New Drug Application 22-275New Drug Application 22-275Tolvaptan for the Treatment of Tolvaptan for the Treatment of
HyponatremiaHyponatremia
New Drug Application 22-275New Drug Application 22-275Tolvaptan for the Treatment of Tolvaptan for the Treatment of
HyponatremiaHyponatremia
Cardiovascular and Renal Drugs Advisory Cardiovascular and Renal Drugs Advisory Committee Meeting Committee Meeting June 25, 2008June 25, 2008
Cardiovascular and Renal Drugs Advisory Cardiovascular and Renal Drugs Advisory Committee Meeting Committee Meeting June 25, 2008June 25, 2008
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
Tolvaptan for Hyponatremia:Tolvaptan for Hyponatremia:FDA Overview of FDA Overview of
Patient Reported OutcomesPatient Reported Outcomes
Tolvaptan for Hyponatremia:Tolvaptan for Hyponatremia:FDA Overview of FDA Overview of
Patient Reported OutcomesPatient Reported Outcomes
Elektra Papadopoulos, M.D.Study Endpoints and Labeling
Office of New DrugsFood and Drug Administration
June 25, 2008
Elektra Papadopoulos, M.D.Study Endpoints and Labeling
Office of New DrugsFood and Drug Administration
June 25, 2008
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Tolvaptan for HyponatremiaTolvaptan for HyponatremiaTolvaptan for HyponatremiaTolvaptan 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
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Proposed ClaimProposed 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
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Hyponatremia Indication:Hyponatremia Indication:PRO EndpointsPRO Endpoints
Hyponatremia Indication:Hyponatremia Indication:PRO EndpointsPRO Endpoints
12-item Short Form Health Survey (SF-12) Only secondary PRO endpoint
Study 156-02-235 (Study 235)Study 156-03-238 (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 156-02-235 (Study 235)Study 156-03-238 (Study 238)
Hyponatremia Disease-specific Survey (HDS) Only exploratory PRO endpoint
Study 238 only Added in protocol amendment
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Congestive Heart Failure Studies:Congestive Heart Failure Studies:Other PRO EndpointsOther PRO Endpoints
Congestive Heart Failure Studies:Congestive Heart Failure Studies:Other PRO EndpointsOther 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.
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FDA PRO Guidance and Concepts
FDA PRO Guidance and Concepts
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FDA Draft PRO GuidanceFDA Draft PRO GuidanceFDA Draft PRO GuidanceFDA Draft PRO Guidance
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Treatment BenefitTreatment BenefitTreatment BenefitTreatment Benefit
An improvement in how a patient survives, feels, or functions as a result of treatment
An improvement in how a patient survives, feels, or functions as a result of treatment
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Patient Reported OutcomesPatient Reported OutcomesPatient Reported OutcomesPatient 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
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Content ValidityContent ValidityContent ValidityContent 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
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PRO Measurement Issues PRO Measurement Issues
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Hyponatremia ManifestationsHyponatremia ManifestationsHyponatremia ManifestationsHyponatremia 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
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SF-12 SF-12
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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 EndpointSF-12 EndpointSF-12 EndpointSF-12 Endpoint
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SF-12: SF-12: Review of Content ValidityReview of Content Validity
SF-12: SF-12: Review of Content ValidityReview 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?”
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SF-12: SF-12: Item Content SummaryItem Content Summary
SF-12: SF-12: Item Content SummaryItem 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 like3b. 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 like3b. Limited in kind of work or other activities
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SF-12: SF-12: Item Content SummaryItem Content Summary
SF-12: SF-12: Item Content SummaryItem Content Summary
4. As a result of any emotional problems: 4a.Accomplished less than you would like4b.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 like4b.Didn’t do work or other activities as
carefully as usual
5. How much did pain interfere with your normal work?
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SF-12: SF-12: Item Content SummaryItem Content Summary
SF-12: SF-12: Item Content SummaryItem 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?
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SF-12:SF-12: Scoring/Interpretation Scoring/Interpretation
SF-12:SF-12: Scoring/Interpretation 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
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SF-12: MCS/PCSSF-12: MCS/PCSSF-12: MCS/PCSSF-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
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ResultsResults
Cardiorenal Drugs Cardiorenal Drugs Advisory Committee Advisory Committee June 25, 2008 23
Study 235: SF-12 MCS/PCSStudy 235: SF-12 MCS/PCSStudy 235: SF-12 MCS/PCSStudy 235: SF-12 MCS/PCS
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Study 238: SF-12 MCS/PCSStudy 238: SF-12 MCS/PCSStudy 238: SF-12 MCS/PCSStudy 238: SF-12 MCS/PCS
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SF-12 MCS DataSF-12 MCS DataSF-12 MCS DataSF-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
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SF-12: SummarySF-12: SummarySF-12: SummarySF-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)
Hyponatremia Disease-Specific Survey(HDS)
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Hyponatremia Disease-Specific Hyponatremia Disease-Specific SurveySurvey
Hyponatremia Disease-Specific Hyponatremia Disease-Specific SurveySurvey
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
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HDS: HDS: Item Content SummaryItem Content SummaryHDS: HDS: Item Content SummaryItem Content Summary
1. In general, would you say your health over the past two days is:
1. In general, would you say your health over the past two days is:
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HDS: HDS: Item Content SummaryItem Content SummaryHDS: HDS: Item Content SummaryItem 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?
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?
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HDS: HDS: Item Content SummaryItem Content SummaryHDS: HDS: Item Content SummaryItem 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)?
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HDS: HDS: Item Content SummaryItem Content SummaryHDS: HDS: Item Content SummaryItem 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.
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HDS: IssuesHDS: IssuesHDS: IssuesHDS: 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
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Summary of PRO Summary of PRO Measurement IssuesMeasurement IssuesSummary of PRO Summary of PRO
Measurement IssuesMeasurement 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
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ConclusionsConclusions
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ConclusionsConclusionsConclusionsConclusions
• 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