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

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Methods used to assess and report pain-related endpoints in NDA 21-801 Ethan Basch, MD, MSc Center for Drug Evaluation and Research Disclosures Current position ... – PowerPoint PPT presentation

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Title: 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 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.

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

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

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
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

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
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