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 invite Cooperative Agreement (U24) applications to develop research resources that will encourage a consensus on how Quantitative Imaging (QI) methods are optimized to improve correlation of results for co-clinical trials.

The scientific goals of this FOA are to: (a) perform the appropriate optimization of the pre-clinical quantitative imaging methods, (b) implement the optimized methods in the co-clinical trial, and finally (c) populate a web-accessible research resource with all the data, methods, workflow documentation, and results collected from the co-clinical investigations.

Co-clinical trials are defined in this FOA as investigations in patients and in parallel (or sequentially) in mouse or human-in-mouse models of cancer that mirror the genetics and biology of the patients malignancies or pre-cancerous lesions.

The co-clinical trial should include either (a) a therapeutic goal, such as the prediction, staging, and/or measurement of tumor response to therapies, or (b) a screening and early detection or a cancer risk stratification goal for lethal cancer versus non-lethal disease.

Applicants are encouraged to organize multi-disciplinary teams with experience in mouse model research, human investigations, imaging platforms, QI methods, and decision support software and informatics to populate the research resource.

Best practices for mouse models. The oncology research community increasingly employs mouse models to test potential agents for therapy and prevention, and methods to screen and detect cancers. There is now an extensive repertoire of available mouse models and their derivatives, including cell lines, cell-line xenografts, patient-derived tumor xenografts (PDXs), and genetically engineered mouse models (GEMMs), and a wide range of validated translational applications. Because of the increasing importance of translational mouse model research, NCI is establishing the Oncology Models Forum (OMF) as described in PAR-14-239. The rationale for the OMF is that, despite the growing adoption of mouse and human-in-mouse models for translational cancer research, investigators often do not have a comprehensive dynamic resource for information to guide generating, validating, and credentialing new models, informing their practical uses, and advancing modeling techniques, or to provide catalogs of available models resources, programs, and services.

The OMF goal is to evolve and sustain information resources that enable effective, reliable use of mice, mouse models, and human-in-mouse models in translational cancer research, and support other mouse modeling needs that the oncology community identifies. The OMF is designed to facilitate community-wide input to establish best practices for validation and credentialing of mouse and human-in-mouse models. Within this context, in vivo imaging has an important role as an enabling technology for preclinical research that would allow imaging data to be robustly integrated with other research data as required for precision medicine.

Reliable, reproducible animal models research. NCI’s precision medicine initiative emphasizes the biological and molecular basis for cancer prevention and treatment, and also addresses consistency in in preclinical research and clinical research. The need for cost-effective, integral research and clinical use of appropriately designed and selected animal models has never been greater. There are increasing numbers of publications that document the significant potential of well-designed and controlled co-clinical human and animal model testing to support precision medicine. At the same time, there are mounting concerns across all research sectors about the reliability of animal models to reflect human biology and diseases, the reproducibility of animal experimentation to inform clinical choices, and the dearth of research-community based best practices and appropriate standards for design, validation, and use of animal models and their associated data. Through implementation of the OMF, the NCI has chosen to establish an open environment in which the oncology community may collaborate to tackle the sundry issues that pertain to reproducibility of animal model research as required for precision medicine. Prominent among those issues is transparency of details that document development of standards and their application to translational research.

Mouse Model Selection and Laboratory Practice: For therapy trials, the mouse models, by way of example, could be patient-derived tumor xenografts (PDXs), or genetically engineered mouse models (GEMMs), or both. There needs to be a match between the mouse tumor and the human tumor, which is usually determined by histological or genomics analysis, for example EGFR+, Her2, ER+. The drug must have demonstrated some efficacy in treating the specific tumor in humans preferably not in every patient, or known resistance after successful treatments. Use of a generic model with a drug whose effect in matched humans is not known is not appropriate for this FOA. The choices of mouse models for the screening/early detection goal or risk assessment are likely to pose additional or different considerations that applicants should address, as there are fewer published examples in these translational research areas. Thus, the requirements for model selection and laboratory practice need to reflect the limited state of the art for cancer screening/detection. In their research scope, all applicants should document best practices for animal husbandry, as these requirements are significant for serial imaging studies. The latter includes consistency in anesthesia administration, physiology monitoring, use of contrast media, and therapy administration, as well as reproducible animal positioning in imaging platforms where technically possible.

