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In Reply

Mayo Clinic, Rochester, MN

Benjamin Djulbegovic

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Gordon H. Guyatt

McMaster University, Hamilton, Ontario, Canada

Victor M. Montori

Mayo Clinic, Rochester, MN

We appreciate Pater et al's interest in our recently published review of oncology trials stopped early for benefit.¹ Their letter underscores how important it is for clinical trialists and members of data monitoring boards to become aware of the potential dangers involved in interim analyses and early trial termination. We agree with Pater et al that early interim analyses may estimate large treatment effects after observing only a few events. In fact, the implausibility of such large treatment effects observed after few events may lead trial investigators to continue a trial despite the results satisfying a stopping rule, as occurred in the United Kingdom Medical Research Council's 12th acute myeloid leukemia trial.²

The degree to which these trials overestimate the true treatment effect is unknown but may be small in some cases (perhaps those in which trialists looked infrequently, late, using stringent criteria, and confirming trends with subsequent observations). Of course, this uncertainty may be avoided altogether if trials are allowed to proceed to completion. Granted, one must weigh the potential harms and benefits of continuing a trial despite an apparently large treatment effect at an interim analysis, including the costs of any future trials that may become necessary to address the uncertainty that remains after premature termination of any earlier trial.³ With the increasing prevalence of trials stopped early for benefit, it is important to identify predictors of the magnitude of bias introduced by early termination, a question our group is actively investigating. In the meantime, clinicians should interpret trials stopped early for benefit with caution, recognizing that such trials may significantly overestimate the true treatment effect.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Wilcox RA, Djulbegovic B, Guyatt GH, et al: Randomized trials in oncology stopped early for benefit. J Clin Oncol 26:18-19, 2008[Free Full Text]

2. Wheatley K, Clayton D: Be skeptical about unexpected large apparent treatment effects: The case of an MRC AML12 randomization. Control Clin Trials 24:66-70, 2003[CrossRef][Medline]

3. Mueller PS, Montori VM, Bassler D, et al: Ethical issues in stopping randomized trials early because of apparent benefit. Ann Intern Med 146:878-881, 2007[Abstract/Free Full Text]

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Related Correspondence

• Stopping Trials for Benefit Can (Sometimes) Benefit Patients
  Joseph L. Pater, Paul Goss, and Ralph Meyer
  JCO 2008 26: 2787-2788 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wilcox, R. A. Articles by Montori, V. M. Search for Related Content PubMed Articles by Wilcox, R. A. Articles by Montori, V. M. Related Articles Related Correspondence Social Bookmarking                            What's this?