1. The Impact of IMMPACT Bob A. Rappaport, M.D. Director Division of Anesthesia, Analgesia and Rheumatology Products Center for Drug Evaluation and Research Food and Drug Administration American Society for Experimental Neurotherapeutics Workshop on Disease Specific Clinical Trial Think Tanks March 9, 2007 Washington, D.C.

2. FDA and IMMPACT In the beginning… A brief history of analgesics at FDA –Neuropharmacology –Pilot Drugs –Anesthesia vs Analgesia ‘96 –White Oak Reorganization ’05 –The new DAARP

3. IMMPACT Initiative on Methods, Measurements and Pain Assessments in Clinical Trials http://www.immpact.org/ Co-Chairs: Dennis Turk, Ph.D. (University of Washington) and Robert Dworkin, Ph.D. (University of Rochester)

4. FDA and IMMPACT Reps at every meeting (DAARP; SEALD team) Our role: –Provide regulatory insight –Provide insight as to what we need Trial design Drug development –Comment on proposals –We do not approve any decisions or recommendations –Although we do put our names on the publications (with a disclaimer)

5. IMMPACT I and II: Core Outcome Domains Clear agreement: Pain is #1 Much debate about what level of importance for each of the others –E.g., function – should it be a required outcome? How did we resolve this? –Each domain should be included in a study unless a justification is provided as to why it was not necessary in this case –Not a regulatory requirement!

6. IMMPACT I & II: Core Outcome Domains Of course, pain has always been #1 for us We request that sponsors include the other domains (as appropriate) –As secondary outcome measure –Must trend in the right direction, but statistical significance not required Examples of how this has influenced us –Stopped requiring multiple primaries for pain of RA, OA, etc. –Evaluation of “clinical significance” based on secondary outcomes

7. IMMPACT III: Metrics Process VAS most commonly used (except for rheum endpoints: WOMAC) –Not the most reliable for particular populations –NRSs more reliable and equally sensitive/specific –We allow either for most studies as populations of concern less prominent in pivotal efficacy studies for approval Children are not little adults –Faces Scale: Wong-Baker vs. the Modified Faces Scale

10. IMMPACT III: Metrics Children are not little adults –No validated scales for neonates –Even less validity of available metrics for other domains

11. IMMPACT III: Metrics Objective data?…not likely – Need to validate PROs! –PRO Guidance Document: http://www.fda.gov/cd er/guidance/index.htm –E.g., a new scale has been studied and validated after collaborative efforts: Standard treatment results in unpleasant, potentially harmful side effect Novel product to reduce that side effect But, for the most part, the effect and counter-effect are PROs Studies designed to validate the outcome measures Approved by Agency Validation successful! Efficacy studies ongoing

12. IMMPACT IV: Clinically Meaningful Differences What were we thinking? What we learned –Not really possible to define MIDs for measures of central tendency The impact: –No further minimal clinical difference requirement on measures of central tendency Although secondaries must be supportive –Request Cumulative Proportion of Responders Analysis for all chronic pain trials –CPRAs in labels, even though not primary

13. CPRA for Lyrica

14. IMMPACT V: Multiple Endpoints and Multiple Comparisons Defined acceptable statistical analysis methodologies Compared and contrasted the problems associated with multiplicity Outcomes?

15. IMMPACT VI: Clinical Trial Designs “Placebo-Controlled Designs and Their Alternatives” Our major impact: No non-inferiority trials! Missing data in some (opioid) chronic pain trials complicates design –Randomized withdrawal (incorporating features to account for opioid withdrawal) –Enriched enrollment –The Totally Titratable Trial

16. washout baseline titration Painacea™ Placebo Week 2* * Taper off drug complete Week 12** ** Endpoint for analysis A Successful New Trial Design

17. Peds IMMPACT Reviewed most of the topics previously discussed, but from a pediatric perspective Came to the same conclusions in most cases Assessed the information that is still missing (e.g., the scales for neonates)

18. Planned IMMPACT VII Acute Pain issues –Domains and outcome measures –Length of trials –Appropriate clinical “models” What we won’t ask –How many trials for a specific indication? –What are the correct indications?

19. The Impact of IMMPACT An essential collaborative effort Open door? No, but→Transparency Exploration followed by Validation The (draft) Analgesic Drug Development Guidance Document A wealth of opportunity for communication, and Advancing the science, approving new analgesic drug products

20. OMERACT “Outcome Measures in Rheumatology” (originally, “Outcome Measures in Rheumatoid Arthritis Clinical Trials”) Developed ACR20 for RA clinical trials –Expert opinion on “paper patients” –Delphi technique –Other methodologies

21. OMERACT Developed standards for metrics in SLE –Recommended validated instruments for domains –Developed “disease activity” measures –Recently, involvement of patient reps Developed the Pediatric ACR30, the current standard metric for JRA outcomes

22. Other Collaborative Efforts in Rheumatology ACR consensus group developed highly sensitive metric for improvement in RA Consensus group on outcome measures in AS GRAPPA – consensus group on outcome measures in PA EULAR – requested our participation in consensus group on conduct of clinical trials in RA Thanks, Jeff Siegel!