Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This Funding Opportunity Announcement (FOA) invites revision applications from investigators with active NCI U01 research project awards with at least two years of support remaining on the parent grant at the estimated time of award. This FOA encourages sound and innovative research that directly addresses the PQs, including research that helps validate PQ research outcomes or adopt and disseminate PQ research results that impact cancer research and clinical care (http://provocativequestions.nci.nih.gov). Studies proposed in the revision applications must correspond to additional specific aims, expanding the scope of individual, already funded projects of the parent U01 award.

To be responsive to this FOA, each application must specifically address a particular scientific problem identified as one of the PQs listed in this FOA.

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 but understudied problems in cancer research to create a list of PQs.

The PQs included in this revision application FOA are identical to the PQs in RFA-CA-15-008 (R01) and RFA-CA-15-009 (R21). The current list of 12 PQs represents diverse fields relevant to cancer research, but all are framed to inspire interested scientists 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 cancer 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 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.

Each application must address one and only one specific PQ from the list below, exactly as defined in this FOA. In order to facilitate the submission and peer-review processes, PQs are numbered 1-12. However, the order of the numbering of questions is arbitrary and should not be construed to indicate any order of priority or funding potential.

1. For tumors that arise from a pre-malignant field, what properties of cells in this field can be used to design strategies to inhibit the development of future tumors?

Intent: This Provocative Question seeks research that would identify changes in histologically normal cells surrounding or within close proximity of a cancer and that were induced in pre-malignant stages of tumor development. These changes should also be detected in the tumor itself, but not found in truly normal cells of that organ. Such changes might include, but need not be limited to, mutations, epigenetic alterations, or other detectable biochemical events. The identified changes could then be used to design therapeutic or preventive interventions to inhibit the development of future tumors, either at this site or in other pre-malignant fields with similar characteristics. Successful applications could be directed to any of the stages of this characterization target identification drug development pipeline as long as they rely on characteristics of the pre-malignant field. In most cases the tissue/cancer type chosen should have a well-documented pre-malignant field (e.g., lung, head & neck, esophageal, colon, or bladder).

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

2. What molecular mechanisms influence disease penetrance in individuals who inherit a cancer susceptibility gene?

Intent: Individuals who carry a mutation in a cancer susceptibility gene, for example individuals with Li-Fraumeni, Cowden, or Lynch Syndrome, have a dramatically increased risk over non-carriers of developing cancer. This Provocative Question calls for research to determine how the rate of disease penetrance is influenced by various life experiences such as environmental exposure, patient natural history (e.g., abnormal changes in hormone levels), or interactions with other genes/biological pathways. The intent of this question is to go beyond association studies, which identify factors that change disease penetrance in individuals with an inherited cancer susceptibility gene, and determine the mechanisms that explain how these changes influence disease occurrence. Mechanistic studies of events that either increase or decrease rates of penetrance are suitable for study. Preclinical or computational models may also be used to understand how disease penetrance may be altered.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

3. How do variations in tumor-associated immune responses contribute to differences in cancer risk, incidence, or progression?

Intent: Tumors vary in the extent and character of immune cell infiltration and other tumor-associated immune responses. These variations may be due to many factors, including differences in heterogeneous variations of the malignant cell phenotype or genotype or in the potential range of immune responses seen when comparing individuals or populations. This Provocative Question asks scientists to propose research into the causes of variable tumor-associated immune responses and/or how these variations relate to cancer risk, incidence, or progression. Successful applications might range from mechanistic studies that attempt to understand how tumor-associated immune responses can contribute to cancer development in an individual to studies of how population-based differences in immune traits (e.g., across such populations as racial/ethnic groups or various age groups) might explain variations in cancer risk, incidence, or progression.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

4. Why do some closely related tissues exhibit dramatically different cancer incidence?

Intent: The same organ site can develop different types of cancers (e.g., adeno- versus squamous carcinoma). In contrast, many tissues with closely related developmental histories have wide variations in cancer incidence (e.g., left versus right colon cancers, seminal vesicle versus prostate, etc.). This Provocative Question seeks research applications that will explain the molecular mechanisms that account for different rates of cancer development among closely related tissues.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

5. How does mitochondrial heterogeneity influence tumorigenesis or progression?

Intent: Mitochondria within one cell, among closely related cells, or between different individuals can display heterogeneity in mtDNA sequences, dynamic spatial and communication patterns, and functional capacities. This Provocative Question asks researchers to propose mechanistic studies that will characterize how mitochondrial variation within individual tumor cells, among cells within tumor microenvironment(s), or in the same cell types from different individuals influences tumorigenesis or progression. How do these differences vary over time and how do they alter or contribute to tumor development, adaptation, or response to therapy? Successful applications will examine how key aspects of mitochondrial heterogeneity contribute to important steps in tumor development and phenotypic plasticity.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

6. What are the underlying molecular mechanisms that are responsible for the functional differences between benign proliferative diseases and premalignant states?

Intent: Different populations of cells that continue to proliferate in inappropriate settings or at inappropriate times can pose variable risks to human health. Some cell populations will continue to divide over a lifetime (e.g., ductal hyperplasias, benign lipomas, or papillomas) but pose no or little risk of advancing to malignancy, while other populations will progress to cancer with higher frequency (e.g., adenomas changing to adenocarcinomas). This Provocative Question seeks to stimulate research that will compare the range of these states and determine the underlying molecular and cellular regulatory mechanisms that distinguish these populations.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

7. What in vivo imaging methods can be developed to determine and record the identity, quantity, and location of each of the different cell types that contribute to the heterogeneity of a tumor and its microenvironment?

Intent: The demonstration of the extensive heterogeneity of cell types within a tumor and its microenvironment is one of the most intriguing research surprises of the last decade. This heterogeneity includes variations in the tumor cells within a single cancer, extensive differences among tumor cells from similar cancers that arise from the same tissue of origin, and in the variety of associated cells found in the tumor microenvironment, which range from stromal cells to endothelial cells to infiltrating immune cells of many different types. This heterogeneity contributes to a multitude of tumor behaviors and is thought to be one of the reasons that tumors pose such a complicated therapeutic challenge. This Provocative Question seeks the development of new in vivo imaging methods to allow the rapid identification, quantitation, and location of the different cell types within a tumor and its microenvironment. Work at any stage of technical development of imaging methods in the pursuit of these goals is appropriate. Development and validation of imaging methods for various subsets of cell types for the purpose of building a complete set in future work are also considered responsive.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

8. What cancer models or other approaches can be developed to study clinically stable disease and the subsequent transition to progressive disease?

Intent: What biological mechanisms keep some cancers in a stable state and how do we study the transitions from stable to progressive disease? In this Provocative Question we seek the development of new models or approaches to foster the study of both the stable state including but not necessarily limited to dormant or indolent tumors as well as those meeting the Response Evaluation Criteria in Solid Tumors (RECIST) definition for stable disease and the progression of such tumors to more aggressive phenotypes. These new approaches might take advantage of advances in various preclinical models or strategies, combinations of biological and computational models, or other approaches that could help us understand the biology of these important stable states. Studies of tumors that are held in stasis by continued drug treatment are not responsive to this request and will not be reviewed.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

9. What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?

Intent: While many acute toxicities can be adequately managed during cancer therapy (e.g., febrile neutropenia, acute nausea and vomiting) and will resolve once therapy has been completed (e.g., mucositis), there are other adverse sequelae that persist after completion of therapy and for which there are no effective management strategies. These include, but are not limited to, therapy-induced peripheral neuropathy, neurocognitive impairments, cardiovascular toxicity, pulmonary fibrosis, arthralgias, and immune system-related adverse events. This Provocative Question seeks research that will (1) identify novel mechanisms that induce such chronic sequelae, (2) apply the knowledge gained from understanding these mechanisms to facilitate design of new treatments (or approaches) that may decrease or reverse adverse cancer therapy effects, or (3) facilitate mechanism-based design of new cancer therapies that are expected to show decreased adverse effects when compared with existing therapies. Such studies may be performed in pre-clinical, non-clinical, and/or clinical settings. Successful applications must focus on adverse therapy related sequelae (whether immediate or delayed in onset) for which current management or treatment strategies are limited or ineffective.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

10. How do microbiota affect the response to cancer therapies?

Intent: This Provocative Question seeks grant applications that use our increasing knowledge of the normal human microbiota to understand how these organisms or their secreted products affect cancer therapies. Approaches may include studies that focus on effects of the changing microbiota within an individual patient undergoing treatment or among different patients undergoing identical therapy but with different outcomes. Analogous studies in pre-clinical models are also invited. Key aspects of study might include either how the microbiota alter the composition, concentration, stability, or effectiveness of standard or experimental classes of therapies, or the identification and study of microbial regulatory mechanisms that mediate these changes.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

11. What mechanisms of action of standard-of-care cytotoxic, radiologic, or targeted therapies affect the efficacy of immunotherapy?

