Data and Safety Monitoring of NCCIH-Funded Clinical Research
NCCIH supports an extensive portfolio of interventional clinical trials and observational studies varying in size and complexity. The Center has established the following guidelines for the appropriate oversight and monitoring of NCCIH-supported clinical research to ensure the safety of participants, the validity and integrity of the data, the conduct of the study, and the availability of data in a timely manner. The oversight and monitoring of clinical research activities is a joint responsibility of both the grantee(s) and NCCIH.
NIH policy stipulates that a system be in place for appropriate oversight and monitoring to ensure the safety of participants and the validity of the data in all NIH-sponsored or NIH-conducted clinical trials. The policy provides each Institute or Center (IC) with the flexibility to implement the requirement for data and safety monitoring as appropriate for its clinical research activities. Further guidance (NIH) related to the policy released in June 2000 stated that investigators must submit a monitoring plan for clinical trials to the IC before the trial begins.
This policy applies to all NCCIH-supported grants, cooperative agreements, or contracts that include clinical research requiring informed consent. This includes observational, mechanistic, and epidemiologic studies that involve human subjects. For purposes of this document, a clinical trial is operationally defined as a 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 (grants.nih.gov/grants/glossary.htm#C).
Formats for Independent Data and Safety Monitoring (DSM)
A Data and Safety Monitoring Board (DSMB) is an independent group of experts that advises NCCIH and the study investigators. The DSMB is charged with reviewing study data for subject safety, study conduct and progress, and providing formal recommendations regarding study continuation, modification, and termination. For the majority of studies that require a DSMB, NCCIH will select and appoint the board members. All NIH-sponsored Phase III trials require DSMB oversight. DSMB oversight should also be considered for other clinical trials with associated safety risk, including Phase I and Phase II trials.
Independent Monitoring Committee
An Independent Monitoring Committee (IMC) is an independent group of experts constituted by the study team to advise NCCIH and the study investigators. The guidance of such a body may be required for human or clinical studies that involve an intervention or when the nature, size, complexity, or programmatic importance of the study justifies additional oversight. The primary responsibilities of the IMC are to monitor participant safety and assess study progress (including participant confidentiality, recruitment and retention, and data quality and management). Roles and responsibilities are similar to those of a Data and Safety Monitoring Board (DSMB). The IMC must be able to convene on an ad hoc basis when immediate safety or study concerns arise. Additionally, it is recommended that IMC members not be affiliated with the investigator's institution; however, it may be acceptable in some instances. If members from the investigator's institution are included in the IMC, they should not be directly involved with the study, be recent or active collaborators (within the previous 3 years) with any of the investigators in the current study, or be under the any of the investigators’ direct supervision.
An Independent Monitor (IM) may be allowable for studies which involve no more than minimal risk and do not involve randomization or blinding. An Independent Monitor is an independent physician or other appropriate expert with relevant expertise in the health condition under study that advises NCCIH and the study investigators. The primary responsibility of the IM is to provide independent monitoring of smaller trials or clinical studies not involving an intervention (typically small, early phase testing; observational studies; or studies of short duration). The IM regularly reviews participant safety and assesses study progress (including patient confidentiality, recruitment and retention, and data quality and management). The IM may be from the investigator's institution but should not be directly involved with the study, be recent or active collaborators (within the previous three years) with any of the investigators in the current study, or be under the investigators’ direct supervision.
NCCIH Requirements for Data and Safety Monitoring
Data and Safety Monitoring Plan
The following Key Elements should be addressed in the DSM Plan:
- Study Identification Information
- NIH study number
- Study title
- Principal Investigator
- Study Overview
- Brief description of the purpose of the study
- Adherence statement
- Protection of subject privacy
- Database protection
- Confidentiality during adverse events reporting
- Adverse Event Information
- Definition of adverse event/serious adverse event
- Classification of adverse event severity
- Adverse event attribution scale
- Expected risks
- Adverse event/serious adverse event reporting
- Data Quality and Safety Review Plan and Monitoring
- Data quality and management
- Assessment of subject accrual and compliance
- Justification of sample size
- Stopping rules (if applicable)
- Designation of Independent Monitor(s), and CVs
- Safety review plan
- Informed Consent
- Process to obtain and ensure informed consent
The NCCIH Program Official’s Role
The NCCIH Program Official must review and approve the data and safety monitoring plan prior to study initiation. The format for independent data and safety monitoring plan will be commensurate with risk, primary outcome, and study objectives.
The NCCIH Program Official will provide guidance on which format of monitoring oversight (DSMB, IMC, IM) should be implemented for the clinical study or trial, and will also provide guidance on how the data and safety monitoring plan should be documented.
On-Site Monitoring by NCCIH
The monitoring of clinical research sites is another element of a monitoring system to assist NCCIH and its grantees in fulfilling the mutual responsibilities for ensuring participant safety and adherence of studies to applicable regulations, and verifying data quality, completeness, and accuracy.
The NCCIH clinical research portfolio is very diverse, spanning many disciplines, conditions, and study designs. In addition to supporting studies conducted under a Food and Drug Administration Investigational New Drug Application, NCCIH also supports clinical research that may involve other types of interventions, which may include associated risks to participants or involve vulnerable populations. These various risks, size, scope, complexity of the research, and the experience of the investigator and institution will influence the type and extent of site monitoring required.
For most interventional studies and large observational studies, clinical site monitors designated by NCCIH will conduct periodic on-site review of source documents, case report forms and other participant records, regulatory files, facilities, laboratories, and pharmacies (if applicable). For studies that will undergo site monitoring, NCCIH staff will discuss relevant requirements with Principal Investigators.
Other relevant Department of Health and Human Services, NIH, and NCCIH policies regarding conduct and oversight of clinical research include:
- Required Education in the Protection of Human Research Participants (September 5, 2001)
- Revised Policy for IRB Review of Human Subjects Protocols in Grant Applications (May 1, 2000)
- NIH Policy on Reporting Race and Ethnicity Data: Subjects in Clinical Research (August 8, 2001)
- NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research (October 9, 2001)
- NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects (March 6, 1998)
- Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials (June 11, 1999) Note: While this policy applies specifically to DSMBs, applicability should be considered for all monitoring formats.
- Department of Health and Human Services Policies on Research With Human Participants
- Up-to-Date Information on NIH Research Grants From the Office of Extramural Research