1. 1 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

2. 2 PRO Claims Physician Assessed and Patient Reported Physician Assessed and Patient Reported  Performance  Symptoms of Anemia  Quality of Life (QOL)  Health-Related Quality of Life (HRQL)

3. 3 Background Amgen Postmarketing Commitment  Reassessment of PRO claims PRO dataPRO data FDA PRO GuidanceFDA PRO Guidance  Provide recommendations for labeling revisions revisions

4. 4 FDA Preliminary Findings Based upon the principles of the draft Based upon the principles of the draft PRO guidance: PRO guidance: The PRO claims are not adequately supported by the instruments used or by the clinical studies reviewed to date. The PRO claims are not adequately supported by the instruments used or by the clinical studies reviewed to date.

5. 5 FDA PRO Guidance Overview

6. 6 Draft FDA PRO Guidance

7. 7Definitions  Patient Reported Outcome (PRO) Assessment 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

8. 8 Definitions (cont)  Quality of Life (QOL)  an evaluation of all aspects of life  includes non-health related concerns  inappropriate for medical product labeling  Health-Related Quality of Life (HRQL) (HRQL)  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

9. 9 Definitions (cont)  Content Validity Evidence that the concepts, domains, and items in an instrument are: Evidence that the concepts, domains, and items in an instrument are: appropriateappropriate comprehensivecomprehensive interpretableinterpretable (Based upon input from target population) (Based upon input from target population)

10. 10 Definitions (cont)  Measurement Properties Assessing the instrument’s ability to measure a concept Content validityContent validity Construct validityConstruct validity ReliabilityReliability Ability to detect changeAbility to detect change

11. 11 Draft PRO Guidance Principles: Summary Draft PRO Guidance Principles: Summary  PRO Measurement Development Same standards as other endpointsSame standards as other endpoints  Patient Input  Instrument Modification Reassess measurement propertiesReassess measurement properties  Study Design Adequate and well-controlledAdequate and well-controlled BlindedBlinded

12. 12 PRO Claims

13. 13 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. 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.

14. 14 PRO Claim Categories  Physical Function and Activity Level Activity Level  Anemia Symptoms: Decreased EnergyDecreased Energy Muscle WeaknessMuscle Weakness Shortness of BreathShortness of Breath

15. 15 PRO Claim Issues  Clinical Study Design  Instruments

16. 16 Clinical Study Design Inadequacies

17. 17 Clinical Studies Study 8601 Basis of PRO Claims Study 8701 Study 8904 Study EP 86-004 Open-Label, Single Arm Randomized, Double Blind, Partial Cross- over Randomized, Double Blind, Partial Cross- over Randomized, Double Blind Acute Phase (target Hct 32- 38) Acute Phase (target Hct 32- 38) Maintenance Phase Maintenance Phase 12 Week Epoetin vs. Placebo 12 Week Open- label 12 Week Epoetin vs. Placebo 12 Week Open- label 26 week Epo: Hb 9.5-11 Epo: Hb 9.5-11 Epo: Hb 11.5-13 Epo: Hb 11.5-13 Placebo Placebo

18. 18 Study Design Inadequacies  Open-label design  No prospective plan for missing data/multiplicity data/multiplicity  Post-hoc statistical analyses  No correlation with Hct/Hb and anemia symptoms anemia symptoms

19. 19 Instrument Issues Instrument Issues

20. 20 Instrument Examples  Karnofsky Performance Scale  National Kidney Dialysis and Kidney Transplantation Study (NKDKTS) Transplantation Study (NKDKTS) Symptom List Symptom List

21. 21 Karnofsky Performance Scale (KPS)

22. 22 NKDKTS Symptom List (Revised by sponsor) Pain Pain Tiring easily, no energy Tiring easily, no energy Weakness, lack of strength Weakness, lack of strength Aches, swelling, sick feeling Aches, swelling, sick feeling Fainting spells, dizziness Fainting spells, dizziness Nervousness, tension, anxiety Nervousness, tension, anxiety Shortness of breath, trouble breathing Shortness of breath, trouble breathing Depression Depression Tremors Tremors Muscle weakness Muscle weakness Leg cramps Leg cramps Muscle spasms Muscle spasms Shaky hands Shaky hands

23. 23 Instrument Deficiencies  Lack of Content Validity (appropriate, comprehensive, interpretable) (appropriate, comprehensive, interpretable) Population Population Indication Indication  Post-hoc selection of items/subscales

24. 24 Summary  The clinical studies provided were not adequately designed to not adequately designed to measure HRQL/anemia symptoms. measure HRQL/anemia symptoms.  The instruments used in the clinical trials submitted are not adequate trials submitted are not adequate measures of anemia or HRQL for measures of anemia or HRQL for the target population/indication. the target population/indication.

25. 25 Endpoint Review Findings The clinical benefit of Epoetin Alfa in improvement of patient performance, anemia symptoms or HRQOL has not been adequately established. Return to Trentcosti