Computational Modeling of Hormone Homeostasis Research Opportunity Announcement

Navigation #navigation

• Overview Information
• Agency Contacts
• Background
• Award Information
• Program Formation and Governance
• Outline of This Opportunity
  1. Requirements –  Computational Modeling of Hormone Homeostasis Initiative
  2. Eligible Organizations
  3. Eligibility Requirements
  4. Multiple Principal Investigators and Partnerships among Applicants’ Institutions
  5. Project Manager/Director (PM/PD) Requirements 
  6. Financial and Risk Assessment
  7. Cost Sharing
  8. Developing Applications
     • 8.1    Application Submission Instructions
     • 8.2    Letter of Intent
     • 8.3    Full Application
     • 8.4    Milestones and Deliverables
     • 8.5    Budget Details
     • 8.6    Systems Registration
  9. Objective Review
     • 9.1     Review of Full Applications 
     • 9.2     Post-review Funding Plan 
  10. Special Award Terms and Information
      • 10.1    NIH Discretion
      • 10.2    Award Governance
      • 10.3    OT Agreement Governance
      • 10.4    Reporting and Project Meetings
      • 10.5    Management Systems and Procedures
      • 10.6    Financial Management System Standards
      • 10.7    Organizational Conflicts of Interest (OCIs)
      • 10.8    Monitoring
      • 10.9    Audit
      • 10.10    Public Policy Requirements and Objectives

Overview Information #overview

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Agency Contacts #agencycontacts

NIH encourages inquiries concerning this announcement and welcomes the opportunity to answer questions from potential applicants

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Background #background

The overall goal of the Computational Modeling of Hormone Homeostasis initiative is to advance the development of in silico computational approaches that model and simulate hormone signaling pathways and homeostasis, with an emphasis on applicability to sex-specific efficacy and toxicity evaluation of therapeutics.  Through this Initiative, the NIH seeks to enable the research community to identify nascent opportunities and priorities for technology-led, innovative, high-impact research that will generate the critical empirical support needed for evaluating an intervention’s clinical benefit in a sex-specific manner, thereby transforming women’s health outcomes. 

There are clinically significant sex differences in pharmacokinetics, dosing, treatment response, and toxicity of drugs and biologics.  Yet the molecular mechanisms underlying these differences are poorly understood.  Sex differences can emerge from a variety of mechanisms.  In addition to reproductive tissues, sex hormones interact with multiple tissues and body systems such as the lungs, bones, and immune system, and are integral to shaping and maintaining the balance of both the gut and vaginal microbiomes.  Further, dynamic changes in hormonal homeostasis over the lifespan, such as those associated with puberty, fertility, menstrual cycle, pregnancy, and menopause, can trigger systemic responses such as immune pathway reactions or signal transduction effects.  Incorporating such hormonal complexity into biomedical research has been challenging.  Animal models often fail to reliably predict nuanced human physiological responses by sex.  Most non-human mammals do not menstruate or undergo menopause, thereby further limiting the utility of animal models in research on the health of women.  How sex influences the biological and physiological processes relevant to therapeutic efficacy and toxicity remains a significant knowledge gap.  

In silico computational techniques have strong potential in closing the knowledge gap.  In particular, modeling frameworks designed to integrate multiple mechanistic- and data-driven components have strong potential to capture complex, systems-level interactions between hormone homeostasis, cellular responses, and tissue/organ-level physiology.  While the number of computational studies examining drug toxicity and efficacy have grown significantly over the past years, very few explicitly address sex differences in treatment response.  There is an urgent need to develop better systems-level models that are tailored to complex female/male physiology, accounting for sex as a biological variable.  As such, expanding our mechanistic understanding of the relationship between hormones and therapeutics holds promise for streamlining drug/biologics testing and propelling bench-to-bedside translation.  A deeper understanding of these mechanisms will not only improve predictive accuracy, but enhance study design by enabling more precise modeling of the breadth of sex-specific physiological and treatment responses.  Ultimately, the NIH envisions a technological breakthrough that has so far remained beyond reach—a simulated whole person or multi-organ, multi-scale system able to generate scientifically realistic and clinically meaningful predictions.  If successful, this initiative will take the first step towards accelerating regulatory approval pathways and transforming the development of safer, more effective drugs and biologics. 

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Award Information #awardinformation

The Computational Modeling of Hormone Initiative will utilize Other Transaction (OT) awards. 

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Program Formation and Governance #proforgov

Close interactions between the recipient and NIH will be required to maintain this initiative.  Program governance will rest with the prime recipient in collaboration with NIH Program staff from DPCPSI and from multiple NIH Institutes, Centers, and Offices.  DPCPSI program staff will be primarily responsible for the stewardship of the initiative and report to the Directors of Office of Research on Women’s Health and the Division of Program Coordination, Planning, and Strategic Initiatives for final funding decisions.

NIH will provide funds on a cost-reimbursement basis, and as agreed upon and included in the Terms and Conditions of Award.  Funds may be increased, extended, reallocated, recovered, or terminated in cases where unexpected findings, bottlenecks, or roadblocks may modify plans or prevent completion of the project.

