Part 1. Overview Information

Key Dates

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.

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.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. 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.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
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

Purpose

This Notice of Funding Opportunity (NOFO) will support extramural research to investigate and mitigate challenges in clinical assay development and subsequent analytical validation due to preanalytical variability in biospecimens as described in this NOFO. Research funded under this NOFO may include investigations of preanalytical variability associated with the procurement and study of small biopsies (core biopsies, small excision samples), blood utilized for "liquid biopsies", tissue swabs, tissue secretions, pleural and esophageal aspirates, feces, or bodily fluids like sweat, urine, CSF, breast milk and saliva. Investigator-designed experiments will explore how different biospecimen preanalytical conditions affect emerging and clinically relevant biomarkers quantified by a variety of testing platforms. The results from this research program will improve the understanding of how analytical quantification of clinically relevant biomarkers is affected by variation in biospecimen collection, processing, and storage procedures. The overall goal is to expedite biomarker clinical assay development through evidence-based standardization of biopsy handling practices.

Background

Importance of preanalytical factors in biospecimen research

Biospecimen preanalytical variability can affect the reproducibility of clinical research. Biospecimens are the essential starting materials for the biomarker assays that will enable precision medicine. Clinical assays used for diagnosis and therapeutic decision-making are based on assessment of biological molecules (e.g., DNA, RNA, proteins) from a patient’s biospecimen. Such assays are often based on the detection of one or more biomarkers and must be both accurate and reproducible. False positive or negative results from the evaluation of biomarkers in clinical assays can directly affect patient diagnosis, treatment, and outcomes and can lead to over-treatment, under-treatment, or incorrect treatment.

An increasing number of reports demonstrate that preanalytical factors such as the handling of a clinical biospecimen prior to analysis can have a significant impact on assay results, which can in turn affect patient care. Biospecimen preanalytical factors can directly influence molecular results from assays conducted for basic research, biomarker discovery, biomarker validation, and development of validated clinical assays. In fact, preanalytical processing has been highlighted as a significant impediment in the development of predictive biomarkers for oncology. Preanalytical variability has also been identified as a challenge in the implementation of next-generation technologies in the analysis of tissue biopsies. The methods used to collect, process and store small biopsy biospecimens such as core biopsies, fine needle aspirates (FNAs), and lung aspirates, for example, can vary widely within and across medical institutions and laboratories, introducing variability in such preanalytical factors as biopsy method, needle gauge, vacuum-assistance, biospecimen size/volume, duration and temperature of transport, preservation method, temperature and duration of storage, and number of freeze thaw cycles. A wide variety of preanalytical factors, alone and in combination, are known to affect the accurate assessment of biomarkers, adding to the complexity of biospecimen challenges for the clinical laboratory.

New knowledge about preanalytical effects can support evidence-based biospecimen procedures for cancer research activities including clinical trials. Smaller biopsies such as FNAs, core biopsies, and lung aspirates present a unique set of preanalytical factors and associated challenges for reliable biomarker assay results. Such biopsies are clinically valuable now and in the future for assessing current and recurrent disease state as well as for assessing the likely efficacy of therapeutic intervention. Research has shown discordant biomarker assay results when comparing such small biopsies with larger tumor resections.

Detection of biomarkers in blood analytes such as cfDNA (cell-free DNA) and CTCs (circulating tumor cells) is a promising approach for non-invasively tracking tumor behavior over time, potentially enhancing cancer management by assessing tumor burden, detecting recurrence, monitoring early response and identifying drug resistance. Preanalytical considerations are also challenging for such liquid biopsies, as inconsistency between sample handling protocols and lack of standardization among analytical techniques has created obstacles for translating cfDNA analysis to clinical practice. CTC analysis, including enumeration and characterization, is also affected by preanalytical factors. Challenges introduced by preanalytical variability also affect the isolation and analysis of exosomes and other extracellular vesicles, underscoring the need for rigorous analytical validation.

