PRO Guidance: Theory and Practice

1. PRO Guidance: Theory and Practice Ari Gnanasakthy Head, Patient Reported Outcomes Novartis Pharmaceuticals 15 Oct 2013

2. Clinical Outcome Assessments (COAs) • Patient Reported Outcome (PRO) • A measurement based on a report that comes directly from the patient (i.e., study subject) about the status of particular aspects of or events related to a patient’s health condition. • Clinician Reported Outcome (ClinRO) • An assessment that is determined by an observer with some recognized professional training that is relevant to the measurement being made. • Observer Reported Outcome (ObsRO) • An assessment that is determined by an observer who does not have a background of professional training that is relevant to the measurement being made, i.e., a non-clinician observer such as a teacher or caregiver. | PRO Guidance - Theory and Practice / 18 Oct 2013

3. Assessing disease activity and treatment outcomes Physiological Clinician Patient Caregiver Biomarkers • Lab values & tests • Functional tests • Blood tests • Biopsies • Tolerance tests • Vital signs Signs • Physical examination • Visual inspection • Palpation • Auscultation • Clinical impression • History experience • Symptoms • Activity tolerance • Cognitive function • Physical function • Psych distress • Rx satisfaction History experience • Symptoms • Activity limitations • Cognitive function • Physical function • Psych distress • Burden “Subjectivity” 0 Patient-reported outcomes allow a holistic view of treatment effects 3 | PRO Guidance - Theory and Practice / 18 Oct 2013

4. What Is a Patient-Reported Outcome? • A PRO is a measurement of any aspect of a patient’s health status that comes directly from the patient • Without the interpretation of the physician or anyone else • PRO Elements • Function • Feeling • PRO concept • Simple (e.g., bone pain) • Complex (e.g., treatment satisfaction/preference) | PRO Guidance - Theory and Practice / 18 Oct 2013

5. Guidance for the Industry (2009) Draft PRO Guidance: published December 2006 Final FDA PRO Guidance: published December 2009 Guidance developed by the SEALD group within the Office of New Drugs (OND) at FDA SEALD serves as an advisory group to all reviewing divisions | PRO Guidance - Theory and Practice / 18 Oct 2013

6. Purpose of the PRO Guidance • To emphasize that FDA recognizes the importance of the patient perspective where appropriate • To explain how FDA evaluates PRO instruments for their usefulness in measuring & characterizing treatment benefit as perceived by the patient. • To explain how FDA reviews evidence that a PRO instrument measures the concept represented in the study objectives and intended to support claims. | PRO Guidance - Theory and Practice / 18 Oct 2013

7. PRO Instruments Symptom Diary Physical Activity measure GI-symptom measure Linking PRO Concepts to Claims Desired Claim PROConcept SymptomRelief Product X relieves symptoms, improves physical activity, without upsetting stomach Physical Activity UpsetStomach 8 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

8. Some specifics from the guidance . . . • PRO instruments will be evaluated in the context of stated labeling goals. • Instrument development must be based on patient input • A recall period that captures the patient’s current state is preferred • Content validity is paramount and must be documented • Instrument adequacy for one purpose does not guarantee its adequacy for another purpose • In order to support claims, criteria for statistical analysis and interpretation of PRO results, including clear specification for a “positive” study conclusion should be clearly stated in the study protocol and statistical analysis plan • Statistical adjustments for multiple endpoints and a plan for dealing with missing PRO data are required | PRO Guidance - Theory and Practice / 18 Oct 2013

9. Emphasis of the guidance is on five aspects • The link between the endpoints and the proposed study claims (specific to the protocol) • The conceptual framework – a clear description or diagram of the relationship among concepts, domains and items (specific to the instrument) • Documentation of validity and measurement properties • Content validity / Reliability / Construct validity / Responsiveness • Definition of a responder • Documentation of instrument modification Burke, LE., Kennedy DL, Miskala, PH., et. el., The use of PRO measures in the evaluation of the medical products for regulatory approval. Clinical Pharmacology and Therapeutics June 2008 | PRO Guidance - Theory and Practice / 18 Oct 2013

10. COA instrument Development and Application: Framework in Final PRO Guidance 2009 for PROs essential works for all Clinical Outcome Assessments

13. Endpoint Model

14. Endpoint Model • Clear statement as to the role a PRO endpoint is intended to play in the clinical trial (e.g. primary, co-primary, secondary, exploratory) • A diagram or description of the hierarchy of hypothesized relationships among all endpoints in a clinical trial and how the PRO endpoints relate to the others • Explains the demands to be placed on the PRO instrument in order to attain the evidence to meet study objectives

