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Epoetin Alpha:Epoetin Alpha:FDA Overview of FDA Overview of

Patient Reported OutcomePatient Reported Outcome(PRO)(PRO)ClaimsClaims

Ann Marie Trentacosti, M.D.Ann Marie Trentacosti, M.D.Study Endpoints and LabelingStudy Endpoints and Labeling

Office of New DrugsOffice of New DrugsFood and Drug AdministrationFood and Drug Administration

September 11, 2007September 11, 2007

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PRO ClaimsPRO Claims

Physician Assessed and Patient ReportedPhysician Assessed and Patient Reported

PerformancePerformance

Symptoms of AnemiaSymptoms of Anemia

Quality of Life (QOL)Quality of Life (QOL)

Health-Related Quality of Life (HRQL)Health-Related Quality of Life (HRQL)

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BackgroundBackground

Amgen Postmarketing CommitmentAmgen Postmarketing Commitment

Reassessment of PRO claimsReassessment of PRO claims• PRO dataPRO data• FDA PRO GuidanceFDA PRO Guidance

Provide recommendations for labelingProvide recommendations for labeling

revisionsrevisions

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FDA PreliminaryFDA PreliminaryFindingsFindings

Based upon the principles of the draftBased upon the principles of the draft

PRO guidance:PRO guidance:

The PRO claims are not adequately The PRO claims are not adequately supported by the instruments used or supported by the instruments used or by the clinical studies reviewed to by the clinical studies reviewed to date.date.

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FDA PRO Guidance OverviewFDA PRO Guidance Overview

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Draft FDA PRO GuidanceDraft FDA PRO Guidance

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DefinitionsDefinitions

Patient Reported Outcome (PRO)Patient Reported Outcome (PRO)

AssessmentAssessment

A measurement reported directly by the A measurement reported directly by the patientpatient

Physician Outcome AssessmentPhysician Outcome Assessment

A measurement derived from a physician A measurement derived from a physician rating of a patient’s condition or statusrating of a patient’s condition or status

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DefinitionsDefinitions(cont)(cont)

Quality of Life (QOL)Quality of Life (QOL) an evaluation of all aspects of lifean evaluation of all aspects of life

includes non-health related concernsincludes non-health related concerns

inappropriate for medical product labeling inappropriate for medical product labeling

Health-Related Quality of Life Health-Related Quality of Life

(HRQL)(HRQL) an evaluation of physical, psychological, and social functioningan evaluation of physical, psychological, and social functioning

captures the overall impact of an illness and its treatment captures the overall impact of an illness and its treatment

may be appropriate for medical product labelingmay be appropriate for medical product labeling

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DefinitionsDefinitions(cont)(cont)

Content ValidityContent Validity

Evidence that the concepts, domains, and Evidence that the concepts, domains, and items in an instrument are: items in an instrument are: • appropriate appropriate • comprehensive comprehensive • interpretableinterpretable

(Based upon input from target population)(Based upon input from target population)

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DefinitionsDefinitions(cont)(cont)

Measurement Properties Measurement Properties Assessing the instrument’s ability to Assessing the instrument’s ability to measure a conceptmeasure a concept

• Content validityContent validity• Construct validityConstruct validity• ReliabilityReliability• Ability to detect changeAbility to detect change

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Draft PRO Guidance Principles: Draft PRO Guidance Principles: Summary Summary

PRO Measurement DevelopmentPRO Measurement Development• Same standards as other endpointsSame standards as other endpoints

Patient InputPatient Input

Instrument ModificationInstrument Modification• Reassess measurement propertiesReassess measurement properties

Study DesignStudy Design• Adequate and well-controlledAdequate and well-controlled• BlindedBlinded

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PRO ClaimsPRO Claims

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Approved Epoetin Alfa LabelApproved Epoetin Alfa LabelClinical Experience/Clinical Experience/

Chronic Renal FailureChronic Renal Failure Once the target hematocrit (32% to 38%) was achieved, Once the target hematocrit (32% to 38%) was achieved,

statistically significant improvements were demonstrated statistically significant improvements were demonstrated for most quality of life parameters measured, including for most quality of life parameters measured, including energy and activity level, functional ability, sleep and energy and activity level, functional ability, sleep and eating behavior, health status, satisfaction with health, sex eating behavior, health status, satisfaction with health, sex life, well-being, psychological effect, life satisfaction, and life, well-being, psychological effect, life satisfaction, and happiness. Patients also reported improvement in their happiness. Patients also reported improvement in their disease symptoms. They showed a statistically significant disease symptoms. They showed a statistically significant increase in exercise capacity (VO2 max), energy, and increase in exercise capacity (VO2 max), energy, and strength with a significant reduction in aching, dizziness, strength with a significant reduction in aching, dizziness, anxiety, shortness of breath, muscle weakness, and leg anxiety, shortness of breath, muscle weakness, and leg cramps.cramps.

