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Coronavirus disease 2019 (COVID-19) vaccines are being developed and implemented with unprecedented speed. Accordingly, trials considered ethical at their inception may quickly become concerning. We provide recommendations for Data and Safety Monitoring Boards (DSMBs) on monitoring the ethical acceptability of COVID-19 vaccine trials, focusing on placebo-controlled trials in low- and middle-income countries.

This review article aims to explain the important issues that data safety monitoring boards (DSMB) face when considering early termination of a trial and is specifically addressed to the needs of clinical and research cardiologists. We give an insight into the overall background and then focus on the three principal reasons for stopping trials, i.e. efficacy, futility, and harm. The statistical essentials are also addressed to familiarize clinicians with the key principles. The topic is further highlighted by numerous examples from lipid trials and antithrombotic trials. This is followed by an overview of regulatory aspects, including an insight into industry–investigator interactions. To conclude, we summarize the key elements that are the basis for a decision to stop a randomized clinical trial (RCT).

The National Institutes of Health requires data and safety monitoring boards (DSMBs) for all phase III clinical trials. The National Heart, Lung and Blood Institute requires DSMBs for all clinical trials involving more than one site and those involving cooperative agreements and contracts. These policies have resulted in the establishment of DSMBs for many implementation trials, with little consideration regarding the appropriateness of DSMBs and/or key adaptations needed by DSMBs to monitor data quality and participant safety. In this perspective, we review the unique features of implementation trials and reflect on key questions regarding the justification for DSMBs and their potential role and monitoring targets within implementation trials.

In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, the majority of patients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial.In this multicenter trial, we randomly assigned 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock to one of two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end point was a composite of death or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke.At 30 days, the composite primary end point of death or renal-replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit-lesion-only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.01). The relative risk of death in the culprit-lesion-only PCI group as compared with the multivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P=0.03), and the relative risk of renal-replacement therapy was 0.71 (95% CI, 0.49 to 1.03; P=0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups.Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI. (Funded by the European Union 7th Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549 .).

Data and Safety Monitoring Boards (DSMBs) derived from the need to monitor large federally funded multi-center clinical trials and evolved to include commercial and other large and complex trials. Eventually, academic health centers also created institutionally focused trial monitoring mechanisms. The basic general principles that define traditional DSMBs extend to the institutional level. The primary responsibilities are assuring safety of the participants, preserving the integrity of the trial, and ensuring the reliability of the results. Institutionally chartered DSMBs meet these responsibilities but usually have fewer members, have a structure specific to the needs of the trial, are more focused and/or have different scope reviewing smaller, single site, higher risk, and investigator-initiated studies and are flexible to accommodate institution-specific requirements and approaches. Their purpose is to meet the responsibilities of oversight for safety and data integrity, ensure proper study design, rigor and conduct, as well as provide statistical support appropriate to the setting of the research. Academic health centers should recognize the importance and existence of institution level safety and data monitoring and provide support as much as possible. Investigators should have sufficient resources available to assemble DSMBs. The Clinical and Translational Science Awards Collaborative DSMB Workgroup provides an online manual to assist investigators.

The overall purpose of the Data Safety Monitoring Board, or Data Monitoring Committee, is to insure the integrity and safety of clinical trial research. Federal guidelines have been established by the Food and Drug Administration and the National Institutes of Health regarding when a board or committee is required for federally funded research. These boards or committees serve to advise the sponsor and/or researchers of the study on the safety of the trial, the continuing validity of the trial, and the scientific merit of the trial. A data safety monitoring board charter is typically created prior to initiation of a clinical trial to explicitly address the mission and operating procedures for the committee. Committees can terminate trials early for either futility or reaching an early conclusion from interim analysis showing clear benefit. Even if a Data Safety Monitoring Board is not required, most clinical research trials should have a data safety monitoring plan.

This article describes vignettes concerning interactions with Data Safety Monitoring Boards during the design and monitoring of some clinical trials with an adaptive design. Most reflect personal experiences by the author.

Clinical trial Data and Safety Monitoring Boards (DSMBs) have a primary obligation of ensuring study participant safety, while maintaining trial integrity. The role of DSMBs is expanding, and ideally should include post-hoc reporting of deliberative processes related to clinically important safety issues or factors that could impact on future trial designs. We describe how the TOPCAT DSMB detected, investigated, and adjudicated an unexpectedly large renal adverse event signal midway through the trial, and offer general guidelines for dealing with similar unanticipated occurrences in future trials. The detection of a greater than expected incidence of deterioration in renal function, occurring in 6.1% of patients in the spironolactone arm compared with 3.9% in the placebo arm (P = 0.009), led to an in-depth DSMB review of associated study medication withdrawals and adverse events. The trial continued uninterrupted throughout the review, which reached the conclusions that spironolactone-associated renal dysfunction did not compromise overall patient safety or interfere with a perceived efficacy signal. Although no discrete mechanism for the spironolactone-associated renal adverse event signal was identified, likely possibilities are discussed. In clinical trials, DSMBs and co-ordinating centres should have the resources to detect, investigate, and adjudicate unexpected safety issues, with goals of ensuring patient safety and preserving the potential for detection of therapeutic effectiveness. In TOPCAT, spironolactone-associated renal dysfunction emerged as a potentially trial-threatening adverse event and, although clinically important, did not lead to compromise of patient safety, trial interruption, termination, or apparent loss of treatment effectiveness.

