Guidelines for Establishing and Operating a Data and Safety Monitoring Board

Introduction

This document has been created to assist grantees in establishing and operating a Data and Safety Monitoring Board (DSMB) for clinical trials sponsored by the National Institute on Drug Abuse (NIDA). Monitoring by a DSMB is required by NIH for some trials or may be implemented by a grantee whenever he/she feels it is appropriate. Investigators may however use alternative approaches to operate their DSMBs, as long as they are in compliance with the current NIH requirements on this topic. DSMBs are playing an increasingly important role in the process of ensuring the highest standards for research participants medical safety and data quality of clinical trials. Clinical investigator grantees, IRBs, NIH, as well as regulators, industry, and sponsors are all affected by the emerging role of DSMBs.

The purpose of the DSMB is to assure that the safety of study subjects is protected while the scientific goals of the study are being met. Specifically, the DSMB is charged with monitoring the safety of participants and the quality of the data, as well as the appropriate termination of studies either when significant benefits or risks have been uncovered or when it appears that the clinical trial cannot be concluded successfully.

NIH requires data and safety monitoring, generally, in the form of DSMBs for phase III clinical trials. For earlier trials (phase I and II), a DSMB may be appropriate if the studies have multiple clinical sites, are blinded (masked), are First-in-Man, or employ particularly high-risk interventions or vulnerable populations. A DSMB might be considered for practical reasons such as for trials with high chance of early termination for safety or efficacy reasons, or to have an independent review group that may help to add validity to the trial.

NIH policy provides each IC with the flexibility to implement the requirement for data and safety monitoring as appropriate for its clinical research activities. More information about those policies can be found at:

Grant applications involving clinical trials that are required to have a DSMB must submit a general description of the DSMB plan as part of the Data and Safety Monitoring Plan (DSMP). The Scientific Review Group reviews the DSMP and includes any comments or concerns in the summary statement for that application. A detailed DSMP including the operations of the DSMB must be submitted to and approved by NIDA before the trial begins. The DSMB should have clear standard operating procedures. The responsibility for compliance with the DSMP rests with the grant recipient. NIDA's guidelines for DSMP can be found at: www.nida.nih.gov/Funding/DSMBSOP.html

These guidelines are in compliance with, and do not take the place of Institutional Review Board (IRB) guidelines, Food and Drug Administration (FDA) regulations, or special NIH policies or guidelines; e.g., NIH Guidelines for Research Involving Recombinant DNA Molecules. Specifically, Phase I and II gene transfer trials must comply with additional requirements imposed by NIH Guidelines, e.g., reporting of adverse events to the Office of Science Policy.

Background

In June of 1998, NIH issued a policy stating that "each Institute or Center (IC) in NIH should have a system for the appropriate oversight and monitoring of the conduct of clinical trials to ensure the safety of participants and the validity and integrity of the data for all NIH-supported or conducted clinical trials." According to this policy, data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III); etc. It includes all types of intervention studies, whether medication or non-medication (e.g., behavioral, prevention, diagnostic) trials and monitoring should be commensurate with the study risks. The role of DSMBs has increased due to the increased number of trials with mortality or severe morbidity as endpoints, the greater need to monitor the quality of the data of clinical trials, and the demand for approaches to the issue of early termination of trials for safety or efficacy reasons. The decision to establish a DSMB rests with the sponsoring Institute or Center and is commensurate with the level of risks, type of clinical trial, and/or the number of treatment sites participating in the study.

The International Conference on Harmonization (ICH) mentions Data Monitoring Committees (DMC) in the guidelines, ICH E3 (Structure and Content of Clinical Study Reports), ICH E6 (Good Clinical Practice), and ICH E9 (Statistical Principles for clinical trials.) They describe appropriate administrative and statistical analysis procedures for trial safety monitoring and analysis of study data required for the DSMB to fulfill its responsibilities. ICH E6 (Good Clinical Practice) guidelines state that the sponsor may consider establishing an independent data-monitoring committee to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify or stop a trial. The committee should have written operating procedures and maintain written records of all its meetings. More information about ICH guidelines can be obtained at: https://www.ich.org/

The FDA has issued a draft guidance for clinical trials sponsors on the establishment and operation of Data Monitoring Committees (DMC). This guidance is available on the web at https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm127073.pdf. The document is intended to assist sponsors of clinical trials evaluating new drugs, biologics or devices in determining the need of a DMC and how it may be operated.

Objectives of the DSMB

  1. To review the initial protocol and assess that it will capture the information necessary to evaluate the safety and efficacy of the study when it is ongoing and completed and to provide recommendations that may improve the protocol. The protocol should include the DSMP, with a plan for the DSMB describing the DSMB's composition, operating procedures, frequency of ongoing DSMB monitoring based on anticipated recruitment and/or identified safety concerns, and the specific content of reports to the DSMB. The Board may request that an adverse event be considered serious for the purpose of monitoring any given study when it believes that doing so is required to protect the safety of study subjects. Appendix 1 provides an outline of the areas to be evaluated by the DSMB in the initial protocol review.
  2. To monitor the ongoing protocol to evaluate:
    1. The safety of the subjects as pre-specified in the DSMP of the protocol and independently make recommendations to researchers to continue, to amend or to terminate a clinical trial based on the interim analysis of the safety data (e.g., terminate a clinical trial because of high incidence of an SAE).
    2. The efficacy of the treatments being tested as pre-specified in the interim monitoring plan of the protocol and independently make recommendations to researchers to continue, to amend or to terminate a clinical trial based on the interim analysis for efficacy (e.g., terminate a clinical trial because the analyses indicate the study is having a negative effect, the intervention is not adequately implemented or there is no evidence of a treatment effect after the prescribed level of power is reached).
    3. The presence of early unanticipated therapeutic results, side effects or adverse consequences and independently make recommendations to continue, to amend or to terminate a clinical trial based on the interim analysis for efficacy (e.g., terminate a clinical trial because it would be unethical to continue the non-treatment/ treatment as usual arm).
    4. The performance of the trial (e.g., protocol violations, improper entry criteria, slow accrual rate, low participation rate, failure of randomization, inadequate treatment adherence, inadequate follow-up rate, severely compromised validity) and to independently make recommendations for improvement or termination if the trial would be unable to prove anything meaningful, regardless of modifications.

Scope of Data Monitoring

The precise nature of the data to be monitored and the analyses used should depend on the design of a study and the issues of concern to the DSMB. The primary source of the data should be the Case Report Form developed for each protocol. Data regarding serious adverse events should be supplemented with any additional detailed information obtained from study investigators (Appendix 2).

Study admission data

Monitoring of admission data should include the number of subjects requesting participation in the study, number of subjects screened and number of subjects admitted to the study. Depending on the trial, the DSMB may request a report of the reason why subjects were disqualified from participating in the study. For subjects admitted to the study, the DSMB reviews eligibility criteria for admitted subject, any protocol deviations and/or violations, and the demographic distribution of the subjects by group.

Protocol Compliance

The DSMB should monitor the data to assess compliance with the protocol including adherence to protocol participation rules for safety or administrative reasons. Examples of participation rules might include, for example, stopping participation or withholding treatment for elevations of liver function tests, severe neuropsychiatric disturbances or changes in vital signs. The DSMB should also monitor the quality and completeness of the data being collected. For data collected at specified times the Board should monitor the frequency of missing or erroneous data, and presence and frequency of outliers.

Safety Data

Monitoring of safety data should include review of AEs and SAEs, and data commonly accepted to reflect differences in safety between treatment groups such as clinical laboratory data, treatment retention, and reason for drop out. Safety information for all studies should be reported to the Board in an unblinded manner. Formal statistical analyses of the safety data may be requested by the Board.

For non-serious AEs, data should be summarized by treatment groups with data on individual subjects available for DSMB review as needed. For SAEs, data should include all the adverse event data meeting the FDA definition of serious adverse events. In the assessment of SAEs, the DSMB should review each individual case including treatment group assignment.

After each meeting of the DSMB, the executive secretary should forward a summary report of all serious and unexpected adverse experiences to each investigator. The report should document a review of data and outcomes across all sites took place on a given date. It should summarize the Board's review of cumulative serious and unexpected adverse events reported from all participating sites without specific disclosure by treatment arm. Furthermore, the report should inform investigators of the Board's recommendations with respect to progress or need for modification of the protocol. The principal investigator from each research center involved in the trial is required to transmit the report to the local IRB.

The DSMB should follow up on the outcome of AEs and SAEs, and that all appropriate AEs and/or SAEs are reported to the IRB, FDA, NIH or other pertinent regulatory agency.

Efficacy Data

Efficacy data determined by the protocol is based on the primary and secondary outcome variables. DSMB monitoring of study efficacy data will depend on the type of study being monitored (e.g., sample size, length of treatment, nature of treatment, and the nature of the primary outcome variable), the nature of the blinding employed in the study and the existence of a plan for interim analysis in the DSMP that has been reviewed and accepted by the DSMB.

The data may be presented for all treatment groups combined or by treatment groups. Data by treatment groups can be presented to the DSMB in blinded fashion and then the DSMB may request to unblind the data (if necessary). In the event that a safety concern arises that requires an interim analysis of efficacy data, an analysis may be made on a for-cause basis. Any for-cause interim analysis requested by the DSMB should specify in advance the efficacy outcome of interest, the number of comparisons to be made for purposes of the analysis, the statistical method to be employed in the analysis, the significance required to reach a decision, and the new p value necessary to reject the null hypothesis should the study run to completion (such that the probability of a Type 1 error is maintained at <0.05 for all primary analyses that would be conducted).

For studies that are conducted in a blinded manner, the presentation of data relating specifically to outcome measures should be presented to the DSMB in the manner and timing described in the DSMP for that study. Studies that include interim analysis of efficacy data should provide the proposed number of interim analyses to be made, the specific comparisons to be made at each such analysis, the stopping rules on the basis of efficacy findings, including both standards for the determination of 'overwhelming efficacy' and an 'inevitable failed trial', and the methods of statistical correction to be used to control the final overall Type 1 error. When defining this interim review in the protocol, consideration should be given to whether the data can be prepared for the DSMB review in a sufficiently timely manner so that any resulting decision can in fact impact on the study Ð if the study is largely completed before the conclusions are made, the interim review maybe unnecessary.

Establising a DSMB

Board membership

The DSMB is generally appointed by the sponsor or by the Principal Investigator (in the case of NIH grants). The number of DSMB members and composition of the Board depends on the type and of complexity of the trials to be conducted. Members should be of multidisciplinary background. Areas of expertise desirable for DSMB members might include clinical medicine (appropriate specialty), biostatistics, bioethics, pharmacology (if applicable), clinical trials methods, and sometimes a patient advocate or a community representative. Board members should have no financial and/or scientific ties to the outcome of the clinical trial to avoid any real or perceived conflict of interest.

The Chairperson of the DSMB should have previous experience in monitoring clinical trials. That person should be a good facilitator, communicator and consensus builder. The Board may include one ex officio member with no voting privileges who functions as the Board's executive secretary. The ex officio member should attend all Board meetings including the open, closed and executive sessions. Due to the nature of the ex officio's responsibilities, this should be the only individual outside the Board membership who is privy to the interim analysis data.

Since Board members must have no financial interest related to the outcomes of any studies reviewed by the Board, some type of financial disclosure documentation is necessary. This disclosure information is necessary to avoid real or apparent conflict of interest of the DSMB. Individuals invited to serve on the DSMB should disclose in writing to the sponsor any potential conflicts of interest, actual or implied by appearance. At the start of each new member's term, the individual should sign a confidentiality statement promising not to disclose any proprietary and nonproprietary data. Furthermore, no disclosure should be made of the deliberations of the Board.

Board meeting schedule

The frequency of DSMB meetings depends on the nature and risk of the studies to be monitored. The meeting can be face-to-face or over teleconference call. The Board should have the option of expedited meetings to review unexpected SAEs or other urgent issues that may arise during the curse of the trials. Unscheduled meetings may be recommended and initiated by the Chair of the DSMB or the sponsor (or the principal investigator) of the study. The data to be reviewed by the DSMB should be available to the Board members at least two weeks before the meeting.

Conduct of the Meetings

DSMB meetings are generally divided into three sessions: open, closed and executive. The Principal Investigator, co-investigators, and statisticians may attend the open session and present during the meeting. The purpose of the open session is to provide relevant information to the Board about general aspects of the trial. The open session may focus on the background of the study, the protocol, status of the study, problems with accrual and follow-up, baseline demographic data, compliance issues, frequency of adverse events, documentation of endpoints, data quality issues, flow of forms, data based protocol modification issues, external monitoring of coordinating center operations in multicenter trials, and any other issue regarding the studies under review that can be discussed without reference to interim comparative results.

Following the open session, a closed session should be held. During the closed session, the chairperson conducts the review of all issues and puts each issue to a vote. This session is usually attended by the DSMB members, the DSMB executive secretary, and if necessary the statistician, principal investigator or the sponsor. During the closed session, the discussions should focus on the treatment safety, efficacy data, whether the primary study question has been answered, the interim results by treatment arm (usually masked), determining when study data may be released and reviewing requests for access to the results of the interim analysis, and updating the Board on actions taken related to their actions and recommendations of the previous meeting.

Following the closed session, an executive meeting may be held. The executive meeting is restricted to DSMB members. During these sessions, the Board may discuss any unmasked analysis of a blind clinical trial and any sensitive issues surrounding the clinical trials under review.

Report Format

Recommendations related to clinical trials should be made in writing by the Board's Chairperson to the principal investigator and/or the sponsor of the trial. Normally, results of the interim analysis should not be disseminated. Only under certain conditions should the results be released. The Board should make the final decision related to the release of this information.

The Board Chairperson should prepare the draft report of the meeting, with the assistance of the Executive Secretary. The Executive Secretary should be responsible for the preparation of meeting minutes for inclusion in the DSMB report. The report should outline and summarize all discussions during the open and closed sessions of the meeting. Recommendations and action items should be clearly marked within the body of the report. If the DSMB decides to conduct an executive session, a statement should be included in the Minutes of the Meeting stating an executive session was conducted, but should not disclose the contents of the discussions. The draft report shall be reviewed and edited by all Board members prior to issuance of the final report. The final report must be forwarded to NIDA, IRB, and FDA as applicable.

For questions or comments please contact:

Ivan D. Montoya, M.D., M.P.H.
Deputy Director, Division of Therapeutics and Medical Consequences
6001 Executive Blvd.
Bethesda, MD 20892-9551
Phone: (301) 827-5936
Fax: (301) 443-2599
e-mail: imontoya@mail.nih.gov

Appendices

  1. Initial Protocol Review
  2. Ongoing Protocol Review