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Background The independent oversight of clinical trials, which is recommended by the Medical Research Council (MRC) Guidelines for Good Clinical Practice, is typically provided by an independent advisory Data Monitoring Committee (DMC) and an independent executive committee, to whom the DMC makes recommendations. The detailed roles and function of this executive committee, known as the Trial Steering Committee (TSC), have not previously been studied or reviewed since those originally proposed by the MRC in 1998. Methods An expert panel (n = 7) was convened comprising statisticians, clinicians and trial methodologists with prior TSC experience. Twelve questions about the role and responsibilities of the TSC were discussed by the panel at two full-day meetings. Each meeting was transcribed in full and the discussions were summarised. Results The expert panel reached agreement on the role of the TSC, to which it was accountable, the membership, the definition of independence, and the experience and training needed. The management of ethical issues, difficult/complex situations and issues the TSC should not ask the DMC to make recommendations on were more difficult to discuss without specific examples, but support existed for further work to help share issues and to provide appropriate training for TSC members. Additional topics discussed, which had not been identified by previous work relating to the DMCs but were pertinent to the role of the TSC, included the following: review of data sharing requests, indemnity, lifespan of the TSC, general TSC administration, and the roles of both the Funder and the Sponsor. Conclusions This paper presents recommendations that will contribute to the revision and update of the MRC TSC terms of reference. Uncertainty remains in some areas due to the absence of real-life examples; future guidance on these issues would benefit from a repository of case studies. Notably, the role of a patient and public involvement (PPI) contributor was not discussed, and further work is warranted to explore the role of a PPI contributor in independent trial oversight.

To examine whether primary reports of randomized clinical trials (RCTs) in six high-impact, general medical journals reported (1) whether or not a Data Monitoring Committee/Data and Safety Monitoring Board (DMC/DSMB) was used and (2) the composition of the responsibilities of the reported DSMB/DMCs. Systematic review of RCTs published in 2014 in Annals of Internal Medicine, BMJ, NEJM, JAMA, JAMA Internal Medicine, and Lancet. Of the 294 articles identified, 174 (59%) mentioned using a DMC/DSMB. Of these 174, 126 (72%) indicated at least one responsibility of the DMC/DSMB, 26% listed the names of the DMC/DSMB members, and another 14% listed both their names and affiliations. Only one article stated that a DSMB was not used. The remaining 119 articles did not report whether or not a DMC/DSMB was used, although 59 had previously stated in a clinical trials registry entry or a published protocol that a DMC/DSMB was to be used. Considering the major role that DMC/DSMBs play in protecting participant safety, data quality, and interim analyses in RCTs, we recommend that authors of publications of RCTs report whether a DMC/DSMB was used and the responsibilities and members of DMC/DSMBs to increase transparency regarding study conduct.

Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.

Adjudication committees (ACs) are recommended in randomized controlled trials (RCTs) to standardize the assessment of events. We aimed to assess the reporting and functioning of ACs (synonyms: clinical event committees, endpoint committees) in clinical trials. We searched five high-impact-factor medical journals for reports of RCTs with clinical event endpoints published between January 1, 2004 and December 31, 2005. ACs were reported in 33.4% of the 314 reports of RCTs. ACs were reported in 29.6% of trials with low risk of misclassification (i.e., “hard” main outcome), in 47.5% of trials with medium risk of misclassification (i.e., subjective main outcome and intervention delivered in a blinded fashion) and in 31% of trials with high risk of misclassification (i.e., subjective main outcome without intervention delivered in a blinded fashion). Selected cases to be adjudicated consisted largely of events identified by site investigators (93.3%). Data provided to the AC were reported for 47.4% of ACs. Reporting of ACs is not fitted to the risk of biased misclassification. Important aspects of the functioning of ACs are insufficiently reported or raise methodological issues. We propose some recommendations for planning and reporting ACs in clinical trials.

Background Despite long-standing problems in decisions to stop clinical trials, stopping guidelines are often vague or unspecified in the trial protocol. Clear, well-conceived guidelines are especially important to assist the data monitoring committees for effectiveness trials. Main text To specify better stopping guidelines in the protocol for such trials, the clinical investigators and trial statistician should carefully consider the following kinds of questions: How should the relative importance of the treatment benefits and hazards be assessed? For decisions to stop a trial for benefit: What would be the minimum clinically important difference for the study population? How should the probability that the benefit exceeds that difference be assessed? When should the interim analyses include data from other trials? Would the evidence meet state-of-the-art standards for treatment recommendations and practice guidelines? Should less evidence be required to stop the trial for harm than for benefit? When should conventional stopping guidelines for futility be used for comparative effectiveness trials? Conclusion Both clinical and statistical expertise are required to address such challenging questions for effectiveness trials. Their joint consideration by clinical investigators and statisticians is needed to define better stopping guidelines before starting the trial.

This article describes oversight mechanisms for clinical research that have developed substantially over the last few decades, including institutional review boards and data safety and monitoring boards. LeRoy Walters and others in the 1970s in the US thoughtfully described the importance of fundamental ethical principles and the application of bioethics to clinical research. Dr. Walters's important essay and work with the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research helped identify and explain ethical principles that guide research. These principles, subsequently enunciated by the Commission in the Belmont Report, remain central to our understanding of the ethics of clinical research and are the foundation of our regulations. In this article, I review some history, successes, and challenges of IRBs and DSMBs to exemplify the significance of understanding and applying ethical principles to the design and conduct of clinical research, and to honor Dr. Walters's contributions.

