National Eye Institute Guidelines for Data and Safety Monitoring of Clinical Trials
National Eye Institute
The National Eye Institute (NEI) is establishing 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 from all NEI-supported or -conducted clinical trials (http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
A detailed data and safety monitoring plan for all clinical trials must be submitted as part of the Research Plan portion 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. The initial review group will review this plan, and 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). 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 Safety Officer to the organization of a formal Data and Safety Monitoring Board (DSMB). Ongoing review of the data by an independent individual or DSMB 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, FDA, or NIH requirements for timely review and reporting of serious adverse events.
For studies co-funded with other ICs, the lead IC will be responsible for monitoring the study and establishing a DSMB if necessary. Oversight of the DSMB 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 Safety Officer and the NEI. The PI and the NEI should appoint the Safety Officer 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 DSMB. Masked Phase II therapeutic trials should be monitored by a DSMB. 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. Treatment allocations are randomly assigned, and the data are usually masked. Such trials usually involve a large number of participants followed for longer periods of treatment exposure. In a Phase III trial, the PI must consider the long-term effects of a study agent for safety or efficacy differences between the control and study groups. All Phase III clinical trials require monitoring by a DSMB (http://www.nih.gov/grants/guide/notice-files/not98-084.html). The implementation of this approach should be part of the monitoring plan. The organization, responsibilities, and operation of the DSMB are described below.
DATA AND SAFETY MONITORING BOARDS
Responsibilities of the DSMB
- Review and approve the research protocol(s) and plans for data and safety monitoring. The DSMB, 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 DSMB and the format for reporting cumulative data at intervals.
- Review 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 DSMB reviews trial performance information such as patient recruitment and retention, clinical center and resource center performance, and proposals for ancillary studies. It provides advice to the investigators and the NEI on these topics. The DSMB also recommends whether and to whom outcome results should be released prior to the reporting of study results.
- Review and approve the primary trial manuscript(s) with regard to determining that the results are fairly presented and the conclusions appropriate.
- Review published reports of related studies submitted by NEI, the study leadership, or DSMB members to determine whether the monitored study needs to be changed or terminated.
- Review 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 DSMB meeting, provide 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 DSMB voting members, including the DSMB chair, 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. NEI program staff may serve as non-voting ex officio members. The study Chair and representatives from the Coordinating Center may also serve as non-voting ex officio members at the discretion of the voting members of the DSMB.
Voting members of the DSMB 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 DSMB members by the Coordinating Center to allow sufficient time for the DSMB 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 DSMB 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 DSMB meetings will depend on the nature of the trial. However, a DSMB should meet at least annually. Interim meetings may be held at the request of DSMB 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, representatives from the NEI, and others may be present, at the request of the DSMB, to review the conduct of the trial and to answer questions from members of the DSMB. 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 and appropriate non-voting DSMB members should be held. The outcome results and toxicity information, if any, will be presented to the DSMB by treatment group. Third, an executive session involving only voting DSMB members should be held to allow them the opportunity to discuss the general conduct of the trial and all outcome results, including toxicities and adverse events; develop recommendations; and vote as necessary. At the request of the DSMB, some non-voting members may attend portions of the executive session to respond to questions or to clarify issues.
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, trial investigators, NEI 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. It is the responsibility of NEI staff to keep the DSMB apprised of any programmatic concerns related to the trial being monitored.
DSMB recommendations will be provided to the study leadership and to the NEI. If the DSMB 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 DSMB's recommendation, it will be the responsibility of the NEI Director or designee, study leadership, and DSMB 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 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 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 DSMB. Any release of outcome data to individuals outside of the DSMB must be reviewed and approved by the DSMB, the NEI, and the study leadership.
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
Individuals invited to serve on the DSMB, as either a voting or non-voting member, 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.