Abstract
BackgroundInterim 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.MethodsSystematic 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.ResultsWe 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.ConclusionThe 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.
Highlights
Interim analysis of accumulating trial data is important to protect participant safety during randomized controlled trials (RCTs)
We conducted a systematic search of eight journals, Annals of Internal Medicine, BMJ, Circulation, Clinical Infectious Diseases (CID), JAMA, the Journal of Clinical Oncology (JCO), Lancet and the New England Journal of Medicine (NEJM), to identify RCTs reporting the use of interim analysis with or without specification of a Data Monitoring Committees (DMCs), between June 2000 and June 2005
A further 116 trials reported some form of interim analysis without explicit mention of a DMC, giving a total of 586 (33%; 586/1772) trials that reported the use of interim analysis
Summary
Interim analysis of accumulating trial data is important to protect participant safety during randomized controlled trials (RCTs). The International Conference on Harmonisation (ICH) recommends that such analyses be conducted by individuals with no vested interest in the outcome of the trial where possible, in large confirmatory Phase III trials [3]. When formalized, this role is commonly performed by a multi-disciplinary group of specialist, often referred to as a Data Monitoring Committee (DMC), which makes recommendations to those in charge of the overall management of the trial, often referred to as the Trial Steering Committee (TSC). DMC recommendations typically include either: continuing the trial as planned; stopping early for hazard; stopping because efficacy is unequivocally established; or stopping because continuing the trial is futile [4]
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