1. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development in Support of Labeling Claims Final Guidance from a Medical Writing Perspective FDA – CDER, CBER, CDRH December 2009 Presentation to DIA Medical Writing SIAC Carol Jamieson PRO Group, WW Market Access Johnson & Johnson Pharmaceutical Services August 5, 2010 1

2. Disclaimers This presentation represents my personal views rather than the views of Johnson & Johnson Pharmaceutical Services In this presentation I am not providing any advice or counsel, nor legal or consulting advice.

3. Take Away Points Follow the FDA guidance to enhance probability of a successful claim – Early consideration of the issues included in the guidance are more likely to allow success. Appropriate documentation is essential to a successful review – FDA assumes that evidence does not exist if they are not informed about it. 3

4. Overview Final FDA Guidance on PROs (Guidance for Industry, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims) was issued in December, 2009. The guidance has direct relevance for medical writing as it impacts the content of several key documents including protocols, statistical analysis plans, clinical study reports and NDAs. – The guidance establishes the content of the “PRO Evidence Package” – a compilation of evidence supporting the development and measurement properties of a PRO, which is included in the NDA. Partnership of PRO representatives with medical writing in interpreting and implementing these guidelines is important in gaining successful NDA submission and label claims for PRO data – Common understanding of requirements will assist in ensuring documents have appropriate content and structure. 4

5. The Final PRO Guidance – What’s New Clarifies FDA policy in response to received comments with no major policy revisions Revised focus: – From: best practices for PRO instrument development – To: FDA review considerations for PRO instruments Content validity: emphasis on documented qualitative research leading to item generation, reduction, and modification decisions to support the conclusion that the instrument measures the claimed concept 5 Adapted from L Burke, DIA webinar “Patient-reported Outcome Measures: Announcing FDA’s Final PRO Guidance, 15 Jan 2010

6. The Final PRO Guidance – What Else Is New? Wheel and spokes diagram: Spokes added and modified to correspond with FDA review issues Endpoint model: New tool to define role of PRO in context of ALL non-exploratory endpoints in a clinical trial Clinical trial interpretation: MID deleted; responder definition and Cumulative Distribution Function (CDF) analysis emphasized Appendix: Information on a PRO Instrument reviewed by the FDA (“PRO Evidence Package” template) 6 Adapted from L Burke, DIA webinar “Patient-reported Outcome Measures: Announcing FDA’s Final PRO Guidance, 15 Jan 2010

7. Background 7

8. Definitions PRO – “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else”* A PRO instrument is “a means to capture data plus all the information and documentation that supports its use” including the concepts being measured, number of items, conceptual framework of the instrument, medical condition, patient population, data collection method, administration method, etc – The use of a PRO instrument is advised when measuring a concept that is best known by the patient or best measured from the patient’s perspective” “Claims can appear in any section of the labeling and PRO instrument evaluation principles apply regardless of location” 8 * Italics are quotes from the final FDA Guidance on PROs

9. PRO Endpoints are the Same as All Other Endpoints “Sponsors should avoid separate consideration of PRO endpoints from the clinical trial’s primary objectives in terms of clinical trial design or data analysis.”* Impact – Where relevant, full integration of PRO into development plans with no separate sections for PROs in protocols, etc. 9 * Italics are quotes from the final FDA Guidance on PROs

10. Prospective Measures of Risk PRO data can be collected to support safety or efficacy claims – A PRO instrument “is a means to capture PRO data used to measure treatment benefit or risk in medical product clinical trials.”* – “Treatment benefit can be demonstrated by either an effectiveness or safety advantage” The proposed approach should be described in the safety or efficacy sections of the protocol as appropriate Impact – Potential claims should be based upon use of appropriate measures, and study design identified and integrated early in compound development 10 * Italics are quotes from the final FDA Guidance on PROs

11. Evaluation of a PRO Instrument 11

12. FDA Review of a PRO Instrument Includes the following considerations: – The population enrolled in the clinical trial – The clinical trial objectives and design – The PRO instrument’s conceptual framework – The PRO’s instrument’s measurement properties Impact – FDA will look at the PRO instrument in the context in which it is used, not just measurement properties of the instrument 12

