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Continuous safety monitoring for randomized controlled clinical trials
Contemporary Clinical Trials 32 (2011) S1
Contents lists available at ScienceDirect
Contemporary Clinical Trials j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c o n c l i n t r i a l
Editorial
Continuous safety monitoring for randomized controlled clinical trials
The monitoring of patient safety is arguably the most fundamental of obligations of clinical trial leadership, even exceeding that of treatment efficacy assessments. The establishment of a clear hazard to participants makes the decision obvious to stop a trial; the suggestion of hazard presents a shakier platform from which to base decisions. Ball and colleagues, acknowledging the arduous task given clinical trial leadership in exercising their ethical and scientific responsibility to stop—or continue—a blinded clinical trial in the face of possible adverse consequences to its participants, propose a set of early statistical stopping rules for harm that involve continuous safety monitoring using blinded treatment data. Such objective procedures would offer greater reassurance to all concerned: to potential participants uneasy about leaders waiting too long to stop a trial, to trial leadership charged with determining the strength of evidence vs. ramifications of multiple data looks and possible premature trial cessation; to trial sponsors, often perceived to put fiduciary interests above those of patient safety, and, finally, to the public, the ultimate beneficiaries of wellconducted clinical trials. As the authors point out, early discontinuation of a study, while potentially providing a safety net for some participants, may have negative outcomes for others. High early adverse event rates may induce a data monitoring board to stop a study, but may, were the study to proceed, disappear as the study progressed. Patients whose only hope for recovery lies in the possibility of an active study treatment would be denied that hope with early (and, possibly, unnecessary) termination of the study. In evaluating external and internal data, trial leaders are deluged with ethical, scientific, and practical considerations as to if and when to halt a trial. The optimal plan, both for the safety of the patients and the scientific integrity of the study, is an objective, standardized method of continuous safety monitoring, by which the
1551-7144/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.cct.2011.03.014
strength of still masked treatment information can be continually assessed even in clinical trials with relatively infrequent data monitoring board evaluations. This plan includes statistical rules which would serve as a guide intended to supplement board reviews and to aid trial investigators in decision-making when faced with worrisome trends, especially early in the study. At present such circumstances stand to compromise a trial in which decisions are made based on impulsive and premature views of unprepared data. An objective plan of continuous monitoring offers a satisfying and effective alternative. In their first three papers, Ball and colleagues present a strategy for developing continuous safety monitoring of patients in randomized, controlled clinical trials, using blinded treatment information, against a background of ethical and statistical considerations as well as considerations of trial design. The fourth paper presents a plan, using Bayesian methods which allow for continuous monitoring using multiple comparisons. Their intent, “to help the trial leadership decide whether the balance of interests between current and future patients is best served by stopping or continuing the trial,” bespeaks what we all attempt to do in clinical trials— “First, do no harm,” not only for the patient, but also for the public's health. Linda B. Piller Michael H. Silverman Greg Ball* ⁎Corresponding author. Tel.: +1 847 317 8986. E-mail address: [email protected] (Greg Ball). 9 February 2011
Contents lists available at ScienceDirect
Contemporary Clinical Trials j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c o n c l i n t r i a l
Editorial
Continuous safety monitoring for randomized controlled clinical trials
The monitoring of patient safety is arguably the most fundamental of obligations of clinical trial leadership, even exceeding that of treatment efficacy assessments. The establishment of a clear hazard to participants makes the decision obvious to stop a trial; the suggestion of hazard presents a shakier platform from which to base decisions. Ball and colleagues, acknowledging the arduous task given clinical trial leadership in exercising their ethical and scientific responsibility to stop—or continue—a blinded clinical trial in the face of possible adverse consequences to its participants, propose a set of early statistical stopping rules for harm that involve continuous safety monitoring using blinded treatment data. Such objective procedures would offer greater reassurance to all concerned: to potential participants uneasy about leaders waiting too long to stop a trial, to trial leadership charged with determining the strength of evidence vs. ramifications of multiple data looks and possible premature trial cessation; to trial sponsors, often perceived to put fiduciary interests above those of patient safety, and, finally, to the public, the ultimate beneficiaries of wellconducted clinical trials. As the authors point out, early discontinuation of a study, while potentially providing a safety net for some participants, may have negative outcomes for others. High early adverse event rates may induce a data monitoring board to stop a study, but may, were the study to proceed, disappear as the study progressed. Patients whose only hope for recovery lies in the possibility of an active study treatment would be denied that hope with early (and, possibly, unnecessary) termination of the study. In evaluating external and internal data, trial leaders are deluged with ethical, scientific, and practical considerations as to if and when to halt a trial. The optimal plan, both for the safety of the patients and the scientific integrity of the study, is an objective, standardized method of continuous safety monitoring, by which the
1551-7144/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.cct.2011.03.014
strength of still masked treatment information can be continually assessed even in clinical trials with relatively infrequent data monitoring board evaluations. This plan includes statistical rules which would serve as a guide intended to supplement board reviews and to aid trial investigators in decision-making when faced with worrisome trends, especially early in the study. At present such circumstances stand to compromise a trial in which decisions are made based on impulsive and premature views of unprepared data. An objective plan of continuous monitoring offers a satisfying and effective alternative. In their first three papers, Ball and colleagues present a strategy for developing continuous safety monitoring of patients in randomized, controlled clinical trials, using blinded treatment information, against a background of ethical and statistical considerations as well as considerations of trial design. The fourth paper presents a plan, using Bayesian methods which allow for continuous monitoring using multiple comparisons. Their intent, “to help the trial leadership decide whether the balance of interests between current and future patients is best served by stopping or continuing the trial,” bespeaks what we all attempt to do in clinical trials— “First, do no harm,” not only for the patient, but also for the public's health. Linda B. Piller Michael H. Silverman Greg Ball* ⁎Corresponding author. Tel.: +1 847 317 8986. E-mail address: [email protected] (Greg Ball). 9 February 2011