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Regulatory Background and Past FDA Approvals in Colorectal Cancer

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

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Regulatory Background and Past FDA Approvals in Colorectal Cancer

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  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

  11. Historical Endpoints for Approval • OS • TTP & RR • Superiority • Noninferiority

  12. Agents for Adjuvant Therapy

  13. Levamisole (Adjuvant Rx)

  14. Agents for First-line Therapy

  15. 5FU+leucovorin (First-line Rx)

  16. Irinotecan (First-line Rx)

  17. Capecitabine (First-line Rx)

  18. Oxaliplatin (First-line Rx) * RR and TTP based on unblinded investigator assessment

  19. Bevacizumab (First-line Rx) * Comparison statistically significant for Study 2

  20. Agents for Refractory Cancer

  21. Irinotecan (Refractory; AA)

  22. Irinotecan (Refractory; reg. approval)

  23. Oxaliplatin (Refractory; AA)

  24. Cetuximab (Refractory; AA)

  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

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