Methods used to assess and report pain-related endpoints in NDA 21-801

1. Methods used to assess and report pain-related endpoints in NDA 21-801 Ethan Basch, MD, MSc Center for Drug Evaluation and Research

2. Disclosures • Current position • Memorial Sloan-Kettering Cancer Center • Medical oncologist • Patient-reported outcomes research • Current role • Uncompensated FDA Guest Worker • Research funding • NCI, ASCO, DOD, NY State • Financial disclosures: None

3. Background • Pain is an important endpoint in metastatic prostate cancer • Methodologically challenging • Draft FDA Guidance for Industry • “Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims”

4. Proposed Claim in NDA 21-801 • Progression-free survival (PFS) composite endpoint 1. Radiographic progression OR: 2. Skeletal-related events OR: 3. “Symptomatic progression”

5. Proposed Claim in NDA 21-801 • “Symptomatic progression” 2nd-level composite endpoint 1) Worsened performance status OR: 2) 10% Weight loss OR: 3) Clinical events attributable to prostate cancer OR: 4) “Pain progression”

6. Proposed Claim in NDA 21-801 • “Pain progression” 3rd-level composite endpoint i. Increased “Present Pain Intensity” (PPI) score OR: ii. Increased opioid use

7. Phase III trial: GPC SAT-03-01 • RCT of satraplatin + prednisone vs. placebo + prednisone, as second-line chemotherapy • 51% received prior docetaxel

8. Pain Assessment in GPC SAT-03-01 Opioid use “PPI” score

9. “Present Pain Intensity” (PPI) Item • Single question • Plucked from McGill Pain Questionnaire • Developed in 1970s • Used in mitoxantrone approval

10. “Present Pain Intensity” (PPI) Item • Report average pain intensity over the past 24 hours: 1-Mild 2-Discomforting 3-Distressing 4-Horrible 5-Excruciating

11. Data Analysis • Calculated weekly average PPI scores • Calculated weekly average opioid scores • “Pain progression” = 2 consecutive weeks: Increase in weekly average PPI score by 1-point from baseline OR 2-points from PPI nadir OR: Increase in weekly average opioid score by 25%

12. Methodologic Issues • Questionnaire • Study design • Results

13. Support Materials Submitted • Melzac, 1975:Melzac R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975;1:277-299. • Graham, 1980:Graham C, Bond S, Gerkovich M, Cook M. Use of the McGill Pain Questionnaire in the assessment of cancer pain: replicability and consistency. Pain 1980;8:377-387. • Tannock, 1996:Tannock I, Osaba D, Stocker M, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;14:1756-1764. • Tannock, 2004:Tannock I, de Wit R, Berry W, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. NEJM 2004;351:1502-1512. • Berthold, 2006 (abstract):Bethold DR, Pond G, de Wit R, et al. Association of pain and quality of life response with PSA response and survival of patients with metastatic hormone refractory prostate cancer treated with docetaxel or mitoxantrone in the TAX-327 study. 2006 ASCO Prostate Cancer Symposium, Abstract No. 140.

14. Validity • Content validity • Construct validity

15. Content Validity • Relevance to study population • Interpretable by patients • Map to clinical states • Essential to include patient input 1-Mild 2-Discomforting 3-Distressing 4-Horrible 5-Excruciating

16. Construct Validity • Compare with independent similar measure • Discriminate between clinically distinct patient groups in terms of concept of interest • Poor correlation with other domains

17. Validity • Mitoxantrone and docetaxel papers • Not evaluated • Treatment trials • No dedicated patient interviews • Primary pain endpoint model in satraplatin application differs

18. Reliability • Reproducibility • Ability to detect change

19. Item “Tweaking” Altered from original PPI Altered from mitoxantrone and docetaxel* *Progression endpoint: no results provided

20. Score Averaging • Averaged PPI scores over each 1-week period (DISTRESSING + EXCRUCIATING)/2 =?= HORRIBLE

21. Language Translation • 16 countries, 10 languages • Language translations by local research assistants • No standardized approach • No prospective confirmatory patient interviews • No “back translations”

22. Establishing Clinical Relevance • Essential for any questionnaire • What PPI score change is meaningful? • “No pain” to “mild pain” meets PFS criteria • Merit use of cytotoxic agent? • Is 25% increase in opioid meaningful? • Merit use of cytotoxic agent?

23. Clinical Relevance Time to pain progression (TTPP) 2° endpoint events: • Between-group difference in TTPP events overall is driven only by opioid use

24. Conclusions • Concerns regarding measurement of pain-related endpoints • Validity • Reliability • Clinical relevance • PFS endpoint comes into question • Blinding

25. Broader Perspective • Sponsor included pain-related endpoints • Important to patients and providers • Difficult to measure • FDA Guidance created to assist sponsors with patient-reported endpoints