the “pharmaco” in pharamcoepidemiology
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The “Pharmaco” in Pharamcoepidemiology. Alec Walker September 2013. Who Needs the “Pharmaco”?. Epidemiology 221 is a course is for Epidemiologists in training New to drug safety research To explore recurring topics pharmacoepidemiology Through lectures and discussion, we will explore - PowerPoint PPT PresentationTRANSCRIPT
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
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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!