Quantitative Imaging (QI) Methods. Community-wide efforts for the development of a consensus on QI methods and related imaging standards as related to the prediction and response to therapy have been transformative for the implementation of clinical therapeutic trials over the last decade. For example, these efforts have recently positioned imaging as a key element in the design of adaptive therapy trials and use of combination therapies. As a result, there is increased interest by the academic and industry sectors to participate in open science environments and use web accessible research resources to develop consensus approaches to validate QI methods for the next generation of clinical trials and subsequent clinical practice. Examples of these resources are: 1) the NCI-supported Cancer Imaging Archive (TCIA); 2) the National Cancer Informatics Program (NCIP-Hub) for sharing imaging methods and related software tools; 3) the NCI-funded Quantitative Imaging network (QIN; NCI PAR 14-116), which addresses the role of QI as applied to prediction and response to therapy is. Leveraging the open science experience of the QIN network and the OMF are critical goals of this FOA.

Pre-Clinical Quantitative Imaging Methods. Compared to clinical investigations, the technical challenges are significantly more difficult for the optimization of mouse model imaging protocols and QI methods. First, preclinical imaging platforms are reduced in scale compared to the corresponding clinical platforms. As a result, their physical performance characteristics are often very different from their clinical counterparts. In addition, these imaging platforms and related software tools are typically designed and optimized for imaging of small animals only, and many of these platforms/methods are unique compared to clinical platforms. To minimize this specific problem for the therapeutic goal for this FOA will require the use of the same class of commercially supported imaging platforms and software tools for the mouse models as the imaging platforms currently employed in the clinical trial setting, such as PET, CT, MRI, or US. For the prevention and screening/early detection or cancer risk assessment goal, however, the use of advanced prototype platforms/methods may also be required for either pre-clinical or the clinical studies.

Specific Research Objectives

The purpose of this Funding Opportunity Announcement (FOA) is to invite Cooperative Agreement (U24) applications to develop research resources that will encourage a consensus on how Quantitative Imaging (QI) methods are optimized to improve correlation of results for co-clinical trials. Co-clinical trials are defined in this FOA as investigations in patients and in parallel (or sequentially) in mouse or human-in-mouse models of cancer that mirror the genetics and biology of the patients malignancies or precancerous lesions.

The scientific goals of this FOA are to:

• perform the appropriate optimization of the pre-clinical quantitative imaging methods;
• implement the optimized methods in the co-clinical trial; and finally
• populate a web-accessible research resource with all the data, methods, workflow documentation, and results collected from the co-clinical investigations.

The co-clinical trial should include either:

(a) a therapeutic goal, such as the prediction, staging, and/or measurement of tumor response to therapies; or

(b) a cancer prevention or an early cancer detection goal, i.e., approach resulting in improved prevention, screening, detection, cancer risk stratification, or the early identification of lethal cancer versus non-lethal disease.

Applicants are encouraged to organize multi-disciplinary teams with experience in mouse models research, the proposed mouse model and human investigations, imaging platforms, QI methods, decision support software and informatics to populate the research resource. They should provide a research plan that includes collaborating with the OMF, particularly in the context of formulating and testing best practices for co-clinical mouse model research, and the QIN network where appropriate to implement state of the art QI methods. Partnerships with industry are strongly encouraged, but are not required, to encourage a broader adoption of QI methods for co-clinical trials

To be considered for funding, applicants must address the primary goal of this FOA namely to populate a web-accessible research resource and demonstrate its functionality. This resource should be designed to encourage other investigators to explore additional approaches for QI methods for future investigations. They are strongly encouraged to use the NCI-supported research resources to host image, metadata and software tools/methods; namely (a) the Cancer Imaging Archive (TCIA) that is fully HIPAA compliant; (b) The NCI-CBIIT funded National Biomedical Imaging Archive (NBIA), an open source computer platform that supports TCIA, and (c) the NCI NCIP Hub is employed by the OMF for sharing data, methods and software tools and cloud computing.

The following types of projects are not appropriate for this FOA:

• The planned prospective clinical trial or intervention study
• The development of new quantitative imaging methods or software tools for co-clinical trials
• The development of new imaging platforms for co-clinical trials
• The employment of non FDA approved imaging platforms for the clinical trial
• The development of new mouse models that have not been validated and credentialed
• The development of new laboratory based assays or biomarkers

Alternative/Related Funding Initiatives

• Investigators seeking support for imaging clinical trials, as such, are referred to the following initiatives: PAR-14-16; NCI Imaging Program Clinic Trials; and NCI Radiation Research Program Trials;
• Academic and Industry investigators seeking complementary support for related research in areas such as the development and translation of new imaging platforms, component technologies, quantitative imaging methods, and related research resources for pre-clinical, co-clinical or clinical research are encouraged to use the following initiative: PAR-13-169;
• Investigators seeking complementary support for related research in areas such as the informatics research resources (U 24's) for pre-clinical, co clinical or clinical research are encouraged to use the following informatics initiative: PAR-14-239

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
• 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) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not 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:

Huiming Zhang, Ph.D.
Division of Cancer Diagnostic and Treatment
National Cancer Institute (NCI)
Telephone: 240-276-5979
Fax: 240-276-7890
Email: zhanghui@mail.nih.gov

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

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

Multi-disciplinary Teams: Applicants are encouraged to organize multi-disciplinary teams with experience in mouse models research, the proposed mouse model and human investigations, imaging platforms, QI methods, decision support software and informatics to populate the research resource as described in this FOA

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

In the application, research project budget requests must include costs for:

Travel: Applicants should budget funds for travel for the PI(s)/PD(s) and two additional senior members to two network wide meetings per year.

