REVISED OCTOBER 2018. This document applies to all NIH grants and cooperative agreements for budget periods beginning on or after October 1, 2018

Human subjects protections, phs act, federalwide assurance, FWA, HHS office for human research protections, OHRP, guidance on engagement of institutions in human subjects research, IRB, certification of IRB approval, reporting to funding agency and OHRP, OHRP oversight, education in the protection of human research participants, data and safety monitoring, inclusion of children as subjects in clinical research, inclusion of women and minorities as subjects in clinical research, reporting sex gender racial and ethnic participation, informed consent for research on dried blood spots obtained through newborn screening, good clinical practice training for NIH awardees involved in NIH-funded clinical trials, GCP, GCP training

4.1.15 Human Subjects Protections

The HHS regulations for the protection of human subjects, in 45 CFR 46, implement Section 491(a) of the PHS Act and provide a framework, based on established, internationally recognized ethical principles, to safeguard the rights and welfare of individuals who participate as subjects in research activities supported or conducted by the NIH or other HHS components.

The HHS regulations stipulate that the recipient organization(s), whether domestic or foreign, bears ultimate responsibility for safeguarding the rights and welfare of human subjects in HHS-supported activities (46.101(a) and 46.103(a)). Recipient institutions "engaged" in human subjects research must obtain a Federalwide Assurance (FWA) with the HHS Office for Human Research Protections (OHRP), and establish appropriate policies and procedures for the protection of human subjects. An institution is engaged in human subjects research if:

  1. the institution's employees or agents intervene or interact with human subjects for research purposes;
  2. the institution's employees or agents obtain individually identifiable private information about human subjects for research purposes; or
  3. the institution receives a direct HHS award to conduct human subjects research, even where all activities involving human subjects are carried out by a subcontractor or collaborator.

The OHRP's document entitled Guidance on Engagement of Institutions in Human Subjects Research provides additional guidance on "engagement".

The HHS regulations at Subparts B, C, and D include additional protections for specific populations as follows:

  1. human fetuses, pregnant women, and neonates (45 CFR 46, Subpart B);
  2. prisoners (45 CFR 46, Subpart C); and
  3. children (45 CFR 46, Subpart D).

Certain research activities are exempt from regulatory requirements for an FWA and IRB oversight (45 CFR 46.101(b)). OHRP guidance states that institutions must adopt clear procedures under which the IRB (or some authority other than the investigator) determines whether proposed research is exempt from the human subjects regulations. NIH will make a final determination as to whether proposed activities are covered by the regulations or are in an exempt category, based on the information provided in the Research Plan.

Unless all research activities meet the criteria for one or more exemptions from 45 CFR 46, research involving human subjects may only be conducted under an HHS award if the organization has a current OHRP approved FWA and provides certification that an Institutional Review Board (IRB)An administrative body established to protect the rights and welfare of human research subjects recruited to participate in research activities conducted under the auspices of the organization with which it is affiliated. The Institutional Review Board has the authority to approve, require modifications in, or disapprove all research activities that fall within its jurisdiction. registered under the specific Assurance has reviewed and approved the proposed activity in accordance with the HHS regulations.

In accepting an award that supports human subjects research, the recipient institution assumes responsibility for all research conducted under the award, including protection of human subjects at all participating and consortium sites, and for ensuring that an FWA and certification of IRB review and approval exists for each site before human subjects research may begin. When consultants are performing research involving human subjects on NIH-funded projects, the consultant's institution must establish an approved FWA.

The NIH Office of Extramural Research Human Subjects Web site contains additional information and Frequently Asked Questions that are available to help investigators understand how these Federal requirements apply to their research. See http://grants.nih.gov/grants/policy/hs/index.htm.

