An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules
Open accessAbstract
Objectives To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications.Study design and setting We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada.Results Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%).Conclusion Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.
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Interim analyses were described in a third of 894 trial protocols approved from 2000 to 2003 in Switzerland, Germany, and Canada.
“Interim analyses were described in a third of 894 trial protocols approved from 2000 to 2003 in Switzerland, Germany, and Canada.454”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [454]
The use of a data monitoring committee was reported for 29% of trial protocols approved from 2000 to 2003 in Switzerland, Germany, and Canada, and for about 40% of trials registered on ClinicalTrials.gov from 2007 to 2010.
“The use of a data monitoring committee was reported for 29% of trial protocols approved from 2000 to 2003 in Switzerland, Germany, and Canada,453 454 and for about 40% of trials registered on ClinicalTrials.gov from 2007 to 2010.”
From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [454]
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SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials
Hróbjartsson, A., Boutron, I., Hopewell, S., Moher, D., Schulz, K. F., Collins, G. S., Tunn, R., Aggarwal, R., Berkwits, M., Berlin, J. A., et al. (2025) · BMJ · doi:10.1136/bmj-2024-081660 · Cited by 171 · see citing works
- Authors
- Stegert, M., Kasenda, B., von Elm, E., You, J. J., Blümle, A., Tomonaga, Y., Saccilotto, R., Amstutz, A., Bengough, T., Briel, M., Stegert, M., Kasenda, B., Elm, E. V., You, J. J., Blümle, A., Tomonaga, Y., Saccilotto, R., Amstutz, A., Bengough, T., Meerpohl, J. J., Tikkinen, K. A. O., Neumann, I., Carrasco-Labra, A., Faulhaber, M., Mulla, S., Mertz, D., Akl, E. A., Bassler, D., Busse, J. W., Ferreira-González, I., Lamontagne, F., Nordmann, A., Gloy, V., Olu, K. K., Raatz, H., Moja, L., Rosenthal, R., Ebrahim, S., Schandelmaier, S., Sun, X., Vandvik, P. O., Johnston, B. C., Walter, M. A., Burnand, B., Schwenkglenks, M., Hemkens, L. G., Bucher, H. C., Guyatt, G. H., & Briel, M.
- Affiliations
- University of Basel (CH)
- ORCID
- Meerpohl, Joerg J.
- Tikkinen, Kari A.O.
- Neumann, Ignacio
- Mertz, Dominik
- Akl, Elie A.
- Bassler, Dirk
- Busse, Jason W.
- Gloy, Viktoria
- Raatz, Heike
- Moja, Lorenzo
- Ebrahim, Shanil
- Schandelmaier, Stefan
- Sun, Xin
- Vandvik, Per O.
- Johnston, Bradley C.
- Walter, Martin A.
- Burnand, Bernard
- Schwenkglenks, Matthias
- Hemkens, Lars G.
- Bucher, Heiner C.
- Guyatt, Gordon H.
- Venue
- Journal of Clinical Epidemiology
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 69
- Pages
- 152-160
- ISSN
- 0895-4356 (ISSN-L)
- OpenAlex
- W1414339606
- Cited by
- 30
- References
- 24
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 5 · 2018: 2 · 2017: 3 · 2016: 4
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- 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
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmaceutical industry and healthcare
- Keywords
- trial discontinuation, interim analysis, stopping rules, randomized controlled trials, futility, research ethics committee approval
- MeSH terms
- Clinical Protocols, Periodicals as Topic, Randomized Controlled Trials as Topic, Clinical Trials Data Monitoring Committees, Early Termination of Clinical Trials
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