1. Regulatory Considerations for Endpoints Ann T. Farrell, M.D. FDA/CDER/DODP

2. Requirements for Drug Approval Safety (FDAC 1938) Efficacy established in adequate and well- controlled investigations (FDAC 1962) Use of data from one trial plus supportive evidence (FDAMA 1997)

3. Approval Mechanisms Regular Approval –Clinical Benefit (CB), or –Established Surrogate for Clinical Benefit Accelerated Approval –Surrogate (reasonably likely to predict CB)

4. Accelerated Approval Serious and life-threatening illness New therapy must provide advantage over available therapy –ability to treat patients unresponsive to or intolerant of –improved patient response

5. Accelerated Approval Based on – surrogate endpoint reasonably likely to predict clinical benefit or –effect on a clinical endpoint other than survival or irreversible morbidity Post-marketing studies to verify clinical benefit

6. Evidence for Accelerated Approval Substantial evidence from well-controlled clinical trials regarding a surrogate endpoint NOT: Borderline evidence regarding a clinical benefit endpoint

7. Number of clinical trials needed Usual requirement for more than one trial: “Substantial Evidence from adequate and well- controlled investigations” Single trial may sometimes suffice (FDAMA, 1998 Effectiveness Guidance) –single trial plus other supportive evidence –characteristics of single trial

8. Supportive Evidence Examples of situations where extrapolation from existing studies combined with a single clinical trial could support –pediatric uses –bioequivalence –modified-release dosage forms –different doses –different regimens

9. Characteristics of Single Trials Supporting Approval Large, multicenter trial Consistent results across study subsets Multiple studies in a single study (e.g., factorial design) Results from secondary endpoint analyses are also positive Statistically persuasive results

10. Single Trials for Oncology Supplemental Applications Different stages of disease (e.g., metastatic vs. adjuvant settings) Different treatment settings (e.g., refractory vs. first-line Rx) Combination therapy vs. monotherapy Closely related cancers

11. Approval for Oncology Products Safe and Effective Regular and Accelerated 1 trial plus supportive evidence