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	Biomarkers: Bridging Pediatric and Adult Therapeutics (R21)
Activity Code	R21 Exploratory/Developmental Grant
Announcement Type	Reissue of PAR-11-324
Related Notices	February 21, 2017 - This PAR has been reissued as PAR-17-169. NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications.
Funding Opportunity Announcement (FOA) Number	PAR-13-295
Companion Funding Opportunity	PAR-13-296, R01 Research Project Grant PAR-13-299, R03 Small Grant Program
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.865
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) encourages grant applications that propose adapting adult biomarkers to children. This would include the application and validation of biomarkers developed in adults to pediatric diagnosis, prognosis, and estimation of disease progression, toxicity and response to therapy. Projects supported by this FOA will be confined to those biomarkers that correlate with a clinical observation, have been extensively studied in adults, and for which there is solid evidence that they have pediatric applications. Discovery of new biomarkers for use in new drug development or in preclinical studies is not part of this FOA. Also excluded are biomarkers for diseases that are unique to children and have no adult correlates.

Posted Date	August 1, 2013
Open Date (Earliest Submission Date)	September 16, 2013
Letter of Intent Due Date(s)	30 days prior to the application due date
Application Due Date(s)	Standard dates apply, 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.
AIDS Application Due Date(s)	Standard AIDS dates apply 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.
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	September 8, 2016
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the 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 the 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

This Funding Opportunity Announcement (FOA) encourages grant applications that propose adapting adult biomarkers to children. This would include the application and validation of biomarkers developed in adults to pediatric diagnosis, prognosis, and estimation of disease progression, toxicity and response to therapy.

Projects supported by this FOA will be confined to those biomarkers that correlate with a clinical observation, have been extensively studied in adults, and for which there is solid evidence that they have pediatric applications. Discovery of new biomarkers for use in drug development or in preclinical studies are not part of this FOA. Also excluded are biomarkers for diseases that are unique to children and have no adult correlates.

A biomarker has been defined as a characteristic that is objectively measured and evaluated as indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to therapeutic interventions (Biomarkers Definitions Working Group, NIH (Clin. Pharmacol. Ther. 2001, 69:89-95).

Different types of biomarkers have been identified. Biomarkers may play different roles in their use in pediatrics including but not limited to:

• Diagnostic biomarkers to identify the presence of a disease.
• Toxicity biomarkers to serve as early sensitive indicators of treatment-induced toxicity, before significant harm occurs.
• Biomarkers of risk which may identify subpopulations that respond to a treatment in different ways. For example, they may correlate with an increased risk of drug toxicity, or a risk of reduced drug efficacy. Such biomarkers serve as a cornerstone in personalizing medicine, enabling practitioners to select the most appropriate treatment for individual patients.
• Response predictive biomarkers to differentiate between patient populations that have a greater potential to respond to the particular treatment in question (favorably or unfavorably), as opposed to those that are physiologically unlikely to have that response. These may identify subpopulations that can respond to a medical treatment in different ways. For example, they may correlate with an increased risk of drug toxicity, or an increased chance of drug benefit. Such biomarkers serve as a cornerstone in personalizing medicine, enabling practitioners to select the most appropriate treatment for individual patients/animal populations.
• Prognostic biomarkers that identify a baseline patient or disease characteristic that categorizes patients by degree of risk for disease occurrence or progression. A prognostic biomarker informs about the natural history of the disorder in that particular patient in the absence of a therapeutic intervention. Prognostic biomarkers may assist in targeting appropriate populations for inclusion in clinical trials or general practice treatment with the approved therapy.
• Response identification biomarkers (pharmacodynamic biomarkers) early post-treatment biomarkers that indicate the particular patient has shown some biological response to the treatment, and thereby has the potential to receive benefit as compared to those who have not shown that biological response and cannot benefit.
• Biomarkers as surrogate endpoints in clinical trials to predict the clinical efficacy response to a treatment intervention. Surrogate endpoints may be of particular value in diseases where prolonged follow-up is required to determine the clinical outcome, such as neurodegenerative diseases, cancer, metabolic diseases, and infectious diseases that cause morbidity and mortality over a prolonged period of time. Surrogate endpoints may replace hard clinical end points as a measure of the effect of new therapies.

