NCCIH Clinical Terms of Award for Human Subjects Research: Guidance for Compliance

I. Overview

The National Center for Complementary and Integrative Health (NCCIH) supports studies involving human subjects, including clinical trials, and must ensure compliance with human subjects regulations.

This document provides guidance for compliance with the NCCIH Clinical Terms of Awards for Human Subjects Research.

The NCCIH Clinical Terms of Awards for Human Subjects Research requirements are in addition to the guidance and requirements listed in the following documents:

• National Institutes of Health (NIH) Grants Policy (Guidance on Changes That Involve Human Subjects in Active Awards and That Will Require Prior NIH Approval) and relevant notices to this policy (NOT-OD-12-129)
• Instructions in the PHS 398 Grant Application for paper application
• Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan in the SF424 (R&R) Application Guide for NIH and Other PHS Agencies (4.0MB PDF)
• PHS 2590 Non-Competing Continuation Progress Report (252KB PDF)
• NCCIH solicitations, requests for applications, program announcements
• Other U.S. state and local regulations
• For studies conducted outside the United States, regulations of a host country. If regulations differ, the more restrictive regulation applies.

To enable NCCIH to properly monitor studies, additional information is required beyond that normally submitted with a competitive application, contract proposal, or annual grant/cooperative agreement progress report. These Clinical Terms of Award define the awardee's/grantee’s responsibilities for submitting required documentation to NCCIH and other NIH offices, if applicable. They apply to all NCCIH-supported human subjects research. Clinical investigators must include the following in an application or proposal:

1. Research plan (including protocol, if required by a specific Funding Opportunity Announcement (FOA)
2. Data and safety monitoring plan (DSMP).

NCCIH requires independent monitoring for clinical research that necessitates informed consent. 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 (hyperlink to NCCIH Clinical Terms of Award for Human Subjects Research). Data and safety monitoring is intended to provide an independent objective review of the conduct of the research, interim safety and efficacy data, and progress towards achieving the goals of the study.

The terms will be summarized and attached to the Notice of Award or addressed in the terms of the contract.

II. Submission Requirements Before Enrolling Participants

Before enrolling participants, the awardee/grantee will submit the following (as applicable) to the designated NCCIH program director or the contracting officer's representative for review and approval according to the review mechanisms.

A. Study Protocol

The awardee/grantee will submit the IRB-approved protocol (as well as case report forms, informed consent documents, and the DSMP) identified by version number and date, including details of study design, proposed interventions, participant eligibility and enrollment, exclusion/inclusion criteria, study procedures, safety assessments, statistical considerations, data collection and quality assurance, and participant rights and confidentiality. The study protocol requires NCCIH approval before enrollment begins.

A protocol for a human study or clinical trial must adhere to International Conference on Harmonization E6: Good Clinical Practices, Section 6, and must address the following issues related to safety:

• Plans for managing side effects
• Procedures for assessing and reporting adverse events and serious adverse events
• Plans for data and safety monitoring and monitoring of the clinical study site, pharmacy, and laboratory (as applicable).

B. Institutional Review Board or Independent Ethics Committee Approval

IRB approval is required for all human studies, unless exemptions have been allowed. The awardee/grantee is responsible for submitting all IRB notifications of protocol approval to the responsible NCCIH program director or the contracting officer's representative, including the name of the IRB, its Office for Human Research Protections (OHRP) registration number, and OHRP Federalwide Assurance (FWA) number.

If other institutions are involved in the research (e.g., a multicenter clinical trial or study) the IRB at each institution should review and approve the protocol. Alternatively, multiple institutions may cede IRB approval to a single (central) IRB, provided each local IRB has documented the ceding authority to the central IRB. Provide written documentation of approval from each institution to NCCIH. Include a copy of the IRB-approved informed consent document identified by version number and date and include the dates through which the revised approved protocol is valid.

Some countries have a national IRB that requires protocol and informed consent approval in addition to or in lieu of local IRB approval. For countries with multiple levels of IRB review, provide NCCIH with written documentation of protocol approval from each IRB along with a copy of the IRB-approved informed consent document, identified by version number and date, and include the dates through which the revised approved protocol is valid.

C. Data and Safety Monitoring

NCCIH requires independent monitoring for clinical research that necessitates informed consent. 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. Discussions with the designated NCCIH program director regarding appropriate format and documentation of the DSMP and approval of the final DSMP by NCCIH must occur before participant enrollment begins, and may include discussions about 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 of the IM 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 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 involving 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. NCCIH and the investigator may consider DSMB oversight for other human studies with associated safety risk, including Phase I and Phase II trials. Please refer to the NCCIH Data and Safety Monitoring (DSM) guidelines.

When a monitor, monitoring committee, 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. Please refer to the NCCIH DSM guidelines.

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.