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PRO Claim CategoriesPRO Claim Categories

Physical Function andPhysical Function and Activity LevelActivity Level

Anemia Symptoms:Anemia Symptoms:• Decreased EnergyDecreased Energy• Muscle WeaknessMuscle Weakness• Shortness of BreathShortness of Breath

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PRO Claim IssuesPRO Claim Issues

Clinical Study DesignClinical Study Design

InstrumentsInstruments

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Clinical Study Design Clinical Study Design InadequaciesInadequacies

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Clinical StudiesClinical StudiesStudy 8601Study 8601

Basis of Basis of

PRO ClaimsPRO Claims

Study 8701Study 8701 Study 8904Study 8904 Study EP 86-004Study EP 86-004

Open-Label,Open-Label,

Single ArmSingle Arm

Randomized, Randomized, Double Blind,Double Blind,

Partial Cross-Partial Cross-overover

Randomized, Randomized, Double Blind, Double Blind,

Partial Cross-Partial Cross-overover

Randomized, Randomized, Double BlindDouble Blind

Acute Phase Acute Phase (target Hct 32-(target Hct 32-38)38) Maintenance Maintenance PhasePhase

12 Week 12 Week Epoetin vs. Epoetin vs. Placebo Placebo

12 Week Open-12 Week Open-labellabel

12 Week 12 Week Epoetin vs. Epoetin vs. Placebo Placebo

12 Week Open-12 Week Open-labellabel

26 week26 week Epo: Hb 9.5-11Epo: Hb 9.5-11 Epo: Hb 11.5-13Epo: Hb 11.5-13 PlaceboPlacebo

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Study Design Study Design InadequaciesInadequacies

Open-label designOpen-label design No prospective plan for missingNo prospective plan for missing

data/multiplicity data/multiplicity Post-hoc statistical analyses Post-hoc statistical analyses No correlation with Hct/Hb andNo correlation with Hct/Hb and

anemia symptomsanemia symptoms

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Instrument IssuesInstrument Issues

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Instrument ExamplesInstrument Examples

Karnofsky Performance ScaleKarnofsky Performance Scale

National Kidney Dialysis and Kidney National Kidney Dialysis and Kidney

Transplantation Study (NKDKTS) Transplantation Study (NKDKTS)

Symptom ListSymptom List

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Karnofsky Performance ScaleKarnofsky Performance Scale(KPS)(KPS)

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NKDKTSNKDKTSSymptom List Symptom List (Revised by sponsor)(Revised by sponsor)

Pain Pain Tiring easily, no energyTiring easily, no energy Weakness, lack of strengthWeakness, lack of strength Aches, swelling, sick feeling Aches, swelling, sick feeling Fainting spells, dizzinessFainting spells, dizziness Nervousness, tension, anxiety Nervousness, tension, anxiety Shortness of breath, trouble breathingShortness of breath, trouble breathing Depression Depression TremorsTremors Muscle weaknessMuscle weakness Leg cramps Leg cramps Muscle spasms Muscle spasms Shaky handsShaky hands

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Instrument DeficienciesInstrument Deficiencies

Lack of Content ValidityLack of Content Validity

(appropriate, comprehensive, interpretable)(appropriate, comprehensive, interpretable) • PopulationPopulation

• IndicationIndication

Post-hoc selection of items/subscalesPost-hoc selection of items/subscales

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SummarySummary

The clinical studies provided were The clinical studies provided were not adequately designed tonot adequately designed to measure HRQL/anemia symptoms.measure HRQL/anemia symptoms.

The instruments used in the clinicalThe instruments used in the clinical trials submitted are not adequatetrials submitted are not adequate measures of anemia or HRQL for measures of anemia or HRQL for the target population/indication.the target population/indication.

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Endpoint Review FindingsEndpoint Review Findings

The clinical benefit of Epoetin Alfa in The clinical benefit of Epoetin Alfa in

improvement of patient performance, improvement of patient performance,

anemia symptoms or HRQOL has not beenanemia symptoms or HRQOL has not been

adequately established. adequately established.

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