Regulatory Background and Past FDA Approvals in Colorectal Cancer

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Regulatory Background and Past FDA Approvals in
Colorectal Cancer

• Amna Ibrahim M.D
• DODP, FDA

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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

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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)

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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

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Regular Approval Endpoints in Oncology
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Clinical Benefit Endpoints

• Survival
• Improvement in tumor-related symptoms

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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)

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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

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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

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Agents Approved
Adjuvant First-Line Refractory
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
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Historical Endpoints for Approval

• OS
• TTP RR
• Superiority
• Noninferiority

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Agents for Adjuvant Therapy
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Levamisole (Adjuvant Rx)
Arms N Follow up (Yrs) Reduction in Recurrence Reduction in Death
Study 1 Duke C Subset 5FUlev 262 5 36 27
Study 1 Duke C Subset lev 262 5 28 28
Study 1 Duke C Subset Observe 262 5
Study 2 5FUlev 929 2 41 33
Study 2 lev 929 2 2 6
Study 2 Observe 929 2
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Agents for First-line Therapy
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5FUleucovorin (First-line Rx)
Study Arms N RR TTP mo OS mo P (one-sided)
1 5FU 70 10 2.9 7.7
1 5FULV(HD) 69 26 6.7 12.2 0.04
1 5FULV(LD) 73 44 6.7 12 0.05
2 (Study 1 ext) 5FULV(HD) 149 31 12.7 0.04
2 (Study 1 ext) 5FULV(LD) 153 42 12.7 0.01
2 (Study 1 ext) 5FUMTXLV 155 14 8.4
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Irinotecan (First-line Rx)
Study Arms N RR TTP OS P (one-sided)
1 CPT 11 wkly x 4 (q 6 wks) 226 18 4.2 12
1 CPT11 5FU/LV wkly x 4 (q 6 wks) 231 39 7 14.8 lt0.05
1 5FU/LV qd x 5 (q 6 wks) 226 21 4.3 12.6 lt0.05
2 CPT11 inf 5FU/LV 198 35 6.7 17.4 lt0.05
2 5FU/LV 187 22 4.4 14.1 lt0.05
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Capecitabine (First-line Rx)
Study Arms N RR () TTP (mo.) OS (mo.) Hazard ratio
1 Cap 302 21 4.3 12.7 1.00 0.84 1.18
1 5FU/LV 303 11 4.4 13.6 1.00 0.84 1.18
2 Cap 301 21 4.6 13.5 0.92 0.78 1.09
2 5FU/LV 301 14 4.4 12.3 0.92 0.78 1.09
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Oxaliplatin (First-line Rx)
Study Arms N RR TTP OS HR for OS
1 IFL 264 33 6.9 14.6 0.65 (0.53-0.8)
1 FOLFOX4 267 45 8.7 19.4 0.65 (0.53-0.8)
1 IROX 264 35 6.5 17.6
RR and TTP based on unblinded investigator
assessment
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Bevacizumab (First-line Rx)
Study Arms N RR () PFS (mo.) OS (mo.) HR for OS
1 IFL 411 35 6.4 15.6 0.66
1 IFL Bev 402 45 10.6 20.3 0.66
2 5FU/LV 36 17 5.2 13.6
2 5FU/LV Bev (5mg) 35 40 9 17.7
2 5FU/LV Bev (10 mg) 33 24 7.2 15.2
Comparison statistically significant for Study 2
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Agents for Refractory Cancer
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Irinotecan (Refractory AA)
Study Arms N RR () TTP (mo.) OS (mo.) Med Resp Duration
1 Wkly CPT 11 48 21 6.4 10.4 5.8 mo. (2.6-15.2)
2 Wkly CPT 11 90 13 5.9 8.1 5.8 mo. (2.6-15.2)
3 Wkly CPT 11 125 mg/m2 64 14 5.6 10.7 5.8 mo. (2.6-15.2)
3 Wkly CPT 11 100 mg/m2 102 9 6.4 9.3 5.8 mo. (2.6-15.2)
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Irinotecan (Refractory reg. approval)
Study Arms N OS (mo.) p
1 CPT 11 189 9.2 0.0001
1 Best Supportive Care 90 6.5 0.0001
2 CPT 11 127 10.8 0.035
2 5FU-based regimens 129 8.5 0.035
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Oxaliplatin (Refractory AA)
Study Arms N RR () TTP (mo. with 95 CI) P for RR
1 Oxaliplatin 5FU/LV (FOLFOX4) 152 9 4.6 (4.2 6.1) 0.0002
1 5FU LV 151 0 2.7 (1.8-3.0) 0.0002
1 Oxaliplatin 156 1 1.6 (1.4-2.7)
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Cetuximab (Refractory AA)
Study Arms N RR () TTP (mo) HR
1 CPT-11 Cet 218 22.9 4.1 0.54 (0.42-0.71)
1 Cet 111 10.8 1.5 0.54 (0.42-0.71)
2 CPT-11 Cet 138 15
3 Cet 57 9
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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

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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)