Quantitative Methods for Safety Monitoring of Rare Serious Adverse Events

Background Rare but serious adverse events are often reasons for the modification of drug product labelling, termination of further development and even withdrawal of a treatment from the market. Objective Our objective was to use analytical methods to evaluate adverse events of special interest to aid in the determination of whether a particular treatment increases risk above what would be expected in the target population. These methods could be used during drug development and in the post-marketing setting as a supplement to the program safety analysis plan for compounds that have potential for rare serious adverse events. Methods Two well-known statistical methods were used in a new way by a cross-functional internal matrix team of safety physicians, scientists, epidemiologists and statisticians to compare background adverse event rates in a specific disease population with the observed rate in clinical trials to date. If the clinical trial rate is similar to the background rates, one can surmise that the study drug has not increased the risk of the event. Method 1 uses binomial probabilities to calculate the probability of observing the event; method 2 uses incidence rates to assess risk. To illustrate our methods, we evaluated two compounds with immunosuppressive characteristics for cases of progressive multifocal leukoencephalopathy or herpes zoster due to reactivation of the varicella zoster virus. A literature search was used to help determine background rates of these adverse events in the populations of interest. Results For method 1, data are presented in tabular form to show the estimated probability of observing one or more cases of progressive multifocal leukoencephalopathy, assuming a background rate of 0.4% as a result of the disease and 500 subjects exposed to the study medication. For herpes zoster, a background rate of 0.32 per 100 patient-years was predicted from the literature and steps to assess the likelihood of the incidence rates occurring by chance are shown in tabular form. Conclusions These analytical tools may contribute to a better understanding of the association of rare serious adverse events with an approved or experimental compound by helping distinguish rates related to the drug vs. that of the underlying disease or other factors. These methods can aid the drug safety professional by providing a quantitative context of a medicine’s benefit-risk profile during drug development and the post-marketing setting.