D. 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 officer will inform the awardee/grantee of requirements prior to initiating participant enrollment.

Please refer to the NCCIH Policy on Monitoring.

• 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.

E. Investigational New Drug or Investigational Device Exemption Requirements

Consistent with Federal regulations, clinical 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.

F. Requirements for Training in Human Subjects Protection

Once the principal investigator provides all just-in-time (JIT) materials, please document training for all new study staff. The awardee/grantee is responsible for submitting written documentation to NCCIH 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.

G. 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 NCCIH review and approval:

• The IRB-approved clinical research protocol document and case report forms identified by version number, date, or both, including details of study design, proposed interventions, participant eligibility and enrollment, exclusion/inclusion criteria, study procedures, safety assessments, statistical considerations, data collection and quality assurance, and participant rights and confidentiality
• Documentation of the IRB, including the OHRP Federalwide Assurance number, the IRB registration number, and the IRB name
• The IRB-approved informed consent document, identified by version number, date, or both, and dates through which it is valid
• Plans for the management of side effects
• Procedures for assessing and reporting adverse events and serious adverse events
• DSMP (see C above) and monitoring of the clinical study site, pharmacy, and laboratory as applicable
• Documentation that the awardee/grantee and all study staff responsible for the design or conduct of the research have received training in the protection of human subjects.

NCCIH staff will forward comments to the awardee/grantee within 4 weeks of receipt of the above information (A–E). The awardee/grantee must address in writing all safety, regulatory, ethical, and conflict of interest concerns raised by NCCIH staff to their satisfaction before enrolling participants. The IRB must review and approve any changes to the protocol before participant enrollment.

III. Ongoing Reporting Requirements

Awardees/grantees must comply with the Clinical Terms of Award throughout the course of the research. These requirements include the following:

A. Institutional Review Board Actions

Unless otherwise directed, the awardee/grantee is responsible for submitting to NCCIH all IRB notifications of protocol renewal, amendment, suspension, and/or termination. When other institutions are involved in the research (e.g., a multicenter study), each institution's IRB should review and approve the protocol. The IRB for each site will conduct continuing reviews of research at intervals appropriate to the degree of risk, but not less than once per year, as described in 45 CFR 46.109.

1. Continuing review and approval
   The awardee/grantee is required to submit to the designated NCCIH program director or the contracting officer's representative (and contracting officer, if applicable) documentation of the continuing IRB review and approval annually, at a minimum. The submission must include the following:
   • A copy of the IRB letter of renewal
   • A copy of the current IRB-approved protocol, identified by version number and date; it must include the dates through which the revised approved protocol is valid
   • A copy of the current IRB-approved informed consent document, identified by version number and date; it must include the dates through which the revised approved protocol is valid.
2. Amendment, suspension, termination
   The awardee/grantee is required to submit to the designated NCCIH program director (and contracting officer, if applicable) written documentation of any changes in IRB approval status, including the following:
   • All amendments or changes to the protocol, identified by protocol version number and date, and must include the dates through which the revised approved protocol is valid
   • All changes in informed consent documents, identified by version number and date, and 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 IRB approval
   • Any other problems or issues that could affect the participants in the studies.

B. Data and Safety Monitoring Reviews

When an independent monitor or independent monitoring committee (or board) is organized, the awardee/grantee 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.

C. Safety Reporting Requirements

1. IND or IDE reporting

The awardee/grantee must notify the designated NCCIH program director or the contracting officer's representative in writing within 3 business days if the FDA places the study on clinical hold at any time during the conduct of the human study.

1. Required Time-Sensitive Notifications for Clinical Trials and Clinical Studies
   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)

In case of problems or issues, the NCCIH program director will contact the awardee/grantee within 10 working days by email, followed within 30 calendar days by an official (electronic) letter 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 will be made jointly by NCCIH and the awardee/grantee and outlined in the study DSMP document.

D. Institutional Biosafety Committee (IBC)

The awardee/grantee submits to the NCCIH program director copies of the adverse event and annual reports required by the site IBC, if applicable.

E. Requirements for Training in Human Subjects Protection

The awardee/grantee is required to submit documentation in the annual progress report that new staff members responsible for the design or conduct of the research have received training in the protection of human subjects.

F. Inclusion Enrollment Reports

The “Inclusion Enrollment Report” includes cumulative accrual and demographic information for enrolled human subjects. This report must be submitted annually. The annual submission of the enrollment report will coincide with each noncompeting renewal or annual progress report. For paper applications, see PHS 398 for more detailed instructions. For electronic applications, see the SF 424 Application Guide for your grant application package.

