Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

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

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from 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 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background: NIGMS has invested significantly in studies to reveal the complexity of sepsis through preclinical animal model-based research as well as non-clinical trial-based human studies. Despite the recognized contribution of animal models to this area of study, researchers face a challenging gap with poor translatability of existing molecular information into the nation’s pharmaceutical and biotech development pipeline for diagnostics and therapies for human sepsis. In particular, lack of understanding of the complexities of the heterogeneity, stratification, and staging of sepsis are fundamental blocks to further progress in the field. A report from the Sepsis Working Group of the National Advisory General Medical Sciences Council identified opportunities to use discovery approaches in characterizing sepsis and emphasized the importance of using human biospecimens. Responses to a Request For Information to Support Acquisition and Use of Biospecimens for Research on Sepsis in Humans identified challenges in gaining widespread access to human sepsis biospecimens by investigators, and noted that the scientific value of the resources already existing has not been explored in a systematic manner.

The R21 phase of this FOA encourages pilot-scale exploratory sample collection, validation and/or analysis studies, with little or no preliminary data required. However, a strong rationale and evidence of sample accessibility or collectability must be presented. The R33 phase should be used to demonstrate the utility of the existing or newly collected biospecimens and associated clinical data and should generate hypothesis-stimulating data that could form the foundation for future mechanistic studies. Participation by, or collaboration with, clinicians for access to and interpretation of the clinical datasets and biospecimens is strongly encouraged.

Critically Ill Patients: For this FOA, critical illness is defined as life-threatening processes involving infections (bacterial, viral, or fungal), complications of traumatic injury, or post-surgical systemic inflammatory response syndrome, on the continuum that may or may not lead to the development of sepsis. Hospitalized patients at risk for sepsis or diagnosed with sepsis or septic shock are the target group. The patient population recruited will be defined by the applicant and should be justified as the most relevant, consistent with the goals of this initiative, representing a diverse population that is appropriate for sepsis (e.g., age, sex, race/ethnicity, socio-economic status, etc.), to include septic and septic shock patients as well as their appropriate comparators, e.g., critically ill patients (due to infection or trauma) who do not develop sepsis. Patients should be clinically characterized as thoroughly as possible to aid in future studies to distinguish between critical illness syndromes that may overlap with sepsis, and to better understand the mechanisms of development and resolution of sepsis, treatment responsiveness, and/or the acute consequences and long-term outcomes.

Human biospecimens from critically ill patients: Biospecimens tested may be from currently banked and stored collections, or from previous clinical studies or routine patient care, or may be freshly collected in observational clinical studies. Rigorous sample and clinical data collection practices should be documented to ensure rigor and reproducibility. Conditions and timing of specimen collection should be justified to optimize the research outcomes (e.g., longitudinal samples throughout disease progression at defined time points during the development of sepsis, or after the resolution of sepsis, or standardized clinical features documented at the time of sample collection). The types of clinical biospecimens may include routinely collected samples or innovative methods of sample collection, separation, or processing. Examples include but are not limited to: plasma, whole blood, other body fluids such as urine, cerebral spinal fluid, bronchial alveolar lavage, crude cell populations such as peripheral blood mononuclear cells or cells from bronchoscopy, flow-sorted cells, sampling at the infection sites, exhaled breath condensate, microbiome swabs (rectal, oral, nasal, etc.), cell-free RNA and DNA from blood and urine, tissue biopsy, or planned autopsy. The procedures for sample collection, preparation, aliquoting, storage, and processing must be documented. The rationale for novel methods to improve the efficiency of sample collection, storage, and utilization should be provided, e.g., methods to increase the utility of very small sample volumes. Validation steps for sample quality must be included. Appropriate sample and data storage and archival practices must be described and utilized to ensure future independent validation of results from the current study and to set best practices for future sample collections. Procedures piloted to secure necessary approvals to allow efficient access to stored biospecimens by members of the broader research community should also be well-described.

Clinical datasets from critically ill patients: Access to clinical, laboratory, imaging, treatment, and other data that accompany patients’ clinical course and timing of collected biospecimens is critical. The types of defined metrics for sepsis-related data may include, but are not limited to: patient electronic health record information, demographics, socioeconomic history, etiology, comorbidity, mortality, sequential organ failure assessment (SOFA), acute physiology and chronic health evaluation (APACHE) and other risk scores, culture of infectious agents, use of antibiotics, oxygen saturation, imaging (e.g., x-ray), and others. A de-identifying process should be properly designed and/or all identifying data should be properly consented for sharing in current and future research, including for independent validation studies. Modern approaches to data protection that enable maximal sharing of the datasets are highly encouraged, for example, the generation of synthetic health records.

