Randomized trials stopped early for benefit: A systematic review

Victor Manuel Montori, P. J. Devereaux, Neill K J Adhikari, Karen E A Burns, Christoph H. Eggert, Matthias Briel, Christina Lacchetti, Teresa W. Leung, Elizabeth Darling, Dianne M. Bryant, Heiner C. Bucher, Holger J. Schünemann, Maureen O. Meade, Deborah J. Cook, Patricia J. Erwin, Amit Sood, Richa Sood, Benjamin Lo, Carly A. Thompson, Qi ZhouEdward Mills, Gordon H. Guyatt

Research output: Contribution to journalArticle

504 Citations (Scopus)

Abstract

Context: Randomized clinical trials (RCTs) that stop earlier than planned because of apparent benefit often receive great attention and affect clinical practice. Their prevalence, the magnitude and plausibility of their treatment effects, and the extent to which they report information about how investigators decided to stop early are, however, unknown. Objective: To evaluate the epidemiology and reporting quality of RCTs involving interventions stopped early for benefit. Data Sources: Systematic review up to November 2004 of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify RCTs stopped early for benefit. Study Selection: Randomized clinical trials of any intervention reported as having stopped early because of results favoring the intervention. There were no exclusion criteria. Data Extraction: Twelve reviewers working independently and in duplicate abstracted data on content area and type of intervention tested, reporting of funding, type of end point driving study termination, treatment effect, length of follow-up, estimated sample size and total sample studied, role of a data and safety monitoring board in stopping the study, number of interim analyses planned and conducted, and existence and type of monitoring methods, statistical boundaries, and adjustment procedures for interim analyses and early stopping. Data Synthesis: Of 143 RCTs stopped early for benefit, the majority (92) were published in 5 high-impact medical journals. Typically, these were industry-funded drug trials in cardiology, cancer, and human immunodeficiency virus/AIDS. The proportion of all RCTs published in high-impact journals that were stopped early for benefit increased from 0.5% in 1990-1994 to 1.2% in 2000-2004 (P<.001 for trend). On average, RCTs recruited 63% (SD, 25%) of the planned sample and stopped after a median of 13 (interquartile range [IQR], 3-25) months of follow-up, 1 interim analysis, and when a median of 66 (IQR, 23-195) patients had experienced the end point driving study termination (event). The median risk ratio among truncated RCTs was 0.53 (IQR, 0.28-0.66). One hundred thirty-five (94%) of the 143 RCTs did not report at least 1 of the following: the planned sample size (n=28), the interim analysis after which the trial was stopped (n=45), whether a stopping rule informed the decision (n=48), or an adjusted analysis accounting for interim monitoring and truncation (n=129). Trials with fewer events yielded greater treatment effects (odds ratio, 28; 95% confidence interval, 11-73). Conclusions: RCTs stopped early for benefit are becoming more common, often fail to adequately report relevant information about the decision to stop early, and show implausibly large treatment effects, particularly when the number of events is small. These findings suggest clinicians should view the results of such trials with skepticism.

Original languageEnglish (US)
Pages (from-to)2203-2209
Number of pages7
JournalJournal of the American Medical Association
Volume294
Issue number17
DOIs
StatePublished - Nov 2 2005

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Randomized Controlled Trials
Sample Size
Clinical Trials Data Monitoring Committees
Odds Ratio
Information Storage and Retrieval
Drug Industry
Cardiology
MEDLINE
Acquired Immunodeficiency Syndrome
Epidemiology
Therapeutics
Research Personnel
HIV
Databases
Confidence Intervals
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Montori, V. M., Devereaux, P. J., Adhikari, N. K. J., Burns, K. E. A., Eggert, C. H., Briel, M., ... Guyatt, G. H. (2005). Randomized trials stopped early for benefit: A systematic review. Journal of the American Medical Association, 294(17), 2203-2209. https://doi.org/10.1001/jama.294.17.2203

Randomized trials stopped early for benefit : A systematic review. / Montori, Victor Manuel; Devereaux, P. J.; Adhikari, Neill K J; Burns, Karen E A; Eggert, Christoph H.; Briel, Matthias; Lacchetti, Christina; Leung, Teresa W.; Darling, Elizabeth; Bryant, Dianne M.; Bucher, Heiner C.; Schünemann, Holger J.; Meade, Maureen O.; Cook, Deborah J.; Erwin, Patricia J.; Sood, Amit; Sood, Richa; Lo, Benjamin; Thompson, Carly A.; Zhou, Qi; Mills, Edward; Guyatt, Gordon H.

In: Journal of the American Medical Association, Vol. 294, No. 17, 02.11.2005, p. 2203-2209.