13. Inclusion of Endpoint Model “ Endpoint model – a diagram of the hierarchy of relationships among all endpoints, both PRO and non-PRO, that corresponds to the clinical trial’s objectives, design, and data analysis plan.”* Impact – Graphical presentation of all study endpoints (not just PROs) to be presented to FDA at EOP2 and upon submission – Defines the role a PRO endpoint is intended to play in the clinical trial (i.e., primary, key secondary) so that the instrument development and performance can be reviewed in the context of the intended role, and appropriate statistical methods can be planned and applied – It is important to plan these approaches in an endpoint model. 13 * Italics are quotes from the final FDA Guidance on PROs

14. Figure 2. Endpoint Model: Treatment of Disease Y 1 PRO Primary ConceptsEndpoints IndicationPrimary Treatment of symptoms of disease Y Total disease Y symptom score (PRO assessment) Supportive Concepts Improvements in symptoms/ Signs of disease Y Secondary Physical performance (PRO or non PRO assessment) Disease Y-related physical limitations (PRO assessment) 1 Adapted from FDA PRO Guidance (2009) p4 14

15. Strong Emphasis on Content Validity Content validity – “Evidence from qualitative research demonstrating that the instrument measures the concept of interest including evidence that the items and domains of an instrument are appropriate and comprehensive relative to its intended measurement concept, population and use. “* Impact – “Testing other measurement properties will not replace or rectify problems with content validity” Development of new measures must begin with establishing content validity Existing instruments with insufficient documentation of content validity may require additional qualitative work – FDA review considerations (documentation should include the following): Derivation of all items including theoretical approach if used Qualitative interview schedule Interview or focus group transcripts Items derived from the transcripts Composition of patients used to develop content Cognitive interview transcripts to evaluate patient understanding – includes instructions, recall period, and response options 15 * Italics are quotes from the final FDA Guidance on PROs

16. Content validity: Additional Documentation Suggested Saturation – “…. the point when no new relevant or important information emerges and collecting additional data will not likely add to the understanding of how patient perceive the concept of interest and the items in the questionnaire”* “Item tracking matrix – a record of the development (e.g., additions, deletions, modifications and the reasons for changes) of items used in an instrument” 16 * Italics are quotes from the final FDA Guidance on PROs

17. Hypothetical Example of Saturation Matrix Focus Group (in temporal sequence) Concepts (in order of mentions) ABCDEF InattentionXXXXXX Impaired memoryXXXX Difficulty problem solvingXXX HyperactivityXXXXX ImpulsivityXXX 17 Note: Column’s represent separate focus groups. Rows indicate concepts. X’s indicate the concept was mentioned by the group. Concepts are listed in the order in which they are mentioned. No new concepts were introduced after group D. Interviews were continued to ensure that new concepts were not missed.

18. Example of Item Tracking Matrix 18 Patrick DL, et al. Value in Health 2007

19. Clinical Trial Design Planning for Interpretation 19

20. Emphasis on Responder Analyses to Interpret Clinical Trial Results (1) “ Responder definition – A score change in a measure, experienced by an individual patient over a predetermined time period that has been demonstrated in the target population to have a significant benefit.”* “Alternatively, it is possible to present the entire distribution of responses for treatment and control group, avoiding the need to pick a responder criterion….Such cumulative distribution displays show a continuous plot of the percent change from baseline on the x-axis and the percent of patients experiencing that change on the Y axis.” 20 * Italics are quotes from the final FDA Guidance on PROs

21. Cumulative Distribution Function Example 21 Patrick DL, et al. Value in Health 2007

22. Missing PRO Data Can lead to biased estimates “The clinical trial protocol should describe how missing data will be handled in the analysis.”* “Patients should remain in the clinical trial, even if they have discontinued treatment and should continue to provide PRO data” “In clinical trials of terminal illness, it is critical to plan ahead for how missing data because of death will be handled.” “We recommend that in the protocol the sponsor propose two or more sensitivity analyses with different methods for missing data imputation.” Impact – Detailed planning around clinical trial design to account for missing data – Detailed discussion of missing data approaches 22 * Italics are quotes from the final FDA Guidance on PROs