Background Conducting research can be time consuming, difficult and challenging. Guidance and pragmatic advice focussing on randomised controlled trial conduct are available but do not necessarily constitute comprehensive guidance. A successful trial is one that recruits to time and target and collects high-quality data within the originally agreed budget. Standardised trial management tools have outlined key project management elements for a successful trial as a method of ensuring good practice in research trials: initiation, planning, execution, monitoring and closure. Lessons are also frequently learnt during the development and conduct of trials but rarely shared for the benefit of others. For the wider research team, the key focus will always be on the execution and delivery of a study. The aim of this study was to evaluate the acceptability of clinical trials management methods, focussing on study execution and monitoring, as implemented in the National Institute for Health Research Health Technology Assessment Programme-funded Obsessive Compulsive Treatment Efficacy Trial (OCTET). Methods Workshops, questionnaires and semi-structured interviews were used to explore acceptability of trial management methods with members of the OCTET Trial research team. Nine members participated in the focus group, 10 completed a questionnaire and 20 were interviewed as part of qualitative work for the main OCTET study. Data was collected and analysed using thematic analysis. Results Six key themes were identified: support; communication; processes; resources; training and ethos. Clear and open communication, enthusiasm and accessibility of the trial managers and chief investigator were consistently noted as an important facet of the successful running of the trial. Clear resources and training materials were also found to be crucial in helping staff to work within the trial setting. Constructive suggestions were also made for improvement of these resources; for example, including both checklists and flowcharts within trial processes. Conclusion Organisation, openness and positivity are crucial for executing a trial successfully, whilst clear and focussed processes and resources are essential in monitoring and controlling the trial progress. Although derived from a single study, these findings are likely to be applicable to the successful conduct of all trials. Trial managers should consider developing these elements when setting up a study. Trial registration Clinical Trial Registry, ID: ISRCTN73535163 . Registered prospectively on 5 April 2011.

Data Monitoring Committees (DMCs) have the important task to protect the safety of current and future patients during the conduct of a clinical study. Unfortunately, their work is often made difficult by voluminous DMC reports that are poorly structured and difficult to digest. In this article, we suggest improved solutions. Starting from a principled approach and building upon previous proposals, we offer concrete and easily understood displays, including related computer code. While leveraging modern tools, the most important is that these displays support the DMC’s workflow in answering the relevant questions of interest. We hope that the adoption of these proposals can ease the task of DMCs, and importantly, lead to better decision-making for the benefit of patients.

Best practices of data monitoring committees (DMCs) in randomized clinical trials are well established. Independent oversight provided by DMCs is particularly important in trials conducted in public health emergencies, such as in HIV/AIDS or coronavirus epidemics. Special considerations are needed to enable DMCs to effectively address novel circumstances they face in such settings. In the COVID-19 pandemic, these include the remarkable speed in which data regarding benefits and risks of interventions are accumulated. DMCs must hold frequent virtual meetings, using state-of-the-art communication software that protects against risk for security breaches. Data capture and DMC reports should be focused on the most informative measures about benefits and risks. Because numerous clinical trials are being concurrently conducted in the COVID-19 setting, often addressing closely related scientific questions, structures for DMC oversight should be efficient and adequately informative. When these concurrently conducted trials are evaluating related regimens in related clinical settings, often individually underpowered for safety and having separate DMCs, processes should be implemented enabling these DMCs to share with each other emerging confidential evidence to better assess risks and benefits. Ideally a single DMC would monitor a portfolio of clinical trials or a trial with multiple arms, such as a platform trial. •For 5 decades, DMCs have monitored RCTs for safety and benefit.•In 2020, the World Health Organization declared covid-19 disease to be a pandemic.•Numerous trials have emerged to evaluate potential therapeutics and vaccines.•Covid-19 trials bring new challenges to the DMC process, due to the epidemic speed.•Patients are being recruited and outcome data accumulating very rapidly.•DMCs oversight very important for extreme emergencies such as coronavirus epidemics.

Purpose Monitoring is a costly requirement when conducting clinical trials. New regulatory guidance encourages the industry to consider alternative monitoring methods to the traditional 100 % source data verification (SDV) approach. The purpose of this literature review is to provide an overview of publications on different monitoring methods and their impact on subject safety data, data integrity, and monitoring cost. Methods The literature search was performed by keyword searches in MEDLINE and hand search of key journals. All publications were reviewed for details on how a monitoring approach impacted subject safety data, data integrity, or monitoring costs. Results Twenty-two publications were identified. Three publications showed that SDV has some value for detection of not initially reported adverse events and centralized statistical monitoring (CSM) captures atypical trends. Fourteen publications showed little objective evidence of improved data integrity with traditional monitoring such as 100 % SDV and sponsor queries as compared to reduced SDV, CSM, and remote monitoring. Eight publications proposed a potential for significant cost reductions of monitoring by reducing SDV without compromising the validity of the trial results. Conclusions One hundred percent SDV is not a rational method of ensuring data integrity and subject safety based on the high cost, and this literature review indicates that reduced SDV is a viable monitoring method. Alternative methods of monitoring such as centralized monitoring utilizing statistical tests are promising alternatives but have limitations as stand-alone tools. Reduced SDV combined with a centralized, risk-based approach may be the ideal solution to reduce monitoring costs while improving essential data quality.