On this page:
- NCCIH Review Process Before Participant Enrollment Begins
- Safety and Monitoring Issues
- Investigational New Drug or Investigational Device Exemption Requirements
- Required Time-Sensitive Notification
For guidance using this document, see the NCCIH Clinical Terms of Award for Human Subjects Research: Guidance for Compliance.
Awardees/grantees must comply with the NCCIH Clinical Terms of Award that will be incorporated in their Notices of Award or contracts. Potential applicants are encouraged to contact appropriate NCCIH program staff concerning this policy.
NIH policy requires certain information regarding research that involves human subjects. The terms outlined here are in addition to and not in lieu of other NIH policies, including instructions in the PHS 398 Grant Application for paper application, the Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan in the SF 424 (R&R) Application Guide for NIH and other PHS Agencies (3.5MB Word), and the PHS 2590 Non-Competing Continuation Progress Report (252KB PDF), as well as NCCIH solicitations, requests for applications, program announcements, the Department of Health and Human Services (HHS) regulations (45 CFR 46), Public Health Service guidelines, HHS grant administration regulations (45 CFR parts 74 and 92), and Office of Management and Budget administrative guidelines.
Clinical Terms of Award
These Clinical Terms of Award detail an agreement between NCCIH and the awardee/grantee; they apply to all grants, cooperative agreements, and contracts that involve research with human subjects.
A. NCCIH Review Process Before Participant Enrollment Begins
NCCIH has a responsibility to ensure that mechanisms and procedures are in place to protect the safety of participants in NCCIH-supported human studies. Therefore, before participant accrual or enrollment, the awardee/grantee must provide the following (as applicable) for review and approval by NCCIH:
- IRB-approved human research protocol document and case report forms identified by version number, date, or both, including details of study design, proposed interventions, subject eligibility and enrollment exclusion/inclusion criteria, study procedures, safety assessments, statistical considerations, data collection and quality assurance, and participant rights and confidentiality
- Documentation of IRB, including the Office for Human Research Protections Federalwide Assurance (FWA) number, IRB registration number, and IRB name (see B below)
- IRB-approved informed consent document, identified by version number, date, or both, and dates through which it is valid
- Plans for managing side effects
- Procedures for assessing and reporting adverse events and serious adverse events
- Data Safety Monitoring Plan (DSMP) (see B below) and monitoring of the clinical study site, pharmacy, and laboratory as applicable
- Documentation that the awardee and all study staff responsible for the design or conduct of the research have received training in the protection of human subjects.
NCCIH staff comments will be forwarded to the awardee/grantee within 4 weeks of receiving the above information. The awardee/grantee must address in writing all safety, regulatory, ethical, and conflict of interest concerns raised by NCCIH staff to their satisfaction before participant accrual or enrollment can begin.
B. Safety and Monitoring Issues
Institutional Review Board
Before the award, the awardee/grantee must submit to NCCIH a copy of the current IRB-approval, and approval and the FWA number for the institution or site. At the time of annual progress reports, the awardee/grantee must provide the date of continuing approval by the IRB.
If other institutions are involved in the research (e.g., multicenter clinical trial or study), each institution’s IRB must review and approve the protocol. Alternatively, it is acceptable for multiple institutions to cede IRB approval to a single (central) IRB, provided each local IRB has documented the ceding authority to the central IRB. The primary awardee/grantee must also provide NCCIH with initial and annual documentation of continuing review and approval, including the FWA number of the other institutions.
The awardee/grantee institution must ensure that the application, as well as all protocols, is reviewed by their IRB.
To help ensure the safety of participants enrolled in NCCIH-funded studies, the awardee/grantee must provide NCCIH with copies of documents related to all major changes in the status of ongoing protocols, including the following:
- All amendments or changes to the protocol, identified by protocol version number and date, must include the dates through which the revised approved protocol is valid
- All changes in informed consent documents, identified by version number and date, must include the dates through which the revised approved documents are valid
- All changes to the DSMP
- Termination or temporary suspension of participant accrual
- Termination or temporary suspension of the protocol
- Any change in the IRB approval
- Any other problems or issues that could affect the study participants.
Awardees/grantees must notify NCCIH of any of the above changes within 3 working days by e-mail, detailing notification of the change of status to the local IRB and providing a copy of any responses from the IRB. Investigators should follow their institutional policies for notifying the institutional business official about the above changes. Documents related to an amended protocol must be approved by NCCIH before implementing the changes. Awardees/grantees must also comply with NIH policy on changes that involve human subjects in active awards (NOT-OD-12-129).
Data and Safety Monitoring Requirements
NCCIH requires independent monitoring for research involving human subjects. Independent monitoring can take a variety of forms. Final decisions regarding the type of monitoring to be used must be made jointly by NCCIH and the awardee/grantee before enrollment starts. The DSMP components should include study identification and overview, confidentiality protections, adverse event reporting, data quality/safety review monitoring, and data table templates. Investigators should discuss the appropriate DSMP format and documentation with the designated NCCIH program director. NCCIH approval of the final DSMP, including the monitor(s), must occur before participant enrollment begins, and may include the appointment of one of the following:
- Independent Monitor (IM)—An IM is an independent physician or other appropriate expert who advises NCCIH and the study investigators. The primary responsibility is to provide independent monitoring of smaller human 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 (for an interventional study) and assesses study progress (including participant confidentiality, recruitment and retention, and data quality and management). The IM may be from the investigator's institution or other participating sites, but should not be directly involved with the study. The IM should not be a recent or active collaborator with any of the investigators in the current study, or be under the investigator's supervision.
