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

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to support research projects designed to use sound and innovative strategies to solve specific problems and paradoxes in childhood cancer research identified by the National Cancer Institute (NCI) as the NCI’s Pediatric Provocative Questions (Pediatric PQs).

This program covers two companion FOAs of identical scientific scope. This FOA encourages applications for well-developed research projects using the NIH R01 funding mechanism. The companion FOA, PAR-16-217, is a companion announcement for exploratory/developmental projects using the NIH R21 mechanism.

To be appropriate for this FOA, each application must specifically address a single Pediatric PQs listed in this FOA.

Background

The objective of the Pediatric Provocative Questions (Pediatric PQ) program is to extend the successful NCI PQ Initiative to childhood cancers. The Pediatric PQ program is intended to stimulate specific areas of childhood cancer research that are understudied, neglected, paradoxical, and/or have been difficult to address in the past. To identify such areas, the NCI sponsored workshops to identify, articulate, and prioritize particularly compelling but understudied problems in pediatric cancer research to create a list of Pediatric PQs

This FOA includes 9 Pediatric PQs that represent diverse fields relevant to childhood cancer research, but all are framed to inspire interested scientists to conceive new approaches and/or feasible solutions. These Pediatric PQs are not intended to represent the full range of NCI's priorities in childhood cancer research. Rather, they are meant to challenge cancer researchers to think about and elucidate specific problems in key areas of pediatric cancer research that are deemed important but have not received sufficient attention.

The Nature of Scientific Problems Underlying Pediatric PQs

Regardless of topical area, most scientific problems underlying the corresponding PQs fall into one of three broad types:

• Ignored or neglected cancer-relevant problems that are brought back into focus. These problems typically relate to intriguing older observations or unresolved issues, for which satisfactory, rigorous research answers may open up qualitatively new research avenues and/or result in substantial progress in a given area.
• More recent findings that are perplexing or paradoxical, revealing important gaps in current knowledge. Research answers to these problems are expected to have exceptionally high potential to re-shape current key conception and paradigms about cancer.
• Problems of recognized high importance that were previously particularly difficult to explore but became more addressable because of recent scientific discoveries and technical advances.

List of Pediatric PQs for this FOA:

Each application must address one and only one specific Pediatric PQ from the list below, exactly as defined in this FOA. To facilitate the submission and peer-review processes, PQs are numbered 1-9. However, the order of the numbering of questions is arbitrary and should not be construed to indicate any order of priority or funding potential.

PPQ-1: What are the processes of normal development that are permissive to the development of specific pediatric cancers?

Intent: Genomic alterations in childhood cancer show remarkable specificity by site and by age at presentation. As examples, H3K27M mutations in histone 3 variants are found almost exclusively in brainstem gliomas that typically arise in 5-10 year old children. MLLT1 mutations are found exclusively in Wilms tumor arising in young children, while BCOR internal tandem duplications are found exclusively in clear cell sarcoma of the kidney typically presenting before 5 years of age, and PAX-FKHR fusion genes are found exclusively in alveolar rhabdomyosarcoma typically presenting in older children and adolescents. The gene-cancer specificity illustrated by these examples suggests that the organs in which these cancers develop have cells that pass through a developmental stage in which they are uniquely vulnerable to oncogenic transformation by specific gene alterations. This provocative question seeks applications that will contribute to understanding this specificity. Applications need not focus solely on the developmental sensitivity to particular mutations but could be directed to any aspect of development that might lead to more favorable conditions for tumorigenesis. For example, applications of interest might address the epigenetic state of cells at different developmental stages, the contribution of germline variation to this specificity, the identification of cells of origin for specific childhood cancers, the effects of specific genomic alterations at different stages of development, or any other developmental events that can promote childhood tumor occurrence.

PPQ-2: What is the functional mechanism by which gains and losses of large segments of chromosomes contribute to childhood cancer development and response to treatment?

Intent: Some childhood cancers are typified by gains and losses of whole chromosomes and/or large segments of chromosomes that by unknown mechanisms contribute to cancer development and to the biological characteristics of these cancers. Examples include the segmental chromosomal gains and losses that occur in high-risk neuroblastoma (e.g., chromosome 1p deletion, chromosome 11q deletion and/or chromosome 17q gain), the whole chromosome gains and losses of hyperdiploid ALL, the gain of a copy of chromosome 8 (trisomy 8) in multiple pediatric sarcomas, and the gain of chromosome 1q in Wilms tumor and other cancers. This provocative question seeks research applications that will explain the molecular mechanisms by which gains and losses of large chromosomal regions promote childhood cancer development and affect tumor behavior including response to therapy.