See Section 10 for special award terms and additional information about program governance.

Objective Review: NIH will convene an appropriate review group to evaluate applications. See the Objective Review section of this opportunity for further details.

Eligibility: See the Eligibility section of this opportunity.

Application budget: The NIH may allocate up to $5,000,000 (direct + F&A) costs per year for up to three years per award for the Computational Modeling of Hormone Homeostasis initiative awards. The NIH anticipates issuing multiple awards contingent upon NIH appropriations, availability of funds, programmatic priorities, and the submission of a sufficient number of meritorious applications.

The application budget should reflect the proposed activities and personnel needs of the project. The OT mechanism allows for significant flexibility to make budget adjustments as needed to meet NIH’s programmatic priorities.  Award levels may increase or decrease over time based on funding availability, establishment or termination of sub-awards, recipient performance, and other programmatic priorities. It is anticipated that funds will be allocated on a yearly basis.

Cost sharing is not required but may be proposed.  However, including a cost share will not impact an applicant’s chances of selection.

Anticipated number of Awards: NIH anticipates making approximately four (4) awards.

Award Project Duration: Project duration is anticipated to be up to three (3) years, subject to program needs, scientific progress, and availability of funds. Research activities and the associated milestones may be shortened or extended as needed within that project period.  Workplans for research activities and the associated milestones will be negotiated with the NIH staff annually at a minimum.

Authority: Other Transactions awards will be made pursuant to current authorizing legislation, including Section 402(n) of the Public Health Service Act, 42 U.S.C. 282(n)(1)(c), as amended.

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Outline of This Opportunity #outline

1. Requirements – Computational Modeling of Hormone Homeostasis
2. Eligible Organizations
3. Eligibility Requirements
4. Multiple Principal Investigators and Partnerships among Applicants’ Institutions
5. Project Manager/Director (PM/PD) Requirements
6. Financial and Risk Assessment
7. Cost Sharing
8. Developing Applications
9. Objective Review
10. Special Award Terms and Information

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1. Requirements - Computational Modeling of Hormone Homeostasis Initiative #requirements

This Research Opportunity Announcement (ROA) requires the development of computational models of the dynamic changes of biological processes and pathways mediated by hormone homeostasis, in order to advance mechanistic understanding of sex-specific therapeutic efficacy and toxicity.  For the purpose of this ROA, such therapeutics may include drugs and biologics intended to treat, cure, prevent or mitigate diseases, injuries, or conditions in humans.  The application must describe the capability of the proposed approach in characterizing, by sex, the extent to which a drug or biologic engages the intended targets and leads to functional improvement, while limiting possible toxicity and side effects.

Consistent with the Advisory Committee to the Director working group recommendations, this ROA seeks applications intended to develop any computational techniques that integrate biological data with mathematical representations to construct computer-based models and simulations of human biology. Examples of in silico computational approaches appropriate for this ROA include but are not limited to:

• Kinetic and dynamic modeling;
• Digital twins;
• Systems level biological modeling; 
• Multi-scale models; and
• Data-driven predictive models.

This ROA specifically calls for models strongly coupled with computational platforms and environments enhanced by artificial intelligence (AI), interactive machine learning, and/or natural language processing capabilities to automate, streamline and optimize data processing and model parametrization.  This ROA intends to support projects with a primary focus on innovative, early-stage, or unique computational methods development rather incremental extensions or applications of existing methods.  If the proposed model builds upon an existing model, the applicant must address how the proposed approach represents a new breakthrough in the field.

The computational models developed under this initiative can draw on a variety of data sources (e.g., experimental, observational, clinical, human -omics, and tissue chip data) and have implications for many diseases, chronic conditions, and aspects of human biology relevant to women’s health.  The application must delineate how the scientific topic focuses on women’s health.  Comparison of males and females is appropriate, so long as the application addresses how females may differ from males in a clinically meaningful manner.  Examples of scientific topics appropriate for this ROA include but are not limited to:

• Kinetic and dynamic models of the chemical cascades of systematically administered drugs to establish relevant links to hormone homeostasis;
• Three-dimensional cellular spatial organization and tissue microenvironment modeling;
• Characterization of hormonal effects on the female microbiome;
• Integration of hormone homeostasis into the modeling of mechanical features and mechanical environment of organs/tissues; and
• Systemic models of hormone influence on human drug-gene interactions;

Examples of research NOT appropriate for this ROA include but are not limited to:

• Research that lacks a substantial focus on computational methods development;
  • Primary experimental data generation and data collection from human participants may be proposed, but such activity must be model driven.  Applicants are encouraged to reuse existing data where appropriate. 
• Correlative models (e.g., polygenic risk scores) that lack mechanistic representation of human biology or physiology;
• Research that does not include clear relevance for therapeutic evaluation in humans;
• Research that does not include clear relevance to women’s health.  Comparison of males and females to elucidate sex differences IS appropriate; 
• Research that involves invertebrate or vertebrate animals; and 
• Clinical trials.

