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 for Regular Approval Durable Complete Response –leukemias –some solid tumors Partial Response –hormonal therapy of breast cancer

5. DODP : Endpoints for Approval 1/1/90 - 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