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Global Pharmacovigilance A Brief History and Thoughts on What to Expect May 2009 Alexander Global Pharmacovigilance A Brief History and Thoughts on What to Expect May 2009 Alexander M. Walker MD, Dr. PH

Thomas Quasthoff o o o o German bass-baritone Born 1959 Recordings on Philips, EMI, Thomas Quasthoff o o o o 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, Quasthoff’s Mother Took Thalidomide Many European women used thalidomide, an apparently safe sleeping medication, during pregnancy in the late 1950 s and 1960. Quasthoff, like thousands of others, was born with phocomelia.

Thalidomide in 1960 o o Painkiller, sedative Already in wide use around the world Thalidomide in 1960 o o 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. 4

Frances Oldham Kelsey o Pharmacology student at University of Chicago n Participates in the Frances Oldham Kelsey o Pharmacology student at University of Chicago n Participates in the Elixir of Sulfanilamide debacle o Pharmacologist at Chicago n During WWII South Pacific fight cut off access to cinchona trees n Spent much of WWII looking for a quinine substitute n In so doing learned about difference in metabolism between nonpregnant, pregnant and embyonic rabbits o Goes on to medical school n MD in 1950, at the age of 36 n Joins the FDA in 1960 5

Frances Oldham Kelsey o Francis Kelsey n Public health hero? n Foot-dragging bureaucrat? o Frances Oldham Kelsey o Francis Kelsey n Public health hero? n Foot-dragging bureaucrat? o Spontaneous reports & pharmacovigilance 6

Delay in US Approval 1961 Florence AL. BMJ 1960(2): 1954 o Heavy pressure for Delay in US Approval 1961 Florence AL. BMJ 1960(2): 1954 o Heavy pressure for approval by Christmas o December reports of peripheral neuropathies in BMJ o Phocomelia epidemic has been noted in Europe and Australia, cause unknown o Kelsey keeps asking for more data 7

Meanwhile … 1961 o November 16 Wedekund Lenz identifies half of phocomelia patients as Meanwhile … 1961 o November 16 Wedekund Lenz identifies half of phocomelia patients as having been exposed to thalidomide at a conference o December 2 (Lancet) UK Manufacturer notes rarity, lack of statistics, appeals for case reports, suspends sales o December 16 (Lancet) Mc. Bride notes 20% major malformation risk in thalidomide pregnancies 8

Meanwhile … 1962 o Richardson-Merrell withdraws application 9 Meanwhile … 1962 o Richardson-Merrell withdraws application 9

Fêted as a Hero o Distinguished Federal Civilian Service Award, August 7, 1962 o Fêted as a Hero o Distinguished Federal Civilian Service Award, August 7, 1962 o Glowing write-up in Life 10

The Verdict of History www. fda. gov/cder/pike/julyaug 2001. htm 11 The Verdict of History www. fda. gov/cder/pike/julyaug 2001. htm 11

FDA Recognizes Dr. Kelsey's Induction into Women's Hall of Fame Frances O. Kelsey, Ph. 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/julyaug 2001. htm 12

IOM’s Review of FDA Recommendations to Congress ESTABLISH PERFORMANCE GOALS FOR SAFETY HOLD INDUSTRY 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 13

US FDA Risk Evaluation and Mitigation Strategies o What are the known or suspected US FDA Risk Evaluation and Mitigation Strategies o What are the known or suspected risks for this product? n n Mechanisms of action Animal and human complications to date Analogy to existing products Susceptible populations o How will the manufacturer evaluate these after launch? n n n Monitor usage esp off-label & contraindicated Registry or automated cohort for outcomes Pharmacovigilance o What will the manufacturer do from the start & with results of asessments? n n n Medication guides Physician communication Restrictive distribution (Provider Training, Certified Dispensers, Certified Settings, Patient Certification, Patient Monitoring, Patient Registry) 14

S Perez-Gutthann; www. rtihs. org/request/index. cfm? fuseaction=display&PID=8896 15 S Perez-Gutthann; www. rtihs. org/request/index. cfm? fuseaction=display&PID=8896 15

Proactive Use of Existing Data Proactive Use of Existing Data

Zelnorm Approved in US despite early concerns about cholecystectomy. Not approved in Europe on 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 30 March 2007 Available for this Public Health Advisory

Reanalysis of Earlier Trials for CV Endpoints o o o 29 Trials Ave Age Reanalysis of Earlier Trials for CV Endpoints o o o 29 Trials Ave Age 43 88% F Patients MI Unstable Angina Stroke Risk Tegaserod Placebo 11, 614 7, 031 4 0 6 0 3 1 ~0. 1% ~0. 0%

Zelnorm Actions and Lessons o Meta-analytic review of trials data for rare effects becoming Zelnorm Actions and Lessons o Meta-analytic review of trials data for rare effects becoming a common Agency activity o Small effects can lead to removal when the evidence for efficacy is thin o Cost-benefit is not explicit, but is surely implicit when there are marginal safety questions. Follow-up o Zelnorm later returned to the market under a restricted access program o Novartis discontinued program after a year

Massive Trials to Define Safety 21 Massive Trials to Define Safety 21

Vesikari 2006 22 Vesikari 2006 22

Lesson: Take No Chances 23 Lesson: Take No Chances 23

60, 000 Person Years o Following on the confusion and debate after the rosiglitazone 60, 000 Person Years o Following on the confusion and debate after the rosiglitazone meta-analyses, o FDA now requesting that manufacturers of new anti -diabetes medicines establish the long-term cardiovascular safety of new agents before approval 24

Alogliptin 25 Alogliptin 25

Proactive Exploration of Large Data Sets Proactive Exploration of Large Data Sets

Sentinel 27 Sentinel 27

FDA Sentinel System This is the context within which we’ll be working shortly. Manufacturer 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. o Large numbers of users o Real-world use o Rapid feedback o Comprehensive outcome monitoring o Ability to dive deeper o Target sizes n 25 million by 2010 n 100 million by 2012 28

Sentinel Architecture 29 Sentinel Architecture 29

Research Database Claims Data • • • Member Identifier Plan Gender Age Dates of Research Database Claims Data • • • 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 • • 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 30

Generations of Data Source Data Research Data Mart Analysis Elements Simple-Structure Files 31 Generations of Data Source Data Research Data Mart Analysis Elements Simple-Structure Files 31

Distributed Processing Source data Data Mart Staging Area Local Centers create staging areas in Distributed Processing Source data Data Mart Staging Area Local Centers create staging areas in common format Central office distributes analytic programs and receives intermediate files. 32

Menactra Menactra

Menactra Chart Menactra Chart

Countries with Existing Large Automated Research Databases North America o US o Canada o Countries with Existing Large Automated Research Databases North America o US o Canada o Mexico Europe o UK o Germany o Sweden o Denmark o Italy Asia o Taiwan o Japan o Korea 35

Summary o Pharmacovigilance has historically and continues to be largely a function of health Summary o Pharmacovigilance has historically and continues to be largely a function of health care providers recognizing and reporting. o Governments are seeking to formalize and institutionalize surveillance by manufacturers n RMP n REMS o Governments are doing and forcing manufacturers to proactively review data on file. o There is a major movement to proactive use of very large automated insurance and electronic medical record data. 36

Thank You! Thank You!