The dilemma of data-safety monitoring: provision of significant new data to research participants.

An important ethical cornerstone of research on human beings is the requirement that participants give informed consent. People must be informed of the nature of the research, possible risks and benefi ts of participation, alternatives to participation, and their right to withdraw from the study at any time. However, new information relevant to the individual’s decision to participate in a clinical trial can emerge during the course of a study. Additionally, US federal regulations governing research on human beings state that “as new information important to the participants becomes known, that information will be communicated to the participants.” Several research ethics codes reiterate the necessity for informed consent throughout the research process. Although the quality of information provided to potential participants at the time of trial initiation has received much attention, there has been relatively little discussion, and no consensus, about the delivery and adequacy of information provided to individuals after their enrolment. This concern applies particularly to large randomised controlled trials, in which consideration of new information is often delegated to a data-monitoring committee. Such committees do periodic interim analyses during a trial to assess outcome and toxicity data as it emerges. They are charged with protecting the interests of participants, partly by assuring that no important diff erences exist between study arms, and that there are no external scientifi c data that would make continuation of a trial unethical. Additionally, they are also responsible for maintenance of the scientifi c integrity of the clinical trial as it attempts to address an important medical question in the interest of society. On the basis of the interim analysis, the datamonitoring committee might allow a trial to continue as planned until the next analysis, stop the trial, or allow the trial to continue—either after providing additional information to the participants or after both providing information and obtaining renewed consent from participants. We discuss the ethical challenges that can emerge as a data-monitoring committee considers the interests of research participants and the validity and importance of interim results on the basis of experience from a large randomised controlled trial. Prostate cancer is the most common cancer in men in the USA, estimated to develop in more than 230 000 men each year. Between January 1994 and May 1997, the Prostate Cancer Prevention Trial randomised 18 882 healthy men, in a double-blinded way, to either fi nasteride, an oral 5-α reductase inhibitor, or to placebo, to assess fi nasteride for the prevention of prostate cancer. An independent data-monitoring committee was established to do interim analyses every 6 months. No rules for stopping the trial at an interim analysis were specifi ed. Further details of the study have been published previously. Once biopsies from patients completing 7 years of therapy began to become available, the interim analyses showed clearly that the primary endpoint, prevention of prostate cancer, would be signifi cantly in favour of fi nasteride. However, there was an unanticipated absolute increase in the incidence of high-grade prostate cancer in recipients of fi nasteride. From a scientifi c standpoint, this new information raised questions regarding the safety of fi nasteride for prevention of cancer. Because of this concern, the data-monitoring committee decided to delay closing the trial until the validity of the diff erences in rates of high-grade cancers could be determined. A subsequent analysis in February 2003, with 81·3% of men having reached the study endpoint, showed signifi cant prevention in favour of fi nasteride (prevalence of prostate cancer 18·4% in those on fi nasteride vs 24·4% in those on placebo, p<0·001) and a now signifi cant increase in high-grade cancers in the fi nasteride arm (prevalence of high-grade cancer 6·4% vs 5·1% for placebo, p=0·005). Additionally, sensitivity analyses suggested that these results were unlikely to change with additional data. The data-monitoring committee then recommended stopping the study, and it ended before the planned completion date of May, 2004. On deciding to continue the trial, should the datamonitoring committee have informed participants of the potential, though not scientifi cally proven, risk of high-grade prostate cancer, despite the signifi cant diff erence in the primary endpoint? Because of the actions of the committee in this case, the integrity of the study was protected, the results were clinically meaningful and the contributions of more than 18 000 participants yielded valuable medical knowledge. However, thousands of men who had not yet completed their 7 years of treatment when the committee fi rst noted a possible link between fi nasteride and high-grade cancer were not given information that some might have deemed relevant to their willingness to continue in the trial. This example raises larger issues about the mandate of the datamonitoring committee and the degree to which it has discretion over sharing information with research participants. Viewed at its most polarised, the ethical dilemma can be seen as a confl ict between the interests of future patients who might benefi t from continuation of the research and current participants who might benefi t from disclosure of additional information about potential risks and benefi ts of continued trial participation. However, this dichotomous picture contains substantial exaggeration. A commonly Lancet 2008; 371: 527–29