Ethics
Clinical Trials Stopped Early For Benefit Warrant Skepticism
By JAMA
Nov 2, 2005, 03:29

A review article in the November 2 issue of JAMA suggests clinicians ought to view with skepticism the results of randomized clinical trials stopped early because of apparent benefit.

Victor M. Montori, M.D., M.Sc., from McMaster University, Hamilton, Ontario, and colleagues conducted a review of the medical literature to identify randomized clinical trials (RCTs) of any intervention reported as having been stopped earlier than planned because of results favoring the experimental intervention.

"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 authors found. "The proportion of all RCTs published in high-impact journals that were stopped early for benefit increased from 0.5 percent in 1990 � 1994 to 1.2 percent in 2000 � 2004. On average, RCTs recruited 63 percent of the planned sample and stopped after a median (mid-point) of 13 months of follow-up, one interim analysis, and when a median of 66 patients had experienced the end point driving study termination (event)." The authors also note that "trials with fewer events yielded greater treatment effects."

The authors conclude: "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."

In an accompanying editorial, Stuart J. Pocock, Ph.D., from the London School of Hygiene and Tropical Medicine, writes: "In this issue of JAMA, Montori and colleagues provide a valuable extensive and critical systemic review of clinical trials that were stopped early for benefit."

"The skeptic should ask first whether correct and appropriate structures were in place for analyzing and reviewing, and making decisions based on, the trial�s accumulating interim data. Having the members of an effective independent data monitoring committee (DMC) or data and safety monitoring board as the only individuals accessing and interpreting interim data split by treatment group is now considered an essential part of good practice for major randomized trials. Still, a substantial minority of reported major trials appear not to have a DMC in place. Second, with or without a formal DMC recommendation, another question is whether the decision to stop a trial early and report the results was an appropriate judgment."

Dr. Pocock notes, "The ethical dilemma is to safeguard the interests of patients randomized in the current trial while also protecting society from overzealous premature claims of treatment benefit."

"In summary, all major randomized trials should have an independent DMC that functions effectively and makes wise judgments aided by stringent statistical stopping boundaries for benefit. It is critical that the DMC, principal investigators, executive committees, and sponsors all recognize the full public health implications of their recommendations and decisions."

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