Linda's Blog #2 Establishment and Operation of Clinical Trial Data Monitoring Committees

Name of the Guidance:
Guidance for Clinical Trial Sponsors – Establishment and Operation of Clinical Trial Data Monitoring Committees
Status of the Guidance:
This guidance document is final.
When the Guidance was Released:
The guidance was finalized in March 2006. The draft guidance was distributed for comment in November 2001.
Link to the Guidance:
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126578.pdf
Target Audience:
This guidance is targeted to sponsors of clinical trials for drugs, biologics, and medical devices, or to any contract research organization that has been delegated these responsibilities.
Laws and Regulations Referenced:
The regulations referenced in the guidance relate to the monitoring of clinical trials; 21 CFR 312.50 and 21 CFR 312.56 (for drugs and biologics) and 21 CFR 812.40 and 21 CFR 812.46 (for devices). The FDA mandates the use of an independent data monitoring committee only for clinical trials that are conducted in emergency settings where the requirement for informed consent has been waived (21 CFR 50.24).
Summary:
This guidance outlines the agencies current thinking on the creation and operation of Data Monitoring Committees (DMCs). A DMC is a formal committee made up of individuals who are independent from the sponsor of the clinical trial and who have relevant experience and expertise to monitor the progress of the trial on an ongoing basis. While the FDA recognizes that a DMC is not needed for most clinical trials, the agency does recommend that an independent DMC be formed for clinical trials with mortality or major morbidity as a primary endpoint, for trials that are large or lengthy, trials where the study population is vulnerable, or the where the study treatment has potential for serious outcomes or severe toxicity. The FDA does require the use of a DMC for clinical trials in emergency settings where the requirement for informed consent is waived.
The composition of the DMC is critical to ensure the committee is truly independent and adequately qualified for the data monitoring activities. When selecting members of the DMC the FDA recommends that the sponsors consider the level of each member’s expertise in the therapeutic area of interest and experience with clinical trials, and ensure that there are no conflicts of interest that would affect the DMC member’s decision-making ability. The FDA also recommends that the DMC operate under a written charter that includes standard operating procedures. It is recommended that the procedures cover the meeting schedule and format, requirements for recordkeeping, specifications for review of the data, process for review and protection of unblinded data, and requirements for reporting to the sponsor. Critical considerations when forming and operating a DMC include defining practical and applicable interim analysis time points, defining the statistical methods and type of data used for the interim analyses, and maintaining the integrity of the study blind.
Rationale:
A DMC is required by some government funding agencies, such as National Institute of Health for use in certain clinical trials; however, the FDA only requires the use of an independent safety monitoring committee for trials that will recruit subjects in emergency settings where the requirement for informed consent is waived. However, to improve the safety of study participants, this guidance recommends that sponsors consider using a DMC for large, multicenter trials that have mortality rates or major morbidity as primary endpoints or where there is a substantial risk to study participants. In order for the DMC to be effective, there must be standards for the appointment of committee members and the functioning of the committee.
Resulting Recommendations:
The FDA recommends the use of a DMC for large multicenter clinical trials where mortality rate or major morbidity is the primary endpoint or where the risk to study participants is significant.
Impact:
While the use of a DMC can substantially add to the administrative burden for a sponsor and can have an adverse impact on both trial timelines and budgets, independent monitoring of a clinical trial by a DMC can significantly increase the safety and welfare of research participants and improve scientific integrity of the clinical trial.