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Endpoints for Past Approvals

Endpoints for Past Approvals. Ramzi Dagher DODP/CDER/FDA. Endpoints in Oncology. Survival (gold standard) TTP (advantages and challenges) DFS (adjuvant setting) ORR (treatment responsible for tumor reduction) Tumor related symptoms/PRO. Clinical Benefit Endpoints : Regular Approval.

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Endpoints for Past Approvals

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  1. Endpoints for Past Approvals Ramzi Dagher DODP/CDER/FDA

  2. Endpoints in Oncology • Survival (gold standard) • TTP (advantages and challenges) • DFS (adjuvant setting) • ORR (treatment responsible for tumor reduction) • Tumor related symptoms/PRO

  3. Clinical Benefit Endpoints : Regular Approval • Survival • Improvement in tumor related symptoms • DFS (adjuvant setting, breast cancer)

  4. Surrogates Used forRegular Approval • Durable Complete Response • leukemias • some solid tumors • Partial Response • hormonal therapy of breast cancer

  5. DODP : Endpoints for Approval1/1/90 - 11/1/02 Approvals not based on survival: • 73% (48/66) of all approvals • 67% (37/55) excluding AA

  6. Endpoints for DODP Regular Approvals (1/1/90 - 11/1/02)*

  7. Tumor Related Symptoms • Mitoxantrone for HRPC • pain scale • Photofrin for obstructive lesions • dysphagia scale • Bisphosphonates • skeletal related events

  8. Trial Designs and Surrogate Endpoints for AA • Single-arm trials or comparison of two dose levels • 15 out of 22 AA indications • objective response rate (e.g. imatinib, gefitinib) • Randomized trials : placebo or active comparator • DFS (anastrozole) • RR/TTP (oxaliplatin)

  9. AA and Confirmatory Study Design Strategy 1: • AA based on RR as the endpoint in single arm studies of refractory patients • subsequent confirmatory studies in less refractory patients • Pro: • rapid completion of single arm studies expedites drug availability

  10. AA and Confirmatory Study Design : Strategy 1 (cont’d) • Cons: • AA may influence the ability to enroll patients to confirmatory studies • challenge of evaluating marginal benefits • may miss an active drug • limitations of single arm trials • endpoints • toxicity evaluation

  11. AA and Confirmatory Study Design Strategy 2: • AA based on interim analysis of a surrogate endpoint in a randomized study • Clinical benefit established by final analysis of the same study • Pros: • same population for AA and regular approval • facilitates completion of confirmatory study • randomized setting allows comparison to available therapy and evaluation of toxicity profile

  12. AA and Confirmatory Study Design Strategy 2 (continued): • Cons: • May require more time and patients than single arm study • AA could influence completion of study

  13. Summary • Survival, tumor symptom improvement as evidence of CB • Surrogates for CB • CR’s in leukemia • PR’s in hormonal breast cancer therapy • ORR in single-arm trials basis of approval in most AA’s

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