Applications will be considered incomplete if they do not address the involvement of human subjects in the Research Plan of the application. If human subjects research is anticipated within the period of the award but definite plans for involvement of human subjects cannot be described in the application (referred to as "delayed onset human subjects research" in the NIH grant application instructions), applicants must provide a detailed explanation of why it is not possible to develop definite plans. Prior to the involvement of human subjects the recipient must submit to the NIH awarding ICThe NIH organizational component responsible for a particular grant program or set of activities. The terms "NIH IC," or "awarding IC" are used throughout this document to designate a point of contact for advice and interpretation of grant requirements and to establish the focal point for requesting necessary prior approvals or changes in the terms and conditions of award. for prior approvalWritten approval by an authorized HHS official, e.g., a designated IC GMO, evidencing prior consent before a recipient undertakes certain activities or incurs specific costs (see Administrative Requirements-Changes in Project and Budget-Prior Approval Requirements). either (1) detailed information as required in the Research Plan of the application, and meet the FWA and IRB certification requirements, or (2) if all of the research meets the criteria for one or more exemptions, identification of which exemptions(s) is/are applicable to the research, and a justification for the exemption with sufficient information about the involvement of human subjects to allow a determination that the claimed exemption is appropriate. Typically, recipients that are part of large clinical research networks or consortia that plan to add new protocols after the award must follow the awarding ICThe NIH organizational component responsible for a particular grant program or set of activities. The terms "NIH IC," or "awarding IC" are used throughout this document to designate a point of contact for advice and interpretation of grant requirements and to establish the focal point for requesting necessary prior approvals or changes in the terms and conditions of award.'s procedures for approval of new protocols. Institutions with award mechanisms that allow them to select new projects, typically small future research projects (e.g., pilot projects), for support by their NIH award are responsible for ensuring that the selected projects follow all relevant regulations and policies including those governing the involvement of human subjects in research, including prior approvalWritten approval by an authorized HHS official, e.g., a designated IC GMO, evidencing prior consent before a recipient undertakes certain activities or incurs specific costs (see Administrative Requirements-Changes in Project and Budget-Prior Approval Requirements). from the institutional IRB if applicable. They must follow the awarding ICThe NIH organizational component responsible for a particular grant program or set of activities. The terms "NIH IC," or "awarding IC" are used throughout this document to designate a point of contact for advice and interpretation of grant requirements and to establish the focal point for requesting necessary prior approvals or changes in the terms and conditions of award.'s procedures for prior approvalWritten approval by an authorized HHS official, e.g., a designated IC GMO, evidencing prior consent before a recipient undertakes certain activities or incurs specific costs (see Administrative Requirements-Changes in Project and Budget-Prior Approval Requirements). of new protocols and updating the ICThe NIH organizational component responsible for a particular grant program or set of activities. The terms "NIH IC," or "awarding IC" are used throughout this document to designate a point of contact for advice and interpretation of grant requirements and to establish the focal point for requesting necessary prior approvals or changes in the terms and conditions of award. on the status of funded projects in annual progress reports which are typically described in the FOA and/or NoANotice of Award: The official, legally binding document, signed (or the electronic equivalent of signature) by a Grants Management Officer that: (1) notifies the recipient of the award of a grant; (2) contains or references all the terms and conditions of the grant and Federal funding limits and obligations; and, (3) provides the documentary basis for recording the obligation of Federal funds in the NIH accounting system..

Recipients may not draw funds from the payment system, request funds from the paying office, or make obligations against Federal funds for research involving human subjects at any site engaged in nonexempt research for any period not covered by both an FWA and IRB approval consistent with 45 CFR 46. Costs associated with IRB review of human research protocols are not allowable as direct charges to NIH-funded research unless such costs are not covered by the organization's F&A rate.

The use of autopsy materials is governed by applicable State and local law and is not directly regulated by 45 CFR 46.

4.1.15.1 Federalwide Assurance Requirements

The Federalwide Assurance (FWA) commits the institution to compliance with the requirements set forth in 45 CFR 46, and the Terms of Assurance. Each institution that is "engaged" in HHS supported human subjects research must be covered by an FWA approved by OHRP. (See http://www.hhs.gov/ohrp/assurances/assurances/index.html.)

