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Guidance for Complying with the NIDCR Clinical Terms of Award

Overview
Submission Requirements Prior to Enrolling Subject
Ongoing Reporting Requirements
NIDCR Clinical Terms of Award Checklist
NIDCR Points of Contact
Regulations and Guidelines

I. Overview

The National Institute of Dental and Craniofacial Research (NIDCR) supports clinical research and interventional clinical trials involving human subjects and must ensure compliance with human subjects regulations.

The Clinical Terms of Award requirements are in addition to:

Instructions in the PHS 398 Grant Application for paper application.
Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan in the SF 424 R&R Grant Application Guide for electronic application.
PHS 2590 Non-Competing Grant Progress Report.
NIDCR Funding Opportunity Announcements (requests for proposals, requests for applications, program announcements).
OMB administrative guidelines.
HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and Local Governments are eligible to apply).
Other HHS, PHS, and NIH Grant administration policies.
Other U.S. state and local regulations.

The purpose of the NIDCR Clinical Terms of Award is to ensure that all clinical research and trials involving human subjects and conducted under grants and cooperative agreements supported by NIDCR are well designed, conducted with rigor, monitored commensurate with risk and complexity, and that the Institute is kept informed of study progress through reporting. To enable NIDCR oversight and monitoring of clinical trials and research studies, additional information is required beyond that normally submitted with a competitive grant or cooperative agreement application, or annual non-competing progress report. These Clinical Terms of Award define the grantee institution’s responsibilities for submitting required documentation to NIDCR and other NIH offices if applicable. They apply to all NIDCR-supported clinical research and to each clinical study or clinical trial supported by a grant or cooperative agreement.

As soon as a grant or cooperative agreement is scheduled for award, a NIDCR Program Official will advise the grantee institution to submit the items described in Section II for consideration and approval by the NIDCR.

The terms will be summarized and attached to the Notice of Grant Award (Section IV. Additional Terms and Conditions).

II. Submission Requirements Prior To Enrolling Subject

Prior to enrolling any study subject for any clinical research study, the grantee institution must submit the following (as applicable) to the responsible NIDCR Program Official for consideration and approval. Materials may be submitted electronically or by mail.

A. Clinical Protocol

The grantee institution must submit to the NIDCR the Institutional Review Board (IRB)-approved clinical protocol identified by protocol title, version number, date, or both, including details of study design, proposed interventions, subject eligibility criteria, and risk or anticipated adverse events. The elements contained in the appropriate NIDCR protocol template must be included in the protocol. (For additional information, see NIDCR Protocol Template for a minimal risk, specimen collection study and for a more complex clinical research study.) NIDCR requires the clinical protocol and associated documents, including the consent form, to be submitted to the Program Official for consideration and approval. NIDCR staff comments will be forwarded to the grantee institution within three weeks of receipt of the above information. The grantee institution must address in writing all safety, regulatory, ethical, and conflict of interest concerns raised by NIDCR staff to the satisfaction of NIDCR. Written NIDCR approval of the protocol from the Program Official must be received by the grantee institution before subject accrual or enrollment can begin.

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

Plans for managing adverse events and
Procedures for assessing and reporting serious adverse events
Procedures for assessing and reporting unanticipated problems associated with risk.
Plans for data and safety monitoring and
Plans for Quality Management.

A protocol for clinical research should adhere to International Conference on Harmonisation E6: Good Clinical Practices, Section 6, and the issues related to safety as relevant.

B. Institutional Review Board (IRB) Approval

The applicant institution is responsible for submitting all IRB notifications of protocol and informed consent approval to the responsible NIDCR Program Official including the name of the IRB. This is in addition to the Office of Human Research Protections (OHRP) federal-wide assurance (FWA) number for the institution or site and the IRB approval date that is provided to the NIDCR Grants Management Official as a requirement for grant award. When other institutions are involved in the research, e.g., a multicenter study, each institution's IRB should review and approve the protocol. Written documentation of approval from each institution must be provided to NIDCR. A copy of the IRB-approved consent document identified by version number, date, or both, and dates of validity must also be provided.

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, written documentation of protocol approval from each IRB along with a copy of the IRB approved informed consent document, identified by version number, date, or both and dates it is valid must be provided to NIDCR.

