Evidence synthesis from aggregate recurrent event data for clinical trial design and analysis.

Information from historical trials is important for the design, interim monitoring, analysis, and interpretation of clinical trials. Meta-analytic models can be used to synthesize the evidence from historical data, which are often only available in aggregate form. We consider evidence synthesis methods for trials with recurrent event endpoints, which are common in many therapeutic areas. Such endpoints are typically analyzed by negative binomial regression. However, the individual patient data necessary to fit such a model are usually unavailable for historical trials reported in the medical literature. We describe approaches for back-calculating model parameter estimates and their standard errors from available summary statistics with various techniques, including approximate Bayesian computation. We propose to use a quadratic approximation to the log-likelihood for each historical trial based on 2 independent terms for the log mean rate and the log of the dispersion parameter. A Bayesian hierarchical meta-analysis model then provides the posterior predictive distribution for these parameters. Simulations show this approach with back-calculated parameter estimates results in very similar inference as using parameter estimates from individual patient data as an input. We illustrate how to design and analyze a new randomized placebo-controlled exacerbation trial in severe eosinophilic asthma using data from 11 historical trials.