23. FDA Recommended PRO Content of Protocols: Collaboration Between Medical Writing, PRO and the Clinical Representatives Each PRO endpoint is stated as a specific clinical trial objective and multiplicity concerns are addressed The clinical trial will be adequately blinded Procedures for training are well-described for: – Patients – Interviewers – Clinical investigators Plans for instrument administration are consistent with instrument’s user manual Plans for PRO instrument scoring are consistent with those used during instrument development 23

24. FDA Recommended PRO Content of Protocols: Collaboration Between Medical Writing, PRO and the Clinical Representatives (Cont.) Procedures include assessment of PRO endpoint before or shortly after a patient withdraws from the clinical trial Frequency and timing of PRO assessments are appropriate given patient population, clinical trial design and objectives, and demonstrated PRO measurement properties Clinical trial duration is adequate to support PRO objectives Plans are included for handling missing data Plans are included for a cumulative distribution function comparison among treatment groups Data collection, data storage, and data handling and transmission of procedures, including electronic PROs, are specified 24

25. FDA Recommended PRO Content of Statistical Analysis Plans (SAP) Plans for multiplicity adjustment Plans for handling missing data at both the instrument and patient level Description of how between-group differences will be portrayed (e.g., cumulative distribution function) Not stated, but important to consider including the following in the SAP: – Define PRO scoring – Define PRO statistical endpoint (use of MIC to define responder, etc.) – Define statistical test for PRO objectives 25

26. FDA Recommended PRO Content of Clinical Study Reports No specific recommendations However, many recommendations in the guidance have impact on the study reports. For example: – Full integration of PRO objectives into the study – Adjustments for multiplicity – Cumulative distribution plots – PRO responder analyses – Analyses of missing PRO data 26

27. PRO Evidence Package: Outline of Requirements for FDA PRO Review Exact version of the instrument (including user manual and patient and site training) Targeted claims Endpoint model PRO instrument’s conceptual framework Evidence of content validity (including transcripts from patient interviews and item tracking matrix) Evidence of measurement properties (reliability, construct validity and ability to detect change) Interpretation of scores Evidence of validity of translations and cultural adaptation Discussion of modification to instruments Impact – Requires the compilation of extensive documentation (which needs to be collected throughout the development program) for submission to FDA at EOPII meeting and upon filing 27

28. EMA Perspective on PRO Endpoints EMA has not issued a PRO Guidance – Issues related to PRO endpoints are included in various condition specific guidance documents and the HRQOL Reflection Paper (EMA 2005) Commentary during DIA sponsored webinar on Final PRO Guidance EMA member of panel: – Mira Pavlovic, MD Head of Scientific Advice Unit EMA AFSSAPS, France Q: How much FDA and EMEA coordination went into the final guidance? A: They were in contact. The EMA reflection paper concentrates on HRQOL measures. Pain and WOMAC are not different from other endpoints. Multidimensional measures go well beyond efficacy and safety and therefore cannot be used as primary endpoints. The same principles apply – use the FDA guidance for guidance on content validity etc. 28

29. Conclusions It is important that compounds currently in development follow the guidance if they wish to make claims 1 regarding patient-reported outcomes or outcomes related to other subjective assessments Full integration of PROs into all relevant study documentation is advised Appropriate definitions of PRO statistical endpoints is important for the correct interpretation of treatment benefit Generation of a complete PRO Evidence Package is important to facilitate a successful review: – Ongoing throughout the compound development process: – The strong emphasis on content validity reinforces that the process of including PRO instruments for labeling claims needs to begin early in compound development 29 1 Claims refers to “a statement of treatment benefit. A claim can appear in any section of a medical product’s FDA-approved labeling or in advertising and promotional labeling of prescription drugs and devices.” PRO Guidance, 2009