Mechanistic and Hemodynamic Basis of Diffuse White Matter Disease in Vascular Contributions to Cognitive Impairment and Dementia (VCID) (R01 Clinical Trial Optional)

Mechanistic and Hemodynamic Basis of Diffuse White Matter Disease in Vascular Contributions to Cognitive Impairment and Dementia (VCID) (R01 Clinical Trial Optional) is sponsored by National Institute of Neurological Disorders and Stroke (NINDS). This opportunity supports mission-aligned projects and measurable outcomes.

Expired RFA-NS-19-039: Mechanistic Basis of Diffuse White Matter Disease in Vascular Contributions to Cognitive Impairment and Dementia (VCID)(R01 Clinical Trial Not Allowed) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Neurological Disorders and Funding Opportunity Title Mechanistic Basis of Diffuse White Matter Disease in Vascular Contributions to Cognitive Impairment and Dementia (VCID)(R01 Clinical Trial Not Allowed) R01 Research Project Grant April 5, 2024 - This RFA has been reissued as PAR-24-196 .

Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity See Section III. 3. Additional Information on Eligibility .

Catalog of Federal Domestic Assistance (CFDA) Number(s) Funding Opportunity Purpose The purpose of this funding opportunity announcement (FOA) is to support hypothesis-testing research to elucidate cellular and molecular mechanisms that underlie diffuse white matter disease and small vessel disease in the brain and how they may contribute to cognitive impairment and dementia.

Open Date (Earliest Submission Date) Letter of Intent Due Date(s) August 14, 2019, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s) Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide ,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV . When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information Part 2. Full Text of Announcement Section I.

Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV.

Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII.

Agency Contacts Section VIII. Other Information Part 2. Full Text of Announcement Section I.

Funding Opportunity Description Diffuse brain white matter disease is highly prevalent in the elderly, and has been clinically associated with vascular contributions to cognitive impairment and dementia (VCID) in both men and women. Diffuse white matter disease is thought to include a variety of pathologies including demyelination and/or fiber loss due to multifocal infarction and local ischemia.

It is often accompanied by arteriosclerosis in deep penetrating arteries, multiple infarcts in the basal ganglia, brainstem or cerebellum. Though most commonly extending out from the periventricular surfaces, it may also occur in subcortical white matter.

Diffuse white matter disease is typically detected in clinical settings as hyperintensity on magnetic resonance imaging (MRI) or signal loss on computed tomography x-ray (CT) scan; diffuse white matter disease can be detected histologically as well, for example in human pathology and in studies using animal models.

Despite the prevalence and potential significance of white matter disease for cerebrovascular disease etiology and cognitive outcomes, much remains to be learned about the cellular and molecular causes, regional vulnerability, and progression over time. The physiological consequences of diffuse white matter disease on local axon and neural circuit function are almost completely unknown.

The purpose of this FOA is to address some of the many gaps in knowledge of the biologic mechanisms of the commonly occurring, cerebrovascular disease and age-related diffuse white matter disease at the molecular, cellular, tissue and brain circuit level.

The ultimate goal of this fundamental research is to inform future efforts to reduce the burden of illness due to age-related vascular contributions to cognitive impairment and dementia. This FOA is informed by the outcomes of the 2013 Alzheimer's Disease-Related Dementias Conference (ADRD 2013) held in response to the National Plan to Address Alzheimer's Disease, and by the 2014 Small Blood Vessels: Big Health Problems Workshop .

Characteristics of Responsive Applications Projects that elucidate cellular and molecular causes, progression and neural consequences of diffuse white matter disease including deep, small vessel cerebrovascular disease such as multifocal, small, silent brain infarcts frequently associated with VCID are within the scope of this FOA.

Diffuse white matter disease preferentially affects deep brain regions, and as such has been more difficult to study than cortical based vascular or tissue pathology.

Applications may focus on diffuse white matter disease extending out from the periventricular surfaces, diffuse white matter disease in subcortical white matter, or diffuse white matter disease that is accompanied by arteriosclerosis in deep penetrating arteries and with multiple infarcts in the basal ganglia, brainstem or cerebellum.

