Stakeholders' Perspectives on Current Issues in Data Monitoring Committees.

Data Monitoring Committees (DMCs) are groups of experts that review accumulating data from one or more ongoing clinical studies and advise the Sponsor regarding the continuing safety of study subjects along with the continuing validity and scientific merit of the study. Although DMCs are widely used, considerable variability exists in their conduct. This paper offers recommendations, derived from sessions given at the 2023 Central European Network International Biometric and Statisticians in the Pharmaceutical Industry Conferences' and the authors' experiences. We focus on four topics that are part of the DMC process and where there is unclarity and inconsistency in current practices: (1) Communication with the DMC-We reflect on the importance of effective, proper communication channels between the DMC and relevant stakeholders to foster collaboration and exchange of critical information while retaining study integrity throughout. (2) Open sessions-We discuss the benefits of incorporating open sessions in DMC meetings to enhance transparency, inclusivity, and the consideration of diverse perspectives, as well as pitfalls of open sessions. (3) Access to efficacy data-We highlight the need for appropriate access to efficacy data by DMCs and discuss how to implement this in practice and how to address potential concerns regarding multiplicity. (4) Interactive data displays-We outline the utilization of interactive data displays to facilitate a more intuitive understanding of study results by the DMC. By addressing these topics, we aim to provide comprehensive practical recommendations that bridge the gap between current practices and optimal DMC functionality.

Data Safety Monitoring Boards: Overview of Structure and Role in Spinal Cord Injury Studies.

This paper provides an overview of the history, composition, organization, responsibilities, and regulatory requirements of Data Safety Monitoring Boards (DSMB), with particular reference to the context of clinical trials in spinal cord injury. It is intended to help potential members of such boards and those undertaking the design of new clinical trials to understand the important role of the DSMB in safeguarding the integrity of complex trials, promoting safety, and countering potential bias. An independent DSMB helps to protect research subjects by providing study oversight and serves as an additional step to assure that clinical trials are performed to existing and appropriate standards. The DSMB must meet on a regular schedule, diligently evaluate all the information it receives, and report in a timely and decisive manner. Members must be free of significant conflicts of interest throughout the study and be adequately trained and experienced to serve their roles within the group. DSMB service can be a valuable learning experience and a gratifying opportunity to participate in advancing medicine and helping to maintain and improve the standards of research.

The Case for Access to Data Monitoring Committee Charters.

AbstractClinical trials investigating novel or high-risk interventions often use data monitoring committees (DMCs) to ensure that the participants' best interests are safeguarded. The typical DMC charter describes procedures by which the DMC operates, including important details concerning organizational structure, membership, meeting frequency, statistical monitoring guidelines, and contents of DMC reports for interim review. These charters, however, are not routinely publicly available; in some cases, their access could be important to the interpretation of trial results. We recommend including DMC charters for such trials in ClinicalTrials.gov at the time of trial completion; trial protocols, informed consent documents, and statistical analysis plans are already available in this repository.

Ethical preparedness of data monitoring committees (DMCs) to oversee international clinical trials: a qualitative descriptive study.

INTRODUCTION: A data monitoring committee (DMC) is an independent group of experts who assess the ongoing scientific and ethical integrity of a study through periodic analyses of study data. The objective of this study was to explore the extent to which the structure, membership and deliberations of DMCs enable them to address ethical issues. METHODS: We conducted qualitative individual interviews (n=22) with DMC members from countries across Africa, the Americas, South Asia and the UK. We selected interview respondents through purposive sampling, managed data using NVivo (Release V.1.7) and analysed data thematically. RESULTS: All respondents were highly experienced professionals; many (18/22) had received training in medicine and/or statistics. One respondent had academic qualifications in ethics, and four indicated that they served on DMCs as ethicists. While respondents generally felt DMCs should be required for studies that were high-risk or enrolled vulnerable populations, some were concerned about the overuse of DMCs. There were divergent views on the necessity of geographical and disciplinary representation in DMC membership, including about whether ethicists were helpful. Many respondents described a DMC member recruitment process that they felt was somewhat exclusive. While one respondent received DMC-specific training, most described learning on the job. Respondents generally agreed that study protocols and DMC charters were key guiding documents for addressing ethical issues and described DMC deliberations that often, but not always, involved consensus-building. CONCLUSION: This study is one of the first to consider the ethical implications of DMC structure, membership and deliberations. The potential overuse of DMCs, DMC member recruitment processes that seem somewhat insular, limited training for DMC members, and divergent approaches to deliberation may limit the capacity of DMCs for addressing ethical issues. Further research on DMC structure and processes could help enhance the ethical preparedness of DMCs.

