# Presentation: 706660

## 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
- Uncompensated FDA Guest Worker
- Research funding
- NCI, ASCO, DOD, NY State
- Financial disclosures: None

## 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”*

## Proposed Claim in 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 21-801

_**“**__**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 21-801

_**“**__**Pain progression” **_
**	**_**3**__**rd**__**-level composite endpoint**_
- i. Increased “Present Pain Intensity” (PPI) score
*	**	**OR: *
- ii. Increased opioid use** **

## Phase III trial: GPC SAT-03-01

**RCT of satraplatin + prednisone vs. placebo + prednisone, as second-line chemotherapy**
- 51% received prior docetaxel

## Pain Assessment in GPC SAT-03-01

- Opioid
- use

- “PPI”
- score

## “Present Pain Intensity” (PPI) Item

- Single question
- Plucked from McGill Pain Questionnaire
- Developed in 1970s
- Used in mitoxantrone approval

## “Present Pain Intensity” (PPI) Item

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

## 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%

## Methodologic Issues

**Questionnaire**
**Study design**
**Results**

## 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.*

## Validity

**Content validity**
**Construct validity**

## 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*

## Construct Validity

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

## Validity

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

## Reliability

- Reproducibility
- Ability to detect change

## 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*

## Score Averaging

- Averaged PPI scores over each 1-week period
*	*
*	**(DISTRESSING + EXCRUCIATING)/2 =?= HORRIBLE *

## Language Translation

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

## 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?

## Clinical Relevance

|  | 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 Relevance**_

## Conclusions

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

## 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