PPQ-3: What role do alterations in noncoding sequences play in the development of pediatric cancers?

Intent: Many childhood cancers are characterized by a paucity of recurring mutations within the coding regions of genes in comparison with the cancers of adults. This suggests that alterations in non-coding regions (either germline or somatic) may play important roles in the development of childhood cancers. However, to date only a few examples have been identified by which genomic alterations in noncoding regions are oncogenic for childhood cancers. For example, enhancer hijacking activates GFI1 family oncogenes in medulloblastoma, TERT promoter mutations are observed in pediatric melanoma, and chromosomal rearrangements involving a chromosomal region proximal of the TERT gene occur in approximately 25% of high-risk neuroblastoma cases. The small number of examples identified to date likely reflects a small proportion of all genomic alterations in noncoding sequences that affect childhood cancer development. Successful applications might address the oncogenic contributions of novel genomic alterations affecting non-coding RNA as well as regulatory elements and other non-coding DNA elements. Applications proposing new methods for identifying and validating these alterations as well as applications applying existing methods in an unbiased manner may be considered.

PPQ-4: What are the molecular vulnerabilities for tumors of childhood identified through CRISPR or equivalent screens?

Intent: Many childhood cancers are typified by oncogenic genomic alterations that produce proteins (e.g., transcription factors) that are considered undruggable with current technological capabilities. A strategy to circumvent this situation involves identifying critical dependencies created by the undruggable oncogenic driver. As examples, genomic alterations in SMARCB1 associated with rhabdoid tumor create a requirement for EZH2 for rhabdoid tumors, and MLL fusion gene leukemias require DOT1L activity. Clinical studies that take advantage of these two dependencies are being pursued by pharmaceutical and academic research teams. However, for most childhood cancers, vulnerabilities that create therapeutic opportunities have not been identified. This provocative question seeks applications that take advantage of the capabilities of CRISPR or equivalent screens to identify specific molecular vulnerabilities, thereby providing leads for clinical translation for genomically defined subsets of childhood cancers and providing deeper understanding of the cellular circuitry of these cancers.

PPQ-5: What molecular and cellular mechanisms allow reactivation or bypassing of specific silenced tumor suppressor genes in pediatric cancers?

Intent: Loss of function in tumor suppressor genes is a common feature of many childhood and adult tumors. There are many mechanisms that can cause loss of function of these genes, but most involve some type of alteration that deletes part or all of the targeted gene. One exception to this finding is silencing of gene expression. This can occur on one or both alleles of the tumor suppressor gene. This silencing blocks expression of the tumor suppressor gene, effectively removing the gene function from the developing tumor. This Provocative Question seeks strategies for specific reactivation of the silenced tumor suppressor gene or the development of approaches that overcome the silencing of a particular gene or transcriptional program. Studies that rely solely on inhibitors that act on global transcriptional regulation such as histone deacetylases are not considered appropriate for this FOA because they do not allow specific reactivation of a targeted tumor suppressor gene.

PPQ-6: How can mouse or other preclinical models be used to study how standard of care and investigational therapies affect normal tissue and lead to adverse events later in life?

Intent: An enormous challenge for childhood cancer researchers is achieving long-term cure for children with cancer, while at the same time providing a high quality of survivorship without long-term sequelae of treatment. Preclinical models of late effects have been utilized to study effect of specific agents on normal target tissues and the prevention of specific adverse effects (e.g., anthracycline-induced cardiac toxicity and cisplatin-induced ototoxicity). However, the number of such models is limited, and they have not seen broad application. Additionally, models that might predict both the effects of targeted agents on normal tissues affecting specific signaling pathways and the resulting long-term sequelae are needed. Applications might describe the development and validation of models addressing specific treatment related long-term adverse effects or the use of such models to evaluate specific late effects and potential strategies for their amelioration.

PPQ-7: How can prediction models be developed and used to identify patients at highest risk of treatment-related complications?