A risk-based monitoring approach to source data monitoring and documenting monitoring findings.

BACKGROUND: Clinical trial monitoring is evolving from labor-intensive to targeted approaches. The traditional 100% Source Data Monitoring (SDM) approach fails to prioritize data by significance, diverting attention from critical elements. Despite regulatory guidance on Risk-Based Monitoring (RBM), its widespread implementation has been slow. METHODS: Our study teams assess the study's overall risk, document heightened and critical risks, and create a study-specific risk-based monitoring plan, integrating SDM and Central Data Monitoring (CDM). SDM combines a fixed list of pre-identified variables and a list of randomly identified variables to monitor. Identifying variables follows a two-step approach: first, a random sample of participants is selected, second, a random set of variables for each participant selected is identified. Sampling weights prioritize critical variables. Regular team meetings are held to discuss and compile significant findings into a Study Monitoring Report. RESULTS: We present a random SDM sample and a Study Monitoring Report. The random SDM output includes a look-up table for selected database elements. The report provides a holistic view of the study issues and overall health. CONCLUSIONS: The proposed random sampling method is used to monitor a representative set of critical variables, while the Study Monitoring Report is written to summarize significant monitoring findings and data trends. The report allows the sponsor to assess the current status of the study and data effectively. Communicating and sharing emerging insights facilitates timely adjustments of future monitoring activities, optimizing efficiencies, and study outcomes.

A model for oversight of rare disease studies: The 25-year experience of the cystic fibrosis foundation data safety monitoring board.

This manuscript addresses the development and operating procedures of the Cystic Fibrosis Foundation Data Safety Monitoring Board (CFF-DSMB) and its role in the development and approval of new therapies through complex clinical trials with an emphasis on ensuring patient safety and study integrity. The authors describe the processes that have been developed over the last 25 years including the development of educational curricula for DSMB members and patient representation on DSMBs. The experience and success of the CFF-DSMB can serve as a model for providing high quality oversight of clinical trials for other groups who are dedicated to developing treatments for rare and complex diseases.

Training the Next Generation of Data Monitoring Committee Members: An Initiative of the Heart Failure Collaboratory.

Clinical trials are vital for assessing therapeutic interventions. The associated data monitoring committees (DMCs) safeguard patient interests and enhance trial integrity, thus promoting timely, reliable evaluations of those interventions. We face an urgent need to recruit and train new DMC members. The HFC (Heart Failure Collaboratory), a multidisciplinary public-private consortium of academics, trialists, patients, industry representatives, and government agencies, is working to improve the clinical trial ecosystem. The HFC aims to improve clinical trial efficiency and quality by standardizing concepts, and to help meet the demand for experienced individuals on DMCs by creating a standardized approach to training new members. This paper discusses the HFC's training workshop, and an apprenticeship model for new DMC members. It describes opportunities and challenges DMCs face, along with common myths and best practices learned through previous experiences, with an emphasis on data confidentiality and need for quality independent statistical reporting groups.

Does Central Statistical Monitoring Improve Data Quality? An Analysis of 1,111 Sites in 159 Clinical Trials.

