It is critical that applicants follow 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 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 further optimize and validate molecular/cellular/imaging markers and assays for cancer detection, diagnosis, prognosis, monitoring, and prediction of response or resistance to treatment, as well as markers for cancer prevention and control. This FOA also includes the validation of pharmacodynamic markers and markers of toxicity. Applicants should have assays that work on human samples and whose importance is well justified for development into clinical assays. As chemotherapies and/or radiation therapies are increasingly combined with immunotherapies to enhance durability of anti-cancer responses, multiple assays for measuring multiple markers, including immune markers, can be developed and validated simultaneously.

The UH2 phase of this FOA supports analytical validation of assays for these markers that must be achieved within 2 years before assays may undergo clinical validation. The UH3 phase of this FOA supports clinical validation of established assays for up to 3 years using specimens from retrospective or prospective clinical trials/studies. This FOA may be used to validate existing assays for use in other cancer clinical trials, observational studies, or population studies. Efforts to harmonize clinical laboratory tests, including investigation into the performance and reproducibility of assays across multiple clinical laboratories, are also appropriate for this FOA. Projects proposed for this FOA will require multi-disciplinary interaction and collaboration among scientific investigators, oncologists, statisticians, and clinical laboratory scientists. This FOA is not intended for early-stage development of technology or to support clinical trials, but is intended for analytical and clinical validation of assays to the point where they could be integrated into clinical trials/studies as investigational assays. Investigators responding to this FOA must address both UH2 and UH3 phases.

NCI-supported clinical trials, as well as prevention or cancer control studies, increasingly depend upon essential or integral markers. Many of these diagnostics are proposed from investigators in academic or small biotechnical companies that have developed interesting markers based on discovery research. These markers may be pharmacodynamic, mechanism of action, prognostic, predictive, and/or response markers. They may also be related to risk of cancer in prevention or cancer control studies. Most investigators are generally comfortable developing assays for research purposes, but may not have the expertise for developing assays for clinical purposes and navigating the regulatory requirements that clinical laboratory assays must meet. This can cause considerable delay and added expense to successfully conducting clinical trials. This FOA uses a cooperative agreement that enables NCI staff to proactively assist investigators to meet the requirements for analytical and clinical validation of assays and prepare for their use in clinical trials/studies.

Applications to this FOA must propose to optimize an existing assay(s) using human specimens in a clinical laboratory into assays that can be used in a clinical trial/study for the treatment, prevention or control of cancer. The primary elements for achieving the research objectives are as follows:

• Existing assay: an assay that has been reduced to practice in human tissues. Assay may be from discovery research or based on the scientific investigator's interests.
• Clinical laboratory: a laboratory that provides assay results that either assist in medical decision-making or test postulates or mechanisms of action of clinical, prevention or cancer control treatments or interventions. Assays that support medical decision-making need to be performed in CLIA-certified laboratories. Assays to test postulates or mechanisms should conform to GLP or ISO 17025 standards, in order to assure that the data generated by the assays are of sufficient quality as to be useful in clinical trials and justify sample collection.
• Markers: molecular/cellular/imaging markers that are associated with a clinical endpoint in a pre-defined clinical context or situation that yields usable information about prognosis or response to a clinical intervention for treatment, prevention or control of cancer.

• The project must focus on assays whose marker or classifier is likely to be used in treatment trials, prevention studies, or cancer control studies. There does not need to be a commitment to a particular clinical trial/study.
• Awards will be based on how well the applicant justifies the use of their proposed assay(s) and marker(s) as well as the ability of the applicant's team to perform analytical and clinical validation of assays in their clinical laboratory.
• The status of the existing assays and the plan for optimization in the clinical laboratory are critically important.
• This FOA should use technologies already in use or soon to be approved for use in clinical laboratories since this is not a technology development FOA.
• Applications to improve standardization or harmonization of assays among laboratories for use in clinical trials/studies are appropriate for this FOA. Clinical laboratory assays are deemed to be "harmonized" when the results are independent of the specific assay procedure/protocol and where and when the assays are performed. If a commutable reference material is available and the unit of measurement for the analyte has been standardized, the assays can be harmonized by requiring that all procedures be directly or indirectly calibrated to the primary reference material using the standardized unit of measure. Such harmonization effort would require a multicenter study to evaluate the performance of the assay protocols, including the limit of detection, limit of quantification (as applicable), linearity of the assay across the measuring range, and reproducibility (inter- and intra-assay variability).
• Metrics for analytical and clinical validation as quantitative milestones will be used to assess potential transition from the UH2 to UH3 phase.

