New Drug Application Tolvaptan for the Treatment of Hyponatremia Cardiovascular and Renal Drugs Advisory Committee Meeting June 25, 2008 Center for Drug Evaluation and Research

Tolvaptan for Hyponatremia: FDA Overview of Patient Reported Outcomes Elektra Papadopoulos, M.D. Study Endpoints and Labeling Office of New Drugs Food and Drug Administration June 25, 2008

3 Tolvaptan for Hyponatremia  Patient Reported Outcome (PRO) Measures  FDA Draft PRO Guidance and Concepts  PRO Measurement Issues  Short Form Health Survey (SF-12)  Hyponatremia Disease-Specific Survey  Patient Reported Outcome (PRO) Measures  FDA Draft PRO Guidance and Concepts  PRO Measurement Issues  Short Form Health Survey (SF-12)  Hyponatremia Disease-Specific Survey

4 Proposed Claim Tolvaptan for the treatment of hypervolemic and euvolemic hyponatremia and for the prevention of worsening hyponatremia PRO instruments: to support primary claim Tolvaptan for the treatment of hypervolemic and euvolemic hyponatremia and for the prevention of worsening hyponatremia PRO instruments: to support primary claim

5 Hyponatremia Indication: PRO Endpoints  12-item Short Form Health Survey (SF-12)  Only secondary PRO endpoint  Study (Study 235)  Study (Study 238)  Hyponatremia Disease-specific Survey (HDS)  Only exploratory PRO endpoint  Study 238 only  Added in protocol amendment  12-item Short Form Health Survey (SF-12)  Only secondary PRO endpoint  Study (Study 235)  Study (Study 238)  Hyponatremia Disease-specific Survey (HDS)  Only exploratory PRO endpoint  Study 238 only  Added in protocol amendment

6 Congestive Heart Failure Studies: Other PRO Endpoints  The following PROs were not used for the hyponatremia indication.  Patient assessed global status, Dyspnea Status instrument  The Kansas City Cardiomyopathy Questionnaire. These are not further discussed in this presentation because they are not relevant to the hyponatremia indication.  The following PROs were not used for the hyponatremia indication.  Patient assessed global status, Dyspnea Status instrument  The Kansas City Cardiomyopathy Questionnaire. These are not further discussed in this presentation because they are not relevant to the hyponatremia indication.

7 FDA PRO Guidance and Concepts FDA PRO Guidance and Concepts

8 FDA Draft PRO Guidance

9 Treatment Benefit  An improvement in how a patient survives, feels, or functions as a result of treatment

10 Patient Reported Outcomes  PRO: Any measurement directly from the patient without interpretation by anyone else  Preferred for measuring aspects of treatment benefit known only to patient (e.g., pain)  Not designed to measure cognitive function:  Not reliable in patients with compromised cognition or mental status  PRO: Any measurement directly from the patient without interpretation by anyone else  Preferred for measuring aspects of treatment benefit known only to patient (e.g., pain)  Not designed to measure cognitive function:  Not reliable in patients with compromised cognition or mental status

11 Content Validity  Crucial for any PRO  Input from target population, instrument is:  Appropriate  Comprehensive  Interpretable  “Fit for Purpose”  Assessed in the context of target patient population and indication  Crucial for any PRO  Input from target population, instrument is:  Appropriate  Comprehensive  Interpretable  “Fit for Purpose”  Assessed in the context of target patient population and indication

12 PRO Measurement Issues

13 Hyponatremia Manifestations Primarily neurologic: Osmotic water shifts  brain edema Symptoms may vary depending on chronicity Range from mild confusion, disorientation to obtundation, coma, seizures Other symptoms include nausea and headache Exam: “careful evaluation of mental status and cognitive function” Source: Harrison’s Textbook/ American College of Physicians Primarily neurologic: Osmotic water shifts  brain edema Symptoms may vary depending on chronicity Range from mild confusion, disorientation to obtundation, coma, seizures Other symptoms include nausea and headache Exam: “careful evaluation of mental status and cognitive function” Source: Harrison’s Textbook/ American College of Physicians

14 SF-12

15  Only secondary PRO endpoint (Version 1: one week recall)  Two summary scores:  Mental Component Summary (MCS)  Physical Component Summary (PCS)  No single total score possible  All questions must be complete  Change from baseline PCS and MCS  Study 235: Week 1 and Day 30  Study 238: Week 2 and Day 30  Only secondary PRO endpoint (Version 1: one week recall)  Two summary scores:  Mental Component Summary (MCS)  Physical Component Summary (PCS)  No single total score possible  All questions must be complete  Change from baseline PCS and MCS  Study 235: Week 1 and Day 30  Study 238: Week 2 and Day 30 SF-12 Endpoint

16 SF-12: Review of Content Validity  Measure of overall health status  Developed for use in the general population  Does not assess the symptoms of hyponatremia  Questionable relevance for target population:  “During the past week, how much did pain interfere with your normal work?”  Measure of overall health status  Developed for use in the general population  Does not assess the symptoms of hyponatremia  Questionable relevance for target population:  “During the past week, how much did pain interfere with your normal work?”

17 SF-12: Item Content Summary 1. In general, would you say your health is: 2. Does your health now limit you in: 2a.Moderate activities (e.g., moving a table, pushing a vacuum cleaner, bowling, or playing golf) 2b.Climbing several flights of stairs 3. As a result of your physical health: 3a.Accomplished less than you would like 3b.Limited in kind of work or other activities 1. In general, would you say your health is: 2. Does your health now limit you in: 2a.Moderate activities (e.g., moving a table, pushing a vacuum cleaner, bowling, or playing golf) 2b.Climbing several flights of stairs 3. As a result of your physical health: 3a.Accomplished less than you would like 3b.Limited in kind of work or other activities

18 SF-12: Item Content Summary 4.As a result of any emotional problems: 4a.Accomplished less than you would like 4b.Didn’t do work or other activities as carefully as usual 5.How much did pain interfere with your normal work? 4.As a result of any emotional problems: 4a.Accomplished less than you would like 4b.Didn’t do work or other activities as carefully as usual 5.How much did pain interfere with your normal work?

19 SF-12: Item Content Summary 6. How do you feel and how have things been with you during past week: 6a.Felt calm and peaceful 6b.Have a lot of energy 6c.Felt downhearted and blue 7.How much of the time has your physical health or emotional problems interfered with your social activities? 6. How do you feel and how have things been with you during past week: 6a.Felt calm and peaceful 6b.Have a lot of energy 6c.Felt downhearted and blue 7.How much of the time has your physical health or emotional problems interfered with your social activities?

20 SF-12: Scoring/Interpretation  Results described in two summary scores  Mental Component Score (MCS)  Physical Component Score (PCS)  Same 12 items are used to calculate both PCS and MCS scores, but weighted differently  Results described in two summary scores  Mental Component Score (MCS)  Physical Component Score (PCS)  Same 12 items are used to calculate both PCS and MCS scores, but weighted differently

21 SF-12: MCS/PCS  Higher values indicate better health  Scores standardized to general population  Range (0-100)  Mean= 50; SD=10  All 12 items must be complete to generate MCS and PCS scores  Higher values indicate better health  Scores standardized to general population  Range (0-100)  Mean= 50; SD=10  All 12 items must be complete to generate MCS and PCS scores

22 Results

Cardiorenal Drugs Advisory Committee June 25, Study 235: SF-12 MCS/PCS

24 Study 238: SF-12 MCS/PCS

25 SF-12 MCS Data  Interpretation difficult because:  Content validity not established for hyponatremia patients  MCS does not measure cognitive function or symptoms of hyponatremia  Inclusion criteria did not require patients to have symptoms of hyponatremia at baseline  Interpretation difficult because:  Content validity not established for hyponatremia patients  MCS does not measure cognitive function or symptoms of hyponatremia  Inclusion criteria did not require patients to have symptoms of hyponatremia at baseline

26 SF-12: Summary  SF-12 MCS and PCS are not measures of the clinically important manifestations associated with hyponatremia  MCS does not measure cognitive functioning in hyponatremic patients  PCS does not measure physical functioning in hyponatremic patients  MCS and PCS are not appropriate stand-alone measures to support labeling claims of treatment benefit in patients with hyponatremia  SF-12 MCS and PCS are not measures of the clinically important manifestations associated with hyponatremia  MCS does not measure cognitive functioning in hyponatremic patients  PCS does not measure physical functioning in hyponatremic patients  MCS and PCS are not appropriate stand-alone measures to support labeling claims of treatment benefit in patients with hyponatremia