Intent: A number of childhood cancer survivors develop long-term adverse effects, with some of these effects having a substantial impact on the quality of survivorship. While risk factors for the development of specific long-term adverse effects are well known (e.g., cisplatin cumulative dose and ototoxicity and anthracycline cumulative dose and cardiac toxicity), the range of clinical and biological factors that result in some survivors experiencing a toxicity with others being unaffected are not identified or well understood. The intent of this question is to stimulate research projects that can ultimately lead to robust risk prediction models for specific long-term complications based on clinical and molecular factors that can be identified long before the complications develop. Risk prediction models might incorporate genetic features, demographic characteristics, therapeutic factors, etc.

PPQ-8: What are the molecular mechanisms that define how pediatric solid tumors (both tumor cell and stroma) evolve in response to standard pediatric cancer therapy?

Intent: While long-term survival is achieved for most children with ALL, a substantial proportion of children with high risk solid tumors show tumor recurrence/progression after an initial period of response. The mechanisms by which standard pediatric cancer therapy fails for these children are not well understood. While in some cases, genetic changes due to clonal divergence account for the emergence of mutations in genes known to reduce response to therapy (e.g., TP53), in most cases the evolutionary changes in tumor and/or stroma that result in treatment failure are not known. Successful applications could be directed to relevant patient populations for which suitable specimens are available for addressing molecular mechanisms of tumor evolution in response to therapy. Additionally, applications using animal models to study tumor and stromal evolution in response to standard therapy could be considered.

PPQ-9: What are the underlying molecular mechanisms that cause accelerated aging seen in some pediatric cancer survivors?

Intent: Survivors of childhood cancer have early occurrence of health conditions associated with aging, and they show higher rates of physical impairment, fatigue, and memory impairment compared to age-matched members of the general population. The mechanisms associated with early onset of aging phenotypes are not known, nor is their relationship to systemic chemotherapy and/or radiotherapy. This provocative question seeks to stimulate research relating early onset of aging phenotypes to specific aspects of therapy (including the interactions of therapy with genetic factors associated with cancer susceptibility) and also research regarding mechanisms underlying the early aging phenotype (e.g., telomere shortening, accumulation of free-radical mediated injury, and cellular senescence) and whether these mechanisms represent an acceleration of normal aging processes.

Specific Objectives and Expectations

Scientific Scope. The collective scientific scope of this FOA is defined by the list of Pediatric PQs. These PQs define research areas appropriate for this FOA. They should NOT be construed as examples of specific topics. The scientific scope of an application must clearly and distinctly correspond to one (and only one) of the Pediatric PQs listed above to be considered for funding. Within an area defined by a given PQ, applicants may propose and pursue any topic they deem relevant as a "research answer" to that PQ. It is important, however, that applicants carefully read the Intent Statement for each Pediatric PQ.

Individual Goals. Within the research area defined by a specific Pediatric PQ chosen, the overarching goal of the proposed research project must be an attempt to provide definitive, comprehensive, and thorough research answers to the problem or portions of the problem presented by that question. The proposed research solutions are expected to be creative and highly original with a high potential for transformative impact on current concepts and paradigms in cancer research.

Within this general requirement, specific topics for the proposed investigations, strategies, priority directions, and other details of study design and execution are left to the discretion, originality, and creativity of the applicants. The creativity and originality (combined with scientific rigor) are particularly important, given that the areas identified by the individual Pediatric PQs are generally understudied. Therefore, the applicants have the full freedom to identify the most promising direction(s) to address the selected PQ, formulate Specific Aims, choose optimal experimental approaches, and adapt appropriate specific benchmarks as measures of accomplishing the overarching goal of the project. It is expected that these specific benchmarks will be in line with the Intent Statement for the selected Pediatric PQ.

Original Rigorous Concepts versus Preliminary Data. In general, the R01 funding mechanism is used for research projects for which research approaches, methodologies, and background information are well established and usually documented by extensive preliminary data from researchers laboratories. The requirement for well-developed projects extends to this FOA.

However, it is realized that for many of the Pediatric PQs there could be gaps in background information and original preliminary data may be scarce or difficult to obtain beforehand. Since the intention of this FOA is, by definition, to exploit understudied areas, the emphasis is on the novelty and significance of the concepts to be explored with a relaxed requirement for preliminary data. These concepts must be original but also rigorous in terms of integrating to the extent possible the available incomplete information for a given area from various sources. Reviewers will assess both aspects jointly; if the conceptual aspects of the proposed project are viewed as exceptionally strong, applicants will not be penalized for some gaps in the preliminary data. The focus of the FOA is definitely on the "power of the ideas" (but combined with rigorous plans to validate those ideas).

