New Drug Application 22-275 Tolvaptan for the Treatment of Hyponatremia

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New Drug Application 22-275Tolvaptan for the
Treatment of Hyponatremia

• Cardiovascular and Renal Drugs Advisory Committee
  Meeting
• June 25, 2008

Center for Drug Evaluation and Research
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Tolvaptan for HyponatremiaFDA Overview of
Patient Reported Outcomes

• Elektra Papadopoulos, M.D.
• Study Endpoints and Labeling
• Office of New Drugs
• Food and Drug Administration
• June 25, 2008

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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

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Proposed 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 IndicationPRO 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

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Congestive Heart Failure StudiesOther 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.

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• FDA PRO
• Guidance and Concepts

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FDA Draft PRO Guidance
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Treatment Benefit

• An improvement in how a patient survives, feels,
  or functions as a result of treatment

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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

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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

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• PRO Measurement Issues

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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 Harrisons Textbook/ American College of
  Physicians

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• SF-12

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SF-12 Endpoint

• 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

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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?

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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

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SF-12 Item Content Summary

• 4. As a result of any emotional problems
• 4a. Accomplished less than you would like
• 4b. Didnt 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 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?

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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

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SF-12 MCS/PCS

• Higher values indicate better health
• Scores standardized to general population
• Range (0-100)
• Mean 50 SD10
• All 12 items must be complete to generate MCS
  and PCS scores

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• Results

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Study 235 SF-12 MCS/PCS
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Study 238 SF-12 MCS/PCS
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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

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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

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Hyponatremia Disease-Specific Survey(HDS)
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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

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HDS Item Content Summary

• In general, would you say your health over the
  past two days is

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HDS Item Content Summary

• Has your thinking ability limited you in
  these activities over the past two days?
• Concentrating activities, such as reading a
  paper, watching television, carrying on a
  conversation?
• Calculating activities, such as changing money,
  telling time, simple mathematics?
• Language activities, such as crossword puzzles,
  thinking or speaking words or names?
• Memory activities such as finding misplaced keys,
  remembering appointments?

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HDS Item Content Summary

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

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HDS Item Content Summary

• Right now, do you think your sodium (salt)
  concentration is
• What has your sensation of thirst been over the
  past two days without factoring (or considering)
  the amount of water you drink each day?
• 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 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

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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

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• Conclusions

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Conclusions

• SF-12 (MCS, PCS) and HDS are not valid measures
  of the symptoms of hyponatremia or cognitive
  function
• Treatment benefit of tolvaptanimprovement in how
  patients feel or functionhas not been established