ABSTRACT
In clinical trials, it is unethical to use a placebo control in treating patients with severe or life-threatening diseases such as cancer when approved and effective therapies (e.g., standard of care or active control agents) are available. This has led to active control clinical studies for testing non-inferiority of a test treatment being compared to the standard therapy or an active control agent. In practice, one of the key issues for non-inferiority trials is the selection of non-inferiority margin. This selection has an impact on sample size requirement for achieving a desired power for establishing non-inferiority of the test treatment under investigation. To assist the investigator or sponsor in the investigation of non-inferiority of a test treatment as compared to an active control agent, the FDA published a guidance on non-inferiority clinical trials, which recommends methods for selection of non-inferiority margin (namely M 1 and M 2 approaches) based on historical data. In this chapter, methods that not only adjust for variability associated with the observed data, but also take into consideration the retention rate of the treatment effect as compared the effect of the active control agent, are proposed as alternatives to those methods recommended by the. In addition, a strategy for margin selection based on a risk assessment, to be applied when there is a disagreement between the sponsor and the regulatory agency, is discussed.
