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FDA Approach to Patient-Reported Outcome Measure Development

FDA Approach to Patient-Reported Outcome Measure Development. Risa Hayes, PhD Research Advisor Eli Lilly and Company May 22, 2012. Patient-Reported Outcome (PRO) Measures.

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FDA Approach to Patient-Reported Outcome Measure Development

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  1. FDA Approach to Patient-Reported Outcome Measure Development Risa Hayes, PhD Research Advisor Eli Lilly and Company May 22, 2012

  2. Patient-Reported Outcome (PRO) Measures • A patient-reported outcome (PRO) is any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. • A PRO instrument is used to measure treatment benefitor risk in medical product clinical trials. • A PRO is a clinical outcome assessment (COAs) • Patient-reported outcome assessments (PROs) • Clinician-reported outcome assessments (ClinROs) • Observer-reported outcome assessments (ObsROs)

  3. URINARY INCONTINENCE Labeling claim for ANTUROL Claim first approval:07 December 2011 Patients treated with ANTUROL (84 mg) experienced a statistically significant decrease in the number of urinary incontinence episodes per week from baseline to endpoint (the primary efficacy endpoint) compared with placebo (p=0.0445) and patients treated with the 56 mg dose did not show statistically significant efficacy. Statistically significant improvements in daily urinary frequency (p=0.0010) and urinary void volume (p<0.0001) were also seen with ANTUROL (84 mg) relative to placebo. The mean difference from placebo for ANTUROL (84 mg) was -2.3 for urinary incontinence episodes per week in a group of patients with a mean of greater than 40 incontinence episodes per week at baseline. Mean and median change from baseline in weekly incontinence episodes (primary endpoint), daily urinary frequency, and urinary void volume (secondary endpoints) between placebo and ANTUROL are summarized in Table 3. Source: PROLabels

  4. PRO Measures to Support Labeling • The Food and Drug Administration (FDA) reviews and evaluates existing, modified, or newly created patient-reported outcome (PRO) instruments to support labeling claims • Two methods for development of PRO instruments but one standard of evidence

  5. PRO Instrument Development to Support Labeling Claims NDA/IND process? DDT Qualification process? Guidance for Industry Patient-Reported Measures: Use in Medical Product Development to Support Labeling Claims Guidance for Industry Patient-Reported Measures: Use in Medical Product Development to Support Labeling Claims Guidance for Industry Qualification Process for Drug Development Tools

  6. PRO Consortium Industry Members • Abbott Laboratories • Actelion Pharmaceuticals Ltd. • Amgen Inc. • AstellasPharma US, Inc. • AstraZeneca Pharmaceuticals • BoehringerIngelheim Pharmaceuticals, Inc. • Bristol-Myers Squibb Company • Daiichi Sankyo, Inc. • Eisai • Eli Lilly & Company • Forest Research Institute • GlaxoSmithKline • Ironwood Pharmaceuticals, Inc. • Janssen Pharmaceutical Companies of Johnson & Johnson • Merck Sharp & Dohme • Novartis Pharmaceutical Corporation • Novo Nordisk, Inc. • Pfizer, Inc. • Roche • Sanofi • Shire Corp. • Sunovion Pharmaceuticals Inc. • Takeda Pharmaceuticals US • UCB Pharma Ltd. Working Groups • Asthma • Cognition • Depression • Functional Dyspepsia • Irritable Bowel Syndrome • Non-Small Cell Lung Cancer • Rheumatoid Arthritis

  7. Team for PRO Measure Development • Medical • Regulatory • Outcomes research • Statistics • Data management • Marketing

  8. Pre-IND/Phase 1 Phase 2A Phase 2B Phase 3 NDA Submission PRO Instrument Development within an Individual Drug Development Program Establish Content Validity(e.g., Qualitative Research, Mixed Methods) Define Concept of Measurement and Context of Use Establish other measurement properties (e.g., Quantitative Longitudinal Research) PRO dossier submitted as part of NDA/IND

  9. Treatment Benefit The impact of treatment on how patients survive, feel, or function • Efficacy (e.g., improvement or delay in the development of symptoms) • Comparative safety (e.g., reduction or delay in treatment-related toxicity)

