methods used to assess and report pain-related endpoints in nda 21-801 ethan basch, md, msc center...
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Methods used to assess and report Methods used to assess and report pain-related endpoints in NDA 21-801pain-related endpoints in NDA 21-801Methods used to assess and report Methods used to assess and report pain-related endpoints in NDA 21-801pain-related endpoints in NDA 21-801
Ethan Basch, MD, MSc Ethan Basch, MD, MSc Ethan Basch, MD, MSc Ethan Basch, MD, MSc
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
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DisclosuresDisclosuresDisclosuresDisclosures
• 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
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BackgroundBackgroundBackgroundBackground
• 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”
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Proposed Claim in NDA 21-801Proposed Claim in NDA 21-801Proposed Claim in NDA 21-801Proposed Claim in NDA 21-801
• Progression-free survival (PFS) composite endpoint
1. Radiographic progressionOR:
2. Skeletal-related eventsOR:
3. “Symptomatic progression”
• Progression-free survival (PFS) composite endpoint
1. Radiographic progressionOR:
2. Skeletal-related eventsOR:
3. “Symptomatic progression”
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Proposed Claim in NDA 21-801Proposed Claim in NDA 21-801Proposed Claim in NDA 21-801Proposed Claim in NDA 21-801
• “Symptomatic progression” 2nd-level composite endpoint
1) Worsened performance statusOR:
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 statusOR:
2) 10% Weight loss OR:
3) Clinical events attributable to prostate cancer
OR: 4) “Pain progression”
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Proposed Claim in NDA 21-801Proposed Claim in NDA 21-801Proposed Claim in NDA 21-801Proposed Claim in NDA 21-801
• “Pain progression” 3rd-level composite endpoint
i. Increased “Present Pain Intensity” (PPI) score
OR:
ii. Increased opioid use
• “Pain progression” 3rd-level composite endpoint
i. Increased “Present Pain Intensity” (PPI) score
OR:
ii. Increased opioid use
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Phase III trial: GPhase III trial: GPC SAT-03-01PC SAT-03-01Phase III trial: GPhase III trial: GPC SAT-03-01PC 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
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Pain Assessment in GPain Assessment in GPC SAT-03-01PC SAT-03-01Pain Assessment in GPain Assessment in GPC SAT-03-01PC SAT-03-01
Opioid use
“PPI” score
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““Present Pain Intensity” (PPI) ItemPresent Pain Intensity” (PPI) Item““Present Pain Intensity” (PPI) ItemPresent 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
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““Present Pain Intensity” (PPI) ItemPresent Pain Intensity” (PPI) Item““Present Pain Intensity” (PPI) ItemPresent 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
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Data AnalysisData AnalysisData AnalysisData 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%
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Methodologic IssuesMethodologic IssuesMethodologic IssuesMethodologic Issues
1. Questionnaire2. Study design3. Results
1. Questionnaire2. Study design3. Results
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Support Materials SubmittedSupport Materials SubmittedSupport Materials SubmittedSupport 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.
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ValidityValidityValidityValidity
1. Content validity2. Construct validity1. Content validity2. Construct validity
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Content ValidityContent ValidityContent ValidityContent 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
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Construct ValidityConstruct ValidityConstruct ValidityConstruct 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
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ValidityValidityValidityValidity
• 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
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ReliabilityReliabilityReliabilityReliability
• Reproducibility
• Ability to detect change
• Reproducibility
• Ability to detect change
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Item “Tweaking”Item “Tweaking”Item “Tweaking”Item “Tweaking”
Altered from original PPIAltered from original PPIORIGINAL SATRAPLATIN
Rate over 24-hours Worst PPI score Average PPI score
Altered from mitoxantrone and docetaxel*Altered from mitoxantrone and docetaxel*MITOXANTRONE SATRAPLATIN
Primary Endpoint Pain Relief:2-point PPI decrease from baseline, or 10
Pain Progression:1-point PPI increase from baseline, or 2 from nadir
Opioid Endpoint 50% reductionNon-narcotics included
25% increaseNo non-narcotics
Duration of response 3 weeks 2 weeks
*Progression endpoint: no results provided*Progression endpoint: no results provided
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Score AveragingScore AveragingScore AveragingScore 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
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Language TranslationLanguage TranslationLanguage TranslationLanguage 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”
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Establishing Clinical RelevanceEstablishing Clinical RelevanceEstablishing Clinical RelevanceEstablishing 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?
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Time to pain progression (TTPP) 2° endpoint events:Satraplatin
(n=635)Placebo(n=315)
Absolute Difference
TTPP events overall 217/635 (34%) 130/315 (41%) 7%
• PPI score increase 114/635 (18%) 57/315 (18%) 0%
• Opioid dose increase 103/635 (16%) 73/315 (23%) 7%
• Between-group difference in TTPP events overall is driven only by opioid use
Clinical RelevanceClinical RelevanceClinical RelevanceClinical Relevance
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ConclusionsConclusionsConclusionsConclusions
• 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
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Broader PerspectiveBroader PerspectiveBroader PerspectiveBroader 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