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

The purpose of this funding opportunity announcement (FOA) is to advance our understanding of the risks, development, progression, diagnosis, and treatment of malignancies observed in individuals with an underlying HIV infection or Acquired Immune Deficiency Syndrome (AIDS) through research directed at addressing one of several proposed "Provocative Questions" (PQs). These PQs are not intended to represent the full range of NCI's priorities in HIV/AIDS-related cancer research. Rather, they are meant to challenge researchers to think about and elucidate specific problems and paradoxes in key areas of AIDS-related cancer research that are deemed important but have not received sufficient attention.

This FOA is patterned on, but unrelated to, a series of FOAs for Research Answers to NCI’s Provocative Questions".

This program covers two companion FOAs of identical scientific scope. This FOA solicits applications for well-developed research projects using the NIH R01 funding mechanism. The companion FOA, RFA-CA-15-013, is an announcement for exploratory/developmental projects using the NIH R21 mechanism.

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.

Provocative Questions in Cancer with an Underlying HIV Infection involves a set of 6 PQs. Each research project proposed in response to this FOA must be focused on addressing one particular research problem defined by one specific PQ selected from the list. Projects proposed to address specific PQs may use strategies that incorporate ideas and approaches from multiple disciplines, as appropriate. Transdisciplinary projects are encouraged as long as they serve the scientific focus of the specific PQ chosen.

The Nature of Scientific Problems Underlying PQs

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

• Ignored or neglected cancer-relevant problems in the context of an HIV infection 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.
• Problems of recognized high importance that were previously particularly difficult to explore but became more addressable because of recent scientific discoveries and technical advances.
• Questions that have arisen because combination antiretroviral treatment has resulted in dramatically increasing the life expectancy of patients with HIV infection.

List of PQs for this FOA:

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 1-6. 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. Are there unique features of HIV-associated inflammation and do these contribute to cancer incidence or outcome?

Background: Immunodeficiency is a hallmark feature of HIV infection. Most tumors that are highly associated with HIV infection are caused by oncogenic viruses, such as Kaposi sarcoma-associated herpesvirus, and poor immunologic control of these viruses is a key element in tumor development. There is increasing recognition that systemic or local inflammation, for example from obesity, is an important contributor to cancer development in the general population. Patients with HIV infection have increased inflammation, even when their HIV infection is suppressed with antiretroviral therapy and they have little or no immunodeficiency. For example, they often have increased levels of interleukin-6 and other inflammatory cytokines, and increased levels of immunoglobulin. There is also an increasing body of evidence that many of the tumors whose incidence is increased in HIV infection, such as non-Hodgkin lymphoma, hepatocellular carcinoma, or lung cancer, are related to this increased inflammation. This Provocative Question seeks to determine if there are unique aspects of inflammation in HIV-infected patients and if so, how these aspects can contribute to an increased risk of certain cancers.

Feasibility: It will be important to dissect the specific or unique features of the pro-inflammatory state in HIV infection, the mechanisms leading to this inflammation, and how this inflammation contributes to the development of HIV-associated tumors. There is ongoing research on certain aspects of inflammation in HIV infection, but other areas remain less explored, such as the role of metabolic syndromes and lipid dysregulation or drug toxicity in causing inflammation in these patients.

Implications of success: Identification of the unique characteristics of inflammation that contribute to cancer in HIV-infected patients can enhance our understanding of HIV-associated tumor development and lead to strategies to prevent tumor development or screen for early tumors.

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

PQ2. Other than immune dysfunction (including inflammation), what are the HIV-mediated mechanisms that underlie differential cancer risk in individuals with HIV infection?

Background: It is well established that HIV-induced immunodeficiency and inflammation are key factors leading to the increased risk of certain tumors. There are also some studies showing that HIV may cause cancer, either directly or indirectly through other mechanisms. For example, HIV-encoded Tat protein, a gene activator, can enter uninfected cells, can enhance angiogenesis, and can enhance infection of cells by Kaposi sarcoma-associated herpesvirus. There is also recent evidence suggesting that the integration of HIV near certain oncogenes can lead to enhanced survival of the HIV-infected cells. This Provocative Question seeks to identify other mechanisms, if they exist, by which HIV can directly or indirectly promote tumor development other than through immunodeficiency or inflammation. It also seeks to define the significance of any such mechanisms in the increased risk of various tumors.

Feasibility: Research areas should focus on novel mechanisms by which HIV infection or its resulting gene products can cause or facilitate cancer development and assess the significance of these mechanisms. It may include, for example, molecular mechanistic studies that dissect how certain HIV viral proteins may interact with host cells to initiate an environment for cancer development.

