Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This Funding Opportunity Announcement (FOA) will support extramural research to investigate and mitigate challenges facing clinical assay development due to tissue biopsy biospecimen preanalytical variability. The program will tie in with current efforts to optimize clinical biomarker assays utilized in NCI-sponsored clinical trials. Results from this research program will improve the understanding of how biopsy collection, processing, and storage procedures may affect all aspects of analytical performance for current and emerging clinical biomarkers, as well as expedite clinical biomarker assay development through the evidence-based standardization of biopsy handling practices. Critical information gained through these research awards may increase the reliability of clinical biomarker assays, reduce time requirements for assay development, and decrease assay failure during late-stage testing.

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 (DNA, RNA, and 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 post-resection and prior to analysis can have a significant impact on assay results which can result in potentially serious consequences in terms of 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.

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 and is receiving increased attention by the FDA. Basic and applied biospecimen science investigation will provide valuable insights into how to limit variability in clinical assay results from small biopsies.

Example: Effect 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 breast cancer therapeutic. 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, 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.

Previous support of Biospecimen Science at the National Cancer Institute

To begin to address concerns of preanalytical variability, the NCI established the Biospecimen Research Network (BRN) in 2007. Through an extramural funding program, Biospecimen Research for Molecular Medicine , an online literature database, The Biospecimen Research Database (BRD), and an annual conference, The BRN Symposium , the BRN program advanced the field of biospecimen science through systematic investigation of the effects of different biospecimen collection, processing, and storage procedures on downstream molecular analyses. Research contracts were competitively awarded to identify and develop novel approaches to identify key preanalytical factors associated with collection, processing, and storing of blood, plasma and tissue.

Sponsored studies to date include:

• Studies demonstrating that preservation methods can impact gene expression of a subset of transcripts differentially;
• Studies on the effects of blood biospecimen collection tubes, processing times, time in freezer, and freeze/thaw cycling on protein integrity;
• The effects of tube type, time on bench and storage temperature on circulating miRNA detection;
• An assessment of the effect of cold ischemia on protein detection in breast cancer tissues;
• The effects of cold and warm ischemia on the detection of gene expression and protein phosphorylation in post resection tissues;
• Studies to evaluate the effects of cold ischemic time, specimen preservation, and storage methods on RNA yield, RNA Integrity Number (RIN) values, transcript integrity and microarray-based measurements of gene signatures.

Results of these studies have provided valuable data on how biopsies and resections should be handled (e.g., minimize cold ischemia time and utilize core biopsies when possible for IHC assays; use RNAlater for biopsies if possible when gene expression studies are planned) and have built a solid knowledge base for evidence-based practices for biospecimen collection, processing, and storage when conducting blood-based mass spectrometry investigations. Overall, results from the BRN and work summarized in the BRD suggest that biospecimen preanalytical factors can significantly affect research and clinical assay results. However, preanalytical factors of particular importance for small biopsies relating to procurement and alterations in processing and extraction due to reduced biospecimen size remain largely unexplored. Research also demonstrates 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.

Need for continued funding in biospecimen science

Measurement and validation of clinically relevant biomarkers using diagnostic assays are increasingly challenging as reliance on smaller biospecimens increases and new biomarkers and analysis platforms emerge. Particularly in NCI-sponsored treatment trials such as the NCI Experimental Therapeutics Clinical Trials Network (ETCTN), there is a need for 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.

This FOA will fund research to support clinical assay development and validation through the identification and mitigation of preanalytical factors associated with biopsy biospecimens 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 presented by small biopsies such as FNAs, core biopsies, or pleural fluid aspirates. The research will align with current efforts to optimize clinical biomarker assays utilized in NCI-sponsored treatment trial networks and will produce data needed for evidence-based biospecimen practices to support clinical trials. Applications to improve standardization or harmonization of assays among laboratories for use in clinical trials may be appropriate for this FOA.

The work of the program will be centered on emerging and clinically relevant biomarker assays for a variety of molecular 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. These teams must include investigators currently involved in NCI Phase I and Phase II clinical trials. Applicants must have an established relationship with grantees working in NCI-sponsored early phase treatment trials. The goal is to pair NCI-sponsored clinical trials PIs (e.g. oncologists) with collaborators (e.g. pathologists) to address challenges that arise across early phase treatment trials. The biospecimen science investigations would focus on needs of one trial or common to several trials. Investigators must share experimental designs, progress reports, and pre-published data within the program. Biospecimens must also be shared within the program.

Projects will involve defining workable biospecimen conditions for trials that utilize a particular type of 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 biopsies:

• A promising biomarker or set of biomarkers has been identified for validation and assay development, but little is known about the biospecimen requirements for the assay. How can one determine whether there is an effect of preanalytical factors on assay performance? How is assay performance affected when biopsy 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 altered 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?

Assay Pre-requisites and Preliminary Data: The applicant must have an assay that has been analytically validated within its intended clinical context under particular preanalytical conditions. The assay may measure a single biomarker or may be a multiplex assay but 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.

Analytical performance must meet standard criteria as applicable depending on the type of assay and biomarker for:

• Accuracy, as applicable depending on the type of assay and biomarker
• Precision
• Analytical sensitivity
• Analytical specificity including interfering substances
• Reportable range of assay results for the test system
• Reference intervals (normal values) with controls and calibrators
• Harmonization of the assay methods to achieve harmonization of assay values i.e. reproducibility if the assay is to be performed in multiple laboratories
• Establishment of appropriate quality control and monitoring procedures

This FOA will fund multidisciplinary teams that will constitute a collaborative network. 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. Successful applications will propose work on relevant assays for today and include plans for the five-year funding period, with the understanding that new biomarkers and new assay platforms may emerge over the course of the program. Research ideas, experimental design approaches, biospecimens, and molecular analysis platforms will be shared across the network to maximize research productivity.