Cutting-edge technologies: This FOA promotes the use of contemporary or cutting-edge techniques that enable novel conceptual approaches to understand sepsis and to test the scientific value of existing or newly collected human sepsis biospecimens. Examples of technologies include, but are not limited to: single-cell analysis, proteomics, metabolomics, lipidomics, next-generation sequencing, single-cell flow cytometry (cyTOF), microbiome profiling, microfluidic cell characterization, miRNA detection, glycoscience technology, 3D/4D nucleome mapping, epigenomics, extracellular RNAs, and computational methods including machine learning and artificial intelligence. Conceptual innovation and the creative utilization of already collected samples are strongly encouraged, even when combined with traditional technologies. Use of new technologies and methodologies to improve the efficiency of sample collection and the utility of the samples for research is also encouraged.

Examples of research topics relevant to this FOA: Applicants should identify and justify optimal pilot-testing approaches proposed to enable mechanistic studies using human sepsis biospecimens. Prospective applicants are referred to a list of specific areas of interest to NIGMS in the Notice of Priorities for Sepsis Research, NOT-GM-19-054. The types of research supported under this FOA may include contemporary methodology development accompanied by demonstrated utility for future studies. In all cases, the purpose is to provide generalizable information on the best practices to collect and utilize human sepsis biospecimens valuable for the long-term goal of acquiring new mechanistic knowledge of the development, complexity, and trajectory of human sepsis, and to ultimately make possible new therapeutic strategies for the resolution of sepsis. Examples of possible elements of projects include, but are not limited to:

• Improvement of methods for processing, validating, and storing human sepsis biospecimens, to maximize their utility for future studies and efficiency of their collection and use;
• Innovation of procedures to utilize small biospecimen volumes, thus increasing the use and value of collected materials;
• Standardization of protocols for fresh isolation of materials, including for use with cutting edge technologies (e.g., single-cell sequencing, transcriptomics, genomics, proteomics, lipidomics, metabolomics, 3D/4D nucleome mapping, etc.);
• Determination of optimal time courses to collect human biospecimens and clinical datasets to reveal the molecular basis of the trajectory of sepsis;
• Development of efficient approaches to link patient health record data to biospecimens for research purposes;
• Methods to assess or improve the patient diversity (e.g., age, sex, race/ethnicity, socio-economic status, etc.) represented in biospecimen collections;
• Identification of feasible procedures to provide access to biospecimens and linked clinical data to others in the research community.

Examples of the types of research projects, biospecimens, and linked patient data that should ultimately be useful include, but are not limited to:

• Identification of critical molecules and their assembly into key pathways to characterize the development and resolution of sepsis, especially across cell, tissue, and organ levels;
• Innovative use of information obtained from human sepsis biospecimens to determine the basis of inter-individual heterogeneity in the course of sepsis;
• Improvement of methods to integrate molecular data from biospecimens with clinical data, to understand sepsis prediction, development, resolution, and prognosis;
• Elucidation of the contribution of co-morbidities, or prediction of the basis for outcome differences;
• Data analysis using computational or modeling approaches (such as artificial intelligence and machine learning), that can be validated by molecular studies using human biospecimens.

Exclusions: NIGMS MIRA (R35) PD(s)/PI(s) may apply for and receive funds for R21/R33 awards made under this FOA, in addition to their MIRA awards, because this is intended as a milestone-driven resource activity and not as a substitute for a research program.

Criteria for non-responsive applications: Only applications proposing to conduct studies that will enable utilization (or new collection and banking) and analysis of biospecimens and associated health data from critically ill patients for use in future mechanistic research on sepsis will be accepted. Studies to test already formulated hypotheses should be submitted to other opportunities for research grants (e.g., R01 or R35 applications). Applications proposing only R21 or R33 activities alone will not be accepted. Human biospecimens and clinical datasets must either be in existence at the time of application, or be collected in routine clinical practice, observational studies, or separate clinical trials already ongoing and completely supported and monitored with independent funding support and oversight. Interventional studies that meet the NIH definition for a clinical trial will not be accepted. Due to the short timeframe of the R21 phase, projects proposing to join future clinical trials or future ancillary clinical studies for the purposes of biospecimen collection or analysis are premature; applications will only be accepted once those trials are initiated and recruiting at a rate sufficient to support the timeframe of an R21 award. No pre-clinical studies (e.g., use of vertebrate animals) are permitted under this FOA. Applications to solely support novel technology development should be submitted for the Technology Development program. Non-responsive applications will be withdrawn prior to review.

Phased Innovation Award: This FOA uses the R21/R33 Phased Innovation Award activity code. Proposed projects must include both an R21 phase with milestone-driven developmental activities and an R33 phase with expanded activities that will build upon and extend the initial developmental pilot studies, to achieve the aims of the entire award. Applications proposing only R21 or R33 activities alone will be considered incomplete and will be withdrawn. An R21/R33 award is not renewable. The proposed work must be completed within the timeframe for the entire award. Successful studies will inform future human biospecimen banking and patient data collection.

