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

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Presentation on theme: "Regulatory Background and Past FDA Approvals in Colorectal Cancer Amna Ibrahim M.D DODP, FDA."— Presentation transcript:

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

2 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

3 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)

4 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

5 Regular Approval Endpoints in Oncology

6 Clinical Benefit Endpoints Survival Improvement in tumor-related symptoms

7 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)

8 Endpoints other than Survival Approvals not based on Survival (From 1/1/90 - 11/1/02 )) : –73% (48/66) of all approvals –67% (37/55) excluding accelerated approvals

9 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

10 Agents Approved AdjuvantFirst-LineRefractory Levamisole (+ 5FU) 1990 -Leucovorin (with 5FU) 1991 -Irinotecan (+ 5FU/LV) 2000 -Capecitabine 2001 -Oxaliplatin (+ 5FU/LV) 2004 -Bevacizumab 2004 -Irinotecan 1996,1998 -Oxaliplatin (+ 5FU/LV) 2002 -Cetuximab 2004

11 Historical Endpoints for Approval OS TTP & RR Superiority Noninferiority

12 Agents for Adjuvant Therapy

13 Levamisole (Adjuvant Rx) ArmsN Follow up (Yrs) Reduction in Recurrence % Reduction in Death % Study 1 Duke C Subset 5FU+lev 2625 3627 lev28 Observe Study 2 5FU+lev 9292 4133 lev26 Observe

14 Agents for First-line Therapy

15 5FU+leucovorin (First-line Rx) StudyArmsN RR % TTP mo OS mo P (one-sided) 1 5FU70102.97.7 5FU+LV(HD)69266.712.20.04 5FU+LV(LD)73446.7120.05 2 (Study 1 ext) 5FU+LV(HD)1493112.70.04 5FU+LV(LD)1534212.70.01 5FU+MTX+LV155148.4

16 Irinotecan (First-line Rx) StudyArmsNRRTTPOS P (one-sided) 1 CPT 11 wkly x 4 (q 6 wks) 226184.212 CPT11 + 5FU/LV wkly x 4 (q 6 wks) 23139714.8 <0.05 5FU/LV qd x 5 (q 6 wks) 226214.312.6 2 CPT11 + inf 5FU/LV 198356.717.4 <0.05 5FU/LV187224.414.1

17 Capecitabine (First-line Rx) StudyArmsN RR (%) TTP (mo.) OS (mo.) Hazard ratio 1 Cap302214.312.7 1.00 0.84 – 1.18 5FU/LV303114.413.6 2 Cap301214.613.5 0.92 0.78 – 1.09 5FU/LV301144.412.3

18 Oxaliplatin (First-line Rx) StudyArmsNRR*TTP*OSHR for OS 1 IFL264336.914.6 0.65 (0.53-0.8) FOLFOX4267458.719.4 IROX264356.517.6 * RR and TTP based on unblinded investigator assessment

19 Bevacizumab (First-line Rx) StudyArmsN RR (%) PFS (mo.) OS (mo.) HR for OS 1 IFL411356.415.6 0.66 IFL + Bev4024510.620.3 2 5FU/LV36175.2*13.6 5FU/LV + Bev (5mg) 35409*17.7 5FU/LV + Bev (10 mg) 33247.215.2 * Comparison statistically significant for Study 2

20 Agents for Refractory Cancer

21 Irinotecan (Refractory; AA) StudyArmsN RR (%) TTP (mo.) OS (mo.) Med Resp Duration 1Wkly CPT 1148216.410.4 5.8 mo. (2.6-15.2) 2Wkly CPT 1190135.98.1 3 Wkly CPT 11 125 mg/m 2 64145.610.7 Wkly CPT 11 100 mg/m 2 10296.49.3

22 Irinotecan (Refractory; reg. approval) StudyArmsN OS (mo.) p 1 CPT 111899.2 0.0001 Best Supportive Care 906.5 2 CPT 1112710.8 0.035 5FU-based regimens 1298.5

23 Oxaliplatin (Refractory; AA) StudyArmsN RR (%) TTP (mo. with 95% CI) P for RR 1 Oxaliplatin + 5FU/LV (FOLFOX4) 1529 4.6 (4.2 – 6.1) 0.0002 5FU + LV1510 2.7 (1.8-3.0) Oxaliplatin1561 1.6 (1.4-2.7)

24 Cetuximab (Refractory; AA) StudyArmsN RR (%) TTP (mo) HR 1 CPT-11 + Cet 21822.94.1 0.54 (0.42-0.71) Cet 11110.81.5 2 CPT-11 + Cet 13815 3 Cet 579

25 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”

26 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)

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