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Stop in the name of ethics

A French research team is criticised for allowing a clinical trial to continue even though preliminary results suggested the drug therapies were ineffective.

By | January 4, 2001

A team of French cancer researchers is being criticised for allowing a clinical trial to continue even though preliminary results had suggested the drug therapies being evaluated were of little value. Dr. Sylvie Négrier of the Centre Léon Bérard in Lyon and colleagues found that patients with advanced kidney cancer derived no benefit from a combination of interleukin-2 and interferon alfa-2a with and without the chemotherapy drug fluorouracil (J Clin Oncol 2000 18:4009-4015). A strongly worded editorial published in the same issue of the Journal of Clinical Oncology criticised the French oncologists' decision to "disregard their own study design" and continue the study, even though an interim analysis of the data was "disappointing" (J Clin Oncol 2000 18:4007-4009).

Editorial authors Dr. Sophie Fosså and Dr. Eva Skovlund of the Norwegian Radium Hospital in Oslo were particularly concerned that patients continued to be enrolled in the study while the preliminary trial results analysis was still being conducted. Fosså and Skovlund pointed out that the rapid rate of patient enrolment suggested that some were inappropriately included in the clinical trial. Had the trial been stopped at the time of the research team's preliminary analysis, only 42 patients would have been involved. However, by the time the advanced trial was stopped, over 130 patients had been enrolled.

Fosså and Skovlund claim this was "an example of misconduct of a clinical trial" because "the investigators disregarded their own study design and the role of the predefined interim analysis." The French workers' protocol contained clear trial stopping rules to be based on the results of the interim analysis. Specifically, if a 10% response rate was obtained with either drug treatment alternative (with and without FU) and a difference in response rates of greater than 15% between the two drug treatment alternatives were observed, then the trial would be discontinued. According to the Norwegian scientists, the ethical misconduct occurred when, despite these clearly defined rules, Négrier and co-workers did not follow their own design. Instead, patient enrolment continued during the interim analysis until the French researchers finally terminated the trial prematurely because of an unexpectedly low response rate. At that time, 131 of the 182 planned patients had been entered. However, if the investigators had considered the results of the interim analysis the trial would have been stopped after only 42 patients.

Fosså and Skovlund conclude, "The investigators' choice to continue the trial before the results of the interim analysis were made known to an IDMC, thus neglecting their own stopping rules, cannot be justified." They note, " If an interim analysis is initially planned to monitor treatment effects and the safety of a trial (based on appropriate statistics), and if stopping rules are stated in the protocol, then trialists have to stick to their own rules and await the results of the interim analysis before continuation of the trial." The Norwegian scientists conclude that if other researchers cannot abide by what they term "these elementary rules for clinical research," ethical committees may be reluctant to permit similar trials in the future.

As a result of these criticisms, the researchers added a note to their study explaining how the events had unfolded and saying that they "never considered exposing … patients to a vain and hazardous treatment."

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