  10. Concept of Measurement to Support Direct Evidence of Treatment Benefit 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 S/Ss Related S/Ss Satisfaction withhealth Social functioning Proximal concept to treatment benefit Distal concept to treatment benefit

  11. Example: Direct Evidence of Treatment Benefit in Non-Small Cell Lung Cancer* Disease –defining concepts Proximal disease impact concepts Distal disease impact concepts Distal impact on general life concepts Weight loss Anxiety Social functioning Cough Memory Decreased appetite Concentration/clarity of thinking Overall impact on HRQL Shortness of breath Difficulty swallowing Depression Shoulder Pain Life interference Hoarseness Ambulation Helplessness/hopelessness Chest Pain Sleep disturbance Lack of energy Tightness in chest Phlegm Loss of stamina Independence Wheezing Difficulty breathing Difficulty with activities of daily living Swelling of the face/neck Proximal concept to treatment benefit Distal concept to treatment benefit * Concepts identified through a cursory review of the literature. Graph will evolve based on findings from qualitative research and clinician expertise * Graph does not include concepts measured by biomarkers, ClinRO measures, or ObsRO measures

  12. Context of Use • Disease definition • Target subpopulation (age, disease severity) • Clinical trial design and objectives (targeted claim) • Geographic location of the study sites • Language and culture • Clinical practice variations • Other (e.g., format)

  13. Endpoint Model An Endpoint Model displays the role and hierarchy of relevant outcome concepts in clinical trials (i.e., all primary and secondary endpoints) Endpoints hierachy Concepts COA/Biomarker/Survival Primary • Concept A • Weight loss • OA 1 • % weight lost from baseline to endpoint in kg • Concept B • Blood pressure • Concept C • Ability to do physical activities • OA 2 • Systolic/diastolic • OA 3 • New PRO instrument Secondary withHierarchy Exploratory • Other OA • New PRO instrument Concept D Self-esteem

  14. Pre-IND/Phase 1 Phase 2A Phase 2B Phase 3 NDA Submission PRO Instrument Development within an Individual Drug Development Program Establish Content Validity(e.g., Qualitative Research, Mixed Methods) Define Concept of Measurement and Context of Use

  15. “Well Defined and Reliable” Measurement Properties • Documented in the targeted context of use • Content validity • Includes qualitative research in target population of responders • May include quantitative methods (e.g., Rasch, IRT, classical test theory) to assess item function • Established before study of other measurement properties

  16. Mixed Methods Approach to Assuring Content Validity • Quantitative methods • Content validity state – exploratory • Psychometric analysis stage – confirmatory • Sample Size Considerations • Samples as small as 30 individuals can provide useful descriptive information • Multivariate methods, such as factor analysis can require larger samples

  17. Pre-IND/Phase 1 Phase 2A Phase 2B Phase 3 NDA Submission PRO Instrument Development within an Individual Drug Development Program Establish Content Validity(e.g., Qualitative Research, Mixed Methods) Define Concept of Measurement and Context of Use Establish other measurement properties (e.g., Quantitative Longitudinal Research)

  18. “Well Defined and Reliable” Measurement Properties • Documented in the targeted context of use • Content validity • Includes qualitative research in target population of responders • May include quantitative methods (e.g., Rasch, IRT, classical test theory) to assess item function • Established before study of other measurement properties • Construct validity • Reliability (most critical: test-retest for PRO assessments) • Sensitivity to change (consistent with study objectives) • Responder definition

  19. Pre-IND/Phase 1 Phase 2A Phase 2B Phase 3 NDA Submission PRO Instrument Development within an Individual Drug Development Program Establish Content Validity(e.g., Qualitative Research, Mixed Methods) Define Concept of Measurement and Context of Use Establish other measurement properties (e.g., Quantitative Longitudinal Research) PRO dossier submitted as part of NDA/IND

  20. Pre-IND/Phase 1 Phase 2A Phase 2B Phase 3 NDA Submission Use of a Qualified COA in a Drug Development Program Phase 2A Phase 2B NDA/BLA Submission Define Concept(s) & Context of Use Reference to the DDT PRO qualification specific guidance and submit as part of NDA/IND Qualified DDT COA in its targeted context of use

  21. Thank you.

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