Prevalence and reporting of recruitment, randomisation and treatment errors in clinical trials: A systematic review.

Background/aims In clinical trials, it is not unusual for errors to occur during the process of recruiting, randomising and providing treatment to participants. For example, an ineligible participant may inadvertently be randomised, a participant may be randomised in the incorrect stratum, a participant may be randomised multiple times when only a single randomisation is permitted or the incorrect treatment may inadvertently be issued to a participant at randomisation. Such errors have the potential to introduce bias into treatment effect estimates and affect the validity of the trial, yet there is little motivation for researchers to report these errors and it is unclear how often they occur. The aim of this study is to assess the prevalence of recruitment, randomisation and treatment errors and review current approaches for reporting these errors in trials published in leading medical journals. Methods We conducted a systematic review of individually randomised, phase III, randomised controlled trials published in New England Journal of Medicine, Lancet, Journal of the American Medical Association, Annals of Internal Medicine and British Medical Journal from January to March 2015. The number and type of recruitment, randomisation and treatment errors that were reported and how they were handled were recorded. The corresponding authors were contacted for a random sample of trials included in the review and asked to provide details on unreported errors that occurred during their trial. Results We identified 241 potentially eligible articles, of which 82 met the inclusion criteria and were included in the review. These trials involved a median of 24 centres and 650 participants, and 87% involved two treatment arms. Recruitment, randomisation or treatment errors were reported in 32 in 82 trials (39%) that had a median of eight errors. The most commonly reported error was ineligible participants inadvertently being randomised. No mention of recruitment, randomisation or treatment errors was found in the remaining 50 of 82 trials (61%). Based on responses from 9 of the 15 corresponding authors who were contacted regarding recruitment, randomisation and treatment errors, between 1% and 100% of the errors that occurred in their trials were reported in the trial publications. Conclusion Recruitment, randomisation and treatment errors are common in individually randomised, phase III trials published in leading medical journals, but reporting practices are inadequate and reporting standards are needed. We recommend researchers report all such errors that occurred during the trial and describe how they were handled in trial publications to improve transparency in reporting of clinical trials.

Applying the intention-to-treat principle in practice: Guidance on handling randomisation errors.

BACKGROUND: The intention-to-treat principle states that all randomised participants should be analysed in their randomised group. The implications of this principle are widely discussed in relation to the analysis, but have received limited attention in the context of handling errors that occur during the randomisation process. The aims of this article are to (1) demonstrate the potential pitfalls of attempting to correct randomisation errors and (2) provide guidance on handling common randomisation errors when they are discovered that maintains the goals of the intention-to-treat principle. METHODS: The potential pitfalls of attempting to correct randomisation errors are demonstrated and guidance on handling common errors is provided, using examples from our own experiences. RESULTS: We illustrate the problems that can occur when attempts are made to correct randomisation errors and argue that documenting, rather than correcting these errors, is most consistent with the intention-to-treat principle. When a participant is randomised using incorrect baseline information, we recommend accepting the randomisation but recording the correct baseline data. If ineligible participants are inadvertently randomised, we advocate keeping them in the trial and collecting all relevant data but seeking clinical input to determine their appropriate course of management, unless they can be excluded in an objective and unbiased manner. When multiple randomisations are performed in error for the same participant, we suggest retaining the initial randomisation and either disregarding the second randomisation if only one set of data will be obtained for the participant, or retaining the second randomisation otherwise. When participants are issued the incorrect treatment at the time of randomisation, we propose documenting the treatment received and seeking clinical input regarding the ongoing treatment of the participant. CONCLUSION: Randomisation errors are almost inevitable and should be reported in trial publications. The intention-to-treat principle is useful for guiding responses to randomisation errors when they are discovered.