1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. Design Issues in Colorectal Cancer Trials: Surrogates Endpoints & Non-Inferiority Trials November 12, 2003 Thomas R. Fleming, Ph.D. Professor and Chair of Biostatistics University of Washington Endpoints Workshop: Colorectal Cancer

3. Design Issues Criteria for Study Endpoints Use of Surrogate Endpoints Validation of Surrogates Controversial Issues with AA Non-Inferiority Design Issues Choice of the NI Margin ~ Bio-creep with Repeated NI Trials

4. Criteria for Study Endpoints in Clinical Trials Measurable/Interpretable Sensitive Clinically relevant ~ Overall Survival ~ Disease-Related Symptoms

5. Use of Surrogate Endpoints Treatment Effects on Surrogate Endpoints eg: ~ Tumor Burden Outcomes: TTP, ORR ~ Biomarkers: CEA Establishes Biological Activity But Not Necessarily Clinical Efficacy

6. Figure: Reasons for failure of surrogate endpoints. - The surrogate is not in the causal pathway of the disease process. Time Disease Surrogate True Clinical Endpoint Outcome

7. Time Disease Biomarker True Clinical e.g., CEA Outcome Tumor Burden

8. Time True Clinical Outcome Surrogate Endpoint Disease Intervention Figure: Reasons for failure of surrogate endpoints. - Of several causal pathways of disease, the intervention only affects the pathway mediated through the surrogate. - The surrogate is not in the pathway of the intervention's effect, or is insensitive to its effect. SurrogateTrue Clinical EndpointOutcome Intervention Disease

9. Transient True Clinical Tumor Control Outcome Intervention Disease True Clinical Outcome Tumor Shrinkage Disease Intervention Time

10. Figure: Reasons for failure of surrogate endpoints. The intervention has mechanisms of action independent of the disease process. Dotted lines = mechanisms of action that might exist. Surrogate True Clinical Endpoint Outcome Disease Intervention Time

11. Illustration: Ventricular Arrhythmia After M.I.  Arrhythmia: - Risk factor for Sudden Death  Antiarrhythmic Drugs: - Encainide, Flecainide Cardiac Arrhythmia Suppression Trial: The drugs, relative to placebo, TRIPLE the death rate.

12. Arrhythmia Overall Suppression Survival Disease Intervention Time

13. Design Issues Criteria for Study Endpoints Use of Surrogate Endpoints Validation of Surrogates Controversial Issues with AA Non-Inferiority Design Issues Choice of the NI Margin ~ Bio-creep with Repeated NI Trials

14. Validation of Surrogate Endpoints Property of a Valid Surrogate  Effect of the Intervention on the Clinical Endpoint is reliably predicted by the Effect of the Intervention on the Surrogate Endpoint

15. How does one validate a surrogate endpoint?

16. Prentice’s Sufficient Conditions 1.The surrogate endpoint must be correlated with the clinical outcome 2.The surrogate endpoint must fully capture the net effect of treatment on the clinical outcome

17. Z = 1 : Control ; Z = 0 : Treatment S(t) : Surrogate Endpoint at t (t | Z) = 0 (t) e    (t | Z, S(t) ) = 0 (t) e  Z +  S(t)  Proportion of net treatment effect explained by the surrogate endpoint: p = 1 -  

18. Meta-analyses are required to explore the validity of surrogate endpoints

19. Validation of Surrogate Endpoints Statistical  Meta-analyses of clinical trials data Clinical  Comprehensive understanding of the ~ Causal pathways of the disease process ~ Intervention’s intended and unintended mechanisms of action

20. Endpoint Hierarchy True Clinical Efficacy Measure Validated Surrogate Endpoint (Rare) Surrogate Endpoint that is “reasonable likely to predict clinical benefit” None of the Above: A Correlate that is solely a measure of Biological Activity

21. Design Issues Criteria for Study Endpoints Use of Surrogate Endpoints Validation of Surrogates Controversial Issues with AA Non-Inferiority Design Issues Choice of the NI Margin ~ Bio-creep with Repeated NI Trials

22. FDA Oncology Drugs AC: 3/12-13/03 ’95-’00: 12 Accelerated Approvals Facts presented to ODAC: Of 12 AA, 8 remain unresolved: Average time from AA to Completion of Validation Trial projected to be 10 years In one case, sponsor enrolled 8 pts/year In 3 cases, Validation Trial indicated minimal treatment benefit

23. FDA Oncology Drugs AC: 3/12-13/03 ’95-’00: 12 Accelerated Approvals Disturbing Issues re Validation Trials: Enrollment difficulties into Validation Trials Loss of “sense of urgency” by sponsor Need for a clear vision for proper process when the Validation Trial is not conclusively positive

24. Use of Biological Markers In Screening Trials… Primary Endpoints In Definitive Trials… Supportive Data on Mechanism of Action

25. Design Issues Criteria for Study Endpoints Use of Surrogate Endpoints Validation of Surrogates Controversial Issues with AA Non-Inferiority Design Issues Choice of the NI Margin ~ Bio-creep with Repeated NI Trials

26. Dual Goals of Non-Inferiority Trials To enable a direct evaluation of the clinical efficacy of EXP relative to Active Control To contribute evidence to the evaluation of efficacy of EXP relative to Placebo

27. Non-Inferiority Trials… Some Requirements Active Control Effect ICH E9: “A suitable active comparator… could be a widely used therapy whose efficacy in the relevant indication has been clearly established & quantified in well-designed & well documented superiority trials & which can be reliably expected to have similar efficacy in the contemplated AC trial.”

28. Non-Inferiority Trials… Some Requirements Active Control should have clinical efficacy that is of substantial magnitude that is precisely estimated with estimates that are relevant to the setting in which the non-inferiority trial is being conducted

29. Factors Influencing Choice of Margin PLA – AC 1-Year Survival Rate Active Control Effect ~ magnitude of Active Control effect Eg:  = 15% – 30% = –15% ~ precision of estimate Eg:  2 s.e. =  5% (500 / arm ) ~ estimates relevant to setting of NI trial Population Supportive care Endpoint assessment * () –20% –15% –10% –5% 0%

30. Factors Influencing the Choice of Margin and Interpretation of NI Trial Results Clinical Relevance of Changes in: Benefits, Risks/Tolerance, Convenience, Drug-Drug Interactions, etc. Active Control Effect

31. Factors Influencing Choice of Margin Clinical Relevance of Changes in: Benefits, Risks/Tolerance, Convenience, Resistance, etc. Clinical importance of: - reduction in efficacy by  - altered safety/tolerance profile - altered convenience of administration - altered resistance or drug/drug interactions

32. ICH E10: “The determination of the margin in a non-inferiority trial is based on both statistical reasoning & clinical judgment, and should reflect uncertainties in the evidence on which the choice is based, and should be suitably conservative.” The Choice of the Margin in an NI Trial

33. “Bio-creep” with Repeated NI Trials Eg: Anti-viral Drugs Advisory Comm (10/4/01) Empiric Anti-fungal therapy of febrile neutropenic patients Amphotericin B Deoxycholate Ambisome vs Amphotericin B 49.9% v 49.1% Mycosis Study Gp #32 Voriconazole vs Ambisome 23.7% v 30.1% 95% CI: ( – 12, – 0.1)

34. Worst Nightmare: Conducting a Non-Inferiority Trial (including justification of a NI Margin) when using a Surrogate Endpoint as the primary endpoint of the trial Surrogate Endpoints and Non-Inferiority Trials