See Section VIII. Other Information for award authorities and regulations.

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
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

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. 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.

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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Applicants must obtain 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, including Supplemental Grant Application Instructions 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:

Sean E. Hanlon, Ph.D.
Center for Strategic Scientific Initiatives (CSSI)
National Cancer Institute (NCI)
Telephone: 240-781-3310
Email: [email protected]

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

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.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: This section must address the expected overall impact of the project outcomes in terms of breadth and magnitude on cancer research.

Research Strategy: This section must contain (place at the beginning of the section and within the standard page limits) the following element:

Pediatric Provocative Question (Pediatric PQ) Choice. Identify one (and only one) specific Pediatric PQ from the list that will be addressed in the proposed project and briefly describe how the project will provide an answer to the selected Pediatric PQ using a conceptually original and rigorous strategy.

Use the standard Research Strategy subsections (Significance, Innovation, and Approach) to describe the proposed project. This description should address also all the specific aspects listed below.

• Explain the likelihood that the project will yield far- or broad-reaching advances in the understanding of the research problem defined by the selected Pediatric PQ.
• For high-risk projects: indicate the potential benefits that would justify taking high risks.
• Explain the originality of the concepts and/or proposed research directions relative to any ongoing work and point to other creative, innovative aspects that go beyond simply taking the next logical step.
• Outline the strategy to optimize the experimental design to ensure generation of informative results for the selected Pediatric PQ (ideally, even negative results should be informative).

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, 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 PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

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 and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

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.

Applicants are required to follow our Post Submission Application Materials policy.

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:

Even though this FOA uses the R01 funding mechanism, there are important differences from standard R01 applications in emphasis on specific aspects of the application. To be viewed as having potential high impact, the proposed research projects, as designed, must be likely to yield far- or broad-reaching advances in the understanding of the research problem defined by the selected Pediatric PQ. Thus, potential impact of the applications will be judged in large part on the power of the ideas behind the proposed research, whereas the completeness of preliminary data, required for conventional R01 applications, is de-emphasized for this FOA

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

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

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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?

Specific to this FOA: To what extent is this research project, as designed, likely to yield far- or broad-reaching advances in our understanding of the selected Pediatric PQ?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

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

Specific to this FOA: To what extent does the proposed project provide opportunity for novel findings that would be informative as answers for the selected Pediatric PQ? For high risk projects, is the potential for benefit justifiably high? In cases where the proposed project is an extension of ongoing work, how well does it address truly original concepts and/or research directions not covered by the ongoing work and/or use preliminary data in a creative, innovative way? Is it clear that that project focuses on innovation as a main benefit rather than simply taking "the next logical step" in research?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

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

Specific to this FOA: To what extent is the experimental design optimal to ensure generation of important information for the selected Pediatric PQ? If negative results are obtained, how likely is it that these results will be informative for our understanding of the selected Pediatric PQ? How well do the applicants propose a conceptually original and rigorous strategy to solve the problem defined by the selected Pediatric PQ? If supporting preliminary data are limited or incomplete, how well are such gaps compensated by exceptional strength of conceptual aspects?

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?

Specific to this FOA: Are there any extraordinary aspects and/or resources that provide novel or enhanced opportunities to investigate the selected Pediatric PQ in a way that would not be possible elsewhere even in generally excellent scientific environments? For example, are there any unique, newly developed/acquired technical capabilities (without which the project could not be proposed) that are not available anywhere else?

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.

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.

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 children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal 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 proposed.

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.

Not Applicable

Not Applicable

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.

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.

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).

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) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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 National Cancer Advisory 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, including clear and distinct correspondence to one (and only one) of the Pediatric PQs listed in Section I.

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this 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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually 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)
Finding Help Online: https://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Sean E. Hanlon, Ph.D.
Center for Strategic Scientific Initiatives (CSSI)
National Cancer Institute (NCI)
Telephone: 301-451-0943
Email: [email protected]

Arnold Revzin, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-1153
Email: [email protected]

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: [email protected]

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 Part 75.