C. Data and Safety Monitoring Plan

Clinical research studies must be monitored for safety and potential risk to the subject. A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. (45 CFR 46.102(i)). For example, the risk of drawing a small amount of blood from a healthy individual for research purposes is no greater than the risk of doing so as part of a routine physical examination.

For clinical studies the IRB determines to be minimal risk, safety oversight is the responsibility of the Principal Investigator and the grantee institution. The NIDCR requires independent safety monitoring for clinical research deemed to be more than minimal risk or clinical research whose nature, size, complexity or importance merit additional oversight. Such clinical research deemed to be more than minimal risk includes clinical trials of investigational drugs, devices, or biologics; clinical trials of licensed products; clinical trials of surgical interventions including dental restorative and periodontal procedures; clinical trials of behavioral interventions; and certain non-interventional clinical research studies such as observational clinical studies, complex specimen collection studies or epidemiologic studies. Independent monitoring can take a variety of forms. Phase III clinical trials must be reviewed by an independent Data and Safety Monitoring Board (DSMB); other trials may require DSMB oversight as well. [See NIDCR Policy for Data and Safety Monitoring of Clinical 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. NIH policies require: 1) Applications that propose studies with more than minimal risk to human subjects include a plan for data and safety monitoring; 2) protocols for clinical trials include detailed plans for monitoring; and 3) Phase III trials have an independent data and safety monitoring board (DSMB).

Final decisions regarding the type of data and safety monitoring to be used will be made jointly by NIDCR and the applicant institution prior to enrolling any subject. Discussions with the responsible NIDCR Program Official regarding appropriate safety monitoring and approval of the final monitoring plan by NIDCR must occur before patient enrollment begins. (For additional information, see NIDCR Policy for Data and Safety Monitoring of Clinical Research.) These discussions may involve the appointment of the following:

Data and Safety Monitoring Board (DSMB) – an independent committee charged with reviewing safety and trial progress and providing advice with respect to study continuation, modification, and termination. The grantee institution may be required to use an established NIDCR DSMB or to organize an independent DSMB. A DSMB must review all phase III clinical trials, including those studying interventional or licensed products; other trials may require DSMB oversight as well.
Safety Monitoring Committee (SMC) – a small group of independent experts who review data from a particular study.
Clinical Study Oversight Committee (CSOC) – an independent group of experts that advises NIDCR and study investigators on clinical studies including behavioral interventions where the nature, size, complexity, or programmatic importance justifies additional oversight
Independent Safety Monitor (ISM) – a physician or other appropriate expert who is independent of the study and available in real time to review and recommend appropriate action regarding adverse events and other safety issues.
Principal Investigator (PI) – The PI may provide the safety and data quality oversight of a minimal risk clinical study. This should be done by implementing an internal quality assurance plan to assess the conduct of the study and the integrity of the data.

For each study, roles and responsibilities for oversight and monitoring must be defined and documented prior to subject enrollment.

When a monitor or monitoring board is organized by the grantee institution, the grantee institution must, submit a description of the monitor or board, 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. NIDCR must approve all documents before enrollment of subjects. When safety oversight and reporting responsibilities reside with the grantee institution, written summaries of all safety monitoring reviews will be provided to the NIDCR Program Official within 10 days of the meeting.

The grantee institution must develop and implement a quality management plan appropriate for the type of study being conducted to ensure compliance with human subject safety, quality and integrity of the data, and compliance with the protocol. The grantee institution must have standard operating procedures (SOPs) for quality management which describe this process. The grantee institution must make the quality management plan and SOPs available to the NIDCR Program Official upon their request for review.

D. Investigational New Drug Application (IND) or Investigational Device Exemption (IDE) Requirements

Consistent with federal regulations, clinical research in humans involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products or devices used for a purpose other than that for which they were licensed) under a research protocol should be performed under a U.S. Food and Drug Administration (FDA) IND or IDE. Exceptions must be granted in writing by the FDA.

If a proposed clinical trial will be performed under an IND or IDE, the grantee institution must provide NIDCR 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 written responses to those comments. In addition, submit risk information (e.g., product development plan, investigator’s brochure, or information obtained through published literature review.)

The grantee institution must wait at least 30 days from FDA receipt of initial IND or IDE application for the IND/IDE to be in effect before enrolling subjects. The grantee institution must notify NIDCR if FDA places the study on clinical hold and provide NIDCR any written comments from the FDA, written responses to the comments, and documentation in writing that the hold has been lifted. The grantee institution must not use grant, cooperative agreement, contract funds to enroll new subjects in a clinical study during a clinical hold.

