

Phase 1

Phase 2

Phase 3

Drug approval

Phase 4

Human subjects

•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• About 4% of drugs are ultimately withdrawn for safety reasons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

Case report

Case series

Ecologic

Descriptive

Cohort

Case-control

Non-experimental

RCT

Experim ental

Analytic

Epidemiologic study designs

Hypothesis generating

Hypothesis strengthening

Hypothesis testing

Case Reports & Case SeriesCerivastatin (Baycol), an effective and inexpensive lipid lowering drug, was introduced in 1997. 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

0

50

100

150

200

250

500 700 900 1100 1300 1500 1700

Fat intake (kcal/d)

Inc

ide

nc

e p

er

10

0,0

00

p-y

Japan

RomaniaYugoslavia

Hong Kong

IsraelItaly

HungaryPoland

Spain

SwedenUK

N ZealandFrance

SwitzerlandUSA

Case report

Case series

Ecologic

Descriptive

Cohort

Case-control

Non-experimental

RCT

Experim ental

Analytic

Epidemiologic study designs

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.