National Eye Institute Guidelines for Data and Safety Monitoring of Clinical Trials
National Eye Institute
The National Eye Institute (NEI) has established the following guidelines 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 from all NEI-supported or -conducted clinical trials (http://grants.nih.gov/grants/guide/notice-files/not98-084.html(link is external)) and (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html(link is external)).
A detailed data and safety monitoring plan for all clinical trials must be submitted as part of the application. This plan should address how the investigator will implement the data and safety monitoring activities. The monitoring plan must include a general description of the mechanisms for reporting adverse events to the Institutional Review Board(s) (IRB), the Food and Drug Administration (FDA), and the National Institutes of Health (NIH). Oversight of the monitoring activity will be the joint responsibility of the investigator and the NEI program director. Additional program-specific instructions related to safety monitoring may be found in applicable Funding Opportunity Announcements (FOAs).The Scientific Review Group will review the data and safety monitoring plan and additional FOA-specific information provided any comments and concerns will be included in an administrative note in the summary statement (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html(link is external)). NEI staff will ensure that all concerns are resolved before any award is made.
Responsibility for Data and Safety Monitoring
The following material provides illustrative examples of appropriate types of monitoring and oversight for different types of studies. NEI-supported or -conducted clinical trial monitoring activities should be commensurate with the nature, size, and complexity of the trial. The data and safety monitoring plan may range from the appointment of a Medical Monitor to the organization of a formal Data and Safety Monitoring Committee (DSMC). Ongoing review of the data by an independent individual or DSMC assures the investigator(s) that the trial can continue without jeopardizing patient safety. These monitoring activities are distinct from the requirement for study review and approval by an IRB.
All studies of gene transfer or studies involving vulnerable study populations will have a data safety and toxicity review group to conduct timely reviews of all unexpected, serious adverse events. This requirement does not take the place of IRB, United States Food and Drug Administration (FDA), or NIH requirements for timely review and reporting of serious adverse events.
For studies co-funded with other Institutes or Centers (ICs), the lead IC will be responsible for monitoring the study and establishing a DSMC, if necessary. Oversight of the DSMC will be the collaborative responsibility of the lead IC and the NEI.
A typical Phase I trial of a new agent frequently involves relatively high risk to a small number of participants. The Principal Investigator (PI) and occasionally others may have the only relevant knowledge regarding the treatment because Phase I involves the first use in humans. A study investigator may perform continuous monitoring of participant safety with frequent reports to a Medical Monitor and the NEI. The PI and the NEI will jointly appoint the Medical Monitor and agree on the frequency and contents of the monitoring reports. The implementation of this approach should be part of the monitoring plan.
A typical Phase II trial follows Phase I studies and provides more information regarding risks, benefits, and monitoring procedures. Phase II trials involve more participants and the toxicity and outcomes may be confounded by the disease process. Monitoring may be similar to that of a Phase I trial, or it may be necessary either to appoint individuals with expertise relevant to the study who might assist in interpreting the data to ensure patient safety or to appoint a DSMC. Phase II therapeutic trials should be monitored by a DSMC. The implementation of this approach should be part of the monitoring plan.
A Phase III clinical trial typically compares a new treatment to a standard treatment or to no treatment in order to determine the safety and efficacy of the treatment. Treatment allocations may be randomly assigned. Such trials usually involve a large number of participants followed for longer periods of treatment exposure to monitor adverse events and to collect information that will allow the treatments to be used safely. All Phase III clinical trials require monitoring by a DSMC (http://www.nih.gov/grants/guide/notice-files/not98-084.html(link is external)). The implementation of this approach should be part of the monitoring plan. The organization, responsibilities, and operation of the DSMC are described below.
DATA AND SAFETY MONITORING COMMITTEES
Responsibilities of the DSMC
- Reviews and approves the research protocol(s) and plans for data and safety monitoring. The DSMC, in collaboration with the study leadership, should establish specific guidelines for monitoring for safety. This should include a listing of events that should be reported immediately to the DSMC and the format for reporting cumulative data at intervals.
- Reviews interim analyses of outcome data and cumulative toxicity data for safety and efficacy to determine whether the trial should continue as originally designed, should be changed, or should be terminated. The DSMC reviews trial performance information such as patient recruitment and retention, clinical center and resource center performance, and evaluates any additional studies proposed for their impact on the conduct and integrity of the parent project. It provides advice to the investigators and the NEI on these topics. The DSMC also recommends whether and to whom outcome results should be released prior to the reporting of study results.
- Reviews and approves the primary trial manuscript(s) with regard to determining that the results are fairly presented and the conclusions appropriate.
- Reviews published reports of related studies submitted by NEI, the study leadership, or DSMC members to determine whether the monitored study needs to be changed or terminated.
- Reviews proposed modifications to the study prior to their implementation (e.g., increasing target sample size, dropping an arm based on other trial outcomes or toxicity results).
- Following each DSMC meeting, provides the study leadership and the NEI with written recommendations related to continuing, changing, or terminating the trial. The study leadership will provide information on relevant recommendations to each clinical center director to be shared with their IRBs.
