Development of Biomarkers or Composite Biomarkers for Neurological and Neuromuscular Disorders (R61/R33 - Clinical Trial Optional)

Development of Biomarkers or Composite Biomarkers for Neurological and Neuromuscular Disorders (R61/R33 - Clinical Trial Optional) is sponsored by National Institute of Neurological Disorders and Stroke (NINDS). Supports development of biomarkers for neurological and neuromuscular disorders to aid in diagnosis and treatment.

PAR-25-024: Development of Biomarkers or Composite Biomarkers for Neurological and Neuromuscular Disorders (R61/R33 - Clinical Trial Optional) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Neurological Disorders and Funding Opportunity Title Development of Biomarkers or Composite Biomarkers for Neurological and Neuromuscular Disorders (R61/R33 - Clinical Trial Optional) R61 / R33 Exploratory/Developmental Phased Award Notices of Special Interest associated with this funding opportunity January 28, 2026 - NIH Removing AIDS Application Due Dates from NOFOs.

See Notice NOT-OD-26-029 . March 31, 2025 - This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission.

April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 . August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023.

See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189 .

Funding Opportunity Number (FON) Companion Funding Opportunity See Section III. 3. Additional Information on Eligibility .

Assistance Listing Number(s) Funding Opportunity Purpose The purpose of this Notice of Funding Opportunity (NOFO) is to promote the development of fit-for-purpose candidate biomarkers and composite biomarker that enable more efficient clinical trials advance therapeutic development or clinical practice help guide clinical care decisions.

Specifically, the goal of this phased funding mechanism is to first identify or confirm candidate biomarker(s) or biomarker signatures using human samples and/or data, followed by an independent retrospective or prospective clinical study to conduct initial clinical validation of the biomarker/signature’s clinical utility for one or two defined Context(s) of Use.

In the first phase, applicants are expected to demonstrate that the biomarker acceptably identifies or predicts the concept of interest and may include optimization of the detection method using carefully standardized human samples or datasets. The overarching purpose of this initiative is to deliver candidate biomarkers or biomarker signatures that are ready for definitive analytical and clinical validation studies.

Open Date (Earliest Submission Date) The following table includes NIH standard due dates marked with an asterisk. Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization.

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

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

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

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

Overview Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Section II.

Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V.

Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII.

Other Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description The purpose of this Notice of Funding Opportunity (NOFO) is to conduct proof of concept biomarker discovery and development studies followed by preliminary clinical validation to evaluate if the candidate biomarker or composite biomarker may be fit-for-purpose for use in clinical trials or clinical practice.

This NOFO uses a phased R61/R33 mechanism in which the R61 phase is used to test a hypothesis regarding the candidate biomarker or composite biomarker’s relationship to the biological concept of interest and may also be used to develop or optimize the method for measuring the biomarker or composite biomarker (the method of detection).

The R33 phase is to conduct the preliminary clinical validation to test the utility of the biomarker or biomarker signature for one or two specified Context(s) of Use.

Applications should directly address how the candidate biomarker(s) or biomarker signature would fill an unmet need (i.e. better reliability, more cost-effective, significantly improved sensitivity and specificity, etc.) and how the biomarker/composite would be an advantage over existing standards.

The Context(s) of Use should be carefully considered and clearly described as studies are expected to directly test the candidate biomarker or composite biomarker for one or more Context of Uses in the R33 phase .

Biomarkers are used to make decisions at the level of the individual patient or person; therefore, the study design and analyses proposed are expected to establish initial decision-making criteria for how the readout of the biomarker result would be used for the proposed context of use.

The rationale for the proposed studies should be supported by strong biological plausibility linking the candidate biomarker or composite with the pathophysiological process(es) of interest.

Applications focused on understanding biological mechanisms, networks, or other fundamental knowledge rather than focused on developing biomarkers for use as a clinical trial tool or for use in clinical practice to help guide clinical care decisions are not appropriate for this funding opportunity.

