NIDCR Clinical Terms of Award

1.   Introduction 

Grantee institutions must comply with the National Institute of Dental and Craniofacial Research (NIDCR) Clinical Terms of Award that will be incorporated into the Notice of Grant Award (NGA) for grants and cooperative agreements. Potential applicants are encouraged to contact appropriate NIDCR Program Officials or Office of Clinical Trial Operations and Management staff concerning this policy. 

NIH policy requires certain information regarding research involving human subjects. The terms outlined here are in addition to and not in lieu of other NIH policies. These include instructions in the PHS 398 Grant Application for paper applications, the Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan in the SF 424 R&R Grant Application Guide for electronic applications, and the PHS 2590 Non-Competing Grant Progress Report as well as NIDCR’s funding opportunity announcements (requests for proposals, requests for applications, and program announcements), the Department of Health and Human Services (DHHS) regulations (45 CFR 46), Public Health Service guidelines, DHHS grant administration regulations (45 CFR parts 74 and 92), and Office of Management and Budget administrative guidelines. 

The NIDCR Clinical Terms of Award policy requires that all clinical research and clinical trials 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. These Clinical Terms of Award detail an agreement between the NIDCR and the grantee institution; they apply to all grants and cooperative agreements that involve human subjects, and are also defined by the NIH as “clinical research”. 

2.  Safety and Monitoring 

a.  Institutional Review Board (IRB) Approval

Before award, and then with the annual non-competing grant progress report, the grantee must submit to the NIDCR Program Official, a copy of the current IRB-approved consent form and current IRB approval for each discrete clinical research study contained within a grant.  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. 

If other institutions are involved in the research (e.g. a multicenter clinical trial or study), each institution's IRB must review and approve the clinical protocol and consent form. They must also provide NIDCR initial and annual documentation of continuing review and approval, including the current approved informed consent document and FWA number. 

The grantee institution must ensure that the application, all clinical protocols and informed consent documents are reviewed by their IRB. 

To help ensure the safety of subjects enrolled in NIDCR-funded studies, the grantee institution must provide NIDCR 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 title, protocol version number, version date, or both.
• All changes in informed consent documents, identified by version number, version date, or both and dates for which informed consent documents are valid.
• Termination or temporary suspension of subject accrual.
• Termination or temporary suspension of the protocol.
• Any change in IRB approval and continuing reviews.
• Any changes in key clinical personnel conducting the study
• Any other problems or issues that could affect the safety of enrolled subjects or the integrity of the primary endpoint of the clinical research or clinical trial.  

Grantee institutions must notify NIDCR of any amendments or changes to the protocol or consent form at least 14 (fourteen) days prior to implementing such change. Grantee institutions must notify NIDCR of any of the other above changes within 3 (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. 

If a clinical protocol has been reviewed by an institutional biosafety committee (IBC) or the NIH Recombinant DNA Advisory Committee (RAC), the grantee institution must provide information about the initial and ongoing review and approval, if any. See the NIH Guidelines for Research Involving Recombinant DNA Molecules.  

b.  Data and Safety Monitoring Requirements

NIH Policy For Data and Safety Monitoring states “each institute should have a system for oversight and monitoring the conduct and integrity of clinical trials to ensure the safety of subjects and the validity and integrity of the data for all NIH supported or conducted clinical trials.” [NOT-98-084]

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 Part 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 (45 CFR 46.102I). 

For clinical studies the IRB determines to be minimal risk, safety oversight is the responsibility of the Principal Investigator and the grantee institution. However, the NIDCR requests that a quality management plan be submitted to NIDCR for review and comment.  NIDCR reserves the right to conduct site monitoring by contract monitors at any time in cooperation with the grantee institution. 

The NIDCR requires independent safety monitoring for clinical research deemed to be more than minimal risk or for clinical research where the nature, size, complexity or importance of the study merits additional oversight. Such clinical research 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] 

Final decisions regarding the type of monitoring to be used must be made jointly by NIDCR and the grantee institution before study enrollment starts. Discussions with the responsible NIDCR Medical Monitor regarding appropriate safety monitoring and approval of the final monitoring plan by NIDCR must occur before subject enrollment begins and may include discussions about the appointment of the following: 

• Data and Safety Monitoring Board (DSMB) – an independent committee charged with reviewing study data for subject safety and study conduct and progress and providing recommendations with respect to study continuation, modification, and termination of the trial. The grantee institution may be required to use an established NIDCR DSMB or to organize an independent DSMB. All phase III clinical trials must be reviewed by a DSMB; other trials may require DSMB oversight as well.
• Safety Monitoring Committee (SMC) – a small group of independent experts who review study data primarily to monitor subject safety in Phase I or smaller Phase II trials.
• Clinical Study Oversight Committee (CSOC) – an independent group of experts that advises NIDCR and study investigators on clinical studies including behavioral interventions where 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 by implementing an internal quality assurance plan to assess the conduct of the study and integrity of data.

