Protecting Clinical Trial Participants and Protecting Data Integrity: Are We Meeting the Challenges?

A long-standing tenet of clinical trial conduct is that the accumulating data must be monitored, if not continuously then at regular intervals during the trial. Such regular review helps to ensure that risks to participants are not greater than anticipated and that the study is being conducted appropriately. Early randomized trials were typically monitored by the investigator(s), the research funder (a government agency or a pharmaceutical company), or by a steering committee appointed by the funder [1], with no wellaccepted quantitative criteria for decisionmaking and often with the accumulating data widely known. The practices of data monitoring committees (DMCs; also known as Data and Safety Monitoring Boards [DSMBs]) have evolved substantially over the last 40 years. Statistical methods to guide early termination decisions have been developed [2– 5]; the principle of confidentiality of interim data has become widely accepted; and the actual conduct of DMC meetings has become more standardized. Many publications, an international US National Institutes of Health (NIH) symposium [6], and at least three books [7–9] have addressed the philosophical and operational issues faced by DMCs; in the United States, the NIH and the US Food and Drug Administration (FDA) have established policies regarding DMC establishment and operation [10,11], as have international organizations [12,13]. A large study of DMC practices commissioned by the United Kingdom’s Health Technology Assessment group has provided substantial detail regarding current DMC practices [14–16]. Despite the increased attention to DMC function, some issues remain controversial. Two of particular importance are 1) the extent to which DMC members and the statistician analyzing interim data and reporting to the DMC should be independent of the trial sponsor and investigators; and 2) the criteria that should be used to guide early termination decisions. A third issue, of increasing concern to scientists serving on DMCs, is that of liability of DMC members.