15. Endpoint Model Example I Concepts Indication: Treatment of cancer X Supportive Concepts: Other treatment benefit Endpoints Primary: Survival (Progression Free) Secondary/Exploratory: Pain palliation Serologic markers HRQOL

16. Endpoint Model Example 2 Concepts Indication: Treatment of pain due to cancer X Supportive Concepts: Other treatment benefit Endpoints Primary: Pain palliation Secondary/Exploratory: HRQOL Survival

17. Conceptual Framework

18. Conceptual Framework of a PRO Instrument • A diagram of instrument items that explains how each item contributes to specific concepts represented and how each score is generated • Provides a clear description of the relationship among concepts, domains, and items

19. Lack of Conceptual FrameworkExample Pain severity Sitting Pain frequency Walking Swelling Standing Overall Score

20. Conceptual Framework Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Domain Concept A Overall Concept Domain Concept B Domain

21. Conceptual Framework: Example Domains Pain Physical functioning Swelling Items Pain severity Pain frequency Sitting Walking Standing Swelling Total Score

22. Enough of theory “In theory, there is no difference between theory and practice. But in practice, there is.” Yogi Berra “How empty is theory in the presence of fact!” Mark Twain, A Connecticut Yankee in King Arthur's Court | PRO Guidance - Theory and Practice / 18 Oct 2013

23. | PRO Guidance - Theory and Practice / 18 Oct 2013

24. What types of PRO labels claims have been granted by the FDA since the release of the guidance (Jan 06 – Dec10)? | PRO Guidance - Theory and Practice / 18 Oct 2013

25. Most Frequently Reported Reasons for Denial of Claim DeMuro C, Clark M, Mordin M, Fehnel S, Copley-Merriman C, Gnanasakthy A. Reasons for rejection of patient-reported outcome label claims: a compilation based on a review of patient-reported outcome use among new molecular entities and biologic license applications, 2006-2010. Value Health 15, 443-448 (2012). | PRO Guidance - Theory and Practice / 18 Oct 2013

26. Reasons for rejection of PRO Label • Fit for purpose – content validity, validation evidence in target population, lack of evidence of translation/cross cultural validation • Interpretation – issues of potential bias (open label design, etc.), recall period, clinical meaningfulness, missingness, poor compliance • Statistical considerations – no adjustment for multiplicity, inappropriate or missing SAP • Concepts – lack of link between concept and claim, failing to measure full constellation of symptoms • Administration considerations – lack of documentation for use of measure, copy of measure not provided to agency • No treatment benefit – measures did not support treatment benefit | PRO Guidance - Theory and Practice / 18 Oct 2013

27. Evidence suggests . . . • Since the release of the Draft PRO Guidance, many PRO claims continue to be approved by FDA reviewing divisions • The FDA favors PRO label claims for 1st order impacts • Certain FDA reviewing divisions (e.g. DAARP, DPAP) appear to be more comfortable allowing claims using specific PRO measures (usually as primary endpoints) • Reviewing divisions do not always follow the recommendation by SEALD • Reviewing divisions may or may not be adhering to the current standards when assessing PRO data for a claim | PRO Guidance - Theory and Practice / 18 Oct 2013

28. Expectations and consequences • Delays in product development • The PRO Guidance may have become a hurdle to innovation | PRO Guidance - Theory and Practice / 18 Oct 2013

29. But . . . It’s not all about the labels • PRO data are often requested by advisory boards and reimbursement authorities to evaluate drugs in a holistic manner • Patient reported outcomes enables holistic evaluation of new medications • Even after product launch PROs can help us to understand • patients’ satisfaction with treatment • factors that may affect adherence, and • other patient centric outcome data to support market access. | PRO Guidance - Theory and Practice / 18 Oct 2013

30. The case of Avastin in metastatic breast cancer | PRO Guidance - Theory and Practice / 18 Oct 2013

31. Jakafi™ Case Study • “It was a secondary endpoint, but in our mind this is why we gave the application full approval. One could quibble about the importance of reduction in spleen size, but with reduction in all the symptoms,” full approval was warranted, Pazdur said. • Quote from Richard Pazdur, director of FDA’s Office of Hematology Oncology Products, BioCentury, December 5, 2011

32. Need for PRO data is more than ever • The industry can no longer rely on traditional pharmaceutical sales models alone • An article demonstrating the benefits of a drug treatment based on data from a well developed PRO scale is likely to have a far reaching impact through patient-based websites • These are precisely the kind of data that patient advocacy groups feel they need in order to lobby payers and politicians in order to gain access to newer, often more expensive medical products | PRO Guidance - Theory and Practice / 18 Oct 2013

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