When an applicant organization proposes non-exempt human subjects research and does not have a FWA, the AOR signature on the application constitutes declaration that the organization will comply with 45 CFR 46 and proceed to obtain a FWA. The NIH awarding component will place a restriction in the NoANotice of Award: The official, legally binding document, signed (or the electronic equivalent of signature) by a Grants Management Officer that: (1) notifies the recipient of the award of a grant; (2) contains or references all the terms and conditions of the grant and Federal funding limits and obligations; and, (3) provides the documentary basis for recording the obligation of Federal funds in the NIH accounting system. so that no human subjects research may be conducted under the award until the FWA and certification of IRB review and approval (or certification of institutional determination of exemption, if applicable) have been obtained and accepted by NIH.

Each recipient institution must file its own FWA even if the organization does not operate its own IRB and designates another IRB for that purpose. IRBs must be registered with OHRP before the IRB may be designated on an FWA as reviewing proposed research for the FWA-holding institution.

Organizations that will serve as additional performance sites that are conducting non-exempt human subjects research under the award must obtain an FWA, or, under specified circumstance, may be covered by the recipient's FWA in accordance with the OHRP's Guidance on Extension of an FWA to Cover Collaborating Individual Investigators and Introduction of the Individual Investigator Agreement.

It is the recipient organization's responsibility to ensure that all sites engaged in research involving human subjects are covered by an appropriate FWA and have IRB approval consistent with 45 CFR 46. It also is the recipient's responsibility to comply with NIH prior approvalWritten approval by an authorized HHS official, e.g., a designated IC GMO, evidencing prior consent before a recipient undertakes certain activities or incurs specific costs (see Administrative Requirements-Changes in Project and Budget-Prior Approval Requirements). requirements related to the addition of sites not included in the approved application (see Administrative Requirements-Changes in Project and Budget-Prior Approval Requirements). A list of organizations with approved assurances is available at the OHRP Web site (http://www.hhs.gov/ohrp).

No individual may receive NIH grant funds for nonexempt research involving human subjects unless the individual is affiliated with or sponsored by an organization that assumes responsibility for the research under an FWA or the individual makes other arrangements with OHRP.

Detailed information concerning FWAs, including the OHRP Assurance Training Module, is available on the OHRP Web site (http://www.hhs.gov/ohrp/).

4.1.15.2 Certification of IRB Approval

Recipients must provide a certification to NIH that the research application has been approved by an appropriate IRB, consistent with 45 CFR 46 and OHRP guidance. IRB approval must have been granted within 12 months before the budget period start date to be valid. Note that NIH requires the date of final IRB approval; conditional IRB approval is not sufficient. According to OHRP, in the case of IRB approval with conditions, IRB approval only becomes effective when the IRB has approved all information submitted in response to their conditions.

Certification of IRB approval may be filed at any time before award in accord with Just-in-TimeNIH policy allows the submission of certain elements of a competing application to be deferred until later in the application process, after review when the application is under consideration for funding. Within the Status module of the eRA Commons, users will find a feature to submit Just-In-Time information when requested by the NIH. Through this module, institutions can electronically submit the information that is requested after the review, but before award. See Completing the Pre-Award Process-Just-In-Time Procedures for additional information. procedures, unless required earlier by the ICThe NIH organizational component responsible for a particular grant program or set of activities. The terms "NIH IC," or "awarding IC" are used throughout this document to designate a point of contact for advice and interpretation of grant requirements and to establish the focal point for requesting necessary prior approvals or changes in the terms and conditions of award.. Therefore, following peer review and notification of impact score/percentile, applicant organizations with OHRP FWAs may wish to proceed with IRB review for those applications that have not yet received IRB approval and that appear to be in a fundable range.

The HHS regulations require that the IRB review the actual application or proposal for HHS support (45 CFR 46.103(f)). OHRP's 5/31/2000 memo IRB Review of Applications for HHS Support (http://www.hhs.gov/ohrp/policy/aplrev.html) recommends that IRBs ensure that all research described in the application or proposal is entirely consistent with any corresponding protocol(s) submitted to the IRB.