Implications of success: Discovering new mechanisms by which HIV can directly or indirectly initiate cancer development and progression may lead to novel approaches to prevent cancer development in this setting. It may also lead to the development of tools to screen for cancers and even novel therapeutic approaches.

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

PQ3. Other than immune dysfunction (including inflammation), and known oncogenic mechanisms or risk factors that affect HIV-uninfected individuals, what if any are the mechanisms that play a role in the differential cancer risk in individuals with well-treated HIV infection?

Background: Highly active antiretroviral therapy (HAART) significantly improves immune function in HIV-positive individuals and as a result has reduced the incidence of some AIDS-defining malignancies (e.g. Kaposi sarcoma and non-Hodgkin lymphoma), especially those associated with profound immunodeficiency. However, there is increasing evidence that these patients are at increased risk for developing a number of other tumors, such as anal cancer, lung cancer, or hepatocellular carcinoma. In some cases, this increased risk occurs because HIV-infected patients often have higher exposure to other factors known to be linked to these tumors; for example, increased rates of cigarette smoking and increased exposure to human papilloma virus. There is evidence, however, that other mechanisms may contribute, and it has even been suggested that certain antiretroviral drugs could play a role. This Provocative Question calls for the identification of such factors and the elucidation of their role in cancer development.

Feasibility: Research proposed should focus on factors contributing to the increased risk of cancers in patients with well-controlled HIV infection after excluding immunodysregulation and known cancer risk factors. There is no guarantee that such factors will be identified but clues may come from these studies that may help identify the risk factors for various cancers in HIV infected patients. One approach may be through the study of individuals with well-controlled HIV infection and relatively intact immune systems.

Implications of success: This study may lead to novel approaches to prevent or screen for cancer in HIV-infected individuals on effective antiretroviral therapy. It also may enhance our understanding of the oncogenesis of tumors in other settings and may lead to improved therapy for certain HIV-associated tumors.

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

PQ4. How do the biology of aging and HIV infection interact in the development of various cancers?

Background: The number of older individuals (50 and older) living with HIV/AIDS has risen dramatically over the last decade, mainly due to the availability of effective combination antiretroviral treatment. Moreover, there has been a substantial increase in the incidence of non-AIDS-defining cancers likely driven to a large extent by the growth and aging of the HIV/AIDS population. HIV-infected patients not infrequently manifest certain aspects of accelerated aging, such as increased frailty or cognitive changes. However, little is understood on the interplay between HIV infection, various aspects of aging, long-term exposure to antiretroviral or other drugs, and other risk factors in cancer development in the elderly HIV-infected population. This Provocative Question seeks to stimulate research in this area.

Feasibility: Proposed research should provide insight into how aging and HIV infection interact in promoting tumor development. A variety of eclectic approaches may be involved in addressing this question. One approach may be through a study of elderly patients with HIV infection. Alternatively, it may involve investigation of similarities between aspects of aging and HIV infection at the cellular or molecular level and how these may interact to promote tumor development.

Implications of success: Given the aging of the HIV-infected population and the importance of cancer as a cause of death in this population, addressing this question will be of substantial importance in providing guidance on how to address this problem. It may lead to effective preventive, screening, or therapeutic approaches for cancer in the elderly HIV-infected patient.

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

PQ5. What are the differences between analogous tumors of the same tissue type or subtype in HIV vs. non-HIV infected patients and can these differences inform prognosis or treatment decisions?

Background: Patients with HIV infection are at increased risk of a number of tumors. For some of these tumors, there are substantial differences between the types that develop in HIV-infected vs. HIV-uninfected patients. For example, HIV-infected patients with Hodgkin’s disease most commonly have mixed cellularity or lymphocyte-depleted histology, whereas HIV-uninfected patients most often have nodular sclerosis histology. Even in cases where HIV-infected and HIV-uninfected patients have what appears to be the same histologic tumor type, there may be differences at the genetic level, the epigenetic level, or in the tumor microenvironment. Understanding these differences will provide important clues to the pathways for development of various tumors in HIV infection. This Provocative Question seeks to stimulate other research to delineate the differences and similarities between tumors arising in HIV-infected patients and the same tumor type or subtype arising in non-infected patients.

Feasibility: A variety of approaches may be taken. Proposed research may for example study the tumor microenvironment and determine if tumor development and progression are different in HIV-positive versus HIV-negative patients. Alternate approaches may for example involve exploring epigenetic differences, host genetic factors, or differential expression of tumor biomarkers.

Implications of success: Insights from these studies will provide valuable insights into the pathogenesis of HIV-associated tumors. These data may also inform strategies for cancer prevention, detection, diagnosis, and treatment.

