Regulatory Background and Past FDA Approvals in Colorectal Cancer Amna Ibrahim M.D DODP, FDA.

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Presentation transcript:

Regulatory Background and Past FDA Approvals in Colorectal Cancer Amna Ibrahim M.D DODP, FDA

Presentation Outline Regulatory background Past endpoints in Oncology Approvals for colon cancer (adjuvant, first- line and second-line therapy) Studies supporting drug approval Endpoints supporting approval in CRC

Requirements for Drug Approval Safety (FDAC, 1938) 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 + other supportive evidence –1998 FDA Effectiveness Guidance: Multicenter trial Statistically strong evidence Important clinical benefit Additional trials not ethical

Regular Approval Endpoints in Oncology

Clinical Benefit Endpoints Survival Improvement in tumor-related symptoms

Established Surrogates 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)

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

Accelerated Approval (AA) 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

Agents Approved AdjuvantFirst-LineRefractory Levamisole (+ 5FU) Leucovorin (with 5FU) Irinotecan (+ 5FU/LV) Capecitabine Oxaliplatin (+ 5FU/LV) Bevacizumab Irinotecan 1996,1998 -Oxaliplatin (+ 5FU/LV) Cetuximab 2004

Historical Endpoints for Approval OS TTP & RR Superiority Noninferiority

Agents for Adjuvant Therapy

Levamisole (Adjuvant Rx) ArmsN Follow up (Yrs) Reduction in Recurrence % Reduction in Death % Study 1 Duke C Subset 5FU+lev lev28 Observe Study 2 5FU+lev lev26 Observe

Agents for First-line Therapy

5FU+leucovorin (First-line Rx) StudyArmsN RR % TTP mo OS mo P (one-sided) 1 5FU FU+LV(HD) FU+LV(LD) (Study 1 ext) 5FU+LV(HD) FU+LV(LD) FU+MTX+LV

Irinotecan (First-line Rx) StudyArmsNRRTTPOS P (one-sided) 1 CPT 11 wkly x 4 (q 6 wks) CPT11 + 5FU/LV wkly x 4 (q 6 wks) <0.05 5FU/LV qd x 5 (q 6 wks) CPT11 + inf 5FU/LV <0.05 5FU/LV

Capecitabine (First-line Rx) StudyArmsN RR (%) TTP (mo.) OS (mo.) Hazard ratio 1 Cap – FU/LV Cap – FU/LV

Oxaliplatin (First-line Rx) StudyArmsNRR*TTP*OSHR for OS 1 IFL ( ) FOLFOX IROX * RR and TTP based on unblinded investigator assessment

Bevacizumab (First-line Rx) StudyArmsN RR (%) PFS (mo.) OS (mo.) HR for OS 1 IFL IFL + Bev FU/LV *13.6 5FU/LV + Bev (5mg) 35409*17.7 5FU/LV + Bev (10 mg) * Comparison statistically significant for Study 2

Agents for Refractory Cancer

Irinotecan (Refractory; AA) StudyArmsN RR (%) TTP (mo.) OS (mo.) Med Resp Duration 1Wkly CPT mo. ( ) 2Wkly CPT Wkly CPT mg/m Wkly CPT mg/m

Irinotecan (Refractory; reg. approval) StudyArmsN OS (mo.) p 1 CPT Best Supportive Care CPT FU-based regimens

Oxaliplatin (Refractory; AA) StudyArmsN RR (%) TTP (mo. with 95% CI) P for RR 1 Oxaliplatin + 5FU/LV (FOLFOX4) (4.2 – 6.1) FU + LV ( ) Oxaliplatin ( )

Cetuximab (Refractory; AA) StudyArmsN RR (%) TTP (mo) HR 1 CPT-11 + Cet ( ) Cet CPT-11 + Cet Cet 579

Summary of FDA Requirements 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”

Basis of Approval Adjuvant Therapy (1 reg approval) Superiority in Survival (1) First-line Therapy (5 reg approvals) Superiority in Survival (4) Non-inferiority in Survival (1) Therapy for Refractory Disease (3 AA, 1 reg) Survival (1 reg for CPT-11) RR and/or TTP (3 AA)