Post-Marketing Studies from the Industry Perspective

1. Gretchen S. Dieck, Ph.D. Vice President, Risk Management Strategy Post-Marketing Studies from the Industry Perspective

2. Key Risk Management Assumptions • Each new drug is unique • No drug is risk free • Safety-related decisions must be evidence-based • Industry is responsible for bringing evidence-based information forward • No individual information source should be viewed in isolation • Good communications with regulators and medical community are essential • Ensure patient safety • No surprises

3. Value of Risk Management Across the Lifecycle Exposure (Potential Denominator) Ph IV Ph III Ph II Ph I FIM Product Life Cycle Approval Post Marketing Pharmacovigilance Drug Discovery/Preclinical Clinical Development • Estimate potentialmarkets • Predict potentialcandidates • Initiate studies to understand treatment population, risks, concomitant diseases, etc. • Promote faster approval • Convert non-approvable to approvable • Achieve appropriate label • Understand absolute and relative risks • Maintain patient safety

4. Tools for Evaluating Drug Safety Profile • Clinical data • Epidemiology • Spontaneous reports DecreasingScientific Rigor Data from all sources are necessary to evaluate a drug’s safety profile

5. Risk Identification Pre- & Post- Approval Public expectation of risk knowledge at approval is greater than reality Risk Identification 1/100,000 Risk Identification 1/10,000 1/1000 Post Approval1 Million Patients 1/1000 1/500 1/100 Pre-Approval10,000 Patients Reality Public Expectation How to Get There from Here

6. Building Risk Knowledge Base Post-approval experience allows for identification of smaller risks SpontaneousReports ObservationalStudies Other Activities Background Epidemiology POTENTIAL SIGNALS OF RARE EVENTS HYPOTHESIS TESTING INCIDENCE OF COMMONLY OCCURRING EVENT FROM CLINICALTRIALS INCIDENCE OF EVENT IN GENERAL POPULATION IDENTIFICATION OF RISK FACTORS 1/1,000,000 1/100,000 1/500,000 1/10,000 1/1,000 1/50,000 1/100,000, 1/500 1/10,000 1/5,000 1/100 1/1,000 Risk Management/Assessment Strategy Building knowledge through experience

7. Peri-Approval Risk Assessment Risk Assessment – Important part of Risk Management • Risk Management should start early in drug development • Covers the entire drug life cycle • Issues may arise during review period • Assessment of risk • Understanding the population being treated • Obtaining information to put AEs into context Important to identify subgroups at risk

8. Post-Approval Studies • Classical epidemiological studies • Cohort • Case-control • Case-crossover • Large Simple Trial • Registries • Replicate findings using different study designs and populations

9. Post-Approval StudiesRisk Assessment Example: Geodon Large Simple Trial • First launched September 2000 in Sweden and launched March 2001 in the United States • Modestly prolongs the QTc interval - unknown whether modest QT prolongation results in an increased risk of serious cardiac events

10. Post Approval Safety Study – Large Simple Trial • Designed to study cardiovascular outcomes (sudden cardiac death and hospitalization due to cardiovascular events) in a ‘real life’ setting • A large, naturalistic, prospective study with random assignment of patients to antipsychotic treatment, to control for channeling bias • 18,000 patients randomized to ziprasidone or olanzapine • No additional study-required monitoring or tests after randomization • Follow up during usual care

11. Why a Large Simple Trial? • Strongest of observational study designs • Random allocation eliminates possibility that patients are high risk of cardiovascular disease are preferentially prescribed ziprasidone, i.e. channeling bias • Eliminates others forms of selection bias/confounding by indication • Use of External Scientific Committees for highest scientific standards • Scientific Steering Committee • Safeguard interests of participating patients and act on recommendations of DSMB • Scientific oversight of study conduct • Data Safety Monitoring Board (DSMB) • Biannual review of study endpoints and recruitment, discontinuation and retention rates • Endpoint Committee • Medical records reviewed by blinded reviewers using standard criteria - Reviewer consensus in cases of disagreement

12. Study Status • Patient enrollment on projected schedule • First patient enrolled February 2002 • > than 6000 patients enrolled in US, Brazil and Sweden • 360 sites enrolling patients in US • More than 80% of sites are private practice • Other sites are primarily mental health centers and Veteran’s Administration/psychiatric hospitals • Further recruitment ongoing

13. Post-Approval StudiesUnderstanding about the underlying population Example: Relpax • Triptan for use in treating migraines • Due to a vasoconstriction effect, there has been concern whether triptans can cause serious cardiovascular and/or cerebrovascular disease • Lack of data on incidence of cardiovascular and cerebrovascular diseases, or mortality among migraine triptan users and non-triptan users • Epidemiologic Studies • Incidence of serious cardiovascular and cerebrovascular disease and mortality among migraine patients (triptan users and non-users) • GPRD study (UK) • UnitedHealthcare Research Database study (US)

14. Relpax - United HealthCare Study: Study Design • Retrospective cohort study 1995-99 • All patients with a diagnosis of migraine or a dispensing for a triptan • Age-, sex-, and health plan-matched controls were randomly selected from individuals w/o migraine diagnosis and dispensing of triptans or ergot alkaloids Non Migraineurs n=130,411 Migraineurs n=130,411 Non-triptan users n=80,028 Triptan users n=50,383

15. Relpax - United HealthCare: Study Results *Rate per 1000 person-years. †Rate ratio comparing migraineurs to nonmigraineurs, adjusted for age, gender, year of cohort entry, comorbidities in year prior to study entry, oral contraceptive use, and estrogen replacement therapy use.

16. Relpax - United HealthCare: Study Results *Rate per 1000 person-years. †Rate ratio compared to periods of non-use among migraineurs, adjusted for age, gender, year of cohort entry, current and recent use of ergot alkaloids, comorbidities in year prior to study entry, oral contraceptive use and estrogen replacement therapy use.

17. Post-Approval StudiesUnderstanding about the underlying population Conclusions • Increased risk of IHD/unstable angina and stroke/TIA is observed in migraine patients. However, the increased risk is does not appear to be associated with the use of triptans • The use of triptans is not associated with increased risk of acute MI, IHD/unstable angina, ventricular arrhythmias, stroke/TIA, all-cause mortality or cardiovascular mortality

18. Post-Approval StudiesPutting adverse events in perspective - Geodon • Epidemiology of schizophrenia • Understanding underlying disease or condition • Providing background rates for outcomes of interest • Cardiovascular morbidity and mortality in schizophrenics • Epidemiologic studies • Saskachewan Health Databases • United HealthCare Research Database • Swedish National Board of Health and Human Welfare

19. Study Design Geodon – Saskatchewan Health Study • Retrospective cohort using longitudinally collected data: • Individuals diagnosed with schizophrenia between 1994 and 1995 (n=3022) • General population matched by age and sex (1:4) for comparison (n=12,088) • Prevalence study period (baseline risk factors): 1994-1995 • Incidence follow-up period: 1996-March 1999 Curkendall SM, Mo J, Stang MR, Jones JK, Glasser DB. Cardiovascular disease in patients with schizophrenia, Saskatchewan, Canada. Submitted to The Journal of Clinical Psychiatry

20. Relative Risk of CV Disease and Diabetes: Schizophrenia Patients vs. General Population1996-March 1999, Saskatchewan, Canada RR 95% CI P-value Acute MI 0.86 0.61-1.22 NS Arrhythmias 1.16 0.96-1.40 NS Vent. Arrhythmias 2.03 1.10-3.77 <0.05 Syncope/collapse 1.51 0.84-2.72 NS Stroke 1.34 1.01-1.77 0.05 TIA 0.86 0.58-1.26 NS Diabetes 1.62 1.19-2.20 <0.01

21. Relative Risk of Mortality Schizophrenia Patients vs. General Population1996-March 1999, Saskatchewan, Canada RR 95% CI P-value All-Cause 2.69 2.31-3.13 <0.0001 Suicide 7.00 2.55-19.27 <0.0005 Non-suicide 2.62 2.24-3.07 <0.0001 Sudden Death 3.44 1.43-8.30 <0.05 CV Death 2.04 1.60-2.60 <0.0001 Non-CV Death 3.08 2.48-3.81 <0.0001

22. Post-Approval StudiesPutting adverse events in perspective - Geodon Conclusions • Schizophrenics have a significantly increased risk of cardiovascular morbidity and mortality compared to general population • These findings were generally consistent across three geographically different study populations • These factors need to be considered when evaluating serious cardiovascular AEs for Geodon

23. Registries: Function of a Pregnancy Exposure Registry • Provide an estimate of an increased risk over background or to provide margins of reassurance regarding lack of risk • Monitor ongoing postmarketing situation for suspected and emerging risks • Identify factors that affect known risks • Serve as hypothesis-generating tools • Avert consequences of poor information • Patients denied treatment • Wanted pregnancies terminated Overall goal: to provide clinically meaningful data to help prescribers and patients make decisions about drug use during pregnancy

24. When is a Product a Good Candidate for a Pregnancy Exposure Registry? • Likely to be used during pregnancy as therapy for a new or chronic condition • High likelihood of use by women of childbearing age • Potential to cause harm during pregnancy, as identified from toxicology studies, structure-activity relationships, class effects, human case reports • New product for a disease for which therapy has historically been teratogenic

25. Ideal Registry Design • Actively collects information • Study population: exposed and unexposed groups with the same baseline risk, identified prospectively • Exposure measurement: dose, duration, and timing of all relevant medications • Outcome measurement: complete ascertainment of outcome in both groups • Covariates: complete information on all potential confounders and effect modifiers • Follow-up: complete follow-up for time period sufficient to observe outcomes • Power: ability to detect or rule out an increased risk of X over the exposed or observed in the unexposed group

26. Post-Approval StudiesChallenges • Low recruitment of physicians and patients into study • Carry out survey to identify potential barriers • Viagra: Changed questionnaire, went into additional countries • Geodon LST: Went into additional countries, added additional investigator sites • Can’t answer risk question • Relpax: What is risk of ischemic events in migraine population –sample size needed made study not feasible. Proposed focused monitoring of ischemic AEs instead • Viagra: What is unique risk of CV events due to Viagra alone – can’t separate out effect of Viagra from risk with sexual activity. Upfront agreement with regulators over interpretation of study results

27. Post-Approval StudiesChallenges • Risk questions can’t be answered using observational methods • Geodon: what is risk of Qt prolongation. Suggested harder endpoints such as CV death and hospitalization • Investigational drug: what is risk of decreased pulmonary function – can’t measure lung function in a purely observational setting. Need formal clinical trial • Other challenges • Lack of information on specific data needed – past medical history, OTC medication use, etc. May need to carry out several studies to get around limitation of one study design

28. Post-Approval StudiesConclusion • Post-Approval studies are an important source of information to round out safety profile of a drug • Manufacturers need to work closely with regulators on design and interpretation of key studies • Risk assessment can be used to identify subgroups of patients at risk – gives a more favorable benefit-risk balance • Industry is interested in working to improve the tools available for post-marketing studies