IV. NCCIH Clinical Terms of Award Checklist

This checklist serves as a reminder of information that an awardee/grantee must submit to NCCIH:

Requirements at Time of Competitive Application and Proposal

• Research plan
• Data and safety monitoring plan
• Targeted/Planned Enrollment Table

Requirements Before Study Enrollment

• IRB documents and protocol/protocols, identified by version number, date, or both; attach the following for each investigative site or IRB:
  • IRB name
  • Federalwide Assurance number for institution or site
  • IRB OHRP registration number
  • IRB notification of protocol approval
  • IRB-approved protocol
  • IRB-approved consent forms, identified by dates through which they are valid
• DSMP (including operating procedures, proposed roster, and CVs)
• Additional information for human studies with INDs or IDEs:
  • Name, institution, and address of IND or IDE sponsor
  • FDA IND or IDE number (attach copy of letter from the FDA)
  • FDA correspondence (attach copies of all written communication with the FDA)
  • Risk information (e.g., investigator's brochure or information obtained through published literature review or other venue)
• Safety reporting for research not performed under an IND or IDE
• Documentation of training in human subjects protection for all study staff responsible for design or conduct of the research

Ongoing Reporting Requirements

• Documentation of IRB continuing reviews—attach the following for each investigative site:
  • IRB OHRP registration number
  • OHRP Federal-wide assurance number for site
  • IRB continuing review and approval
  • IRB-approved consent form identified by version number, date, or both and dates for which it is valid
  • IRB-approved protocol identified by version number, date, or both, unless otherwise directed
  • Documents related to protocol amendments, suspensions, or termination
• For the duration of the award, the awardee/grantee must notify NCCIH of protocol amendments or changes in IRB approval status within 3 business days of the IRB's decision. Documents related to an amended protocol must be approved by NCCIH before implementing changes.
  • Data and safety monitoring study reports and signed recommendations—submit within 30 days of the review or meeting
• IND or IDE safety reports:
  • For 7-day IND telephone or fax reports, send a copy to the NCCIH program director or the contracting officer's representative at the time of the FDA notification
  • For 15-day IND written reports, send a copy to the NCCIH program director or the contracting officer's representative at the time of the FDA notification
  • For IDE reports of unanticipated adverse device event, send a copy to the NCCIH program director or the contracting officer's representative at the time of the FDA notification
  • Report adverse events not included in expedited reports in the annual IND or IDE report
• Training in human subjects protection for new study staff, if applicable—submit annually to coincide with each noncompeting renewal or annual progress report
• Inclusion enrollment reports—submit annually to coincide with each noncompeting renewal or annual progress report
• Notify NCCIH within 3 business days if the FDA places the study on clinical hold; provide NCCIH any written comments from the FDA, written responses, and documentation in writing that the hold has been lifted. Cannot use grant, cooperative agreement, or contract funds for any activities restricted by the clinical hold.

V. NCCIH Points of Contact

Inquiries and Document Submission

Direct inquiries about a grant, cooperative agreement, or contract to the appropriate NCCIH program director or the contracting officer's representative. All information and documentation required by the NCCIH Clinical Terms of Award must be forwarded electronically or by mail to the designated NCCIH program director or the contracting officer's representative according to the review mechanisms applicable to the awarding division.

VI. Regulations and Guidelines

The NCCIH Clinical Terms of Award conform with NIH policy on human subjects research and are consistent with and complementary to requirements stated in the instructions for your application, NCCIH solicitation, request for applications, or program announcement. NCCIH-supported clinical research must adhere to applicable human subjects protection regulations and guidelines, including those listed below.

Policy References

Office for Human Research Protections

All clinical research supported by NCCIH must comply with OHRP requirements for human subjects protection, informed consent, IRB registration, assurances and responsibilities, including ongoing review. Please refer to the OHRP website and the NIH Office of Extramural Research website on research involving human subjects.

Required Education in the Protection of Human Research Participants

All investigators receiving NCCIH funds for research involving human subjects are required to receive education on the protection of human subjects—Code of Federal Regulation Title 45 Part 46. All clinical research supported by NCCIH must comply with applicable Parts of U.S. Code of Federal Regulations, Title 45, Part 46 “Protection of Human Subjects.”

International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP)

All human studies supported by NCCIH shall comply with ICH and GCP guidelines. Please refer to Guidance for Industry for a complete list.

FDA Guidance Documents

Find guidance documents that represent the FDA's at the Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research. For questions, consult the FDA Good Clinical Practice Program.

Find the FDA's Information Sheet Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors, which represents the agency's current guidance on protection of human subjects of research.

Requirements for Research Conducted Under an IND/IDE

NCCAM-supported human studies conducted under an FDA IND/IDE application must comply with relevant parts of CFR Title 21:

• Title 21, Part 50, “Protection of Human Subjects”
• Title 21, Part 54, “Financial Disclosure by Clinical Investigators”
• Title 21, Part 56, “Institutional Review Boards”
• Title 21, Part 312, “Investigational New Drug Application”
• Title 21, Part 812, “Investigational Device Exemptions”