Assay Pre-requisites and Preliminary Data: The applicant must have a working assay(s) using human specimens. The assays may be derived from discovery research or result from previous hypothesis-driven clinical studies. The assay(s) may be multiplex assay or a classifier but must, after conversion to a clinical assay, be suitable for performing in a clinical trial/study. Preliminary data should define the current status of the assays as well as justify support for optimization and usability in a clinical trial/study.

Two-phase Projects: Initial cooperative agreement awards for up to 2 years will be granted for analytical validation of the assays in the UH2 phase. If the project meets the metrics described for the UH2 phase, then the project will proceed to the UH3 phase pending review and availability of funds as described below.

Objectives for the UH2 Analytical Validation Phase: During the UH2 phase, the investigators must complete analytical validation of their assays. Since this is not likely to require large numbers of samples, the investigators are expected to have access to samples that are appropriate for the clinical context of the intended use of the assays. Attention needs to be paid to preanalytic variables and their effect on marker stability within specimens appropriate for the clinical context of use.

Expectations for the UH2 Analytical Validation phase include determining the following metrics:

• Accuracy;
• Precision;
• Analytical sensitivity;
• Analytical specificity, including in the presence of interfering substances;
• Reportable range of test results for the test system;
• Reference intervals (normal values) with controls and calibrators;
• Standardization of methods if the assays are to be performed in multiple laboratories;
• Establishment of appropriate quality control/assurance measures and improvement procedures;
• Any other performance characteristic required for test performance with determination of calibration and quality control procedures.

Transition from UH2 to UH3: After administrative review by NCI program staff, successful UH2 projects will be prioritized for selection and transition to the UH3 phase.

Objectives for the UH3 Validation Phase: The UH3 phase will complete the analytic and clinical validation of the markers/assays and prepare them for use in a clinical trial/study.

Expected outcomes of the UH3 phase that should be met by each project:

• Demonstration of the association of the result of the assays with a clinical endpoint (e.g., survival, response, disease presence or absence) in samples from patients that have been treated or exposed to a uniform intervention or observation in treatment, prevention or cancer control studies;
• Definition of the sensitivity and specificity of the assay results with the defined clinical endpoint;
• Estimation of the prevalence of the markers within subjects or patients for the intended clinical context;
• Establishment of an appropriate cut-off or threshold for the assays using appropriate statistical analysis.

Investigators with assays that have already met the above criteria for analytical validation may apply directly for the UH3 phase funding of the clinical validation of assays through PAR-17-309.

Research projects that are not appropriate for this FOA

This FOA is not meant to support clinical trials but is intended to get assays to the point where they can be integrated into future clinical trials/studies. Projects that are not appropriate for this FOA include technology development such as those covered by the Innovative Molecular Analysis Technologies Program (IMAT) or the Early Detection Research Network (EDRN) at the NCI.

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

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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).