Bodily fluids such as urine and cerebrospinal fluid (CSF) are other examples of biospecimens that could be utilized for detection of biomarkers in clinical assays that may be helpful in patient diagnosis, treatment selection, and prediction of outcomes. Additional biospecimen types such as tissue swabs, tissue secretions, pleural and esophageal aspirates, feces, sweat, breast milk and saliva have potential application in clinical biomarker research and are included in this NOFO.

Differences in assay results can be a result of differences in preanalytical factors such as ischemia times, preservation method, and tumor heterogeneity. Such preanalytical factors may alter biomarker measurements and influence the performance of assay technologies. Variability and biases introduced in the early stages of biomarker assay development, if not addressed and understood, can increase the likelihood of irreproducible data and incorrect conclusions. This is of significant concern for NCI clinical research. Basic and applied biospecimen science investigation will provide valuable insights into how to limit variability in clinical assay results from small biopsies.

Examples: Effects of preanalytical factors on diagnostic assays

A classic example of how biospecimen preanalytical factors can have a dramatic influence on assay results is companion diagnostic HER2 assays that guide the therapeutic use of trastuzumab, a targeted therapy for breast cancer. Recommendations for the reliable assessment of HER2 status in patient biospecimens were established 14 years after the initiation of phase 1 clinical trials in 1992. These measures were developed in response to multiple issues with HER2 reproducibility including preanalytical variability. For example, one study showed that the number of patients reported to overexpress HER2 differed by approximately 20% between specimens processed in local pathology departments and those processed in centralized laboratories.

When investigating whether non-standardized approaches between laboratories directly influenced the clinical assay results, the American Society of Clinical Oncologists (ASCO) and the College of American Pathologists (CAP) concluded that several biospecimen preanalytical factors including fixative composition, delay time to tissue fixation, method of tissue processing, and time in fixative could influence HER2 assay results. A major issue for such guidelines is that there is often a lack of fundamental scientific data on the behavior of clinical biomarker assays in response to biospecimen preanalytical factors. Systematic evaluation and increased understanding of the impact of these factors in the context of particular assay platforms and tissue types, and how to mitigate their impact, are necessary to improve current clinical assays and the development of new biomarker assays.

Preanalytical factors also impact the reproducibility of highly sensitive liquid biopsy assays that require optimized conditions for identification of circulating tumor material. For example, blood collection tube type and a time-to-assay delay affect CTC enumeration and characterization of breast cancer patient samples using the high-definition single-cell analysis assay (HD-SCA). CTC recovery, EpCAM and cytokeratin immunostaining, and nuclear content are also affected by storage time and tube type. Concentration and fragmentation of circulating cell free DNA (cfDNA) are also influenced by differences in sample handling procedures. These examples highlight the crucial importance of biospecimen science in effective development and application of clinical diagnostic assays.

Support of Biospecimen Science at the NCI

Past research funded by NCI included the Biospecimen Research Network (BRN) program, which advanced the field of biospecimen science through systematic investigation of the effects of different biospecimen collection, processing, and storage procedures on downstream molecular analyses.  The NCI Biospecimen Preanalytical Variables (BPV) research program was a multi-site study of specific biospecimen handling issues, including cold ischemic time (delay to formalin fixation), time in formalin, freezing methods, and storage temperatures and durations.

Overall, results suggest that biospecimen preanalytical factors can significantly affect research and clinical assay results. The research also demonstrated that the downstream effects of different preanalytical factors can vary with respect to the specific analyte being evaluated and the analytical platforms and/or assays being used. Thus, new and emerging clinical biomarkers and assays could be affected to unknown extents.

The NCI continues to actively curate and maintain an online biospecimen science database, the Biospecimen Research Database (BRD). The BRD is a free and publicly accessible database that contains summaries of peer-reviewed primary and review articles as well as SOPs in the field of human Biospecimen Science. In addition, and as an adjunct to the NCI Best Practices for Biospecimen Resources, the NCI develops the Biospecimen Evidence-based Best Practices (BEBPs) series, an expanding collection of procedural guidelines developed using, and annotated with, evidence from primary research publications in the field of human Biospecimen Science.

