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 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 Regulatory background and summary of previous approvals provided by FDA Five presentations Five presentations Interactive discussion by speakers and multidisciplinary panel Interactive discussion by speakers and multidisciplinary panel Discussion of questions posed by FDA Discussion of questions posed by FDA

4. Goals of This Presentation Capsule summary of presentations and main points of discussion Capsule summary of presentations and main points of discussion Focus on possible new endpoints for regulatory approval of drugs for colorectal cancer Focus on possible new endpoints for regulatory approval of drugs for colorectal cancer Help ODAC advise FDA 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 Not possible to consistently predict clinical benefit based on reduction of CEA ASCO guidelines do not recommend other biomarkers for CRC 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 Methodologic issues of paramount importance if QOL used as endpoint Unknown whether changes in QOL reliably occur with effective chemo Unknown whether changes in QOL reliably occur with effective chemo Cannot discriminate between safety and efficacy Cannot discriminate between safety and efficacy Best use of resources in colon cancer? 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) Clinical Benefit Response (Pain, performance status, weight loss) CBR does not adequately encompass symptoms experienced by patients CBR does not adequately encompass symptoms experienced by patients Methodologic issues in assessment Methodologic issues in assessment Not useful if asymptomatic (colon vs rectum) 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 Locoregional failures are usually symptomatic in rectal cancer “Local tumor control at 3 years is an appropriate endpoint for full approval” “Local tumor control at 3 years is an appropriate endpoint for full approval” Pathologic complete response (pCR) - quality control issues Pathologic complete response (pCR) - quality control issues Colostomy-free survival – applies mainly to low lying tumors 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) Primary endpoints: sensitive, measurable, and clinically relevant (eg. Survival; decreased symptoms) Surrogate endpoints 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 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 1 st Line MCRC (Dr. Langdon Miller) Multiple effective therapies for metastatic colorectal cancer have confounded the relationship between early tumor control and survival 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 Evaluation of symptoms problematic as endpoint because progression frequently not symptomatic, is subjective, and difficult to measure

12. TTP: Clinical Benefit Endpoint in 1 st Line MCRC (Dr. Langdon Miller) Arguments for TTP as endpoint for full approval 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 1 st 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 1 st Line MCRC (Dr. Langdon Miller) Correlation of TTP and Survival Was Highly Significant: two examples 1.1000 patients in two phase III trials with primary patient data 1.Meta-analysis on published summary results of 29 trials involving 13,000 patients

15. TTP: Clinical Benefit Endpoint in 1 st Line MCRC (Questions and Comments) 1.Need for objective and reliable methodology for assessing TTP 2.Does TTP reflect clinical benefit in its own right? (Full approval) 3.Is TTP reasonably likely to predict clinical benefit? (Accelerated approval) 4.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 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 1. 3-YR DFS seems to be an excellent predictor of 5-YR OS 2. Event rates were virtually identical (no impact on sample size) 3. 3-YR DFS may slightly overestimate differences in 5-YR OS 4. Three studies – significant difference in 3- YR DFS (borderline p values) but no significant difference in 5-YR OS 5. Not a formally validated surrogate

18. 3-YR DFS as Endpoint in Adjuvant Colon Cancer (Questions and Comments) 1.Work in progress – updated analysis today! 2.Does improvement in 3-YR DFS represent clinical benefit in its own right? 3.DFS is used for full approval in breast cancer adjuvant therapy

19. Key Questions for ODAC 1. Should the following endpoints be recommended to FDA for new drugs in colorectal cancer? 2. Full or Accelerated approval? Setting Endpoint Setting Endpoint Colon adjuvant 3-YR DFS 1 st line metastatic TTP Rectal adjuvant 3-YR local control