Buttons to access the online ASSIST system or to download application forms 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.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, 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:

Tracy G. Lively, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5944
Email: [email protected]

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

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

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

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

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

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

The Investigative Team should include:

• Clinical Investigator: Investigator(s) who define the intended clinical context of use for the markers and assays and will oversee their incorporation into a potential clinical trial/study likely to be oncologist(s) who treat patients but may be a translational scientist(s).
• Clinical Laboratory Staff: Staff who will perform the translation of the assays into clinical assays. The staff may work in a CLIA-certified clinical laboratory but do not need to do so if the assays are not intended to be used for medical decision-making. In that case, the assays are likely to be for hypothesis or mechanism of action testing and the clinical laboratory staff and their laboratory need to be aware of Good Laboratory Practices and/or ISO 17025 standards and perform to that level of quality but not necessarily be certified. In any case the clinical laboratory staff need to be aware of the Westgard rules. Clear involvement of clinical laboratory staff must be demonstrated in the application.
• Statistician: A statistician familiar with the needs of marker studies should be part of the team, especially for the UH3 phase when power calculations need to be provided for assessing the use of the assays and markers within the intended clinical context.
• Commercial Developer: While not necessary for all projects, successful assays will need to be distributed and supported. Plans for collaboration with a commercial partner who will support the distribution and commercialization of the assays are encouraged but not required.

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: Provide the overall goals for the entire application and indicate separately Specific Aims to be accomplished in the UH2 phase and in the UH3 phase.

Research Strategy: Organize the Research Strategy in the subsections identified below.

1) Background and Significance

• Define the cancer problem to be addressed, including the markers and assays and how they fit the intended clinical context in which they will be used.
• Provide the biologic or discovery research rationale for the marker(s) and its importance.
• Outline the proposed assays and marker, and their potential for affecting the intended clinical context in treatment trials, prevention studies or cancer control studies.
• The intended clinical context of use for the proposed molecular diagnostic must be clearly defined and include the type of specimen to be used for the assays and how the assay results will be used.

2) Preliminary Data

• Describe the current state of development of the assays and their use in preclinical development
• Demonstrate the function of the assays with human specimens, including the current reagents and technologies and types of specimens that the assays will use (e.g., fresh frozen or formalin-fixed tissue, serum or plasma)
• Identify if any of the analytical validation metrics listed in Section I above as expectations for the UH2 phase have been analyzed or completed.

3) Approach divided into two parts corresponding to the UH2 and UH3 phases.

UH2 Analytical Validation Phase should address each of the items listed below:

• Plan to perform analytical validation of the assays and markers within the matrix of its intended use;
• Plan to obtain appropriate specimens for developing and optimizing assays;
• Plan to initiate method validation of the assays and to initiate evaluation of the marker's (analyte's) stability within the matrix of the specimens to be used;
• Plan to evaluate (i) accuracy, (ii) precision, (iii) analytical sensitivity, (iv) analytical specificity including in the presence of interfering substances, (v) reportable range of test results for the test system, (vi) reference intervals (normal values) with controls and calibrators, (vii) harmonization of analytical performance if the assays are to be performed in multiple laboratories, (viii) establishment of appropriate quality control and improvement procedures, and (ix) any other performance characteristic required for test performance with determination of calibration and control procedures;
• Potential clinical utility of the marker in its intended clinical context;
• Plans to address the regulatory issues regarding use of the marker in clinical trials/studies and assays within the intended clinical context. This includes the possibility of controlling intellectual property, evaluation of the significant risk of the assays and markers within the clinical context of a clinical trial and plans for collaboration with commercial entities to support the assays if successful.
• Specific performance metrics or milestones to be achieved during analytical validation of items (i) - (ix) above.

Milestones and Timeline

A timeline (Gantt chart) including milestones is required. Milestones are goals that create go/no-go decision points in the project and must include clear and quantitative objective criteria for success. Yearly quantitative milestones are required to provide clear indicators of a project's continued progress or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years. The application must include well-defined milestones, such as: appropriate objective performance targets, quantitative for go/no go decision points such as an appropriate level of detection and coefficient of variation, or sensitivity and specificity; and timelines for assessing progress in both the UH2 and UH3 phases, including specific milestones for progressing from the UH2 phase to the UH3 phase. Milestones and timelines for each stage must be provided in a separate heading at the end of the Approach section for each UH2 and UH3 subsection, and should:

• Provide appropriately detailed (quantitative) criteria by which milestone achievement will be assessed.
• Provide a detailed timeline for the anticipated attainment of each milestone and the overall goal.
• Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

