The “Pharmaco” in Pharamcoepidemiology

Alec Walker September 2013

1

Who Needs the “Pharmaco”?

Epidemiology 221 is a course is for Epidemiologists in trainingNew to drug safety researchTo explore recurring topics pharmacoepidemiology

Through lectures and discussion, we will explore Examples of discovery of adverse drug effectsUse of large databasesStudy designs for

Large data resourcesControl for unmeasured confounding factors

Institutional sensitivitiesStudents will acquire

Relevant vocabularyKey conceptsAbility to pursue each of these topics in more depth

2

Epidemiology 221

Early StoriesDiscovery of Drug EffectsCommon Epidemiologic Designs Applied to Drugs

Fall 2013

Alexander M. Walker MD, DrPH

Thomas Quasthoff

German bass-baritone Born 1959 Recordings on Philips, EMI, BMG,

Haenssler 1988 ARD International Music

Competition in Munich 1996 Shostokovich Prize 1999 Tanglewood (Boston Symphony

Orchestra) debut 1999 Exclusive Deutsche Grammophon

contract Profiled in Time, People, Esquire, 60

Minutes

Quasthoff’s Mother Took Thalidomide

Many European women used thalidomide, an apparently safe sleeping medication, during pregnancy in the late 1950s and 1960.

Quasthoff, like thousands of others, was born with phocomelia.

The FDA as Public Health Guardians

6

Thalidomide in 1960 Painkiller, sedative Already in wide use around the world Generally felt to be harmless Over the counter in Germany since 1957

Richardson-Merrell submits application in USHoping for approval by Christmas, when sedative sales

generally peaked.

7

Frances Oldham Kelsey Francis Kelsey

Public health hero? Foot-dragging bureaucrat?

Spontaneous reports & pharmacovigilance

8

Delay in US Approval Heavy pressure for approval December reports of peripheral neuropathies in BMJ

Kelsey keeps asking for more data

9

Flor

ence

AL.

BM

J 1

960(

2):1

954

Meanwhile …1959 – 1969 Phocomelia epidemic recognized but not

understood1961 November 16 Wedekund Lenz identifies half of

phocomelia patients as having been exposed to thalidomide at a conference

December 2 (Lancet) UK Manufacturer notes rarity, lack of statistics, appeals for case reports, suspends sales

December 16 (Lancet) McBride notes 20% major malformation risk in thalidomide pregnancies

10

1962 Richardson-Merrell withdraws application

Phocomelia

Fêted as a Heroes Distinguished Federal

Civilian Service Award, August 7, 1962

Glowing write-up in Life

12

The Verdict of History

13www.fda.gov/cder/pike/julyaug2001.htm

Induction into Women's Hall of Fame

Frances O. Kelsey, Ph.D., M.D., was praised for her courage and influence at a special FDA reception to commemorate her induction last October into the National Women's Hall of Fame.

Center Director Janet Woodcock, M.D., noted that Dr. Kelsey, a pharmacologist and physician, has long been honored for her role in blocking approval of the drug thalidomide. Dr. Kelsey's refusal to approve thalidomide for use in the United States earned her national recognition, and her work led to strengthened regulation of the pharmaceutical industry.

Dr. Woodcock said that Dr. Kelsey has been an inspiration to many scientists in the Center who "stuck to their guns under great pressure.”

