Review ArticleEarly stopping of randomized clinical trials for overt efficacy is problematic
Section snippets
Four reasons for early termination
There are four major reasons for stopping a randomized clinical trial (RCT) early. First, the trial may show serious adverse effects and may be stopped for unacceptable safety. This was the case, for instance, in an RCT that investigated the effect of hydrocortisone treatment on survival without bronchopulmonary dysplasia in preterm infants [1]. This study was discontinued early because of gastrointestinal perforations in the hydrocortisone group [1].
Second, investigators may stop the trial if
Motivations for early stopping
There are two potentially justifiable reasons for early termination of a trial showing apparent large benefit. First, one might make an argument that it is unethical to continue to randomize patients in the face of such a result. This consideration may be compelling for investigators, patients, and their advocates, and DMCs. Second, scarce research resources might be better invested in addressing other questions if one believes an apparent large benefit has adequately addressed a research
Acknowledgment
We wish to thank the UK MRC for supporting our ongoing work on the impact of early stopping of trials. Matthias Briel is supported by a grant from the Swiss National Science Foundation.
References (35)
- et al.
Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants
J Pediatr
(2005) - et al.
The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials
Lancet
(2001) - et al.
Systematic reviewers neglect bias that results from trials stopped early for benefit
J Clin Epidemiol
(2007) - et al.
Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses
Lancet
(1999) - et al.
Multiplicity in randomised trials. II: Subgroup and interim analyses
Lancet
(2005) - et al.
Trials stopped early: too good to be true?
Lancet
(1999) - et al.
Effect sizes in cumulative meta-analyses of mental health randomized trials evolved over time
J Clin Epidemiol
(2004) - et al.
Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial
Lancet
(2007) - et al.
Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial
Lancet
(2007) - et al.
A randomized, double-blind, placebo-controlled trial of combined nevirapine and zidovudine compared with nevirapine alone in the prevention of perinatal transmission of HIV in Zimbabwe
Clin Infect Dis
(2007)