BACKGROUND: In order to monitor the safety of patients in clinical trials, data safety monitoring boards (DSMB) are organised. These DSMB contain independent volunteer experts in the medical field of the research (clinician, pharmacologist, methodologist or statistician). They give their advice about the continuation with or without modification or stopping of the study. They are increasingly questioned by competent authorities during the study authorisation. This is an ambitious challenge to improve the organisation of these DSMB which requires time and work, and relatively few studies have looked at this topic. PURPOSE: On which types of studies should we concentrate our efforts to implicate experts and optimise these DSMB? MATERIAL AND METHODS: The study design is an observational retrospective study, based on a register of an academic sponsor. It provides data from August 2011 until September 2017 on 89 clinical trials (investigational medical products, medical devices, other than health products) with DSMB. We have analysed the following parameters: type of study, meeting before patient inclusion, meetings during studies and actions taken following the decisions of the DSMB. The implication of experts after a meeting was measured by the decision of experts for all types of studies. We tested the hypothesis that initial meeting before the start of trials may aid a superior involvement of the DSMB members. A Chi-(2) test was used in order to compare observed proportions. RESULTS: Seventy-eight per cent of DSMB recommendations were to modify or stop the trial in Phase I or I/II drugs trials against 36% in the medical devices study, 11% in Phase II and III drugs trials, and 8% in trials other than for health products. The establishment of initial meetings has highlighted the percentages of recommendations by DSMB members of 86% compared to 15% without initial meetings (p

Background: A rare coding variant (rs72824905, p.P522R) conferring protection against the susceptibility to Alzheimer's disease (AD) was recently identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2). Here, we explore the protective nature of this variant with regard to AD pathology indicated by biomarkers, cognitive decline, and potential underlying biological mechanisms. Methods: Association of p.P522R with CSF levels of pTau181, total Tau and Aβ1-42 was assessed in 1,282 patients with mild cognitive impairment (MCI) or AD-dementia syndrome. In addition, the association with longitudinal cognitive decline was tested in 3,010 MCI patients from memory clinic cohorts and 10,100 individuals from population-based studies using latent process linear mixed models. Finally, unsupervised co-trans-regulatory network analysis and biological experiments were conducted. Findings: Carriers of the p.P522R variant showed lower pTau181 levels in CSF compared to non-carriers, specifically in the presence of amyloid pathology. In MCI patients but not in population-based cohorts, the p.P522R variant was associated with slower cognitive decline with an effect size similar to that of APOE-e4. We identified a network of coregulated proteins linking PLCG2 to APOE and TREM2. Finally, in vitro experiments confirmed that inflammasome activation upon phospholipase C stimulation might act downstream of PLCG2. Implication: Our data link the protective effect of p.P522R in PLCG2 to reduced Tau pathology, to a slower cognitive decline in MCI patients and to underlying inflammatory processes. Therapies targeting the enzyme PLCG2 might provide a therapeutic approach for AD. Funding Statement: EU Joint Programme Neurodegenerative Disease Research, Innovative Medicines Initiative 2, Instituto de Salud Carlos III, La Caixa, Grifols SA, German Federal Ministry of Research and Education, Sanofi Laboratories, Fondation pour la Recherche Medicale, Fondation Plan Alzheimer, Stichting Alzheimer Nederland, Stichting VUmc fonds, Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care, Netherlands Organization for Scientific Research (NWO), EMGO+ Research Institute. Declaration of Interests: All authors report no conflict of interest. PL received consultation and/or lecture honoraria from IBL International, Fujirebio Europe, AJ Roboscreen, and Roche. JW received honoraria for consulting activities, lectures or advisory board participation from Pfizer, Eli Lilly, Hoffmann-La-Roche, MSD Sharp + Dome, Janssen-Cilag GmbH, Immungenetics AG, Boehringer Ingelheim. LF received honoraria for consulting activities, lectures or advisory board participation from Allergan, Eli Lilly, Avraham Pharmaceuticals, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, Lundbeck, MerckSharpe & Dohme, Novartis, Pfizer, Pharnext, Roche, Schwabe Pharma; he served on Data and Safety Monitoring boards or endpoint committees with Avraham Pharmaceuticals, Axon Neuroscience, Forschungszentrum Julich, Novartis, Pharmatropix. JP received honoraria for consulting activities, lectures or advisory board participation from Fujirebio Europe, Ono Pharma, Eli Lilly, and Nestle Institute of Health Sciences. ARu reports consulting Fees: Landsteiner Genmed, Grifols, Araclon biotech. And Lecture Fees: Araclon Biotech.PA reports personal fees from Servier, Total, Genoscreen, Takeda, Foundation Alzheimer. OP received research funding, consultancy fees or speech honoraria from Axovant, Biogen, Genentech, Lilly, Lundbeck, Novartis, Pharmatrophix, Piramal, Probiodrug, Roche, Takeda and TauRx Pharmaceuticals. MB receives fees or has received for consulting from Lab. Servier, Roche, Lilly, Avid, Bayer, Elan, Janssen, Neuroptix, Sanofi. She receives or has received fees for lectures from Lilly, Nutricia, Roche, Schwabe, Araclon, Esteve, Grifols, Janssen, Novartis, Piramal, Pfizer-Wyett, Servier. She receives fees for being part of the Advisory Board of Lilly and Schwabe. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, S.A, Merck Sharp & Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma iberica SLU, all outside the submitted work. She has not received personal compensations from these organizations Ethics Approval Statement: The individual studies were approved by the respective ethics committees.