Research Projects that are not appropriate for this FOA include:

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 related to early detection biomarker assays
• Projects related to global cancer genomic/proteomic studies

Alternative Opportunities

Awardees may also wish to apply for complementary UH2/UH3 grant funding to assist in the development and validation of clinical assays through PAR-15-095 and PAR-15-096.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

A multidisciplinary research team is encouraged.

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

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

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

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

Applicants must obtain the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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

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

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

The letter of intent should be sent to:

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

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

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

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

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

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

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

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

The budget should include costs of biospecimen collections, histology, analyte extraction and analytic platforms.

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

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

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

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

Research Strategy: Describe the following:

Overview

The application should clearly define the context of the proposed study and markers in current clinical trials, as well as the ability of the applicant’s team to perform 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;
• Determine the specificity and sensitivity and other assay performance parameters of a biomarker assay in the context of specific preanalytic conditions

Study Design

• Objectives of the study should be clearly stated and scientific goals or hypotheses should be described 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;
• Provide a clear statement of how the proposed research addresses an unmet clinical need
• 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 SF424 (R&R) Application Guide, with the following modification:

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

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

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

Form only available in FORMS-E application packages for use with due dates on or after January 25, 2018.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study: All instructions in the SF424 (R&R) Application Guide must be followed.

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

Applicants are required to follow our Post Submission Application Materials policy.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

This FOA will support extramural research to investigate and mitigate challenges facing clinical assay development due to tissue biopsy biospecimen preanalytical variability. 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 review criteria and additional review criteria (as applicable for the project proposed).

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

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

Specific for this FOA:

• How well is the project focused on the biospecimen preanalytical variability in small tissue biopsies (such as FNAs, core biopsies, and pleural aspirates) that affects the development and validation of a clinical biomarker assay(s) that will be used in cancer treatment trials?
• Is there 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?
• Does the proposed biomarker assay(s) address a significant cancer clinical problem?
• Will the results of the project contribute to expediting clinical biomarker assay development through the evidence-based standardization of biopsy handling practices?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific for this FOA:

• Does the proposed team include multidisciplinary scientific and medical expertise related to biopsy biospecimens accrual, preservation and annotation?
• Is there appropriate team expertise on clinical biomarker assays utilized in NCI-sponsored treatment trials, biology and technology platforms for existing and emerging clinical assays, and experimental design and analysis?

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

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

Specific for this FOA:

• Have the investigators proposed reasonable plans for acquiring biospecimens for the study and subjecting them to known preanalytical variations?
• Have the investigators shown that the biospecimens can be collected within the time frame?
• Have mitigation strategies to ensure successful biospecimen collections been proposed, such as partnering with other medical institutions as needed?
• Have a sufficient number of biospecimens and biomarker evaluations for each biospecimen been proposed, to ensure that the experimental results will be statistically significant?
• Are quality management of biospecimens, reagents, and analytical platforms addressed to ensure that preanalytical and analytical variability are known as experiments are conducted?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

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

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

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

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

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

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

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

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

Not Applicable

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

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

Not Applicable

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

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

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

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

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

As part of the scientific peer review, all applications:

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

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

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

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

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

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

• Defining the overall research objectives and approaches;
• 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;
• Participating in monthly teleconferences with NCI program staff;
• Awardees will retain custody of and have primary rights to the data, technologies, and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies

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

An NCI Program staff member(s) acting as a Project Scientist(s) will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NCI staff members may be designated to have substantial involvement.

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

• Providing input on experimental and clinical approaches, and consulting on updates for project milestones;
• Providing advice to the awardees on specific scientific, analytical, and clinical issues;
• Assisting and advising awardees with regard to various regulatory and compliance issues;
• BBRB’s Comprehensive Data Resource (CDR), an information technology infrastructure, may be utilized by the network to support the conduct and annotation of biospecimen science experiments, clinical annotation of the biospecimens, and integration of biospecimen information. NCI’s Biospecimen Research Database (BRD) will serve as a resource tool for supported investigators to identify published effects of preanalytical factors on particular analytes.
• Participating in monthly teleconferences with PDs/PIs to monitor progress and facilitate cooperation;
• Monitoring progress of the projects towards meeting milestones and adherence to the strategic goals of the program;
• Participating in the activities of the Steering Committee and the implementation of its guidelines and procedures;
• Stimulating interactions among awardees;
• Contributing to publications and presentations resulting from the project if appropriate.

Additionally, an NCI Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. NCI reserves the right to terminate or curtail any individual award, if there is insufficient progress towards meeting milestones.

Areas of Joint Responsibility include:

Steering Committee: 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.

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 Cooperative Agreement 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, serving as a resource for a broader outreach to the entire extramural cancer research community.

External Scientific Panel

The NCI Project Scientist will form an External Scientific Panel (ESP) composed of senior federal and non-federal scientific experts, including Food and Drug Administration (FDA) and National Institute of Standards and Technology (NIST) scientists.. The ESP would advise NCI on the progress and effectiveness of the Program and assist the Steering Committee in the development of best practices. NIST would provide input on standardization and FDA would provide perspective on the relevance of experimental design and results to regulatory challenges.

Dispute Resolution

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

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

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

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

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

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726

Email: [email protected]

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

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

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

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

Renee Carruthers
National Cancer Institute (NCI)
Telephone: 240-276-6477
Email: [email protected]

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

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