Title: Methods used to assess and report pain-related endpoints in NDA 21-801
1Methods used to assess and report pain-related
endpoints in NDA 21-801
Center for Drug Evaluation and Research
2Disclosures
- 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
3Background
- 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
4Proposed Claim in NDA 21-801
- Progression-free survival (PFS) composite
endpoint - 1. Radiographic progression
- OR
- 2. Skeletal-related events
- OR
- 3. Symptomatic progression
5Proposed 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
6Proposed Claim in NDA 21-801
- Pain progression
- 3rd-level composite endpoint
- i. Increased Present Pain Intensity (PPI) score
- OR
- ii. Increased opioid use
7Phase III trial GPC SAT-03-01
- RCT of satraplatin prednisone vs. placebo
prednisone, as second-line chemotherapy - 51 received prior docetaxel
8Pain Assessment in GPC SAT-03-01
Opioid use
PPI score
9Present Pain Intensity (PPI) Item
- Single question
- Plucked from McGill Pain Questionnaire
- Developed in 1970s
- Used in mitoxantrone approval
10Present Pain Intensity (PPI) Item
- Report average pain intensity over the past 24
hours -
- 1-Mild
- 2-Discomforting
- 3-Distressing
- 4-Horrible
- 5-Excruciating
11Data 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
12Methodologic Issues
- Questionnaire
- Study design
- Results
13Support Materials Submitted
- Melzac, 1975 Melzac R. The McGill Pain
Questionnaire major properties and scoring
methods. Pain 19751277-299. - 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 19808377-387. - 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 1996141756-1764. - Tannock, 2004 Tannock I, de Wit R, Berry W, et
al. Docetaxel plus prednisone or mitoxantrone
plus prednisone for advanced prostate cancer.
NEJM 20043511502-1512. - 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.
14Validity
- Content validity
- Construct validity
15Content 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
16Construct Validity
- Compare with independent similar measure
- Discriminate between clinically distinct patient
groups in terms of concept of interest - Poor correlation with other domains
17Validity
- Mitoxantrone and docetaxel papers
- Not evaluated
- Treatment trials
- No dedicated patient interviews
- Primary pain endpoint model in satraplatin
application differs
18Reliability
- Reproducibility
- Ability to detect change
19Item Tweaking
- Altered from original PPI
ORIGINAL SATRAPLATIN
Rate over 24-hours Worst PPI score Average PPI score
- Altered from mitoxantrone and docetaxel
MITOXANTRONE SATRAPLATIN
Primary Endpoint Pain Relief 2-point PPI decrease from baseline, or 1?0 Pain Progression 1-point PPI increase from baseline, or 2 from nadir
Opioid Endpoint 50 reduction Non-narcotics included 25 increase No non-narcotics
Duration of response 3 weeks 2 weeks
- Progression endpoint no results provided
20Score Averaging
- Averaged PPI scores over each 1-week period
-
- (DISTRESSING EXCRUCIATING)/2 ? HORRIBLE
21Language Translation
- 16 countries, 10 languages
- Language translations by local research
assistants - No standardized approach
- No prospective confirmatory patient interviews
- No back translations
22Establishing 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?
23Clinical Relevance
Time to pain progression (TTPP) 2 endpoint
events
Satraplatin (n635) Placebo (n315) 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
24Conclusions
- Concerns regarding measurement of pain-related
endpoints - Validity
- Reliability
- Clinical relevance
- PFS endpoint comes into question
- Blinding
25Broader Perspective
- Sponsor included pain-related endpoints
- Important to patients and providers
- Difficult to measure
- FDA Guidance created to assist sponsors with
patient-reported endpoints