Research output: Contribution to journalArticle

Montori, VM, Devereaux, PJ, Adhikari, NKJ, Burns, KEA, Eggert, CH, Briel, M, Lacchetti, C, Leung, TW, Darling, E, Bryant, DM, Bucher, HC, Schünemann, HJ, Meade, MO, Cook, DJ, Erwin, PJ, Sood, A, Sood, R, Lo, B, Thompson, CA, Zhou, Q, Mills, E & Guyatt, GH 2005, 'Randomized trials stopped early for benefit: A systematic review', Journal of the American Medical Association, vol. 294, no. 17, pp. 2203-2209. https://doi.org/10.1001/jama.294.17.2203
Montori, Victor Manuel ; Devereaux, P. J. ; Adhikari, Neill K J ; Burns, Karen E A ; Eggert, Christoph H. ; Briel, Matthias ; Lacchetti, Christina ; Leung, Teresa W. ; Darling, Elizabeth ; Bryant, Dianne M. ; Bucher, Heiner C. ; Schünemann, Holger J. ; Meade, Maureen O. ; Cook, Deborah J. ; Erwin, Patricia J. ; Sood, Amit ; Sood, Richa ; Lo, Benjamin ; Thompson, Carly A. ; Zhou, Qi ; Mills, Edward ; Guyatt, Gordon H. / Randomized trials stopped early for benefit : A systematic review. In: Journal of the American Medical Association. 2005 ; Vol. 294, No. 17. pp. 2203-2209.
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abstract = "Context: Randomized clinical trials (RCTs) that stop earlier than planned because of apparent benefit often receive great attention and affect clinical practice. Their prevalence, the magnitude and plausibility of their treatment effects, and the extent to which they report information about how investigators decided to stop early are, however, unknown. Objective: To evaluate the epidemiology and reporting quality of RCTs involving interventions stopped early for benefit. Data Sources: Systematic review up to November 2004 of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify RCTs stopped early for benefit. Study Selection: Randomized clinical trials of any intervention reported as having stopped early because of results favoring the intervention. There were no exclusion criteria. Data Extraction: Twelve reviewers working independently and in duplicate abstracted data on content area and type of intervention tested, reporting of funding, type of end point driving study termination, treatment effect, length of follow-up, estimated sample size and total sample studied, role of a data and safety monitoring board in stopping the study, number of interim analyses planned and conducted, and existence and type of monitoring methods, statistical boundaries, and adjustment procedures for interim analyses and early stopping. Data Synthesis: Of 143 RCTs stopped early for benefit, the majority (92) were published in 5 high-impact medical journals. Typically, these were industry-funded drug trials in cardiology, cancer, and human immunodeficiency virus/AIDS. The proportion of all RCTs published in high-impact journals that were stopped early for benefit increased from 0.5{\%} in 1990-1994 to 1.2{\%} in 2000-2004 (P<.001 for trend). On average, RCTs recruited 63{\%} (SD, 25{\%}) of the planned sample and stopped after a median of 13 (interquartile range [IQR], 3-25) months of follow-up, 1 interim analysis, and when a median of 66 (IQR, 23-195) patients had experienced the end point driving study termination (event). The median risk ratio among truncated RCTs was 0.53 (IQR, 0.28-0.66). One hundred thirty-five (94{\%}) of the 143 RCTs did not report at least 1 of the following: the planned sample size (n=28), the interim analysis after which the trial was stopped (n=45), whether a stopping rule informed the decision (n=48), or an adjusted analysis accounting for interim monitoring and truncation (n=129). Trials with fewer events yielded greater treatment effects (odds ratio, 28; 95{\%} confidence interval, 11-73). Conclusions: RCTs stopped early for benefit are becoming more common, often fail to adequately report relevant information about the decision to stop early, and show implausibly large treatment effects, particularly when the number of events is small. These findings suggest clinicians should view the results of such trials with skepticism.",
author = "Montori, {Victor Manuel} and Devereaux, {P. J.} and Adhikari, {Neill K J} and Burns, {Karen E A} and Eggert, {Christoph H.} and Matthias Briel and Christina Lacchetti and Leung, {Teresa W.} and Elizabeth Darling and Bryant, {Dianne M.} and Bucher, {Heiner C.} and Sch{\"u}nemann, {Holger J.} and Meade, {Maureen O.} and Cook, {Deborah J.} and Erwin, {Patricia J.} and Amit Sood and Richa Sood and Benjamin Lo and Thompson, {Carly A.} and Qi Zhou and Edward Mills and Guyatt, {Gordon H.}",
year = "2005",
month = "11",
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language = "English (US)",
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pages = "2203--2209",
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TY - JOUR

T1 - Randomized trials stopped early for benefit

T2 - A systematic review

AU - Montori, Victor Manuel

AU - Devereaux, P. J.

AU - Adhikari, Neill K J

AU - Burns, Karen E A

AU - Eggert, Christoph H.

AU - Briel, Matthias

AU - Lacchetti, Christina

AU - Leung, Teresa W.

AU - Darling, Elizabeth

AU - Bryant, Dianne M.

AU - Bucher, Heiner C.

AU - Schünemann, Holger J.

AU - Meade, Maureen O.

AU - Cook, Deborah J.

AU - Erwin, Patricia J.

