PAR-25-227: Natural History of Disorders Screenable in the Newborn Period (R01 Clinical Trial Optional)

PAR-25-227: Natural History of Disorders Screenable in the Newborn Period (R01 Clinical Trial Optional) is sponsored by National Institutes of Health (NIH). Supports research on the natural history of disorders detectable in newborns, including leukodystrophies.

PAR-25-227: Natural History of Disorders Screenable in the Newborn Period (R01 Clinical Trial Optional) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ) Funding Opportunity Title Natural History of Disorders Screenable in the Newborn Period (R01 Clinical Trial Optional) R01 Research Project Grant March 31, 2025 - This funding opportunity was updated to align with agency priorities.

Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 .

August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy.

See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Funding Opportunity See Section III. 3.

Additional Information on Eligibility. Assistance Listing Number(s) Funding Opportunity Purpose This Notice of Funding Opportunity (NOFO) encourages applications that will expand knowledge of the natural history of disorders that currently are, or may become, part of statewide newborn screening programs.

A comprehensive understanding of the natural history of a condition is necessary to facilitate appropriate interventions for infants identified by newborn screening. Characterization of the sequence and timing of symptom development provides information crucial for developing targeted, age-appropriate treatments and for establishing a baseline against which to assess novel interventions.

In addition, for some conditions, establishment of genotype-phenotype correlations may facilitate prediction of the clinical course; for others, identification of modifying genetic, epigenetic, or environmental factors may enhance understanding of clinical outcomes.

Comprehensive data on the natural history of a condition will facilitate the field’s ability to: 1) identify the underlying biological mechanisms; 2) understand the genetic and clinical heterogeneity and phenotypic expression of the condition; 3) improve diagnostic accuracy; 4) facilitate clinical trials by providing comprehensive natural history data; 5) prevent, manage, and treat symptoms and complications of the condition; 6) furnish physicians and families with needed support and predictive information about the condition; and 7) establish data collection systems or patient registries to collect longitudinal data (e.g., child/family outcomes following newborn screening).

Funding Opportunity Goal(s) This purpose of this Notice of Funding Opportunity (NOFO) encourages applications that will expand knowledge of the natural history of disorders that currently are, or may become, part of statewide newborn screening programs. A comprehensive understanding of the natural history of a condition is necessary to facilitate appropriate interventions for infants identified by newborn screening.

Characterization of the sequence and timing of symptom development provides information crucial for developing targeted, age-appropriate treatments and for establishing a baseline against which to assess novel interventions.

In addition, for some conditions, establishment of genotype-phenotype correlations may facilitate prediction of the clinical course; for others, identification of modifying genetic, epigenetic, or environmental factors may enhance understanding of clinical outcomes.

Comprehensive data on the natural history of a condition will facilitate the field’s ability to: 1) identify the underlying biological mechanisms; 2) understand the genetic and clinical heterogeneity and phenotypic expression of the condition; 3) improve diagnostic accuracy; 4) facilitate clinical trials by providing comprehensive natural history data; 5) prevent, manage, and treat symptoms and complications of the condition; 6) furnish physicians and families with needed support and predictive information about the condition; and 7) establish data collection systems or patient registries to collect longitudinal data (e.g., child/family outcomes following newborn screening).

Open Date (Earliest Submission Date) The following table includes NIH standard due dates marked with an asterisk. Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization.

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.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH 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.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. Part 1.

Overview Information Part 2. Full Text of Announcement Section 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 Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description This Notice of Funding Opportunity (NOFO) encourages applications that will expand knowledge of the natural history of disorders that currently are, or may become, part of statewide newborn screening programs.

A comprehensive understanding of the natural history of a condition is necessary to facilitate appropriate interventions for infants identified by newborn screening. Characterization of the sequence and timing of symptom development provides information crucial for developing targeted, age-appropriate treatments and for establishing a baseline against which to assess novel interventions.

In addition, for some conditions, establishment of genotype-phenotype correlations may facilitate prediction of the clinical course; for others, identification of modifying genetic, epigenetic, or environmental factors may enhance understanding of clinical outcomes.

Comprehensive data on the natural history of a condition will facilitate the field’s ability to: 1) identify the underlying biological mechanisms; 2) understand the genetic and clinical heterogeneity and phenotypic expression of the condition; 3) improve diagnostic accuracy; 4) facilitate clinical trials by providing comprehensive natural history data; 5) prevent, manage, and treat symptoms and complications of the condition; 6) furnish physicians and families with needed support and predictive information about the condition; and 7) establish data collection systems or patient registries to collect longitudinal data (e.g., child/family outcomes following newborn screening).

The Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) advises the Secretary of the Department of Health and Human Services on the most appropriate application of universal newborn screening tests, technologies, policies, and standards to effectively reduce morbidity and mortality in newborns and children with, or at risk for, heritable disorders.

Since 2006, the ACHDNC has worked with the Secretary to identify heritable disorders to comprise the Recommended Uniform Screening Panel (RUSP), a list of conditions that the Secretary recommends that all states include in their newborn screening (NBS) programs. The RUSP originally included 29 “core conditions” along with 25 secondary conditions detectable in the differential diagnoses of core conditions.

Now, the RUSP has expanded to include 38 core and 26 secondary disorders . Under the Newborn Screening Saves Lives Act of 2007 and its 2014 reauthorization, the Hunter Kelly Newborn Screening Research Program within NICHD is authorized to carry out, coordinate, and expand research in newborn screening.

State determinations of which conditions are included on newborn screening panels rely on an analysis of the severity and incidence of each condition under consideration, the specificity and sensitivity of the screening test, the natural history of the condition, the efficacy and safety of available treatments, and the public health impact of adding the condition to the panel.

Much recent research has focused on the development of screening tools and treatments for conditions identifiable through newborn screening and, as a result, a comprehensive understanding of the natural history of specific conditions is often lacking.

This knowledge gap impedes the development and assessment of the efficacy of treatments and interventions for infants and children identified via newborn screening, particularly as they age. In addition, many conditions are characterized by genetic and clinical heterogeneity, including in the time of onset.

Without a deeper knowledge of disease progression, it is often difficult to identify candidate individuals for interventions and the proper ages at which to initiate treatment in late-onset forms of conditions identified through newborn screening. Improved understanding of the clinical aspects of these conditions throughout the lifespan would enhance the development of targeted, age-appropriate therapeutics.

Advances in technology continue to provide new opportunities to improve the scope and quality of newborn screening services. The Hunter Kelly Newborn Screening Research Program prioritizes the development of new (or improved) screening tests, novel interventions for conditions which are not yet treatable, and improved intervention strategies for conditions with existing treatments.

Furthermore, NICHD supports the identification of additional conditions appropriate for newborn screening; support of systems to facilitate data collection and long-term patient follow-up; education of the provider workforce; development and implementation of appropriate communication systems for parents and providers; recruitment and inclusion of research participants from groups historically underrepresented in clinical research; and sponsorship of an ongoing program of research and researcher training.

As part of the Hunter Kelly Newborn Screening Research Program, this NOFO is designed to facilitate research that will lead to expanded knowledge of the natural history of conditions that currently, or will likely in the future, benefit from newborn screening.

Disorders to be considered include, but are not limited to: inborn errors of metabolism, lysosomal storage disorders, hemoglobinopathies, congenital immunodeficiency syndromes, mitochondrial disorders, neuromuscular disorders (such as spinal muscular atrophy (SMA) and muscular dystrophies), and genetic and/or epigenetic syndromes including Fragile X and others.

Projects may propose the study of multiple conditions as long as the need for natural history data is demonstrated for each. Applicants may also propose multi-state consortia of screening programs to provide natural history information for one or more disorders.

Applications Responsive to this NOFO Applications must be relevant to one or more conditions that each either 1) already benefits from newborn screening, but requires further natural history information to better understand and/or treat the conditions, or 2) is a condition that could benefit from newborn screening in the future.

Applicants can design their studies to address one or more of the following goals related to the target condition(s): Identify the biological mechanisms underlying the condition(s); Improve the understanding of the genetic and clinical heterogeneity and phenotypic expression of the condition(s) – including the factors that can facilitate distinction between early- and late-onset forms of disease; Improve diagnostic accuracy; Facilitate clinical trials by providing comprehensive natural history data; Prevent, manage, and treat symptoms and complications of the condition(s); Furnish physicians and families with needed support and predictive information about the condition(s); Establish data collection systems or patient registries to collect longitudinal data (e.g., child/family outcomes following newborn screening).

Applications Not Responsive to this NOFO Applications must address one or more of the above issues in order to be considered responsive to this NOFO. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs. See Section VIII.

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

Application Types Allowed The OER Glossary and the How to Apply 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).

Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Application budgets are not limited but need to reflect the actual needs of the proposed project.

The scope of the proposed project should determine the project period. 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 NOFO.

Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education 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 Organizations) Non-domestic (non-U.S.) Entities (Foreign Organizations) 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 How to Apply- 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 late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

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. 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. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registrations; 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 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 their organization to develop an application for 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 How to Apply-Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

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, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

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 NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). 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 solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - 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. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. 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 this NOFO.

All instructions in the How to Apply - Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement All instructions in the How to Apply- Application Guide must be followed.

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: Research Strategy: Applications must be relevant to one or more conditions that each either 1) already benefits from newborn screening, but requires further natural history information to better understand and/or treat the condition, or 2) is a new condition that would benefit from newborn screening.

Sufficient evidence must be provided for how further natural history knowledge would either: 1) improve clinical decision-making for infants identified with the condition(s) through newborn screening, or 2) provide evidence to justify the addition of the condition(s) to newborn screening panels.

If the application focuses on late-onset forms of screenable conditions, it must be clear how the study results could aid clinicians in distinguishing between early- and late-onset forms and/or to properly time treatments and interventions.

Additionally, the Research Strategy section must address one or more of the following goals related to the target condition(s): Identify the biological mechanisms underlying the condition(s); Improve the understanding of the genetic and clinical heterogeneity and phenotypic expression of the condition(s); Improve diagnostic accuracy; Facilitate clinical trials by providing comprehensive natural history data; Prevent, manage, and/or treat symptoms and complications of the condition; Furnish physicians and families with needed support and predictive information about the condition(s); Establish data collection systems or patient registries to collect longitudinal data (e.g., child/family outcomes following newborn screening).

Note that a natural history study by its nature may not be hypothesis-driven or innovative in design.

However, it must still provide innovation in other aspects of the study, such as, but not limited to: Novel methods for screening and/or diagnosis, such as those that improve sensitivity, efficiency, or reliability; Novel insights regarding stratification of the affected population for understanding the etiology, disease progression, or response to therapy; Novel approaches for identifying biomarkers or phenotypic features that predict disease course and/or response to intervention; Novel methods of reaching underserved patient populations.

It should be evident 1) why further natural history data for the chosen condition(s) is needed and 2) how the proposed studies could move the field forward. Furthermore, the current research landscape for the chosen condition(s) must be described to ensure that the study properly addresses any condition-specific considerations.

Applications are encouraged to describe how the standardization of data collection and data collection instruments – including the use of existing NIH Common Data Elements (CDEs) – will be promoted, and how these data collection techniques will facilitate data integration and collaboration. Additionally, applications should describe how proposed assessments have been, or will be, validated.

If the application proposes the development of a data collection system, it must be clear how that system will support and advance the goals of the study. Resource Sharing Plan : Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions: All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan.

All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan. Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

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 How to Apply- 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 How to Apply- 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 How to Apply- Application Guide must be followed. PHS Assignment Request Form All instructions in the How to Apply- Application Guide must be followed.

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement , and procedures for foreign organizations described throughout the How to Apply- Application Guide. 3. Unique Entity Identifier and System for Award Management (SAM) See Part 2.

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. 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 Grants Policy Statement Section 2. 3. 9.

2 Electronically Submitted Applications . 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 How to Apply-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 Section 7.

9. 1 Selected Items of Cost. 7.

Other Submission Requirements and Information Applications must be submitted electronically following the instructions described in the How to Apply 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 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 NIH. 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’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply 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 NICHD. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Requests of $500,000 or more for direct costs in any year Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200. 113 and NIH Grants Policy Statement Section 4.

1. 35 . Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected] .

Post Submission Materials Applicants are required to follow the instructions for post-submission materials, as described 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 scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. Factor 1.

Importance of the Research (Significance and Innovation) Evaluate the importance of the proposed research in the context of current scientific challenges and opportunities, either for advancing knowledge within the field, or more broadly. Assess whether the application addresses an important gap in knowledge in the field, would solve a critical problem, or create a valuable conceptual or technical advance.

Evaluate the rationale for undertaking the study, the rigor of the scientific background for the work (e.g., prior literature and/or preliminary data) and whether the scientific background justifies the proposed study. Evaluate the extent to which innovation influences the importance of undertaking the proposed research.

Note that while technical or conceptual innovation can influence the importance of the proposed research, a project that is not applying novel concepts or approaches may be of critical importance for the field. Evaluate whether the proposed work applies novel concepts, methods or technologies or uses existing concepts, methods, technologies in novel ways, to enhance the overall impact of the project.

Evaluate the extent to which the investigated condition(s) each either (1) already benefits from newborn