1. Labeling claims for patient- reported outcomes (A regulatory perspective) FDA/Industry Workshop Washington, DC September 16, 2005 Lisa A. Kammerman, Ph.D. Division of Biometrics 2 FDA/Industry Workshop Washington, DC September 16, 2005 Lisa A. Kammerman, Ph.D. Division of Biometrics 2 Center for Drug Evaluation and Research

2. FDA/Industry Workshop September 16, 2005 2 DisclaimerDisclaimer Views expressed in this presentation are those of the speaker and not, necessarily, of the Food and Drug Administration.

3. FDA/Industry Workshop September 16, 2005 3 Introduction Start early in development program –Instrument selection –Role of outcome in clinical study Issues to address –Development and validation –Clinically meaningful difference –Implementation Start early in development program –Instrument selection –Role of outcome in clinical study Issues to address –Development and validation –Clinically meaningful difference –Implementation

4. FDA/Industry Workshop September 16, 2005 4 Introduction Trial Design Conduct of clinical study FDA review –Instrument –Study results And then …. Labeling Claims Trial Design Conduct of clinical study FDA review –Instrument –Study results And then …. Labeling Claims

5. FDA/Industry Workshop September 16, 2005 5 To support a PRO claim Reliable and valid instrument Instrument measures concepts claimed Instrument measures impact of an intervention Well-controlled investigations Reliable and valid instrument Instrument measures concepts claimed Instrument measures impact of an intervention Well-controlled investigations

6. FDA/Industry Workshop September 16, 2005 6 Early in product development Identify endpoints Identify desired claims Discuss with FDA Identify endpoints Identify desired claims Discuss with FDA

7. FDA/Industry Workshop September 16, 2005 7 Selection of PRO Instrument Measures the claimed treatment benefit from the patients perspective Measures both the positive and negative benefits of the intervention Measures the claimed treatment benefit from the patients perspective Measures both the positive and negative benefits of the intervention

8. FDA/Industry Workshop September 16, 2005 8 Selection of PRO Instrument Specific to the intended population Specific to the characteristics of the conditions or disease treated Specific to the intended population Specific to the characteristics of the conditions or disease treated

9. FDA/Industry Workshop September 16, 2005 9 Selection of PRO Instrument Three possible choices –Existing instrument –Modification of existing instrument –New instrument Three possible choices –Existing instrument –Modification of existing instrument –New instrument

10. FDA/Industry Workshop September 16, 2005 10 Document, document, document! Development of instrument –Patient involvement –Population –Goals Validation of instrument –Format, wording –Cultural issues, multinational studies –Drug intervention studies Development of instrument –Patient involvement –Population –Goals Validation of instrument –Format, wording –Cultural issues, multinational studies –Drug intervention studies

11. FDA/Industry Workshop September 16, 2005 11 Document, document, document! Concepts: what will be measured Examples: –Pain severity –Psychological function –Physical function Concepts: what will be measured Examples: –Pain severity –Psychological function –Physical function

12. FDA/Industry Workshop September 16, 2005 12 Document, document, document! Domain: Q concept Examples: –PFSF: Desire, Responsiveness, Disinterest –Physical function: symptom improvement, physical abilities, ADL Domain: Q concept Examples: –PFSF: Desire, Responsiveness, Disinterest –Physical function: symptom improvement, physical abilities, ADL

13. FDA/Industry Workshop September 16, 2005 13 Document, document, document! Clinically meaningful difference –Prospective plan –Patient involvement Planned use in clinical study –Primary evidence for efficacy –Value-added Intended population Clinically meaningful difference –Prospective plan –Patient involvement Planned use in clinical study –Primary evidence for efficacy –Value-added Intended population

14. FDA/Industry Workshop September 16, 2005 14 Document, document, document! Implementation –Training and instructions –Format Implementation –Training and instructions –Format

15. FDA/Industry Workshop September 16, 2005 15 Trial Design Issues Prospectively defined Blinding Use of instrument –Standardized instructions –Standardized training –Training and blinding of interviewers –Recall to baseline Prospectively defined Blinding Use of instrument –Standardized instructions –Standardized training –Training and blinding of interviewers –Recall to baseline

16. FDA/Industry Workshop September 16, 2005 16 Trial Design Issues Data capture –Paper –Electronic Data capture –Paper –Electronic

17. FDA/Industry Workshop September 16, 2005 17 Role of PRO as an endpoint Primary evidence of efficacy Value-added –Pre-specify –Report findings, regardless of statistical significance and direction Primary evidence of efficacy Value-added –Pre-specify –Report findings, regardless of statistical significance and direction

18. FDA/Industry Workshop September 16, 2005 18 Analysis Plan Missing data –Entire instruments –Domains –Items –Visits Multiple endpoints Missing data –Entire instruments –Domains –Items –Visits Multiple endpoints

19. FDA/Industry Workshop September 16, 2005 19 And finally … Labeling! Well-controlled studies Instrument reliably and validly measures the concepts claimed Convey both positive and negative effects Specific to the concept measured Well-controlled studies Instrument reliably and validly measures the concepts claimed Convey both positive and negative effects Specific to the concept measured

20. FDA/Industry Workshop September 16, 2005 20 SummarySummary Start early in clinical development program Talk to FDA review divisions Document, document, document –Development of instrument –Validation of instrument –Clinically meaningful difference –Implementation Start early in clinical development program Talk to FDA review divisions Document, document, document –Development of instrument –Validation of instrument –Clinically meaningful difference –Implementation

21. FDA/Industry Workshop September 16, 2005 21 SummarySummary Study Design –Blinding –Use of instrument –Prospectively defined Analysis plan Study Design –Blinding –Use of instrument –Prospectively defined Analysis plan

22. FDA/Industry Workshop September 16, 2005 22 SummarySummary Labeling –Conveys both negative and positive effects –Specificity to concepts measured Labeling –Conveys both negative and positive effects –Specificity to concepts measured