With few exceptions, the identification of biomarkers for use in pediatrics has followed the drug developmental process in which a drug is developed and studied in adults and subsequently considered for use in pediatrics.

The majority of candidate biomarkers have been studied in adult medicine. The identification and adaptation of adult biomarkers, for those conditions that are similar in children and adults, is an efficient, expedient and economical way to advance knowledge in the use of biomarkers in pediatrics.

Many biomarkers proposed or developed in pediatrics have not been subjected to the rigorous evaluation and validation process needed for their use in clinical trials. Cross-age studies of biomarkers, whether between children of different ages or between children or adolescents and adults, can provide new insights in disease, response to treatment and toxic effects

Data supporting the use of most biomarkers have been derived from a small number of patients, often without controls and without knowledge of the variability and time course in untreated patients.

There are a number of factors that may affect the usefulness of potential biomarkers and surrogate endpoints in pediatrics.

The marked difference in the natural history of some pediatric diseases when compared to adults, e.g., diabetes, asthma or epilepsy, must be taken into account when biomarkers that have been developed for the adult population are used in pediatrics. In addition, children are undergoing development and hence are not a homogeneous population. The amount or activity of many biomarkers used in pediatrics varies according to age and development; examples include glycosylated hemoglobin, prealbumin, beta-2 microglobulin, adhesion molecules and host immunologic markers such as CD4 counts. These differences may render adult biomarkers unsuitable for use in pediatrics. Conversely, uncovering age related changes may contribute to the understanding of the etiology, pathophysiology and drug effects in the pediatric population. The assumption that disease etiology, pathophysiology and drug effects are similar in children and adults may prove to be wrong in a number of pediatric disorders. Biomarkers may play an important role in identifying dissimilarities.

The small sample sizes characteristic of pediatric drug trials may also prevent the validation of surrogate endpoints and, for certain conditions such as hypertension and hyperlipidemias, the time to outcome endpoint is very long.

The majority of candidate biomarkers that are associated with a specific mechanism relevant to disease progression or toxicity, or are affected by drug treatment, have been studied in adult medicine. Advances in -omics technology provide a plethora of analytical tools to discover and analyze mechanism- and disease-specific biomarkers for drug development. Translation of innovative systems approaches such as genomics, proteinomics and metabolomics into a developmental framework has not been exploited to understand mechanisms of drug efficacy and toxicity in pediatrics. New technologies such as nanotechnology or functional imaging may need to be adapted for pediatric use before related biomarkers can be used in pediatric subpopulations.

There is paucity of pharmacodynamic studies in children that can be compared to similar measurements in adults. Most pediatric studies only provide pharmacokinetic data preventing the determination of pharmacokinetics-pharmacodynamics correlations and the target concentration that produces the desired effect. Some adult pharmacodynamic biomarkers may need to be adapted for pediatric use. Measurement devices may need to be specifically designed for children instead of as miniature versions of adult devices.

This FOA will foster collaboration between pediatric and adult medicine investigators in related disciplines.

Development of biomarkers entails a number of phases, from identification of promising molecular targets to longitudinal clinical trials in association with a treatment. The proposed research may use animal models in support of pediatric studies, stored clinical samples or new clinical testing. This FOA does not specify the type of biomarker. The proposed research should address issues of clinical significance in pediatric therapeutics. Proposed biomarkers must be biologically plausible, with limited inter-patient variability, and exhibit significant changes in activity, concentration or other appropriate quantitative measurement in response to treatment (effectiveness biomarkers) or in relation to severity and/or recurrence of a disease. The proposed research may uncover dissimilarities of adult biomarkers when applied to pediatric diseases.

The studies proposed in response to this FOA may require the resources of a clinical trial. Applicants for this FOA may be investigators of the parent clinical trial(s) whose data and/or materials and/or subjects they propose to use. It is expected that PDs/PIs who are not parent study investigators will work together with the parent study investigators in developing their applications. All ancillary study applications MUST include a letter or statement documenting that the patients, samples, data, and/or materials are available from the parent clinical trial and that the proposed ancillary study has the approval of the parent study’s investigators.

Applicants must submit a time line in their application demonstrating that the ancillary study can be completed within a reasonable timeframe.

Applicants can propose planning activities and pilot studies for validation of biomarkers that have shown early promise for use in pediatrics, with the goal that these biomarkers could be tested in larger clinical trials. They may also propose ancillary studies to ongoing or completed clinical trials.

The use of multi-disciplinary teams is strongly encouraged in order to test the use, in pediatrics, of adult biomarkers and bring new ideas, expertise and methodologies. This FOA seeks to encourage the use of innovative technologies.

Specific areas of research interest include, but are not limited to, the following:

• Identification or application of biomarkers for diagnosis, prognosis, and/or disease activity and validated in adult studies and drug trials.
• Application or adaptation and testing of reproducible and non-invasive toxicity biomarkers identified and validated in adult studies to detect subtle liver, kidney or CNS damage for a specific drug or a therapeutic class.
• Application and/or adaptation for use in children of pharmacodynamic endpoints developed in adults and capable of evaluating drug effects. Adaptation of adult devices may involve miniaturization and or development of child-friendly, e.g., non-invasive and discomfort- free measurements.
• Study of the effect of ontogeny at different pediatric age groups on adult pharmacodynamic biomarkers.
• Study of novel sepsis biomarkers in pediatric subpopulations (e.g., newborns and infants).
• Study of treatment effects of additional outcome variables not included in the parent trial which relate to biomarkers.
• Use of non-invasive measures of organ function (e.g., functional MRI, magnetic resonance spectroscopy, ultrasound, PET) to identify, characterize, and validate diagnostic biomarkers, intermediate surrogate endpoints, and prognostic biomarkers in children.
• Application of adult cDNA microarray, proteomics and metabolomics biomarkers for pediatric indications.
• Characterization of the effect of development in the amount or concentration, activity or other quantifiable measurement of an adult biomarker applicable to children.
• Miniaturization of methodologies of biomarker measurements and adaptation for pediatric use.
• Biomarkers to assess immune responsiveness in children compared to adults at different developmental stages.
• Identification and development of biomarkers that can be used in combination with, or substitute for, severity of illness scoring systems that are inadequate for stratification of patients according to disease severity or for estimation of a treatment effect.
• Study of related biomarkers (e.g., biomarkers of inflammation, oxidation or hypoxia) to determine whether the most specific and valid measurements of a composite marker provide a more accurate estimate of underlying pathogenic mechanisms than the individual biomarkers.
• Application of genetic and other novel diagnostic biomarkers for the diagnosis of a disease or condition.

The evolution and vitality of the biomedical sciences require a constant infusion of new ideas, techniques, and points of view. These may differ substantially from current thinking or practice and may not yet be supported by substantial preliminary data. By using the R21 mechanism, the NIH seeks to foster the introduction of novel scientific ideas, model systems, tools, agents, targets, and technologies that have the potential to substantially advance biomedical research.

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
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.
Award Budget	Direct costs are limited to $275,000 over a two-year period, with no more than $200,000 in direct costs allowed in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined two-year award period. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project period is two years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

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

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• 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

Other

• 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
• Regional 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

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) (formerly CCR) 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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.

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.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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:

George P. Giacoia, MD
Obstetric and Pediatric Pharmacology and Therapeutics Branch
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
6100 Executive Boulevard, Room 4A01C, MSC 7510
Bethesda, Maryland 20892-7510
(Rockville, Maryland 20852 for non USPS/courier service)Telephone: 301-496-5589
Email: gg65m@mail.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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.

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.

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, with the following additional instructions:

Research Strategy: Applicants must submit a time line in their application demonstrating that the ancillary study can be completed within a reasonable timeframe.

Letters of Support: The studies proposed in response to this FOA may require the resources of a clinical trial. All ancillary study applications MUST include a letter or statement documenting that the patients, samples, data, and/or materials are available from the parent clinical trial and that the proposed ancillary study has the approval of the parent study s investigators.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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.

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.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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.

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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.

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 Applying Electronically.

Important reminders:
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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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?

Innovation

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?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment

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?

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 six 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 six 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 Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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 proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the Center for Scientific Review in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY: 301-451-5936
Email: GrantsInfo@nih.gov

George P. Giacoia, MD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-5589
Email: gg65m@mail.nih.gov

John Firrell, Ph.D.
Center for Scientific Review
Telephone: 301-435-2598 (CSR)
Email: firrellj@csr.nih.gov

Bryan S. Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clark1@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.