Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

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

This program covers two parallel FOAs of identical scientific scope. This FOA solicits exploratory/developmental projects using the NIH R21mechanism. The companion FOA, RFA-CA-20-004, solicits applications for well-developed research projects using the NIH R01 funding mechanism.

To be responsive to this FOA, each application must specifically address a particular scientific problem identified by a PQ listed in this FOA.

Background

The objective of the Provocative Questions Initiative is to stimulate specific areas of cancer research that are understudied, neglected, paradoxical, and/or have been difficult to address in the past. As with past issuances of the program, FOA publication has been preceded by several NCI-sponsored workshops to identify, articulate, and prioritize particularly compelling and understudied problems in cancer research to create a list of PQs.

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

The Nature of Scientific Problems Underlying PQs

Regardless of the 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 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 conceptions of 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 PQs for this FOA

Each application must address a specific PQ from the list below, exactly as defined in this FOA. Applications that do not explore issues presented in the Intent Statement of the selected PQ will be considered nonresponsive. In order 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.

PQ1: What are the underlying causes of the unexplained rising incidence in early-onset cancers?

Intent:Recent data show an increased incidence of several cancers in people younger than 50 years of age. This includes, but is not limited to, increased incidence of noncardia gastric cancer, colorectal cancer, and breast cancer. Data further suggest that overall cancer incidence may increase by an additional 11%-12% by 2030 in 25- to 39-year-olds and that early-onset cancers are mainly sporadic. This PQ seeks applications that investigate the etiologic factors responsible for the alarming increase in sporadic early-onset cancers. The nature of early-onset cancers suggests that altered gene-environment interactions are a major contributor to increased risk. Several major risk factors documented to have a co-incident increase with early onset cancer have been identified, including higher rates of obesity, changes in diet and food processing, microbial dysbiosis, and early antibiotic exposure. The goal of the PQ is to accelerate research to understand why certain cancers are occurring in younger populations and to identify biomarkers for early detection and better screening approaches for these cancers. Approaches can include epidemiological or clinical cohort studies (retrospective or prospective) to establish risk factors or identify biomarkers, or preclinical studies that are focused on the etiologic factors that affect development of early-onset cancer. These studies may include examining how risk factors alter immune function, metabolism, and/or microbial interactions with host that contribute to initiation or progression of early-onset cancer. Studies that consider race and ethnicity are encouraged.

Applications focused primarily on germline mutations will be considered nonresponsive.

PQ2: How does intermittent fasting affect cancer incidence, treatment response, or outcome?

Intent:The intent of this question is to better understand the effects of intermittent fasting (IF) in humans on cancer risk factors, cancer incidence, treatment response, or cancer related outcomes (such as disease recurrence or survival). We highly encourage transdisciplinary and integrative approaches that bridge mechanisms and human research. For the purposes of this PQ, IF involves restricting caloric intake during specific hours of the day or to specific days of the week or month. IF is in contrast to standard fasting, where an individual restricts caloric intake daily, but does not restrict the time during the day when they eat. Successful applications may investigate 1) the relationship between IF and cancer risk factor modification (e.g., weight loss, dietary patterns), 2) the approach to IF (e.g., duration/timing, combination therapy with a nonpharmacologic intervention such as exercise) which leads to optimal cancer outcomes, and/or 3) an individual’s adherence to IF. All applications must examine the direct effect of IF on cancer risk factors, cancer incidence, treatment response, toxicity, and/or other related cancer outcomes and specify the mechanism(s) by which this occurs. Human studies are required, supported when deemed appropriate by preclinical investigations. Clinical trials are welcomed but not required.

PQ3: How do selective pressures affect cell competition and cooperation during cancer initiation and development?

Intent:Cell competition denotes the process by which differences in fitness among neighboring cells results in the loss of less fit cells. Although cell competition has been described in multiple tissues during development and tissue regeneration, its role and regulation in cancer is less well defined and can be tumor suppressive or tumor-promoting depending on the context studied. Understanding how cells interact with each other in response to selective pressures to drive competition and cooperation and acquire fitness-enhancing traits that allow cells to out-compete their neighbors may provide opportunities to develop targets for cancer prevention or treatment, including opportunities to manipulate treatment responses. This PQ seeks applications that investigate how cell-autonomous or extrinsic selective pressures affect cell competition and cooperation amongst cells of the same lineage during cancer initiation, development, or treatment response and resistance. Applications may involve vertebrate, non-vertebrate and other model systems, including quantitative mechanistic models (e.g., mathematical and simulation models), to demonstrate the dynamics of cell competition and cooperation to selective pressures, provided relevance to human cancer can be demonstrated. Applications focused on in silico models must include some biological validation of the model. Successful applications should be mechanistic and include analyses of cell competition or cooperation within the tumor and its microenvironment or explore how genetic or epigenetic variation affects cancer cell fitness within the context of same cell lineage host-tumor interactions.

PQ4: What mechanisms explain sex differences in cancer incidence, lesion location, or response to therapy?

Intent:Accumulating data suggest that differences in the biology across sexes influence the incidence of cancer types, molecular and histological characteristics, severity, progression trajectories, therapeutic responses, and overall survival of cancer patients. This PQ invites research applications for elucidating molecular and cellular mechanisms underlying sexual dimorphisms in cancer. Applicants may seek to advance our understanding of the etiology of sex-specific differences in cancer to inform targeted prevention efforts. Applicants may also seek to demonstrate how a mechanistic understanding of sex differences can lead to safer and more efficacious sex-specific therapeutic strategies. Applicants may use pre-clinical model systems and/or conduct molecular epidemiology, translational, or clinical studies. Responsive applications must go beyond characterization studies and test specific hypotheses that are not solely attributable to known hormonal differences.

PQ5: What strategies can block or reverse the emergence of new cell lineage states induced by cancer treatments?

Intent:Recent data indicate that drug resistance mechanisms arise in which cancer cells acquire alternative cell lineage(s) in response to treatment to sustain their survival. These resistance mechanisms, termed lineage plasticity, transdifferentiation, or pathway indifference are evident in prostate cancer, melanoma, lung cancer, and other malignancies, and are often associated with poor prognosis in the clinic. The goal of this PQ is to identify strategies to block or reverse the emergence of new cell lineages associated with drug treatment. Strategies are encouraged that are feasible for future clinical trials and based on understanding of the fundamental pathways and molecular drivers of lineage transition.

Applications that propose clinical trials, solely focus on mechanistic studies, or lack translational potential will not be considered responsive.

PQ6: How can cancer cachexia be reversed?

Intent:Cancer cachexia is associated with many types of cancer, involves dysfunction of multiple tissues and organs systems, and is a significant determinate in patient survival. This PQ seeks applications that leverage a mechanistic understanding of cancer cachexia and systemic processes to develop treatment strategies designed to reverse cachexia that encompass pre-cachexia, cachexia, and refractory cachexia states. Applications may provide evidence for interventions that identify those at risk of cachexia and strategies to prevent progression. Successful applications may include objective measures that can be used as a basis for diagnosis across the cachectic spectrum, disease monitoring, and understanding response to new anti-cachectic treatment strategies developed in the project period. Research that seeks to address how cancer cachexia processes can be reversed at its earliest indications are strongly encouraged. Applicants may use pre-clinical model systems and/or human studies.

PQ7: What methods can be developed to integrate patient-generated health data into electronic health records?

Intent:Patient-generated health data (PGHD) are health-related data created, recorded by, or gathered directly from patients. Examples include patient-reported data (e.g., health-related quality of life, health status, and health behaviors), as well as passively collected biometrics (e.g., heart rate and skin temperature). PGHD has the potential to support or inform numerous aspects of cancer care, such as monitoring patient symptoms between visits, personalizing care recommendations, and identifying those at increased risk for poor outcomes (e.g., treatment discontinuation). Few data standards exist for the integration of PGHD into electronic health records (EHRs). Additionally, best practices for use of PGHD in cancer care settings is limited. This PQ calls for: (1) development and evaluation of methods to successfully integrate accurate, interpretable, and time-sensitive PGHD data into EHRs and clinical workflows, and (2) research that combines PGHD with EHR clinical data (e.g., clinical history, cancer histology, genomic data) to better predict and monitor cancer-related outcomes. The intent of this question is to support new analytic and data science methods to improve the capture and use of PGHD sources to inform cancer care.

Applications will be considered non-responsive if they only propose PGHD integration methods without a related cancer-focused research question targeting patient and/or clinician decision-making, patient care, healthcare utilization, or health outcomes.

PQ8: What strategies improve and sustain coordination of comprehensive healthcare for underserved cancer patients with comorbidities?

Intent: The presence of multiple chronic diseases in a patient has a profound impact on health, healthcare utilization, and associated costs. This PQ calls for studies that develop and test intervention strategies for improving coordination of comprehensive healthcare for underserved populations with comorbidities who undergo cancer treatment or are cancer survivors. Specifically, interventions should aim to improve teamwork and coordination among those engaged in supporting the health and care of underserved cancer patients and survivors with comorbidities. Multilevel interventions are encouraged to target modifiable characteristics at two or more levels that include the patient, caregiver, provider, healthcare teams, clinics, delivery organizations, and community. Research applications may examine the association of interventions with a range of outcomes among underserved cancer patients or survivors, and should aim to identify the mechanisms (e.g., teamwork processes, cognitive states) by which multilevel relationships occur. Applications should apply and evaluate strategies within a healthcare setting. For this question, underserved populations include NIH-designated health disparity populations.

PQ9: What methods can be developed to effectively study small or rare populations relevant to cancer research?

