Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Cancer Institute (NCI)

Funding Opportunity Title

Assay Validation For High Quality Markers For NCI-Supported Clinical Trials (UH2/UH3)

Activity Code

UH2/UH3 Phase Innovation Awards Cooperative Agreement

Announcement Type

New

Related Notices
  • NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015)
  • NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015)
  • NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015)
Funding Opportunity Announcement (FOA) Number

PAR-15-095

Companion Funding Opportunity

PAR-15-096, UH3 Exploratory/Developmental Cooperative Agreement Phase II

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.394

Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to improve the development and validation of molecular diagnostics for the treatment, control, or prevention of cancer. This FOA includes, but is not limited to, the validation of prognostic, predictive or response markers for treatment and markers for cancer control or prevention trials. Applicants should have an assay that works in human samples and whose importance is well justified for development into a clinical assay. The UH2 phase of this FOA supports analytical validation of assays for these markers that must be achieved within two years before an assay may undergo clinical validation. The UH3 phase of this FOA supports the clinical validation of established assays for up to three years using specimens from retrospective or prospective studies from NCI-supported or other clinical trials. In both the UH2 and UH3 phases, clinical laboratory staff, technical and other needs must be an integral part of the application. Assays proposed for this FOA may be used to validate existing assays for use in other cancer clinical trials, observational studies or populations. Projects proposed for this FOA will require multi-disciplinary interaction and collaboration among scientific investigators, clinicians, statisticians and clinical laboratory scientists and staff. This FOA is not intended to support trials that assess the clinical utility of a marker/assay but is intended to develop assays to the point where their clinical utility could be assessed in other trials. Investigators responding to this FOA must address both UH2 and UH3 phases.

Key Dates
Posted Date

January 21, 2015

Open Date (Earliest Submission Date)

February 26, 2015

Letter of Intent Due Date(s)

30 days prior to the application due date

Application Due Date(s)

March 26, 2015; July 8, 2015; October 7, 2015; February 9, 2016; July 8, 2016; October 7, 2016; February 9, 2017; July 7, 2017; October 6, 2017, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

July 2015; November 2015; February 2016; July 2016; November 2016; February 2017; July 2017; November 2017; February 2018

Advisory Council Review

October 2015; January 2016; May 2016; October 2016; January 2017; May 2017; October 2017; January 2018; May 2018

Earliest Start Date

December 2015; February 2016; June 2016; December 2016; February 2017; June 2017; December  2017; February 2018; June 2018

Expiration Date

October 7, 2017

Due Dates for E.O. 12372

Not Applicable

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.

There are several options to submit your application to the agency through Grants.gov. You can use the ASSIST system to prepare, submit and track your application online. You can download an application package from Grants.gov, complete the forms offline, submit the completed forms to Grants.gov and track your application in eRA Commons. Or, you can use other institutional system-to-system solutions to prepare and submit your application to Grants.gov and track your application in eRA Commons. Learn more.

Problems accessing or using ASSIST should be directed to the eRA Service Desk.
Problems downloading forms should be directed to Grants.gov Customer Support.
Table of Contents

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

Part 2. Full Text of Announcement
Section I. Funding Opportunity Description

This Funding Opportunity Announcement (FOA) is a phased initiative to improve the development of molecular diagnostics for use in NCI-supported clinical trials in cancer. This FOA includes, but is not limited to, the validation of prognostic, predictive or response markers for treatment and markers for cancer control or prevention trials. Applicants should have an assay that works in human samples and whose importance is well justified for development into a clinical assay.

Two-phase Projects: Investigators responding to this FOA must address plans for both UH2 and UH3 phases.

  • The UH2 phase of this FOA supports analytical validation of assays for markers that must be achieved within two years before an assay may undergo clinical validation. The technology for the assay should be available in clinical laboratories now. Assays must meet the standards for analytical validation as specified for Clinical Improvement Act (CLIA) certified laboratories or for the Food and Drug Administration (FDA) Good Laboratory Practices regulations for drug and device premarket development before they may proceed to the UH3 phase. Collaboration with commercial entities that may ultimately distribute or otherwise support successful assays is encouraged but not necessary for a successful application.
  • The UH3 phase of this FOA supports the clinical validation of established assays. Support may be sought to obtain retrospective or prospective specimens from NCI-supported or other clinical trials.

