Novel Approaches to Support Therapeutic Development in Ultra-Rare Cancers

Novel Approaches to Support Therapeutic Development in Ultra-Rare Cancers is sponsored by FDA Oncology Center of Excellence (OCE). Funds research to develop approaches to support drug development in ultra-rare pediatric and adult cancers, including molecularly-defined subsets of more common cancers, especially those with high unmet medical need and little economic incentive for commercial entities to conduct research.

Expired RFA-FD-24-038: Novel Approaches to Support Therapeutic Development in Ultra-Rare Cancers (U01) Clinical Trial Optional 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) U.S. Food and Drug Administration ( FDA ) NOTE: The policies, guidelines, terms, and conditions stated in this Notice of Funding Opportunity (NOFO) may differ from those used by the NIH. Where this NOFO provides specific written guidance that may differ from the general guidance provided in the grant application form, please follow the instructions given in this NOFO.

The FDA does not follow the NIH Page Limitation Guidelines or the NIH Review Criteria. Applicants are encouraged to consult with FDA Agency Contacts for additional information regarding page limits and the FDA Peer Review Process.

of Participating Organizations Office of the Commissioner ( OC ) / Oncology Center of Excellence ( OCE ) Funding Opportunity Title Novel Approaches to Support Therapeutic Development in Ultra-Rare Cancers (U01) Clinical Trial Optional Research Project Cooperative Agreements Funding Opportunity Number (FON) Companion Notice of Funding Additional Information on Eligibility .

Assistance Listing Number(s) Funding Opportunity Purpose The purpose of this NOFO is to encourage new approaches to support therapeutic development in ultra-rare pediatric and adult cancers, including molecularly-defined subsets of more common cancers. Open Date (Earliest Submission Date) Letter of Intent Due Date(s) April 05, 2024 by 11:59 PM Eastern Time.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission Applicants should be aware that on-time submission means that an application is submitted error free (of both Grants. gov and eRA Commons errors) by 11:59 PM Eastern Time on the application due date. applications will not be accepted for this NOFO.

AIDS Application Due Date(s) It is critical that applicants follow the Research (R) Instructions in How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from the HHS Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) 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 the Announcement I.

Notice of 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 Section I. Notice of Funding Opportunity Description Promoting the development of safe and effective drugs and biologics to treat patients with ultra-rare cancers is a priority for the FDA Oncology Center of Excellence (OCE),and was discussed at the 2022 AACR Annual Meeting in a session organized by FDA, Successful Development of Cancer Therapies for Ultra-Rare indications.

Many pediatric cancers are ultra-rare, and OCE developed a Pediatric Oncology program and recently launched the Rare Cancers Program to facilitate and expedite drug development for rare cancers.

FDA also published a Draft Guidance for Industry in 2019, Rare Diseases: Common Issues in Drug Development and recently launched the Accelerating Rare Diseases There is no official FDA definition for ultra-rare cancers; however, for the purposes of this NOFO, the FDA OCE refers to cancers with an approximate annual incidence in the US of 300 people or less as ultra-rare (a more stringent criterion compared to the threshold for a rare disease specified in the Orphan Drug Act based on a U.S. prevalence of <200,000 people).

Advancing technologies such as single cell multi-omic analyses - have helped define some ultra-rare cancers at the molecular level, providing new opportunities for targeted drug development. Pediatric oncology has several examples of tumor types with known translocation-induced, oncogenic driver fusion proteins.

Other examples of ultra-rare cancers defined today by molecular pathology include: neuroectodermal tumors, pulmonary blastoma, desmoplastic small round cell tumor (DSRCT), epithelioid sarcoma, diffuse intrinsic pontine glioma, fibrolamellar carcinoma, and malignant rhabdoid tumors.

Many of the challenges involved in drug development for ultra-rare cancers are similar to those for rare diseases and can include: Difficulty enrolling sufficient numbers of patients to clinical Limited financial incentives for drug development Insufficient understanding of the cancer pathophysiology, molecular characteristics, and natural history Limited or lack of timely access to molecular testing to determine eligibility for treatment with targeted therapies Complexities associated with designing clinical trials that are adequate to establish safety and effectiveness challenges, advances in understanding the molecular underpinnings of cancer through multi-omic analyses including genomics, epigenomics, transcriptomics, proteomics, and metabolomics is providing new opportunities in this field.

Purpose and Research Objectives The purpose of this NOFO is to fund research to develop approaches to support drug development in ultra-rare pediatric and adult cancers, including molecularly-defined subsets of more common cancers.

The NOFO focuses on supporting studies to improve therapeutic development in ultra-rare cancers with high unmet medical need where there is little economic incentive for commercial entities to conduct the research.

The primary focus of this NOFO is to support research that incorporates new approaches that could be either be applied to facilitate the development of new drugs for the treatment of ultra-rare cancers in general, or one or more specific ultra-rare cancers, including but not necessarily limited Studies to investigate the natural history of ultra-rare cancers.

This work could involve analyses of registries and/or other real world data Innovative approaches to identify new biologically-driven opportunities for clinical development of previously approved drugs or biologics (hereafter referred to as drugs), including drugs for which development has been discontinued, in ultra-rare cancers.

Research to exhaustively characterize the plasma-membrane protein expression (surfaceome) of an ultra-rare cancer and the presumed healthy tissue of origin, as well as the resident-tissue stem cells, by single-cell transcriptomics and proteomics.

These studies, and available correlative database analyses, should be designed to identify possible combinatorial signatures of plasma membrane proteins unique to the ultra-rare tumor Research to develop novel approaches to preserve the availability of drugs for which commercial developers have discontinued adult development that have strong potential in ultra-rare cancers but lack financial incentives for commercial development Direct funding of interventional trials is outside the scope of this NOFO.

In addition, studies with a primary goal of developing a specific therapeutic product will not be supported. VIII. Other Information for award authorities and regulations.

Section II. Award Information Cooperative Agreement: A financial assistance mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, FDA scientific or program staff will assist, guide, coordinate, or participate in project activities.

See Section VI. 2 for additional information about the substantial involvement Application Types Allowed Resubmissions, and New applications and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Optional: Accepting applications that either propose or do not propose clinical trial(s) determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards The number of awards is contingent upon FDA appropriations and the submission of a sufficient number of meritorious applications.

Award(s) will provide one (1) year of support and include future recommended support for (2) (two) additional year(s) contingent upon annual appropriations, availability of funding and satisfactory recipient performance. FDA /OCE intends to commit $500,000 in FY 2024 to fund 1 Application budgets need to reflect the actual needs of the proposed project.

and should not exceed the following in total costs (direct The scope of the proposed project should determine the project period. The maximum project period is THREE (3) years.

HHS grants policies as described in the HHS Grants Policy Statement will apply to the applications submitted and awards 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 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 Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Nonprofits without 501(c)(3) IRS Status (Other than Institutions 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 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 Organizations) Non-domestic (non-U.S.) Entities (Foreign Organizations) are Non-domestic (non-U.S.) components of U.S. Organizations are eligible Foreign components, as defined in the HHS 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.

Failure to complete registrations in advance of a due date is not a valid reason for a Award Management (SAM) Applicants must complete and maintain an active registration, 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.

and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM. gov registration process.

The same UEI must be used for all registrations, as well as on the grant application. - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registration; 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 Applicants must have an active SAM registration in order to complete the Grants. gov 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 Eligible Individuals (Program Director/Principal 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 their organization to develop an application for support.

Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for FDA 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) This NOFO does not require cost sharing as defined in the HHS 3. Additional Information Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The FDA will not accept duplicate or highly overlapping applications under review at the same time. This means that the FDA will A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application. 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 NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system 2.

Content and Form of Application It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this notice of funding opportunity 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 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: All page limitations described in the How to Apply Application Guide of Page Limits must be followed.

with the following exceptions or additional For this specific NOFO, the Research Strategy section is Instructions for Application Submission The following section supplements the instructions found in the How to Apply Application Guide and should be used for preparing an application to All instructions in the SF424 (R&R) Application Guide SF424(R&R) Project/Performance Site Locations All instructions in the SF424 (R&R) Application Guide must SF424(R&R) Other Project Information All instructions in the SF424 (R&R) Application Guide SF424(R&R) Senior/Key Person Profile All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide must be followed.

with the following additional instructions: Applications requesting multiple years of support must complete and submit a separate detailed budget breakdown and narrative justification for each year of financial support requested. If an applicant is requesting indirect costs as part of their budget, a copy of the most recent Federal indirect cost rate or F&A agreement must be provided as part of the application submission.

This agreement should be attached to the RESEARCH & RELATED Other Project Information Component as line #12 'Other Attachments'. If the applicant organization has never established an indirect cost rate and/or does not have a negotiated Federal indirect cost rate agreement, a de minimis indirect cost rate of 10 percent (10%) of modified total direct costs (MTDC) will be allowed.

MTDC means all direct salaries and wages, applicable fringe benefits, materials and supplies, services, travel, and subaward and subcontracts up to the first $25,000 of each subaward or subcontract.

MTDC excludes equipment, capital expenditures, charges for patient care, rental costs, tuition remission, scholarships and fellowships, participant support costs and the portion of each subaward and subcontract in Indirect/F&A costs under grants to foreign and international organizations will be funded at a fixed rate of 8 percent of modified total direct costs (MTDC), exclusive of tuition and related fees, direct expenditures for equipment, and subawards in excess of $25,000.

(With the exception of the American University of Beirut and the World Health Organization, which are eligible for full F&A cost reimbursement). Awards to domestic organizations with a foreign or international consortium participant may include 8 percent of MTDC, exclusive of tuition and related fees, direct expenditures for equipment, and subawards in excess of $25,000.

All instructions in the SF424 (R&R) Application Guide must PHS 398 Cover Page Supplement All instructions in the SF424 (R&R) Application Guide All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: Research Strategy: The research strategy is limited to 30 pages.

It should include a description of the specific aims and research strategy, and other research plan sections as normally required by PHS 398.

In addition, applicants should also propose a plan for scientific discussions and interactions with FDA to obtain regulatory science input to ensure that the project continues to address applied science of high Where applicable, applicants should describe any organizational partnerships with institutions and organizations serving historically underserved communities such as: Historically Black Colleges and Universities (HBCUs); Minority Serving Institutions (MSIs); Hispanic-Serving Institutions; Tribal Colleges and Universities; Asian American and Pacific Islander-Serving Institutions; Women&rsquo;s Colleges and Universities; Organizations serving veterans, individuals with disabilities, LGBTQIA+ individuals, economically Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification: All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Generally, Resource Sharing Plans are expected, but they are not applicable for this NOFO. Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: A Data Management and Sharing Plan is not applicable for 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 human subjects research, clinical research, and/or NIH-defined 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 Record: PHS Human Subjects and Clinical Trials Information All instructions in the SF424 (R&R) Application Guide must does NOT apply to a study that can be described but will not start immediately All instructions in the SF424 (R&R) Application Guide PHS Assignment Request Form All instructions in the SF424 (R&R) Application Guide Foreign (non-U.S.) organizations must follow policies described Grants Policy Statement , and procedures for foreign organizations.

3. Unique Entity Identifier and System for Award 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 , FDA's electronic system for grants administration.

FDA 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. Late applications will not be accepted for this NOFO.

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. This initiative is not subject to intergovernmental review.

All FDA awards are subject to the terms and conditions, cost principles, and other considerations described in the HHS Grants Policy Statement and 45 CFR 75, currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions. Pre-award costs are allowable only as described in the HHS Grants Policy Statement .

Additional funding restrictions may be part of the Notice 7. Other Submission Requirements and Information Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications 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, 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 form .

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 FDA. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization&rsquo;s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the assigned Grants Management Specialist and responsiveness by components of participating organizations , FDA.

Applications that are incomplete, non-compliant and/or nonresponsive will Post Submission Materials Post-submission materials are those submitted after submission of the grant application but prior to objective review. They are not intended to correct oversights or errors discovered after submission of the application.

FDA accepts limited information between the time of initial submission of the application and the time of objective review. Applicants must contact the assigned Grants Management Specialist to receive approval, prior to submitting any post submission materials. Acceptance and/or rejection of any post submission materials is at the sole discretion of the FDA.

Any inquiries regarding post submission materials should be directed to the assigned Grants Management Specialist. Section V. Application Review Information FDA grants management and program staff will review all applications sent in response to this NOFO.

To be responsive, an application must be submitted in accordance with the requirements of this notice. Applications found to be non-responsive will receive notice that the application will not be reviewed. The following criteria will be used to determine whether an application is responsive to this NOFO.

The disease to be studied is an ultra-rare cancer (consistent with the definition above) and is of high unmet medical need. Studies of molecular subsets of more common cancers that meet this definition are within Lack of economic and commercial incentives to conduct the proposed research and evidence that ongoing efforts by other stakeholders are not likely to achieve the goals of the proposed research.

Proposed research does not involve an interventional trial. Observational trials, or studies of approaches/innovations to implement in interventional trials for ultra-rare cancers may be supported under this NOFO.

Primary goal of the research must NOT be to develop a specific therapeutic product; however, novel approaches (e.g., CRISPR CAS mediated genomic deletion of fusion genes) to target specific biological pathways directly involved in the genesis and maintenance of the neoplastic phenotype, or identification of combinatorial cell membrane epitopes highly specific to an ultra-rare tumor, Applications should include information to support fulfillment of each of the above criteria Additional information may be required upon request after submission of an application to determine responsiveness, for example, regarding population estimate and rationale.

Only the review criteria described below will be considered Reviewers will consider each of the review criteria below in the determination of scientific/technical merit. 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? Investigator(s) (20 Points) 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?

Program Alignment (20 Points) Does the project address a specific, practical problem of significance to regulatory science (defined as the science of developing new tools, standards and approaches to assess the safety, efficacy quality and performance of some FDA-regulated products) or regulatory decision making rather than expanding general knowledge?

Does the proposal include robust support for how achievement of the research objectives will provide a meaningful, direct effect on drug development for one or more ultra-rare cancers? Does the proposal contain specific, well-defined objectives and a clear plan to address each objective? 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 If the project involves human subjects and/or 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 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 but will not give separate scores for these items and should not consider them in providing an overall score.

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 The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research.

Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous