Part 1. Overview Information

Key Dates

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

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

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

Through this Funding Opportunity Announcement (FOA), the National Cancer Institute (NCI) intends to support multidisciplinary research projects that examine the relative biological effectiveness (RBE) of high linear energy transfer (high LET) radiation on cell and tissue targets in comparison to low linear energy transfer (low LET) radiation. Applicants funded through this FOA are expected to develop contextual volumetric models of RBE that consider high LET radiation in both normal and tumor tissues and expand current concepts on the radiobiology of high LET across spatial and temporal scales. The ultimate goals of these studies are to 1) provide a foundation for mechanistic understanding of high LET radiation effects in diverse tissue and tumor types relative to low LET radiation; and 2) reduce uncertainties in dose calculation, treatment planning, and delivery to inform the potential for broader implementation of high LET-based approaches into treatments of patients with cancer.

Key Terms for This FOA

Dosimetry: The measurement, calculation, and assessment of the ionizing radiation dose absorbed by cells and tissues, both normal and cancer-associated. Dosimetry is performed for all forms of radiation therapy and can also be thought of as a temporal and spatial biomarker.

Linear Energy Transfer (LET): It is the measure of energy that ionizing radiation deposits or transfers into a medium per unit distance traversed by the radiation track. The LET is expressed as kiloelectron volt per micrometer (keV/ m) and is used to understand the effects of radiation in the traversed medium. The density of ionization events, or LET, is higher for radiation with heavy ions such as carbon and oxygen than for photons (x-rays and gamma-rays) and protons (except for small areas of the proton beam in the lateral penumbra and at the Bragg peak where LET is elevated as the protons slow). While the LET values in this high LET regime that includes heavy ions and some unique components of proton beams are typically over 20 to 30 keV/ m, the LET values for low LET photons are typically <1 keV/ m

Relative Biological Effectiveness (RBE): It is the ratio of biological effectiveness of one type of ionizing radiation relative to another, given the same amount of absorbed energy. The relationship between LET and RBE varies widely depending on the nature of the biological material, and the choice of endpoints to define effectiveness. Different radiation spectra that shared the same LET have significantly different RBE. X-ray radiation is often used as a conventional low LET reference radiation for calculating high LET RBE.

Background

The molecular and biological effects of radiation therapy depend on both the type of radiation and the physiologic context of tumor and normal tissues being exposed. The potential for using radiation that generates high linear energy transfer (high LET) effects targeted to tumors while having differential sparing of normal tissue has generated interest to build systems that exploit accelerators that deliver beams of ion particles (e.g., helium, carbon, oxygen) or delivered systemically by targeted alpha particle delivery (e.g., radium-223, bismuth-213, astatine-211). The theoretical advantages of high LET irradiation have spurred interest in the clinical development of these approaches for the treatment of patients having cancers with inherent resistance to conventional radiation (e.g., pancreatic cancer, sarcoma, or glioblastoma). However, fundamental questions remain regarding high LET radiobiology thus necessitating mechanistic studies that examine biological effect parameters in cancer-relevant models to integrate high LET dosimetry, RBE, and biomarkers, which have the potential to optimize high LET treatment planning and delivery in combination with other therapeutic interventions.

Overall Scope and Goals, and Main Requirements of the FOA

Scientific Focus

To be responsive to this FOA, applicants must propose experiments that examine the radiation biology of high LET in the context of cancer therapy and normal tissue toxicity avoidance. Applicants may propose to study specific cancer or multiple cancer types and associated tissues or organ(s) as appropriate. Applicants must integrate high LET data into a relative biological effectiveness (RBE) model(s) that assess the potential for high LET treatment planning and therapy.

Radiation Quality and Dosimetry

To meet the requirement of this FOA for the integration of high LET data into an RBE model, it is expected that applications will include approaches to characterize high LET radiation effects in comparison to a robust conventional radiation exposure (e.g., X-ray radiation). For this purpose, applicants must be able to perform dosimetry using a National Institute of Standards and Technology-traceable standard (e.g., via working with an Accredited Dose Calibration Laboratory (ADCL)).

Hypothesis-Driven Research Focus

NCI strongly encourages applicants to frame the collection of these data around a central hypothesis(es) that defines the Specific Aims of the pre-clinical research projects to be conducted

Possible research directions for proposed radiation biology projects include, but are not limited to, the following:

• Mechanisms of high LET damage at therapy relevant doses alone and in combination with other agents as a function of tissue types and state (e.g., metabolism, stemness, cell cycle, oxygenation/hypoxia) and target (DNA, protein, lipid, organelle) as distinguished from conventional radiation exposures;
• Determination of how the above mechanisms differ between cancer and normals cells;
• Distribution of molecular effects with respect to different parts of particle beams (entry, Bragg peak and tail components, beam center versus penumbral edge) and influence of high LET irradiation dose-rate on biological processes;
• Identification and validation of unique characteristics of high LET radiation that can serve as biomarkers and be exploited for therapeutic gain in cancer treatment;
• Studies that explore mechanisms for synergies between high LET radiation and other therapeutic interventions, including other forms of radiation (photons), radiosensitizers and immunotherapy in relevant pre-clinical models.

