A Guide to Data and Safety Monitoring Boards (DSMB)

Reference: Data Monitoring Committees in Clinical Trials; A Practical Perspective By: Susan S. Ellenberg, Thomas R. Fleming and David L. DeMets

 

Key Points

  • The purpose of data monitoring committees (DMCs) is to protect the safety of trial participants, the credibility of the study and the validity of study results.
  • DMCs have a long history in trials sponsored by government agencies in the USA and Europe.
  • Pharmaceutical companies are increasing their use of DMCs in trials of investigational drugs, biologics and medical devices.
  • Statistical methods have been developed for interim monitoring of clinical trials.
  • While not all trails need DMCs, trials that address major health outcomes and are designed to definitively address efficacy and safety issues should incorporate DMC oversight.

Responsibilities of the Data Monitoring Committee

  • The DMC may perform a variety of tasks in meeting its overall responsibilities for safeguarding trail participants and trial integrity.
  • These tasks may address primarily scientific issues, such as an advisory review of the study protocol, as well as primarily practical issues such as quality assurance.
  • Trials may be considered for early termination based on proven efficacy, unfavorable results ruling out benefit, safety concerns, or low probability of achieving the trial objectives.
  • All trials monitored by a DMC should function under a charter, agreed to by the trial sponsor and the committee members, that describes the structure and operation of the committee.

Composition of a Data Monitoring Committee

  • DMCs should be multidisciplinary, and should always include individuals with relevant clinical and statistical expertise.
  • Different trials may require the inclusion of different disciplines on a DMC.
  • The appropriate size of a DMC depends on the type of trial and types of expertise needed.
  • The study sponsor either appoints the DMC, or delegates this responsibility to another group such as a steering committee.
  • Training programs for DMC service are needed.

Independence of the Data Monitoring Committee: Avoiding Conflicts of Interest

  • Individuals with important conflicts of interest in regard to a particular clinical trial should not serve on a DMC for that trail.
  • The most obvious conflicts are financial, but there can also be intellectual and emotional conflicts of interest.
  • Complete elimination of all real, potential and perceived conflicts of interest is generally not possible if one wishes to include DMC members who are knowledgeable and experienced in the medical area being studied.

Confidentiality Issues Relating to the Data Monitoring Committee

  • Trial integrity is best protected when interim data comparing treatment groups are seen only by DMC members and the statistician preparing the interim reports.
  • Separate reports presenting aggregate data on administrative aspects of the trial can be shared with the sponsor and trial leadership.
  • In limited circumstances there may be a strong rational for wider access to comparative interim data.
  • The DMC should have access to fully unblinded data, with actual treatments and not just codes available for its review.

Data Monitoring Committee Meetings

  • Standard operating procedures for a DMC should be established.
  • Early in the trail, DMC review will focus more on safety, quality of conduct and trail integrity than on efficacy evaluation..
  • Interim data reports submitted to the DMC should be as accurate and as up to date as it is feasible to accomplish.
  • DMC meetings may include open and closed sessions, with trial leadership permitted to attend open sessions and comparative interim data presented and discussed only in closed sessions.
  • Minutes should be kept for all DMC sessions.

Data Monitoring Committee Interactions with other Trail Components or Related Groups

  • DMCs will interact, occasionally or routinely, with other trial components, such as the trial sponsor and the study chair.
  • Different models for such interaction have been developed, but problems can arise when these other components are provided access to comparative interim data.
  • An independent statistician, separate from the primary (steering committee) statistician for the trial, can be a useful addition to the trial structure by preserving the ability of the trial statistician to participate in unbiased interim decision-making with other members of the trial leadership.
  • Sharing of interim data between DMCs monitoring similar trials can be valuable but needs to be done judiciously.

 

Statistical, Philosophical and Ethical Issues in Data Monitoring

  • Specialized statistical methods are needed for monitoring clinical trials data to differentiate between 'evidence providing reliable conclusions' and 'fluctuations over calendar time that are consistent with random variability'.
  • Several statistical approaches have been developed for evaluating and interpreting data at interim time points during a clinical trial.
  • Flexibility, in terms of number and timing of interim analyses, can be built into the statistical monitoring plan.
  • DMCs must be in agreement with trial sponsors and trail leadership regarding the statistical and other criteria that will guide recommendations for early termination of the trial.

Determining When a Data Monitoring Committee is Needed

  • All trials need careful monitoring, but not all trials need independent DMcs.
  • Independent DMCs are most needed for randomized trials intended to provide definitive data regarding treatments intended to save lives or prevent serious disease.
  • Independent DMCs are needed when interim analyses of safety and efficacy are considered essential to ensure the safety of trail participants.
  • 'Internal" DMCs may be valuable in some trails that do not need independent monitoring.

Regulatory Considerations for the Operation of Data Monitoring Committees

  • FDA regulations require ongoing safety monitoring of clinical trials, but DMCs are only minimally addressed in government regulations.
  • Despite lack of requirements for DMCs, regulators generally expect randomized trials with mortality or major morbidity endpoints to be monitored by an independent DMC.
  • FDA reviewers generally do not participate in DMC meetings or serve on DMCs of trials they regulate, and there are good reasons why they should not.
  • The FDA issued a draft guidance document on the establishment and operation of DMCs in 2001.

Helpful Websites for Developing a Data and Safety Monitoring Plan:

UTMB Procedure for Developing a Data Safety Monitoring Plan
Adverse Event Reporting on Patient Safety at UTMB
Adverse Event Reporting of Events with Human Subjects at UTMB
UTMB Data & Safety Monitoring Planning Computer-Based Course
HHS OHRP: Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events
NIH Guidelines for Adverse Event Reporting
NIH Guidelines for Data and Safety Monitoring
Further NIH Guidance on Data and Safety Monitoring for Phase I and Phase II Trials
National Center for Complementary and Alternative Medicine
National Cancer Institute
National Cancer Institute Guidance for Conducting Clinical Trials
National Heart, Lung and Blood Institute
National Institute on Aging
National Institute on Aging – Sample DSMP
National Institute of Allergy and Infectious Diseases
National Institute for Arthritis and Musculoskeletal and Skin Diseases
National Institute of Child Health and Human Development
National Institute on Drug Abuse
National Institute of Dental and Craniofacial Research
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke