Introduction
This guidance is intended to assist the National Institute on Alcohol Abuse and Alcoholism (NIAAA)-supported extramural researchers in establishing and operating a Data and Safety Monitoring Board (DSMB) for clinical trials[1] funded by NIAAA.
 
The purpose of the DSMB is to provide oversight and monitoring of the conduct of clinical trials to ensure the safety of participants and the validity and integrity of study data. The National Institutes of Health (NIH) strongly recommends data and safety monitoring in the form of a DSMB for all Phase III clinical trials.  For Phase I and Phase II clinical trials, a DSMB may be established if the principal investigator, their institution, or the clinical trial sponsor deems it necessary. For example, a Phase I or II clinical trial that has multiple clinical sites, is blinded (masked), is studying a particularly high-risk intervention(s), is involving a vulnerable population(s), or has a high probability of early termination for safety or efficacy, should consider establishing a DSMB.
 
Responsibilities of the Data and Safety Monitoring Board
 
The DSMB is responsible for reviewing study documentation (e.g., study protocol, the informed consent and other participant handouts, etc.) and ensuring that it has adequate information to assess the safety of the study participants and the efficacy of the intervention during both the treatment and follow-up periods.  A comprehensive description of the data and safety monitoring plan, including details about the DSMB composition, safety and operating procedures, frequency of DSMB monitoring (based on anticipated recruitment and/or identified safety concerns), and reporting requirements, should be outlined in the study protocol.  The DSMB must ensure that the data and safety monitoring plan is sufficient given the complexity of the study and patient population(s).
 
The DSMB shall evaluate participant safety data throughout the duration of the trial; evaluate the efficacy of the study intervention(s) at intervals specified in the DSMB charter (described below); and independently provide recommendations to the study sponsor to either continue, amend or terminate a clinical trial based on this information. The presence of early unanticipated therapeutic results, side effects, or adverse events are all reasons that a DSMB might recommend termination of a clinical trial early due to safety or efficacy matters.
 
In addition, the DSMB is responsible for monitoring the performance of each clinical site (e.g., protocol violations, improper participant enrollment criteria, slow accrual rate, low participation rate, failure of randomization, inadequate treatment adherence, inadequate follow-up rate, severely compromised validity).  The DSMB should independently make recommendations for improving the performance of the clinical trial or terminating the trial if it determines the study would be unable to provide useful data, regardless of modifications. A summary of each board meeting and the board recommendation(s) must be provided to the clinical trial sponsor for distribution to each participating clinical site.
 
Establishing a Data and Safety Monitoring Board
 
Board Membership
 
DSMBs are either appointed by NIAAA and act as an independent advisory group to the NIAAA Director, or are appointed locally for investigator-initiated studies[2].
 
In general, the DSMB voting members are appointed by the clinical trial sponsor or by the Principal Investigator. A DMSB may have as few as three voting members; however, the number of members and the specific composition of the Board will depend on the type and complexity of the clinical trial.  The DSMB composition should be multidisciplinary, including but not limited to clinical medicine (appropriate specialty), biostatistics, bioethics, pharmacology (if applicable), clinical trial methodologies, and other disciplines relevant to the study. For logistical reasons, the clinical trial sponsor or principal investigator may strive to have the fewest number of DSMB members possible while maintaining representation of all needed expertise. The DSMB may also include a patient advocate or a community representative who would bring the perspectives of the population under study but not be enrolled in the study.
 
DSMB members shall have no real or perceived conflicts of interest with the clinical trial, including any financial and/or scientific ties to the outcome of the study.  Individuals who are invited to serve on the DSMB should disclose in writing to the clinical trial sponsor or principal investigator any potential conflicts of interest, actual and perceived, and provide documentation of financial disclosures.  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 or deliberations of the DSMB.
 
The Chairperson of the DSMB should be selected among the voting members and have previous experience in monitoring clinical trials.  The Chairperson should be a good facilitator, communicator, and consensus builder.
 
An Executive Secretary may be designated to facilitate effective functioning of the DSMB. For locally-appointed boards, the DSMB Chairperson may designate the Executive Secretary, and in the case of NIAAA-appointed DSMBs, the Executive Secretary is either a NIAAA employee or a contractor with clinical trial expertise. The Executive Secretary may not vote or be present during closed or executive sessions of the DSMB, and must maintain all information reviewed, discussed and recorded during DSMB meetings with strict confidentiality.
 
Non-voting, non-member ex officio attendees may participate in DSMB meetings to provide information and answer questions as needed, e.g. research staff involved with the study.  Ex officio attendees must be limited in number and are not permitted to attend the closed or executive sessions of DSMB meetings. 
 
 
Data and Safety Monitoring Board Charter
 
NIAAA recommends that DSMBs establish and operate under a written charter that includes well-defined standard operating procedures. The clinical trial sponsor or principal investigator may draft this charter and present it to the DSMB for agreement, or the DSMB may draft the charter with subsequent concurrence by the clinical trial sponsor or principal investigator.  The charter should at a minimum specify: the meeting schedule and format, the format for presentation of data, the individuals who may attend all or part of the DSMB meetings, the individuals who will have access to interim data, the method and timing for providing interim reports to the DSMB, procedures for assessing conflict of interest of potential DSMB members, and other issues relevant to committee operations.
 
 
Data and Safety Monitoring Board Meeting Schedule
 
The frequency and format of DSMB meetings depends on the nature and risk of the studies to be monitored. Meetings may be face-to-face or by teleconference. The Board shall have the option for expedited meetings to review unexpected Serious Adverse Events[3] or other urgent issues that may arise during the course of the trial. Unscheduled meetings may be recommended and initiated by the DSMB Chairperson, the clinical trial sponsor, or the principal investigator.  Clinical trial documentation and data should be available to the Board members at least two weeks prior to the meeting.
 
 
Conduct of the Meetings
 
DSMB meetings are generally divided into three sessions: open, closed and executive.
 
  • Open Session
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[4], 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 study-related issues that can be discussed without reference to interim comparative results. The principal investigator, co-investigators, and statisticians may attend the open session and present information during the meeting.
 
For NIAAA-appointed boards, the number of coordinating center and NIAAA representatives in attendance should be limited as not to overwhelm free and open exchange among board members.
 
For locally-appointed DSMBs, NIAAA staff may participate as ex officio attendees unless the board chair decides that the presence of NIAAA staff may inhibit free and open discussion, or compromise the Board’s independence. The issue should be addressed in the DSMB charter. The NIAAA program official involved with the study should be informed of upcoming board meetings at least two weeks in advance, and receive the appropriate meeting materials at the same time as the Board members.
 
  • Closed Session
During the closed session, the DSMB reviews and votes on all issues.  This session is usually attended by the DSMB members only. The principal investigator or clinical trial sponsor may attend the closed session at the request of the DSMB. During the closed session, the discussions should focus on: treatment safety, efficacy data, whether the primary study question has been answered, the interim results by treatment arm (usually masked), determination of when study data may be released, review of requests for access to the results of the interim analysis, and results of Board actions and recommendations made in the previous meeting.
 
For NIAAA-appointed boards, NIAAA staff members involved in the conduct and oversight of the trial are not permitted to attend the closed session.
 
For locally-appointed boards, NIAAA staff may participate at the discretion of the DSMB Chair.
 
  • Executive Session
It is recommended that the DSMB have the option of conducting an executive session with DSMB members only. During these sessions, the Board may discuss any unmasked analysis of a blinded clinical trial and other sensitive issues related to the clinical trial. 
 
 
Data and Safety Monitoring Board Recommendations and Meeting Records
 
The DSMB should keep a record or minutes of all meetings.  Minutes of open session discussions should be kept separately from the minutes of closed and executive session discussions. The Executive Secretary is responsible for preparing the open session meeting minutes. The Board Chairperson should prepare the meeting minutes from the closed and executive sessions and distribute only to the other Board members.
 