Need for continued research in biospecimen science

Measurement and validation of clinically relevant biomarkers using diagnostic assays are increasingly challenging as reliance on smaller biospecimens and liquid biopsy increases and new biomarkers and analysis platforms emerge. For example, NCI-sponsored treatment trials need accurate assays for integral markers used for selection of patients, integrated markers for evaluation of the clinical correlation of biomarkers for new agents, and pharmacodynamic markers that indicate whether the target has been engaged.

To generate the biospecimen science data needed to address today’s clinical biomarker assay challenges, an integrated approach is required that addresses how preanalytical factors introduced during biospecimen handling affect clinical biomarker assay performance. The need is critical given that diminished reliability and effectiveness of clinical biomarker assays could adversely affect patient care and drug development.

Research Objectives and Scope

This Notice of Funding Opportunity (NOFO) will support extramural research to investigate and mitigate challenges in clinical assay development and subsequent analytical validation due to preanalytical variability in tumor biopsies, blood biospecimens utilized as liquid biopsies, and other biospecimen types as described in this NOFO. This NOFO will fund research to support clinical assay development and validation through the identification and mitigation of preanalytical factors associated with collection, processing, and storage that negatively influence clinical assay results and reproducibility.

Using a cooperative agreement mechanism, the research will be conducted by a collaborative, interdisciplinary network that integrates clinical researchers with academic and private sector scientists in projects that focus on preanalytical challenges specific to:

• tumor tissue biopsies such as FNAs, core biopsies, small excisions, or pleural fluid aspirates, and/or
• blood liquid biopsy assays targeting cfDNA, microRNA, CTC s, exosomes and metabolites, and/or
• other biospecimens such as tissue swabs, tissue secretions, esophageal aspirates, feces, sweat, urine, CSF, breast milk, BAL and/or saliva

Potential preanalytical issues to address in solid tumors (FNA, Core biopsies, Excisions) may include but are not limited to biopsy methodology in a medical setting, tumor heterogeneity, preservation method (formalin, RNAlater, frozen, other), tissue processing, timing and temperature considerations, tradeoffs (morphology vs. molecular preservation), and shipping and storage considerations. Similarly, potential preanalytical issues to address in liquid biopsies may include but are not limited to collection device in a medical setting, collection methodology in a medical setting, timing and temperature considerations, sample processing, and shipping and storage considerations.

The NOFO intends to fund dedicated studies in biospecimen science to increase the success of clinical biomarker assays in cancer research. The research will align with current efforts to optimize clinical biomarker assays utilized in clinical trials networks and produce data needed for evidence-based biospecimen practices to support clinical trials. Applications to improve standardization or harmonization of assays targeted for use in clinical trials may be appropriate for this NOFO.

The work of the program will be centered on emerging and clinically relevant biomarker assays for a variety of molecular analysis platforms. The NOFO intends to fund clinically relevant emerging/established biomarkers (not discovery approaches) and may involve existing and emerging analysis platforms. Investigators will propose and design experiments to test assay performance and limits of detection of biomarkers under different preanalytical conditions. The work will be conducted by multidisciplinary scientific teams that may include pathologists, oncologists, radiologists, molecular biologists, and statisticians, as the work requires expertise and perspectives in clinical medicine, knowledge of the unique issues related to obtaining biopsy biospecimens, biology and technology platforms, and experimental design and analysis. A particular focus of this funding program is to address biomarker assay challenges that arise across early phase treatment trials. To best understand and address these challenges, applicant teams may wish to include investigators currently involved in Phase I and Phase II treatment trials.

This NOFO will fund multidisciplinary teams that together will constitute a U01 collaborative network. These teams may include but are not limited to oncologists, pathologists, radiologists, statisticians, molecular biologists etc. Each team’s application will focus on specific biomarker assays and associated questions in biospecimen science and present a research plan for acquiring the needed biospecimens. The assay may measure a single biomarker or may be a multiplex assay and must be amenable to conversion to a clinical assay that can be used in a clinical trial setting. Preliminary data should define the current status of the assay as well as justify support for optimization and usability in a clinical trial. Research ideas, experimental design approaches, biospecimens, and molecular analysis platforms will be shared across the network as possible to maximize research productivity.

Projects will involve defining workable biospecimen conditions for trials that utilize a particular type of tissue and/or liquid biopsy (e.g. lung aspirates, liver biopsies) in a biomarker assay system (e.g., Next Generation sequencing for mutation-targeted drug trials; multi-analyte IHC/IFA or targeted mass spec for pharmacodynamic assays/pathway analysis) to detect emerging clinical biomarkers. Projects may address biospecimen challenges that are relevant to multiple trials with assays utilizing similar platforms, and/or challenges relevant to specific assays in specific trials. Applications must propose biospecimen science research for assays that are relevant today and for the five-year funding period, with the understanding that new biomarkers and assay platforms may emerge within this time frame.

The program will address the following research questions in biospecimen science to enable clinical assay development utilizing small tissue biopsies and liquid biopsies:

• When a promising biomarker or set of biomarkers has been identified for validation and assay development, how can one determine whether there is an effect of biospecimen preanalytical factors on assay performance?
• How is assay performance affected when biopsy (solid and/or liquid) biospecimens are subjected to different preanalytical conditions?
• Is it likely that preanalytical factors will affect clinical diagnosis using this biomarker and analytical platform?
• Are different analytical platforms currently targeted for clinical use, e.g., RNAseq or multi-analyte IHC panels, more or less sensitive to preanalytical factors? Can such effects be mitigated with modified biospecimen practices? What stabilization approaches work better for a specific analysis platform?
• How can the sensitivity of phosphoproteins to preanalytical conditions be mitigated, so that critical phosphoprotein biomarkers can be reliably measured?
• Can analysis and mitigation of preanalytical variability contribute to an improved, more streamlined approach to assay standardization that reduces expense and increases assay reproducibility and utility?

Non-responsive Applications

Research Projects that are not responsive to this NOFO :

• Technology development projects that are supported by the NCI Innovative Molecular Analysis Technologies (IMAT) program, such as development of novel biospecimen fixatives/technologies.
• Biomarker discovery projects, projects related to early detection biomarker assays, or projects related to global cancer genomic/proteomic studies.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local 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).

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)

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

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the 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.

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.

2. Cost Sharing

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

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, 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.

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: 

Lokesh Agrawal, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5718;
Email: [email protected]

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

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.

SF424(R&R) Cover

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.

R&R or Modular Budget

All instructions in the How to Apply- Application Guide must be followed.

R&R Subaward Budget

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.

PHS 398 Research Plan

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

Specific Aims: In addition to the specific aims and approach(es), applicants should include the relevance of the research to the objectives of this NOFO.

Research Strategy: Describe the following:

Overview

The application should clearly define the context of the proposed study and biomarkers in current clinical trials, as well as the ability of the applicant’s team to perform preanalytical, analytical, and clinical validation of assays in their laboratory. Applications should outline the overall theme of the proposed research and the unmet clinical need that the proposed research addresses as well as the significance of the proposed studies.

The following strategies should be used, wherever relevant:

• Define the nature and scope of the investigative and established research approach(es) proposed
• Define how well the project is focused on the biospecimen preanalytical variability in small tumor tissue and liquid biopsies (such as FNAs, core biopsies, blood and other biospecimen types as listed in this NOFO).
• Define whether the proposed biomarker assay(s) will advance, improve and address a significant cancer clinical problem.
• Provide a clear statement of how the proposed research addresses an unmet clinical need.
• Define how the project will advance, improve and affect the development and validation of a clinical biomarker assay(s) that has a clinical significance and can help patient diagnosis, prognosis or treatment.
• Provide evidence to suggest that the proposed preanalytical factors for study are problematic for the proposed clinical biomarker assay(s), and that strategies for improvement can be identified.
• Define how the results of the project will advance and contribute to expediting clinical biomarker assay development through the evidence-based standardization of biospecimen handling practices.

Study Design

• Clearly state the objectives of the study and describe the scientific goals or hypotheses in sufficient detail that they can be unambiguously evaluated. Example goals might include assessment of the analytical performance characteristics (e.g., specificity, sensitivity, precision, as applicable) of a biomarker assay in the context of specific biospecimen preanalytic conditions.
• State how the results of the proposed project will contribute new knowledge in biospecimen science and advance clinical biomarker assay development through the evidence-based standardization of biospecimen handling practices.
• Applications should include a statistical justification for the study design regarding the number of specimens required, the number of biomarker evaluations needed for each specimen and so forth; the justification would typically be based on calculation of statistical power, precision of parameter estimates, probability of detection of an effect, or evaluation of other operating characteristics of the study design, as applicable.

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.

Other Plan(s): 

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 amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply- Application Guide must be followed.

Delayed Onset Study

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

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

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

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply Application Guide. Paper applications will not be accepted.

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

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

For this particular announcement, note the following: This NOFO will support extramural research to investigate and mitigate challenges in clinical assay development due to tumor tissue biopsy, liquid biopsy, and other biospecimen preanalytical variability as defined in this NOFO. The program will tie in with current efforts to optimize clinical biomarker assays utilized in NCI-sponsored clinical trials. Therefore, reviewers will emphasize:

• Potential of the proposed project to substantially improve the reliability of specific, clinically relevant biomarker assays;
• Potential of the proposed project to improve understanding of how biopsy collection, processing, and storage procedures may affect all aspects of analytical performance for current and emerging clinical biomarkers.

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 scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

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

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the 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 will receive a written critique.

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.

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 NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

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 2 CFR Part 200, 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 recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

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

• Defining the overall research objectives and approaches;
• Determining experimental approaches, designing protocols, setting project milestones, and overseeing the conduct of experiments, including statistical analysis for assessing the use of the assay within the intended clinical context;
• Overseeing and coordinating the effort of the multi-disciplinary team and participating institutions and ensuring their optimal integration; sharing of biospecimens, if feasible;
• 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 quarterly updates on human subject and accrual reports;
• Participating as Members of the Steering Committee;
• Implementing guidelines and procedures developed by the Steering Committee.
• Recipients 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

NCI program staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards. The substantially involved NCI program staff member(s), acting as Project Scientist(s), will coordinate the various activities of the recipients. Specific responsibilities of the NCI Project Scientist(s) will include the following aspects:

• Providing input on experimental and clinical approaches, as needed;
• Providing input to the recipients on specific scientific, analytical, and clinical issues;
• Assisting and advising recipients with regard to various regulatory and compliance issues;
• NCI’s Biospecimen Research Database (BRD)- http://brd.nci.nih.gov will serve as a resource tool for supported investigators to identify published effects of preanalytical factors on particular analytes.
• Monitoring progress of the projects towards meeting milestones and adherence to the strategic goals of the program;
• Participating in the activities of the Steering Committee and the implementation of its guidelines and procedures;
• Stimulating interactions among recipients;
• Contributing to publications and presentations resulting from the U01 network projects, if appropriate.

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

NCI reserves the right to terminate or curtail any individual award, if there is insufficient progress towards meeting milestones.

Areas of Joint Responsibility include:

Steering Committee: The Steering Committee (SC) will consist of PI s, NCI Project Scientist(s), and other scientific experts, including Food and Drug Administration (FDA) and National Institute of Standards and Technology (NIST) scientists and a patient advocate. NIST may provide input on standardization and FDA may provide perspective on the relevance of experimental design and results to regulatory challenges. 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. The members of the Steering Committee will meet at least semi-annually by conference calls, and annually in-person, as possible.

Primary responsibilities of the Steering Committee include, but are not limited to, the following activities:

• Establishing policies and procedures for collaborative projects and protocols
• Setting the overall research priorities for the collaborative network and identifying emerging research opportunities which can be best explored through a joint collaborative effort
• Participating in efforts to develop biospecimen research evidence-based best practices, to serve as a resource for the cancer research community

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: 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 recipient. This special dispute resolution procedure does not alter the recipient'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.

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Lokesh Agrawal, Ph.D.
National Cancer Institute (NCI)
Telephone:240-276-5718
Email: [email protected]

Abhi Rao, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5715
Email: [email protected]

Ping Guan, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5711
Email: [email protected]

Miguel Ossandon, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5714
Email: [email protected]

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

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

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.