Assays proposed for this FOA may be used to validate existing assays for use in other trials, observational studies or populations involving cancer. Projects that improve standardization of assay performance among laboratories are also encouraged. Projects proposed for this FOA will require multi-disciplinary interaction and collaboration among scientific investigators, clinicians, statisticians and clinical laboratory scientists and staff.

Background

NCI-supported clinical trials increasingly depend upon molecular diagnostics to be measured as targets for therapy (companion diagnostics) or other essential or integral markers for treatment, prevention or cancer control trials. 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 as well as predictive or response markers. They may also be related to risk of cancer in prevention or cancer control trials. NCI’s experience is that these investigators generally do not understand the rigor and regulations that clinical laboratory assays must meet. This causes considerable delay and added expense to the performance of 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.

Research Objectives

Applications to this FOA must propose to develop an existing assay using human specimens in a clinical laboratory into a molecular diagnostic assay that can be used in a clinical trial for the treatment, prevention or control of cancer.  The primary elements for achieving the research objectives are:

  • Existing assay: an assay that has been reduced to practice in human tissues. An 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 tests 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 assay are of sufficient quality as to be useful in clinical trials and justify sample collection.
  • Molecular diagnostic: a marker measured in a validated assay that is 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.
Project Characteristics
  • The project must focus on assays whose marker or classifier is likely to be used in treatment, prevention, or cancer control trials. There does not need to be a commitment to a particular trial.
  • Awards will be based on how well the applicant justifies the use of their proposed assay and its marker 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 assay and the plan for its 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 are appropriate for this FOA.
  • Metrics for analytical and clinical validation as 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 using human specimens that may be derived from discovery research or the result of previous hypotheses or biological or clinical rationale. The assay may be a multiplex assay or a classifier but must be able after conversion to a clinical assay to be performed in a clinical trial. Preliminary data should define the current status of the assay as well as justify support for optimization and usability in a clinical trial.

Two-phase Projects: Initial cooperative agreement awards for up to 2 years will be granted for analytical validation of the assay 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 assay. Since this is likely not to require large numbers of samples, the investigators are expected to provide samples that are appropriate for the clinical context of the intended use of the assay. 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 interfering substances
  • Reportable range of test results for the test system
  • Reference intervals (normal values) with controls and calibrators
  • Harmonization of analytical performance if the assay is to be performed in multiple laboratories
  • Establishment of appropriate quality control and improvement procedures
  • Any other performance characteristic required for test performance with determination of calibration and 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 assay and prepare it and its marker for use in a clinical trial.

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

  • Demonstration of the association of the result of the assay 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 for treatment, prevention or cancer control trials
  • Definition of the sensitivity and specificity of the assay result with the defined clinical endpoint
  • Estimation of the prevalence of the marker within subjects or patients for the intended clinical context
  • Establishment of an appropriate cut-off or threshold for the assay using appropriate statistical analysis

Assays that have already met the above criteria for analytical validation may apply directly to the companion PAR-15-096 for clinical validation of the assay.

Research projects that are not appropriate for this FOA

Because this FOA is not meant to support trials that assess the clinical utility of a marker/assay but is intended to get assays to the point where their clinical utility could be assessed in other trials, 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. 

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New
Resubmission
Revision

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Applicants may request up to $275,000 direct costs for the entire UH2 phase and up to $250,000 direct costs for the UH3 phase per year.

Award Project Period

The proposed project period for the initial development phase (UH2) must not exceed 2 years (but may be shorter).

The proposed project period for the second validation phase (UH3) must not exceed 3 years.

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.

Section III. Eligibility Information
1. Eligible Applicants
Eligible Organizations

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
Foreign Institutions

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.

Required Registrations

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.
  • 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.

Eligible Individuals (Program Director/Principal Investigator)

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.

2. Cost Sharing

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

3. Additional Information on Eligibility
Number of Applications

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

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

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

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows.  The NIH will accept submission:

  • To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
  • Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
  • Of an application with a changed grant activity code.
Section IV. Application and Submission Information
1. Requesting an Application Package

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.

2. Content and Form of Application Submission

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.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Tracy G. Lively, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5944
Email: livelyt@mail.nih.gov

Page Limitations

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

Instructions for Application Submission

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.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

The Investigator's Team should include:

  • Clinical Investigator: Investigator(s) who define the intended clinical context of use for the marker and its assay and will oversee their incorporation into a potential trial – likely to be oncologist(s) who treat patients but may be a translational scientist.
  • Clinical Laboratory Staff: Staff who will perform the translation of the assay into a clinical assay. The staff may work in a CLIA-certified clinical laboratory but do not need to do so if the assay is not intended to used for medical decision-making. In that case the assay is 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.
  • 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 assay and its marker 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 assay are encouraged but not required.
  • Clear involvement of clinical laboratory staff must be demonstrated in the application.
R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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 marker and its assay and how they fit the intended clinical context in which they will be used.
  • Provide the biologic or discovery research rationale for the marker and its importance
  • Outline the proposed assay and its marker and its potential for affecting the intended clinical context in treatment, prevention or cancer control trials.
  • 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 assay and how the assay result will be used.

2) Preliminary Data

  • Describe the current state of development of the assay and its use in preclinical development
  • Demonstrate the function of the assay with human specimens, including the current reagents and technologies and types of specimens that the assay 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 - address each of the items listed below.

  • Plans to perform analytical validation of the assay and its marker within the matrix of its intended use that include but are not limited to:
  • Plan to obtain appropriate specimens for developing and optimizing assay
  • Plan to initiate method validation of the assay and to initiate evaluation of the marker’s (analyte’s) stability within the matrix of the specimens to be used
  • The plan for evaluation of (i) Accuracy, (ii) Precision, (iii) Analytical sensitivity, (iv) Analytical specificity including 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 assay is to be performed in multiple laboratories, (viii) Establishment of appropriate quality control and improvement procedures, (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 and its assay within its intended clinical context. This includes the possibility of controlling intellectual property, evaluation of the significant risk of the assay and marker within the clinical context of a clinical trial and plans for collaboration with commercial entities to support the assay if it is successful.
  • Specific performance metrics or milestones to be achieved during analytical validation of items 1- 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: e.g., 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 – address each of the items listed below.

  • Plans for additional optimization of analytical validation including establishing threshold or cut-off for assay
  • Plans to accrue specimens to perform clinical validation of assay including identification of the clinical resource or trial 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 assay within the intended clinical context of use
  • Plans to address regulatory requirements needed to get assay into clinical trial
  • Identification of Potential Pitfalls and Alternative Approaches to overcome obstacles to clinical validation of the assay
  • Delineate metrics for clinical validation of the assay 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 submitted for the January 25, 2015 due date or after are expected to comply with the NIH Genomic Data Sharing Policy as detailed in NOT-OD-14-111, as applicable.
  • 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.

Planned Enrollment Report

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

PHS 398 Cumulative Inclusion Enrollment Report

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

3. Submission Dates and Times

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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

6. Other Submission Requirements and Information

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

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

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

Section V. Application Review Information

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

1. Criteria

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 development and validation of clinical assays that will be used in cancer treatment, prevention or cancer control trials. Therefore, the potential of the proposed project to develop and validate such an assay and its marker for a specific cancer-related clinical context is essential and will be a main factor in assessing the overall merit of the applications. 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.

Overall Impact

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).

Scored Review Criteria

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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 assay and its marker address an important cancer problem that is significant within the clinical context? What is the potential of the proposed assay to be broadly adopted by the health care community for use in treatment, prevention or cancer control?