Data Monitoring Committees, also known as Data and Safety Monitoring Boards, are often established as a component of clinical trial oversight to review interim data of the ongoing trial so that safety concerns or problematic operational issues can be identified rapidly and corrective measures can be undertaken. Such committees may be independent of the trial sponsor and investigator to ensure recommendations are as objective as possible and unaffected by conflicts of interest. Federal funding and regulatory agencies have issued policy documents concerning the establishment and operation of Data Monitoring Committees, but substantial variation exists in committee processes. Keywords: clinical trial; interim analysis; safety; oversight

Continuing review is an important responsibility of Institutional Review Boards (IRBs). Though being mentioned by many of the national and international guidelines, it is carried out routinely only in UK. The reasons may be inadequate training, overworked IRBs, less enthusiasm among the IRB members, cost bearing, etc. So, the oversight mechanism at the local site, which is the responsibility of IRB is not fulfilled. Are there any solutions to overcome these difficulties? The IRBs should have a Standard operating procedure for continuing review, members can be regularly trained, institutions can create their own internal Data and Safety Monitoring Boards who will only monitor studies where monitoring systems are non-existing and there can be budget allocated at the start of the study by the sponsor or the institution. In this way, we can try to safeguard the rights and well-being of the study participants.

Background: Any therapeutic intervention carries with it the potential for benefit and harm. Generally, benefit is far more common than risk; however, risk aversion drives many of the treatment decisions made by patients and their physicians. Objective: To provide guidelines to help clinicians improve their understanding of causality and the interpretation of harm. Methods: A group of dermatologists involved in data safety monitoring boards, clinical trial investigators, and a clinical epidemiologist identified the need for practical advice on how to understand and explain causality and harm and combined to share their knowledge. Results: An explanation of how data are collected and the environment that shapes the data seen by clinicians is presented. The article spans an overview of the regulatory environment that informs trial design for regulatory approval to a description of types of designs that inform safety and techniques, such as the rule of three, to provide guidance to clinicians in interpreting the data. Conclusion: Communicating the potential for harm to patients is critical. Placing the potential for rare and serious risks into perspective for the patient is as important as discussing the potential benefits of medication.

There is little to no empirical data available on how data and safety monitoring boards (DSMBs) are structured and how they operate. The purpose of this study was to provide data on this. To accomplish this goal, we administered a random survey on current structure and management practices and opinions as reported by principal investigators (PIs) and biostatisticians. We also surveyed Institutional Review Board (IRB) community members, as proxies for the public, as to their opinions on how DSMBs should be structured and managed. A final purpose was to compare opinions about what should be taking place to what is actually happening.

Randomized trials designed a priori to test particular hypotheses provide the most reliable evidence concerning the most plausible small-to-moderate effects of drug therapies or interventions and are a necessary component of a totality of evidence upon which to make rational clinical decisions for individual patients and policy decisions for the health of the general public. As the methodology for the design, conduct and analysis of randomized trials continues to evolve, so do the principles and practical suggestions for their Data and Safety Monitoring Boards (DSMB)s. The implementation of these principles and practical suggestions should enhance the functioning of DSMBs, trial investigators and sponsors, protect the safety of the randomized subjects as well as the independence and integrity of the randomized trials.

The authors wish to add the following sentence into the 'Competing interests' section of this Article: "P.W.K. has investment interest in Context Therapeutics LLC, DRGT, Placon, Seer Biosciences and Tarveda Therapeutics, is a company board member for Context Therapeutics LLC, is a consultant and scientific advisory board member for BIND Biosciences, Inc., BN Immunotherapeutics, DRGT, GE Healthcare, Janssen, Metamark, New England Research Institutes, Inc., OncoCellMDX, Progenity, Sanofi, Seer Biosciences, Tarveda Therapeutics and Thermo Fisher, and serves on data safety monitoring boards for Genentech/Roche and Merck." This has now been included.

Those charged with assuring research accountability have little guidance as to how to best structure and manage data safety monitoring boards (DSMBs). One major concern is increased litigation surrounding human subject research which has led research institutions and those asked to serve on DSMBs to seek legal counsel regarding their risk of liability for DSMB activities. A major challenge is assessing the risk of potential liability. Yet, potential liability for DSMBs and their members has not been adequately addressed in the literature. The purpose of this article is to provide a legal and accountability analysis to begin to fill this gap. This article undertakes an analysis and exploration of the potential liability that exists for DSMBs and their members under negligence theory and discusses the means by which DSMBs and their members may avoid litigation or defend themselves in the face of a lawsuit. Research accountability implications of imposing liability, or not, on DSMBs are also considered. It is suggested that legislation be contemplated requiring sponsors to indemnify DSMBs and their members in the face of litigation.

Randomization is the standard means for addressing known and unknown confounders within the patient population in clinical trials. Although random assignment to treatment arms on a 1:1 basis has long been the norm, many 2-armed confirmatory trials now use unequal allocation schemes where the number of patients receiving investigational interventions exceeds those in the comparator arm. In what follows, we offer 3 arguments for why investigators, institutional review boards, and data and safety monitoring boards should exercise caution when planning or reviewing 2-armed confirmatory trials involving unequal allocation ratios. We close by laying out some of the conditions where uneven allocation can be justified ethically.

