Performance Outcome Measures: A Regulatory Perspective

Transcription

1 Performance Outcome Measures: A Regulatory Perspective International Society for Pharmacoeconomics and Outcomes Research (ISPOR) May 18, 2015 Ashley F. Slagle, MS, PhD Study Endpoints and Labeling Development (SEALD) Office of New Drugs (OND) Center for Drug Evaluation and Research (CDER) Disclaimer The views expressed in this presentation are those of the speaker, and do not necessarily represent an official FDA position. 2 1

2 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 3 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 4 2

3 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: 5 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 Evidentiary Standards to Document Treatment Benefit Documented by Substantial evidence (21 CFR (a)(3)) Evidence from Adequate and well-controlled clinical trials The methods of assessment are well-defined and reliable (21 CFR ) 6 3

4 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 6MWT Blood Pressure PSA Direct Evidence Evidence Continuum Indirect Evidence 8 4

5 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. 9 Fit For Purpose The tool is sufficiently well-defined and reliable Adequately measures the concept of interest in the context or clinical setting of interest PRO guidance* provides optimal approach to PRO development and implementation Can be useful to consider for other COAs Flexibility and judgment needed to meet practical demands Consider the tool s measurement properties: Content validity Construct validity Reliability Ability to detect change Information to support interpretation of change 10 * 5

6 Thinking about Performance Outcome Measures Many of the principles described in the PRO Guidance are relevant to PerfOs Consider: endpoint model, choice of instrument, content validity and other measurement properties, clinical trial design elements, data analysis What aspect of daily life is the performance outcome measure intended to represent? Is this a direct or indirect measure of treatment benefit? Is other supportive information needed to help interpret findings? 11 What is Content Validity PROs: Are we asking the right questions in our assessments? Do clinical trial participants consistently interpret and understand the questions and instructions on the PRO assessment? What does the score of the questionnaire represent? PerfOs: Are we measuring the right aspect in our assessment? Do clinical trial participants and investigators consistently interpret and understand the instructions for the PerfO assessment? What does the score of the assessment represent? 12 6

7 To Illustrate (Lack of) Content Validity with a PerfO Are we measuring the right aspect in our assessment? Study population reports that mobility is a significant problem While interviewing patients, it is identified that their biggest concern/challenge is the ability to stand up from a chair and start walking Performance measure used in clinical trials: 6 minute walk test No assessment of the relevant aspect of mobility that is meaningful to this population of patients in their daily lives 13 More on Content Validity of PerfOs Do clinical trial participants and investigators consistently interpret and understand the instructions for the PerfO assessment? Similar to cognitive debriefing interviews when developing PRO assessments, patient (and test administrators) can be interviewed to ensure they understand the instructions of the performance outcome measure This relates to validity and can also help to improve reliability 14 7

8 More on Content Validity of PerfOs What does the score of the assessment represent? Does it represent something that is clear treatment benefit (i.e., how patients survive or feel or function in daily life)? Consider the 6MWT as a measure of walking speed Consider the delayed word recall test as a measure of memory Consider the 9-hole peg test 15 Direct Verses Indirect Evidence of Treatment Benefit Performance Outcome Measures 6MWT Delayed Word Recall Test Direct Evidence Evidence Continuum Indirect Evidence 16 8

9 Thinking about Meaningful Change How much change is meaningful?

10 Final Thoughts on PerfOs Performance outcome measures may have the benefit of being more sensitive to small changes than other COAs, however, must understand: Whether the assessment represents important daily life benefits Whether detectable but small score changes are meaningful to patients PerfOs might maximize sensitivity at the expense of interpretability of treatment benefit Additional evidence may be needed to help interpret PerfO data 19 10