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Results for “Clinical Trials Data Monitoring Committees”

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PubMed2006

Adaptive designs in clinical drug development--an Executive Summary of the PhRMA Working Group.

A PhRMA Working Group on adaptive clinical trial designs has been formed to investigate and facilitate opportunities for wider acceptance and usage of adaptive designs and related methodologies. A White Paper summarizing the findings of the group is in preparation; this article is an Executive Summary for that full White Paper, and summarizes the findings and recommendations of the group. Logistic, operational, procedural, and statistical challenges associated with adaptive designs are addressed. Three particular areas where it is felt that adaptive designs can be utilized beneficially are discussed: dose finding, seamless Phase II/III trials designs, and sample size reestimation.

Biomedical Research↗
PubMed2004

Evaluating and implementing data and safety monitoring plans.

Data and safety monitoring plans are essential for fulfilling assurances that are given to patients enrolling in clinical trials that they will not be exposed to avoidable risks and that any information that may influence their willingness to participate in the clinical trial will be made available to them whether the clinical trial is a phase I, phase II, or phase III effort. In addition to the often explicitly detailed nomination of members of an independent data and safety monitoring board and selection of interim analysis plans for control of type I error and avoidance of conduct of a futile study, data and safety monitoring requires organization with regard to schedules for data collection, active surveillance for adverse events, with special emphasis on serious or unexpected events, and the ability to bring all information within a study and newly accruing information external to the research project together as needed for assessment of patient safety.

Clinical Trials Data Monitoring Committees↗
PubMed2006

An Institutional Review Board dilemma: responsible for safety monitoring but not in control.

Clinical trials have become a major research tool to evaluate new medical interventions. Most trials require some level of data monitoring for quality control and many trials require special monitoring for participant safety. For national multicenter trials, independent data monitoring committees have become the standard for monitoring for evidence of participant benefit or harm in trials with irreversible outcomes such as death or serious morbidity. The Institutional Review Board (IRB) is held responsible for monitoring local trials. Often local institutions do not have an infrastructure in place to meet this responsibility, and therefore local IRBs cannot fulfill this obligation. In addition, IRBs are currently inundated with individual safety reports from local and multi-institutional trials which may appear to provide some level of safety monitoring, but in fact gives a false sense of security. We propose the establishment of institutional data monitoring committees and appropriate informatics infrastructure to monitor local trials.

Clinical Trials Data Monitoring Committees↗
PubMed2006

Comparing classifications of death in the Mode Selection Trial: agreement and disagreement among site investigators and a clinical events committee.

Clinical events committees (CECs) are the current standard for endpoint adjudication in clinical trials. However, little data exist with which to compare CEC and site investigator determinations or to evaluate internal agreement among CEC members. Using data from the Mode Selection Trial in Sinus Node Dysfunction (MOST), we analyzed classifications of death in order to compare internal agreement among CEC physician reviewers and agreement between the CEC and site investigators. Death was classified at 2 levels: by major cause (cardiac, noncardiac, or unknown) and by minor subclassification of the major classifications. Reviewer agreement was tabulated at the major and minor levels, and standard and weighted kappa statistics were calculated. Disagreement at both levels was also determined. Individual decision-making was tabulated in terms of frequency in classifying death as unknown. All 404 deaths were classified by the CEC. Site investigators determined major classifications in 382 cases and minor classification in 379 cases. The CEC and the site investigators disagreed in classifying 41 cases (10.7%) at the major level and 117 (30.9%) at the minor level. CEC reviewers disagreed internally at the major level in 64 cases (15.8%), at the minor level in 63 cases (15.6%), and at any level in 127 cases (31.4%) (kappa = 0.60, 95% confidence interval (CI) [0.55, 0.66]; weighted kappa = 0.66, 95% CI [0.62, 0.75]). In resolving internal disagreements, the full CEC agreed with 1 of 2 CEC reviewers in 85.9% of cases. Disagreements occurred between site investigators and CEC reviewers in classifying deaths. Endpoint determination and decision-making varied among individual CEC reviewers, but second-tier reviews by the full CEC resolved all disagreements. These findings support continued use of CECs for endpoint adjudication in clinical trials.

Cause of Death↗
PubMed1995

The data and safety monitoring board and acquired immune deficiency syndrome (AIDS) clinical trials.

The urgency of the Acquired immune deficiency syndrome (AIDS) epidemic has mandated that multiple therapeutic approaches be developed and that these approaches be evaluated through clinical trials. To oversee these trials, the National Institute of Allergy and Infectious Diseases (NIAID) has created three large clinical trial programs monitored by a Data and Safety Monitoring Board (DSMB). For each clinical trial, this Board uses a standardized approach employing contemporary biostatistical, medical, and ethical principles. The DSMB is responsible for reviewing interim data on clinical trial performance, treatment safety and efficacy, and overall study progress. If interim results provide convincing evidence of either excessive adverse effects or significant treatment benefit, the DSMB may recommend early termination of the trial to the NIAID and the study investigators. The responsibility, organization, and operating procedures of this DSMB are presented and illustrated through three clinical trials sponsored by NIAID and monitored by the Board. The rationale and operational model for the DSMB may be a useful example for the development of similar review processes in other HIV clinical trial settings.

