Anti-Adhesion Therapies and the Rule of 3 for Rare Events

During the open-label trial of natalizumab for Crohn's disease, an isolated case of progressive multifocal leukoencephalopathy (PML) was found. This prompted a more careful review by regulators, physicians, and the pharmaceutical industry. A new gut-specific monoclonal antibody, vedolizumab, has been shown to be effective in inflammatory bowel disease, and in continued trials no patients have developed PML. Given the mortality of PML and lack of effective treatments, patients may remain concerned that PML is a possible risk factor. So, going forward, how do we quantify the risk of this serious adverse event? This review details how we define the maximum risk when no (or very few) events have occurred with an easy-to-use equation.