Projects that successfully complete both the R61 and R33 phases should meet the entry criteria for the later stage Analytical and Clinical Validation PARs. A biomarker is a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention, including therapeutic interventions.

A composite biomarker is a combination of multiple variables analyzed to yield a patient-specific indicator of normal biological processes or response to an exposure or intervention including therapeutic interventions. Biomarker modalities are diverse, and can include genomic, transcriptomic, proteomic, histologic, metabolomic, imaging, behavioral, physiologic and digital measures.

Biomarkers are critical to the discovery and development of therapeutics. For example, they can serve as indicators of therapeutic target engagement and pharmacodynamic (PD) response and provide an early signal of treatment response in a clinical trial. Biomarkers can also improve the efficiency of clinical trials by stratifying patients to reduce the impact of the variability associated with phenotypic heterogeneity.

In addition, biomarkers allow the evaluation and monitoring of therapeutic intervention on disease progression or recurrence, as well as on the clinical manifestation of disease phenotype or severity.

Finally, biomarkers are important tools in the evaluation of susceptibility and risk for developing a disease or disorder, thereby improving early diagnosis and therapeutic outcomes in cases where disease or disorder manifestation could be significantly attenuated or prevented with treatment.

Despite the active pace of discovery of novel biomarker candidates, few biomarkers progress into clinical use, and robust, well-validated biomarkers for use in Phase II clinical trials remain scant. Thus, there is a critical need to advance biomarkers to improve clinical research and therapeutic development, particularly for diseases and disorders of the nervous system where failures to advance therapeutics remains a challenge.

While many candidate biomarkers may represent pathophysiological processes that be useful in a variety of contexts, studies are needed to evaluate and validate candidate biomarkers within the context they are proposed to be used to establish the evidence needed to inform decision making at the participant or patient level .

The goal of this NOFO is to promote a rigorous early evaluation of the candidate biomarkers and composite biomarkers for use as fit-for-purpose tools in clinical trials or in clinical practice. Phased Award Mechanism Research Objectives and Transition to R33 Phase This funding opportunity uses a R61/R33 Phased Innovation Award mechanism.

The R61 phase will support biomarker and biomarker signature proof of concept studies to test a hypothesis that a candidate biomarker or biomarker signature is an indicator of a particular concept (a biological process or response to an intervention). Studies must use clinical samples, tissues, and/or data to evaluate the candidate biomarker or biomarker signature ( animal studies are not allowed ).

Studies may also include optimization or additional development of the detection method including preliminary analytical validation needed to measure the biomarker/composite. The purpose of the R33 phase is to conduct preliminary clinical validation of the biomarker or composite biomarker for a specified Context of Use.

Context of Use should include defining the category of biomarkers defined in the Biomarkers, EndpointS, and other Tools ( Biomarkers, EndpointS, and other Tools (BEST) Resource and how it will be measured and used in clinical trials or clinical practice. Transition from the R61 to the R33 phase is contingent upon the successful completion of Go/No-Go milestones.

The milestones should include pre-specified quantitative metrics that demonstrate the construct validity of the biomarker(s) and the concept of interest to demonstrate potential clinical utility, as well as the sensitivity, specificity, and internal validity of the detection method to measure the biomarker or signature.

Milestones must be clearly defined, quantifiable, and scientifically justified to allow the investigator and program staff to assess progress in the R61 phase (Please refer to Project Milestones, end of Section I).

Completion of a research project resulting from successful application to this NOFO should result in a candidate biomarker or biomarker signature that meets the entry criteria for the companion NOFOs supporting definitive analytical validation of the detection method ( PAR-24-095 , PAR-24-098 ) ) or definitive clinical validation ( PAR-24-097 , PAR-24-096 ).

The definitions of terms within this NOFO: Proof of Concept: Establishing that the biomarker acceptably identifies, measures or predicts the concept of interest.

Internal Validation of the detection method: Establishing that the performance characteristics of a measurement are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include sample collection and standardization procedures).