BACKGROUND: Central monitoring aims at improving the quality of clinical research by pro-actively identifying risks and remediating emerging issues in the conduct of a clinical trial that may have an adverse impact on patient safety and/or the reliability of trial results. This paper, focusing on statistical data monitoring (SDM), is the second of a series that attempts to quantify the impact of central monitoring in clinical trials. MATERIAL AND METHODS: Quality improvement was assessed in studies using SDM from a single large central monitoring platform. The analysis focused on a total of 1111 sites that were identified as at-risk by the SDM tests and for which the study teams conducted a follow-up investigation. These sites were taken from 159 studies conducted by 23 different clinical development organizations (including both sponsor companies and contract research organizations). Two quality improvement metrics were assessed for each selected site, one based on a site data inconsistency score (DIS, overall -log10 P-value of the site compared with all other sites) and the other based on the observed metric value associated with each risk signal. RESULTS: The SDM quality metrics showed improvement in 83% (95% CI, 80-85%) of the sites across therapeutic areas and study phases (primarily phases 2 and 3). In contrast, only 56% (95% CI, 41-70%) of sites showed improvement in 2 historical studies that did not use SDM during study conduct. CONCLUSION: The results of this analysis provide clear quantitative evidence supporting the hypothesis that the use of SDM in central monitoring is leading to improved quality in clinical trial conduct and associated data across participating sites.

Assessing the impact of risk-based data monitoring on outcomes for a paediatric multicentre randomised controlled trial.

BACKGROUND/AIMS: Regulatory guidelines recommend that sponsors develop a risk-based approach to monitoring clinical trials. However, there is a lack of evidence to guide the effective implementation of monitoring activities encompassed in this approach. The aim of this study was to assess the efficiency and impact of the risk-based monitoring approach used for a multicentre randomised controlled trial comparing treatments in paediatric patients undergoing cardiac bypass surgery. METHODS: This is a secondary analysis of data from a randomised controlled trial that implemented targeted source data verification as part of the risk-based monitoring approach. Monitoring duration and source to database error rates were calculated across the monitored trial dataset. The monitored and unmonitored trial dataset, and simulated trial datasets with differing degrees of source data verification and cohort sizes were compared for their effect on trial outcomes. RESULTS: In total, 106,749 critical data points across 1,282 participants were verified from source data either remotely or on-site during the trial. The total time spent monitoring was 365 hours, with a median (interquartile range) of 10 (7, 16) minutes per participant. An overall source to database error rate of 3.1% was found, and this did not differ between treatment groups. A low rate of error was found for all outcomes undergoing 100% source data verification, with the exception of two secondary outcomes with error rates >10%. Minimal variation in trial outcomes were found between the unmonitored and monitored datasets. Reduced degrees of source data verification and reduced cohort sizes assessed using simulated trial datasets had minimal impact on trial outcomes. CONCLUSIONS: Targeted source data verification of data critical to trial outcomes, which carried with it a substantial time investment, did not have an impact on study outcomes in this trial. This evaluation of the cost-effectiveness of targeted source data verification contributes to the evidence-base regarding the context where reduced emphasis should be placed on source data verification as the foremost monitoring activity.

Training New DMC Members: A Call to Action.

Historically, clinical trialists developed DMC expertise and experience with "on the job training". Clinical trialists have recognized a large and growing gap between the demand and supply of trained DMC members due in part to the huge increase in ongoing clinical trials. A critical need exists to increase the supply of DMC trained clinicians and biostatisticians. Despite a rich collection of published training material, many have recommended a mentoring process to train clinical trialists and data scientists lacking DMC experience. We propose that academic, regulatory, industry and other leaders in clinical trials support including investigators lacking DMC experience as members of a DMC so that they can be trained to learn about the DMC processes during conduct of an actual trial".

Data Monitoring Committees and clinical trials: From scientific justification to organisation.