In the 1960s and 1970s, almost all clinical trials were designed with a single efficacy analysis at the end. Despite this design, many NIH-sponsored clinical trials were reviewed periodically by Policy Advisory Boards (now called Data and Safety Monitoring Boards). At these reviews, clinicians on the Board often asked: “If the current trend continues, what is the chance that we will have a positive study at the end?” We discuss how to put this question into a statistical framework and provide a simple answer. The “chance” is called conditional power (CP) or predictive power (PP). We discuss the use of CP and PP for early termination of a clinical trial. The concepts of CP and PP can also be applied to sample size determination for a new study or reestimation of sample size in an adaptive design.

Data Safety and Monitoring Boards (DSMBs) have been referred to as a “growth industry,” and this trend continues to be fueled by recent FDA guidance and the NIH's requirement that DSMBs be employed in virtually all phase III clinical trials. The widening role of DSMBs has been sporadically questioned on ethical grounds, but growth has continued, despite the fact that many of the questions endure, unanswered, save for repeated references to safeguarding the scientific integrity of trials. This may be about to change. The recently appointed director of the Office for Human Research Protections (OHRP), Jerry Menikoff, is on record as regarding current practices — where consent forms often promise what the DSMB has been assembled to specifically not provide — as constituting fraudulent behavior. That is, a subject may inherently rely on, to their detriment, information that has been misrepresented in the consent document. In this paper, we assemble some of the enduring questions and top them off with Menikoff's tour de force to present what we hope will be a compelling argument to require that consent forms fairly represent what the DSMB will do — and not do — with trial data as they accumulate. We argue that DSMBs should be used only in rare circumstances, and question the practice of precluding principal investigators from DSMB membership, but our main thrust is to ensure that DSMBs, when used at all, are properly described in trial consent forms.

Background: Data Safety Monitoring Boards primarily review accumulating data on clinical trials and provide recommendations to sponsors on whether a protocol should continue as planned, be modified, or be terminated. Data Safety Monitoring Boards often provide their recommendations based upon accumulating data to which only their members are given access. Despite the substantial responsibilities assumed by Data Safety Monitoring Board members, there is limited information in the literature about the unique knowledge they must possess and, consequently, the training content needs that are required in order for them to fulfill their obligations. Purpose: This article describes how the National Institute of Allergy and Infectious Diseases identified the knowledge that Data Safety Monitoring Board members should acquire and the computer-based training they developed to address the learning needs of the National Institute of Allergy and Infectious Diseases assembled Data Safety Monitoring Board members. Methods: The National Institute of Allergy and Infectious Diseases conducted a comprehensive literature search and interviewed Data Safety Monitoring Board subject matter experts, including Data Safety Monitoring Board members and chairs from academic institutions, pharmaceutical companies, and the National Institutes of Health to (1) assess whether Data Safety Monitoring Board training is an identified need, (2) evaluate whether Data Safety Monitoring Board training has been developed, and (3) formulate suitable learning objectives. Data Safety Monitoring Board training modules were developed based on the identified learning objectives identified from the interviews. Results: Three Data Safety Monitoring Board training modules were developed and formatted for web-based access, which is free of charge to the public at https://dsmblearningcenter.niaid.nih.gov . The modules include the following: an introduction to the objectives and purpose of Data Safety Monitoring Boards, the organization and responsibilities of Data Safety Monitoring Boards, and a review of statistical topics. Limitations: The complex concepts that Data Safety Monitoring Board members must apply to their deliberations and decisions require practice and application that come through hands-on experience. To build competency in the Data Safety Monitoring Board member role, not only does a member need to understand these complex concepts but also the member must have the opportunity to practice and apply this knowledge to real-life situations. Additional resources to facilitate practice and application of the complex issues that Data Safety Monitoring Boards deal with should be considered. The computer-based training is targeted to new and inexperienced Data Safety Monitoring Board members. Ongoing learning opportunities should be developed for experienced Data Safety Monitoring Board members. Non-English training must also be considered. Conclusion: The National Institute of Allergy and Infectious Diseases identified that training is not widely available for Data Safety Monitoring Board members to build the unique knowledge and skills necessary to serve on Data Safety Monitoring Boards. Consequently, National Institute of Allergy and Infectious Diseases developed publicly available web-based Data Safety Monitoring Board training modules for new or inexperienced members. Additional tools and resources are needed to help Data Safety Monitoring Board members acquire the knowledge and skills to serve their critical function in clinical research and to maximize research participant protections.

Background Models for the structure and procedures of data and safety monitoring boards (DSMBs) continue to evolve in response to issues of new and of old concern. Some authors have called for an open dialogue on these questions through publication of the experiences of DSMBs in addressing them. Purpose The goal of this paper is to add to the current discussion about acceptable models for establishing, serving on, and reporting to monitoring committees, particularly those that oversee multiple studies in less developed countries. The paper seeks to do so by describing the establishment and subsequent operation of one such multi-trial DSMB over a five-year period. This DSMB was formed to monitor trials conducted by members of the International Centers for Tropical Disease Research (ICTDR) network of the National Institute of Allergy and Infectious Diseases (NIAID). Methods The operational model and experiences are summarized by the authors, who had immediate responsibilities for directing the DSMB's activities. Results The board played an active, traditional role in assuring that patient safety was maintained and that current standards for clinical research were met. In addition, both NIAID and the board members viewed education of investigators to be an important role for the board to play in this particular setting. This affected the threshold for identifying which trials would be monitored, and it impacted several procedures adopted by the board. Limitations This report reflects the observations of those involved in managing the DSMB, including comments offered by the DSMB and by investigators, but not data gathered in a systematic way. Conclusions The operational model described here has allowed the DSMB to fulfill its role in the oversight of the trials. We hope that the ideas we present may help others facing similar situations and may stimulate further critical thinking about DSMB structure and function.