Advisory Committees↗
PubMed1991

Data monitoring committees for multicenter clinical trials sponsored by the National Institutes of Health. I. Roles and membership of data monitoring committees for trials sponsored by the National Eye Institute.

The operational aspects of data monitoring committees for multicenter clinical trials have received little attention in the published literature, in contrast to a wealth of publications concerning the statistical aspects of data monitoring. Occasional anecdotal reports suggest that the role of these committees is complex and that responsibilities and decisions extend beyond choice of a stopping rule. In an effort to gain a better appreciation of the domain of responsibilities shared by all or most of the data monitoring committees (DMCs) for the 20 multicenter studies (30 clinical trials) sponsored by the National Eye Institute, one of the National Institutes of Health, published information was studied and key members of the DMCs for these studies were surveyed. Information about the membership of these important groups also was sought in order to guide those with responsibility for appointing future DMCs. Three tasks--all directly associated with monitoring accumulating data for evidence of benefit or harm to trial patients--were reported unanimously to be the responsibility of the DMCs. In addition, many responsibilities concerned with study oversight rather than data monitoring were assigned to the DMC in 75% or more of the trials. The domain of responsibilities common to a majority of the DMCs suggests that these groups function in most NEI-sponsored multicenter trials as combined data monitoring and policy boards, even when not so designated. The median size of the 20 DMCs was 10 members, with six appointed and four ex officio members. Ophthalmologists accounted for 38% of all DMC positions and statisticians for 33%.

Clinical Trials as Topic↗
PubMed2004

Conflicts of interest in data monitoring of industry versus publicly financed clinical trials.

The FDA Guidance, while highly appropriate for industry sponsored trials, need not be imposed on publicly (e.g. NIH) financed clinical trials. While the potential for conflicts of interest exist in the latter, they are in general manageable and pose an acceptable low risk of threatening the integrity of a study. However, the Guidance should heighten the awareness of all investigators in public trials to the potential for the appearance of conflicts and to the need for full and open participation in the management of dualities of interest.

Clinical Trials Data Monitoring Committees↗
PubMed2006

Clinical trials in children--How are they implemented?

Drug metabolism in children may differ from adults and adverse events may occur that are not predictable from the adult experience. Clinical trials of safety and efficacy are needed both for new treatments and those that may already be in use but have not been tested in infants and children. The role and responsibilities of different participants in a trial are discussed, including the steering committee, the clinical and statistical co-ordinating centers, and the data and safety monitoring board. Advantages of external vs internal pilot studies are reviewed. Information that is available on the websites of the Food and Drug Administration and the National Institute of Neurological Disorders and Stroke may be helpful to those planning clinical trials of interventions in children.

Adult↗
PubMed2005

[DSMB. 2. The importance of an efficient DSMB: some examples of high-risk clinical trials].

The DSMB (data safety and monitoring board) takes an increasing role in the monitoring of clinical trials, especially in large multicenter trials conducted in populations at high risk of morbidity or mortality. The DSMB is a an expert committee, independent from the investigators and the sponsor of the trial, which periodically examines the safety data accumulated during progress of the trial and ensures that the benefit/risk ratio remains acceptable for participating patients. A few examples, derived for recent experience of clinical trials conducted in acutely ill patients, illustrate the importance of an efficient and reactive DSMB to monitor patients' safety, especially during large multicenter trials.

Clinical Trials Data Monitoring Committees↗
PubMed2004

New developments in medical clinical trials.

This paper reviews several new developments and long-standing good practices for conducting clinical trials. Discussion starts with the need for clear statements of study objectives, proceeds to clarify target and sample population, and elaborates on primary vs. secondary variables with the need for alpha adjustment in the presence of multiple outcomes. Here we also review the issue of surrogate endpoints. Study design issues--including blinding, randomization, and multicenter studies--come next. Then we discuss the current trend of the replacement of placebo-controlled trials by active controlled non-inferiority trials, the increasing use of Independent Data Monitoring Committees, the prominence of analysis on Intention-to-Treat samples, and the importance of imputation of missing data. We close with a brief discussion of the unit of analysis, the role of newer statistical analysis methods, safety issues, subset analysis, and, most importantly, clinical significance.

Clinical Trials Data Monitoring Committees↗
PubMed2003

Toward protecting the safety of participants in clinical trials.

It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.

Clinical Trials Data Monitoring Committees↗
PubMed2003

Acute stroke: trial by jury. The toothless tiger (role of the principal investigator).

All trials require a principal investigator to take the lead role and act as main contact amongst the various groups of participants. His role ranges from assistance in protocol design; through selection of investigators, monitoring of study conduct and responding to Safety Committee recommendations; to involvement in study reporting and in maintaining access to the data set after the conclusion of the trial. This article describes the role of the principal investigator and Steering Committee in more detail and discusses the issues that arise out of the organisational requirements of modern clinical trials and the potential tensions between the various participating groups.

Acute Disease↗