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Regulatory Background Grant Williams, M.D. Deputy Director, DODP

Acknowledgements Planning: NCI, AACR, ASCO ASCO –Logistics and panelist support –Mary Wilson, Deborah Kamin FDA –Dianne Spillman

Workshop outline Background presentations –Regulations and past endpoints –Time to Progression (TTP) –Surrogates and non-inferiority Question-based discussions –First-line treatment setting –Second and subsequent therapy –Other endpoints –Adjuvant treatment setting –Rectal cancer and neoadjuvant therapy

Outline of Presentation FDA requirements for new drug approval Regular approval of cancer drugs: end points used Accelerated approval of cancer drugs

Requirements for Drug Approval Safety (FDAC, 1933) Efficacy demonstrated in adequate and well controlled studies (1962) Basis for efficacy: –Regular approval Clinical benefit, or Established surrogate for clinical benefit –Accelerated approval Surrogate (reasonably likely to predict CB)

How many trials? Usually more than one trial is needed. Substantial evidence: “Adequate and well- controlled investigations” Sometimes a single trial may suffice. –FDAMA (1997) single trial plus other supportive evidence –1998 FDA Effectiveness Guidance: Multicenter trial Statistically strong evidence Important clinical benefit Additional trials not ethical

Oncology Efficacy Supplements Only one additional trial may be needed for closely related indications 1 : –Advanced cancer and earlier cancer –Different dosing regimens –New combinations of drugs 1

Regular Approval Endpoints in Oncology

Clinical Benefit Endpoints Supporting Regular Drug Approval Survival Improvement in tumor-related symptoms

Established Surrogates Supporting Regular Approval Disease-free survival (selected settings) Complete response rates in some settings (e.g., acute leukemia) Partial response rate in some settings (e.g., hormonal treatment of breast cancer)

DODP: Endpoints for Approval (1/1/ /1/02 ) Approvals not based on Survival : –73% (48/66) of all approvals –67% (37/55) excluding accelerated approvals

Tumor-related symptoms Mitoxantrone-Pain Bisphosphonates-Skeletal morbidity scale Daunozome-Visible lesions of KS Photofrin-Dysphagia scale

Accelerated approval Serious or life-threatening disease Drug must provide benefit over available therapy Surrogate endpoint may be used Surrogate endpoint must be reasonably likely to predict clinical benefit Post marketing studies must verify clinical benefit

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

Single Arm Trials (SAT) and Accelerated approval (AA) SAT require few patients SAT for AA limit study to refractory disease SAT have limited ability to evaluate valuable endpoints such as TTP, QOL, and Survival

Randomized Trials (RT) and Accelerated approval (AA) Allows AA at any disease stage (surrogate beats available therapy) Allows “add-on” design (A vs A + B) Allows a variety of endpoints Defines individual drug contribution –(oxaliplatin vs 5FU/LCV versus oxaliplatin + 5FU/LCV)

ODAC Meeting on: Accelerated Approvals (March 2003) 19 NDAs or BLAs for new treatment indications (involving 16 drugs) Confirmatory studies should be part of drug development plan Consider interim analysis of surrogate endpoint for AA

Summary of Presentation FDA requirements –Evidence from Trials or Trial+ –RA: Clinical Benefit or accepted surrogate –AA: Advantage over available therapy with regard to a “reasonably likely surrogate” Cancer Approvals Important question: –Should TTP be considered an accepted surrogate in any colon cancer setting?