ASENT 13 th Annual Meeting Outcome Measures to Support Labeling Claims: What is new FDA Guidance?

1. ASENT 13th Annual MeetingOutcome Measures to Support Labeling Claims: What is new FDA Guidance? Elektra J. Papadopoulos, M.D., M.P.H. Study Endpoints and Labeling Development CDER/FDA February 24, 2011

2. Disclosures • No conflicts

3. Presentation Outline • FDA review of rating scales • Drug development tool qualification process

4. FDA Review of Rating Scales

5. Characteristics of an Adequate and Well-Controlled Study • 21 CFR 314.126 (b) (1) Clear statement of objectives (2) Study design permits valid comparison (appropriate control) (3) Select patients with disease/condition (treatment) or at risk of disease (prevention) (4) Baseline comparability (randomization) (5) Minimize bias (blinding, etc.) (6) Appropriate methods for assessment of outcome (7) Appropriate methods of analysis

6. 21 CFR 314.126(b)(6) “The methods of assessment of subjects’ response are well-defined and reliable. The protocol for the study and the report of results should explain the variables measured, the methods of observation, and the criteria used to assess response.” • A well-defined and reliable endpoint measure is needed as part of an adequate and well-controlled study to support labeling claims • Consideration of context of use is needed in this assessment

7. Endpoint Measure • The measurement that will be statistically compared among treatment groups to assess the effect of treatment and corresponds with the clinical trial’s objectives, design, and data analysis plan • Clinical Endpoint: A characteristic or variable that reflects how a patient feels, functions, or survives • Biomarkers Definitions Working Group. Clin Pharmacol Ther 2001; 69:89-95

8. Claim • Any statement of treatment benefit • Can be found anywhere in FDA-approved labeling or in advertising • Must be supported by substantial evidence • Must not be false or misleading

9. Concept: The specific goal of measurement (i.e., the thing or event that is to be measured) Forms the basis for describing claims in labeling Examples: Asthma Symptoms Cognitive Functioning Congestive Heart Failure Signs and Symptoms Goal of Measurement: “Concept”

10. Types of Endpoint Measures • Patient-reported outcomes • Observer-reported outcomes (e.g., caregiver-reported) • Clinician-reported outcomes • Objective tests (e.g., lab or device measurements)

11. Patient Reported Outcome (PRO) • Any report of the status of a patient’s health condition coming directly from the patient, without interpretation by physicians or anyone, about how the patient functions or feels in relation to a health condition and its treatment • Examples: • Pain intensity • Symptoms of community acquired pneumonia • Physical functioning in chronic heart failure

12. Clinician Reported Outcome (ClinRO) • Clinician can be any type of trained professional (e.g., physician, study nurse) rating study participants at a study site • Generally rate concepts that require clinical judgment • Cannot validly be used to measure patient symptoms (e.g., pain, dyspnea) or other unobservable concepts

13. Observer Reported Outcome (ObsRO) (1) • The observer is typically the person who takes care of the patient (e.g., caregiver, parent) or another observer (e.g., teacher) • Should not rate concepts that require clinical judgment • Useful when the patient is unable to report for themselves (e.g., infants, young children, cognitive impairment)

14. Observer Reported Outcome (ObsRO) (2) • Provides observations, but not interpretations, of the patient’s health condition from the observer • Cannot validly be used to measure patient symptoms (e.g., pain) or other unobservable concepts • Ratings of unobservable concepts are proxy reports • Proxy reports of unobservable concepts are NOT well-defined and reliable endpoint measure capable of supporting labeling claims

15. The adequacy of a PRO instrument as a measure to support medical product labeling claims depends on its documented measurement properties that demonstrate the instrument is “fit for purpose” FDA PRO Guidance http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf

16. Measurement Properties • Content Validity • Critical for interpretation and labeling • Should be established prior to evaluating other measurement properties • Construct Validity: • Evidence that the PRO concepts measured conform to a priori hypotheses concerning expected relationships with other measures or characteristics of patients/patient groups • Reliability • Test-retest: Stability of scores over time when not change expected in the concept of interest • Internal Consistency: Intercorrelation of items that contribute to a score • Ability to detect change • Evidence that the PRO instrument can identify differences in scores over time (individual or group) who have changed with respect to measurement concept

17. Content Validity • Evidence that the instrument measures the concept of interest including evidence that the items and domains of an instrument are meaningful, comprehensive, appropriate, and interpretable, relative to its intended measurement concept, population, and use • Established by: • Literature review • Expert opinion • Responder input in form of qualitative research in the target patient population • Content validity cannot be evaluated independent of the context of use

18. FDA Review Considerations: PRO Measures and Other Rating Scales • General context of use within the trial • Items • Response options • Recall period • Structure (e.g., subscales) • Scoring • Instructions for use • Guidelines for interpretation of change • Translation and cultural adaptation • Measurement property documentation

19. Drug Development Tool (DDT) Qualification Process

20. Qualification process for drug development tools (DDTs): Biomarkers PRO tools and other rating scales New and existing DDTs DDT Guidance (Draft) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf

21. DDT Qualification: What is it? • Regulatory conclusion that within the stated context of use, the results of the drug development tool (DDT) measurement can be relied upon to have a stated interpretation and utility-“fit for purpose” • Context of use • Target population • Targeted labeling claims • Endpoint model • Endpoint assessment tools (primary or key secondary) • Well-defined and reliable • Clinically meaningful within a specified context of use • Adequate to support a claim of treatment benefit

22. Rationale for DDT Qualification • Multidisciplinary, formal review of scale development data • Allows a scientifically well-supported statement by CDER of qualification • Efficient use of resources for industry and FDA • Publicly available DDTs

23. DDT Qualification: Framework • A Critical Path Initiative • Voluntary process • Builds on developing public-private partnerships between FDA and consortia representing medical product industry, instrument developers, NIH, academia • Collaboration allows FDA to work with multiple partners to leverage expertise and resources • Examples of collaborative efforts • Critical Path Institute: PRO Consortium • FDA-NIH Interagency Outcomes Assessment Working Group (IOAWG)

24. DDT Qualification: A New Process • The qualification process provides an additional option for submission of DDT development and validation data that is outside of a specific medical product development program FDA Consultation & Advice Planning Phase FDA Review Statement of Qualification DDT Publicly Available Define scope & context of use Methods & Results Sharing Dossier Submission; FDA Review   

25. Conclusions • Endpoint measures need to be well-defined and reliable • FDA PRO Guidance document (2009) provides the standard of evidence for FDA evaluation of PRO measures to support labeling claims; many principles also applicable to other types of rating scales • PRO measures and other rating scales should be “fit for purpose” within the proposed context of use • Draft FDA Qualification Guidance (2010) for DDTs provides a path for qualification of both new and existing instruments