The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
Early stopping of randomized clinical trials for overt efficacy is problematic.
Abstract
Objective To illustrate controversial issues associated with stopping randomized controlled trials (RCTs) early for apparent benefit.Study design and setting The article presents our review of prior relevant work and our research group's reflections on early stopping.Results Compelling evidence suggests that trials stopped early for benefit systematically overestimate treatment effects, sometimes by a large amount. Unresolved controversies in trials stopped early for benefit include ethical and statistical problems in the interpretation of results.Conclusions The best strategy to minimize the problems associated with early stopping of RCTs for benefit is not to stop early. As an alternative, we suggest a threefold approach: a low P-value as the threshold for stopping at the time of interim analyses, not to look before a sufficiently large number of events has accrued and continuation of enrollment and follow-up for a further period.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The authors determined that a sufficient number of clusters had completed implementation of the planned intervention to allow analysis of the primary outcome but were unable to use the final 3 months of the stepped-wedge design (after the policy change) for the planned analysis.”
In the citing paper
“In a multicenter stepped-wedge cluster randomized pragmatic trial, regional government enacted a policy change partway through the rollout that mandated widespread use of a modified version of the experimental intervention as the new standard of care.”
In the citing paper
“The trialists identified this policy change as an extenuating circumstance leading to a premature and unanticipated modification to the implementation schedule at 9 months, before the planned completion at 12 months.”
In the citing paper
“The international survey yielded examples of trials that encountered extenuating circumstances including regulatory changes, new standards of care, and security threats (Table).”
In the citing paper
“The trial by Vaillancourt et al 20 on out-of-hospital cervical spine immobilization was stopped early when regional authorities enacted a new policy mandating a modified immobilization rule and adopting many aspects of the trial's experimental intervention as standard of care (Table).”
In the citing paper
“The investigators' mitigating strategies included omission of the final study period from the randomized clinical trial analysis, an extended observational data collection period for 3 months beyond the anticipated stop date, and a revised design and analysis plan to include 3 conditions: usual care, planned intervention, and an uncontrolled modified intervention condition.”
Citations
Cites
Peto, R., Pike, M. C., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, N., McPherson, K., Peto, J., & Smith, P. G. (1977) · British Journal of Cancer · doi:10.1038/bjc.1977.1 · Cited by 8,285
Moher, D., Schulz, K. F., & Altman, D. G. (2001) · The Lancet · doi:10.1016/s0140-6736(00)04337-3 · Cited by 5,373
Moher, D., Cook, D. J., Eastwood, S., Olkin, I., Rennie, D., & Stroup, D. F. (1999) · The Lancet · doi:10.1016/s0140-6736(99)04149-5 · Cited by 4,826
A Multiple Testing Procedure for Clinical Trials
O'Brien, P. C., & Fleming, T. R. (1979) · Biometrics · doi:10.2307/2530245 · Cited by 3,311
Sleight, R. B., Sleight, P., Parish, S., Appleby, P. N., Collins, R., & Baigent, C. (1988) · PubMed · Cited by 2,868
急性心筋梗塞の疑いのある17187症例におけるストレプトキナーゼ静脈内投与,アスピリン経口投与,上記2つの併用または無処置の無作偽試験 ISIS-2
Dienstl, F., Backer, G. D., Cairns, J., Pedersen, F., Kala, R., Boissel, J., Schroeder, R., Horgan, J., & Tognoni, G. (1988) · The Lancet · Cited by 2,754
What Makes Clinical Research Ethical?
Emanuel, E. J. (2000) · JAMA · doi:10.1001/jama.283.20.2701 · Cited by 2,710
Auvert, B., Taljaard, D., Lagarde, E., Sobngwi-Tambekou, J., Sitta, R., & Puren, A. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020298 · Cited by 2,451
Equipoise and the Ethics of Clinical Research
Freedman, B. (1987) · New England Journal of Medicine · doi:10.1056/nejm198707163170304 · Cited by 2,339
Discrete sequential boundaries for clinical trials
GORDON LAN, K. K., & DEMETS, D. L. (1983) · Biometrika · doi:10.1093/biomet/70.3.659 · Cited by 2,310
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–129 of 129
How consistent are recent neonatal resuscitation guidelines?
Kuitunen, I., & Davis, P. G. (2026) · Resuscitation Plus · doi:10.1016/j.resplu.2026.101314 · Cited by 1
Cândia, R., & Gabriel Rada, G. (2015) · ARS MEDICA Revista de Ciencias Médicas · doi:10.11565/arsmed.v39i1.9 · Cited by 1
Sénior, J. M., Muñoz-Ortiz, E., & Díaz, J. (2017) · Revista Colombiana de Cardiología · doi:10.1016/j.rccar.2017.01.003 · Cited by 1
Tools for Assessment of Cardiovascular Tests and Therapies
Antman, E. M., Califf, R. M., & Kupersmith, J. (2007) · Elsevier eBooks · doi:10.1016/b978-1-4160-3358-5.50007-3 · Cited by 1
Stopping Trials Early: Responsibility and Risks
McGuire, W. L., & Halliday, H. L. (2021) · Neonatology · doi:10.1159/000514990 · Cited by 1
Lure, A. C., Sánchez, P. J., & Slaughter, J. L. (2023) · Journal of Perinatology · doi:10.1038/s41372-023-01769-3 · Cited by 1
Bayesian sequential monitoring strategies for trials of digestive cancer therapeutics
Mulier, G., Lin, R., Aparicio, T., & Biard, L. (2024) · BMC Medical Research Methodology · doi:10.1186/s12874-024-02278-3 · Cited by 1
“Lastly, it has been shown that in the setting of frequentist approaches with efficacy stopping rule, more frequent looks can sometimes lead to an increased proportion of positive trials and thus to an overestimation of the efficacy, for example [36].”
BackgroundThe Influence of the Thermal Environment Upon the Survival of Newly Born Premature Infants
Osborn, D. (2024) · doi:10.1093/med/9780197646953.003.0024 · Cited by 1
Dodd, L. E., Lantos, J. D., & Pinheiro, J. C. (2016) · Clinical Trials · doi:10.1177/1740774516657547 · Cited by 1
Exploring the regulatory decision-making process for medicines
Tafuri, G. (2013) · Utrecht University Repository (Utrecht University) · Cited by 1
Sinert, R. H., Doty, C., & Brown, M. D. (2008) · Annals of Emergency Medicine · doi:10.1016/j.annemergmed.2008.10.032 · Cited by 1
Blood pressure lowering in the oldest old: a step toward abandoning arbitrary blood pressure targets
Gueyffier, F., Perez, M. I., Wright, J. M., Marchant, I., Musini, V. M., & Bejan‐Angoulvant, T. (2010) · Journal of Hypertension · doi:10.1097/hjh.0b013e3283409240 · Cited by 2
The removal-associated sepsis prevention trial in preterm newborns was ended in an untimely manner
Degraeuwe, P. L. J., & Kessels, A. G. H. (2012) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0b013e318238b453 · Cited by 1
Should we ever stop clinical trials for efficacy?
Fergusson, N. A., & Griesdale, D. E. G. (2018) · Canadian Journal of Anesthesia/Journal canadien d anesthésie · doi:10.1007/s12630-018-1207-y · Cited by 1
Andexanet for factor Xa inhibitor-associated acute intracerebral hemorrhage
Leafloor, C. W., Green, R. S., & Sharif, S. (2025) · Canadian Journal of Emergency Medicine · doi:10.1007/s43678-024-00845-7 · Cited by 1
Ensayos interrumpidos precozmente por beneficio. ¿Es oro todo lo que reluce?
Alonso‐Coello, P., Comas, D. R., Urrútia, G., & Solà, I. (2009) · FMC - Formación Médica Continuada en Atención Primaria · doi:10.1016/s1134-2072(09)71971-1
Giard, R. W. M. (2009) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2008.12.012
“There are several reasons for a DMSC to stop an ongoing trial: evident superiority of the experimental treatment, futilityofthetrialoremergingharm[ 6 ,8].However,tostopatrial for any of these reasons, we must avoid jumping to conclusions, and proof beyond reasonable doubt is clearly needed [14].”
BackgroundInfluentialShould patients at lower cardiac risk receive beta-blockers before noncardiac surgery?
Williams, J. S., Will, K. K., Hartsell, Z. C., & Budavari, A. I. (2010) · JAAPA · doi:10.1097/01720610-201003000-00010
Tools for Assessment of Cardiovascular Tests and Therapies
Antman, E. M., Califf, R. M., & Choudhry, N. K. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4557-0101-8.00001-1
Randomized Controlled Clinical Trials
Dumitrescu, A. L. (2012) · Springer eBooks · doi:10.1007/978-3-642-28923-1_4
Diabetes and Cardiovascular Disease
Gore, M. O., Inzucchi, S. E., & McGuire, D. K. (2011) · Elsevier eBooks · doi:10.1016/b978-1-4377-1366-4.00021-4
Evaluation of Strategies for the Phase II to Phase III Progression in Treatment Discovery
Sanchez, B. J. (2014) · ResearchWorks at the University of Washington (University of Washington)
An Investigation and Review of Futility Analysis Methods in Phase III Oncology Trials.
Winch, C. (2012) · QSpace (Queen's University Library)
Loytved, C., & Zeeb, D. (2020) · Hebamme · doi:10.1055/a-1247-8648
Ellenberg, S. S., Fleming, T. R., & DeMets, D. L. (2019) · Wiley eBooks · doi:10.1002/9781119512684.ch11
Medical Masks Versus N95 Respirators for Preventing COVID-19 Among Health Care Workers
Loeb, M. B., Mertz, D., Chagla, Z., & Conly, J. M. (2023) · Annals of Internal Medicine · doi:10.7326/l23-0077
CADTH (2024) · Canadian Journal of Health Technologies · doi:10.51731/cjht.2024.913
Integrity of Clinical RCTs: Safeguarding Trust, Evidence, and Patient WelfarePreprint
Mansmann, U. (2026) · Qeios · doi:10.32388/mac10d
Metadata
- Authors
- Bassler, D., Montori, V. M., Briel, M., Glasziou, P., & Guyatt, G.
- Affiliations
- University Children's Hospital Tübingen (DE)
- University of Basel (CH)
- University of Oxford (GB)
- McMaster University (CA)
- Venue
- Journal of Clinical Epidemiology
- Publisher
- Elsevier BV
- Published
- 2008-03
- Volume
- 61
- Issue
- 3
- Pages
- 241-246
- ISSN
- 0895-4356 (ISSN-L)
- OpenAlex
- W2042803707
- Cited by
- 130
- References
- 38
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 7 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 6 · 2019: 6 · 2018: 9 · 2017: 4 · 2016: 7 · 2015: 9 · 2014: 9 · 2013: 8 · 2012: 9
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- DigitalGeorgetown (Georgetown University Library) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Medical Research Council
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
- Keywords
- early stopping, randomized controlled trials, interim analysis, overestimation of treatment effects, statistical power, p-value threshold, trial ethics
- MeSH terms
- Decision Making, Humans, Motivation, Bias, Randomized Controlled Trials as Topic, Treatment Outcome, Ethics, Research
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