UH3 validation phase should address each of the items listed below:

• Plan for additional optimization of analytical validation including establishing threshold or cut-off for assays;
• Plan to accrue specimens to perform clinical validation of assays including identification of the clinical trial/study that will provide specimens, documentation of appropriate availability and pre-approvals to get specimens (i.e. indication that the repository holder identifies availability of specimens and that there is an appropriate process to get the specimens with reasonable certainty);
• Provision of a statistical power analysis that defines the number of specimens needed;
• Plan for clinical validation of the assays within the intended clinical context of use;
• Plan to address regulatory requirements needed to get assays into clinical trial/study;
• Identification of Potential Pitfalls and Alternative Approaches to overcome obstacles to clinical validation of the assays;
• Metrics for clinical validation of the assays to be achieved during the UH3 phase.

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

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

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a 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

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, 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 the policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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.

This FOA is focused on the validation of clinical assays that will be used in trials or clinical studies of cancer treatment, prevention or cancer control. Therefore, the potential of the proposed project to validate or harmonize such assays and biomarkers for a specific cancer-related clinical context is essential and will be a main factor in assessing the overall merit of the applications.

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

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

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

Specific for this FOA: Do the proposed assays and markers address an important cancer problem that is significant within the clinical context? What is the potential of the proposed assays to be broadly adopted by the healthcare community for use in treatment, prevention or cancer control? Priority will be given to technologies for assays that are currently or likely to be FDA cleared in the near future for use in clinical laboratories.

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage 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 for this FOA: Is the team expertise appropriate and sufficiently diverse to manage the development and clinical validation of the assays within the specified clinical context of use? Will the team be able to manage the further development of the assays should the assays be successful so that it is distributed and available ultimately to the healthcare community?

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 for this FOA: If the markers are already established in practice, are the investigators proposing to develop assays for a novel clinical context of use? If the projects involve harmonization studies, then innovation criteria may not apply in the traditional sense. The investigators need to justify this critical need for harmonization and identify innovative steps in assay procedures (e.g., new technology, new reference standard) that would enable success in harmonization efforts.

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

Specific for this FOA: How well considered is the plan to develop and validate or to harmonize the clinical assays and markers? Is the analytical validation appropriate with sufficient attention to pre-analytic variables for stabilizing the analytes (markers), the rigor needed to meet the specific elements of Preliminary Data? Does the project plan for assay distribution to assure its availability for the healthcare community? Does the plan for clinical validation of the assays include an appropriate number of specimens for testing prevalence of the marker and for associating assay results with a pre-specified clinical endpoint? Does the plan for the validation of clinical performance of the assays and markers in the UH3 phase identify sufficient appropriate specimens for testing prevalence of the marker including a statistical plan for associating assay results with a specified clinical endpoint within the intended clinical context? Are the milestones clearly specified for transitioning from the UH2 to the UH3 phase? Do the milestones involve quantitative metrics? Do the milestones deal with assay performance characteristics that are pertinent to the intended use of the assays?

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?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

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

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

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

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

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

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

Not applicable

Not applicable

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

Not applicable

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

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

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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

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

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

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

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

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

After administrative review by NCI program staff, successful UH2 projects will be prioritized for selection and transition to the UH3 phase.

Criteria used to evaluate such transition will include:

• Successful achievement of the milestones for analytical validation;
• Clear delineation of the intended use of the assays in a clinical trial/study;
• Potential for completing clinical validation of the assays within its intended clinical use including access to appropriate specimens from prior trials/studies, statistical power analysis based on the analytical performance of the assays, plans for IRB approval;
• Availability of funds;
• NCI program priorities.

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see 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 http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://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 http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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.

Cooperative Agreement Terms and Conditions of Award

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

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

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

• Defining the overall research objectives and approaches of the consortium;
• Determining experimental approaches, designing protocols, setting project milestones, and overseeing the conduct of experiments;
• Overseeing and coordinating the effort of the multi-disciplinary team and participating institutions and ensuring their optimal integration;
• Overseeing the conduct of UH2/UH3 research projects and ensuring their scientific rigor;
• Ensuring compliance with the applicable mandatory regulations (including protection of human subjects);
• Adhering to the NIH policies regarding intellectual property, data release, and other policies that might be established during the course of this activity;
• Submitting periodic updates on human subject and accrual reports upon initiation of validation studies;
• Participating as Members of the Steering Committee;
• Implementing guidelines and procedures developed by the Steering Committee;
• Participating in monthly teleconferences with NCI program staff;
• Attending annual Steering Committee meetings organized by the NCI;
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

NCI Program staff member(s) acting as a Project Scientist(s) will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NCI staff members may be designated to have substantial involvement. The NCI Project Scientist(s) and any other substantially involved staff members will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is deemed essential, these individuals will seek NCI waivers according to the NCI procedures for management of conflict of interest.

The main activities of the NCI substantially involved staff members include but are not limited to the following aspects:

• Providing input on experimental and clinical approaches, assisting in designing protocols, and consulting on updates to project milestones;
• Providing advice to the awardees on specific scientific, analytical, and clinical issues;
• Assisting and advising awardees with regard to various regulatory and compliance issues;
• Participating in monthly teleconferences with PDs/PIs to monitor progress and facilitate cooperation;
• Monitoring progress of the projects towards meeting milestones and adherence to the strategic goals of the program;
• Tracking monthly accrual of participants for clinical testing to ensure proper completion of this essential step;
• Participating in the activities of the Steering Committee and the implementation of its guidelines and procedures;
• Stimulating interactions among awardees;
• Attending annual Steering Committee meetings organized by the NCI; and
• Contributing to publications and presentations resulting from the project if appropriate.

Additionally, an NCI Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

NCI reserves the right to terminate or curtail any individual award, including the UH3 phase, if there

is insufficient progress towards meeting milestones.

Areas of Joint Responsibility include:

Steering Committee: The Steering Committee will consist of the following voting members:

• PDs/PIs from each cooperative agreement UH2/UH3 award (one vote per award even when multiple PDs/PIs are designated);
• NCI-assigned Project Scientist;
• One representative each from the Cancer Diagnosis Program of the Division of Cancer Treatment and Diagnosis, the Cancer Therapy Evaluation Program of the Division of Cancer Treatment and Diagnosis, the Division of Cancer Prevention, and the Division of Cancer Control and Population Sciences, who along with the NCI Project Scientist will collectively have one vote for the NIH.

The Committee will be chaired by one of the UH2/UH3 PDs/PIs.

Other NIH staff members may participate in the activities of the Committee as needed as nonvoting members.

The Steering Committee will be responsible for communication and coordination among funded projects, including sharing ideas, logistics, and solutions to technical issues. When feasible and appropriate, the Steering Committee will seek to establish consensus on platform interoperability in areas such as control software, data analysis, communication protocols, and standard power sources. Other shared advice may include promise of clinical potential, manufacturability, regulatory issues, and deployment into local resource-limited settings. The members of the Steering Committee will meet once a year in person and by conference calls as needed.

Dispute Resolution:

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

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

A final 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 agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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.

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

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Tracy G. Lively, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5944
Email: [email protected]
(For response, resistance and risk stratification markers for treatment trials)

Sumana Dey, Ph.D.
National Cancer Institute
Telephone: 240-276-5748
Email: [email protected]

Minkyung (Min) Song, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276- 6139
Email: [email protected]
(For companion diagnostics and pharmacodynamic and safety markers for treatment trials)

Lynn Sorbara, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-7135
Email: [email protected]
(For assays involving screening and early detection)

Rao Divi, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6913
Email: [email protected]
(For assays involving cancer epidemiology and population science)

Mukesh Verma, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276- 6889
Email: [email protected]
(For assays involving cancer epidemiology and population science)

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: [email protected]

Shane Woodward
National Cancer Institute (NCI)
Telephone: 240-276-6303
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.