By the end of the three-year period of performance, the model developed should demonstrate extensible, foundational capabilities that effectively, accurately and consistently predict sex-specific efficacy and toxicity of drugs and biologics. 

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2.    Eligible Organizations #eligibleorg

Non-domestic (non-U.S.) Entities (Foreign applicants) are not eligible to apply.

Non-domestic components of domestic organizations are not eligible.

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

Any public or private non-domestic entity is ineligible to apply for this program as a primary applicant. Additionally, any non-domestic components of U.S. Organizations are ineligible to apply for this program as a primary applicant. Public or private non-domestic entities and non-domestic components of U.S. Organizations are eligible to be listed as sub-contractors/recipients, so long as they are not excluded from applying for Federal programs throughout the U.S. Government (unless otherwise noted) and from receiving certain types of Federal financial and nonfinancial assistance and benefits.

Letters of Intent (LOIs), due by the “Letters of Intent Due Date” as shown at the top of this notice, are required.

The following entities are eligible to apply under this ROA:

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)
• Faith-based or Community-based Organizations
• Regional Organizations

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• American Indian/Native American Tribal Governments (Federally Recognized)
• American Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government having statutory authority to receive funding beyond their congressional appropriation.
• U.S. Territory or Possession

Other

• Independent School Districts
• Native American Tribal Organizations (other than Federally recognized tribal governments)

Applications that are submitted by or involve federal agencies other than NIH must include the citation of the agency's statutory authority to receive funding beyond their congressional appropriation.

NIH Intramural Research Program (IRP) investigators are not eligible to apply as the prime recipient agency Principal Investigator but may collaborate with extramural investigators on the project as co-Investigators, collaborators, or consultants if the IRP investigator(s) have expertise that could contribute to the goals of the initiative. Applications that include IRP investigators must include a signed letter from their Scientific Director that describes the intramural aim(s), the staff time in person months for the IRP investigator(s), and any requested budget and justification for the intramural activity. See additional information in Section 8. Developing Applications. 

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3.    Eligibility Requirements #eligrequire

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

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4.    Multiple Principal Investigators and Partnerships among Applicants’ Institutions #multipis

More than one individual may be named Principal Investigator (PI) in the application. One individual must be identified as the contact Principal Investigator. The contact PI must be employed by or affiliated with the applicant organization. The PI and any multiple PIs (MPIs) must collectively commit a total of at least 20% level of effort to the project.  If a multiple Principal Investigator (MPI) application is submitted, an MPI Leadership plan is required.

Partnerships among institutions with investigators having complementary skills and expertise to meet the requirements of this ROA are not required but are allowed.

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5.    Project Manager/Director (PM/PD) Requirements #pmpdrequire

NIH expects the proposed project to include an individual that will serve as the PM/PD for the project, with the appropriate scientific expertise and project management experience, who would support the PI(s) with project management and organizational oversight. Such an individual must commit at least 50% level of effort to the project.

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6.    Financial and Risk Assessment #finandrisk

Applicants may be subject to financial analysis and risk assessment conducted by NIH staff.

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7.    Cost Sharing #costshare

Cost Sharing is not required but may be proposed. Those proposing to develop commercial applications or who are using other state or government resources may consider identifying a cost share percentage. Applicants may voluntarily choose to propose a financial plan that includes non-federal resources. The budget submission must clearly identify and justify the use of these resources. Any voluntary cost share must be supported in the application by including a letter of support from the providing organization(s)/individual(s). Inclusion of cost sharing will have no influence on application selection.

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8.    Developing Applications #devapps

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8.1    Application Submission Instructions #appsubs

Complete applications must be submitted under OTA-26-004 via NIH eRA Commons ASSIST no later than the “Application Due Date” shown at the top of this notice, by 5:00 PM local time of applicant organization.

Late applications submitted to this ROA will not be accepted. Applications that do not include an Invitation to Submit will not be accepted.  

Questions about the scientific scope of this announcement should be addressed to: Jielu Lin, Ph.D., Program Officer, DPCPSI (Email: [email protected])

Letters of Intent (LOIs), due by the “Letters of Intent Due Date” as shown at the top of this notice, are required.

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8.2    Letter of Intent #loi

Interested applicants must submit a Letter of Intent (LOI).  LOIs will only be accepted from entities listed in the Eligible Organizations section of this Announcement that meet the criteria listed in the Eligibility Requirements.  LOIs submitted from organizations not included in the Eligibility section will not be considered.  The information in the LOI also will be used to identify and mitigate potential conflicts of interest (COIs) for prospective reviewers.

