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Global Pharmacovigilance
A Brief History and Thoughts on What to Expect
May 2009
Alexander M. Walker MD, DrPH
Thomas Quasthoff
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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.
Thalidomide in 1960
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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 US
Hoping for approval by Christmas, when sedative sales
generally peaked.
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Frances Oldham Kelsey
 Pharmacology student at University of Chicago
 Participates in the Elixir of Sulfanilamide debacle
 Pharmacologist at Chicago
 During WWII South Pacific fight cut off access to
cinchona trees
 Spent much of WWII looking for a quinine substitute
 In so doing learned about difference in metabolism
between nonpregnant, pregnant and embyonic
rabbits
 Goes on to medical school
 MD in 1950, at the age of 36
 Joins the FDA in 1960
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Frances Oldham Kelsey
 Francis Kelsey
 Public health hero?
 Foot-dragging bureaucrat?
 Spontaneous reports & pharmacovigilance
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Delay in US Approval 1961
Florence AL. BMJ
1960(2):1954
 Heavy pressure for approval by Christmas
 December reports of peripheral neuropathies in BMJ
 Phocomelia epidemic has been noted in Europe and
Australia, cause unknown
 Kelsey keeps asking for more data
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Meanwhile …
1961
 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
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Meanwhile …
1962
 Richardson-Merrell withdraws application
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Fêted as a Hero
 Distinguished Federal
Civilian Service Award,
August 7, 1962
 Glowing write-up in Life
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The Verdict of History
www.fda.gov/cder/pike/julyaug2001.htm 11
FDA Recognizes Dr. Kelsey's 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.”
From “CDER News Along the Pike July & August 2001”
www.fda.gov/cder/pike/julyaug2001.htm
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IOM’s Review of FDA
Recommendations to Congress
ESTABLISH
PERFORMANCE GOALS
FOR SAFETY
HOLD INDUSTRY AND
RESEARCHERS
ACCOUNTABLE FOR
MAKING DRUG SAFETY
STUDY RESULTS PUBLIC
APPROPRIATE
ADEQUATE RESOURCES
FOR DRUG SAFETY
http://www.iom.edu/Object.File/Master/37/331/11750_report_brief_congress.pdf
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US FDA
Risk Evaluation and Mitigation Strategies
 What are the known or suspected risks for this product?
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Mechanisms of action
Animal and human complications to date
Analogy to existing products
Susceptible populations
 How will the manufacturer evaluate these after launch?
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Monitor usage esp off-label & contraindicated
Registry or automated cohort for outcomes
Pharmacovigilance
 What will the manufacturer do from the start & with results of
asessments?
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Medication guides
Physician communication
Restrictive distribution (Provider Training, Certified Dispensers,
Certified Settings, Patient Certification, Patient Monitoring, Patient
Registry)
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S Perez-Gutthann; www.rtihs.org/request/index.cfm?fuseaction=display&PID=8896
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Proactive Use of Existing Data
Zelnorm
Approved in US despite early concerns about cholecystectomy.
Not approved in Europe on efficacy grounds.
30 March 2007
Available for this Public Health Advisory
Reanalysis of Earlier Trials for CV Endpoints
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29 Trials
Ave Age 43
88% F
Patients
Tegaserod
Placebo
11,614
7,031
MI
4
0
Unstable
Angina
6
0
Stroke
3
1
~0.1%
~0.0%
Risk
Zelnorm Actions and Lessons
 Meta-analytic review of trials data for rare
effects becoming a common Agency activity
 Small effects can lead to removal when the
evidence for efficacy is thin
 Cost-benefit is not explicit, but is surely
implicit when there are marginal safety
questions.
Follow-up
 Zelnorm later returned to the market under a
restricted access program
 Novartis discontinued program after a year
Massive Trials to Define Safety
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Vesikari 2006
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Lesson: Take No Chances
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60,000 Person Years
 Following on the confusion and debate after the
rosiglitazone meta-analyses,
 FDA now requesting that manufacturers of new
anti-diabetes medicines establish the long-term
cardiovascular safety of new agents before
approval
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Alogliptin
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Proactive Exploration
of Large Data Sets
Sentinel
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FDA Sentinel System
This is the context within which we’ll be working
shortly. Manufacturer may not be the sole or
event the primary source of safety data.
 Large numbers of users
 Real-world use
 Rapid feedback
 Comprehensive outcome monitoring
 Ability to dive deeper
 Target sizes
 25 million by 2010
 100 million by 2012
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Sentinel Architecture
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Research Database
Claims Data
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Member Identifier
Plan
Gender
Age
Dates of Eligibility
Administrative
Data
• Member identifier
• Prescribing
physician
• Drug dispensed
(NDC)
• Quantity and
date dispensed
• Drug strength
• Days supply
• Dollar amounts
Pharmacy
Claims
Data
• Member identifier
• Physician or Facility
identifier
• Procedures (CPT-4,
revenue
codes, ICD-9)
• Diagnosis (ICD-9-CM,
DRG)
• Admission and
discharge dates
• Date and place of
service
• Dollar amounts
Physician and
Facility Claims
Data
• Member identifier
• Lab Test Name
• Result
Lab Test
Results
Data
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•
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•
•
Member identifier
Income
Net Worth
Education
Race & Ethnicity
Life Stage
Life Style Indicators
Consumer
Elements
Machine Readable Dataset
Possible Supplementary Per-Project Data (Expensive, Slow)
Chart
Reviews
Surveys
Hospital
Inpatient
Clinical
Measures
Tissue
Samples
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Generations of Data
Source
Data
Research Data Mart
Analysis Elements
Simple-Structure Files
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Distributed Processing
Source
data
Data
Mart
Staging
Area
Source
data
Data
Mart
Staging
Area
Source
data
Data
Mart
Staging
Area
Source
data
Data
Mart
Staging
Area
Local Centers create staging
areas in common format
Central office
distributes
analytic
programs and
receives
intermediate
files.
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Menactra
Menactra Chart
Countries with Existing
Large Automated Research Databases
North America
 US
 Canada
 Mexico
Europe
 UK
 Germany
 Sweden
 Denmark
 Italy
Asia
 Taiwan
 Japan
 Korea
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Summary
 Pharmacovigilance has historically and continues to
be largely a function of health care providers
recognizing and reporting.
 Governments are seeking to formalize and
institutionalize surveillance by manufacturers
 RMP
 REMS
 Governments are doing and forcing manufacturers
to proactively review data on file.
 There is a major movement to proactive use of very
large automated insurance and electronic medical
record data.
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Thank You!