How do multi-stage, multi-arm trials compare to the traditional two-arm parallel group design – a reanalysis of 4 trials

<p>Abstract</p> <p>Background</p> <p>To speed up the evaluation of new therapies, the multi-arm, multi-stage trial design was suggested previously by the authors.</p> <p>Methods</p> <p>In this paper, we evaluate the performance of the two-stage, multi-arm design using four cancer trials conducted at the MRC CTU. The performance of the design at fictitious interim analyses is assessed using a conditional bootstrap approach.</p> <p>Results</p> <p>Two main aims are addressed: the error rate of correctly carrying on/stopping the trial at an interim analysis as well as quantifying the gains in terms of resources by employing this design. Furthermore, we make suggestions for the best timing of this interim analysis.</p> <p>Conclusion</p> <p>Multi-arm, multi-stage trials are an effective way of speeding up the therapy evaluation process. The design performs well in terms of the type I and II error rates.</p

The use of interim data and Data Monitoring Committee recommendations in randomized controlled trial reports: frequency, implications and potential sources of bias

Background: Interim analysis of accumulating trial data is important to protect participant safety during randomized controlled trials (RCTs). Data Monitoring Committees (DMCs) often undertake such analyses, but their widening role may lead to extended use of interim analysis or recommendations that could potentially bias trial results.Methods: Systematic search of eight major publications: Annals of Internal Medicine, BMJ, Circulation, CID, JAMA, JCO, Lancet and NEJM, including all randomised controlled trials ( RCTs) between June 2000 and May 2005 to identify RCTs that reported use of interim analysis, with or without DMC involvement. Recommendations made by the DMC or based on interim analysis were identified and potential sources of bias assessed. Independent double data extraction was performed on all included trials.Results: We identified 1772 RCTs, of which 470 (27%; 470/1772) reported the use of a DMC and a further 116 (7%; 116/1772) trials reported some form of interim analysis without explicit mention of a DMC. There were 28 trials ( 24 with a formal DMC), randomizing a total of 79396 participants, identified as recommending changes to the trial that may have lead to biased results. In most of these, some form of sample size re-estimation was recommended with four trials also reporting changes to trial endpoints. The review relied on information reported in the primary publications and methods papers relating to the trials, higher rates of use may have occurred but not been reported.Conclusion: The reported use of interim analysis and DMCs in clinical trials has been increasing in recent years. It is reassuring that in most cases recommendations were made in the interest of participant safety. However, in practice, recommendations that may lead to potentially biased trial results are being made