For all intervention studies, the grantee institution must obtain regulatory oversight by either the FDA (under an IND or IDE) or the regulatory body of the country where the research is to be conducted. In the case of a foreign regulatory body, the grantee institution must provide NIDCR with written documentation from the regulatory body that the grantee institution is in compliance with local regulatory laws.

E. Recombinant DNA Advisory Committee and Institutional Biosafety Committee

For clinical trials involving the deliberate transfer of recombinant DNA, or DNA or RNA derived from recombinant DNA, into humans (human gene transfer), the grantee institution must provide NIDCR written documentation that the NIH Office of Biotechnology Activities (OBA) Recombinant DNA Advisory Committee (RAC) review process has been completed and the grantee’s institutional biosafety committee approval (from the clinical trial site) has been obtained. (For additional information see the NIH Guidelines for Research Involving Recombinant DNA Molecules.)

NIDCR staff will forward written comments to the grantee institution within 21 days of receipt of the above information. The grantee institution must address in writing all study design, safety, regulatory, ethical, and conflict of interest concerns raised by NIDCR staff to the satisfaction of NIDCR before enrolling subjects. The IRB must review and approve any changes to the protocol before subject enrollment.

III. Ongoing Reporting Requirements

Grantee institutions 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 grantee institution is responsible for submitting to NIDCR all IRB notifications of protocol renewal, amendment, suspension, and termination. If other institutions are involved in the research (e.g. a multicenter study), each institution's IRB must review and approve the protocol. The IRB for each site must 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.

Continuing Review and Approval
The grantee institution is required to submit to the responsible NIDCR Program Official (and grants management official) 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 continuing review (renewal).
- A copy of the current IRB approved protocol, identified by version number, date, or both (unless otherwise directed).
- A copy of the current IRB approved consent document, identified by version number, date, or both, and dates it is valid.
For studies or research sites with multiple levels of IRB review, written documentation of protocol review and approval from each IRB should be provided to NIDCR, along with a copy of the IRB-approved informed consent document, identified by version number, date, or both, and dates it is valid.
Amendment, Suspension, Termination
The grantee institution is required to submit to the responsible NIDCR Program Official in addition to the Grants Management Official, written documentation of any changes in IRB approval status, including the following:
- All amendments or changes to the protocol, identified by protocol title, version number and date. (Except in the case of imminent danger to subjects, the IRB must approve changes to the protocol before they are implemented clinically).
- All changes in informed consent documents, identified by version number, date, or both. The IRB must approve changes to the protocol before they are implemented clinically.
- Termination or temporary suspension of subject accrual.
- Termination or temporary suspension of the protocol.
- Any change in IRB approval status.
- Any change in key clinical personnel conducting the study.
- Any other problems or issues that could affect the subjects of the study.
Grantee institutions must notify NIDCR of any amendments or changes to the protocol at least 14 days prior to implementing such change. Notification of any other of the above changes must be made within three days by email or fax. Information provided must include plans to address the issue, details of notification of the IRB and any responses from the IRB. NIDCR recognizes that this information may need to be provided in stages following initial notification. NIDCR will review and officially respond to the proposed plans.

B. Data and Safety Monitoring Reviews

When a safety monitor or data and safety monitoring entity is organized, the grantee institution must submit written summaries of all reviews conducted by the data and safety monitoring entity to the responsible NIDCR Program Official within 10 days of reviews or meetings. When reviews are frequent, semiannual or quarterly reports are sufficient.

C. Safety Reporting Requirements

IND or IDE Reporting
The grantee institution must notify the responsible NIDCR Program Official in writing if the FDA places the study on clinical hold at any time during the conduct of the clinical trial.
Safety Reporting
An adverse event (AE) is any untoward medical occurrence in a clinical research subject that does not necessarily have a causal relationship with the test product. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a test product, and related or not related to the test product.

A serious adverse event (SAE)is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other important medical events that, when based upon appropriate clinical judgement, may jeopardize the patient or subject and meay require medical or surgical intervention to prevent one of the outcomes listed earlier. The protocol may include additional events to be reported similarly to an SAE.

