NDA 21-063

1. NDA 21-063 Oxaliplatin in combination with 5-FU and leucovorin for first line therapy for colorectal cancer

2. Regulatory standard for first line therapy of colorectal cancer is to improve overall survivalOncologic Drugs Advisory Committee Recommendation contained inFDA Guidance on Requirements for Approval of New Drugs for Treatment of Colon and Rectal Cancers

3. 5-FU plus leucovorin has been the standard of care and will prolong survival compared to 5-FU monotherapy

4. Survival Results from various 5-FU/LV Regimens Biweekly Regimen (n=2) Monthly LD LV (n=3) Monthly HD LV (n=15) Mayo Clinic/ NCCTG Regimen (n=7)

5. Lack of correlation between response rate and overall survival in 23 published controlled studies

6. Lack of correlation between progression free survival and overall survival in 7 published controlled studies

7. Regulatory History • No prior discussions with the FDA with regard to trial design • In 1996, FDA stated “Approval of any new product in previously untreated advanced colorectal cancer would require demonstration of a survival advantage when adding oxaliplatin to an acceptable US-based 5-FU regimen.” • In 1998, FDA stated that for survival analysis the greatest weight will be placed on the logrank test.”

8. The sponsor submitted information on 33 clinical studies, and provided datasets for 8 studies of which 2 were randomized controlled studies comparing 5-FU/LV to 5-FU/LV plus oxaliplatin in first line treatment of patients with colorectal cancer Contents of NDA 21063

9. Study 2961-Enrolled patients June 1994 - March 1996 • The primary endpoint specified in the protocol was response rate. • Secondary endpoints were progression free survival, overall survival, and toxicity. • Two interim analyses planned • Primary analysis for survival was log rank test • Regimen based on chronomodulated schedule

10. Study 2962-Enrolled patients August 1995 - July 1997 • The primary endpoint in the protocol was progression free survival. • Secondary endpoints were response rate, tolerance, quality of life and overall survival • Two interim analyses planned • Primary analysis for survival was log-rank test • Regimen based on biweekly infusion schedule

11. Study 2962 Amended Analysis Plan • An amended analysis plan was appended to the protocol in February 1998, 6 months after the last patient enrolled and 5 months prior to the cut off date for survival. • The plan once again affirmed the use of the log-rank test for overall survival and stated that a multivariate analysis would be provided using 12 co-variates (defined by terms such as renal function and liver function tests) and furthermore stated that “if other parameters seem to be pertinent for this analysis, they will be used.”

12. Survival Results for Randomized Studies All calculations confirm the applicant’s results except for the hazard ratio, which was not submitted

13. Kaplan-Meier Survival Curves for Study 2961

14. Kaplan-Meier Survival Curves for Study 2962

15. Clinical Benefit Assessments The FDA agrees with the sponsor analysis that there were no statistically significant differences in performance status, pain scores, weight change, symptom improvement, or quality of life between the study arms in study 2962

16. Adverse Event Differences in Study 2961

17. Adverse Event Differences in Study 2962

18. Neurotoxicity in Study 2962

19. Cumulative Neurotoxicity in Study 2962

20. randomized controlled multicenter studies Strengths of the Application

21. Weaknesses of the Application • Results consistent with 5-FU/LV alone • Reliance on adjusted analysis to demonstrate efficacy with • large number of covariates • selection of covariates in statistical model dependent upon study outcome

22. Weaknesses of Application • Lack of basis for extrapolation to 5-FU/LV regimens used in the United States • Greater toxicity, particularly neurotoxicity, with oxaliplatin containing regimens

23. Substantiation of Results • “A single clinical experimental finding of efficacy, unsupported by other independent evidence, has not usually been considered adequate scientific support for a conclusion of effectiveness. • Independent substantiation of a favorable result protects against the possibility that a chance occurrence in a single study will lead to an erroneous conclusion that a treatment is effective.”FDA Guidance on Providing Clinical Evidence of Effectiveness, 1998

24. “Moreover, a single favorable study among several similar attempts that failed to support a finding of effectiveness would not constitute persuasive support for a product use”FDA Guidance on Providing Clinical Evidence of Effectiveness, 1998 Interpreting Results

25. “Although an unexplained failure to substantiate the results of a favorable study in a second controlled trial is not proof that the favorable study was in error — studies of effective agents can fail to show efficacy for a variety of reasons — it is often reason not to rely on the single favorable study.”FDA Guidance on Providing Clinical Evidence of Effectiveness, 1998 Interpreting Results

26. Criteria for submitting a single study • Findings should be clinically important • The study should have a “statistically very persuasive finding.” • ..”confirmation of the result in a second trial would be practically or ethically impossible.” FDA Guidance on Providing Clinical Evidence of Effectiveness, 1998

27. Multivariate Analysis • “Pre-study deliberations should identify those covariates • . When the potential value of an adjustment is in doubt, it is often advisable to nominate the unadjusted analysis as one for primary attention, the adjusted analysis being supportive.” • ICH/FDA Guideline, • Statistical Principles for Clinical Trials

28. Biopharmaceutics Primary: Brian Booth, PhD Elena Mishina, PhD, Team Leader: Atiquar Rahman, PhD, Biometrics Mark Rothmann, PhD, Team Leader : Gang Chen, PhD Chemistry Chengyi Liang PhD Hari Sarker, PhD Team Leader : Eric Duffy, PhD Clinical Steven Hirschfeld, MD PhD, Fumikata Nagamura, MD Team Leader : John R. Johnson, MD Deputy Division Director Robert Justice, MD Pharmacology/Toxicology Hua Zheng, PhD, Team Leader : Paul Andrews, PhD Project Management Christy Wilson Supervisor: Dotti Pease FDA Review Team