new drug application 22-275 tolvaptan for the treatment of hyponatremia cardiovascular and renal...

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


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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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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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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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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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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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

new drug application 22-275 tolvaptan for the treatment of hyponatremia cardiovascular and renal...

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