An IND safety report is a written notification to FDA of any adverse experience associated with the use of a test product that is both serious (as defined above) and unexpected; or any finding from tests in laboratory animals that suggest a significant risk for human subjects.

All clinical trials funded by NIDCR require that the NIDCR be immediately notified in an expedited fashion, through its centralized SAE system, if a serious adverse event occurs using the guidelines below:
1. Safety Reporting for Clinical Trials Under IND or IDE
  For clinical trials performed under an IND or IDE, the IND or IDE sponsor is required to provide the FDA with safety reports of serious adverse events. Under the Clinical Terms of Award, the grantee institution must submit safety reports as follows:
  - Expedited safety report of unexpected or life-threatening experience or death: A copy of any report of unexpected or life-threatening experience or death associated with the use of an IND drug, which must be reported to FDA by telephone or fax as soon as possible but no later than seven days after the IND sponsor’s receipt of the information, must be submitted to the NIDCR centralized SAE Rporting System within 24 hours of FDA notification or sooner if agreed upon at study initiation.
  - Expedited safety reports of serious and unexpected adverse experiences: A copy of any report of unexpected and serious adverse experience associated with use of an IND drug or any finding from tests in laboratory animals that suggests a significant risk for human subjects, which must be reported in writing to FDA as soon as possible but no later than 15 calendar days after the IND sponsor’s receipt of the information, must be submitted to the NIDCR centralized SAE Reporting System within 24 hours of FDA notification or sooner if agreed upon at study initiation.
  - IDE reports of unanticipated adverse device effect: Unanticipated adverse device effects occurring during a clinical investigation must be reported to FDA as soon as possible, but not later than 10 working days after the investigator (grantee institution) first learns of them. A copy of any reports of unanticipated adverse device effect submitted to FDA must be submitted to the NIDCR centralized SAE Reporting System within 24 hours of FDA notification or sooner if agreed upon at study initiation; and
  - Expedited safety report of any other unexpected serious adverse event - A copy of any report of other serious adverse event associated with the use of an IND drug or biological, which must be reported to FDA by telephone or fax as soon as possible but no later than ten calendar days after the IND sponsor’s receipt of the information, must be submitted to the NIDCR centralized SAE Reporting System within 24 hours of FDA notification
  - Expedited safety reports: should be reported to the NIH Office of Biotechnology Activities concurrently with the report to FDA.
  - Other adverse events documented during the course of the trial should be included in the annual IND or IDE report and reported to NIDCR annually.
2. Safety Reporting for Research Not Performed Under IND/IDE
  Final decisions regarding ongoing safety reporting requirements for research not performed under an IND or IDE will be made jointly by NIDCR and the grantee institution.
Unanticipated problem reports (UPR)
An unanticipated problem includes any incident, experience, or outcome that meets all of the following criteria:
1. unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
2. related or possibly related to participation in the research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and;
3. suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
For all clinical research, the grantee institution will send a copy of the report that was submitted to the IRB simultaneously to NIDCR.

D. Recombinant DNA Advisory Committee and Institutional Biosafety Committee (IBC)

The grantee institution is required to submit to the NIDCR Program Official copies of the adverse event and annual reports required by NIH Office of Biotechnology Activities and by the site IBC, if applicable. (For additional information see the NIH Guidelines for Research Involving Recombinant DNA Molecules.)

E. Inclusion Enrollment Reports

The "Inclusion Enrollment Report" includes cumulative accrual and demographic information for human subjects enrolled in the clinical research protocol. This report must be submitted annually. The annual submission of the enrollment report must coincide with each noncompeting renewal or annual progress report. For paper applications, see the PHS 398 Grant Application for more detailed instructions. For electronic applications, see the Grant Application Guide for your Grant Application Package.

IV. NIDCR Clinical Terms of Award Checklist

This checklist serves as a reminder of information that a grantee institution must submit to NIDCR when there is a notified intent to fund the grant or cooperative agreement supporting the clinical research or clinical trial. The institution may complete this checklist and attach it to a submission to the Program Official.