Intent:Small and rare populations present significant challenges for cancer research across the biological scale, including molecular, cellular, tumor, or human population levels. This PQ encourages innovative scientific approaches that may include the development of novel study designs, statistical approaches, or computational tools for describing, analyzing, or monitoring small or rare populations, as well as interpreting the effects of interventions or exposures in small or rare populations. As part of the application, the usefulness of the methods developed must be demonstrated through application to one or more cancer-relevant questions and may utilize data at or across any of the aforementioned levels. Validation of the method is encouraged where appropriate.

Applications that do not explore issues presented in the relevant Intent Statement will be considered nonresponsive.

Specific Requirements

Scientific Scope. The collective scientific scope of this FOA is defined by the list of PQs and each application must clearly and distinctly correspond to a PQ listed above. Within an area defined by a PQ, applicants may propose any research they deem relevant to yield a "research answer" to that PQ. It is important, however, that applicants carefully read and address the Intent Statement for each PQ. Additional information for each PQ pertaining to context, background, and feasibility is available on the Provocative Questions web site (provocativequestions.cancer.gov).

Individual Goals. 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 PQ. The proposed research solutions are expected to be creative and highly original with 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 PQs are generally understudied. The applicants have full freedom to identify the most promising direction(s) to address the selected PQ, formulate Specific Aims, choose optimal experimental approaches, and apply appropriate benchmarks as measures of accomplishing the overarching goal of the project. The proposed project should align with the Intent Statement for the selected PQ.

Original Rigorous Concepts versus Preliminary Data. In general, the R21 funding mechanism is used for pilot, exploratory research projects. For such projects, preliminary data are not required, although may be included if available. It is realized that for the areas of the PQs, there could be gaps in background information and original preliminary data may be particularly scarce or hard to get beforehand. The intention of this FOA is, by definition, to exploit understudied areas. Therefore, the emphasis of this R21 FOA is on concepts to be explored, i.e. the power of ideas behind the proposed research. These concepts and ideas must be original but also rigorous in terms of integrating to the best extent possible the available incomplete information for a given area from various sources. These requirements are similar to those for the companion R01 FOA (RFA-CA-20-004), except that the scope of R21 projects is expected to be narrower and in some cases the projects may be based on more speculative, high-risk concepts.

Non-Responsive Projects

The following types of projects are non-responsive for this FOA, and applications meeting these criteria will not be reviewed:

• Applications that fail to choose a specific PQ from the list above and/or re-write a PQ.
• Applications that do not address the issues presented in the Intent Statement for the selected PQ

IMPORTANT NOTE: Applicants uncertain as to whether their intended project meets the requirements of this FOA are encouraged to contact the Scientific/Research Contact listed below in Section VII.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

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) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons.Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

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.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guideexcept 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.

Letter of Intent

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 Hanlon, PhD
National Cancer Institute (NCI)
Telephone: 240-781-3310
Email: sean.hanlon@nih.gov

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: Define Specific Aims of the project and indicate how they will advance answers to the selected PQ. Outline the expected overall impact on cancer research.

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

Provocative Question (PQ) Choice. Identify the specific PQ from the list that is being addressed in the proposed project and briefly describe how you propose to provide an answer to the selected PQ.

Use the standard Research Strategy subsections (Significance, Innovation, and Approach) to describe the proposed project. This description should also address 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 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.
• If supporting preliminary data are limited or incomplete, explain and justify the exceptional strength of conceptual aspects.
• Outline the strategy to optimize the experimental design to ensure generation of informative results for the selected 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.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

3. Unique Entity Identifier and System for Award Management (SAM)

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

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

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

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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

Section V. Application Review Information

1. Criteria

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

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 emphasize 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.

In addition, for applications involving clinical trials:

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

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 PQ?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Investigator(s)

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?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

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?

Specific to this FOA: Does the proposed project provide opportunity for novel findings that would be informative as answers for the selected PQ? For high risk projects, is the potential for benefit justifiably high? In cases where the proposed project is an extension of ongoing work, 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 rather than simply taking the next logical step?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

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

Specific to this FOA: Is the experimental design optimal to ensure generation of important information to address the selected PQ? If negative results are obtained, how likely is it that these results will be informative for our understanding of the selected PQ?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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

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?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Study Timeline

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

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.

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

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.

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) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCI, 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.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

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 submitted in response to this FOA. 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.

3. Anticipated Announcement and Award Dates

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.

Section VI. Award Administration Information

1. Award Notices

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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety

Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

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.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.htmlor 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.

Not Applicable

3. Reporting

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 RPPR, 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 agreementsare 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM)about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings.Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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, application errors and warnings, documenting system problems that threatensubmission by the due date, and post-submission issues)

Finding Help Online:http://grants.nih.gov/support/(preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email:GrantsInfo@nih.gov(preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support(Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email:support@grants.gov

Sean Hanlon, PhD
National Cancer Institute (NCI)
Telephone: 240-781-3310
Email: sean.hanlon@nih.gov

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: ncirefof@dea.nci.nih.gov

Sean Hine
National Cancer Institute
Telephone: 240-276-6291
Email: hines@mail.nih.gov

Section VIII. Other Information

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.