High LET Radiation Facility

Each applicant team must have the capacity to generate high LET radiation effects in relevant systems that model cancer therapy and normal tissue toxicity. If the applicant institution does not have such capacity, appropriate partnerships are required. Such partnerships may involve a National Laboratory or Center, either domestic or foreign, or a commercial entity with the capacity for high LET radiation research and development. Note: Applicants are encouraged to discuss with NCI Program staff members a planned partnership(s) prior to application submission

Examples of enabling technologies and approaches in the context of high LET radiobiology include, but are not limited to, the following:

• Particle beam linear accelerators;
• Synchrotrons and cyclotrons (and hybrid) particle accelerators;
• Photon delivery devices;
• Laser-driven accelerators;
• Alpha emitter radiobiology;
• Facilities optimized for small animal imaging high LET radiobiology.

Team Expertise

To address the goals of this FOA, the applicant team is expected to include the following types of experts:

• Biologists and/or oncologists actively pursuing cancer research concerning the mechanisms of radiation damage-repair and cellular effects using relevant model systems;
• High LET physics researchers, technologists, etc., as needed for the design and execution of experiments that involve both high LET and reference radiation (e.g., X-rays); and
• Experts in advanced computational and dosimetry analysis necessary to support data efforts (e.g., acquisition, processing, harmonization, modeling);
• Biostatistical and/or data science experts necessary to support data efforts and/or study design and analysis

Note on projects not fully supported by preliminary data: Since research on the integration of high LET radiation dosimetry, RBE, and biomarkers for optimizing cancer treatment remains an understudied area, a particular novelty and significance of the proposed hypothesis(es) to be tested may compensate for insufficiency in supportive preliminary data. However, projects must still be conceptually well developed and supported by sound rationale based on data from all available sources.

Non-responsive Applications

Applications with the following attributes will be deemed non-responsive and will not be reviewed:

• Projects that model high LET effects in silico without validation of high LET effects from experiments in biological systems (e.g., tumor and normal tissue);
• Applications seeking to advance high LET approaches that are not integrated with the development of RBE model comparisons to conventional radiation;
• Applications that do not perform dosimetry using NIST traceable standards; and/or
• Applications solely focused on carcinogenesis and/or carcinogenic events.

Note:

Applicants, uncertain as to whether their intended framework for the envisioned project meets the requirements of this FOA, are encouraged to contact NCI scientific staff early in their planning in advance of the application submission deadline.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

• Eligible Agencies of the Federal Government

• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant organizations

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

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

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

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

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

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

Any individual designated as a PD/PI must not be designated as a PD/PI on another application in response to this FOA.

Applicants proposing multiple PDs/PIs are encouraged to consider at least one PD/PI with primary expertise in radiation biology/oncology or cancer biology research and another one with primary expertise in radiation physics and dosimetry.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

More than one application may be submitted by an applicant organization provided that each application is scientifically distinct and are submitted by different teams.

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

Letter of Intent

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

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

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

The letter of intent should be sent to:

Jeffrey Buchsbaum, M.D., Ph.D., A.M.,
National Cancer Institute (NCI)
Telephone: 240-276-5690
Email: jeff.buchsbaum@nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed.

Facilities and Other Resources

In addition to standard items, describe existing facilities and/or other resources (such as existing institutional shared resource cores) available for the proposed research. As applicable and pertinent to the proposed research, describe partnerships (e.g., with National Laboratories or industry partners) that will provide relevant capabilities (e.g., radiation sources capable of generating high LET effects, technology development, fabrication, probes, reagents, cancer biology models, small animal imaging, computational expertise). All instructions in the SF424 (R&R) Application Guide must be followed.

To address the goals of this FOA, the applicant team is expected to include the following types of experts:

• Biologists and/or oncologists actively pursuing cancer research concerning the mechanisms of radiation damage-repair and cellular effects using relevant model systems;
• High LET physics researchers, technologists, etc., as needed for the design and execution of experiments that involve both high LET and reference radiation (e.g., X-rays); and
• Experts in advanced computational and dosimetry analysis necessary to support data efforts (e.g., acquisition, processing, harmonization, modeling);
• Biostatistical and/or data science experts necessary to support data efforts and/or study design and analysis.

