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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 Memorial Sloan-Kettering Cancer Center Medical oncologist Patient-reported outcomes research Current role

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Methods used to assess and report pain related endpoints in nda 21 801 l.jpg

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

Ethan Basch, MD, MSc

Center for Drug Evaluation and Research


Disclosures l.jpg
Disclosures NDA 21-801

  • 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


Background l.jpg
Background NDA 21-801

  • 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”


Proposed claim in nda 21 801 l.jpg
Proposed Claim in NDA 21-801 NDA 21-801

  • Progression-free survival (PFS) composite endpoint

    1. Radiographic progression

    OR:

    2. Skeletal-related events

    OR:

    3. “Symptomatic progression”


Proposed claim in nda 21 8015 l.jpg
Proposed Claim in NDA 21-801 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”


Proposed claim in nda 21 8016 l.jpg
Proposed Claim in NDA 21-801 NDA 21-801

  • “Pain progression”

    3rd-level composite endpoint

    i. Increased “Present Pain Intensity” (PPI) score

    OR:

    ii. Increased opioid use


Phase iii trial g pc sat 03 01 l.jpg
Phase III trial: G NDA 21-801PC SAT-03-01

  • RCT of satraplatin + prednisone vs. placebo + prednisone, as second-line chemotherapy

    • 51% received prior docetaxel


Pain assessment in g pc sat 03 01 l.jpg
Pain Assessment in G NDA 21-801PC SAT-03-01

Opioid

use

“PPI”

score


Present pain intensity ppi item l.jpg
“Present Pain Intensity” (PPI) Item NDA 21-801

  • Single question

  • Plucked from McGill Pain Questionnaire

  • Developed in 1970s

  • Used in mitoxantrone approval


Present pain intensity ppi item10 l.jpg
“Present Pain Intensity” (PPI) Item NDA 21-801

  • Report average pain intensity over the past 24 hours:

    1-Mild

    2-Discomforting

    3-Distressing

    4-Horrible

    5-Excruciating


Data analysis l.jpg
Data Analysis NDA 21-801

  • 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 Issues NDA 21-801

  • Questionnaire

  • Study design

  • Results


Support materials submitted l.jpg
Support Materials Submitted NDA 21-801

  • 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.


Validity l.jpg
Validity NDA 21-801

  • Content validity

  • Construct validity


Content validity l.jpg
Content Validity NDA 21-801

  • 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


Construct validity l.jpg
Construct Validity NDA 21-801

  • Compare with independent similar measure

  • Discriminate between clinically distinct patient groups in terms of concept of interest

  • Poor correlation with other domains


Validity17 l.jpg
Validity NDA 21-801

  • Mitoxantrone and docetaxel papers

    • Not evaluated

    • Treatment trials

    • No dedicated patient interviews

  • Primary pain endpoint model in satraplatin application differs


Reliability l.jpg
Reliability NDA 21-801

  • Reproducibility

  • Ability to detect change


Item tweaking l.jpg
Item “Tweaking” NDA 21-801

Altered from original PPI

Altered from mitoxantrone and docetaxel*

*Progression endpoint: no results provided


Score averaging l.jpg
Score Averaging NDA 21-801

  • Averaged PPI scores over each 1-week period

    (DISTRESSING + EXCRUCIATING)/2 =?= HORRIBLE


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Language Translation NDA 21-801

  • 16 countries, 10 languages

  • Language translations by local research assistants

    • No standardized approach

    • No prospective confirmatory patient interviews

    • No “back translations”


Establishing clinical relevance l.jpg
Establishing Clinical Relevance NDA 21-801

  • 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?


Slide23 l.jpg

Clinical Relevance NDA 21-801

Time to pain progression (TTPP) 2° endpoint events:

  • Between-group difference in TTPP events overall is driven only by opioid use


Conclusions l.jpg
Conclusions NDA 21-801

  • Concerns regarding measurement of pain-related endpoints

    • Validity

    • Reliability

    • Clinical relevance

  • PFS endpoint comes into question

  • Blinding


Broader perspective l.jpg
Broader Perspective NDA 21-801

  • 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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