Assay Validation of High Quality Markers for Clinical Studies in Cancer (PAR-25-075 and PAR-25-074)

Assay Validation of High Quality Markers for Clinical Studies in Cancer (PAR-25-075 and PAR-25-074) is sponsored by National Cancer Institute (NCI). These opportunities support the validation of high-quality markers for clinical studies in cancer. This could include the validation of AI-derived biomarkers for early detection and screening.

PAR-25-074: Assay Validation of High Quality Markers for Clinical Studies in Cancer (UH2/UH3 Clinical Trial Not Allowed) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. 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 of High Quality Markers for Clinical Studies in Cancer (UH2/UH3 Clinical Trial Not Allowed) UH2 / UH3 Phase Innovation Awards Cooperative Agreement Notices of Special Interest associated with this funding opportunity March 31, 2025 - This funding opportunity was updated to align with agency priorities.

Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 .

August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy.

See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Funding Opportunity Exploratory/Developmental Cooperative Agreement Phase II See Section III. 3.

Additional Information on Eligibility .

Assistance Listing Number(s) Funding Opportunity Purpose Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) invites applications to support the validation of molecular/cellular/imaging markers (referred to as "markers" or "biomarkers") 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 NOFO will support investigator-initiated research for both analytical, and clinical validation of assays to be used in cancer treatment, control, or prevention trials supported by the NCI. This NOFO will also support 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, assays for measuring multiple markers, including immune markers, can be developed and validated simultaneously.

The UH2 phase of this NOFO supports analytical validation of assays for these molecular/cellular/imaging markers, which must be achieved within 2 years before assays may undergo clinical validation. The UH3 phase of this NOFO supports clinical validation of analytically validated assays for up to 3 years using well-annotated biospecimens from retrospective or prospective clinical trials or studies.

This NOFO 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 funding opportunity.

Projects proposed for this NOFO will require multi-disciplinary interaction and collaboration among scientific investigators, oncologists, statisticians, and clinical laboratory scientists. This NOFO is not intended to support early-stage development of technology or the conduct of clinical trials but is intended for validation of assays to the point where they could be integrated into clinical trials/studies as investigational assays.

Investigators responding to this NOFO must address both UH2 and UH3 phases. Milestones to be accomplished in the UH2 phase for transition to the UH3 phase must be proposed by the investigators. Open Date (Earliest Submission Date) Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization.

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.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) 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 available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. Part 1.

Overview Information Part 2. Full Text of Announcement Section I. Notice of 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.

Notice of Funding Opportunity Description Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) invites applications to further optimize and validate molecular/cellular/imaging markers (referred to as "markers" or "biomarkers") 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 NOFO will support investigator-initiated research for both analytical, and clinical validation of assays to be used in cancer treatment, control, or prevention trials supported by the NCI. This NOFO will also support 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 the durability of anti-cancer responses, assays for measuring multiple markers, including immune markers, can be developed and validated simultaneously.

The UH2 phase of this NOFO supports analytical validation of assays for these molecular/cellular/imaging markers, which must be achieved within 2 years before assays may undergo clinical validation. The UH3 phase of this NOFO supports clinical validation of established assays for up to 3 years using specimens from retrospective or prospective clinical trials/studies.

This NOFO 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 NOFO.

Projects proposed for this NOFO will require multi-disciplinary interaction and collaboration among scientific investigators, oncologists, statisticians, and clinical laboratory scientists.

This NOFO 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 NOFO must address both UH2 and UH3 phases.

Milestones to be accomplished in the UH2 phase for the transition to the UH3 phase must be proposed by the investigators. NCI-supported clinical trials, as well as prevention or cancer control studies, increasingly depend upon essential or integral marker-based assays for eligibility, stratification, disease monitoring, or primary study endpoints.

These markers and assays may be for pharmacodynamic, mechanism of action, prognostic, predictive, and/or for treatment response. They may also be related to the risk of cancer in prevention or cancer control studies. Many of these assays are proposed by investigators in academic laboratories or small biotechnical companies that have developed interesting markers based on discovery research.

Most investigators are generally comfortable developing assays based on discovered markers for research purposes but may not have the expertise and support for developing validated assays for clinical purposes as well as for navigating the regulatory requirements that clinical laboratory assays must meet. This can cause considerable delay and added expense to successfully conducting clinical trials.

This NOFO 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 the assays for their use in clinical trials/studies.

Applications in response to this NOFO 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.

However, efforts to harmonize clinical laboratory tests, including investigation into the performance and reproducibility of assays across multiple clinical laboratories, are also appropriate for this funding opportunity. In the context of these NOFOs “imaging” refers to in vitro imaging modalities such as microscopy but not clinical radiology.