The LOI must be no more than six (6) pages with sections outlining the following: 

• Heading: Title, Contact PI, Business Official, and Applicant Institution. 
• Project Summary (no more than 2-pages): The Project Summary page limit applies to text and non-text elements (e.g., tables, figures, images). Inclusion of URLs in the Project Summary is not allowed.  The Project Summary must include the following: 
  • Scientific Rationale: describe the proposed computational model for the specific research topic. Briefly address how the proposed work advances the goal of the initiative if successfully completed.  Literature citations are allowed but not required. 
  • Research Strategy: state the overall objective, specific aims and one or two major milestones. This should include a brief description of the plan for assessing the credibility of the proposed model.
• List of Key Personnel (no more than 4 pages): Provide a table that lists all planned key personnel for the proposed project and for any subprojects, providing the following information in separate columns:
  • Last name
  • First name
  • eRA Commons ID (if available)
  • Institutional affiliation
  • Current title 
  • Email address
  • Role(s) and responsibilities for the proposed project
  • A 1-2 sentence statement of their scientific expertise relevant to the proposed project

The LOI must be submitted by email as a single PDF attachment to [email protected] by the “Letters of Intent Due Date” shown at the top of this notice.  The LOI may only be submitted by one of the applicant institution PIs (either the Contact PI or other PI) with the institutional Signing Official (SO) or Recipient Business Official (RBO) for the prime recipient’s organization copied on the email. Alternatively, the LOI may be submitted by the institutional SO or RBO for the prime recipient’s application.  LOIs submitted by other means or from other parties will not be considered.  Email confirmation will be provided (as a “reply all” response) acknowledging receipt of the LOI.

The LOI will be reviewed by NIH staff for responsiveness and likelihood of success based on the following criteria: 

• How well the proposed project addresses the goal of the initiative
• How well the specific aims, major milestones, plan for assessing model credibility are aligned with the overall objectives stated in the LOI
• Appropriateness of key personnel’s scientific expertise and experience to successfully complete the proposed work

Following review of the LOI, each applicant will be notified as to whether they are invited to submit a full application. However, the applicant will not receive feedback on their project. 

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8.3    Full Application #fullapp

Only applicants who have submitted an LOI, and have received an Invitation to Submit a full application from NIH eligible to submit a full application. Applications will be accepted only from entities listed in the Eligible Organizations section of this Announcement and only from applicants who meet the criteria listed in the Eligibility Requirements. Applications submitted from organizations not included in the Eligibility section will not be reviewed. Applications must be prepared and submitted using NIH eRA Commons ASSIST. For instructions on how to submit through ASSSIST, refer to ASSIST-Instruction-Guide-for-NIH-Other-Transactions.docx. Complete applications must be submitted by the Recipient Business Official (RBO). The organization must be registered in eRA Commons with one person designated as the contact PI and one person designated as the RBO. The registration process can take several weeks, so applicants should begin registration as soon as possible. Failure to complete registrations in advance of the due date is not a valid reason for a late submission. The RBO’s signature certifies that the applicant has the ability to provide appropriate administrative and scientific oversight of the project and agrees to be fully accountable for the appropriate use of any funds awarded and for the performance of the OT award-supported project or activities resulting from the application.

Application Format

Full applications must include the following components. All attachments must be submitted as PDF using formatting standards provided at https://grants.nih.gov/grants/how-to-apply-application-guide/format-and-write/format-attachments.htm#papersizeandmargins. Do not include additional project data, images, graphics, etc. in sections other than Research Strategy in order to circumvent page limits. The required application components (with page limits in parentheses) are the following:

• Abstract (1 page): Provide a summary of the planned activities and approaches and key achievable goals.
• Specific Aims (1 page): Describe the specific aims and objectives the application proposes to achieve.
• Public Health Relevance (1 page): Include a 2-3 sentence statement of the project’s public health relevance.
• Invitation to Submit (1 page): Provide a copy of the NIH email, inviting submission of a full application.
• Project Information Summary (no more than 2 pages): Provide the information about (note: do not upload this into the “Cover Letter Attachment” field in the ASSIST form but provide it as part of the Attachments section in the form):
  • Project Title.
  • Number and title of this Research Opportunity Announcement.
  • Principal Investigator(s) first and last name, title, institution, mailing address, email address, and phone number. If multiple Principal Investigators are named, the Contact Principal Investigator must be clearly identified.
  • Name and address of the submitting organization and department, if any, with the organizational Unique Entity Identifier (UEI) number and employment identification number (EIN) provided.
  • Recipient Business Official/Signing Official first and last name, title, institution, mailing address, email address, and phone number.
  • Proposed budgets per year for 3 years (direct, indirect, and total costs).
  • Proposed project period dates.
  • Identify if the work involves human subjects.
• Research Strategy (no more than 10 pages, including text and non-text elements): Provide the following:
  • Scientific rationale and justification of the approach
  • Short-term (first year) and long-term (second and third year) objectives of the proposed work
  • A detailed description of the proposed model, including advantages and strengths. Include a brief description of how the model addresses or account for sex as a biological variable as appropriate for the application 
  • Strategies for assessing the proposed model’s validity and credibility 
  • The proposed work’s potential scientific impact and clinical relevance 
  • Examples illustrating the experience and past success of the project team and team members in projects of similar scope
  • Discussion of potential risk and alternative plans for mitigating risk
  • Plans for reusing existing resources such as data repositories and biobanks, if applicable 
  • Plans for primary data collection (experimental or observational), if applicable, and an explanation why such activity is an integral part of model development or model performance evaluation.
• Intellectual Property (IP) Strategy (1 page): Applicants must describe the IP landscape surrounding the applications. This should include known constraints, if any, that could impede model development and data sharing (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar technologies that are under patent and/or on the market, etc.) and how these issues could be addressed as appropriate and consistent with achieving the goals of the program. If patents pertinent to the proposed work have been filed, the applicants should indicate the details of filing dates, what types of patents were filed, application status, and associated United States Patent Office (USPTO) links, as applicable. Applicants must also discuss future IP filing plans.
• Leadership Plan (1 page): This includes organizational and reporting structure and personnel responsibilities, relevant past performance for the team working in or leading projects that are similar in scope and objectives to the project being proposed in the application and any prior experience of the team working together such as in consortium or other multi-institution projects. If applicable, include a MPI leadership plan.
• Milestones and Deliverables (no more than 6 pages): All applications must provide detailed information on milestones and deliverables for planned activities and partnerships, as further described below in Section 8.4.
• Project Team (see page limits below); Provide the requested information in the specified format per the instructions below.
  • All Personnel (no more than 2 pages): Provide a table of key personnel and any additional paid and volunteer personnel (e.g., data coordinator, collaborator, partner, consultant, advisor, trainee, student, staff scientist, etc.) contributing in a substantial or meaningful way for the proposed project and for any subprojects, listing the following information in separate columns for each individual:
    • Last name
    • First name
    • eRA Commons ID (if available)
    • Institutional affiliation
    • Current title
    • Email address
    • Percent Effort and
    • Role in the project.
  • Subrecipients (no more than 1 page): Provide a list of additional entities or organizations proposed to receive subawards and their roles.
  • Biosketches (no more than 2 pages per individual): Provide a biosketch of each named key individual. The information in the biosketch should include the name and position title; education/training including institution, degree, date (or expected date), and field; list of positions and employment in reverse chronological order (including dates); list of up to three (3) past projects and activities (including the resulting accomplishments and deliverables) that are similar in scope and objectives and most relevant to the proposed work. The format used for an NIH grant application is acceptable: https://grants.nih.gov/grants-process/write-application/forms-directory/biosketch
• Other Support (no page limitation): Provide Other Support for all key personnel using the NIH grant application Other Support Format Page work document as found here: https://grants.nih.gov/grants-process/write-application/forms-directory/other-support. Other Supports must be included with the application, not submitted through SciENcv.
• Equipment and Facilities (no more than 3 pages): Provide the information about the equipment and other physical resources available to the project team to adequately complete the project milestones. This should include a computing infrastructure that can adequately support the successful execution of the proposed work.
• Institutional Letter of Support (no more than 2 pages): Provide a letter of support from the applicant organization indicating institutional commitment for the project (e.g., relaying support for contributions, including, but not limited to, support for training activities, licenses, and other resources) and preparations to enter into a negotiated Other Transaction Agreement.
• Additional letters of support (no more than 2 pages per individual or organization): Letters of support will be reviewed. Only include letters from persons who have an assigned role in the project.
• Budget and Budget Justification (no page limitation): All applications must provide detailed budget information for planned activities and partnerships, as further described below in Section 8.5.
• Bibliography (no page limitation).
• Resource Sharing Plan: (2 pages). Individuals are required to develop a Resource Sharing Plan in accordance with the NIH Research Tools Policy. Specifically for this opportunity, it is expected that the proposed model is developed with an architecture that will facilitate model sharing. All applicants must include a plan for sharing model components, modeling parameters, as well as associated scientific data (also see Data Management and Sharing Plan).  The plan should describe how applicants will provide a sufficient amount of accurate information and model documentation to allow others to reproduce the model and perform external validation.  The plan should also include an appropriate timeline for sharing.  Applicants are required to make the mathematical model and associated data publicly available before a formal patent application is filed.  Delayed disclosure of research findings for the purpose of evaluating an invention for patent application or filing a patent application is not allowed.
• Data Management and Sharing Plan (2 pages):  Responsible data management and sharing have many benefits to the scientific community, including enabling independent validation of research results. All applications must develop a Data Management and Sharing (DMS) Plan in accordance with the NIH Data Management and Sharing Policy, with the following modification: 
  • Scientific data generated as a result of awards under this initiative must be made publicly available before a formal patent application is filed.  Such scientific data include, but are not limited to, primary experimental data, primary observational data, derived data from public repositories or non-public sources, and simulation data that are collected and generated as an integral part of model development and model performance evaluation.  Some data employed for model development or performance evaluation may have restricted access (e.g., human research participant data).  The DMS policy outlies factors that might limit data sharing,  including when sharing would compromise the privacy or safety of participants and when limitations are explicitly described in informed consent documents.  The application must address in the plan any potential limitations needed to protect privacy and confidentiality of participants and how access to the restricted data can be requested for independent model validation and assessment purposes by third parties.  Delayed data sharing for the purpose of evaluating an invention for patent application or filing a patent application is not allowed.  
• PHS Human Subjects and Clinical Trials Information (up to 25 pages): When involving human subjects research, clinical research, and/or NIH-defined clinical trials, follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:
  • If human subjects are involved, 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.
  • All instructions in the SF424 (R&R) Application Guide must be followed. Additional information can be found here: Study Record - Section 1 Basic Information (nih.gov)
  • 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.

