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Synopsis of FDA Colorectal Cancer Endpoints Workshop

Synopsis of FDA Colorectal Cancer Endpoints Workshop

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Synopsis of FDA Colorectal Cancer Endpoints Workshop

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  1. Synopsis of FDA Colorectal Cancer Endpoints Workshop Michael J. O’Connell, MD Director, Allegheny Cancer Center Associate Chairman, NSABP Pittsburgh, PA

  2. FDA Colorectal Cancer Workshop (11/12/03) • Purpose • Discussion of positive and negative aspects of various endpoints for approval of new drugs for colorectal cancer • Identify areas for further research • Provide information to ODAC for recommendations to FDA

  3. Colorectal Endpoints Workshop Format • Regulatory background and summary of previous approvals provided by FDA • Five presentations • Interactive discussion by speakers and multidisciplinary panel • Discussion of questions posed by FDA

  4. Goals of This Presentation • Capsule summary of presentations and main points of discussion • Focus on possible new endpoints for regulatory approval of drugs for colorectal cancer • Help ODAC advise FDA

  5. Biomarkers or QOL in CRC Drug Approvals(Dr. Charles Blanke) • Not possible to consistently predict clinical benefit based on reduction of CEA • ASCO guidelines do not recommend other biomarkers for CRC

  6. Biomarkers or QOL in CRC Drug Approvals(Dr. Charles Blanke) • Methodologic issues of paramount importance if QOL used as endpoint • Unknown whether changes in QOL reliably occur with effective chemo • Cannot discriminate between safety and efficacy • Best use of resources in colon cancer?

  7. Biomarkers or QOL in CRC Drug Approvals(Dr. Charles Blanke) • Clinical Benefit Response (Pain, performance status, weight loss) • CBR does not adequately encompass symptoms experienced by patients • Methodologic issues in assessment • Not useful if asymptomatic (colon vs rectum)

  8. Endpoints in Neoadjuvant and Adjuvant Rectal Cancer(Dr. Meg Mooney) • Locoregional failures are usually symptomatic in rectal cancer • “Local tumor control at 3 years is an appropriate endpoint for full approval” • Pathologic complete response (pCR) -quality control issues • Colostomy-free survival – applies mainly to low lying tumors

  9. Surrogate Endpoints and Non-Inferiority Trials(Dr. Thomas Fleming) • Primary endpoints: sensitive, measurable, and clinically relevant (eg. Survival; decreased symptoms) • Surrogate endpoints • May reflect biological activity without establishing clinical efficacy • Meta-analyses required to validate • Validated surrogate endpoints are rare • FDA has granted approval using surrogate endpoints not formally validated

  10. Surrogate Endpoints and Non-Inferiority Trials(Dr. Thomas Fleming) • Non-inferiority trials • Insufficient for curves to overlap • Conservative margins to exclude significant decrease in efficacy • Rigorous study conduct to avoid incorrect conclusion of non-inferiority • Will results move the field forward (eg significant decrease in toxicity)?

  11. TTP: Clinical Benefit Endpoint in 1st Line MCRC(Dr. Langdon Miller) • Multiple effective therapies for metastatic colorectal cancer have confounded the relationship between early tumor control and survival • Evaluation of symptoms problematic as endpoint because progression frequently not symptomatic, is subjective, and difficult to measure

  12. TTP: Clinical Benefit Endpoint in 1st Line MCRC(Dr. Langdon Miller) • Arguments for TTP as endpoint for full approval • Directly evaluates changes in disease burden • Correlates with other outcomes (in particular, survival) • Not confounded by subsequent therapies • Offers utility as an endpoint in non-inferiority trials (more rapid completion)

  13. TTP: Clinical Benefit Endpoint in 1st Line MCRC(Dr. Langdon Miller) • Can be objectively quantified, reviewed, and audited • Offers clear interpretation and straightforward analysis • Conserves patient resources and hastens drug development

  14. TTP: Clinical Benefit Endpoint in 1st Line MCRC(Dr. Langdon Miller) Correlation of TTP and Survival Was Highly Significant: two examples • 1000 patients in two phase III trials with primary patient data • Meta-analysis on published summary results of 29 trials involving 13,000 patients

  15. TTP: Clinical Benefit Endpoint in 1st Line MCRC(Questions and Comments) • Need for objective and reliable methodology for assessing TTP • Does TTP reflect clinical benefit in its own right? (Full approval) • Is TTP reasonably likely to predict clinical benefit? (Accelerated approval) • RR, survival and toxicity also important

  16. 3-YR DFS as Endpoint in Adjuvant Colon Cancer (Dr. Dan Sargent) • Preliminary findings of meta-analysis to determine if 3-YR DFS can replace 5-YR OS as endpoint for colon cancer adjuvant trials • 12 clinical trials • 38 treatment arms • > 10,000 patients

  17. 3-YR DFS as Endpoint in Adjuvant Colon Cancer (Dr. Dan Sargent) Preliminary Conclusions • 3-YR DFS seems to be an excellent predictor of 5-YR OS • Event rates were virtually identical (no impact on sample size) • 3-YR DFS may slightly overestimate differences in 5-YR OS • Three studies – significant difference in 3-YR DFS (borderline p values) but no significant difference in 5-YR OS • Not a formally validated surrogate

  18. 3-YR DFS as Endpoint in Adjuvant Colon Cancer (Questions and Comments) • Work in progress – updated analysis today! • Does improvement in 3-YR DFS represent clinical benefit in its own right? • DFS is used for full approval in breast cancer adjuvant therapy

  19. Key Questions for ODAC • Should the following endpoints be recommended to FDA for new drugs in colorectal cancer? • Full or Accelerated approval? SettingEndpoint Colon adjuvant 3-YR DFS 1st line metastatic TTP Rectal adjuvant 3-YR local control