4.1.15.3 Reporting to Funding Agency and OHRP

Under the HHS regulations, recipient institutions must have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the NIH of any unanticipated problem involving risks to subjects or others or any serious or continuing noncompliance with 45 CFR 46 or IRB requirements (45 CFR 46.103(b)(5)). Any IRB suspension or termination of approval must include a statement of the reasons for the IRB's action and must be reported promptly to the investigator, appropriate institutional officials, and NIH (45 CFR 46.113). Recipient institutions must also file incident reports with OHRP of unanticipated problems involving risks to subjects or others, serious or continuing noncompliance with 45 CFR 46 or with the requirements or determinations of the IRB, and suspension or termination of IRB approval. See OHRP 6/20/2011 Guidance on Reporting Incidents to OHRP (http://www.hhs.gov/ohrp/compliance/reports/index.html).

4.1.15.4 OHRP Oversight

OHRP has regulatory responsibility for oversight of recipient compliance with the HHS human subjects regulations. In carrying out this responsibility, OHRP evaluates all written allegations or indications of non-compliance with the HHS regulations it receives from any source. All compliance oversight evaluations are predicated on the HHS regulations and the organization's assurance of compliance. Any corrective actions imposed as a result of a compliance oversight evaluation are intended to remedy identified non-compliance and prevent reoccurrence. Because each case is different, OHRP tailors corrective actions to foster the best interest of human research subjects and, to the extent possible, of the organization, research community, and HHS. Most compliance oversight evaluations and resultant corrective actions are resolved at the OHRP level. However, OHRP may recommend actions to be taken by other HHS officials.

Information about the FWA submission process and about OHRP activities related to oversight and compliance, as well as copies of the human subjects regulations, may be obtained from OHRP at the address shown in Part III or from its home page at http://www.hhs.gov/ohrp/.

4.1.15.5 Education in the Protection of Human Research Participants

Before funds are awarded for competing applications involving human subjects, applicants must submit documentation that all senior/key personnel involved in human subjects research have received training in the protection of human subjects. Senior/key personnel include all individuals responsible for the design or conduct of the study, including senior/key personnel of consortium participants or alternate performance sites if they are participating in research that involves human subjects. This documentation should be included in the cover letter signed by the AOR that accompanies the description of other support, IRB and IACUC approval, and other information submitted prior to funding in accordance with Just-in-TimeNIH policy allows the submission of certain elements of a competing application to be deferred until later in the application process, after review when the application is under consideration for funding. Within the Status module of the eRA Commons, users will find a feature to submit Just-In-Time information when requested by the NIH. Through this module, institutions can electronically submit the information that is requested after the review, but before award. See Completing the Pre-Award Process-Just-In-Time Procedures for additional information. procedures. For non-competing continuation awards, the description of education for new senior/key personnel should be part of the progress report submitted as a prerequisite to award. Additional information about this education requirement is available on the NIH Web site at: http://grants.nih.gov/grants/policy/hs_educ_faq.htm.

4.1.15.6 Data and Safety Monitoring

The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. The NIH policies on data and safety monitoring specify that the level and frequency of monitoring should be commensurate with the risks, nature, and complexity of the clinical trial, and are in addition to any monitoring requirements imposed by FDA or the NIH Guidelines for Research Involving Recombinant DNA Molecules ("NIH Guidelines"). There are a number of options for monitoring clinical trials including, but not limited to, monitoring by a/an:

  • PD/PI (required),
  • IRB (required),
  • Independent individual/safety officer,
  • Designated medical monitor,
  • Internal committee or board with explicit guidelines,
  • DSMB (required for multi-site trials).

Applications that include clinical trials must include a general description of the data and safety monitoring plan. The description of the data and safety monitoring plan in competing applications will be reviewed by the SRG. A general description of a monitoring plan establishes the overall framework for data and safety monitoring. It must describe the entity that will be responsible for monitoring how adverse events will be reported to the IRB and the NIH and, when appropriate, how the NIH Guidelines and FDA regulations for INDs and IDEs will be satisfied.

A detailed monitoring plan must be included as part of the research protocol, be submitted to the local IRB, and be reviewed and approved by the NIH awarding ICThe NIH organizational component responsible for a particular grant program or set of activities. The terms "NIH IC," or "awarding IC" are used throughout this document to designate a point of contact for advice and interpretation of grant requirements and to establish the focal point for requesting necessary prior approvals or changes in the terms and conditions of award. prior to the accrual of human subjects. The awarding ICThe NIH organizational component responsible for a particular grant program or set of activities. The terms "NIH IC," or "awarding IC" are used throughout this document to designate a point of contact for advice and interpretation of grant requirements and to establish the focal point for requesting necessary prior approvals or changes in the terms and conditions of award. may specify the reporting requirements for adverse events, which are in addition to the annual report to the IRB. The clinical trial monitoring function is above and beyond that traditionally provided by IRBs; however, the IRB must be cognizant of the procedures used by clinical trial monitoring entities and the monitor must provide periodic reports to investigators for transmittal to the local IRB.

NIH specifically requires the establishment of DSMBs for multi-site clinical trials involving interventions that entail potential risk to the participants, and generally for Phase III clinical trials. Although Phase I and Phase II clinical trials also may use DSMBs, smaller clinical trials may not require this oversight format, and alternative monitoring plans may be appropriate.

For multi-site Phase I and II trials, investigators should organize a central reporting entity that will be responsible for preparing timely summary reports of adverse events for distribution among sites and the IRBs of participating sites. The frequency of summary reports will depend on the nature of the trial. Organizations with a large number of clinical trials may develop standard monitoring plans for Phase I and II clinical trials. However, such plans always should be evaluated for appropriateness for the particular investigation.

All multi-site trials with DSMBs are expected to forward summary reports of adverse events to individual IRBs so they can address reports related to the site for which they have responsibility. Recipients should address questions on this subject to the NIH PO.

Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

4.1.15.7 Inclusion of Individuals Across the Lifespan as Participants in Research Involving Human Subjects

For all competing grant applications for due dates on or after January 25, 2019, individuals of all ages, including children (i.e. individuals under the age of 18) and older adults, must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific or ethical reasons not to include them. The inclusion of individuals across the lifespan as subjects in research must be in compliance with all applicable subparts of 45 CFR 46 as well as with other pertinent federal laws and regulations.

Applications or proposals for research involving human subjects must address the age-appropriate inclusion or exclusion of individuals in the proposed research project. Applications/proposals must include a description of plans for including individuals across the lifespan, including a rationale for selecting the specific age range justified in the context of the scientific question proposed. If individuals will be excluded from the research based on age, the recipient/offeror must provide an acceptable justification for the exclusion.

Scientific review groups at the NIH will assess each application/proposal as being "acceptable" or "unacceptable" with regard to the age-appropriate inclusion or exclusion of individuals in the research project, in addition to evaluating the plans for conducting the research in accord with these provisions. NIH staff will monitor implementation of this policy during the development, review, award and conduct of research; and manage the NIH research portfolio to comply with the policy.

NIH recipients must submit data on participant age at enrollment in progress reports. Investigators planning to conduct research involving human subjects should design their studies in such a way that de-identified individual-level participant data on sex/gender, race, ethnicity, and age at enrollment may be provided to NIH in progress reports.

Ongoing, non-competing awards and competing applications submitted prior to January 25, 2019, will not be expected to comply with this policy until the grantee submits a competing renewal application. For these projects, the previous policy on the inclusion of children (NOT-98-024) continues to apply.

4.1.15.8 Inclusion of Women and Minorities as Subjects in Clinical Research and Reporting Sex/Gender, Racial, and Ethnic Participation

NIH-conducted and supported Clinical research must conform to the NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research in accord with Public Health Service Act sec. 492B, 42 U.S.C. sec 289a-2. The policy requires that women and members of minority groups and their subpopulations be included in NIH-conducted or supported clinical research, unless a clear and compelling rationale and justification establishes to the satisfaction of the NIH ICThe NIH organizational component responsible for a particular grant program or set of activities. The terms "NIH IC," or "awarding IC" are used throughout this document to designate a point of contact for advice and interpretation of grant requirements and to establish the focal point for requesting necessary prior approvals or changes in the terms and conditions of award. Director that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Exclusion under other circumstances may be made by the Director, NIH, upon the recommendation of an ICThe NIH organizational component responsible for a particular grant program or set of activities. The terms "NIH IC," or "awarding IC" are used throughout this document to designate a point of contact for advice and interpretation of grant requirements and to establish the focal point for requesting necessary prior approvals or changes in the terms and conditions of award. Director based on a compelling rationale and justification.