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8.4    Milestones and Deliverables #milestones

The expected project duration is 3 years. Provide a table of milestones and deliverables for each year of the three-year application. Milestones must be specific, quantifiable, and scientifically justified. Milestones, due dates, risk, risk mitigation, and estimated costs must be provided in the table. An example table template is provided below for reference.

Example table of milestones and deliverables:

• Note 1: Applicants must ensure that the total budget request is consistent with the sum of item budget estimates in Milestones and Deliverables table for the project.
• Note 2: Provided costs for the task should include all the costs for personnel, facilities, other resources, travel, and other associated costs.
• Note 3: Total cost (the sum of direct and indirect) for the tasks must be provided.
   

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8.5    Budget Details #budget

The NIH may allocate up to $5,000,000 (direct + F&A) costs per year for up to three years per award. Support of approximately four (4) projects is anticipated. The funding will depend on (1) the objectives for the project proposed by the applicants and how well they fit with the goals of the Computational Modeling of Hormone Homeostasis initiative, (2) the quality of the applications received, (3) availability of funds, and (4) programmatic priorities. The NIH may elect to negotiate any or all elements of the proposed budget. Institutions with an established F&A rate should use their federally approved rate to calculate F&A costs or elect to use de minimis rate.

In ASSIST Core tab, applicants should enter the total dollar number in the field of Total Requested Funds. For budget details, applicants must download the form from https://commonfund.nih.gov/OTforms and then complete SF424 budget forms on their own computers instead of in internet browsers. The prime applicant is responsible for including all third parties’ budgets -and budget justifications. In order to successfully upload budget forms as an attachment into ASSIST, the applicant should flatten the fillable PDF. There are a number of methods to flatten a PDF, the easiest of which is to print it as a PDF.

The detailed budget request must provide the overall expected cost for each of the following categories and for each of the three years: personnel, travel, funds for third parties (i.e., subrecipients) if applicable, other direct costs, and total costs (with F&A costs included).

Budgets must adhere to latest NIH salary limitation notice (See Salary Cap Summary (FY 1990 - Present) | Grants & Funding).

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8.6    Systems Registration #systemsreg

Applicants must submit the full application via the NIH eRA Commons ASSIST system no later than the “Application Due Date” shown at the top of this notice, by 5 PM local time of applicant organization. Here are instructions for submitting via the NIH eRA ASSIST system including specific guidance for OTAs: https://www.era.nih.gov/help-tutorials/assist/era-training-assist.htm. Technical assistance is available from the eRA Service Desk: https://www.era.nih.gov/need-help.

To submit a full application via ASSIST, the applicant organization must have already registered for and been granted the following, which may take several weeks to complete: 

• System for Award Management (SAM): https://sam.gov/content/home – Applicants must complete and maintain an active registration, which requires renewal at least annually. 
• Unique Entity Identifier (UEI): A UEI is issued as part of the SAM.gov registration process.
• eRA Commons: Once the unique organization identifier (UEI after April 2022) is established organizations can register with eRA Commons (https://www.era.nih.gov/) in tandem with completing their full SAM and Grants.gov registrations.

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.

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9.    Objective Review #objrev

The intent of the Objective Review for Computational Modeling of Hormone Homeostasis initiative is to determine whether the proposed activities meet the goals and vision of this project.

Applications to Other Transactions Research Opportunity Announcements, such as this one, are not reviewed by the standard NIH peer review process, but use custom processes referred to as Objective Review. Responsive, full applications submitted in response to the ROA will be reviewed by subject matter experts via an Objective Review process. Objective Review will involve the submission of written critiques by subject matter experts against the Review Criteria described below and may involve interactive discussions between those experts and NIH Program staff. The subject matter experts will include NIH staff, other federal staff, and may include individuals external to the federal government. Applications may be accepted into the final plan in whole, in part, or not at all. The outcome of each review could result in a modified work plan for each application based on reviewers’ comments and recommendations as well as alignment with programmatic priorities. The modified workplan, as shaped by the review process, will serve as a blueprint for the final negotiated terms and milestones for the resulting award(s).

NIH will NOT provide feedback on applications, except as a part of follow-up on an as-needed basis. 

NIH will not accept an appeal of the Objective Review or funding decision outcomes. 

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9.1     Review of Full Applications #revfullapp

Full applications will undergo Objective Review by subject matter experts including NIH employees, employees of other agencies, and outside experts, as needed. 
The Overall Impact will be assessed by the Review Criteria outlined below: 

• Scientific merit as well as innovation and/or transformational potential of the proposed approach. Specifically: 
  • Likelihood of advancing the goals of the initiative if the proposed work is completed successfully
  • Scientific knowledge gain and improvements in technical capabilities if the proposed work is completed successfully
  • Soundness, practicability, and completeness of the proposed approach
  • The potential to develop standardized, scalable, extensible, and foundational technical capabilities
  • The transformative potential of the proposed approach
  • Availability of data to be used for model development and assessment of model performance
  • Appropriateness of milestones, deliverables, and timeline for fulfilling the planned activities within the three-year project period
  • Adequacy of resource sharing and data management and sharing plans
  • Adequacy of human subjects protection, if applicable
• Feasibility to deliver the proposed solutions within the 3-year project period.
• Appropriateness of key personnel. This includes adequate demonstration of expertise and experience of the team members and evidence of the team’s ability to perform the proposed work.
• Appropriateness of facilities and other resources
• Appropriateness of proposed budget
• Any potential risks

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9.2     Post-review Funding Plan #postrevplan

NIH intends to fund approximately four (4) awards.

Funding decisions and the level of funding for each award made under this solicitation will depend on (1) the objectives proposed by the applicants and how well they fit with the goals of the Computational Modeling of Hormone Homeostasis initiative, (2) the quality of the applications received, (3) availability of funds, and (4) programmatic priorities. Programmatic priorities specifically include complementarity to and synergy with other funded projects, and representation of a varied collection of diseases, conditions and aspects of human biology relevant to the health of women. The OT mechanism allows for significant flexibility to make budget adjustments as needed to meet NIH’s programmatic priorities. Award levels may increase or decrease over time based on funding availability, establishment or termination of subcontracts, recipient performance, and other program priorities.

Following the review of applications, NIH may assemble teams from all or parts of applications to establish the Computational Modeling of Hormone Homeostasis initiative. Individual components from distinct applications may be selectively funded to achieve the goals set forth herein. Additionally, if, over the duration of the project, some of the components either gain relevance or lose relevance to programmatic goals, the funding for such components may be increased, decreased, or be discontinued.

At any relevant point in the process, including the Objective Review, NIH reserves the right to:

1. Select for negotiation all, some, one, or none of the applications received response to this solicitation.
2. Accept applications in their entirety or select only portions of the application for award.
3. Invite all, some, one, or none of the Principal Investigators (PIs) submitting applications in response to this solicitation to present their application in a web-based videoconference or a teleconference.

Appeals of the Objective Review will not be accepted for applications submitted in response to this ROA.

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10.    Special Award Terms and Information #specialaward

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10.1    NIH Discretion #nihdiscretion

The OT award mechanism allows significant ongoing involvement from NIH Program and Project Managers and OT Agreements Officer and Agreements Staff and provides the NIH the flexibility to alter the course of the project in real-time to meet the overarching goals. This may mean an awarded activity could be expanded, modified, partnered, not supported, or discontinued based on program needs, emerging methods or approaches, performance, or availability of funds.

Performance during the award period will be reviewed on an ongoing basis and course corrections will be made, as necessary. As a result, the NIH reserves the right to:

1. Fund projects in increments and/or with options for continued work depending on agreed upon milestones;
2. Specify milestones that either result in project continuation if achieved, or termination if not achieved, by the specified milestone timepoint;
3. Fund a project composed of entities included in different applications as part of a reorganized collaboration, teaming arrangement, or other means acceptable to the government and recipient;
4. Request additional documentation (certifications, etc.), and;
5. Remove participants from award consideration should the parties fail to reach a finalized agreement by addressing the concerns identified in the Objective Review, and any additional concerns identified by NIH Program staff, or the proposer fails to provide requested additional information in a timely manner.

Applications selected for award negotiation may result in the issuance of an OT award based on the nature of the work proposed, the required degree of interaction between parties, and other factors. The NIH reserves the right and sole discretion to engage in negotiation with the selectees submitting a full application under this solicitation.

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10.2    Award Governance #awardgov

The NIH will actively engage with awardee(s) to establish the vision and capabilities for the Computational Modeling of Hormone Homeostasis initiative and to oversee the effort of the awardee to achieve that vision. The NIH staff involved in award governance are the Other Transactions Agreements Officer (OTAO); the Other Transactions Agreements Specialist (OTAS); and the Other Transactions Program Official (OTPO). Information on the respective responsibilities of these NIH roles will be provided in the OT Agreement.

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10.3    OT Agreement Governance #otagree

Other Transactions (OT) are a special type of legal instrument other than contracts, grants, or cooperative agreements. Generally, these awarding instruments are not subject to the regulations for federal contracts or grants, unless otherwise noted for certain provisions in the terms and conditions of award. They are, however, subject to the OT authorities that govern the initiative and/or programs as well as applicable legislative mandates. The NIH and its components, including the Office of Director, have been authorized by Congress to use them. They provide considerable flexibility to the government to establish terms and conditions of the OT Agreement.

For the awards funded under this ROA, the NIH will engage in negotiations, and all agreed-upon terms and conditions will be incorporated into the OT Agreement.  Notice of Award (NoA) will be used as the official OT Agreement. Submission of the application and the signature of the RBO certifies that the organization complies, or intends to comply, with all applicable terms and conditions, policies, and certifications and assurances referenced (and, in some cases, included) in the application instructions.

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10.4    Reporting and Project Meetings #repprojmeet

The terms and conditions of award will address these criteria as appropriate based upon the final negotiated terms and agreed upon budget. However, the recipient and key project team members will be required to:

• Participate in an initial virtual kick off meeting with NIH staff and the Computational Modeling of Hormone Homeostasis initiative collaborators.
• Participate in site visits or reverse site visits as deemed necessary by the OTPO.
• Participate in virtual progress meetings with NIH staff to ensure the initiative continues to achieve objectives and to discuss progress and strategies. 
• Submit written budget and milestone reports.
• Collaborate with other awardees in the timely dissemination of program results and the eventual release to the scientific community of methods, tools, results, and other resources.

Costs associated with these activities must be appropriately reflected in the proposed budget.

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10.5    Management Systems and Procedures #mansysproc

Recipient organizations are expected to have systems, policies, and procedures in place by which they manage funds and activities. Recipients may use their existing systems to manage OT award funds and activities as long as they are consistently applied regardless of the source of funds and across their business functions. To ensure that an organization is committed to compliance, recipient organizations are expected to have in use clearly delineated roles and responsibilities for their organization’s staff, both programmatic and administrative; written policies and procedures; training; management controls and other internal controls; performance assessment; administrative simplifications; and information sharing.

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10.6    Financial Management System Standards #finmansys

Recipients must have in place accounting and internal control systems that provide for appropriate monitoring of other transaction accounts to ensure that obligations and expenditures are congruent with programmatic needs and are reasonable, allocable, and allowable. The systems must be able to identify unobligated balances, accelerated expenditures, inappropriate cost transfers, and other inappropriate obligation and expenditure of funds, and recipients must notify NIH when problems are identified. A recipient’s failure to establish adequate control systems constitutes a material violation of the terms of the award.

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10.7    Organizational Conflicts of Interest (OCIs) #ocis

Applicants are required to identify and disclose all facts relevant to potential OCIs involving subrecipients, consultants, etc. Under this section, the proposer is responsible for providing this disclosure. The disclosure must include the PI/Collaborators’, and as applicable, proposed member’s OCI mitigation plan. The OCI mitigation plan must include a description of the actions the proposer has taken, or intends to take, to prevent the existence of conflicting roles that might bias the proposer’s judgment and to prevent the proposer from having an unfair competitive advantage.

The government will evaluate OCI mitigation plans to avoid, neutralize, or mitigate potential OCI issues before award issuance and to determine whether it is in the government’s interest to grant a waiver. The government will only evaluate OCI mitigation plans for applications that are determined selectable. The government may require applicants to provide additional information to assist the government in evaluating the proposer’s OCI mitigation plan. If the government determines that a proposer failed to fully disclose an OCI or failed to reasonably provide additional information requested by the government to assist in evaluating the proposer’s OCI mitigation plan, the government may reject the application and withdraw it from consideration for award.

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10.8    Monitoring #monitor

Recipients are responsible for managing the day-to-day operations of OT award-supported activities using their established controls and policies. However, to fulfill their role in regard to the stewardship of federal funds, NIH staff will monitor their OT awards to identify potential problems and areas where technical assistance might be necessary. This active monitoring is accomplished through review of reports and correspondence, audit reports, site visits and other information, which may be requested of the recipient. The names and contact information of the individuals responsible for monitoring the programmatic and business management aspects of awards will be provided to the recipient at the time of award.

Monitoring of a project or activity will continue for as long as NIH retains a financial interest in the project or activity as a result of property accountability, audit, and other requirements that may continue for a period of time after the OT award is administratively closed out and NIH is no longer providing active OT award support.

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10.9    Audit #audit

NIH OT recipients for the Program are subject to the audit requirements of OMB 2 CFR 200, Subpart F – Audit Requirements, as implemented by DHHS 45 CFR, Subpart F. In general, 45 CFR 75, Subpart F – Audit Requirements requires that a state government, local government, or non-profit organization (including institutions of higher education) that expends $1,000,000 or more per year under federal awards must have a single or program-specific audit conducted for that year in accordance with the provisions in Subpart F. Please consult the provisions within Subpart F to determine requirements for the program-specific audit requirements.

For-profit organizations have two options regarding the type of audit that will satisfy the audit requirements. The recipient either may have (1) a financial-related audit (as defined in, and in accordance with, the Government Auditing Standards (commonly known as the “Yellow Book”), GPO stock 020-000-00-265-4, of a particular award in accordance with Government Auditing Standards, in those cases where the recipient receives awards under only one DHHS program, or (2) an audit that meets the requirements of 45 CFR 75, Subpart F-Audit Requirements.

Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. If a recipient has failed to materially comply with the terms and conditions of award, NIH may take one or more enforcement actions, which include disallowing costs, withholding of further awards, or wholly or partly suspending the OT award, pending corrective action. NIH may also terminate the OT award.

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10.10    Public Policy Requirements and Objectives #pubpolicreq

NIH intends to uphold high ethical, health, and safety standards in both the conduct of the research it funds and the expenditure of public funds by its recipients. The signature of the RBO on the application certifies that the organization complies, or intends to comply, with all applicable policies, certifications, and assurances.

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