1. 1 Presented by Kenneth M. Verburg, Ph.D. at the Arthritis Advisory Committee meeting 07/29/02

2. 2 Development of New Guidelines for Analgesics/Drugs Intended for the Treatment of Pain General CommentsGeneral Comments Chronic PainChronic Pain Acute PainAcute Pain

3. 3 New Guidelines: Considerations Mechanistic differences in:Mechanistic differences in: –Type of pain (nociceptive, neuropathic pain) –Nociceptive pain- unclear differences between somatic and visceral pain –Chronicity of pain (acute vs chronic) –Pain severity (differences across models) Different classes of analgesics (monotherapy vs multi-modal) and sites of actionDifferent classes of analgesics (monotherapy vs multi-modal) and sites of action

4. 4 New Guidelines: Objectives Expedite development of therapies to meet the clear unmet medical needExpedite development of therapies to meet the clear unmet medical need Efficient programs that provide the information needed for registrationEfficient programs that provide the information needed for registration Consider conditions of clinical practiceConsider conditions of clinical practice –Pre-operative and/or post-operative administration –Multi-modal analgesic regimens for certain conditions –Differences in treatment of acute vs chronic pain

5. 5 Development of New Guidelines for Analgesics/Drugs Intended for the Treatment of Pain General CommentsGeneral Comments Chronic PainChronic Pain Acute PainAcute Pain

6. 6 Experience with Chronic Pain Models Osteoarthritis/rheumatoid arthritisOsteoarthritis/rheumatoid arthritis Low back painLow back pain Ankylosing spondylitisAnkylosing spondylitis Neuropathic pain (post-herpetic neuralgia, painful diabetic neuropathy)Neuropathic pain (post-herpetic neuralgia, painful diabetic neuropathy) Cancer painCancer pain

7. 7 Approach to the determination of efficacy:Approach to the determination of efficacy: –Pain intensity assessment; –Global assessment –Function/disability assessment Limited number of models suitable for study of 3 months durationLimited number of models suitable for study of 3 months duration –Extended placebo treatment Models chronic intermittent pain: endpoints/ duration of treatment and/or number of cyclesModels chronic intermittent pain: endpoints/ duration of treatment and/or number of cycles Define safety requirementsDefine safety requirements Chronic Pain – Points for Consideration

8. 8 Due to the heterogenous nature of chronic pain conditions, consider a tiered approach with:Due to the heterogenous nature of chronic pain conditions, consider a tiered approach with: –A separate indication for each condition with replicate studies –An indication of chronic musculoskeletal pain with a single study in 3 chronic musculoskeletal models –A general chronic pain indication with a single study in 2 chronic musculoskeletal models and a single study in 2 neuropathic models Chronic Pain – Points for Consideration

9. 9 Development of New Guidelines for Analgesics/Drugs Intended for the Treatment of Pain General CommentsGeneral Comments Chronic PainChronic Pain Acute PainAcute Pain

10. 10 Experience With Acute Pain Models ModelAdvantagesLimitations Dental Pain Low placebo response lends itself to single dose assessments Limited multiple dose utility due to finite duration of moderate to severe pain Post-surgical (abdominal or orthopedic) pain Duration of pain suitable for multiple dose assessment Experience with COX-2’s and opioids suggest good model for combination therapy High placebo response limits determination of analgesia onset Musculoskeletal Pain (OA flare, acute tendinitis) Duration of pain suitable for multiple dose efficacy monotherapy assessment Despite severity of disease, demonstrating single dose efficacy with traditional measures is difficult Primary Dysmenorrhea Multiple-dose intermittent model suitable for onset and duration Pain self-limiting therefore limitations for multiple dose assessment

11. 11 Demonstrating Single Dose Efficacy in Acute Pain Current guidelines provide adequate criteria to evaluate single dose analgesic efficacyCurrent guidelines provide adequate criteria to evaluate single dose analgesic efficacy –Replicate studies in dental pain and post- surgical pain –Well-defined efficacy measures assessing onset, extent, and duration of analgesia –Time to onset of analgesia should be <1 hour –Time to rescue medication is used to support dose regimen on Day 1 and subsequent days

12. 12 Criteria to demonstrate multiple dose efficacy (an effective regimen) are less well defined in current guidelinesCriteria to demonstrate multiple dose efficacy (an effective regimen) are less well defined in current guidelines Study Design/Conduct ConsiderationsStudy Design/Conduct Considerations –Self-limiting nature of pain in some models –Severity of initial pain in some models may not be controlled by monotherapy Demonstrating Multiple Dose Efficacy in Acute Pain

13. 13 Worst Pain in Past 24 Hours % of Patients Mod to Severe Pain 0 25 50 75 100 * Significantly lower than placebo (p<0.05) Day 2 Day 3 Day 4 Day 5 Day 6 Days Post-surgery * * Active Placebo Laparoscopic Cholecystectomy

14. 14 Multi-modal Analgesia Obtain additional clinical benefit by controlling pain with agents from two or more classesObtain additional clinical benefit by controlling pain with agents from two or more classes –Operating through different mechanisms or different sites Efficacy measures vs monotherapy:Efficacy measures vs monotherapy: –Reduced medication requirements –Improved analgesia –Reduce adverse effects –Improved patient global assessment

15. 15 Hours Pain Intensity Difference* * Categorical Scale PI Scale = 0 (none) - 3 (severe) J Morphine + Active 0.5x H Morphine + Active 1x Morphine alone B Total Knee Arthroplasty Mean Score -0.50 0 0.50 1.00 4288162032361224048 BB BBBBB B B JJ J J J J J JJ H H H H H H H H H 0.75 0.25 -0.25 Active 0.5x vs Pbo Active 1x vs Pbo p<0.05

16. 16 Acute Pain – Points for Consideration One acute pain model does not fill all criteria for determination of single dose and multiple dose efficacyOne acute pain model does not fill all criteria for determination of single dose and multiple dose efficacy –Specify which models are best to define: onset, peak effect and duration –Specify compartmental approaches for pain studies e.g. single-dose, multi-dose on day 1 and subsequent days –Propose models best for monotherapy vs combination therapy

17. 17 Specify what acute pain models are needed to obtain broad acute pain indication: by severity and/or etiologySpecify what acute pain models are needed to obtain broad acute pain indication: by severity and/or etiology Specify how many models and whether replication is needed in each. If models are of similar etiology only one model should need replicationSpecify how many models and whether replication is needed in each. If models are of similar etiology only one model should need replication Define safety requirements for acute pain (alone or in combination with chronic pain)Define safety requirements for acute pain (alone or in combination with chronic pain) Acute Pain – Points for Consideration