Cost is not an acceptable reason for exclusion except when the research would duplicate existing data. Women of childbearing potential should not be routinely excluded from participation in clinical research. The policy applies to research subjects of all ages in NIH-supported clinical research studies (see definition of clinical research). The inclusion of individuals on the basis of sex/gender, race, and ethnicity must be addressed in developing a research design appropriate to the scientific objectives of the study. A proposed outreach program for recruiting should also be included. When an NIH-defined Phase III clinical trial is proposed, investigators must consider whether clinically important sex/gender, racial, and/or ethnic differences in the intervention effect are to be expected and plan the research accordingly. When registering in Clincialtrials.gov, applicable clinical trialsApplicable clinical trial is the term used in Title VIII of the Food and Drug Administration Amendments Act (FDAAA) of 2007 (P.L. 110-85) to designate the scope of clinical trials that may be subject to the registration and results reporting requirements in FDAAA. as defined in 42 C.F.R. Part 11, that are also NIH-defined Phase III clinical trials must specify outcomes on sex/gender and race/ethnicity, as required based on prior evidence, and as explained in the NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research. For applicable clinical trialsApplicable clinical trial is the term used in Title VIII of the Food and Drug Administration Amendments Act (FDAAA) of 2007 (P.L. 110-85) to designate the scope of clinical trials that may be subject to the registration and results reporting requirements in FDAAA. that are also NIH-defined Phase III clinical trials, submissions of results to Clinicaltrials.gov must include results of valid analyses by sex/gender and race/ethnicity, as required based on prior evidence.

Investigators must also collect and annually report information on sex/gender, race, and ethnicity in clinical research studies. The OMB minimum standards for maintaining, collecting, and presenting data on race and ethnicity for all grant projects are described in OMB Directive No. 15. The categories in this classification are social-political constructs and should not be interpreted as being scientific or anthropological in nature. The standards include five racial categories: American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, and White. There are two categories for ethnicity: "Hispanic or Latino," and "Not Hispanic or Latino."

For more information on policies and procedures related to inclusion: Inclusion Procedures

4.1.15.9 Informed Consent for Research on Dried Blood Spots Obtained Through Newborn Screening

NIH funded research using newborn dried blood spots collected on or after March 18, 2015, will be considered to be non-exempt human subjects research, and therefore, must follow the HHS protection of human subjects regulations at 45 CFR part 46.

Grant applications and R&D contract proposals submitted to NIH that will use such materials in research should be designated as non-exempt human subjects research and include a complete human subjects section per relevant NIH instructions including plans for inclusion on the basis of sex/gender, race, ethnicity, and age per the NIH Policies on the Inclusion of Women, Minorities, and Children.

Such applications and proposals that are funded by NIH must comply with all the relevant federal regulatory and NIH policy requirements for human subjects research including the requirement that the awardee institution (and all engaged institutions) have a Federalwide Assurance (FWA) from OHRP and certification of IRB approval of the proposed research.

Parental permission must have been obtained in order to use newborn dried blood spots collected on or after March 18, 2015, in NIH-funded research. Waiver of parental permission for such research is not permitted under this legislation.

Continuing NIH awards that are conducting research with newborn dried blood spots collected on or after March 18, 2015, will also have to comply with these new requirements. Awardee institutions will need to meet all NIH requirements for human subjects research, including IRB approval, prior to starting such research.

Non-identifiable newborn dried blood spots collected prior to March 18, 2015, may continue to be used in NIH-funded research without parental permission, and this activity would continue to be considered research that does not involve human subjects under the current human subjects regulations.

NIH recognizes that there is no universal agreement on the optimal timing for collection of parental permission for research purposes. Obtaining permission at the time the dried blood spots are collected may be one option. Ideally, an educational process could take place prior to the process of obtaining permission, and may be provided prenatally or after the birth of the child.