Sharing of imaging protocols, software tools, and data: Applicants are permitted to budget for the following tasks as necessary:

(a) Add any additional validated state of the art quantitative imaging methods/protocols and quantity assurance methods to improve any proposed prospective clinical studies;

(b) Support for the proposed pre-clinical imaging methods necessary to implement the mouse model trial;

(c) Optimization of the pre-clinical imaging methods required to improve correlation of results for the proposed investigations;

(d) Data collection and analysis for the correlations of the co-clinical trial results;

(e) Sharing of image data and metadata, metrology tools, and correlation results; and

(f) Creation of the research resource and demonstration of its functionality.

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:

Research Strategy:The following issues need to be addressed in the research strategy with the understanding that emphasis in each area may vary depending on the specific research goal. Applicants are encouraged to address all areas as listed below and organize multi-disciplinary teams with the appropriate experience.

• Co-Clinical trial design
• Selection of mouse models
• Selection of imaging platforms
• Quantitative Imaging methods
• Research resource design and functionality

Each application need not be strong in all areas of the research areas as detailed below, but must propose a research resource that can effectively serve the research needs of the co-clinical trial community.

1. Co-Clinical Trial Design: Applicants should propose the use of data from a retrospective clinical trial or from a prospective clinical trial(s) or investigations that are clinically significant. Note that the cost of the prospective clinical trial will not be supported by this FOA, but the addition of improved quantitative imaging methods will be supported. The data size, quality and quantity collected should be sufficient to provide a robust statistical comparison of: (a) the QI methods employed, and (b) correlation of results across the co-clinical trial.

2. For the therapeutic goal of this FOA the primary or secondary drug to be tested, or the other types of therapy or interventions proposed for the co-clinical therapy trial, should be known to have a response in tumors that are matched histologically or genomically with the mouse model. For the prevention goal of this FOA the form of intervention should be known to be effective within the context of early cancer detection or prevention.

3. The mouse models and human-in-mouse models for cancer treatment, prevention, or cancer risk assessment studies should be available, validated, and credentialed using published recommended best practices. The research scope should conform to accepted Institutional Animal Care and Use Committee (IACUC) procedures and address best practices for mouse housing and care; anesthesia administration; physiology monitoring; drug, contrast media, or therapy administration; animal positioning/repositioning and data acquisition on imaging platforms.

4. The proposed prospective clinical investigation, if selected, should include state of the art imaging protocols and QI methods using commercially supported, and FDA-approved imaging platforms. The retrospective clinical trial, if selected, should include state-of-the-art QI protocols and methods at the time when data were collected, and must have appropriate documentation of all samples collected and related methods. Advanced prototype imaging platforms, however, may be used such as for screening/early detection and cancer risk assessment investigations, or added to all investigations to improve the interpretation of the correlation studies. The inclusion of other laboratory, molecular biomarker, and pathology correlation studies on commercially supported platforms is encouraged but must be documented.

5. The proposed QI methods for the preclinical studies should be optimized to improve the correlation of the results for the proposed co-clinical trial. The applicants are expected to submit a detailed research strategy to implement the proposed imaging protocols, QI and quality control/assurance (QC/QA) methods currently employed in clinical trials or prevention studies and state of the art preclinical imaging methods.

6. The primary goal of this FOA is to populate an internet-accessible research resource with the collected co-clinical data, detailed methods, related software tools (metrology tools) and the results of the correlation studies for the proposed co-clinical trial. The use of NCI-funded resources is highly recommended, namely the TCIA and NCIP Hub that is being implemented by the OMF. The applicants should submit a research strategy for the creation of the research resource and address how the functionality of the proposed resource will be demonstrated, that permits the research community to explore how the proposed QI methods can be improved. One example is to use the research resource to perform a demonstration study for a software challenge, where the performance of the applicant's existing tools could be compared to the performance of the optimized software tools as supported by this FOA.

7. A list of milestones that measure progress in the development of the proposed research resource must be given in the form of a Gantt Chart. The functionality of the research resource is to be demonstrated before the end of the third quarter of year 5.

