1. Multi-dose Analgesic Development for Acute Pain A Brief to the FDA Arthritis Committee July 30, 2002 Najib Babul, PharmD

2. Conflict of Interest Statement Pharmaceutical sponsors with submissions or pending submissions before Divisions 550 and 170 Funding: No external funding Views expressed are solely those of TheraQuest Biosciences

3. Najib Babul, PharmD Single-Dose Evaluation in Acute Pain Screen patient Initiate acute insult Recovery Pain stimulus threshold Dose patient Evaluate response over one dose Terminate assessments after dosing interval or first rescue

4. Najib Babul, PharmD What about multidose evaluation in acute pain?

5. Najib Babul, PharmD Multidose Analgesic Evaluation Growing request for data “Rhetoric” far outpaces the “science” Objectives: Establish efficacy? Demonstrate effectiveness? Establish dosing frequency? Test draft Package Insert? Evaluate safety?

6. Najib Babul, PharmD Challenges to Multidose Evaluation in Acute Pain Natural trajectory Assay sensitivity Reduced hospitalization Reduced postsurgical pain Consent to multidose placebo control “Data contamination” with rescue use Shortage of trained analgesic observers/raters Approaches to data analysis

7. Najib Babul, PharmD Proposed Solutions Use only active controls Use pseudo-placebos Rescue analgesic consumption as an endpoint Integrate rescue and pain assessment data Substitute serial assessments with pain recall Use take-home diaries

8. Najib Babul, PharmD Integration of Pain and Rescue: Rationale Traditional studies discard data after first rescue Rescue confounds analgesic response evaluation Rescue differentially confounds data within and between treatment groups (single and multiple dose phases) How to evaluate analgesic response in the face of rescue? Integrate pain and rescue scores

9. Najib Babul, PharmD Use of Pain Recall Instruments Pain recall is prominent in diagnosis and Rx Validity of pain recall viewed as “suspect” Recall frequently used in chronic pain RCT’s Frequent serial pain assessments the norm in acute pain RCT’s Hourly assessments a challenge in multidose studies Are less frequent assessments a substitute?

10. Najib Babul, PharmD Study Design 88 patients  77 evaluable Orthopedic surgery Hourly pain intensity VAS assessments (pain now) for 48 hours 24 and 48 hour assessments of “Worst” (maximum), “Least” (minimum) and “Usual” (average) pain Babul et al. Annals of Pharmacotherapy 1993;27:9-12 & Pain 1994;57:131-32

11. Najib Babul, PharmD Experienced vs Recalled Pain Intensity Actual and Recalled Pain Intensity 0-24h0-48h Pain Intensity on VAS(mean+ SE) (mean+SE) Worst (recall)65.4+SE)60.2+3.4 Maximum (hourly VAS)66.2+2.8 66.7+2.8 Difference b -0.8+1.7 -6.4+1.9 c Least (recall)9.7+1.25.0+0.9 Minimum (hourly VAS)9.4+1.2 4.3+0.8 Difference b 0.3+0.7 0.6+0.5 Usual (recall)31.4+2.1 25.2+2.1 Mean (hourly VAS)32.1+1.9 25.8+1.8 Difference b -0.6+0.9 0.6+1.0 a n=77. b Mean recall variable minus corresponding mean hourly VAS variable. c p=0.001 Babul et al. Annals of Pharmacotherapy 1993;27:9-12 & Pain 1994;57:131-32

12. Rescue Analgesic Consumption: Is it a Suitable Endpoint?

13. Rofecoxib Postorthopedic Surgical Pain (Days 2-5) * P=0.005 rofecoxib 50 mg compared with placebo. Data on file. Lortab 7.5 mg Use Postsurgery Mean % 20 40 60 80 Placebo(n=53) Rofecoxib 50 mg (n=54) Patients With Good to Excellent Response 0 1 2 3 4 Placebo(n=53) Rofecoxib 50 mg (n=54) Mean Tablets/Day ± SE * 0 * P=0.005 rofecoxib 50 mg compared with placebo. Data on file. Lortab 7.5 mg Use Postsurgery Mean % 20 40 60 80 Placebo(n=53) Rofecoxib 50 mg (n=54) Patients With Good to Excellent Response 0 1 2 3 4 Placebo(n=53) Rofecoxib 50 mg (n=54) Mean Tablets/Day ± SE * 0 Najib Babul, PharmD

15. 71 mg ± 7 Rofecoxib 107 mg ± 17Celecoxib 117 mg ± 13Placebo Morphine UsedGroup Total Morphine Used for 24 Hours Anesth Analg. 2000;91: 1221-1225. MORPHINE CONSUMPTION Pre-operative Analgesia with Rofecoxib and Celecoxib