R&R or Modular Budget

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:

Outline specific aims in the context of experiments that test hypotheses related to the radiobiology of high LET radiation effects in cancer and normal tissues. Address, as appropriate, how the specific aims have the potential to inform the implementation of high LET approaches in cancer therapy.

Research Strategy:

Use standard sub-sections: Significance, Innovation, and Approach. In addition to the typical aspects covered by the standard application guidelines, the Research Strategy section must address all the aspects identified below:

• State the hypotheses and how they will be tested so as to develop insights into the radiobiology of clinically relevant high LET effects in specific cancer types(s) and normal cells;

• Indicate the rationale for the proposed technical approach(es) (e.g., radiation source(s), cancer-relevant models, imaging systems, dosimetry) intended to address the specific aims;

• Applications are expected to propose experiments with complex models inclusive of intact immune systems.

• Describe the organizational and governance structure of the applicant team that illustrates coordination between the represented expertise (e.g., biology, oncology, physics, computational science) in relation to one another;
• Describe capabilities of each facility component (e.g., radiation exposure and dosimetry, animal care, biospecimen acquisition and handling, biological analysis) and the workflow integration;
• If the proposed research will be conducted at more than one site, explain the logistics and coordination plan for experimentation (animals, biospecimens, data, data analysis, etc.);
• Describe the rationale for the inclusion of partnerships (e.g., industrial, foundations) outside of the applicant institution, if any, and the administrative structure of the applicant institution and partnering institutions.
• The applicants should provide relevant information from all available sources, including preliminary data from the applicant’s research, and integrate them to the extent possible to demonstrate that the project concept is scientifically mature and rigorous.

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

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• The sharing of genomic data should be consistent with the respective NIH and NCI policies.

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by 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 the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

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

For this particular announcement, note the following:

A meritorious application is expected to be well-balanced in terms of interdisciplinary science that spans approaches in both radiation biology and radiation physics research. Priorities for this FOA are on:

• Applications with potential to enhance the understanding of mechanisms related to high LET effects in both cancer and normal tissues; and
• Characterization of high LET effects that have potential to inform treatment strategies for cancers resistant to conventional radiation or other combined modality treatments.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed). Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

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

Specific to this FOA:

What is the potential for the proposed research to inform the wider adoption of high LET approaches for the treatment of cancers resistant to conventional radiation long-term?

If the preliminary data from the applicant’s research are incomplete, how strong and compelling is the project concept and hypotheses and whether these are adequately supported by data from other sources?

Investigator(s)

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

Specific to this FOA:

How well does the proposed research team exhibit and utilize combined expertise in radiation biology and medical physics research? Are the applicant PD(s)/PI(s) recognized as leaders in their respective fields with experience in managing interdisciplinary teams and/or research that spans more than one institution?

Innovation

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

Is the concept to be explored particularly novel or significant in terms of a truly transformative potential for the goals of this FOA (essential for projects not fully supported by preliminary data)? What is the project’s potential to generate innovative approaches to improve cancer treatment?

Approach

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

Specific to this FOA:

1) How well does the application propose experiments with complex models inclusive of intact immune systems?

2) Have the investigators included strategies to evaluate tumor resistance both de novo and acquired and how well do the proposed strategies fit into the overall goal of the project?

3) How well are the approachesthat can be used to define dose in biological terms in a robust and standardized manner presented in the application?

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

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Specific to this FOA:

Does the applicant institution or partnering institutions have existing technologies, infrastructure, resources, or cores to conduct the proposed high LET radiobiology research? If the proposed research will be conducted at more than one site, are the logistics and coordination plan for experimentation clearly articulated?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

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

Applications from Foreign Organizations

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

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications:

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

• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA. Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

2. Administrative and National Policy Requirements

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

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.htmlor call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Not Applicable

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement. A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threatensubmission by the due date, and post-submission issues)

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

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

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

For general inquiries related to the this FOA or Radiation Oncology:

Jeffrey Buchsbaum, M.D., Ph.D., A.M.,
National Cancer Institute (NCI)
Telephone: 240-276-5690
Email: jeff.buchsbaum@nih.gov

For specific inquiries related to high LET physics:

Ceferino Obcemea, Ph.D.,
National Cancer Institute (NCI)
Telephone: 240-276-5690
Email: ceferino.obcemea@nih.gov

For specific inquiries related to radiation biology:

Michael Graham Espey, Ph.D.,
National Cancer Institute (NCI)
Telephone: 240-276-5690
Email: SP@nih.gov

For specific inquiries related to the basic biological mechanisms of DNA repair:
Keren Witkin, Ph.D.
National Cancer Institute (NCI)
Phone: 240-276-6250
Email: keren.witkin@nih.gov

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

Shane Woodward
National Cancer Institute
Telephone: 240-276-6303
Email: woodwars@mail.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.