NIDCD Guidelines for Data and Safety Monitoring of Clinical Trials

• Policy
• Introduction
• Responsibility for Data and Safety Monitoring
• Data and Safety Monitoring Boards
  • Responsibilities of the DSMB
  • Responsibilities of the Study Chair/Coordinating Center, Study Statistician, and the NIDCD Representative to the DSMB
  • DSMB Membership
  • Meetings
  • Recommendations from the DSMB
  • Release of Outcome Data
  • Confidentiality Procedures
  • Conflict of Interest

Policy

The National Institute on Deafness and Other Communication Disorders (NIDCD) uses the following 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 NIDCD-supported clinical studies, including clinical trials.

Introduction

National Institutes of Health (NIH) policy stipulates that a system be in place for appropriate oversight and monitoring to ensure the safety of participants and the validity of data in all NIH-sponsored or NIH-conducted clinical studies. Investigators are required to submit a data and safety monitoring plan (DSMP) for all clinical trials to the funding institute or center (IC) as part of the research application (PHS Human Subjects and Clinical Trials Information Form – section 3.3).

A DSMP establishes the overall framework for data and safety monitoring and details multiple mechanisms for oversight. The mechanism(s) for oversight is to be risk-adjusted for the type and scope of study. In some cases, but certainly not all, an independent Data and Safety Monitoring Board or Committee (DSMB or DSMC) may be indicated. The terms or abbreviations for a Data and Safety Monitoring Plan (DSMP) and Data and Safety Monitoring Board or Committee (DSMB or DSMC) must remain distinct and separate. The DSMP identifies what information will be monitored, the reporting entity, the frequency of reporting, and the individual(s) or groups responsible for the monitoring. The DSMP should include the mechanisms for reporting adverse events to:

• The study team.
• The Institutional Review Board(s) (IRB).
• The Food and Drug Administration (FDA), if applicable.
• NIH program staff.
• The independent monitor or DMSB/DSMC, if applicable.

For each person or group responsible for monitoring, the DSMP should detail the scientific/clinical/clinical trials expertise for each person but should not specify the actual names of proposed members. The DSMP should also specify the central reporting entity (e.g., statistician or statistical center) responsible for preparing and distributing timely adverse events and/or summary reports.

The DSMP should also include the process and timeline by which adverse events, including serious adverse events (SAEs), are managed and reported to ensure that the reporting timelines and requirements of each monitoring entity are met.

Oversight of the monitoring activity will be the joint responsibility of the investigator(s) and the NIDCD program director. The initial review group will review this plan, and any comments and concerns will be included in an administrative note in the summary statement. NIDCD staff will ensure that all concerns are resolved before any award is made. A detailed data and safety monitoring plan must be submitted to the NIDCD program director prior to an award being made. The plan should address how the investigator will implement the data and safety monitoring activities.

Responsibility for Data and Safety Monitoring

NIDCD-supported clinical trial monitoring activities should be commensurate with the risks, size, and complexity of the study. The DSMP may vary in organization and resources from the study team. A DSMP might include, for example:

• Applying a systematic quality assurance and reporting system.
• An independent medical monitor for participant safety and an independent data monitor for data integrity and protocol compliance.
• A multi-member committee—a Data and Safety Monitoring Board or Committee (DSMB or DSMC)—responsible for comprehensive monitoring of the data and safety of the clinical trial.

Ongoing review of the data by an independent individual or DSMB assures the investigator(s) that the study can continue without jeopardizing patient safety and data integrity. These monitoring activities are distinct from the requirement for study review, approval, and oversight by an Institutional Review Board (IRB).

All Phase III clinical trials require monitoring by a DSMB. For earlier trials (such as Phase I and Phase II), a DSMB may be appropriate if the studies have multiple clinical sites, employ particularly high-risk interventions, or involve vulnerable populations. However, other monitoring schemes for earlier clinical trials may be appropriate depending on the risk to participants, the population being studied, and the research environment, etc.

The following provides illustrative examples of appropriate types of monitoring and oversight for different types of trials. These examples are not exhaustive; monitoring activities should be appropriate to the study, population, research environment, and degree of risk involved.

Low-Risk Interventions

The potential of these interventions to cause physical or psychological harm is low. For example:

• Risks that are no greater than those encountered in routine medical care or procedures.
• Clinical trials involving utilization of a licensed product/device for an approved dose, population, and indication that do not require an investigational new drug (IND) or investigational device exemption (IDE).
• Some behavioral interventions that are not distressful, harmful, painful, or invasive to study participants.
• Software devices, including software applications unlikely to cause injury to the operator and study participants.
• Some physical therapy interventions with a low level of exertion and discomfort.

