As required by the National Institutes of Health Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials and NIH Policy for Data and Safety Monitoring, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has developed clinical research monitoring guidelines to assist grantees and to provide a uniform structure for all awardees conducting clinical research. This document provides guidance and information on the development of data and safety monitoring plans (DSMPs), as well as on NIH and NIDDK policy regarding which clinical studies require a Data and Safety Monitoring Board (DSMB). In addition, this guidance provides templates regarding various aspects of DSMPs and DSMBs.
Research involving human subjects encompasses observational or epidemiological studies, clinical trials, and any research studies in which the investigator directly interacts with human subjects. A clinical trial is defined as any prospective study involving human subjects designed to answer specific questions about the effects or impact of particular biomedical or behavioral interventions. These may include drugs, treatments, devices, or behavioral or nutritional strategies. All grant applications involving human subjects (i.e., not just clinical trials) must include a section on Protection of Human Subjects. The scientific review group will review the DSMP and note any comments or concerns in the summary statement. Prior to the issuance of a Notice of Grant Award, NIDDK staff must review and approve the DSMP. The NIDDK may require a more detailed plan than was included in the grant application.
The DSMP should be commensurate with the risk, and the size and complexity of the study. Each DSMP and DSMB should be carefully considered and tailored to the individual clinical study. Investigators are encouraged to contact their program official with any questions.
These guidelines are based on clinical research monitoring guidelines established by NIH, the Code of Federal Regulations (CFR) Title 45 Part 46, Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance (PDF, 262 KB) as described by the International Conference on Harmonization, and applicable U.S. Food and Drug Administration (FDA) regulations. This guidance does not take the place of Institutional Review Board (IRB) guidelines, Food and Drug Administration (FDA) requirements, or any special NIH guidelines for specific circumstances.
Data and Safety Monitoring Plans (DSMP)
As previously noted, all grants involving human subjects require a Data and Safety Monitoring Plan. DSMPs for clinical studies are designed to ensure the safety of participants, and assure the validity of data. In addition, such plans should allow for the appropriate termination of studies for which significant benefits or risks have been uncovered or when it appears that the study cannot be conducted successfully.
Routine Monitoring Requirements
All clinical research studies must have a monitoring plan that includes the following elements:
- How the study will comply with any applicable regulatory requirements
- How the study will monitor site performance - Subject accrual and retention should be monitored and the plan should describe any tracking by sub-group (e.g., age, gender, race/ethnicity). For multi-site studies, plans should be made for monitoring by site and in aggregate. Protocol adherence should also be tracked.
- A discussion of data integrity - This includes protocol adherence, flow of data forms and data quality.
- How participant confidentiality will be protected - The plan should delineate steps that will be taken to monitor and maintain confidentiality of data. An additional level of protection for human subjects involved in clinical studies is a Certificate of Confidentiality, which is issued to a researcher to provide special privacy protection to subjects involved in clinical research. A Certificate of Confidentiality can be used by the researcher to avoid involuntary disclosure (e.g., subpoenas) of identifying information about research subjects. More information on this subject, as well as the application process, can be found at the NIH Office of Extramural Research Certificates of Confidentiality Kiosk.
- Safety reporting - The plan should include a description of the adverse events expected because of the underlying condition, the known side effects of the intervention, and any risks or complications of the outcomes being assessed. Steps to be taken to minimize risk should be described. The plan should describe what adverse events will be tracked, how this will be accomplished and how they will be reported. This includes who has the responsibility for reporting, and the roles and responsibilities of each person on the clinical study team who is involved in safety reporting. The plan should include the timeline for reporting of SAEs and targeted non-serious AEs to the entity doing the monitoring, the IRBs and the FDA, if applicable. Any unexpected safety events should be reported to NIDDK. The minutes from meetings with the Safety Monitor or DSMB (see below) should also be sent as an official communication to NIDDK.