Section 12 of the Newborn Screening Saves Lives Reauthorization Act of 2014 applies to use of newborn dried blood spots in HHS funded research, as "research" is defined in 45 CFR 46.102 (d). Research funded solely by state or private entities does not constitute "Federally funded research" and is not subject to Section 12 of the new law.

4.1.15.10 Good Clinical Practice Training for NIH Awardees Involved in NIH-funded Clinical Trials

NIH expects that all NIH-funded investigators and staff who are involved in the conduct, oversight, or management of clinical trials to be trained in Good Clinical Practice (GCP), consistent with principles of the International Conference on Harmonisation (ICH) E6 (R2). (See https://www.fda.gov/downloads/drugs/guidances/ucm073122.pdf).

The principles of GCP help assure the safety, integrity, and quality of clinical trials. GCP provides a standard for ensuring clinical trial compliance, implementation, data collection, monitoring, and reporting (e.g., safety data, accrual reports, study status, protocol deviations, unanticipated problems, or final data), and outline the responsibilities of Institutional Review Boards (IRBs), investigators, sponsors and monitors. GCP addresses elements related to the design, conduct and reporting (e.g., safety data, accrual reports, study status, protocol deviations, unanticipated problems, or final data) of clinical trials.

GCP principles constitute an international ethical and scientific quality standard for designing, conducting, recording, and reporting clinical trials. The principles were developed in 1996 by the ICH in collaboration with representatives from the European Union, Japan, and the United States. The U.S. Food and Drug Administration (FDA) requires GCP compliance for studies conducted under an investigational new drug application or investigational device exemption.

GCP describes the responsibilities of investigators, sponsors, monitors and IRBs in the conduct of clinical trials. Compliance with GCP provides assurance that the rights, safety and well-being of human subjects are protected, that clinical trials are conducted in accordance with approved plans with rigor and integrity, and that data derived from clinical trials are reliable.

GCP training complements other required training on protections for human research participants. Since June 2000, the NIH Extramural Research Program has required training on protections for human research participants for all NIH-funded investigators and individuals responsible for the design or conduct of a research involving human subjects.

This policy applies to NIH-funded investigators and clinical trial site staff who are responsible for the conduct, management and oversight of NIH-funded clinical trials. GCP training includes the Principles of ICH GCP found in Section 2 of ICH E6. GCP training may be achieved through a class or course, academic training program, or certification from a recognized clinical research professional organization. Acceptable GCP courses include the NIAID GCP Learning Center website (http://gcplearningcenter.niaid.nih.gov) and National Drug Abuse Treatment Clinical Trials Network (https://gcp.nidatraining.org/). Completion of GCP training will demonstrate that individuals have attained the fundamental knowledge of clinical trial quality standards for designing, conducting, recording and reporting trials that involve human research participants. GCP training should be refreshed at least every three years in order remain current with regulations, standards and guidelines. Recipients of GCP training are expected to retain documentation of their training, and make it available to NIH upon request.

For purposes of Good Clinical Practice training the following definitions apply:

Investigator: The individual responsible for the conduct of the clinical trial at a trial site. If a clinical trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator.

Clinical trial staff: Individuals, identified by the investigator, who are responsible for study coordination, data collection and data management. The central focus of clinical trial staff is to manage participant recruitment and enrollment, to maintain consistent study implementation, data management, and to ensure integrity and compliance with regulatory and reporting requirements. These individuals may also seek informed consent from prospective participants, enroll and meet with research participants, and collect and record information from research participants. Clinical trial staff may also be called the research coordinator, study coordinator, research nurse, study nurse or sub-investigator.

4.1.15.11 NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research

Effective for all competing grant applications (new, renewal, revision, or resubmission) with receipt dates on or after January 25, 2018, NIH expects that all sites participating in multi-site studies involving non-exempt human subjects research funded by NIH will use a single Institutional Review Board (sIRB) to conduct the ethical review required by HHS regulations for the Protection of Human Subjects at 45 CFR Part 46. Ongoing, non-competing awards will not be expected to comply with this policy until the grantee submits a competing renewal application.