In a previous paper we considered how pharmaceutical statistics had changed between 1980 and 2000. In this paper we go on to consider some of the likely influences and changes in the world of pharmaceutical statistics over the next twenty years. Statistical research by pharmaceutical companies is supported, although its direct value in boosting company profits is challenged. The duality between fraud and conflict of interest is explored, particularly with regard to data and safety monitoring boards. Political correctness within clinical trials and (allegedly) better patient-oriented outcomes is questioned and the whole notion of intention-to-treat and per-protocol analyses is rejected in favour of pragmatic trials and explanatory trials. The dominance of SAS software within the industry is explored and the possibility for change considered. Finally, whilst the future of pharmaceutical companies is not addressed, the impact of future mergers, collaborations and take-overs between clinical research organizations is considered. Copyright © 2002 John Wiley & Sons, Ltd.

Investigators have legal duties and responsibilities that span the long arc from study design and patient enrollment to well beyond publication of results of clinical trials and other types of studies in peer-reviewed journals. Duties extend to human research participants, institutional review boards (IRBs), data and safety monitoring boards, funders and research sponsors, employers, and finally, journals and their readers. “Scientific misconduct” includes a host of offenses, ranging from plagiarism to fabrication, false claims of authorship, and omission. Among the affirmative duties of authors is making a candid disclosure of the financial interests and affiliations that could affect their judgment and objectivity.1 Investigators who are employees, officers, or owners of for-profit companies, or who have patent or copyright interests, have additional responsibilities and are especially vulnerable to legal and ethical risks. This Viewpoint will focus on the duty of investigators who are authors to report their potential conflicts of interest (COI) and the legal and professional consequences for all involved when authors make COI omissions.

Data and Safety Monitoring Boards (DSMBs) have become an increasingly common feature of clinical trial oversight, yet a paucity of legal or ethical frameworks govern these Boards' composition or operation, or their relationship with other actors with monitoring responsibilities. This paper argues that prevailing structural gaps are impeding harmonized systems for monitoring the ongoing ethical acceptability of clinical trials. Particular tensions stem from DSMBs' sweeping discretion in deciding whether and when to recommend that a trial should be terminated or amended based on safety and efficacy information. This discretion becomes especially challenging in light of DSMBs' monopoly over emerging trial data, which prevents Institutional Review Boards, sponsors, and investigators from participating in certain pivotal and ethically charged decisions. To address these disconnects, I advocate for strengthened pre-trial and post-trial communication in addition to innovative strategies to support DSMB decision making through the life of a trial.

In late September 2004, the cardiovascular risks identified in a placebo-controlled adenoma-prevention trial that was terminated early precipitated the voluntary withdrawal from the market of the cyclooxygenase-2 (COX-2) inhibitor rofecoxib.1 Later that year, in another adenoma-prevention trial, the COX-2 inhibitor, celecoxib, was also associated with an increase in the risk of cardiovascular events.2 For this reason, on December 17, 2004, the data and safety monitoring boards of two celecoxib trials recommended stopping drug administration in the trials.2,3 Articles describing the cardiovascular risks seen in the two adenoma prevention trials were published rapidly.1,4 However, in the absence of evidence . . .