The primary elements for achieving the research objectives are as follows : Existing assay: an assay that has been reduced to practice in human tissues. The 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/Biomarkers: molecular/cellular/imaging markers that are associated with a clinical endpoint in a pre-defined clinical context or situation that yields usable information about diagnosis, prognosis, or response to clinical intervention for treatment, prevention, or control of cancer. NOTE: In the context of these NOFOs "imaging" refers to in vitro imaging modalities (e.g. microscopy) not clinical radiology (e.g. PET or MRI).

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) in clinical trials or clinical studies 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 NOFO should use technologies already in use or soon to be approved for use in clinical laboratories since this is not a technology development NOFO. Applications to improve standardization or harmonization of assays among laboratories for use in clinical trials/studies are appropriate for this NOFO.

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 the 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 marker discovery research or result from previous hypothesis-driven clinical studies.

The assay(s) may be a 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. The UH2/UH3 mechanism has two phases.

The initial cooperative agreement awards will be granted for up to 2 years 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 phase (analytical validation phase) During the UH2 phase, the investigators must complete the 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 pre-analytic variables and their effect on marker stability within biospecimens appropriate for the clinical context of use.

The UH2 Analytical Validation phase should determine the following (but not be limited to) performance characteristics of the assay required for the successful conduct of the study proposed for the UH3 award: 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 the determination of calibration and quality control procedures.

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 the companion NOFO ( PAR-23-314 ). Minimum criteria for 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 phase (clinical validation phase) The UH3 phase will support the 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 The UH3 project should demonstrate 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, for example: Definition of the sensitivity and specificity of the assay results with respect to 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.

Non-responsive Applications The following types of activities remain outside the scope of this NOFO, and applications proposing them are non-responsive to this NOFO and will not be reviewed. Applications with the following attributes will be deemed non-responsive and will not be reviewed: Projects that propose to support clinical trials.

This NOFO is intended to bring assays to the point where they can be integrated into future clinical trials/studies. Applications that propose early-stage development of technologies/assay(s). Applications with assays that have not been demonstrated to work on human samples and where importance is not well justified for development into clinical assays.

Projects focused on technology development for assays or biomarker discovery 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.

Section II. Award Information Cooperative Agreement: A financial assistance 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.

See Section VI. 2 for additional information about the substantial involvement for this NOFO. Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types.

Only those application types listed here are allowed for this NOFO. Not Allowed: Only accepting applications that do not propose clinical trials. Need help determining whether you are doing a clinical trial?

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. Applicants may request up to $275,000 direct costs for the entire UH2 phase with no more than $200,000 requested in any one year and up to $250,000 direct costs for the UH3 phase per year.

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 from this NOFO.

Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education 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 (Other than Small Businesses) 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 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 Non-domestic (non-U.S.) Entities (Foreign Organizations) 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 must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually . The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.

NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM. gov registration process.

The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registrations; all registrations must be in place by time of submission.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants. gov – Applicants must have an active 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 their organization to develop an application for 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 How to Apply-Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility 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, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

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 NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity 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. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- 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 needs 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 How to Apply- Application Guide must be followed.

All instructions in the How to Apply-Application Guide must be followed. PHS 398 Cover Page Supplement All instructions in the How to Apply- Application Guide must be followed.

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: 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. Applicants should organize the Research Strategy into the sub-sections identified below.

Applicants may include other sections as needed but must include the information requested below. Sub-Section A.

Background and Significance Define the specific cancer-related 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 marker(s) and assay(s), and their potential for affecting the intended clinical context in treatment trials, prevention studies or cancer control studies; Include the type of specimen to be used for the assays and how the assay results will be used.

Sub-Section B.

Preliminary Data Describe the current state of development of the assays and their prospect for clinical 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.

Sub-Section C.

Approach (maybe 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 marker(s) and assay(s) within the sample matrix of its intended use; Plan to obtain appropriate well-annotated human specimens for developing and optimizing the assay(s); Plan to evaluate 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 assay(s) 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 in the UH3 study with determination of calibration and control procedures; Plan to address the regulatory issues regarding the use of the marker(s) and assay(s) in clinical trials/studies within the intended clinical context; Plan for the management of the intellectual property and potential collaboration with commercial entities to support the assay(s) if successful.

UH3 Clinical Validation Phase should describe the plan for clinical validation of the assays within the intended clinical context of use and should address each of the items below : Definition of the clinical endpoint of interest (e.g., survival, response, disease presence or absence); Definition of the association(s) of interest between the assay result(s) and the clinical endpoint, such as sensitivity and specificity of the assay with respect to the clinical endpoint or prevalence of the marker within the intended study population; 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 additional optimization such as establishing a clinical threshold or cut-off for assay(s); Plan to address additional regulatory requirements needed to bring assays into a clinical trial/study, including the potential requirement for an Investigational Device Exemption from the FDA.

Sub-Section D. 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.

Milestones must consist of appropriate objective performance targets such as a required limit of detection and coefficient of variation, or sensitivity and specificity.

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 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 UH2 and UH3 stage must be provided in a separate heading at the end of the Approach section 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; 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 How to Apply- Application Guide.

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions: All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the