Clinical trials often last several months or even several years. As the trial progresses, it can be tempting to find out whether the data obtained already answers the question posed at the start of the trial in order to stop inclusions or monitoring earlier. However, knowing and taking into account interim results can sometimes compromise the integrity of the results, which is counterproductive. To minimise this risk and ensure that the treatments are assessed reliably, safety and/or efficacy criteria are monitored during the study by a Data Monitoring Committee. After receiving the results confidentially, the Data Monitoring Committee assesses the benefit/risk ratio of the study treatment and recommends that the trial be continued, modified or terminated. Data Monitoring Committee members issuing these recommendations have an important responsibility: a hasty decision to end the trial may lead to inconclusive results unable to answer the initial question and, inversely, delaying the decision to end the trial may expose the subjects to potentially ineffective or even harmful interventions. The Data Monitoring Committee's task is therefore particularly complex. With this in mind, the round table discussion at the Giens workshops was a chance to review the scientific justification for creating Data Monitoring Committees and to recall the need for their members to receive comprehensive training on the complexities of multiple analyses, confidentiality requirements applying to the results and the need for them to be aware that recommendations to end a trial must be based on data that is robust enough to assess the benefit/risk ratio of the treatment studied.

Guidelines for Data and Safety Monitoring in Pragmatic Randomized Clinical Trials Using Case Studies.

Pragmatic randomized clinical trials (pRCTs) have a unique set of considerations for data and safety monitoring. Because of their unconventional trial designs coupled with collection of multilevel data and implementation outcomes in real-world settings, thoughtful consideration is needed on the presentation of the trial design and accruing data to facilitate review and decision-making by the trial's data and safety monitoring board (DSMB). To our knowledge, there is limited information available in practical guidelines for generalists and medical general practitioners on what to monitor and to report to the DSMB during the conduct of pRCTs and what the DSMB should focus on in its review of reports. This article discusses these matters in the context of 3 case studies focusing on a set of critical data and safety monitoring questions that would be of interest to the generalist conducting pRCTs. In considering these questions, we provide tabular and graphical illustrations of how data can be presented to the DSMB while drawing attention to those areas that the DSMB should focus on in its review of the trial. The strategies and viewpoints discussed herein provide practical guidelines and can serve as a resource for the generalist conducting pRCTs.

Data monitoring committees in pediatric randomized controlled trials registered in ClinicalTrials.gov.

BACKGROUND: Data monitoring committees advise on clinical trial conduct through appraisal of emerging data to ensure participant safety and scientific integrity. While consideration of their use is recommended for trials performed with vulnerable populations, previous research has shown that data monitoring committees are reported infrequently in publications of pediatric randomized controlled trials. We aimed to assess the frequency of reported data monitoring committee adoption in ClinicalTrials.gov registry records and to examine the influence of key trial characteristics. METHODS: We conducted a cross-sectional data analysis of all randomized controlled trials performed exclusively in a pediatric population and registered in ClinicalTrials.gov between 2008 and 2021. We used the Access to Aggregate Content of ClinicalTrials.gov database to retrieve publicly available information on trial characteristics and data on safety results. Abstracted data included reported trial design and conduct parameters, population and intervention characteristics, reasons for prematurely halting, serious adverse events, and mortality outcomes. We performed descriptive analyses on the collected data and explored the influence of clinical, methodological, and operational trial characteristics on the reported adoption of data monitoring committees. RESULTS: We identified 13,928 pediatric randomized controlled trial records, of which 39.7% reported adopting a data monitoring committee, 49.0% reported not adopting a data monitoring committee, and 11.3% did not answer on this item. While the number of registered pediatric trials has been increasing since 2008, we found no clear time trend in the reported adoption of data monitoring committees. Data monitoring committees were more common in multicenter trials (50.6% vs 36.9% for single-center), multinational trials (60.2% vs 38.7% for single-country), National Institutes of Health-funded (60.3% vs 40.1% for industry-funded or 37.5% for other funders), and placebo-controlled (47.6% vs 37.5% for other types of control groups). Data monitoring committees were also more common among trials enrolling younger participants, trials employing blinding techniques, and larger trials. Data monitoring committees were more common in trials with at least one serious adverse event (52.6% vs 38.4% for those without) as well as for trials with reported deaths (70.3% vs 38.9% for trials without reported deaths). In all, 4.9% were listed as halted prematurely, most often due to low accrual rates. Trials with a data monitoring committee were more often halted for reasons related to scientific data than trials without a data monitoring committee (15.7% vs 7.3%). CONCLUSION: According to registry records, the use of data monitoring committees in pediatric randomized controlled trials was more frequent than previously reported in reviews of published trial reports. The use of data monitoring committees varied across key clinical and trial characteristics based on which their use is recommended. Data monitoring committees may still be underutilized in pediatric trials, and reporting of this item could be improved.

