Two-stage single-arm trials are rarely reported adequately

Abstract

Purpose: Two-stage single-arm trial designs are commonly used in phase II oncology to infer treatment effects for a binary primary outcome (e.g., tumour response). It is imperative that such studies be designed, analysed, and reported effectively. However, there is little available evidence on whether this is the case, particularly for key statistical considerations. We therefore comprehensively review such trials, examining in particular quality of reporting. Methods: Published oncology trials that utilised "Simon's two-stage design" over a 5 year period were identified and reviewed. Articles were evaluated on whether they reported sufficient design details, such as the required sample size, and analysis details, such as a confidence interval (CI). The articles that did not adjust their inference for the incorporation of an interim analysis were re-analysed to evaluate the impact on their reported point estimate and CI. Results: Four hundred and twenty five articles that reported the results of a single treatment arm were included. Of these, 47.5% provided the five components that ensure design reproducibility. Only 1.2% and 2.1% reported an adjusted point estimate or CI, respectively. Just 55.3% of trials provided the final stage rejection bound, indicating many trials did not test the hypothesis the design is constructed to assess. Re-analysis of the trials suggests that reported point estimates underestimated treatment effects and that reported CIs were too narrow. Conclusion: Key design details of two-stage single-arm trials are often unreported. Whilst inference is regularly performed, it is rarely done so in a way that removes the bias introduced by the interim analysis. In order to maximise their value, future studies must improve the way that they are analysed and reported.