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Regulatory Considerations for Endpoints

Regulatory Considerations for Endpoints. Ann T. Farrell, M.D. FDA/CDER/DODP. Requirements for Drug Approval. Safety (FDAC 1938) Efficacy established in adequate and well-controlled investigation s (FDAC 1962) Use of data from one trial plus supportive evidence (FDAMA 1997).

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Regulatory Considerations for Endpoints

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  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

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