Approach to Outcome Measure Development or Selection: A Regulatory Perspective

1. Approach to Outcome Measure Development or Selection: A Regulatory Perspective Measures of Outcome for Stimulant Trials (MOST) March 25-26, 2015 Ashley F. Slagle, MS, PhD Study Endpoints and Labeling Development (SEALD) Office of New Drugs (OND) Center for Drug Evaluation and Research (CDER)

2. Disclaimer The views expressed in this presentation are those of the speaker, and do not necessarily represent an official FDA position.

3. Treatment Benefit Treatment benefit is demonstrated by evidence that the treatment has a positive impact on a concept of interest: How long a patient lives How a patient feels or functions in daily life

4. Purpose of Outcome Assessment • To determine whether or not a drug has been demonstrated to provide benefit to patients • A conclusion of treatment benefit is described in labeling in terms of the concept of interest, or the thing measured by the outcome assessment • One of the most important aspects of drug development is how that benefit is measured

5. Types of Outcome Assessments • Survival • Clinical outcome assessments (COAs) • Patient-reported outcomes (PROs) • Clinician-reported outcomes (ClinROs) • Observer-reported outcomes (ObsROs) • Performance outcomes (PerfOs) • Surrogates • Often a biomarker* that is intended as a substitute for how a patient feels, functions, or survives • Two types for use in clinical trials to support product approval: • Established Surrogates (for regular approval) • Reasonably likely to predict clinical benefit (for accelerated approval; require post-marketing studies to confirm clinical benefit) *biomarker: a physiologic, pathologic, or anatomic characteristic that is objectively measured and evaluated as an indicator of some normal or abnormal biologic function, process or response to a therapeutic intervention

6. Evidence of Treatment Benefit • Direct evidence of treatment benefit is derived from studies with endpoints that measure survival, or how patients feel and function in daily life • Indirect evidence of treatment benefit is derived from studies with endpoints that measure other things that are related to how patients survive, feel or function

7. Direct Verses Indirect Evidence of Treatment Benefit Survival Pain Breathlessness Blood Pressure PSA 6MWT Indirect Evidence Direct Evidence Evidence Continuum

8. Evidence of Treatment Benefit (Proximal to Distal) Disease impact on general life concepts Disease-defining concepts Proximal disease Impact concepts Distal disease Impact concepts General psychologicalfunctioning Productivity Core signs,symptomsor decrements in functioning Related functioning Additional functioning Health status General physical functioning Health-related quality of life Additional Signs/ Symptoms Related Signs/ symptoms Social functioning Satisfaction withhealth 9

9. Evidentiary Standards to Document Treatment Benefit • Documented by “Substantial evidence” (21 CFR 201.56(a)(3)) • Evidence from “Adequate and well-controlled clinical trials” • The methods of assessment are “well-defined and reliable” (21 CFR 314.126)

10. When is a Clinical Outcome Assessment Adequate for use? • Regulatory standard: measures are well-defined and reliable • Empiric evidence demonstrates that the score quantifies the concept of interest in the targeted context of use • What does this mean? • This means measuring the right thing (concept of interest), in the right way in a defined population (targeted context of use), and the score that quantifies that ‘thing’ does so accurately and reliably, so that the effects seen in the outcome assessment can be interpreted as a clear treatment benefit.

11. Defines good measurement principles to consider for “well-defined and reliable” (21 CFR 314.126) PRO measures intended to provide evidence of treatment benefit All COAs can benefit from the good measurement principles described within the guidance Provides optimal approach to PRO development; flexibility and judgment needed to meet practical demands Good Measurement Principles http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM205269.pdf

12. Well-defined and Reliable The tool adequately measures the concept of interest in the context or clinical setting of interest To assess this, we review the tool’s measurement properties: Content validity Construct validity Reliability Ability to detect change Information to support interpretation of change 12

13. What is Content Validity Are we asking the right questions in our assessments? Do clinical trial participants consistently interpret and understand the questions on the PRO assessment? What does the score of the questionnaire represent?

14. Thinking about Meaningful Change How much change is meaningful?

15. Roadmap to Patient-Focused Outcome Measurement in Clinical Trials • Intended to illustrate how one might embark upon a sound, orderly, instrument selection or development pathway, beginning with the clinical context in which the instrument is intended to be used. • The graphic here is meant to help identify the types of things that might be considered in order to improve the ability of an outcome assessment to accurately measure treatment benefit. • Most assessment tools are a bit less orderly in their development

17. Defining Context of Use Each of the following variables can impact the adequacy of a COA to support a claim: Disease definition including, if appropriate Disease subtype Disease severity History of previous treatment Patient subpopulations Patient demographics Reporting ability Culture and language Clinical trial design and objectives Endpoint positioning Endpoint definitions Analysis plan Methods for interpretation of study results Targeted labeling claim Clinical practice and study setting Inpatient vs. outpatient Geographic location Clinical practice variation 17

18. Endpoint Definition and Positioning • Create study objectives based on the COI in the COU • Position the outcomes as trial endpoints that will be interpretable in comparison with a control group • Define endpoints using COA scores • Plan analysis • Measurement of change over time in individual patients that are combined for a means of assessing a group score • Analysis of means • Analysis of proportions • Hierarchy for testing multiple assessments

19. Wheel and Spokes Diagram • This diagram identifies the key components of the documentation submitted to CDER to support the use of a clinical outcome assessment • The Wheel and Spokes diagram also represents the general iterative process used in developing a clinical outcome assessment • This type of work has been going on in the social sciences for decades and we are now bringing it to the world of drug development

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21. Clinical Outcome Assessment Considerations • Not all patient reported, clinical-reported, observer-reported, or performance outcome assessments are appropriate Clinical Outcome Assessments for use in clinical trials to support approval and labeling • May be useful for other purposes: • Diagnostic • Prognostic • Trial eligibility and trial enrichment • Epidemiologic or population studies • Clinical practice decision-making • Measures used successfully for these other purposes will not necessarily be appropriate outcomes assessments (i.e., they may not be able to reliably detect treatment benefit in clinical trials or support labeling claims in a non-misleading way)

22. How FDA Can Help: Providing Advice on Clinical Outcome Assessments • Provide advice and recommendations on clinical outcome assessments, including PROs: • For individual drug development programs (within an IND) • Through the Drug Development Tool (DDT) Clinical Outcome Assessment Qualification Program

23. DDT Qualification Guidance http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf • Describe a process NOT evidentiary standards • Qualification process described for Biomarkers, Animal Models, and Clinical Outcome Assessments (COA) • Final Guidance January 2014

24. COA DDT Qualification Website http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284077.htm