Combining risk difference and risk ratio in noninferiority trials of safety.

Prior to marketing, the long-term safety profile of a new therapy is often uncertain. One recommendation for premarket safety studies is to compare the new therapy to an appropriate control to determine whether the 95% confidence interval of the risk ratio is entirely less than a prespecified threshold (e.g., 1.8). The restriction to the risk ratio, however, has consequences that may not be intended. Risk difference may be a more appropriate measure of risk in this setting when event rates are very low. We propose using a suitable combination of risk ratio and risk difference in demonstrating noninferiority.