14From “CDER News Along the Pike July & August 2001”www.fda.gov/cder/pike/julyaug2001.htm

The Recognition of Adverse Drug Reactions

15

It may be obvious: Toxicity is a simple matter of pharmacology

Some Paradigms for Discovery Pattern 1: Unique story Pattern 2: Distinct but delayed Pattern 3: Quantitative

Pattern 1: A Unique Story

Clinically Detectable Effects

Very short time intervalPrior hypothesisKnown mechanismNo alternative explanationSimple exposure

Clinical Recognition A single observer With a class of applicable hypotheses Congruence between event and general rule Lack of competing explanation

Pattern Recognition

Pattern Key

Angioedema and ACE Inhibitors Swelling of lips, mouth, throat Within hours to days of 1st Rx 1 in 200 patients 1 in 100 life-threatening More common in blacks

Discovering Angioedema Case reports Short time Rare in the absence of exposure Distinctive characteristics No alternative etiology No reasonable doubt in after a case series

Pattern 2: Distinct but Delayed Striking, usually rare event Increased frequency leads to search Essentially 100% of cases exposed

Phocomelia

Lancet, Dec 16, 1961

Phocomelia

and Thalidomide

Delayed No precedent (read: no pre-existing hypothesis) Distinctive pattern Became evident after single clinicians themselves

had seen multiple cases

Pattern 3: Quantitative Known event Increased frequency Surveillance systems allow comparisons

Cerivastatin and Rhabdomyolysis

37 deaths reported in US 800,000 users Many months of accumulating reports Vs. 20 deaths in > 20 million users of other statins Rhabdomyolysis relatively common in all statin users For cerivastatin, principally in conjunction with

gemfibrizil

Quantitative not Qualitative Common enough to be well known Infrequent enough that no one observer can

quantify

Informal Inference: When it’s Easy …

Very short time interval Prior hypothesis Known mechanism No alternative explanation Simple exposure Massive increase in frequency

Informal Inference: When it’s Difficult …

Delayed Unanticipated No known mechanism Readily expected in absence of the drug Multiple treatment modalities Increased risk, but not overwhelmingly so

Crossing over from the Clinic to Population

34

How we evaluate causal connections

35

Theory

Prediction

Experiment

Data

Theories for Drug Safety Case Reports Analogy Animal Experience Rumor

A Good Hypothesis Content = Refutability Refutability depends on predictions Make a hypothesis better

By forcing it to make refutable predictions Experiments (studies) are data collection organized in

such a way as to test refutable predictions

ToxicEpidermalNecrolysis

SCARS

Severe Cutaneous Adverse Reaction Syndrome

SCARS

ToxicEpidermalNecrolysis

Stevens Johnson

Syndrome, Rash

Severe Cutaneous Adverse Reaction Syndrome

SCARS

ToxicEpidermalNecrolysis

Case-FindingExamination of Other Reports

Stevens Johnson

Syndrome, Rash

Severe Cutaneous Adverse Reaction Syndrome

SCARS

ToxicEpidermalNecrolysis

Roles of Epidemiology Techniques for quantification

Conceptual tools Mechanics

Repository of experience (of error) Confounded associations Distortions of information

Epidemiology’s Tools

Cohort studies Case control studies Correlational studies Surveillance

Cohort Studies A list of individuals at risk The passage of time The occurrence of events

Superinfection (1970s)

Drug Class Patients Superinf. Risk Aminoglycosides 536 13 2.4% Cephalosporins 1,954 26 1.3% Penicillins 9,948 50 0.5% Tetracylclines 2,262 11 0.5%

Case-Control Studies Cohort studies with sampling Captures covariates that would be difficult to

ascertain Time-varying Resource intensive data collection

Case-Control Advantages Relatively inexpensive Relatively quick Useful for rare outcomes

Case-Control Shortcomings May not yield absolute risk Focuses on a single outcome Difficult to assure ascertainment Difficult to verify suitable controls

MI and CCBs

Correlational Studies Population frequency Population exposure Inference on association The problem of common cause

Suicide v. CCBs in Sweden

Epidemiology as a Language for Evaluating Risk Explicit definitions for concepts of risk Measures for comparison Vocabulary for describing multiple determinants Nosology of induced and artificial associations Experience of error

Wrapping Up Epidemiology needs to formalize, not sterilize our

innate ideas of causality Epidemiology extends the vision beyond

associations that are readily apparent Epidemiologists can play a role in every stage of

drug development

Thank You!