Background JIA is the most common chronic inflammatory rheumatic diseases of childhood. Due to their long-term safety and efficacy, biologic disease modifying antirheumatic drugs (DMARD) are commonly necessary for control of pJIA patients (pts). Objectives To evaluate 6-year (y) safety and 2 y effectiveness profile of Adalimumab with or without methotrexate (ADA±MTX) when used in current clinical practice for the treatment of moderately to severely active pJIA. Methods This is a 6 y interim analysis of an ongoing, multicenter, non-interventional, observational registry of pts with moderately to severely active pJIA with up to10 y safety follow-up. Included pts are treated with either ADA±MTX or MTX alone as part of their routine clinical care enrolled in the US, EU, and Australia. MedDRA observational adverse events (AEs) were recorded from the first day in the registry through last contact, irrespective of the duration of registry treatment. Effectiveness was assessed by 27-joint juvenile arthritis disease activity score (JADAS27), based on CRP. Results As of January 2014, enrollment was complete. As of June 1, 2015 cut-off date, 846 pts (543 in ADA±MTX and 303 in MTX groups) were treated in the registry. There were 39 pts who rolled over from the MTX to the ADA±MTX arm. At registry entry mean pJIA disease duration was 1.4 y and 3.7 y for MTX and ADA±MTX arms, respectively. At baseline (BL), mean AJC71 was 5.8 and 5.3 for MTX and ADA±MTX arms, respectively, and Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI) was 0.6 for both arms. At data cutoff, the mean duration of study exposure was 1.81 y and 2.15 y for MTX and ADA±MTX arms, respectively. Overall, 206 pts (68%) in the MTX and 216 pts (39.8%) in the ADA±MTX arms discontinued registry drug through 6 y. The main reasons for registry drug discontinuation for the MTX arm: pts required additional therapy (32.3%), other (11.9%), lack of efficacy (10.9%), AEs (8.3%), or pts achieved JIA remission (7.6%), and for ADA±MTX arm: lack of efficacy (16%), lost to follow-up (7.2%), other (5.9%), and AEs (5.3%). Frequencies and rates of treatment-emergent AEs were similar to those reported for observational AEs (Table). There were no reports of deaths, malignancies, opportunistic infections, active TB, oral candidiasis, or CHF. Mean JADAS27 (CRP) improved from 12.2 at BL to 9.7, 5.2, 4.4, 3.5, 2.2 at months 1, 6, and 12, 18, 24 for pts in the MTX and from 11.8 at BL to 7.0, 4.-2, 4.2, 3.6, 3.9 in the ADA±MTX arms, respectively (observed data). Conclusions Overall, ADA±MTX was well-tolerated in these pts with pJIA with no new safety signals. Discontinuations from the registry drug were relatively high through 6 y, but greater in the MTX only arm. Acknowledgement AbbVie sponsored the study & contributed with PRINTO & PRCSG to the analysis, review, and approval of the abstract. Xiaolei Leahy & Ashish Deshmukh of AbbVie contributed to the research. Medical writing support was provided by Gaurav Patki, PhD, of AbbVie. Disclosure of Interest N. Ruperto Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfgroupaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Phgroupaceuticals., Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, D. J. Lovell Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, and Genentech, Speakers bureau: Wyeth Pharmaceuticals, and served on data and safety monitoring boards for Amgen and Forest Research, C. Wallace Grant/research support from: Pfizer and Amgen, Consultant for: Amgen and Novartis., M. Toth: None declared, I. Foeldvari Consultant for: AbbVie and Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech and Novartis, E. Rabinovich Grant/research support from: UCB Pharma, Janssen Research & Development, LLC, Hoffmann-La Roche Inc., and AbbVie, D. Kingsbury Grant/research support from: AbbVie, K. Marzan Grant/research support from: AbbVie., P. Quartier Grant/research support from: AbbVie, Novartis, Consultant for: AbbVie, Novartis, K. Minden Grant/research support from: Pfizer and Abbvie, Consultant for: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac and Pharma-Allergan., E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, and Roche, Speakers bureau: AbbVie, Novartis, Pfizer, and Roche, R. M. Kuester Grant/research support from: AbbVie Inc. and Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac, Pfizer, Roche, and UCB, M. Heinrich Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, H. Kupper Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, J. Kalabic Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, A. Martini Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, and MedImmune., H. I. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals.

Data Monitoring Committees, also known as Data and Safety Monitoring Boards, are often established as a component of clinical trial oversight to review interim data of the ongoing trial so that safety concerns or problematic operational issues can be identified rapidly and corrective measures can be undertaken. Such committees may be independent of the trial sponsor and investigator to ensure recommendations are as objective as possible and unaffected by conflicts of interest. Federal funding and regulatory agencies have issued policy documents concerning the establishment and operation of Data Monitoring Committees, but substantial variation exists in committee processes. Keywords: clinical trial; interim analysis; safety; oversight

Background The long-term safety of anti-tumor necrosis factor (TNF) drugs is particularly important in pediatric patients (pts) who may require prolonged treatment of their inflammatory disease. Objectives To evaluate long-term rates of serious adverse events (AE) and anti-TNF AEs of special interest in adalimumab (ADA) clinical trials in pediatric pts with polyarticular or polyarticular course juvenile idiopathic arthritis (pJIA) or enthesitis-related arthritis (ERA). Methods Safety data from pts treated with ADA, either dosed 24 mg/m 2 BSA every other week (eow) or 20 mg eow ( Results ADA was administered to 274 pts, representing 769.0 PY of exposure. Infections, the most common AE, occurred in ≥10% of pts. Serious infection was the most frequently reported SAE (table). One case of latent TB was reported. No malignancies, opportunistic infections, or deaths were reported. 8.4% of pts (23/274) discontinued study due to AE (range, 5.1% in age Conclusions These data provide support for the long-term safety of ADA in pediatric pts aged 2–17 yrs with pJIA or ERA and demonstrate a safety profile consistent with ADA in adult pts and known information about the anti-TNF class. Acknowledgements AbbVie funded the studies (NCT00048542, NCT00690573, NCT00775437, and NCT01166282), contributed to their design and was involved in the collection, analysis, and interpretation of the data, and in the writing, review, and approval of the publication. Medical writing support was provided by Kathleen V. Kastenholz, PharmD, MS, of AbbVie. Disclosure of Interest N. Ruperto Grant/research support from: AbbVie, AstraZeneca, BMS, Janssen, “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, and Wyeth for the PRINTO network paid to GASLINI Hospital, Consultant for: AbbVie, Amgen, Astellas, Alter, AstraZeneca, Biogen Idec, Boehringer, BMS, CD-Pharma, Celgene, Crescendo Bioscience, EMD Serono, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo-Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, Sinergie, Takeda, and Vertex, Speakers bureau: AbbVie, Amgen, Astellas, Alter, AstraZeneca, Biogen Idec, Boehringer, BMS, CD-Pharma, Celgene, Crescendo Bioscience, EMD Serono, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo-Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, Sinergie, Takeda, and Vertex, D. Lovell Consultant for: AbbVie, AstraZeneca, Boehringer Ingelheim, Celgene, Centocor, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Horizon Pharma, Janssen Biologics B.V., Novartis, Pfizer, Regeneron, Hoffman La-Roche, and UBC and served on data and safety monitoring boards for Forest Research, Speakers bureau: Genentech and Wyeth Pharmaceuticals, D. Kingsbury Grant/research support from: AbbVie, R. Burgos-Vargas Grant/research support from: AbbVie, Consultant for: AbbVie, BMS, Janssen, Pfizer, and Roche, Speakers bureau: AbbVie, BMS, Janssen, Pfizer, and Roche, T. Imagawa Grant/research support from: AbbVie/Eisai and Novartis, Consultant for: AbbVie/Eisai, Speakers bureau: AbbVie/Eisai, Chugai, and Mitsubishi Pharma, G. Horneff Grant/research support from: AbbVie, Pfizer, and Roche, Speakers bureau: AbbVie, Novartis, Pfizer, and Roche, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, and Swedish Orphan Biovitrum, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, and Swedish Orphan Biovitrum, S. Goodman Consultant for: Amgen, A. Reiff Consultant for: AbbVie and Amgen, Speakers bureau: AbbVie and Amgen, E. Giannini Consultant for: AbbVie, A. Cardoso Shareholder of: AbbVie, Employee of: AbbVie, J. Anderson Shareholder of: AbbVie, Employee of: AbbVie, N. Varothai Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Grant/research support from: AbbVie, AstraZeneca, BMS, Janssen, “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, and Wyeth for the PRINTO network paid to GASLINI Hospital, Consultant for: AbbVie, Amgen, Biogen Idec, Boehringer, BMS, Celgene, EMD Serono, Janssen, MedImmune, Medac, Novartis, Novo- Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, Takeda, and Vertex, Speakers bureau: AbbVie, Amgen, Biogen Idec, Boehringer, BMS, Celgene, EMD Serono, Janssen, MedImmune, Medac, Novartis, Novo- Nordisk, Pfizer, Roche, Sanofi Aventis, Servier, Takeda, and Vertex

Background Juvenile idiopathic arthritis (JIA) is one of the most common childhood rheumatic diseases. Adalimumab (ADA) is approved for moderate to severe polyarticular JIA (pJIA) in patients (pts) ≥4 yrs in Australia and Japan and for pts ≥2 yrs in the US and EU. Objectives To evaluate long-term safety and effectiveness of ADA in pts with moderately to severely active pJIA who are prescribed and treated with ADA in routine clinical practice. Methods This is an ongoing, multicenter, non-interventional, observational registry of pts with moderately to severely active pJIA who are treated with either ADA ± methotrexate (MTX) or MTX alone as part of their routine clinical care. 800 pts (500 ADA/300 MTX) were to be enrolled in the US, EU, and Australia. The follow-up observational period is 10 yrs from enrollment into one of the treatment arms. Observational adverse events (AEs) were recorded from the first day in the registry through last contact, irrespective of registry treatment duration. Clinical outcomes were assessed by 27-joint juvenile arthritis disease activity score (JADAS27), based on CRP. 5 yr interim data are presented. Results As of January 2014, enrollment is complete. 842 pts (540 ADA/302 MTX) were treated as of the March 28, 2014 cutoff. Mean pJIA disease duration at enrollment was 1.3 and 3.7 yrs and mean duration of study exposure was 643 and 653 days for MTX and ADA arms, respectively. Baseline mean AJC73 was 5.8 and 5.4 for MTX and ADA, respectively, and CHAQ-DI was 0.6 for both groups. Overall, 153 pts (50.7%) in the MTX arm and 132 pts (24.4%) in the ADA arm discontinued registry drug. Of those, 22 (7.3%) and 23 (4.3%) in the MTX and ADA arm, respectively, discontinued due to an AE, and 39 of the 153 pts in the MTX arm discontinued as they switched to the ADA arm. The observational AEs are summarized (Table). No deaths, malignancies, or opportunistic infections were reported. In the ADA arm, there were 13 (2.4%) pts with serious infectious AEs (abdominal abscess, acute tonsillitis, appendicitis, cellulitis, gastroenteritis, mononucleosis, viral meningitis, pneumonia, pyelonephritis, scarlet fever, subcutaneous abscess, tonsillitis, urinary tract infection, and varicella). Frequencies and rates of treatment-emergent AEs were similar to those reported for observational AEs. Mean JADAS27 improved from 12.1 at baseline to 9.4, 6.1, 5.1, 4.4 at months 1, 3, 6, and 12 for pts in the MTX arm and from 12.1 at baseline to 7.4, 5.5, 4.4, 4.5 in the ADA arm, respectively (observed data). Conclusions Overall, ADA is well-tolerated in these pts with active pJIA. No new safety signals were observed, and based on this interim analysis, the known safety profile of ADA remains unchanged. Acknowledgements AbbVie sponsored the study (NCT00783510), contributed with PRINTO and PRCSG to the design, and participated in data collection, analysis, and interpretation, and in the writing, review, and approval of the abstract. Medical writing support was provided by Jessica L. Suboticki, PhD, of AbbVie. Disclosure of Interest N. Ruperto Employee of: GASLINI Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals. NR has served on speaker9s bureau for Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, H. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals, C. Wallace Grant/research support from: Pfizer, Amgen, Consultant for: Amgen, Novartis, M. Toth: None declared, I. Foeldvari Consultant for: AbbVie, Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech, Novartis, E. Rabinovich Grant/research support from: UCB Pharma, Janssen Research & Development, LLC, Hoffmann-La Roche Inc., AbbVie, P. Vavrincova: None declared, D. Kingsbury Grant/research support from: AbbVie, K. Marzan Grant/research support from: AbbVie, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum; Participates on a data management committee of a phase 3 trial by Sanofi, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, K. Minden Grant/research support from: Pfizer, Abbvie, Consultant for: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac, Pharm-Allergan, Speakers bureau: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac, Pharm-Allergan, E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, and Roche and speaker9s fees from AbbVie, Novartis, Pfizer, Roche, R.-M. Kuester Grant/research support from: AbbVie, Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac GmbH, UCB Biosciences, M. Bereswill Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Employee of: GASLINI Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, MedImmune, D. Lovell Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, Genentech; served on data and safety monitoring boards for Amgen, Forest Research, Speakers bureau: Wyeth Pharmaceuticals

Clinical trials are often stopped prematurely by Data and Safety Monitoring Boards, sponsors, or the investigators for reasons such as unexpected harmful effects of the intervention, clear lack of benefit, or futility due to sluggish recruitment or an unexpectedly low outcome rate in the placebo group. Planning for closeout, however, usually does not begin until after the trial is well underway. This article describes the experience of the Heart and Estrogen/progestin Replacement Study (HERS) investigators when data from the first year of follow-up revealed a clear but non-significant divergence in outcome rates between the treatment groups, and planning for early closure was initiated. Three advantages of beginning early to plan for closeout are described and approaches to planning closeout are suggested.

Publisher Summary This chapter discusses the organization, responsibilities, and regulatory considerations of data safety monitoring boards (DSMBs) in neurological clinical trials. DSMBs were introduced in the early 1960s as a means of ensuring the safety of subjects in clinical research. The role of DSMBs is continuing to expand as both the complexity of acute neuroemergency trials and the need for proper safeguards to ensure protection of patients are being subject to increasing, yet appropriate, scrutiny. A well-defined DSMB charter with careful consideration to the specific events to be monitored is becoming increasing critical. The use of independent adjudication committees is more common in the neuroemergency settings as the definitions of clinical outcomes and variations in medical management become increasing difficult to discriminate. An excellent functioning DSMB will be ever more important in the coming years to ensure that trials with significant risk are not continued or recruitment of a sufficient sample size to adequately demonstrate safety and efficacy is ensured.

The use of interim analyses and data safety monitoring boards (DSMBs) can assist greatly in the timely determination of whether or not a medicine has an acceptable benefit-risk profile. Regulatory authorities regard the appropriate use of interim analyses favourably, but will consider the extent to which the conduct of interim analyses and the involvement of DSMBs may have compromised the evidence of efficacy and safety from a clinical trial. Issues of particular concern, which may potentially introduce bias, include the dissemination of interim data and the rules by which a trial might be terminated early. If data from trials which employ a DSMB are to be considered reliable and scientifically valid, it is the responsibility of the trial sponsor to demonstrate that the DSMB is set up and run appropriately and to verify that any bias introduced has had no important effect on the conclusions.

Eric M Ruderman is a professor of medicine at the Northwestern University Feinberg School of Medicine (IL, USA) and the clinical practice director for the division of rheumatology. His clinical interests include the medical management of rheumatoid arthritis and the spondyloarthropathies. In 2001, he established one of the first rheumatology/dermatology cooperative clinics in the USA for the management of of psoriasis and psoriatic arthritis. He has been an investigator in over 50 clinical trials studying both biologic and nonbiologic therapies for rheumatic diseases. In line with his ongoing interest in patient safety, he has served on the data safety monitoring boards for a number of NIH and industry-sponsored clinical trials, and he currently serves as vice-chair for Northwestern University’s Institutional Review Board.

Data monitoring committees in clinical trials , Data monitoring committees in clinical trials , کتابخانه دیجیتال جندی شاپور اهواز

Data and Safety Monitoring Boards (DSMBs) are commonly appointed to monitor emerging data from major clinical trials. This paper describes their organization and remit, and their relationship with other trial committees and structures. The operation of formal stopping rules for safety and efficacy by a DSMB is discussed. The duties of a DSMB, from pre-trial planning through to stopping a study are described in detail, with emphasis on the reporting of information to the DSMB and the reporting of conclusions by the DSM B. The issue of blindness is given prominence and the role of the statistician on the DSM B is explored in detail.

The growth of clinical trials has emerged as an indispensable foundation and major source of advances in medicine and human health. Their proliferation, size, complexity, and cost have engendered several recent consensus conferences; the reports arising reflect broad concern about the future sustainability of the current model of clinical trials.1,2 These initiatives have also variously called for greater efficiency, increasing end point validity and relevance, more adaptable and flexible designs, and better return on the investment of diverse stakeholders.

Studies such as RECORD1 highlight the difficulties of assessing the safety profile of medicines for the treatment of long term conditions. Our response should be measured and recognise the complex issues involved in the design, conduct, and evaluation of studies that explore risks and benefits of treatments. It is too simplistic to assert that collusion between sponsors, investigators, authors, and data and safety monitoring boards is the root cause. With regards to Steinbrook and Kassirer’s (doi:10.1136/bmj.c5391) first criterion, it is hard to imagine any institution—whether academic, industry, or governmental—allowing unfettered analyses of their research data. Many institutions support data release for exploratory research and meta-analyses, protected by formal agreements for …