Context of Use (COU): A statement that fully and clearly describes the way the biomarker is expected to be used. The COU should include the biomarker category (susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, or safety), the modality, method of detection, and clinical population characteristics.

Concept: In a regulatory context, the concept is the aspect of an individual’s clinical, biological, physical, or functional state, or experience that the assessment is intended to indicate. Validation: A process to establish that the performance of a test, tool, or instrument is acceptable for its intended purpose.

Analytical Validation: A process to establish that the performance characteristics of a test, tool, or instrument are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include specimen collection, handling and storage procedures).

This is validation of the test’s, tool’s, or instrument’s technical performance, but is not validation of the item’s usefulness. Clinical Validation : A process to establish that the test, tool, or instrument acceptably identifies, measures or predicts the concept of interest. Biomarker categories as defined in the Biomarkers, EndpointS, and Other Tools (BEST) Resources ( https://www.

ncbi. nlm. nih.

gov/books/NBK338448/ ) include: Monitoring biomarkers to track the success of a therapeutic intervention or the disease progression Diagnostic biomarkers for detecting clinical manifestation of disease or differentiating between diseases and conditions. Prognostic biomarkers used to identify likelihood of a clinical event, disease recurrence or progression in patients who have the disease or medical condition of interest.

Predictive biomarkers for differentiating individuals based on favorable or unfavorable effect from a therapeutic or other intervention. Pharmacodynamic/response biomarkers for demonstrating therapeutic target engagement and response to an intervention.

Safety biomarkers to indicate the likelihood, presence, or extent of an adverse effect Susceptibility/risk biomarkers that indicate the potential for developing a disease or medical condition in an individual who does not currently have a clinically apparent disease. The biomarker or biomarker signature must be focused on a neurological or neuromuscular disease or disorder within the NINDS mission.

Applications are expect to provide: A strong biological rationale: Projects should include a cogent biological rationale supporting the concept and plausibility of the candidate biomarker or biomarker signature.

The biological rationale should include rigorously obtained evidence that the proposed biomarker or biomarker signature concept may be an indicator of normal biological processes, potential susceptibility or risk, pathogenic processes, or response to an exposure or intervention, including therapeutic interventions (as appropriate for the Context of Use).

Clear clinical unmet need and justification for use as a tool in neurotherapeutic development or clinical practice: Projects should address how the candidate biomarker or composite biomarker will fill an unmet need for neurotherapeutic development or clinical practice and address how, if successful, the biomarker would be an improvement on current available tools for the Context of Use(s) proposed.

A rigorous and clearly described study design: In the R61 phase the study should be designed to establish/confirm the candidate biomarker’s ability to be used as an indicator for the biological process or response to an intervention and the relationship to the clinical concept(s) of interest, as well as establish the performance of the detection method; in the R33 phase the study should conduct preliminary clinical validation of the biomarker or composite biomarker using the optimized detection method to test the utility on an independent cohort for one or two Contexts of Use.

The end of the R61 must include milestones defining the performance criteria that need to be met for the biomarker and method of detection in order to be useful for the Context of Use proposed in the R33 phase.

Examples of Biomarker or Biomarker Signature Studies Supported in this NOFO Include, but Are Not Limited to: Characterization of a candidate biomarker in clinical samples or data relative to the biological process and clinical outcomes of interest, as well as optimization of the detection method, followed by retrospective or prospective testing in an independent clinical cohort in the R33 phase to determine the sensitivity and specificity of the biomarker or biomarker signature for a specified Context of Use Development and evaluation of a candidate biomarker signature algorithm from a set of known biological markers associated with neurological or neuromuscular disorders to optimize the algorithm including establishing sample/data curation or collection procedures for one or more Context of Uses, followed by testing the optimized algorithm in an independent cohort in the R33 phase for one or two specified Context(s) of Use Unbiased discovery approaches from one or more large multisite datasets or sample repositories to identify new biomarkers and characterize their relationship to relevant biological processes and outcomes within a disease or condition, followed by prospective validation in the R33 phase for a specified Context of Use Retrospective analyses of longitudinal studies (such as natural history studies) data to evaluate one or more candidate biomarkers' ability to monitor changes in disease state or predict progression followed by independent validation with an optimized protocol in the R33 phase for a specified Context of Use First in human identification or evaluation of a candidate pharmacodynamic/response biomarker to determine the candidate biomarker's ability to be used to demonstrate target engagement or establish dosing decisions in response to a therapeutic intervention and to develop or optimize the detection method using samples and/or data from one or more clinical trials, followed by independent validation using the optimized method in the R33 phase.