Hyponatremia Disease-Specific Survey (HDS)

28 Hyponatremia Disease-Specific Survey Hyponatremia Disease-Specific Survey  Exploratory endpoint in Study 238 only  12 items; two-day recall period  Baseline, Week 2, Day 30, and Post- treatment  Assessed in a subset of patients  Total randomized: N= 234  HDS Baseline: N~ 85  HDS Baseline + Day 30: N~ 62  Exploratory endpoint in Study 238 only  12 items; two-day recall period  Baseline, Week 2, Day 30, and Post- treatment  Assessed in a subset of patients  Total randomized: N= 234  HDS Baseline: N~ 85  HDS Baseline + Day 30: N~ 62

29 HDS: Item Content Summary 1.In general, would you say your health over the past two days is:

30 HDS: Item Content Summary Has your thinking ability limited you in these activities over the past two days? 2.Concentrating activities, such as reading a paper, watching television, carrying on a conversation? 3.Calculating activities, such as changing money, telling time, simple mathematics? 4.Language activities, such as crossword puzzles, thinking or speaking words or names? 5.Memory activities such as finding misplaced keys, remembering appointments?

31 HDS: Item Content Summary Has your strength and coordination limited you in these activities over the past two days? 6.Endurance activities (walking, carrying bags, standing for long periods)? 7.Strength activities (rising from bed, lifting objects, opening doors)? 8.Gross coordination activities (walking steadily, dancing, driving)? 9.Fine coordination activities (writing, drawing, knitting, putting on makeup, working with tools)? Has your strength and coordination limited you in these activities over the past two days? 6.Endurance activities (walking, carrying bags, standing for long periods)? 7.Strength activities (rising from bed, lifting objects, opening doors)? 8.Gross coordination activities (walking steadily, dancing, driving)? 9.Fine coordination activities (writing, drawing, knitting, putting on makeup, working with tools)?

32 HDS: Item Content Summary 10.Right now, do you think your sodium (salt) concentration is: 11.What has your sensation of thirst been over the past two days without factoring (or considering) the amount of water you drink each day? 12.As an overall assessment of how you have been feeling since therapy with tolvaptan started, please select the box which describes how you (or your physician) believe this treatment has affected your activity, symptoms and emotional well-being. 10.Right now, do you think your sodium (salt) concentration is: 11.What has your sensation of thirst been over the past two days without factoring (or considering) the amount of water you drink each day? 12.As an overall assessment of how you have been feeling since therapy with tolvaptan started, please select the box which describes how you (or your physician) believe this treatment has affected your activity, symptoms and emotional well-being.

33 HDS: Issues  Exploratory endpoint  Development history, evidence of content validity, and scoring information not available  Post-hoc definition of MCS and PCS  Not a measure of cognitive function  Questionable content on inspection of individual items  Exploratory endpoint  Development history, evidence of content validity, and scoring information not available  Post-hoc definition of MCS and PCS  Not a measure of cognitive function  Questionable content on inspection of individual items

34 Summary of PRO Measurement Issues Patient population concerns: – Concomitant underlying illnesses – Inpatient vs. outpatient – Chronicity of hyponatremia ill-defined Missing data Inclusion criteria did not require patients to have symptoms of hyponatremia at baseline Multiplicity without pre-specified analysis plan Patient population concerns: – Concomitant underlying illnesses – Inpatient vs. outpatient – Chronicity of hyponatremia ill-defined Missing data Inclusion criteria did not require patients to have symptoms of hyponatremia at baseline Multiplicity without pre-specified analysis plan

35 Conclusions

36 ConclusionsConclusions SF-12 (MCS, PCS) and HDS are not valid measures of the symptoms of hyponatremia or cognitive function Treatment benefit of tolvaptan— improvement in how patients feel or function—has not been established SF-12 (MCS, PCS) and HDS are not valid measures of the symptoms of hyponatremia or cognitive function Treatment benefit of tolvaptan— improvement in how patients feel or function—has not been established