Please note: Even if the risk of the intervention is low, all NIDCD clinical trials should incorporate active routine evaluations and data capture for new adverse events within the protocol’s schedule of evaluations.

Exploratory Studies

Exploratory studies, such as Phase I studies, are usually small, unblinded clinical trials conducted early in the development of an intervention. They are frequently the first administration of the intervention in a study involving humans, e.g., to estimate dosage and safety for a targeted indication. It is acceptable for data and safety to be closely monitored by the investigator and study team for low-risk interventions. For blinded studies, an independent safety or data monitor (a physician or other expert who is independent of the study) is appropriate to monitor safety and/or data integrity.

Confirmatory Studies

Confirmatory studies, such as Phase II studies, are generally larger studies conducted to demonstrate efficacy, establish a safety profile, and/or establish dose-response relationship. For confirmatory clinical trials evaluating the clinical activity of exposure to low-risk intervention(s), data and safety monitoring may be similar to monitoring used in low-risk exploratory studies. However, since these confirmatory studies are often more complex, involve more participants, and are critical to informing decisions for a Phase III or pivotal trial, additional measures for the monitoring of data integrity should be included in the DSMP. The data monitoring should be conducted by an independent, qualified, and experienced person(s)/entity (e.g., contracted clinical research associate, study monitor from the Clinical Coordinating Center, or statistician).

Clinical Use Studies

Clinical use studies, such as Phase III clinical trials, are large pivotal studies intended to provide formal statistical demonstration of efficacy and to monitor adverse events. These studies can directly impact health policy/standard of care and/or FDA approval for marketing; therefore, the data and safety monitoring should be conducted by a DSMB.

Higher-Risk Interventions

Exploratory Studies

A typical exploratory clinical trial evaluating the safety of a new agent, device, or procedure (such as a Phase I study) involves relatively high risk to a small number of participants. The investigator and occasionally others may have the only relevant knowledge regarding the treatment because these are the first human uses. As an example of the type of oversight appropriate for this sort of study, the investigator might perform continuous monitoring of participant safety, with frequent reporting to an independent safety officer/DSMB and to NIDCD staff with oversight responsibility for the study. The investigator and the NIDCD should appoint the independent safety officer/DSMB and agree on the frequency and contents of the monitoring report. A DSMB is often used for studies with high-risk interventions or in vulnerable populations (e.g., neonates, children, pregnant women, people with intellectual disabilities, or incarcerated people). The implementation of this approach should be part of the monitoring plan.

Confirmatory Studies 

A confirmatory clinical trial evaluating the clinical activity of exposure (such as a Phase II trial) typically follows early exploratory studies and provides more information regarding risks, benefits, and monitoring procedures. Since these studies are often blinded, involve more participants, and are critical to informing decisions for Phase III or pivotal trials, a DSMB is more commonly used.

Clinical Use Studies 

The NIH requires data and safety monitoring in the form of DSMBs for multi-site clinical trials involving interventions that entail potential risks to participants, and generally for Phase III clinical trials. Clinical use studies, such as Phase III clinical trials, are large pivotal studies intended to provide formal statistical demonstration of efficacy and to monitor adverse events. These studies can directly impact health policy/standard of care and/or FDA approval for marketing. These large clinical trials compare a new intervention or procedure to a standard intervention or procedure or to no intervention. Treatment allocations are randomly assigned, and the data are usually masked. Such studies involve several clinical sites and usually involve a large number of participants followed for longer periods of treatment exposure. In a Phase III study, the investigators must consider the long-term effects of a study agent or procedure for safety and/or efficacy differences between the control and experimental intervention groups. The implementation of this approach should be part of the monitoring plan for clinical use studies. The organization, responsibilities, and operation of the DSMB are described below.

For studies co-funded with other institutes or centers (ICs), the lead IC will be responsible for monitoring the study and approving a DSMB if necessary. Oversight of the DSMB will be the collaborative responsibility of the lead IC and the NIDCD.

Data and Safety Monitoring Boards

The Data and Safety Monitoring Board (DSMB) serves as an advisory body to both the study investigators and the NIDCD. The DSMB is responsible for oversight of the activities related to the conduct of the clinical trial to ensure patient safety; conformance to the clinical protocol; overall performance of the study components, such as the study chair office, coordinating center, and clinical sites; and integrity of the data being collected.

Each clinical trial supported by the NIDCD has gone through the NIH peer review process plus secondary review by its national advisory board; therefore, it is not the role of the DSMB to serve as a peer review group to redesign any portion of the study, unless the DSMB feels that patient safety or data validity is compromised under the proposed design. In this case, the DSMB should communicate its concerns to the NIDCD and to the study investigators prior to the start of participant recruitment.

Responsibilities of the DSMB

• Review the research protocol(s) and plans for data and safety monitoring. The DSMB, in collaboration with the study leadership, should establish specific guidelines for safety monitoring. This should include a listing of events that should be reported immediately to the DSMB and the format of reporting cumulative data at intervals.
• Review interim analyses of outcome data and cumulative toxicity data for safety and efficacy to determine whether the study should continue as originally designed, be changed, or be terminated. The DSMB reviews clinical study performance information such as participant recruitment and retention, clinical center and resource center performance, and proposals for ancillary studies. It provides advice to the investigators and the NIDCD on these topics. The DSMB also recommends whether and to whom outcome results should be released prior to the reporting of study results.
• Review the primary study abstract(s) and manuscript(s) to determine if the results are fairly presented and the conclusions appropriate.
• Review published reports of related studies submitted to the DSMB by the NIDCD, the study leadership/investigators, or DSMB members to determine whether the monitored study needs to be changed or terminated.
• Review major proposed modifications (e.g., increasing target sample size, dropping an arm based on other study outcomes or toxicity results, modifying outcomes).
• As soon as possible but within 10 business days following each DSMB meeting, provide the study leadership and the NIDCD with a written report summarizing the DSMB’s observations and, where appropriate, recommendations concerning the impact on the study of individually observed or cumulative adverse events. The recommendations should include the decision to continue, change, or terminate the study as well as justification for the decision. 
• Confidential data should not be included in the DSMB recommendation report. The study leadership will provide the DSMB report to each clinical center director to be shared with their IRBs.

Responsibilities of the Study Chair/Coordinating Center, Study Statistician, and the NIDCD Representative to the DSMB

The study chair and/or coordinating center are responsible for providing overall management of the DSMB. Tasks include but are not limited to the following:

• Handle all logistics related to each meeting or conference call, such as booking a group of rooms at a local hotel, providing information to the DSMB, and providing timely reimbursement to each member following each meeting.
• Work with the DSMB to determine what information should be made available for review at each meeting to assist the DSMB in carrying out its primary charge related to participant protection oversight, study operation, and data integrity. Different information or tables may be required from meeting to meeting.

The study statistician must:

• Prepare and provide to the DSMB membership, at least 14 days prior to each meeting, the open and closed reports on the current status of the study, interim analyses, adverse events, and problems encountered. The open report should also be provided to the study chair, designated members of the study team, and NIDCD representative(s) at this time.

The NIDCD representative to the DSMB must: 

• Ensure adequate and direct communication between the study leadership and the DSMB; provide general advice to the study leadership and DSMB related to operational issues; keep the NIDCD leadership apprised of the status of the study; and review the recommendations presented by the DSMB so that informed decisions related to acceptance of recommendations and their potential impact can be assessed.

DSMB Membership

The names of prospective DSMB members should not be included in the clinical trial grant application. The NIDCD representative to the DSMB or designee will appoint the DSMB voting members, including the DSMB chair, based on recommendations from the study leadership and NIDCD program staff. The DSMB shall consist of voting members with expertise necessary to interpret data from the trial including biostatistics, clinical trial methodology, ethics, specialty areas of medicine, and laboratory sciences as appropriate. Selection will be based on experience, knowledge of clinical study methodology, participation on other DSMBs, and absence of apparent conflicts of interest, including financial, proprietary, or intellectual conflicts. In some instances, NIDCD program staff may serve as non-voting ex officio members, affirming objectivity about the outcome(s) of the trial but not attempting to influence the recommendations of the DSMB.

Voting members of the DSMB should be independent of the trial being monitored.

The voting members of the DSMB will be reimbursed for expenses related to serving on the board through funds provided by the NIDCD to either the study chair's cooperative agreement or the coordinating center's cooperative agreement. These funds will be used to reimburse each member for travel expenses (coach fare only), hotel costs, and per diem at the U.S. government rate for the city where the meeting is held, and a daily participation fee at the rate allowed by the U.S. government for each day in attendance at the meeting.

