1. Analgesic Drug Development for Chronic Pain A Brief to the FDA Arthritis Advisory Committee July 29, 2002 Najib Babul, PharmD

2. Conflict of Interest Statement Pharmaceutical sponsors with submissions or pending submissions before Divisions 550 and 170. Views expressed are solely those of TheraQuest Biosciences

3. Najib Babul, PharmD Analgesic Drug Development: Regulatory Framework FDA Guideline for the Evaluation of Analgesic Drugs (December, 1992) EMEA Guidance on Clinical Investigation of Medicinal Products for Treatment of Pain (CPMP Draft, November 2001)

4. Najib Babul, PharmD Supportive Guidelines Clinical development programs for drugs, devices and biological products intended for the treatment of osteoarthritis (FDA Guidance, July 1999) Clinical investigation of medicinal products used in the treatment of osteoarthritis (CPMP PTC, July 1998)

5. Najib Babul, PharmD Gaps in FDA Analgesic Drug Development Regulatory Framework Multidose evaluation in acute pain Slow-onset drugs with utility in acute pain Drugs for neuropathic pain Drugs for cancer pain Guidance for CLBP, fibromyalgia, myofascial pain Chronic pain as an indication

6. Najib Babul, PharmD Potential Models of Chronic Pain Myofascial pain Low back pain Osteoarthritis Fibromyalgia Mixed-model population Neuropathic pain* Cancer pain*

7. Najib Babul, PharmD Response Assessment in Chronic Pain Challenges for Drug Developers Diverse etiology Heterogeneous population within diagnosis Referral patterns Psychological overlay Disability payments and litigation “Unrealistic” outcomes expectations

8. FDA Division 550 has recently suggested replicate evidence in 3 chronic pain states (models) for a chronic pain indication What are the potential implications of this? Najib Babul, PharmD

9. Chronic Pain Indication Absence of established models to provide evidence in 3 models Replicate evidence for a specific sub-indication may be appropriate Replication in two models of chronic pain OR robust and internally consistent evidence in single trials in three models If burden too high for a broad indication, will get sub-indications with attendant off-label use

10. Najib Babul, PharmD Additional Considerations Use of co-primary endpoints  Pain, function, global  Some precedence in OA  Increased statistical burden  May be unrealistic pharmacologic expectation for complex disorders Placebo-control vs. active control Clinimetric flexibility

11. Summary FDA Divisions 550 & 170 face somewhat different issues:  Abuse liability, neuropathic pain  GI and CV outcomes, inflammatory pain, disease modification However, harmonization across Divisions is important to assure cost-effective development, parity and timely patient access Sponsors with clinical development underway or submissions need special consideration Najib Babul, PharmD