Global Pharmacovigilance

A Brief History and Thoughts on What to Expect

May 2009

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.

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.

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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

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

11www.fda.gov/cder/pike/julyaug2001.htm

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.”

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

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

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http://www.iom.edu/Object.File/Master/37/331/11750_report_brief_congress.pdf

US FDARisk Evaluation and Mitigation Strategies What are the known or suspected risks for this product?

Mechanisms of action Animal and human complications to date Analogy to existing products Susceptible populations

How will the manufacturer evaluate these after launch? 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? 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.

         Available for this Public Health Advisory

30 March 2007

Reanalysis of Earlier Trials for CV Endpoints

29 Trials Ave Age 43 88% F

Tegaserod Placebo

Patients 11,614 7,031

MI 4 0

Unstable Angina

6 0

Stroke 3 1

Risk ~0.1% ~0.0%

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

Sentinel Architecture

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AdministrativeData

PharmacyClaims

Data

Physician andFacility Claims

Data

Lab TestResults

Data

Machine Readable Dataset

• Member Identifier• Plan• Gender• Age• Dates of Eligibility

• Member identifier• Prescribing

physician• Drug dispensed

(NDC)• Quantity and

date dispensed• Drug strength• Days supply• Dollar amounts

• 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

Possible Supplementary Per-Project Data (Expensive, Slow)

ChartReviews

SurveysClinical

Measures

• Member identifier• Lab Test Name• Result

Research Database

Consumer Elements

• Member identifier• Income• Net Worth • Education• Race & Ethnicity• Life Stage• Life Style Indicators

Claims Data

TissueSamples

Hospital Inpatient

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Generations of Data

Source Data

Research Data Mart

Simple-Structure FilesAnalysis Elements

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Distributed Processing

Local Centers create staging areas in common format

Central office distributesanalytic programs andreceives intermediatefiles.

Sourcedata

Data Mart

StagingArea

Sourcedata

Data Mart

StagingArea

Sourcedata

Data Mart

StagingArea

Sourcedata

Data Mart

StagingArea

Menactra

Menactra Chart

Countries with ExistingLarge Automated Research Databases

North America US Canada MexicoEurope UK Germany Sweden Denmark Italy

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Asia Taiwan Japan Korea

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!