Transcript Epoetin Alpha: FDA Overview of Patient Reported Outcome (PRO)

Epoetin Alpha:
FDA Overview of
Patient Reported Outcome
(PRO)
Claims
Ann Marie Trentacosti, M.D.
Study Endpoints and Labeling
Office of New Drugs
Food and Drug Administration
September 11, 2007
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PRO Claims
Physician Assessed and Patient Reported
 Performance
 Symptoms of Anemia
 Quality of Life (QOL)
 Health-Related Quality of Life (HRQL)
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Background
Amgen Postmarketing Commitment
 Reassessment of PRO claims
• PRO data
• FDA PRO Guidance
 Provide recommendations for labeling
revisions
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FDA Preliminary
Findings
Based upon the principles of the draft
PRO guidance:
The PRO claims are not adequately
supported by the instruments used or
by the clinical studies reviewed to
date.
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FDA PRO Guidance Overview
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Draft FDA PRO Guidance
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Definitions
 Patient Reported Outcome (PRO)
Assessment
 A measurement reported directly by the
patient
 Physician Outcome Assessment
 A measurement derived from a physician
rating of a patient’s condition or status
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Definitions
(cont)
 Quality of Life (QOL)
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an evaluation of all aspects of life
includes non-health related concerns
inappropriate for medical product labeling
 Health-Related Quality of Life
(HRQL)
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an evaluation of physical, psychological, and social functioning
captures the overall impact of an illness and its treatment
may be appropriate for medical product labeling
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Definitions
(cont)
 Content Validity
Evidence that the concepts, domains, and
items in an instrument are:
• appropriate
• comprehensive
• interpretable
(Based upon input from target population)
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Definitions
(cont)
 Measurement Properties
Assessing the instrument’s ability to
measure a concept
• Content validity
• Construct validity
• Reliability
• Ability to detect change
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Draft PRO Guidance Principles:
Summary
 PRO Measurement Development
• Same standards as other endpoints
 Patient Input
 Instrument Modification
• Reassess measurement properties
 Study Design
• Adequate and well-controlled
• Blinded
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PRO Claims
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Approved Epoetin Alfa Label
Clinical Experience/
Chronic Renal Failure
Once the target hematocrit (32% to 38%) was achieved,
statistically significant improvements were demonstrated
for most quality of life parameters measured, including
energy and activity level, functional ability, sleep and
eating behavior, health status, satisfaction with health, sex
life, well-being, psychological effect, life satisfaction, and
happiness. Patients also reported improvement in their
disease symptoms. They showed a statistically significant
increase in exercise capacity (VO2 max), energy, and
strength with a significant reduction in aching, dizziness,
anxiety, shortness of breath, muscle weakness, and leg
cramps.
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PRO Claim Categories
 Physical Function and
Activity Level
 Anemia Symptoms:
• Decreased Energy
• Muscle Weakness
• Shortness of Breath
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PRO Claim Issues
 Clinical Study Design
 Instruments
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Clinical Study Design
Inadequacies
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Clinical Studies
Study 8601
Basis of
PRO Claims
Open-Label,
Single Arm
Acute Phase
(target Hct 3238)
 Maintenance
Phase
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Study 8701
Study 8904
Study EP 86-004
Randomized,
Double Blind,
Randomized,
Double Blind,
Partial Crossover
Partial Crossover
12 Week
Epoetin vs.
Placebo
12 Week Openlabel
12 Week
26 week
Epoetin vs.
 Epo: Hb 9.5-11
Placebo
 Epo: Hb 11.5-13
12 Week Open-  Placebo
label
Randomized,
Double Blind
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Study Design
Inadequacies
 Open-label design
 No prospective plan for missing
data/multiplicity
 Post-hoc statistical analyses
 No correlation with Hct/Hb and
anemia symptoms
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Instrument Issues
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Instrument Examples
 Karnofsky Performance Scale
 National Kidney Dialysis and Kidney
Transplantation Study (NKDKTS)
Symptom List
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Karnofsky Performance Scale
(KPS)
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NKDKTS
Symptom List
(Revised by sponsor)
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Pain
Tiring easily, no energy
Weakness, lack of strength
Aches, swelling, sick feeling
Fainting spells, dizziness
Nervousness, tension, anxiety
Shortness of breath, trouble breathing
Depression
Tremors
Muscle weakness
Leg cramps
Muscle spasms
Shaky hands
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Instrument Deficiencies
 Lack of Content Validity
(appropriate, comprehensive, interpretable)
• Population
• Indication
 Post-hoc selection of items/subscales
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Summary
 The clinical studies provided were
not adequately designed to
measure HRQL/anemia symptoms.
 The instruments used in the clinical
trials submitted are not adequate
measures of anemia or HRQL for
the target population/indication.
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Endpoint Review Findings
The clinical benefit of Epoetin Alfa in
improvement of patient performance,
anemia symptoms or HRQOL has not been
adequately established.
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