1. Analgesic Drug Development: Towards a Core Development Program NIH-FDA Analgesic Drug Development Workshop Bethesda, MD March 13, 2002 Najib Babul, PharmD

2. Najib Babul, PharmD (Mar 13, 2002) 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)

3. Najib Babul, PharmD (Mar 13, 2002) 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) Clinical investigation of slow-acting anti-rheumatic medicinal products used in the treatment of rheumatoid arthritis (CPMP PTC, Dec 1998)

4. Drug Development Framework Acute Pain Najib Babul, PharmD (Mar 13, 2002)

5. Traditional Analgesic Models Third molar extraction* Mixed general surgery* Mixed orthopedic surgery* Abdominal hysterectomy* C-section* Total hip arthroplasty Total knee arthroplasty Outpatient surgery Musculoskeletal injury Migraine headache Tension headache Dysmenorrhea*

6. Najib Babul, PharmD (Mar 13, 2002) Other Acute Pain States Herniorrhaphy Open cholecystectomy Lap. cholecystectomy Thoracotomy Prostatectomy TURP Renal colic Lap-assist. vag. hysterectomy Mixed lap. surgery Lumbar laminectomy Trauma pain Arthroscopic surgery Sickle cell crisis Burn pain Tonsillectomy Appendectomy Venipuncture Bone marrow biopsy Mastectomy

7. Najib Babul, PharmD (Mar 13, 2002) Issues With Acute Pain Models Mixed surgery vs. specific surgery Drugs with delayed onset Drugs for neuropathic pain or “dual purpose” drugs Opioid analgesic efficacy in dental pain Multidose evaluation (rhetoric vs. “science”) Generalizabilty to major surgery and SOC Time-effect curve replication in other models Generalizabilty to chronic pain

8. Analgesic Evaluation in Chronic Pain Najib Babul, PharmD (Mar 13, 2002)

9. Operational Definition for Clinical Trials Taxonomy Cancer pain Neuropathic pain Chronic inflammatory pain states Chronic non-inflammatory pain states Chronic (non-malignant) pain

10. Najib Babul, PharmD (Mar 13, 2002) Potential Models of Chronic Pain Myofascial pain Low back pain Osteoarthritis Visceral pain Fibromyalgia Cancer pain* Neuropathic pain*

11. Najib Babul, PharmD (Mar 13, 2002) Response Assessment in Chronic Pain: Challenges Diverse etiology Heterogeneous population within diagnosis Referral patterns Psychological overlay Pain, suffering vs. pain-behaviors Disability payments and litigation “Unrealistic” outcomes expectations Pain Relief vs. QOL vs. functional restoration

12. Potential Approaches to Analgesic Evaluation in Chronic Pain Najib Babul, PharmD (Mar 13, 2002)

13. Osteoarthritis Najib Babul, PharmD (Mar 13, 2002)

14. 6-Week Phase III OA Study Pain Walking on a Flat Surface Week -50 -45 -40 -35 -30 -25 -20 -15 -10 -5 Screen Randomize 24 6 P Mean Change (WOMAC 100-mm VAS) Baseline Mean = 75 mm on VAS More Pain Less Pain Saag et al. Arthritis Rheum. 1998;41(suppl):S196. Rofecoxib 12.5 mg Placebo Ibuprofen 2.4 g Rofecoxib 25 mg. p<0.05 for all active groups vs. placebo.

15. Najib Babul, PharmD (Mar 13, 2002) Comparative Effect Size in Osteoarthritis (%) Index Joint Pain Intensity Babul and Peloso, ASCPT, Atlanta March 2002

16. Najib Babul, PharmD (Mar 13, 2002) Chronic Low Back Pain

17. Najib Babul, PharmD (Mar 13, 2002) Etiology of Low Back Pain Idiopathic70% Degenerative10% Disk herniation2-4% Spinal stenosis3% Osteoporosis (compression fracture) 4% Spondylolisthesis2% Deyo and Weinstein. N Engl J Med 2001;344-363

18. Najib Babul, PharmD (Mar 13, 2002) Results: Low Back Pain Intensity Scale (VAS) Study Week Mean change from baseline (± SE) P<0.001 rofecoxib vs placebo Ju et al, AAPM Presentation 2001 Katz et al APS Presentation 2001 Rofecoxib 50 mg Placebo PPP Rofecoxib 25 mg Mean change from baseline (± SE) Protocol 120 Protocol 121

19. Najib Babul, PharmD (Mar 13, 2002) Analgesic Clinical Trials in Chronic Pain Key Considerations Pain model vs. indication Duration of therapy Population: diagnostic criteria and index joint (OA) Monotherapy or polypharmacy (add on therapy) Washout from analgesics vs. flare design Fixed-dose or dose escalation Value of early (“acute”) response evaluation Rescue analgesia Naïve or opioid tolerant patients Endpoints: Pain, Stiffness (OA), Fxn, HR-QOL, Global

20. Najib Babul, PharmD (Mar 13, 2002) Key Questions Do single dose efficacy data support multi-dose efficacy? Do data in acute pain support efficacy in chronic pain? Is dysmenorrhea an acceptable acute pain model (visceral, intermittent pain or acute pain?) How many chronic pain disorders require evaluation? Is replicate evidence necessary for each chronic pain disorder? Is cancer pain a separate indication? Should neuropathic pain be further fragmented?

21. Najib Babul, PharmD (Mar 13, 2002) Core Development Program [505 (b) (1)] for Acute Pain Present standard: Two, adequate & well controlled studies (one model or two models?) It is possible to get approval for an “acute pain” claim without:  convincing efficacy data with repeated dosing  data from a hospitalized/critically ill population  standard of care positive control  data from non-surgical acute pain states

22. Najib Babul, PharmD (Mar 13, 2002) Core Development Program [505 (b) (1)] for Acute Pain Well designed, dose finding data in two models, one of which must be (inpatient) major surgery Plus Evidence of efficacy and safety in at least four studies, including at least one study each in major orthopedic surgery or thoracic surgery and major abdominal or gynecolgic surgery Plus Evidence of safety in both ambulatory and critically ill patients

23. Najib Babul, PharmD (Mar 13, 2002) Core Development Program [505 (b) (1)] for Chronic Pain Dose (and dosing frequency) finding studies in at least two models of chronic pain plus Replicate evidence of 12-week efficacy in at least two models of chronic (non-malignant) pain plus Replicate evidence of 2-week efficacy in cancer pain or one 4-week non-inferiority and one 2-week superiority (placebo or pseudo-placebo controlled) study plus Cognitive impairment evaluation with acute and chronic dosing (for centrally acting drugs) plus Safety in cancer and chronic non-malignant pain

24. Najib Babul, PharmD (Mar 13, 2002) Towards a Core Development Program in Analgesia Should the approach be guided largely by drug development & commercial considerations? (safety + efficacy = drug approval) What are the implications of such an approach?  Broad indication with limited studies  Narrow indication (3 rd molar)  Rapid time to market  Potentially inadequate exploration of drug effect  Off-label use beyond narrow indication

25. Najib Babul, PharmD (Mar 13, 2002) Analgesic Evaluation in the Multidose and Chronic Pain Setting Summary: Efficacy evaluation of analgesics in single dose acute pain models is well established Efficacy evaluation of analgesics in the multi-dose acute pain setting is achievable with design modifications Several models are now available for efficacy evaluation of analgesics in chronic pain Further research is needed to determine optimal endpoints to optimize separation from placebo Core development program for acute and chronic pain needs to be (re)evaluated