For each study, roles and responsibilities for oversight and monitoring will be defined and documented prior to subject enrollment. When a monitor or monitoring board is organized by the grantee institution, a description of it, its charter or operating procedures (including a proposed meeting schedule and plan for review of adverse events), roster and curriculum vitae from all members must be submitted to and approved by NIDCR before enrollment starts. 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 the 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.
 

3.  NIDCR Process Prior to Subject Enrollment for Any Clinical Research   

NIDCR has a responsibility to ensure that mechanisms and procedures are in place to protect the safety of subjects in NIDCR-supported clinical research and to optimize the conduct of high quality clinical research. Therefore, prior to subject accrual or enrollment for any clinical research, the grantee institution must provide the following (as applicable) for consideration and approval by NIDCR: 

• IRB-approved clinical research protocol identified by protocol title, version number and date including details of study design, proposed interventions, subject eligibility criteria ,  risks and/or anticipated adverse events, plans for managing these adverse events, procedures for assessing and reporting serious adverse events, and procedures for assessing and reporting unanticipated problems.  [see Unanticipated Problems]
• Documentation of IRB approval
• IRB approved consent form that is used to document informed consent, identified by version number, date, or both.
• Plans for data and safety monitoring (see 2.b above).

NIDCR staff comments will be forwarded to the grantee institution within three weeks of receipt of the above package of information. The grantee institution must address, in writing, all study design, operational and logistical issues and safety, regulatory, ethical, and conflict of interest concerns raised by NIDCR staff to the satisfaction of NIDCR. Approval of the protocol and associated documents by NIDCR will be conveyed in writing to the grantee institution before subject accrual or enrollment can begin. No funds may be drawn down from the payment system and no obligations may be made against federal funds for any research involving human subjects prior to the NIDCR’s notification to the grantee that the identified issues have been resolved and NIDCR’s acceptance has been provided in writing.
 

4.  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 application (IND) or Investigational Device Exemption (IDE).

Exceptions must be granted in writing by the FDA. If the proposed clinical trial will be performed under an IND or IDE, the grantee institution must provide NIDCR the name and institution of the IND or IDE sponsor, the date the IND or IDE was filed with FDA, the FDA IND or IDE number, copies of transmittal memos to the IND or IDE, all written comments from the FDA, and the written responses to those comments. 

The grantee institution must wait at least 30 days from the FDA receipt of an initial IND or IDE application for the IND/IDE to be in effect before initiating a clinical trial. 

The grantee institution must notify NIDCR if the FDA ever 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 may not use grant or cooperative agreement funds to enroll new subjects in a clinical study during a clinical hold. 

5.   Required Time-Sensitive Notification for Clinical Trials

All clinical trials funded by NIDCR require that NIDCR be notified in an expedited fashion, through its centralized SAE system, if a serious, unexpected, and associated adverse event or unanticipated problem associated with risk occurs using the guidelines below.  In addition, if the study is conducted under an IND or IDE, the IND or IDE sponsor must provide FDA safety reports of reportable (21 CFR 312.32(c)(1)(A)) serious adverse events. Under these Clinical Terms of Award, unless otherwise specified in the protocol, the grantee institution must submit reports as follows:

• Expedited safety report of any 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 or biological, which must be reported to FDA by telephone or fax as soon as possible but no later than seven 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 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.
• IDE reports of unanticipated adverse device effect - A copy of any report of unanticipated adverse device effect, which must be reported to FDA as soon as possible but no later than ten working days after the investigator first learns of the effect, must be submitted to the NIDCR centralized SAE Reporting System within 24 hours of FDA notification.
  
  
• Expedited safety reports for gene transfer studies – 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 the NIDCR annually.
  
  
• 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 NIDCR and the grantee institution.

6.   Required Study Status/Progress Reports and Documentation

In order for NIDCR to stay apprised of NIDCR supported clinical research and clinical trial activities and progress, the grantee institution will at least annually, or at shorter intervals agreed upon by NIDCR and the grantee, provide NIDCR with study information in the form of reports and documentation.  These include:

• Screening and accrual reports for each clinical site.
• IRB continuing review documentation annually or more frequently as required by IRB.
• Reports of unanticipated problems submitted to the IRB

For guidance on using this document, see the Guidance for Complying with the NIDCR Clinical Terms of Award.