Author:
Tharmanathan Puvan,Calvert Melanie,Hampton John,Freemantle Nick
Abstract
Abstract
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.
Publisher
Springer Science and Business Media LLC
Subject
Health Informatics,Epidemiology
Reference39 articles.
1. U.S. Department of Health and Human Services: Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committee. 2006, [http://www.fda.gov/cber/gdlns/clintrialdmc.pdf]
2. European Medicines Agency (Committee for Medicinal Products for Human Use): Guideline on Data Monitoring Committees. 2005, [http://www.emea.europa.eu/pdfs/human/ewp/587203en.pdf]
3. International Conference on Harmonisation Of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Steering Committee: ICH Harmonised Tripartite Guidelines: Statistical Principles For Clinical Trials (E9). ICH. 1998, [http://www.ich.org/LOB/media/MEDIA485.pdf]
4. Ellenberg SS, Fleming TR, DeMets DL: Data Monitoring Committees Committees in Clinical Trials: A Practical Perspective. 2002, Chichester: John Wiley
5. Sydes MR, Spiegelhalter DJ, Altman DG, Babiker AB, Parmar MKB, for the DAMOCLES Group: Systematic qualitative review of the literature on data monitoring committees for randomized controlled trials. Clinical Trials. 2004, 1: 60-79. 10.1191/1740774504cn004rr.