Bringing data monitoring committee charters into the sunlight.

Clinical trials investigating novel or high risk interventions, or studying vulnerable participants, often use a data monitoring committee to oversee the progress of the trial. The data monitoring committee serves both an ethical and a scientific function, by protecting the interests of trial participants while ensuring the integrity of the trial results. A data monitoring committee charter, which typically describes the procedures by which data monitoring committees operate, contains details about the data monitoring committee's organizational structure, membership, meeting frequency, sequential monitoring guidelines, and the overall contents of data monitoring committee reports for interim review. These charters, however, are generally not reviewed by outside entities and are rarely publicly available. The result is that a key component of trial oversight remains in the dark. We recommend that ClinicalTrials.gov modify its system to allow uploading of data monitoring committee charters, as is already possible for other important study documents and that clinical trialists take advantage of this opportunity to voluntarily upload the data monitoring committee charter for trials that have one. The resulting cache of publicly available data monitoring committee charters should provide important insights for those interested in a particular trial, as well as for meta-researchers who wish to understand and potentially improve how this important component of trial oversight is actually being applied.

DMC reports in the 21st century: towards better tools for decision-making.

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.

The Data Monitoring Committee: A Collective or a Collection?

In this commentary, we urge that a Data Monitoring Committee (DMC) should operate as a collective, that is, as a unitary whole. In so doing, its recommendations should emerge through a consensus development process, not through a vote of the members. The summary notes of its closed session, that is, its minutes, should report the recommendations of the DMC and, if necessary, the justification for those recommendations; it should not attribute opinions to individual members. Importantly, the proceedings of the DMC meetings should not be electronically recorded.

Ensuring the Scientific Value and Feasibility of Clinical Trials: A Qualitative Interview Study.

BACKGROUND: Ethical and scientific principles require that clinical trials address an important question and have the resources needed to complete the study. However, there are no clear standards for review that would ensure that these principles are upheld. METHODS: We conducted semi-structured interviews with a convenience sample of nineteen experts in clinical trial design, conduct, and/or oversight to elucidate current practice and identify areas of need with respect to ensuring the scientific value and feasibility of clinical trials prior to initiation and while ongoing. We used a priori and grounded theory to analyze the data and constant comparative method to induce higher order themes. RESULTS: Interviewees perceived determination of scientific value as the responsibility of the investigator and, secondarily, other parties who review or oversee research. Interviewees reported that ongoing trials are rarely reevaluated due to emerging evidence from external sources, evaluation is complex, and there would be value in the development of standards for monitoring and evaluating evidence systematically. Investigators, IRBs, and/or data monitoring committees (DMCs) could undertake these responsibilities. Feasibility assessments are performed but are typically inadequate; potential solutions are unclear. CONCLUSIONS: There are three domains where current approaches are suboptimal and in which further guidance is needed. First, who has the responsibility for conducting scientific review, whether it be the investigator, IRB, and/or DMC is often unclear. Second, the standards for scientific review (e.g., appropriate search terms, data sources, and analytic plan) should be defined. Third, guidance is needed on the evaluation of ongoing studies in light of potentially new and evolving evidence, with particular reference to evidence from outside the trial itself.