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.

The intellectual property associated with the software tools related to clinical decisions will remain with the academic institution or industrial partner, but an agreement to an open science approach to validate tool performance is expected for this FOA.

For this FOA, it is suggested that all U24 applicants submit a plan for sharing collected data (cost sharing for image data sets, annotated data and Meta data for example), posting this data on an imaging archive such as The Cancer Imaging Archive (TCIA), NCIP Hub or equivalent.

A software dissemination plan, with appropriate timelines, is expected to be to meet the goals of this initiative. Grantees are entitled to limited software copyright protections and institutional software licensing agreements.

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.

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, 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 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.

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: Will the proposed research resources for co-clinical trial effectively serve the research needs of the co-clinical trial community?

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?

Specific to this FOA: Does the multi-disciplinary team of investigators have the complementary experience to design and create an effective web accessible public research resource as applied to co-clinical trials of interventional therapies, diagnosis or screening/early detection for the targeted cancer problem?

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: Do the investigators propose state-of-the-art methods for the optimization and validation for the proposed quantitative imaging methods and imaging protocols to improve the correlation of results for the proposed investigation? Is the research resource innovative in terms of its design and data content.

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: Do the investigators propose a coherent translational research strategy to design and implement the proposed research resource, and to demonstrate the functionality of the research resource for the targeted cancer problem?

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: Does the research environment include state of the art research facilities to support (a) the development and implementation of the proposed co-clinical trials; and (b) the creation of a web accessible research resource that will support the co-clinical trial community as described in this FOA?

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

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

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

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

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

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

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

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

The PD(s)/PI(s) will have the primary responsibility for:

The PD(s)/PI(s) will have primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted under this program. The PD(s)/PI(s) assume responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the research supported by the U24 award.

The PD(s)/PI(s) of each funded U24 will be also be expected to work closely with the NCI Program staff in project coordination and management as described under NCI Staff Responsibilities . A Steering Committee (SC) will be formed involving the PD(s)/PI(s) of each U24 as voting members of the SC, and will have a voting rights for how the SC is conducted. Each U24 team will have two votes. The PD(s)/PI(s) and other funded investigators will be expected to participate in the SC and any other cross team (U24's) Working Groups (WG's) that may be formed addressing specific targeted research areas common to all the U24's. One objective of the SC and any WG's will be to explore how to develop a consensus on the best means for the design and implementation of quantitative imaging methods for the planned co-clinical trials, the development of the web accessible research resources and the planned outreach strategy to the research community where appropriate. The SC will also interact with the Oncology Models Forum (OMF) to ensure that validated and credentialed mouse models are employed in the planned co-clinical trials for each U24. The SC will also be expected to interact with the Quantitative Imaging Network (QIN) to explore best practices for QI methods for clinical trials. The SC will be expected to plan annual meetings and, where appropriate, joint annual meetings with the OMF and/or the QIN.

NIH staff has substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

A designated NCI Program Staff member, acting as a Project Scientist, will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards.

Specifically, the NCI Project Scientists will:

• Participate in the above SC to help coordinate the management of the planned network of U24's, and targeted WG's as described above. The NCI program staff will collectively have one vote on the SC. The NCI staff will advise the PD(s)/PI(s) to explore network wide consensus approaches for quantitative imaging methods for each planned co-clinical trial, the design and implementation of the web accessible research resources, and the outreach strategy. The NCI program staff will in consultation with the PD(s)/PI(s) set specific research milestone to be met for each year of the funded U24's. In addition, NCI program staff will assist the PD(s)/PI(s) in the development of annual reports and annual meeting as described above.
• NCI staff members who are substantially involved in the program activities will not attend peer review meetings of renewal and/or supplemental applications. If such participation is essential, these individuals will seek NCI waiver according to the NCI procedures for management of conflict of interest.
• Additionally, an NCI Program staff member acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the award notice.

Areas of joint responsibility include:

Given that the NCI staff members will assist the awardees in various areas, frequent and regular interactions are anticipated between NCI Project Scientist(s) and the PD(s)/PI(s). For example, the awardees and the NCI staff members will collaborate on planning, preparing, and convening the network annual meetings.

The NCI Project Scientist and the PD/PI's will jointly represent the program and participate in appropriate network wide activities

Dispute Resolution:

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

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

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

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the Section 8.4.1.5.5 of 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: commons@od.nih.gov

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: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Huiming Zhang, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5979
Email: zhanghui@mail.nih.gov

Cheryl L Marks, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6217
Email: marksc@mail.nih.gov

Richard V Mazurchuk, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-7126
Email: mazurchukrv@mail.nih.gov

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

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

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.