Using Patient Reported Outcome as Primary or Key Secondary Endpoints-A Regulatory Perspective Shiling Ruan FDA/CDRH/OSB/DBS Advamed-FDA Statistics Workshop, Gaithersburg, MD Apr 29-30, 2009 1
Acknowledgment I would like to thank my colleagues in the Division of Biostatistics, especially Gregory Campbell, Richard Kotz, Chang Lao, Martin Ho, and Thomas Gwise, for their valuable comments. Disclaimer The views expressed here are those of the presenter and not necessarily those of the FDA. 2
Outline 1. Introduction 2. Why use PRO 3. Using PRO to support labeling claims 4. Assessment of Instruments 5. Study design and analysis issues 6. Summary 7. References 3
1. Introduction PRO: Measurements of any aspect of a patient s health status that comes directly from patients. Types 1. Simple: symptom frequency, intensity. 2. Complex: daily functioning ability. 3. Extremely complex concepts: Health-Related Quality of Life (HRQoL), multidomain concept with physical, psychological, and social components. 4
2. Why Use PRO Some treatment effect are known only to the patients (pain intensity, pain duration). Unique perspective on treatment effectiveness. HRQoL: main reason to seek surgical treatment for patients with Stress Urinary Incontinence. May be more reliable and less subject to bias than informal interviews administered by an observer. 5
3. Using PRO to Support Labeling Claims Using validated instruments. Additional validation is needed for modified instruments. The instrument is specific to the intended population (age, sex, cognitive ability, etc.) The instrument is specific to the characteristics of the condition or disease treated. 6
4a. Assessment of Instruments 1. Reliability: reliably measures the concept it was designed to measure. 2. Validity: measures what it claims to measure. 3. Ability to detect change: Demonstrated by comparative study in the time interval appropriate for the study. 4. Interpretability: Definition of Minimum Important Difference (MID). Definition of Responder. 7
4b. Definition of MID PRO-> Non-PRO measurements: i.e, anchor-based approach. PRO-> other PRO scores: i.e., multi-item PROs mapped to a single question Distribution based approach: i.e., MID= 0.2 * standard deviation of baseline scores. Using an empirical rule: i.e., use 10%* maximum range of scores. It is best to use various methods to confirm the choice of MID. 8
4c. Definition of Responders Based on individual patient responses. Pre-specified criteria (i.e., % change from baseline, > a specified threshold). Need evidence to support the definition as a measure of benefit. 9
5a. Study Design Blinding and randomization are critical Patients responses are subjective. PRO from open-label studies are rarely sufficient to support labeling claims on their own. current status assessment is more reliable than comparing current status to baseline. 10
Example 1: UroMed Miniguard (received 510 (K) clearance in 1998) A small, disposable patch to help women reduce leakage from stress urinary incontinence. Design: One-arm open label. Primary endpoints: # of incontinence events. Perceived severity of incontinence (Symptom Questionnaire). HRQoL (Incontinence Impact Questionnaire). Amount of leakage. 11
Example 2: Asthmatx Trial (Cited from Reuters News Article) Device: the Alair(R) Bronchial Thermoplasty System for adults with severe asthma. Design: multi-center, randomized, double-blind, sham-controlled. The primary endpoint: Asthma Quality of Life Questionnaire (AQLQ) score. a validated instrument, developed to measure the functional problems (physical, emotional, social and occupational) that are most troublesome to adults (17-70 years) with asthma. MID: a change in score of 0.5 on the 7-point scale. 12
5b. Other Design and Analysis Issues Multiple endpoints: Control of Type I error, Sample size issues. Composite measures: Individual vs. composite results, Improvement driven by a single domain. 13
5c. Other Design and Analysis Issues Plans to handle missing data: Missing item within a domain, Missing entire domain, Type of missing data. Methods to analyze different types of response data Continuous data Ordinal data Nominal data 14
6. Summary PRO may be used as primary or key secondary endpoints to support the label claims with well-designed and well-controlled clinical trials, well-validated Instruments. The FDA guidance document for using patient reported outcomes provides general recommendations that are applicable to Drug, Devices, and Biologics. http://www.fda.gov/cder/guidance/5460dft.pdf. 15
7. References 1. http://www.fda.gov/cder/guidance/5460dft.pdf. FDA Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims (DRAFT). 2. J. A. Sloan, M. Y. Halyard, M. H. Frost, A. C. Dueck, B. Teschendorf, M. L. Rothman, The Mayo Clinic Manuscript Series Relative to the Discussion,Dissemination, and operationalization of the Food and Drug Administration Guidance on Patient-Reported Outcomes, Volume in Health, 10, 2007, page 59-63 3. Karen M Gil, Amber M Somerville, Sara Cichowski, Jennifer L Savitski, Distress and quality of life characteristics associated with seeking surgical treatment for stress urinary incontinence, Health and Quality of Life Outcomes, 2009, 7:8 4. http://www.reuters.com/article/pressrelease/idus120916+12-jan- 2009+MW20090112, Asthmatx Seeks FDA Approval of New Device-Based Procedure for Severe Asthma. 5. A.V. Karkani, Distribution-based and anchor-based approaches provided different interpretability estimates for the Hydrocephalus Outcome Questionnaire, Journal of Clinical Epidemiology, 59(2), 176-184. 16