Meetings

The frequency of DSMB meetings will depend on the nature of the study. A DSMB should meet at least annually. Meetings are generally divided into four parts:

• An open session at which members of the clinical study team, representatives from the NIDCD, and others may be present, at the request of the DSMB, to review the conduct of the study and to answer questions from DSMB members. The focus in the open session should be on accrual, study conduct, and general toxicity issues. Unblinded data and outcome results by treatment group should not be discussed during this session. The NIDCD representative will provide administrative guidance as needed to ensure stewardship and adherence to NIH policies.
• A second, closed session involving the voting and appropriate non-voting DSMB members should be held. Outcome results and toxicity information, if any, will be presented by the study statistician to the DSMB by treatment group.
• The third part of the meeting may be an executive session (involving only voting DSMB members) to allow discussion of the general conduct of the study and all outcome results, including toxicities and adverse events; develop recommendations; and take votes as necessary. At the request of the DSMB, some non-voting members may attend all or portions of the executive session to respond to questions or to clarify issues. Votes may be done by voice/show of hands or by ballot. A majority vote is required to carry any recommendation.
• In the final wrap-up session, the DSMB chair, with input from other DSMB members, presents and discusses with the NIDCD representative and study leadership the committee's recommendations, along with the rationale/justification for each.

Interim meetings and/or conference calls may be held at the request of DSMB members, the study leadership, or the NIDCD. The DSMB has the right to request and review unmasked data by treatment group or by individual subject at any time if the DSMB feels these data are necessary to evaluate safety or other aspects of the trial. If the NIDCD or the study leadership requests that the DSMB vote on issues using a ballot, the ballots will be returned to the NIDCD representative managing the trial. Only the aggregate vote on each issue will be reported to the study leadership and the NIDCD representative by the DSMB. A majority vote is required to carry any issue.

Please note that these meeting guidelines may be modified in the future. The NIDCD encourages investigators to check this site periodically for any future changes in these guidelines.

Recommendations from the DSMB

DSMB recommendations should be based on results from the trials being monitored as well as on published data from other studies. It is the responsibility of the coordinating center, study chair, study investigators, NIDCD staff, and individual DSMB members to ensure that the DSMB is kept apprised of non-confidential outcome results from other related studies as they become available. NIDCD staff will keep the DSMB apprised of any programmatic concerns related to the study being monitored.

DSMB recommendations are given to the NIDCD to provide oversight and guide the study investigators. DSMB recommendations will be provided to the study leadership and to the NIDCD as soon as possible but no more than 10 business days following the DSMB meeting. No action on the recommendations is to be taken by the study leadership until the recommendations have been reviewed and accepted by the NIDCD. The NIDCD representative to the DSMB will notify the study leadership and the DSMB of the NIDCD's decision(s) on the recommendations.

DSMB recommendations that a study change for patient safety or efficacy reasons, or that a study be closed early due to slow accrual or other reasons should be communicated to the study leadership and the NIDCD immediately following the DSMB meeting. Final determination regarding unscheduled closure of a study will be made by the NIDCD director in consultation with NIDCD staff.

It is the responsibility of the study chair and coordinating center, in collaboration with the NIDCD, to review the recommendation(s) and to implement the change(s) as expeditiously as possible. If the study leadership and/or the NIDCD does not concur with the DSMB's recommendation, it will be the responsibility of the NIDCD representative to the DSMB (or designee), study leadership, and the DSMB chair to reach a mutually acceptable decision about the study. If such an agreement cannot be reached, final authority will rest with the NIDCD. Confidentiality must be maintained during these discussions.

If a recommendation is made to change a protocol for reasons other than patient safety or efficacy or for slow accrual, the DSMB will provide an adequate rationale for its decision. In the absence of disagreement, the coordinating center will be responsible for amending the protocol and notifying the clinical centers as expeditiously as possible. It is the responsibility of the local clinical center directors to notify their local IRBs of any protocol changes.

Release of Outcome Data

Confidential outcome data should not be made available to individuals outside of the DSMB. Any release of outcome data to individuals outside of the DSMB must be reviewed and approved by the DSMB, the NIDCD, and the study leadership.

Confidentiality Procedures

No communication, either written or oral, of the deliberations or recommendations of the DSMB will be made outside of the DSMB except as provided for in these guidelines. Outcome results are strictly confidential and must not be divulged to any non-member of the DSMB. Each member of the DSMB, including non-voting members, must sign a statement of confidentiality.

Conflict of Interest

Every individual invited to serve on the DSMB as a voting or non-voting member will disclose any potential conflicts of interest, whether real or perceived, to the NIDCD Clinical Trial Program Director or designee on an annual basis. The study chair or coordinating center will provide each member with a form (PDF) to be completed and returned to the NIDCD Clinical Trial Program Director. Conflict of interest can include financial interest, professional interest (in the sense of the trial outcome benefiting the individual professionally), proprietary interest, and miscellaneous interest as described in the NIH Grants Policy and 45 CFR Part 94. The NIDCD and the study leadership will make collaborative decisions regarding service by individuals with potential conflicts of interest or the appearance of conflicts of interest.