1. 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 benefit or 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) 2

3. 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 URINARY INCONTINENCE Labeling claim for ANTUROL Claim first approval:07 December 2011

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

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

10. Concept of Measurement to Support Direct Evidence of Treatment Benefit Social functioning General psychological functioning Proximal disease Impact concepts Distal disease Impact concepts Related functioning Related S/Ss Disease-defining concepts Health-related quality of life Disease impact on general life concepts Satisfaction with health Core signs, symptoms or decrements in functioning Additional functioning Additional S/Ss General physical functioning Productivity Health status 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 Cough Shoulder Pain Difficulty breathing Hoarseness Wheezing Swelling of the face/neck Lack of energy Depression Social functioning Overall impact on HRQL Anxiety Weight loss Decreased appetite Memory Ambulation Difficulty with activities of daily living Helplessness/ hopelessness Independence Sleep disturbance Concentration/clarity of thinking Shortness of breath Tightness in chest Phlegm Difficulty swallowing Loss of stamina Life interference 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 Chest Pain

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) 12

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

14. PRO Instrument Development within an Individual Drug Development Program 14 Pre-IND/Phase 1Phase 2APhase 2BPhase 3NDA Submission 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 15

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

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 18

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

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

21. Thank you.