The R61 phase may include preliminary Analytical Validation of the detection method including metrics such as: Analytical specificity including interfering substances or signals Reportable range of test results for the test system Reference intervals (range of normal values) with controls and calibrators Harmonization of analytical performance if the method of detection is to be performed in multiple laboratories Establishment of appropriate quality control and improvement procedures Any other performance characteristic required to test performance with determination of calibration and control procedures The R33 phase may include preliminary Clinical Validation of the biomarker or signature including metrics such as: Demonstration that the result of the biomarker detection method is associated with a clinical endpoint (e.g., response to a therapeutic, target engagement, neuro-pathophysiology or clinical manifestation) in samples or data from patients that have been exposed to an intervention or confirmation that they have or will develop a disease or disorder.

Demonstration of clinical sensitivity and specificity for the intended use of the biomarker or biomarker signature as evaluated through an area under the AUROC and/or continuous outcome measures, as appropriate. Biomarker or biomarker signature studies for diseases or disorders outside the mission of NINDS and NIA Studies using animal models.

Studies where the primary focus is to develop a diagnostic device or detection method without evaluating the utility of the biomarker or composite biomarker for one or more specified Context of Uses Studies where the primary intent is to understand the mechanisms and pathophysiology of a disease or condition Natural history studies aimed at understanding disease pathophysiology, genetic, or epigenetic mechanisms Studies that only propose to do phenotyping or classification studies without also proposing analyses to establish preliminary criteria for interpreting the results of the biomarkers to make decisions at the level of the individual participant (group level comparisons rather than individual level Studies where the primary intent is to develop or test a therapeutic intervention for safety or efficacy endpoints Investigator Team Characteristics Multidisciplinary teams are necessary for successful development of candidate biomarkers and biomarker signatures.

Areas of expertise needed include biomarker development, clinical expertise relevant for the clinical populations of interest, statistical and/or bioinformatics analysis, experience with the use and development of the detection method technology, biosample, data or tissue source standardization, and biological expertise in the disorder/disease pathophysiology.

Investigators are encouraged to form collaborations and seek additional consultants as needed for the project.

Considerations for clinical trials Studies meeting the NIH definition of a clinical trial are allowed when the primary intent is to evaluate the biomarker relative to the intervention of interest, however clinical trials are not supported if the primary intent is to evaluate the intervention's safety, tolerability, clinical efficacy, effectiveness, and/or clinical intervention and management.

For the reasons outlined above, this NOFO typically supports only mechanistic types of clinical trials (Basic Experimental Studies Involving Humans ( BESH )). Leveraging Existing Research Resources Applicants are strongly encouraged to leverage existing NINDS and NIA research resources for their studies whenever possible ( https://www. nlm.

nih. gov/NIHbmic/nih_data_sharing_repositories. html ).

Such resources may include tissue, cellular, or DNA samples from NINDS BioSEND ( https://www. biosend. org/ ) or other existing biospecimen, imaging and data repositories, such as the NINDS Human Cell and Data Repository ( https://nindsgenetics.

org/ ), The Federal Interagency Traumatic Brain Injury Research (FITBIR) informatics system, the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD; https://ncrad. iu. edu/ ) and the Accelerating Medicines Partnership for Alzheimer's Disease ( https://adknowledgeportal.

synapse. org/ ) and Accelerating Medicines Partnership for Parkinson's Disease ( https://amp-pd. org/ ).