Investigator(s)

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 for this FOA: Is the team expertise appropriate and sufficiently diverse to manage the development and clinical validation of the assay within the specified clinical context of use? Will the team be able to manage the further development of the assay should the assay be successful so that it is distributed and available ultimately to the healthcare community?

Innovation

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

Specific for this FOA: How is the applicant's proposed use of the assay and its marker within the clinical context of cancer innovative?    

Approach

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 for this FOA: How well considered is the plan to develop and validate an assay and its marker by the applicant and their team? Is the analytical validation appropriate with sufficient attention to pre-analytic variables for stabilizing the analyte (marker), the rigor needed to meet the specific elements of Preliminary Data? Does the project plan for assay distribution to assure its availability for the health care community? Is the plan for clinical validation of the assay support 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 assay and its marker 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?  

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?

Environment

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

Additional Review Criteria

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.

Protections for Human Subjects

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.

Inclusion of Women, Minorities, and Children 

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.

Vertebrate Animals

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.

Biohazards

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

Resubmissions

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.

Renewals

Not Applicable

Revisions

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.

Additional Review Considerations

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

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications:

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:

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

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons

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

Section VI. Award Administration Information
1. Award Notices

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

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

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

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

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 metrics for the analytical validation metrics
  • Clear delineation of the intended use of the assay in a clinical trial
  • Potential for completing clinical validation of the assay within its intended clinical use including access to appropriate specimens from prior trials, statistical power analysis based on the analytical performance of the assay, plans for IRB approval.
  • Availability of funds
  • NCI program priorities
2. Administrative and National Policy Requirements

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

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:

  • 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 twice a year during the UH2 phase and quarterly during the UH3 phase updates on progress and problems in a brief format as agreed upon with the NCI;
  • Submitting monthly 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, technologies, and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies

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

An 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 waiver 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. Some Program Officials may also have substantial programmatic involvement (as Project Scientists/Coordinators). In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications or will seek NCI waiver as stated above.

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

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); and
  • NCI-assigned Project Scientists, a representative each from the Cancer Diagnosis Program and 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 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.

Panel of External Scientific Consultants

Panel of External Scientific Consultants will operate as a subcommittee to the Steering Committee, advising the Steering Committee and providing technical expertise to awardees. The members of the panel will be selected by NCI in consultation with the UH2/UH3 awardees to provide independent assessments and recommendations to awardees on the progress. The panel will consist of scientists with relevant expertise who are not participants in any of the cooperative agreement awards resulting from this FOA. The ESC will meet once a year. Part of this meeting may be in conjunction with the Steering Committee meeting to allow members of both groups to interact directly with each other.

Dispute Resolution:

Any disagreements that may arise in scientific and/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 HHS regulation 45 CFR Part 16.

3. Reporting

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

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

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

Section VII. Agency Contacts

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

Application Submission Contacts

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: https://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
Email: support@grants.gov

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

Scientific/Research Contact(s)

Magdalena Thurin, PhD
National Cancer Institute (NCI)
Telephone: 240-276-5973
Email: thurinm@mail.nih.gov
(For assays involving immunological diagnostics and non-companion diagnostics for treatment trials)

Tracy G. Lively, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5944
Email: livelyt@mail.nih.gov
(For response, safety, resistance and risk stratification markers for treatment markers)

Minkyung (Min) Song, PhD
National Cancer Institute (NCI)
Telephone: 240-276- 6139
Email: songm@mail.nih.gov
(For companion diagnostics and pharmacodynamic markers for treatment trials)

Asad Umar, DVM, PhD
National Cancer Institute (NCI)
Telephone: 240-276- 7070
Email: umara@mail.nih.gov
(For assays involving assays for cancer prevention)

Mukesh Verma, PhD
National Cancer Institute (NCI)
Telephone: 240-276- 6889
Email: vermam@mail.nih.gov
(For assays involving cancer epidemiology and population science)

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

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

Section VIII. Other Information

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

Authority and Regulations

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 Parts 74 and 92.

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