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. 2 DisclosuresDisclosures 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 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. 3 BackgroundBackground 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” 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. 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” Progression-free survival (PFS) composite endpoint 1. Radiographic progression OR: 2. Skeletal-related events OR: 3. “Symptomatic progression”

5. 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” “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. 6 Proposed Claim in NDA 21-801 “Pain progression” 3 rd -level composite endpoint i. Increased “Present Pain Intensity” (PPI) score OR: ii. Increased opioid use “Pain progression” 3 rd -level composite endpoint i. Increased “Present Pain Intensity” (PPI) score OR: ii. Increased opioid use

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

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

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

10. 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 Report average pain intensity over the past 24 hours: 1-Mild 2-Discomforting 3-Distressing 4-Horrible 5-Excruciating

11. 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% 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. 12 Methodologic Issues 1.Questionnaire 2.Study design 3.Results 1.Questionnaire 2.Study design 3.Results

13. 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. 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. 14 ValidityValidity 1.Content validity 2.Construct validity 1.Content validity 2.Construct validity

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

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

18. 18 ReliabilityReliability Reproducibility Ability to detect change Reproducibility Ability to detect change

19. 19 Item “Tweaking” Altered from original PPI ORIGINALSATRAPLATIN Rate over 24-hoursWorst PPI scoreAverage PPI score Altered from mitoxantrone and docetaxel* MITOXANTRONESATRAPLATIN Primary EndpointPain Relief: 2-point PPI decrease from baseline, or 1  0 Pain Progression: 1-point PPI increase from baseline, or 2 from nadir Opioid Endpoint50% reduction Non-narcotics included 25% increase No non-narcotics Duration of response3 weeks2 weeks *Progression endpoint: no results provided

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

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

22. 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? 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. 23 Time to pain progression (TTPP) 2° endpoint events: Satraplatin (n=635) Placebo (n=315) Absolute Difference TTPP events overall217/635 (34%)130/315 (41%)7% PPI score increase114/635 (18%)57/315 (18%)0% Opioid dose increase103/635 (16%)73/315 (23%)7% Between-group difference in TTPP events overall is driven only by opioid use Clinical Relevance

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

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