Intent: With the increasing and successful use of immunotherapy in cancer treatment, many investigators have begun to consider approaches that combine standard of care treatments, such as chemotherapy, radiotherapy, or targeted therapy for a particular tumor, with immunotherapy. Standard of care is defined as a treatment that is accepted by medical experts as a proper treatment for a certain type of disease and that is widely used by healthcare professionals. There may be more than one standard of care for any individual cancer type. Cancer immunotherapy encompasses a wide range of treatment modalities that harness the anti-tumor effects of the immune system, and the factors that influence the efficacy of immunotherapy alone are becoming understood. However, there is a lack of information on their effects when used in combination with standard of care interventions. This Provocative Question seeks new investigations that will define molecular or cellular mechanisms for enhancements, antagonisms, or toxicities that occur when cancer immunotherapy and standard of care treatments are used in combination (either sequentially or concomitantly) as compared to when cancer immunotherapy is used alone.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

12. What methods and approaches induce physicians and health systems to abandon ineffective interventions or discourage adoption of unproven interventions?

Intent: Well-intentioned efforts to speed diffusion of research results into practice may result in the adoption of new treatments and approaches to care before their effectiveness has been documented. Multiple studies have documented the continued use of some medical treatments and approaches to cancer care known to be ineffective. This Provocative Question seeks hypothesis-driven studies that explicitly examine how physicians and/or health systems can be induced to diminish delivery of ineffective or unproven cancer care. Responsive applications may, for example, involve the study of natural experiments, such as changes in reimbursement or institutional policy, or the development and testing of interventions targeted at providers or delivery systems. Studies focused on patient factors or including interventions involving only patients are not responsive to this question.

Applications that do not explore issues presented in this Intent Statement will be considered nonresponsive to this Provocative Question.

Scientific Scope. The collective scientific scope of this FOA is defined by the list of PQs. These PQs define research areas appropriate for this FOA. They should NOT be construed as examples of specific topics. The scientific scope of each individual application must clearly and distinctly correspond to one (and only one) of the PQs listed above. 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 PQ. Additional information for each PQ pertaining to context, background, feasibility, and expectations of needs to be accomplished for a successful solving of the problem is available on the Provocative Questions web site (provocativequestions.nci.nih.gov).

Individual Goals. Within the research area defined by a specific 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 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 PQ.

Original Rigorous Concepts versus Preliminary Data. In general, the U01 funding mechanism is used for research project cooperative agreements 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 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).

The following types of projects will be considered non-responsive to this FOA, and applications proposing such projects will not be reviewed:

• Applications that fail to choose a specific PQ from the list above, address more than one PQ within a single application, and/or re-write a PQ; and
• Applications that do not explore issues presented in the Intent Statement for the selected PQ (as defined in PQ description above).

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.

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.

The PD/PI (or Contact PD/PI for multi-PD/PI awards) on the parent award must remain the same on the revision application.

If appropriate and desirable, PD(s)/PI(s) may collaborate on other PQ Revision applications based on other parent awards.

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 and each is based on a different eligible parent award.

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 and selected PQ number
• 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:

Emily J Greenspan, Ph.D.
Office of the Director
National Cancer Institute
Telephone: 301-395-2871
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:

Introduction: List specific aims of the parent award and explain how the proposed revision research will add to the original goals and specific aims of the parent award. There should be sufficient information from the original grant application to allow evaluation of the proposed revision in relation to the goals of the original application.

Specific Aims: List the specific objectives of the proposed research in the context of the specific aims of the parent award. The revision application is expected to add one or more separate specific aims in addition to the aims of the parent award. 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 FOA-specific element:

Provocative Question (PQ) Choice. Identify one (and only one) specific PQ from the list that is being addressed in the proposed revision to the project and briefly describe how you propose to provide an answer to the selected PQ using conceptually original but also 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 revision to the parent 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 applicant's other 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 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 and responsiveness by NCI, 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 NOT-OD-13-030.

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

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 revision research as designed, likely to yield far- or broad-reaching advances in our understanding of the selected PQ? How will the PQ research benefit from the context of the goals of the parent award?

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

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 revision research 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 revision research 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?

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?

Specific to this FOA: Is the experimental design optimal to ensure generation of important information for 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? Do the applicants propose a conceptually original and rigorous strategy to solve the problem defined by the selected PQ? If supporting preliminary data are limited or incomplete, how well are such gaps compensated by exceptional strength of conceptual aspects?

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?

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 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.

Not Applicable

Not Applicable

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

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

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 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.

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

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

Each revision award made under this FOA will be subject to the same terms and conditions specified for the original U01 award.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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 CenterTelephone: 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: 301-710-0267

Emily J. Greenspan, Ph.D.
National Cancer Institute (NCI)
Telephone: 301-395-2871
Email: [email protected]

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
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.