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

PQ6. Why are only certain cancer types increased whereas others are unchanged or even decreased in people with HIV infection?

Background: While HIV-infected patients overall are at greater risk for developing cancer overall, the distribution of these cancers is markedly skewed as compared to the general population. Patients with AIDS and profound immunosuppression have a markedly increased risk of developing certain otherwise rare AIDS-defining tumors, such as Kaposi sarcoma or central nervous system lymphoma. We now know that most such tumors are caused by other oncogenic viruses. HIV patients, including those on effective antiretroviral therapy are also at increased risk of a variety of other cancers, including multiple myeloma, anal cancer, lung cancer, hepatocellular carcinoma, and liver cancer. In some cases, we understand the factors behind these increases (for example HIV-infected patients are more likely to be exposed to human papillomavirus or to smoke cigarettes), but in other cases the factors are not known. Moreover, a number of cancers are not increased in incidence in HIV infection or are even decreased, such as breast, or prostate cancer. Why is this, and what does it say about the role of immunosurveillance in the development various tumors? This Provocative Question seeks to stimulate research to better understand the differential effects of HIV infection on various tumors and what insights this provides on the pathogenesis of these tumors.

Feasibility: An eclectic approach may be required to address this question, combining epidemiologic insights, our current understanding of the pathogenesis of various tumors, and our understanding of HIV infection. One approach, for example, may be to delineate the effects of immunosurveillance on different tumors. For those tumors that are decreased in incidence, it may be worthwhile to determine if one or more manifestations of HIV infection interfere with tumor development.

Implications of success: Understanding the factors that may impact differences in risk to develop different cancers will provide insights into the pathogenesis of these tumors, both in HIV-infected patients and the general population. The increased understanding may identify new targets for therapy or prevention and may also help guide the development of screening approaches.

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 all the sections for each PQ.

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-related AIDS 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 Implications of Success statements for the selected PQ.

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

However, it is realized that for many of the 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 in a well-developed project).

For more exploratory projects, applicants should consider the companion FOA (RFA-CA-15-013), which uses the R21 funding mechanism.

The following types of projects will be viewed as non-responsive to this FOA (applications proposing non-responsive 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. Applicants wishing to address more than one PQ may do so by submitting separate applications.
• Applications that do not explore 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 one of the Scientific/Research Contacts 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

• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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

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

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

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

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

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Elizabeth L. Read-Connole Ph.D
Division of Cancer Biology
National Cancer Institute, NIH
Telephone: 301-NNN-NN240-276-6190
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.

Descriptive Title of Applicant's Project: All application titles must begin with the PQ number on which the application is based (insert PQ number at the beginning of the title in parentheses).

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

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

Facilities and Resources: In addition to standard content, identify any extraordinary capabilities 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, describe any unique, newly developed/acquired technical capabilities (without which the project could not be proposed) that are not available anywhere else.

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

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

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

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

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

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

Research Strategy: This section must contain, within the standard page limits and placed at the beginning of this section, the following element:

Provocative Question (PQ) Choice. Identify one (and only one) 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.

In appropriate standard subsections of Research Strategy (Significance, Innovation, and Approach), include the following specific elements:

• Explain potential impact of the proposed research in terms of far- and/or broad-reaching advances in the understanding of the research problem covered by the selected PQ;
• Identify expected novelty of the findings and how they may inform the answers for the selected PQ;
• Justify high risk projects/concepts/approaches by identifying potential benefits;
• In cases where the proposed project is an extension of ongoing work, explain the originality of the concepts and/or research directions in terms of how they go beyond the ongoing work and taking the next logical step;
• If applicable, underscore situations in which creative integration of the available information allowed you to define novel concepts;
• Propose an experimental strategy to address the problem defined by the selected PQ in an original way with sufficient scientific rigor;
• If supporting information is incomplete, provide specific rationale that could be used to assess the conceptual strengths of the proposed concepts, approaches, interpretations, etc.; and
• Explain the optimization of the experimental design to ensure generation of meaningful information for the selected PQ even if the results are negative for the proposed idea(s)/concept(s).

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 Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

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

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

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. 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.

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 or non-compliant will not be reviewed.

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

Important Update: See NOT-OD-16-006 and NOT-OD-16-011 for updated review language for applications for due dates on or after January 25, 2016.

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

For this particular announcement, note the following:

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

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

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

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

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 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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

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

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

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

Not Applicable

Not Applicable

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

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

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

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

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.

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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
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

Elizabeth L. Read-Connole Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6190
Email: [email protected]

Geraldina Dominguez Ph.D.
National Cancer Institute (NCI)
Telephone: 301-3204
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.