- Safety monitoring - The plan should discuss who is responsible for monitoring and how that monitoring will occur. The monitoring plan should be commensurate with the risk, size and complexity of the study. Monitoring may range from a single Safety Officer to a DSMB. The next section delineates requirements for DSMBs. For studies not requiring a DSMB, a Safety Monitor should be designated. In general, the Safety Monitor should not be an individual involved in patient care as part of the study and it is preferable to have a Safety Monitor who is external to the clinical study. The Safety Monitor must be free of any conflicts of interest so that independence and objectivity are maintained. If the trial is not masked and is low risk, it may be appropriate for the PI to be involved with oversight of the study in conjunction with the external Safety Monitor. If there is no external monitor, the plan should include a discussion of how the Institution will avert or manage any conflict of interest (COI) implicit in having the Principal Investigator, or person directly reporting to the PI, as the only monitor of a clinical study. The plan should specify how COI will be ascertained and tracked. For masked studies, the plan should make clear how masking is maintained and under what circumstances unmasking would occur as well as who would be unblinded. Studies conducted in a clinical studies unit may be monitored by its designated team.
- Statistical analysis issues - The plan should include the power calculation(s) to demonstrate feasibility. There should be discussion of any planned interim analyses, including adjustments for spending “alpha” on “multiple looks.” Stopping rules for clinical trials should also be specified. Generally, stopping rules reflect one of the following conditions: 1) there is clear evidence of harm; 2) there is no likelihood of demonstrating treatment benefit (futility); 3) there is overwhelming evidence of the benefit of treatment.
Clinical Studies that Require a Data and Safety Monitoring Board (DSMB)
The purpose of the DSMB is to insure participant safety and oversee the conduct of studies that are large, complex or high risk. NIDDK requires a DSMB for the following clinical studies:
- All phase 3 trials - NIH requires a DSMB for all phase 3 clinical trials. Generally, these trials are large, masked, involve multiple sites, and are intended to change medical practice or product labeling. These characteristics warrant a high level of impartial scrutiny.
- Phase 1 or 2 trials that involve masked interventions - The use of a DSMB ensures oversight of participant safety while the clinicians involved in conducting the study remain blinded to outcome and safety data.
- Multi-center clinical studies - Multi-center studies involve multiple institutions following the same protocol. This imposes a level of complexity which will benefit from impartial scrutiny of safety, study conduct and data quality/ integrity, to ensure that all sites are conducting study procedures in a similar, uniform manner.
- Clinical trials of high risk interventions or clinical studies where the outcome assessment is invasive or involves more than minimal risk - Studies of high risk interventions (e.g., gene transfer studies; drug with significant toxicities) should be monitored by a DSMB. Trials that involve testing of new interventions where limited safety data is available are also considered high risk. In addition, studies where the measured outcome is used solely for research purposes and is invasive or could potentially have adverse effects should utilize a DSMB. Please note that the concept of minimal risk is not up to the investigator, but is defined in 45 CFR Subpart A, Sec. 46.102.
- Clinical studies involving vulnerable populations that are more than minimal risk - The term “vulnerable populations” generally encompasses children, pregnant women, prisoners, elderly or terminally ill individuals, or those with diminished mental capacity. Generally, such studies should be monitored by a DSMB. However, in a single center study, if the intervention or outcomes assessment poses only minimal risk, it may be acceptable to have a Safety Monitor, rather than a DSMB. Such exceptions should be discussed with the appropriate NIDDK program staff. NIDDK, however, may require institution of a DSMB for minimal risk studies based on the population or study design.
The size of the DSMB will depend on the nature and complexity of the study. Members should have expertise appropriate to the science of the study and clinical trial design. At least one biostatistician should be included. For investigator-initiated studies that are not cooperative agreements, the awardee will generally appoint the members of the DSMB. However, the composition of the DSMB must be approved by NIDDK as part of its review of the data and safety monitoring plan. The members of the DSMB must be independent from the study staff and anyone responsible for patient care in the study. DSMB members should not have any scientific, financial or other conflict of interest related to the study. Written documentation attesting to absence of these is required. Waivers may be granted by the NIDDK based on specific considerations.