Transition to the R33 phase of the Award: For funded R21 applications, the grantee institution may submit an R33 transition package to NIGMS with sufficient time to allow for administrative review (e.g., at least 8 weeks in advance). The R33 transition package should describe progress according to the initially approved milestones, with a description of how future research progress during the R33 phase will be achieved. The applicant should clearly indicate which milestones were or were not completed successfully. In the latter case, the applicant should describe why any milestones were not met, alternative strategies that were applied, and how the feasibility and goals of the R33 phase will be impacted and adjusted. The release of R33 funds will be based on original R21/R33 peer review recommendations, administrative evaluation of success in completion of mutually agreed upon R21 scientific milestones, program priorities, and the availability of funds. NIGMS expects that approximately 50% of projects will proceed to the R33 phase. Decisions to approve projects to proceed to the R33 phase are not appealable.

Virtual Meetings: Funded Investigators will be invited and should commit to participation in periodic program teleconferences and webinars during the R21 and R33 phases of the award to describe their scientific progress and to share their data, methods, protocols, quality standards, scientific results, and to arrive at consensus on best practices.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

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

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) – 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 to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but 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 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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

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 FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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.

R&R Budget

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

The budget must be well justified and reflect the actual needs of the proposed project. The application budget must include both the R21 and R33 phases, for a total of up to four years of support.

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:

  The application will be assigned a single overall impact score. Thus, completeness and clarity of the application, the integration and feasibility of each phase, and the milestones are critical. The grant application format includes two sets of specific aims, one for the R21 phase, and one for the R33 phase. The research plan must include R21 milestones and the proposed transition plan from the R21 phase to the R33 phase. The transition between phases will be determined by NIGMS's administrative review, with an evaluation of the achievement of specific milestones set for the R21 phase.

Specific Aims: . In the single attachment allowed for the specific aims, applicants must provide clear and distinct Specific Aims for each of the R21 and R33 phases.

Research Strategy: The Research Strategy section should have a clear separation of the R21 and R33 portions of the application. There should be separate research designs and timelines for the R21 and R33 phases.

The first section of the Research Strategy will be the R21 phase. This section should include the background, optional preliminary evidence of the feasibility of the proposed approach, rationale, and the research plan and methods for the R21 phase. This section must also include milestones, specific estimates of expected progress during the R21 phase including a timeline, discussion of the suitability of the milestones for assessing success in the R21 phase, and discussion of the implications of successful completion of these milestones for the proposed R33 phase. Alternative approaches, in case the proposed milestones are not achieved, should be included.

The second section of the Research Strategy will be the R33 phase scale-up. It is not necessary to repeat background information or details of methods in the R33 section that have been provided in the R21 section. The R33 phase must be described in sufficient detail to permit reviewers to assess the significance and innovation of the proposed work, strength of the experimental design, and impact on the field when the work is completed. No milestones are required for the R33 phase, but the timeline proposed should be sufficiently detailed to predict and monitor progress.

Preliminary Data: The R21 component of an R21/R33 application is considered exploratory, so preliminary data are not required. However, the project must be based on a strong rationale.

Examples of milestones: R21 milestones should be appropriate, specific, quantifiable, scientifically justified, achievable within the allotted time frame, and adequate for evaluation of the possible transition to the R33 phase; they should not simply be a re-statement of the R21 specific aims. The R33 scale-up phase should clearly extend or expand the preliminary studies in the R21 phase and be on pace according to the overall timeline, so as to demonstrate impact on the field upon completion of the studies. Because projects should test new approaches and/or evaluate resources of unknown value, NIGMS expects that not all funded R21 phase projects will successfully achieve their milestones and thus will not proceed to the R33 phase. Information about tried and failed approaches or resources would still be of value to the research community, and the Institute expects negative outcomes to be disseminated.

Examples of possible milestones, as appropriate for the project, expressed in a quantitative and measurable way, might include:

• All functional assays are running successfully and are reproducible;
• Pilot screening is successful and the quality of the biospecimens is validated against standards;
• Modifications to improve methods are tested successfully using a variety of biospecimens;
• Collection of clinical samples is operational, quality-controlled, and scalable;
• Computational methods for datasets are developed and tested;
• Correlation of results from biospecimen assays with clinical datasets is successful;
• Research tools are constructed, stable, and validated;
• All protocols and compliance documents are prepared and IRB-approved;
• Data and biospecimen sharing plans are developed and have all necessary concurrence;
• Appropriately diverse patient populations will be accessible for collection of biospecimens and data.

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.

The following modifications also apply:

All applications should include a Resource Sharing Plan. This should be proposed in the application, piloted and modified as necessary in the R21 phase (with all approvals obtained for scaling up), and implemented fully in the R33 phase. NIGMS intends to achieve maximal sharing and utilization of the biospecimens, datasets, and methods among interested investigators. The procedures to share research materials such as human biospecimens, clinical data, research protocols, and software in a timely manner must be described in sufficient detail that reviewers can evaluate the plans.