The NINDS BioSEND repository receives, processes, stores, and distributes biospecimen resources from NINDS funded studies that can be shared by the neuroscience research community, and currently banks a variety of biospecimens including DNA, plasma, serum, RNA, CSF, and saliva.

The NINDS Human Cell and Data Repository provides 1) disease-relevant stem cell lines for biomarker discovery, and/or 2) the capacity to bank blood for the creation of new cell lines relevant to their disease of interest. Leveraging the resources and support from neurological disorder advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program are also encouraged.

Finally, applicants are encouraged to leverage the resources of ongoing clinical trials supported through other Federal or private funds.

Applications proposing to collect biospecimens are strongly recommended to use the NINDS Biomarkers Repository BioSpecimen Exchange for Neurological Disorders (BioSEND) protocols and procedures, and all specimens collected and banked with BioSEND must come from individuals who have consented to banking and sharing broadly with academia and industry.

Note that costs for collection are NOT included as a component of the NINDS Biomarkers Repository award. Therefore, most costs for the biospecimen banking are borne by the recipients utilizing this resource (see NOT-NS-15-046 ).

Applicants planning projects in which biospecimens will be collected are strongly advised to consult the NINDS Biomarkers Repository website for more information about samples banked at the repository ( https://www. biosend. org ).

In addition, applicants are advised to consult with NINDS Biomarkers Repository staff to obtain a quote for biospecimen banking costs (email: [email protected] ). Pre-Application Consultation Applicants are strongly encouraged to consult with NIH Scientific/Research Staff early on during the planning for an application.

This early contact will provide an opportunity to discuss and clarify NINDS policies and guidelines, including the scope of the project relative to the NINDS or NIA mission and intent of this NOFO. In order to learn more about this NOFO and to have the opportunity to ask questions, a pre-application informational webinar is held at least once a year (usually in December and/or April) and the recordings are posted online at: https://www.

ninds. nih. gov/current-research/focus-tools-topics/focus-biomarkers-research under the News & Events section.

See also Applicant Webinar information under Section IV. 7 below ("Other Submission Requirements and Information"). See Section VIII.

Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs. Section II.

Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity. Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Optional: Accepting applications that either propose or do not propose clinical trial(s). Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Application budgets are not limited but need to reflect the actual needs of the proposed project. The R61 phase can be from 1-3 years and the R33 phase can be 1-3 years, with a total project duration of no more than 5 years NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO. Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement , are allowed. Applicant organizations must complete and maintain the following registrations as described in the How to Apply-Application Guide to be eligible to apply for or receive an award.

All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications .

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 registration; all registrations must be in place by time of submission.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants. gov – Applicants must have an active SAM registration in order to complete the Grants.

gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.

If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply- Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application. A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2. 3. 9.

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

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

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

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced.

Applications that are out of compliance with these instructions may be delayed or not accepted for review. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

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

Timeline and Proposed Milestones(required, 1-2 pages maximum): Timeline and Milestones must be provided under a separate, specific heading at the end of the Research Strategy Section and will be evaluated as part of the scientific and technical merit of the R61/R33 application. Provide an overview and/or Gantt chart of the major activities and timeline of the project for both the R61 and R33 phase.

Provide quantitative Go/No-Go milestones and success criteria that must be achieved by the end of the R61 phase in order to transition to the R33 phase; milestones should provide clear indicators of feasibility and should include performance metrics of the biomarker or biomarker signature and detection method(s) for measuring the biomarker or biomarker signature Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

Intellectual Property Plan (if applicable, 1 page maximum): Applications should include an Intellectual property (IP) strategy unless the products are intended to be provided as open source tools. Applicants are encouraged to consult their institution's technology transfer officials when preparing this section of the application.

Applicants should describe the IP landscape surrounding their biomarker or biomarker signature and its measurement. Applicants should describe any known constraints that could impede biomarker or biomarker signature development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications,