1. Risk Assessment Public Meeting - 4/9/03 1 Premarketing Risk Assessment Robert J. Meyer, MD Director, ODE II / OND / CDER Chair of RA Working Group

2. Risk Assessment Public Meeting - 4/9/03 2 Group 1 - Premarketing Risk Assessment WG: Bob Meyer*Barbara Gould – PM Mary Willy*Ellis Unger * George Rochester Mark Avigan David GrahamJerry Phillips Donna Griebel Robert Temple Zili Li Judy Racoosin Peter Lee David Cho Trish Rohan Janice Newcomb, Aileen Ciampa, Lois Chester

3. Risk Assessment Public Meeting - 4/9/03 3 Premarketing Risk Assessment Presentations:Presentations: –Generating Risk Information General Considerations - Bob MeyerGeneral Considerations - Bob Meyer Special Considerations - Bob TempleSpecial Considerations - Bob Temple –Reporting Risk Information Analyzing and Presenting Risk Information - Ellis UngerAnalyzing and Presenting Risk Information - Ellis Unger

4. Risk Assessment Public Meeting - 4/9/03 4 Premarketing Risk Assessment For Each Topic:For Each Topic: –FDA presentation –Public Comment Period –Panel Discussion (with questions from the attendees)

5. Risk Assessment Public Meeting - 4/9/03 5 Premarketing Risk Assessment What is Risk Assessment?What is Risk Assessment? –Risk assessment is the process of identifying, estimating and evaluating the nature and severity of risk from a product –Good risk assessment underlies good risk management and pharmacovigilance

6. Risk Assessment Public Meeting - 4/9/03 6 Premarketing Risk Assessment Concept Paper and Talk Does NOT cover:Concept Paper and Talk Does NOT cover: –Pre-clinical and clinical pharmacology aspects of development –Efficacy considerations –Post-marketing risk assessment

7. Risk Assessment Public Meeting - 4/9/03 7 Premarketing Risk Assessment Appropriate size of safety database Ideal Size depends on:Ideal Size depends on: –Novelty of the product –Proposed Indication life-sustaining vs. symptom relieflife-sustaining vs. symptom relief –Intended duration of use –Safety concern from pre-clinical, early clinical findings

8. Risk Assessment Public Meeting - 4/9/03 8 Premarketing Risk Assessment ICH E-1 has guidance on long-term treatments (chronic or intermittent, recurrent) for non-life threatening conditionsICH E-1 has guidance on long-term treatments (chronic or intermittent, recurrent) for non-life threatening conditions –1500 patients total, with –300 - 600 for 6-months, 100 for one year

9. Risk Assessment Public Meeting - 4/9/03 9 Premarketing Risk Assessment ICH E-1 does NOT specify what patients should be regarded as contributing to this 1500 patient targetICH E-1 does NOT specify what patients should be regarded as contributing to this 1500 patient target –For chronic use drugs, should come from multiple dose studies of reasonable duration (e.g., 4 weeks or more) –Should be exposed to doses at or above lowest proposed dose

10. Risk Assessment Public Meeting - 4/9/03 10 Premarketing Risk Assessment Rule of Three tells us that for a 1,500 patient database, we have a reasonable chance of identifying a particular event that occurs at a rate of 1 / 500!Rule of Three tells us that for a 1,500 patient database, we have a reasonable chance of identifying a particular event that occurs at a rate of 1 / 500! Yet, drugs commonly are used by thousands to millions of patients shortly after releaseYet, drugs commonly are used by thousands to millions of patients shortly after release

11. Risk Assessment Public Meeting - 4/9/03 11 Premarketing Risk Assessment When are ICH targets not enough?When are ICH targets not enough? ICH: –Cause for concern for time related effect on safety –Need to quantify low-frequency events –Limited or unknown efficacy –Where there is concern that a product may add to a background rate of morbidity/mortality

12. Risk Assessment Public Meeting - 4/9/03 12 Premarketing Risk Assessment When are ICH targets not enough?When are ICH targets not enough? FDA: –Preventive treatments –A very safe alternative already exists –There is a potential for a large market and very fast uptake into the marketplace, particularly for a drug for a non-life-threatening, non- serious condition

13. Risk Assessment Public Meeting - 4/9/03 13 Premarketing Risk Assessment For acute use therapies and/or those for life-threatening diseases, no ICH or FDA guidance exitsFor acute use therapies and/or those for life-threatening diseases, no ICH or FDA guidance exits For life-saving products with mortality trials, these data alone may be enough to demonstrate acceptable risk/benefitFor life-saving products with mortality trials, these data alone may be enough to demonstrate acceptable risk/benefit Accelerated approval - definitive efficacy and full safety may come laterAccelerated approval - definitive efficacy and full safety may come later

14. Risk Assessment Public Meeting - 4/9/03 14 Premarketing Risk Assessment What are the Characteristics of an ideal safety database?What are the Characteristics of an ideal safety database? –Controlled trials performed throughout –Diverse population (age, race/ethnicity, concomitant disease, drugs….) –Range of doses explored throughout development

15. Risk Assessment Public Meeting - 4/9/03 15 Premarketing Risk Assessment What are the Characteristics of an ideal safety database? Controlled trials performed throughoutWhat are the Characteristics of an ideal safety database? Controlled trials performed throughout –essential for detecting treatment relation to common outcomes in the population –helps address confounding by indication –With active comparator, opportunity to judge safety vs. accepted (approved) therapy

16. Risk Assessment Public Meeting - 4/9/03 16 Premarketing Risk Assessment What are the Characteristics of an ideal safety database? Diverse PopulationWhat are the Characteristics of an ideal safety database? Diverse Population –Only patients with obvious contraindications excluded in late phase trials –Allows for better generalizability of safety findings –Develop better clinical data on Rx-demographic, Rx - disease and Rx - Rx interactions

17. Risk Assessment Public Meeting - 4/9/03 17 Premarketing Risk Assessment What are the Characteristics of an ideal safety database? Range of doses studied throughout developmentWhat are the Characteristics of an ideal safety database? Range of doses studied throughout development –Better characterize clinical exposure-response relationship (dose finding not complete at EOP-2) –May help provide important E-R data for dose adjustments in subpopulations –(Also may add important information on the assessment of efficacy - maximizing benefit vs. risk)

18. Risk Assessment Public Meeting - 4/9/03 18 Premarketing Risk Assessment To detect potential interactions not previously identified, sponsors should:To detect potential interactions not previously identified, sponsors should: –Be vigilant for drug-drug interactions, particularly for likely concomitant medications (e.g., binding resins and HMG- CoA reductase inhibitors) –Product -demographic interactions (diverse population studied)

19. Risk Assessment Public Meeting - 4/9/03 19 Premarketing Risk Assessment To detect potential interactions not previously identified, sponsors should:To detect potential interactions not previously identified, sponsors should: –Product-disease interactions (study range of disease and concomitant diseased patients) –Product-food interactions –Product-dietary supplement interactions (for popular supplements for the disease in question)

20. Risk Assessment Public Meeting - 4/9/03 20 Premarketing Risk Assessment To help detect potential interactions:To help detect potential interactions: –An important way of providing data to inform about unanticipated interactions is to perform drug level (e.g., population PK) assessments in phase 3 trails –Could help define E-R relationship for S+E (help validate biomarkers) –Could help define drug level relationship to any unusual, rare AE

21. Risk Assessment Public Meeting - 4/9/03 21 Premarketing Risk Assessment When would comparative safety data be useful?When would comparative safety data be useful? –Expected with some classes of products (e.g., preventive vaccines) –Need to characterize background rates –When there is a well established, well- characterized low toxicity product

22. Risk Assessment Public Meeting - 4/9/03 22 Premarketing Risk Assessment When would comparative safety data be useful?When would comparative safety data be useful? –Where there is a well-established, related therapy –Where there is an established therapy with effect on survival or altering irreversible morbidity –When the sponsor wishes to make comparative claims

23. Risk Assessment Public Meeting - 4/9/03 23 Premarketing Risk Assessment ConclusionConclusion –Pre-marketing Risk Assessment relatively mature, but still evolving –Public Health, Industry and FDA would all benefit from optimizing Risk Assessment allowing for approval of safe drugs with fully informative labeling