This FOA specifically promotes research utilizing methods that can address mechanisms of pathological events in vessels and tissue that were previously poorly accessible and therefore may not have been as well studied, such as periventricular white matter, basal ganglia, brainstem, deep cerebellum or subcortical white matter.

Applications may use (or further develop) state of the art and emergent technologies that are poised to advance mechanistic understanding of diffuse white matter disease in VCID. Accordingly, new tools, some developed as part of the BRAIN Initiative , may be useful to approach the scientific questions posed by this FOA.

Proposed research may be performed using model systems, including in vivo and ex vivo models, as well as models established using cells, including but not limited to human cells. Human subjects research may be proposed only if it further informs cellular and molecular mechanistic studies that are the main focus here.

Cognitive assessments (in humans and animals) as they relate to disease mechanisms and progression are within the scope of this FOA; however, molecular, cellular, tissue mechanisms and the consequences of diffuse white matter disease on neural circuit function are the main foci of interest. Cognitive assessments are not a requirement to be responsive.

Studies that investigate the interplay of vascular mechanisms as well as co-morbidities with diffuse white matter cerebrovascular disease may be of interest, including, for example: hypertension, diabetes and other metabolic disorders, Alzheimer's type dementia, cerebral amyloid angiopathy, inflammation, dyslipidemia, and other known risk factors in cerebro- and cardiovascular disease.

The physiological consequences of diffuse white matter disease on local axon and neural circuit function are almost completely unknown, and are within the scope of this FOA. Non-Responsive Areas of Research No clinical trials, as defined by the NIH , will be supported under this FOA. No epidemiological studies will be supported under this FOA.

Studies of white matter disease that are not directly related to cerebrovascular disease and VCID, such as in multiple sclerosis, traumatic brain injury, chronic traumatic encephalopathy, and concussions are out of scope; the focus here is on diffuse white matter disease related to vascular dysfunction frequently associated with age-related cognitive impairment and dementia.

Applications proposing screens (e.g. 'omics studies, genome wide association, network biology) designed to discover new candidate molecules, genes, etc., are out of scope; however, such approaches may be used to characterize and test hypotheses on specific proposed molecular candidates and mechanisms. Studies that are focused on biomarkers are out of scope, and may consider the following FOAs: RFA-NS-16-019 and RFA-NS-16-020 .

Opportunities for Partnership Projects involving partnerships with industry, small businesses or non-government organizations are encouraged under this FOA. The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds.

Applicants are strongly encouraged to consult with NINDS Scientific/Research Staff early on during the planning stage of their application (see Agency contacts, Section VIII). This early contact will provide an opportunity to clarify the applicant's understanding of NINDS goals, policies and guidelines. See Section VIII.

Other Information for award authorities and regulations. Section II. Award Information Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed ( PAR-18-413 , PA-18-484 ) The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Not Allowed: Only accepting applications that do not propose clinical trials Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards NINDS intends to commit up to $3,750,000 in FY 2020 to fund up to 6 awards.

Application budgets are not limited but need to reflect the actual needs of the proposed project. The maximum project period is 5 years. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education: Hispanic-serving Institutions Historically Black Colleges and Universities (HBCUs) Tribally Controlled Colleges and Universities (TCCUs) Alaska Native and Native Hawaiian Serving Institutions Asian American Native American Pacific Islander Serving Institutions (AANAPISIs) Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized) Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Institutions) Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement , are allowed. Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted.

Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission. Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number.

After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application. System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually.

The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code. NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.

eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants. gov registration , but all registrations must be in place by time of submission.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants. gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.

gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.

If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support.

Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support. For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement. 3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.

A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application. An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101 ) Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced.

Applications that are out of compliance with these instructions may be delayed or not accepted for review. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. By the date listed in Part 1.

Overview Information , prospective applicants are asked to submit a letter of intent that includes the following information: Descriptive title of proposed activity Name(s), address(es), and telephone number(s) of the PD(s)/PI(s) Names of other key personnel Participating institution(s) Number and title of this funding opportunity The letter of intent should be sent to: Roderick A. Corriveau, Ph. D.

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed Instructions for Application Submission The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA. All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations All instructions in the SF424 (R&R) Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the SF424 (R&R) Application Guide must be followed. SF424(R&R) Senior/Key Person Profile All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. PHS 398 Cover Page Supplement All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: Specific Aims : State the aims and hypotheses to be tested. Indicate clearly and succinctly how, via the proposed Specific Aims, this research program will inform mechanistic understanding of diffuse white matter disease in VCID. Research Strategy : Organize the Research Strategy by Significance, Innovation, and Approach.

Significance: Provide a clear rationale that is supported by strong preliminary data. Innovation: Describe innovative aspects of the application that advance mechanistic understanding of diffuse white matter disease in VCID. Approach: Describe the approach clearly, and how it addresses the goals of the FOA.

If an application plans to utilize the infrastructure or resources of existing projects, whether funded by the NINDS, other governmental or nongovernmental entities, letters of support from the project leadership detailing approval, feasibility, terms of collaboration and data sharing must be included.

If utilization of extant samples and data is proposed as an element of the study, appropriate consent must be documented, and letters of support or approval for use of those samples must be included. Resource Sharing Plan : Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide. Appendix: Do not use the Appendix to circumvent page limits.

Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. The Appendix should contain the following materials if appropriate to the proposed study: Human Subjects Research, if applicable: If human subjects research is proposed, appropriate informed consent must be obtained, with supporting documentation included in the Appendix.

IRB approval of the informed consent form(s) is not required at the time of submission of the application. However, drafts of informed consent form(s) must be included.

If an ancillary study to an existing project, include also: The protocol for the parent study Investigator's brochure, if applicable, for the parent clinical study Consent forms (if ancillary, for both the parent clinical study and the ancillary studies, if different) Written agreement to conduct the ancillary study from appropriate officials with signing authority from parent clinical (or contract or resource etc.) study sponsors Ancillary studies must not interfere with the parent study and must not place undue burden on participants.

Informed consent must always meet all NIH and legal requirements for projection of human subjects and for sharing. Resource Sharing Plan : Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide. The following modifications also apply: All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

PHS Human Subjects and Clinical Trials Information When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions: If you answered Yes to the question Are Human Subjects Involved?

on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record. Study Record: PHS Human Subjects and Clinical Trials Information All instructions in the SF424 (R&R) Application Guide must be followed.

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed. PHS Assignment Request Form All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement , and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide. 3. Unique Entity Identifier and System for Award Management (SAM) See Part 1.

Section III. 1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants. gov 4.

Submission Dates and Times Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day. Organizations must submit applications to Grants. gov (the online portal to find and apply for grants across all Federal agencies).

Applicants must then complete the submission process by tracking the status of the application in the eRA Commons , NIH’s electronic system for grants administration. NIH and Grants. gov systems check the application against many of the application instructions upon submission.

Errors must be corrected and a changed/corrected application must be submitted to Grants. gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission. Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission. Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E. O.

12372) This initiative is not subject to intergovernmental review. All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement . Pre-award costs are allowable only as described in the NIH Grants Policy Statement .

7. Other Submission Requirements and Information Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide . If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance . For assistance with application submission, contact the Application Submission Contacts in Section VII .

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide. See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations , NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed. An Applicant Webinar will be scheduled to provide an overview of the FOA and answer questions.

The webinar is open to all prospective applicants. Participation in the teleconference is not a prerequisite for applying, and is not required for a successful application. Information about how to participate in the webinar will be posted at http://www.

ninds. nih. gov .

Potential applicants are encouraged to submit their questions or comments to [email protected] prior to the meeting. Afterwards, the webinar slides and a summary of the questions and answers will be posted on the same site. NIH will also post a list of Frequently Asked Questions (FAQs) and answers; this information may be updated without additional notice.

Post Submission Materials Applicants are required to follow the instructions for post-submission materials, as described in the policy . Any instructions provided here are in addition to the instructions in the policy. Section V.

Application Review Information Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved?

How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field ? Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training?

If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense?

Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project ?

Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults) , justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects .

Inclusion of Women, Minorities, and Individuals Across the Lifespan When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed.

For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research .

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals.

Reviewers will assess the use of chimpanzees as they would any