This policy applies to the domestic sites of NIH-funded multi-site studies where each site will conduct the same protocol involving non-exempt human subjects research. It does not apply to career development, research training or fellowship awards. Foreign sites participating in NIH-funded, multi-site studies will not be expected to follow this policy.

Applicants are expected to submit a plan describing the use of an sIRB that will be selected to serve as the IRB of record for all study sites. The plan should include a statement confirming that participating sites will adhere to the sIRB Policy and describe how communications between sites and sIRB will be handled. If, in delayed-onset research, an sIRB has not yet been identified, applications/proposals should include a statement that awardees will follow this Policy and communicate plans to use a registered IRB of record to the funding NIH Institute/Center prior to initiating a multi-site study. The applicant/offeror may request direct costCosts that can be identified specifically with a particular sponsored project, an instructional activity, or any other institutional activity, or that can be directly assigned to such activities relatively easily with a high degree of accuracy. funding for the additional costs associated with the establishment and review of the multi-site study by the sIRB, with appropriate justification; all such costs must be reasonable and consistent with cost principlesThe government-wide principles, issued by OMB (or, in the case of commercial organizations, the Federal Acquisition Regulation [48 CFR 21], or, in the case of hospitals, 45 CFR 75, Appendix IX, "Principles For Determining Costs Applicable to Research and Development Under Grants and Contracts with Hospitals"), on allowability and unallowability of costs under federally sponsored agreements. See Cost Considerations-The Cost Principles for additional details., as described in Chapter 7 (Cost Consideration) and the Federal Acquisition Regulation (FAR) 31.302 (Direct Costs) and FAR 31.203 (Indirect Costs). The NIH's acceptance of the submitted plan will be incorporated as a term and condition in the Notice of Award"The official, legally binding document, signed (or the electronic equivalent of signature) by a Grants Management Officer that: (1) notifies the recipient of the award of a grant; (2) contains or references all the terms and conditions of the grant and Federal funding limits and obligations; and, (3) provides the documentary basis for recording the obligation of Federal funds in the NIH accounting system.".

Recipients are responsible for ensuring that authorization agreements are in place; copies of authorization agreements and other necessary documentation should be maintained in order to document compliance with this policy, as needed. As appropriate, recipients are responsible for ensuring that a mechanism for communication between the sIRB and participating sites is established.

All sites participating in a multi-site study are expected to rely on an sIRB to carry out the functions that are required for institutional compliance with IRB review set forth in the HHS regulations at 45 CFR 46. Participating sites are responsible for meeting other regulatory obligations, such as obtaining informed consent, overseeing the implementation of the approved protocol, and reporting unanticipated problems and study progress to the sIRB. Participating sites must communicate relevant information necessary for the sIRB to consider local context issues and state/local regulatory requirements during its deliberations. Participating sites are expected to rely on the sIRB to satisfy the regulatory requirements relevant to the ethical review. Although IRB ethical review at a participating site would be counter to the intent and goal of this policy, the policy does not prohibit any participating site from duplicating the sIRB. However, if this approach is taken, NIH funds may not be used to pay for the cost of the duplicate review.

Exceptions

Exceptions to the policy will be made where the proposed sIRB would be prohibited by a federal, state, or tribal law, regulation or policy (policy-based exceptions). Policy-based exceptions are automatically granted when identified in the sIRB plan.

The NIH sIRB policy allows the consideration of requests for other exceptions not based on a legal, regulatory, or policy requirement, if there is a compelling justification for the exception. These other exceptions must be reviewed and approved by NIH.

NIH funds many awards that are ancillary to other ongoing studies, or parent studies. During this transitional time, new multi-site non-exempt human subjects ancillary studies, that would otherwise be expected to comply with the sIRB policy, but are associated with ongoing multi-site parent studies, will not be required to use a sIRB of record until the parent study is expected to comply with the sIRB policy. This is a standing exception until the associated parent study is submitted for competitive renewal after the effective date of the sIRB policy.

The need for this time limited exception for these ancillary studies should be documented in the sIRB plan by identifying the associated parent study and will not require review and approval of the NIH Exceptions Review Committee.