- Independent Monitoring Committee (IMC)—An IMC is an independent group of experts that advises NCCIH and the study investigators. The guidance of such a body may be required for human or clinical studies that may involve an intervention, where their nature, size, complexity, or programmatic importance justifies additional oversight. The primary responsibilities of the IMC are to monitor participant safety (for an interventional study) 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 study concerns arise. It is recommended that members of the IMC 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 with any of the investigators in the current study, or be under the investigator's supervision.
- Data and Safety Monitoring Board—A 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 recommendations regarding study modification, continuation, and termination. The awardee/grantee may be required to use an established NCCIH DSMB or to organize an independent DSMB. Generally, NIH-sponsored Phase III trials require DSMB oversight. DSMB oversight should also be considered for other human studies with associated safety risk, including Phase I and Phase II trials. Please refer to the NCCIH Data and Safety Monitoring guidelines.
When a monitor or monitoring board is organized, its description, its charter or operating procedures (including a proposed meeting schedule and plan for review of adverse events), and roster and curriculum vitae from all members must be submitted to and approved by NCCIH before enrollment starts. Typically, monitoring committees/DSMBs should include at least one member with human subjects research monitoring experience, a member with relevant disease expertise (such as M.D. or equivalent), a member with expertise in the intervention or observation technique being used, and a Ph.D.-level biostatistician.
The awardee/grantee also must submit copies of study reports developed for the monitors, and copies of their signed recommendations. The awardee/grantee also must submit copies of all reviews conducted by the monitoring group to NCCIH within 30 days of the reviews or meetings.
Study Monitoring by NCCIH
Onsite Monitoring—The monitoring of clinical research sites is another element of a monitoring system to assist NCCIH and its awardees/grantees to ensure participant safety and investigator adherence to applicable regulations. It also exists to verify data quality, completeness, and accuracy. For most interventional studies and large observational studies, clinical site monitors designated by NCCIH will conduct periodic onsite 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, the NCCIH program director will inform the awardee of requirements prior to initiating participant enrollment.
Accrual Monitoring—Regular monitoring of accrual and assessment of study feasibility is essential for the ethical conduct of human subjects research and the proper stewardship of public funds. All studies should have accrual plans. NCCIH requires that the awardee submit an accrual timeline prior to initiating research involving human subjects. To ensure that projects are meeting accrual timelines after project initiation, the awardee must provide interim accrual reports at regular intervals, when requested by NCCIH staff. If accrual falls significantly behind the projected timeline, NCCIH will consider taking one or more actions.
C. Investigational New Drug or Investigational Device Exemption Requirements
Consistent with Federal regulations, research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
Exceptions must be granted in writing by the FDA, with copies provided to the NCCIH program director. If the proposed human study will be performed under an IND or IDE, the awardee/grantee must provide NCCIH with the name and institution of the IND or IDE sponsor, the date the IND or IDE was filed with the FDA, the FDA IND or IDE number, any written comments from the FDA, and the written responses to those comments.
The awardee/grantee must wait 30 days from FDA receipt of an initial IND or IDE application before initiating a human study. The awardee/grantee must notify the NCCIH program director within 3 business days if the FDA places the study on clinical hold, and provide NCCIH with any written comments from the FDA, written responses to the comments, and written documentation that the hold has been lifted. The awardee/grantee must not use grant, cooperative agreement, or contract funds for any activities restricted by the clinical hold.
For foreign studies, the awardee/grantee must provide NCCIH with written documentation from the foreign regulatory body that the awardee/grantee is in compliance with local regulatory laws. The awardee/grantee must notify the NCCIH program director within 3 business days if there is any change in status of the study with the foreign regulatory body, and provide NCCIH with any written comments from the foreign regulatory body, as well as written responses to the comments.
Required Time-Sensitive Notification
Clinical trials and clinical studies funded by NCCIH must follow current applicable regulations and guidelines for safety reporting and reporting of unanticipated problems. Information on the required formats, notification time frames, and the agencies, organizations, and offices to be notified can be found using the following links:
- Unanticipated Problem Reporting
- IND Safety Reporting
- Reporting Unanticipated Adverse Device Effects
- NIH Guidelines for Research Involving Recombinant DNA Molecules (See Appendix M-I-C-4)
When safety-related events and unanticipated problems are reported according to these requirements, the awardee/grantee should also submit copies of the reports to NCCIH within 3 business days, using the procedures specified in the clinical protocol.
In case of problems or issues, the NCCIH program director will contact the awardee/grantee within 10 working days by e-mail, followed within 30 calendar days by an official letter (electronic) to the principal investigator, with a copy to the institution's office of sponsored programs, listing issues and appropriate actions to be discussed.
- Safety reporting for research not performed under an IND or IDE:
Final decisions regarding ongoing safety reporting requirements for research not performed under an IND or IDE must be made jointly by the NCCIH and the awardee/grantee, and outlined in the study DSMP document.