TL30: Noninferiority Trial with Survival Endpoints
*Elena Rantou, FDA/CDER *Mengdie Yuan, FDA Keywords: noninferiority trial, survival endpoints, logrank test, sample size calculation In clinical research, investigators are often interested in the occurrence of certain events. Therefore, survival endpoints are commonly used in drug or therapy evaluations, for example, treatments for cancer, and organ transplant. It is often of interest to compare the hazard rate in the experimental group with that in the control group. Sometimes, the experimental therapy may be acceptable as long as there is evidence that it is not worse than the control therapy due to the consideration of toxicity, cost et al. Therefore, noninferiority trials may be conducted. One commonly raised problem is the calculation of the sample size in noninferiority trials with survival endpoints. This roundtable will focus on the discussion of the methodology for sample size determination in clinical trials of this type. We will also discuss some other related issues such as margin determination and multiregion problems. Key discussion questions: 1. What are the current methodologies commonly used in the sample size determination in the noninferiority trial with survival endpoints? Assumptions? 2. Exponential model, Cox’s proportional hazard model and the Logrank test are three commonly used methods to determine the sample size needed in a noninferiority trial. Both the Exponential model and the Cox model assume constant hazard ratios over time. The Logrank test is most powerful under the proportional hazard assumption. Question: what is the consequence of using these methods if the proportional hazard assumption is violated? Larger sample size? 3. When the proportional hazard assumption is violated, simulations may be used to determine the sample size. Weighted Logrank test can be used for testing equality of the hazard ratio functions. How can this approach be extended to a noninferiority test? 4. Methods based on median survival. Advantages and drawbacks? 5. More recently, developed methods based on restricted means? 6. How to incorporate the dropout rate? 7. How to choose the margin in the sample size determination? 8. Many clinical trials involve multiple regions. If the regions are heterogeneous, how to analyze the data? Random effect models? Regionspecific margin?

Key Dates

June 3, 2014  September 7, 2015
Online Registration 
June 3, 2015  August 15, 2015
Housing 
July 31  August 17, 2015
Invited Abstract Editing 
August 10, 2015
Short Course materials due from Instructors 
August 26, 2015
Advanced Registration Deadline 
September 7, 2015
Cancellation Deadline 
September 16  18, 2015
Marriott Wardman Park, Washington, DC