title: Meta-analysis of randomized phase II trials to inform subsequent phase III decisions.
abstract: BACKGROUND
  If multiple Phase II randomized trials exist then meta-analysis is favorable to increase statistical power and summarize the existing evidence about an intervention's effect in order to help inform Phase III decisions. We consider some statistical issues for meta-analysis of Phase II trials for this purpose, as motivated by a real example involving nine Phase II trials of bolus thrombolytic therapy in acute myocardial infarction with binary outcomes.
  
  
  METHODS
  We propose that a Bayesian random effects logistic regression model is most suitable as it models the binomial distribution of the data, helps avoid continuity corrections, accounts for between-trial heterogeneity, and incorporates parameter uncertainty when making inferences. The model also allows predictions that inform Phase III decisions, and we show how to derive: (i) the probability that the intervention will be truly beneficial in a new trial, and (ii) the probability that, in a new trial with a given sample size, the 95% credible interval for the odds ratio will be entirely in favor of the intervention. As Phase II trials are potentially optimistic due to bias in design and reporting, we also discuss how skeptical prior distributions can reduce this optimism to make more realistic predictions.
  
  
  RESULTS
  In the example, the model identifies heterogeneity in intervention effect missed by an I-squared of 0%. Prediction intervals accounting for this heterogeneity are shown to support subsequent Phase III trials. The probability of success in Phase III trials increases as the sample size increases, up to 0.82 for intracranial hemorrhage and 0.79 for reinfarction outcomes.
  
  
  CONCLUSIONS
  The choice of meta-analysis methods can influence the decision about whether a trial should proceed to Phase III and thus need to be clearly documented and investigated whenever a Phase II meta-analysis is performed.
authors.affiliation: Medical Research Council Midland Hub for Trials Methodology Research, School of Health and Population Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. d.burke@bham.ac.uk.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Burke
authors.forename: Lucinda J
authors.initials: LJ
authors.lastname: Billingham
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Girling
authors.forename: Richard D
authors.initials: RD
authors.lastname: Riley
mesh_terms: D001499:Bayes Theorem; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy; D017594:Publication Bias; D016032:Randomized Controlled Trials as Topic; D018401:Sample Size; D015912:Thrombolytic Therapy