Principal Investigator Name:
Date:
Phone:
Fax:
Email:
Grant or Cooperative Agreement Number:
Applicant/Grantee Institution Name:
Address:
Protocol Title:

Requirements Prior to Study Enrollment

Clinical protocol and related IRB-approved consent form. These documents must be identified by version number, date, or both and the approved consent document must indicate duration of validity
IRB name for each investigative site:
Data and safety monitoring plan, if applicable. DSMB, SMC, CSOC or ISM information, if applicable. Attach charter, operating procedures, proposed member roster, and proposed member CVs. If the member is approved, a Conflict of Interest (COI) statement must be submitted to NIDCR. (See NIDCR Safety Oversight link for guidance and COI forms.)
Targeted/Planned Enrollment Table
Additional information for clinical trials 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 plan.
Additional information for gene transfer clinical trials.
NIH Recombinant DNA Advisory Committee initial review.
Date of letter from OBA: _______ NA_______
Public RAC review: Yes: ____ No: ____
Include copy of letter from the Office of Biotechnology Activities either:
1. Stating the protocol has been exempted from public review.
2. Summarizing the RAC suggestions and PI response to the recommendations.
IBC-related documents for human gene transfer protocols.
Name of institution IBC serves.
Copy of written IBC approval of protocol.
Copy of protocol approved by the IBC and IRB.

Ongoing Reporting Requirements

Documentation of IRB continuing reviews – attach the following for each investigative site.
- IRB continuing review and approval
- IRB approved consent form identified by version number, date, or both and dates 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 grantee institution must notify NIDCR of protocol amendments at least 14 days prior to implementing a protocol change. The grantee institution must notify NIDCR of changes in IRB approval status within three days of the IRB’s decision. Documents related to an amended protocol must be submitted to NIDCR before implementing changes unless subjects are in imminent danger.
Data and safety monitoring reviews or summaries, if applicable, must be submitted within 30 days of review or meeting.
IND or IDE safety reports:
- For 7-day IND telephone or fax reports, a copy must be sent to the NIDCR centralized SAE reporting system within 24 hours of FDA notification;
- For 15-day IND written reports, a copy must be sent to the NIDCR centralized SAE reporting system within 24 hours of FDA notification;
- For IDE reports of unanticipated adverse device effect, a copy must be sent to the NIDCR centralized SAE reporting system within 24 hours of FDA notification;
- Safety reports for gene transfer clinical trials must be sent to OBA concurrently with the report to the FDA.
Non-IND or IDE safety reports:
- UPRs should be submitted to the NIDCR simultaneous to reporting to IRB.
- Expedited safety reports must be reported to the NIH Office of Biotechnology Activities.
Documentation for Gene Transfer Clinical Trials
- Annual report and adverse event reports not included in expedited reports to OBA must be reported to NIDCR
- IBC continuing approval must be reported to NIDCR.
NIDCR must be notified within 24 hours if FDA places the study on clinical hold. NIDCR must be provided any written comments from the FDA, any written responses to the FDA, and documentation in writing that the clinical hold has been lifted. Grant or cooperative agreement funds MAY NOT BE USED during a clinical hold period.

V. NIDCR Points of Contact

General Inquiries

Direct general inquiries related to this notice to:

Alicia Dombroski, Ph.D.
Deputy Director
Division of Extramural Activities, NIDCR
6701 Democracy Blvd.
Room 660, MSC 4878
Bethesda, MD 20892
(301) 594-4890
adombroski@mail.nih.gov

Grant or Cooperative Agreement Inquiries and Document Submission

Inquiries about a grant or cooperative agreement should be directed to the appropriate NIDCR Program Official and/or the appropriate Grants Management Official. ( For contact information see the NIDCR Division of Extramural Activities). All information and documentation required by the NIDCR Clinical Terms of Award must be forwarded electronically or by mail to the responsible NIDCR Program Official. All information submitted must be endorsed by an authorized organizational representative.

VI. Regulations and Guidelines

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

Policy References

Office for Human Research Protections

All clinical research supported by NIDCR must comply with OHRP requirements for human subject protection, informed consent, IRB registration, assurances and responsibilities, including ongoing review.

Required Education in the Protection of Human Research Subjects

All investigators receiving NIDCR funds for research involving human subjects are required to receive education on the protection of human subjects. NIH provides an online tutorial, Human Participant Protections Education for Research Teams. Note: Other non-NIH-supported training programs are also available.

Code of Federal Regulation Title 45 Part 46

All clinical research supported by NIDCR must comply with applicable Parts of U.S. Code of Federal Regulations, Title 45, Part 46 "Protection of Human Subjects."