Data and safety monitoring policy for National Institute of Allergy and Infectious Diseases clinical trials.

BACKGROUND: Historically, four divisions of the National Institute of Allergy and Infectious Diseases (NIAID) that manage clinical trials and oversee data and safety monitoring have operated fairly autonomously with respect to their approaches to Data and Safety Monitoring Board (DSMB) operations. We recognized the need for a revised policy on DSMB operations in an effort to encourage greater harmonization of procedures across the four divisions. PURPOSE: The purpose of this article is to describe the considerations that motivated the development of the new policy, summarize current DSMB policies and ongoing harmonization efforts across the four divisions, and offer some recommendations for DSMB operations in the hope that other organizations may benefit from our experience. METHODS: From 2005 to 2009, a working group undertook a review of DSMB responsibilities, policies, and operations. We analyzed and summarized the final policy document that the working group produced, gathered data describing current DSMB activities, and developed a tabular, cross-sectional overview highlighting how divisions are harmonizing their DSMB operations. RESULTS: In 2010, there were 44 DSMBs in NIAID monitoring 169 protocols, and those DSMBs conducted 209 reviews of the protocols. Review and analysis of DSMB practices across the four divisions have led to recommendations for efficient and successful DSMB operations: adopt an inclusive approach, whereby the trial investigators assist in the process of forming and utilizing DSMBs; structures other than DSMBs can often provide many of the features of DSMBs but with greater flexibility in membership, access to interim data, and scheduling; the trial protocol should specify what safety and other concerns should trigger a DSMB review and what data should be included in prespecified reviews; present data in thoughtful and user-friendly ways that answer specific questions; allow sufficient time to plan for working with the DSMB. LIMITATIONS: We recognize that NIAID's specific circumstances and DSMB policy may not apply to the operation of DSMBs in every organization. Nevertheless, we believe that useful lessons can be learned from our experiences and efforts toward harmonization. CONCLUSIONS: Homogeneity in DSMB operations and management has appeal as a matter of organizational policy and efficiency. Some limited flexibility, as long as it honors fundamental principles of independence, confidentiality of interim trial results, and clear lines of reporting and approval, may be appropriate on occasion. NIAID's 2009 institute-level policy established a collective understanding of the important contribution that DSMBs make to the responsible conduct of clinical trials. Thinking will continue to evolve, leading to further policy refinements and the continued assurance of patient safety in our clinical trials.

Development and implementation of clinical trial protocol templates at the National Institute of Allergy and Infectious Diseases.

BACKGROUND: A clinical research protocol document must reflect both sound scientific rationale as well as local, national and, when applicable, international regulatory and human subject protections requirements. These requirements originate from a variety of sources, undergo frequent revision and are subject to interpretation. Tools to assist clinical investigators in the production of clinical protocols could facilitate navigating these requirements and ultimately increase the efficiency of clinical research. PURPOSE: The National Institute of Allergy and Infectious Diseases (NIAID) developed templates for investigators to serve as the foundation for protocol development. These protocol templates are designed as tools to support investigators in developing clinical protocols. METHODS: NIAID established a series of working groups to determine how to improve its capacity to conduct clinical research more efficiently and effectively. The Protocol Template Working Group was convened to determine what protocol templates currently existed within NIAID and whether standard NIAID protocol templates should be produced. After review and assessment of existing protocol documents and requirements, the group reached consensus about required and optional content, determined the format and identified methods for distribution as well as education of investigators in the use of these templates. RESULTS: The templates were approved by the NIAID Executive Committee in 2006 and posted as part of the NIAID Clinical Research Toolkit [1] website for broad access. These documents require scheduled revisions to stay current with regulatory and policy changes. LIMITATIONS: The structure of any clinical protocol template, whether comprehensive or specific to a particular study phase, setting or design, affects how it is used by investigators. Each structure presents its own set of advantages and disadvantages. While useful, protocol templates are not stand-alone tools for creating an optimal protocol document, but must be complemented by institutional resources and support. Education and guidance of investigators in the appropriate use of templates is necessary to ensure a complete yet concise protocol document. Due to changing regulatory requirements, clinical protocol templates cannot become static, but require frequent revisions.

Guidelines for data and safety monitoring for clinical trials not requiring traditional data monitoring committees.

This is a commissioned report by a writing committee formed by the Society for Clinical Trials. The committee was formed with the objectives of 1) reviewing data monitoring guidelines for confirmatory (phase III) trials published by the National Institutes of Health, US Food and Drug Administration, Veterans Administration, and the International Conference on Harmonisation and 2) proposing corresponding guidelines for exploratory clinical trials (ie, most phase I and phase II trials and others not requiring a fully independent data monitoring committee). These trials typically involve fewer subjects and are of shorter duration than phase III trials. Nevertheless there are safety concerns, especially because these are often the first human trials for a new intervention. Recommendations are given for appropriate elements of a data monitoring plan, decision criteria for institution of a data monitoring committee (DMC), and critical elements for a DMC to consider in exploratory trials. Review and approval of data monitoring plans are suggested to fall under Institutional Review Board purview. Forming a committee with all the characteristics of a traditional phase III trial monitoring committee may be warranted for a small fraction of exploratory trials. Such a panel could consist of both trial investigators and outside members. The paper concludes with examples of data and safety monitoring practice from the University of Wisconsin Comprehensive Cancer Center and the AIDS Clinical Trials Groups.

The Society for Clinical Trials supports United States legislation mandating trials registration. Position paper.

The official position of the Society for Clinical Trials is to support legislation in the United States and internationally that mandates registration of all controlled clinicals trials at or before enrollment of the first participant. The major trial sponsor would be responsible for ensuring contribution of trial information. The mechanism for registering trials would be through research ethics review boards, and registration would be required for ethics approval and before trial initiation. Standardized data and a unique identification number would be available for each registered trial.