title: A Bayesian meta-analytic approach for safety signal detection in randomized clinical trials.
abstract: OBJECTIVE
  Meta-analyses are frequently performed on adverse event data and are primarily used for improving statistical power to detect safety signals. However, in the evaluation of drug safety for New Drug Applications, simple pooling of adverse event data from multiple clinical trials is still commonly used. We sought to propose a new Bayesian hierarchical meta-analytic approach based on consideration of a hierarchical structure of reported individual adverse event data from multiple randomized clinical trials.
  
  
  METHODS
  To develop our meta-analysis model, we extended an existing three-stage Bayesian hierarchical model by including an additional stage of the clinical trial level in the hierarchical model; this generated a four-stage Bayesian hierarchical model. We applied the proposed Bayesian meta-analysis models to published adverse event data from three premarketing randomized clinical trials of tadalafil and to a simulation study motivated by the case example to evaluate the characteristics of three alternative models.
  
  
  RESULTS
  Comparison of the results from the Bayesian meta-analysis model with those from Fisher's exact test after simple pooling showed that 6 out of 10 adverse events were the same within a top 10 ranking of individual adverse events with regard to association with treatment. However, more individual adverse events were detected in the Bayesian meta-analysis model than in Fisher's exact test under the body system "Musculoskeletal and connective tissue disorders." Moreover, comparison of the overall trend of estimates between the Bayesian model and the standard approach (odds ratios after simple pooling methods) revealed that the posterior median odds ratios for the Bayesian model for most adverse events shrank toward values for no association. Based on the simulation results, the Bayesian meta-analysis model could balance the false detection rate and power to a better extent than Fisher's exact test. For example, when the threshold value of the posterior probability for signal detection was set to 0.8, the false detection rate was 41% and power was 88% in the Bayesian meta-analysis model, whereas the false detection rate was 56% and power was 86% in Fisher's exact test.
  
  
  CONCLUSIONS
  Adverse events under the same body system were not necessarily positively related when we used "system organ class" and "preferred term" in the Medical Dictionary for Regulatory Activities as a hierarchical structure of adverse events. For the Bayesian meta-analysis models to be effective, the validity of the hierarchical structure of adverse events and the grouping of adverse events are critical.
  
  
  CONCLUSIONS
  Our proposed meta-analysis models considered trial effects to avoid confounding by trial and borrowed strength from both within and across body systems to obtain reasonable and stable estimates of an effect measure by considering a hierarchical structure of adverse events.
authors.affiliation: 1 Data Science, Ono Pharmaceutical Co., Ltd., Osaka, Japan.|2 Department of Biostatistics, Kyoto University School of Public Health, Kyoto, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Odani
authors.affiliation: 1 Data Science, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Fukimbara
authors.affiliation: 2 Department of Biostatistics, Kyoto University School of Public Health, Kyoto, Japan.
authors.forename: Tosiya
authors.initials: T
authors.lastname: Sato
mesh_terms: D001499:Bayes Theorem; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D059411:Lower Urinary Tract Symptoms / Q000188:drug therapy; D008297:Male; D015201:Meta-Analysis as Topic; D015233:Models, Statistical; D058986:Phosphodiesterase 5 Inhibitors / Q000009:adverse effects; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic; D000068581:Tadalafil / Q000009:adverse effects
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil
keywords: Bayesian hierarchical model; adverse event data; drug safety; meta-analysis; randomized clinical trial; signal detection