The NEI Director or designee will appoint DSMC voting members, including the DSMC Chair. DSMC membership will be based on recommendations from the study leadership and NEI program staff. Voting members should include clinicians, statisticians, other scientists, and public representatives. These individuals should be selected for their experience, knowledge of clinical trial methodology, and absence of conflicts of interest. Voting members of the DSMC should be independent of the trial(s) to be monitored. In exceptional circumstances, a voting member may be from an institution participating in the trial. In this situation, the member should view his or her role as representing the interests of the patients enrolled in the trial and not those of the institution.
A written report containing at least the current status of the trial, performance and data quality, interim outcome data, and any toxicity data should be sent to DSMC members by the Coordinating Center to allow sufficient time for the DSMC members to review the report prior to the meeting. This report should address any specific concerns about the conduct of the trial. The report may contain recommendations for consideration by the DSMC concerning clinical center performance, whether to continue accrual and/or follow up, whether to close the trial, and whether the results should be reported.
The frequency of DSMC meetings will depend on the nature of the trial. However, a DSMC should meet at least annually. Interim meetings may be held at the request of DSMC members, the study leadership, or the NEI. Each meeting may be divided into three parts: The first is an open session at which members of the clinical trial team, and the NEI program director and/or designee will be present to review detailed data reports on the conduct of the trial and to answer questions from members of the DSMC. The focus in the open session may be on accrual, protocol compliance, and general toxicity issues. Outcome results by treatment group should not be discussed during this session. A second, closed session involving the voting members, NEI study program directors and select representatives from the data coordinating center should be held. The outcome results and toxicity information, if any, will be presented to the DSMC by treatment group. A third, executive session involving voting DSMC members and the NEI program director (as an objective observer) should be held to allow for the opportunity to discuss the general conduct of the trial and all outcome results, including toxicities and adverse events. During the executive session, voting DSMC members will independently develop recommendations and vote as necessary.
As a steward of public funds for clinical research, the NEI program director is responsible for programmatic and administrative oversight of the clinical trial and oversight of clinical research monitoring activities which is distinct from the monitoring itself. The NEI program director attends the executive session to: respond to questions and provide information; apprise the DSMC of any programmatic considerations related to the trial being monitored; ensure that DSMC monitoring conforms to NIH and NEI policy and procedures; follow DSMC deliberations and recommendations; and, report back to Institute leadership to ensure that DSMC recommendations are acted upon. The NEI program director may provide information but in no way direct the deliberations or recommendations of the DSMC. The program director should affirm his/her objectivity about the outcome of the trial. Any concerns related to staff participation at DSMC meetings should be communicated to the NEI Director.
All NIH and NEI DSMCs have the ability to review unmasked clinical trial data. Decisions regarding the format and timing of unmasked data review are under the purview of each NEI-appointed DSMC. At the initial DSMC meeting, the Board should establish guidelines for conducting unmasked data reviews by some or all of its members. The DSMC can modify these guidelines as it deems necessary during the conduct of the trial. Documentation of the DSMC’s approach to unmasking should be reflected in the meeting minutes and DSMC Charter as applicable.
Recommendations from the DSMC
DSMC 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, trial investigators, NEI staff, and individual DSMC members to ensure that the DSMC is kept apprised of non-confidential outcome results from other related studies as they become available. It is the responsibility of NEI staff to keep the DSMC apprised of any programmatic concerns related to the trial being monitored.
DSMC recommendations will be provided to the study leadership and to the NEI. If the DSMC recommends a change for patient safety or efficacy reasons, or recommends that the study be closed early for slow accrual or other reasons, the study Chair and Coordinating Center, in collaboration with the NEI, must act to implement the change as expeditiously as possible. If the study leadership and/or NEI do not concur with the DSMC's recommendation, it will be the responsibility of the NEI Director or designee, study leadership, and DSMC Chair to reach a mutually acceptable decision. Confidentiality must be maintained during these discussions.
If a recommendation is made to change a protocol for other than patient safety or efficacy reasons or for slow accrual, the DSMC 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 will be 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 DSMC. Any release of outcome data to individuals outside of the DSMC must be reviewed and approved by the DSMC, the NEI, and the study leadership.
No communication, either written or oral, of the deliberations or recommendations of the DSMC will be made outside of the DSMC except as provided for in these guidelines. Outcome results are strictly confidential and must not be divulged to any non-member of the DSMC. Each member of the DSMC, including non-voting members, must sign a statement of confidentiality.
Conflict of Interest
The NEI program director must have no financial or scientific conflicts with the outcome of the trial and will be sure to attest to this fact at the DSMC’s initial meeting and comply with the conflict of interest policy of the DSMC. Individuals invited to serve on the DSMC will disclose any potential conflicts of interest, whether real or perceived, to the Director of the Coordinating Center on an annual basis. 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. Decisions regarding service by individuals with potential conflicts of interest or the appearance of conflicts of interest will be made collaboratively by NEI and the study leadership.
Specific questions about this Notice should be directed to any member of the NEI Collaborative Clinical Research group at 301-451-2020:
Donald F. Everett, M.A.
Maryann Redford, D.D.S., M.P.H.
Sangeeta Bhargava, Ph.D.
Jimmy T. Le, Sc.D.