Generally, the responsibilities of the DSMB include:
- Review the protocol, informed consent documents, and plans for data and safety monitoring;
- Consider major changes to the research protocol, informed consent documents and plans for data and safety monitoring;
- Evaluate the progress of the study, including periodic assessments of data quality and timeliness, participant recruitment, accrual and retention, participant risk versus benefit, performance of the study sites, and other factors that may affect study outcomes;
- Review serious adverse events and other safety reports and make recommendations regarding protection of the safety of study participants;
- Ensure data integrity and confidentiality;
- Review areas of concern regarding the performance of individual sites and provide comment on actions to be considered regarding sites that perform unsatisfactorily;
- Consider factors external to the study when relevant information becomes available, such as scientific or therapeutic developments that may have an impact on the safety of the participants or the ethics of the study;
- Modify the study protocol or make recommendations regarding possible early termination of the study because of attainment of study objectives, safety concerns, low likelihood of showing a benefit of the intervention (futility), or inadequate performance (such as enrollment and retention problems);
- Review the interim analysis of efficacy, if appropriate, in accordance with stopping rules which are clearly defined in the protocol;
- Provide input on the desirability of proceeding to the full-scale study at the completion of a feasibility phase, if appropriate;
- Assess the potential impact of ancillary studies on the integrity of the parent study; and
- Monitor clinical ancillary studies unless an independent monitoring system is used.
The DSMB should have a charter that describes its responsibilities and operating rules. A sample DSMB charter is provided in the model documents section. Each DSMB meeting will have an open session, which includes the PI and the study statistician. The open session generally focuses on study conduct (e.g., recruitment and retention; data quality) and allows the DSMB to interact with study leadership and raise issues about the conduct of the study. Outcome data should not be presented in the open session. Following the open session, the DSMB meets in closed session with the unmasked study statistician(s) who will present outcomes data and answer questions. The DSMB should then have time to deliberate without any study staff present. There should be a summary of each meeting, noting the date/time and means of communication (e.g., in-person, teleconference, etc.), participant list and recommendations. The PI should communicate the deliberations of the DSMB to any other investigators involved with the study, the IRB, NIDDK, and, if appropriate, applicable regulatory agencies. The PI must notify NIDDK of any actions taken by the IRB.
The documents below are meant to provide assistance and are simply examples that can be customized and used as needed for each individual study. There is no requirement to use these particular documents, and investigators are free to use their own materials.
Czaja SJ, Schulz R, Belle SH, Burgio LD, Armstrong N, Gitlin LN, Coon DW, Martindale-Adams J, Klinger J, Stahl SM. Data and safety monitoring in social behavioral intervention trials: the REACH II experience. Clin Trials. 2006;3(2):107-118. PMID: 16773953
DeMets DL, Furberg CD, Friedman LM (eds). Data Monitoring in Clinical Trials: A Case Study Approach. New York: Springer Science & Business Media, Inc.; 2006.
Dixon DO, Weiss S, Cahill K, Fox L, Love J, McNamara J, Soto-Torres LE. Data and safety monitoring policy for National Institute of Allergy and Infectious Diseases clinical trials. Clin Trials. 2011 Dec;8(6):727-735. PMID: 22024105
Ellenberg SS, Fleming TR, DeMets DL. Data Monitoring Committees in Clinical Trials: A Practical Perspective. West Sussex: John Wiley & Sons; 2002.
Ellenberg S, Fernandes RM, Saloojee H, Bassler D, Askie L, Vandermeer B, Offringa M, Van der Tweel I, Altman DG, van der Lee JH; StaR Child Health Group. Standard 3: data monitoring committees. Pediatrics. 2012 Jun;129 Suppl 3:S132-137. PMID: 22661759
Fleming TR, Sharples K, McCall J, Moore A, Rodgers A, Stewart R. Maintaining confidentiality of interim data to enhance trial integrity and credibility. Clin Trials. 2008;5(2):157-167. PMID: 18375654
Freidlin B, Korn EL. Monitoring for lack of benefit: a critical component of a randomized clinical trial. J Clin Oncol. 2009 Feb 1;27(4):629-633. PMID: 19064977
Friedman LM, Furbert CD, and DeMets DL. Fundamentals of Clinical Trials. 4th ed. New York: Springer; 2010.
Herson J. Data and Safety Monitoring in Clinical Trials. Boca Raton, FL:Taylor & Francis Group, LLC; 2009.
Piantadosi, S. Clinical Trials: A Methodologic Perspective. 2nd ed. Hoboken, NJ: John Wiley and Sons; 2005.
SCT Working Group on Data Monitoring, Dixon DO, Freedman RS, Herson J, Hughes M, Kim K, Silverman MH, Tangen CM. Guidelines for data and safety monitoring for clinical trials not requiring traditional data monitoring committees. Clin Trials.2006;3(3):314-319. PMID: 16895048