AU - Sood, Amit

AU - Sood, Richa

AU - Lo, Benjamin

AU - Thompson, Carly A.

AU - Zhou, Qi

AU - Mills, Edward

AU - Guyatt, Gordon H.

PY - 2005/11/2

Y1 - 2005/11/2

N2 - Context: Randomized clinical trials (RCTs) that stop earlier than planned because of apparent benefit often receive great attention and affect clinical practice. Their prevalence, the magnitude and plausibility of their treatment effects, and the extent to which they report information about how investigators decided to stop early are, however, unknown. Objective: To evaluate the epidemiology and reporting quality of RCTs involving interventions stopped early for benefit. Data Sources: Systematic review up to November 2004 of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify RCTs stopped early for benefit. Study Selection: Randomized clinical trials of any intervention reported as having stopped early because of results favoring the intervention. There were no exclusion criteria. Data Extraction: Twelve reviewers working independently and in duplicate abstracted data on content area and type of intervention tested, reporting of funding, type of end point driving study termination, treatment effect, length of follow-up, estimated sample size and total sample studied, role of a data and safety monitoring board in stopping the study, number of interim analyses planned and conducted, and existence and type of monitoring methods, statistical boundaries, and adjustment procedures for interim analyses and early stopping. Data Synthesis: Of 143 RCTs stopped early for benefit, the majority (92) were published in 5 high-impact medical journals. Typically, these were industry-funded drug trials in cardiology, cancer, and human immunodeficiency virus/AIDS. The proportion of all RCTs published in high-impact journals that were stopped early for benefit increased from 0.5% in 1990-1994 to 1.2% in 2000-2004 (P<.001 for trend). On average, RCTs recruited 63% (SD, 25%) of the planned sample and stopped after a median of 13 (interquartile range [IQR], 3-25) months of follow-up, 1 interim analysis, and when a median of 66 (IQR, 23-195) patients had experienced the end point driving study termination (event). The median risk ratio among truncated RCTs was 0.53 (IQR, 0.28-0.66). One hundred thirty-five (94%) of the 143 RCTs did not report at least 1 of the following: the planned sample size (n=28), the interim analysis after which the trial was stopped (n=45), whether a stopping rule informed the decision (n=48), or an adjusted analysis accounting for interim monitoring and truncation (n=129). Trials with fewer events yielded greater treatment effects (odds ratio, 28; 95% confidence interval, 11-73). Conclusions: RCTs stopped early for benefit are becoming more common, often fail to adequately report relevant information about the decision to stop early, and show implausibly large treatment effects, particularly when the number of events is small. These findings suggest clinicians should view the results of such trials with skepticism.

AB - Context: Randomized clinical trials (RCTs) that stop earlier than planned because of apparent benefit often receive great attention and affect clinical practice. Their prevalence, the magnitude and plausibility of their treatment effects, and the extent to which they report information about how investigators decided to stop early are, however, unknown. Objective: To evaluate the epidemiology and reporting quality of RCTs involving interventions stopped early for benefit. Data Sources: Systematic review up to November 2004 of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify RCTs stopped early for benefit. Study Selection: Randomized clinical trials of any intervention reported as having stopped early because of results favoring the intervention. There were no exclusion criteria. Data Extraction: Twelve reviewers working independently and in duplicate abstracted data on content area and type of intervention tested, reporting of funding, type of end point driving study termination, treatment effect, length of follow-up, estimated sample size and total sample studied, role of a data and safety monitoring board in stopping the study, number of interim analyses planned and conducted, and existence and type of monitoring methods, statistical boundaries, and adjustment procedures for interim analyses and early stopping. Data Synthesis: Of 143 RCTs stopped early for benefit, the majority (92) were published in 5 high-impact medical journals. Typically, these were industry-funded drug trials in cardiology, cancer, and human immunodeficiency virus/AIDS. The proportion of all RCTs published in high-impact journals that were stopped early for benefit increased from 0.5% in 1990-1994 to 1.2% in 2000-2004 (P<.001 for trend). On average, RCTs recruited 63% (SD, 25%) of the planned sample and stopped after a median of 13 (interquartile range [IQR], 3-25) months of follow-up, 1 interim analysis, and when a median of 66 (IQR, 23-195) patients had experienced the end point driving study termination (event). The median risk ratio among truncated RCTs was 0.53 (IQR, 0.28-0.66). One hundred thirty-five (94%) of the 143 RCTs did not report at least 1 of the following: the planned sample size (n=28), the interim analysis after which the trial was stopped (n=45), whether a stopping rule informed the decision (n=48), or an adjusted analysis accounting for interim monitoring and truncation (n=129). Trials with fewer events yielded greater treatment effects (odds ratio, 28; 95% confidence interval, 11-73). Conclusions: RCTs stopped early for benefit are becoming more common, often fail to adequately report relevant information about the decision to stop early, and show implausibly large treatment effects, particularly when the number of events is small. These findings suggest clinicians should view the results of such trials with skepticism.

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