Applicants should include the following: 1) proposed protocols and plans to obtain IRB approval for sharing human biospecimens and clinical datasets, for the purpose of independent validation of research findings and potential future collaborations; 2) procedures for collecting and archiving human biospecimens and clinical data; 3) terms of use, procedures, and contact(s) for distributing research materials to the scientific community upon approval. Sharing could be achieved by the deposit of biospecimens to a public or applicable NIH repository, or by handling individual requests on a timely case-by-case basis locally; 4) plans to upload raw data and associated metadata and protocols, including procedures for sample collection and processing, to an existing public database or open website for sharing and independent analysis. Applications should provide justification for the appropriateness of the resource sharing plans based on practical aspects such as research and clinical practice logistics and institutional policies.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the 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 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.

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

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

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

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.

5. Intergovernmental Review (E.O. 12372)

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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 and responsiveness by NIGMS. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

Section V. Application Review Information

1. Criteria

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

For this particular announcement, note the following:

The R21/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. An R21/R33 grant application need not have preliminary data, extensive background material or preliminary information; however, they may be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data.  Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding.  Reviewers will assign a single impact score for the entire application, which includes both the R21 and R33 phases.

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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 to this FOA: Will best practices be set for future human sepsis biospecimen collections to optimize their utility?

Investigator(s)

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?

Innovation

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

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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 to this FOA: Is the approach proposed for biospecimen collection, processing, and storage optimized? Are the plans for validation of sample quality and integrity appropriate? Will the correlation of clinical data with biospecimens be feasible and achievable? Is the patient population consistent with the goals of this initiative, adequately diverse demographically, and are the most appropriate comparator patients included?

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Environment

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

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.

Milestones

Are the proposed R21 milestones appropriate for the evaluation of progress towards achieving the specific aims? Are the milestones achievable within the allotted time frame? Are the milestones substantial and quantifiable? Are the milestones sufficiently rigorous for assessing progress in the R21 phase and useful to predict the success and impact of the R33 phase?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the 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 categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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 individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

Not Applicable

Biohazards

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

Resubmissions

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

Renewals

Not applicable

Revisions

Not applicable

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

Applications from Foreign Organizations

Not applicable

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; (3) Genomic Data Sharing Plan (GDS) and (4) sharing research materials and clinical samples.

Authentication of Key Biological and/or Chemical Resources:

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.

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications will receive a written critique.

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

Applications will be assigned to NIGMS. Applications will compete for available funds with all other recommended applications submitted. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

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

Prior to funding an application, institute staff will contact the applicant to consider and refine the proposed R21 milestones. The program staff and the applicant will negotiate and agree on a final set of milestones. These will be incorporated into the terms and conditions of an award and will be the basis for judging the success of the R21 work.

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.

Requirements for Transition to Phase II (R33)

This Phase I R21 award is eligible for consideration for the transition to a Phase II R33. NIGMS program and grants management staff will conduct an administrative review (possibly with external consultants) of the Phase II R33 transition application according to four criteria: 1.) satisfactory scientific progress and successful completion of scientific milestones under the Phase I R21 award; 2.) review and approval of any documents requested by the IC during the project period; 3.) IC program priorities; 4.) scientific breadth and balance; and 5.) availability of funds

Virtual Meetings: Funded Investigators will be invited and should commit to participation in periodic program teleconferences and webinars during the R21 and R33 phases of the award, to describe their scientific progress and to share their data, methods, protocols, quality standards, scientific results and best practices.

Institutional Review Board or Independent Ethics Committee Approval

Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

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.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides 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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. 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 https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• 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.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Not Applicable

3. Reporting

4. Evaluation

In carrying out its stewardship NIGMS will evaluate the R21/R33 programs, employing the measures identified below. In assessing the effectiveness of its research investments, NIH may request information from databases, PD/PIs, and participants themselves. NIGMS will assess the program's overall outcomes and gauge its effectiveness in increasing the efficiency and efficacy of NIGMS funding.

Evaluation Measures: The overall evaluation of the program will be based on metrics that will include, but are not limited to, the following:

• Successful milestones to progress to the R33 phase
• Conversion rate
• Effectiveness of data/result dissemination
• The number of best practices set for future human sepsis biospecimen collections and utilization
• Acceptance of the set best practices by the sepsis research community

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

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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

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

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-637-3015

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Xiaoli Zhao, Ph.D.
National Institute of General Medical Sciences (NIGMS)
Email: xiaoli.zhao@nih.gov

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Laura Preston
National Institute of General Medical Sciences (NIGMS)
Email: laura.preston@nih.gov

Section VIII. Other Information

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

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.