The DSMB shall provide a meeting report to the clinical trial sponsor or principal investigator that includes the Board’s recommendation(s) and sufficient information to explain the rationale for any recommended changes. The report should also include the minutes of the open session. Meeting minutes of the closed or executive session should not be included, but rather a statement that a closed/executive session was held.  The draft report shall be reviewed, edited, and finalized by all Board members, and signed by the Board Chairperson prior to issuance to the clinical trial sponsor or principal investigator.
 
 
Scope of Data Monitoring
 
The precise nature of the data to be monitored and the analyses used by the DSMB will depend on the design of the study and the issues of concern to the Board. The primary source of the data should be case report forms developed for each protocol. Data regarding severe adverse events should be supplemented with additional detailed information from study investigators.  Specific types of data that DSMBs are required to monitor include:
 
  • 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 explaining why potential study participants were disqualified from participation. For individuals enrolled in the study, the DSMB should review their eligibility criteria, any protocol deviations and/or violations, and the demographic distribution of the study population.
 
  • Protocol Compliance
The DSMB must assess compliance with the protocol, including compliance with safety and administrative procedures. Examples of participation rules include discontinuing participation or withholding treatment due to elevations in liver function tests, severe neuropsychiatric disturbances, or changes in vital signs. The DSMB should also monitor the quality and completeness of the study data being collected. For data collected at specified times, the DSMB should monitor the frequency of missing or erroneous data, as well as the presence and frequency of outliers.
 
  • Safety Data
Monitoring of safety data should include review of adverse events, serious adverse events, and any data that allows for comparisons of safety among treatment (active and control) groups, e.g. clinical laboratory data, treatment retention, and reasons for subject drop out.  Safety information for all studies should be reported to the Board in an un-masked manner.  Formal statistical analyses of the safety data may be requested by the Board.
 
For adverse events, data should be summarized by treatment groups, with individual subject data being available for DSMB review as needed.  Serious adverse events should include all patient outcomes that meet the FDA definition of a serious adverse events. In the assessment of serious adverse events, the DSMB should review each individual case, including treatment group assignment.
 
  • Efficacy Data
Efficacy data as determined by the protocol is based on the primary and secondary outcome variables. DSMB monitoring of efficacy data will depend on: 1) study design (e.g., sample size, length of treatment, nature of treatment, and the nature of the primary outcome variable); 2) the nature of the blinding employed in the study; and 3) procedures for interim analyses in the data and safety monitoring plan.
 
In the event that a safety concern 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 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 I error is maintained at <0.05 for all primary analyses that would be conducted).
 
  • Unblinded Clinical Trial Data
All DSMBs of NIAAA-funded clinical trials can request to review unblinded clinical trial data. The data may be presented for all treatment groups, either combined, by treatment group, or at the participant level.  The presentation of data relating to outcome measures should be presented to the DSMB in the manner and per the timing described in the data and safety monitoring plan for that study.  Clinical trials that include interim analyses of efficacy data should provide the proposed number of analyses to be made, the specific comparisons to be made at each analysis, the termination 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 I error. This interim review should be addressed in the study protocol, including steps for facilitating preparation of the data and review by the DSMB in a timely manner so that any resulting DSMB decision can impact the study.   
 
For questions or comments about these guidelines, please contact:
 
Megan Ryan, M.B.A., C.C.R.P.
Clinical Program Director
SBIR/STTR Program Coordinator
Division of Medications Development
National Institute on Alcohol Abuse and Alcoholism
5635 Fishers Lane, MSC 9304
Bethesda, MD 20892-9304
Tel: (301) 443-4225
 
Updated: 1.13.2017

 

NOTES

[1] NIH Clinical Trial Definition - A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. See more at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html

[2] Site IRBs are responsible for ensuring adequate and appropriate operation of locally (site)-appointed DSMBs.

[3] Serious Adverse Events include adverse events that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. Other important medical events, based upon appropriate medical judgment, may also be considered Serious Adverse Events if a trial participant's health is at risk and intervention is required to prevent an outcome mentioned.

[4] Unfavorable changes in health, including abnormal laboratory findings, that occur in trial participants during the clinical trial or within a specified period following the trial.  Two types of adverse event data are to be reported: "Serious" and "Other (Not Including Serious)" adverse events.