Traditionally, data monitoring committees (DMCs)—the independent bodies tasked with overseeing ongoing clinical trials with the goals of mitigating risks to subjects and protecting the scientific integrity of the trial—have been given substantial latitude in the scope of the information they consider and the types of recommendations they may make. FDA’s thoughts regarding the function of DMCs were captured in a March 2006 FDA Guidance Document entitled “Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees” (see http://www.fda.gov/downloads/Regulatoryinformation/Guidances/ucm127073.pdf).

Since the issuing of the FDA Guidance on DMCs, there has been increasing interest in the use of adaptive clinical trials—trials in which key aspects of the trial are modified during the trial in response to data accumulating within the trial itself, according to pre-specified rules, to achieve goals of efficiency, improved patient outcomes, or better ethical balance—in both the exploratory and confirmatory phases of clinical development. FDA’s current thinking regarding the use of such designs for drugs and biologics, especially in the adequate and well-controlled study setting (confirmatory phase), is largely captured in a 2010 draft Guidance entitled “Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics” (see http://www.fda.gov/downloads/Drugs/Guidances/ucm201790.pdf). A key idea in this guidance is the need for designs to be completely pre-specified to obtain control and understanding of Type I error rates. In addition, CDRH has just issued a draft guidance on the use of adaptive designs for medical device clinical studies (see http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm446729.pdf).

When overseeing the conduct of a confirmatory, adaptive clinical trial, a DMC must balance the need for flexibility in responding to unexpected patterns in efficacy and safety and the need to maintain the pre-specified nature of the trial design and statistical integrity for regulatory review. This requires a sophisticated understanding of these competing considerations, regulatory science, and clinical care by the DMC members. As both traditional and innovative adaptive designs have become more prevalent, previously unconsidered issues have arisen, requiring DMC’s roles and responsibilities to evolve. This session will use the existing FDA Guidance Documents and speaker expertise with both participation on, and support of DMCs to illustrate and explore the potential issues and propose solutions.

The objectives of this session are: (1) to briefly review the current FDA Guidance Document on the responsibilities and operation of DMCs, with particular emphasis on those areas that potentially impact the oversight and integrity of confirmatory or pivotal, adaptive clinical trials; (2) to briefly review the current FDA Draft Guidance Documents on adaptive design clinical trials, with particular emphasis on those areas more likely to impact the roles, responsibilities, and operation of DMCs; (3) to identify and discuss areas of agreement, potential conflicts, and gaps in these FDA Guidance Documents for guiding the oversight of confirmatory adaptive design clinical trials; (4) to suggest operational procedures and clarifications of roles and responsibilities to be included in DMC charters that best address issues identified above; and (5) to identify gaps in regulatory science related to the oversight of confirmatory, adaptive design clinical trials.