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

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. PRO Claims. Physician Assessed and Patient Reported Performance Symptoms of Anemia

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

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

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

  4. FDA PreliminaryFindings 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.

  5. FDA PRO Guidance Overview

  6. Draft FDA PRO Guidance

  7. 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

  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) • 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. Definitions(cont) • Content Validity Evidence that the concepts, domains, and items in an instrument are: • appropriate • comprehensive • interpretable (Based upon input from target population)

  10. Definitions(cont) • Measurement Properties Assessing the instrument’s ability to measure a concept • Content validity • Construct validity • Reliability • Ability to detect change

  11. 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

  12. PRO Claims

  13. Approved Epoetin Alfa LabelClinical 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.

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

  15. PRO Claim Issues • Clinical Study Design • Instruments

  16. Clinical Study Design Inadequacies

  17. Clinical Studies

  18. 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

  19. Instrument Issues

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

  21. Karnofsky Performance Scale(KPS)

  22. NKDKTSSymptom List (Revised by sponsor) • 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

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

  24. 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.

  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

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