Department of Health
and Human Services (HHS)
and Human Services (HHS)
National Institutes of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
None
The purpose of this Funding Opportunity Announcement (FOA) is to promote partnerships between intramural investigators at the NCATS 3-D Bioprinting Laboratory and extramural researchers to jointly develop and demonstrate the use of 3-D biofabricated tissues for disease modeling and drug screening.
May 28, 2021
| Application Due Dates | Review and Award Cycles | ||||
|---|---|---|---|---|---|
| New | Renewal / Resubmission / Revision (as allowed) | AIDS | Scientific Merit Review | Advisory Council Review | Earliest Start Date |
| June 28, 2021 | Not Applicable | Not Applicable | October 2021 | January 2022 | March 2022 |
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.
Not Applicable
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.
Purpose
This Funding Opportunity Announcement (FOA) aims to promote partnerships between National Center for Advancing Translational Sciences (NCATS) intramural investigators (e.g., those conducting research within the labs and clinics of NCATS) and extramural investigators (e.g., those conducting research in labs and clinics outside of the NIH). Specifically, the FOA will provide support to create collaborative partnerships between the NCATS 3-D Tissue Bioprinting Laboratory and extramural research laboratories to significantly improve the drug development process by developing novel, physiologically relevant 3-D biofabricated disease tissue models for drug screening. Through these partnerships, extramural investigators in the basic and clinical research communities will provide disease and tissue physiology expertise, disease tissue models, and will provide critical reagents necessary to produce 3-D biofabricated tissues. Commensurately, the NCATS 3-D Tissue Bioprinting Laboratory will provide expertise in 3-D tissue biofabrication in multi-well plate format and assay development for drug screening, as well as provide 3-D tissue biofabrication resources and drug screening capabilities. The goal of the program is to establish unique partnerships that will demonstrate and significantly advance the development and use of 3-D biofabricated tissues and corresponding assays for drug screening and provide evidence for higher clinical predictability of 3-D biofabricated tissue models over standard 2-D models to identify new therapeutics more effectively.
Background
More than 90% of the drugs being developed fail due to unpredicted clinical toxicity or lack of efficacy in clinic. This high drug development attrition rate in clinic suggests that the in vitro cell assays and/or in vivo animal models used during pre-clinical drug development are overly simplistic and have limited ability to predict outcomes in clinic. 3-D biofabrication of tissue models using human primary cells, allogeneic or autologous human induced pluripotent stem cell (iPSC)-derived cells that faithfully recapitulate native tissues can provide more clinically relevant toxicity and efficacy data. Recent advances in the fields of tissue engineering, biomaterials science, stem cell biology, cell microscopy and medicine have enabled the field of 3-D biofabrication of living tissues. Living cells and scaffolding materials can now be combined into complex 3-D functional tissues produced on multi-well plates (tissue-in-a-well) and be used as pre-clinical drug testing assay platforms. The goal of creating 3-D biofabricated human-like tissues in microplate format for screening is to provide physiological and pharmacological data that predict the effects of drugs better than data from traditional studies using 2-D models. The expectation is that these models will have a long-lasting impact on reducing the cost of drug discovery as well as shortening the time it takes to bring new medicines to more patients.
Funds from the National Institutes of Health (NIH) will be made available through the UH2/UH3 cooperative agreement award mechanism. The FOA will build upon the work that has begun under previous FOAs, RFA-TR-17-007 and RFA-TR-19-020, that have primarily focused on development of 3-D biofabricated skin disease models and their utilization in drug screening platforms. This FOA intends to expand the type of tissue models produced based on preliminary work in the extramural laboratory showing disease modeling data in a 3-D tissue model, readiness of a model to be adapted to a multi-well plate-based platform, and in agreement with the NCATS 3-D Tissue Bioprinting Laboratory. Given previous focus of the program on skin disease models, this FOA will prioritize non-skin disease tissue models.
Leveraging Existing Research Resources:
This initiative will leverage the infrastructure at the NCATS 3-D Tissue Bioprinting Laboratory (https://ncats.nih.gov/bioprinting/capabilities). Applicants are required to utilize the expertise and infrastructure available at the NCATS 3-D Tissue Bioprinting Laboratory. In addition, utilizing the resources and support from patient advocacy groups, private research foundations, academic institutions, for profit organizations and other government agencies and the NIH Intramural Program is also encouraged.
Pre-Application Consultation:
Applicants are strongly encouraged to consult with NCATS Extramural Program Staff early in the planning of an application, i.e., more than two months before the application due date (see NCATS Extramural Program contacts below). This early contact will provide an opportunity to discuss and clarify NIH policies and guidelines, including the scope of the project and intent of this FOA.
Prospective applicants are required to discuss their proposed projects with the Director of the NCATS 3-D Tissue Bioprinting Laboratory and include in their application a letter of support from the Scientific Director of NCATS Division of Preclinical Innovation (DPI) that documents agreement to participate in the proposed collaboration.(See Letters of Support and NCATS Intramural Program contacts below.)
NCATS 3-D Bioprinting Laboratory Capabilities:
This FOA requires partnerships with intramural investigators at the NCATS 3-D Bioprinting Laboratory (https://ncats.nih.gov/bioprinting/work). The objective of the 3-D Tissue Bioprinting Laboratory is to produce 3-D tissue models in multi-well plate platforms as disease relevant assays for drug screening. 3-D tissue models are biofabricated using human primary and iPSC-derived cells and tissue engineering techniques that may and are not required to include 3-D bioprinting technologies. Relevant disease phenotypic detection endpoints are developed that are compatible with high throughput screening (HTS) capabilities at NCATS for drug screening.
NCATS has unique libraries of pharmacological agents, including approved drugs and mechanistically annotated compounds, which will be used to pharmacologically benchmark the 3-D biofabricated tissue models, as well as to repurpose existing drugs and/or understand the pharmacology underlying diseases (https://ncats.nih.gov/preclinical/core/compound).
Research Objectives and Scope
For projects supported under this FOA, the focus is to produce 3-D disease tissue models as multi-well plate assay platforms for drug discovery and development of new therapeutics. Extramural investigators will provide expertise in specific disease models, and relevant clinical biomarkers of the disease of interest in the tissue proposed. The tissue equivalents must be constructed using human cells, including primary cells and/or cells derived from induced pluripotent stem cells (iPSCs). The NCATS 3-D Tissue Bioprinting Laboratory (i.e., intramural investigators) will provide expertise in using 3-D biofabrication technologies such as tissue engineering, 3-D bioprinting and biocompatible polymers and hydrogels, as needed, to produce the tissue equivalents in a multi-well plate format. In addition, the NCATS 3-D Bioprinting Laboratory will provide expertise relevant to the development of phenotypic assays that are compatible with HTS capabilities at NCATS. Finally, the NCATS 3-D Bioprinting Laboratory will provide drug screening expertise and implement drug screening on the model. Once promising compounds are identified, they will be provided to extramural collaborator(s) for subsequent in-depth validation studies.
Specifically, this FOA is seeking to support extramural-intramural collaborations that leverage both the NCATS biofabrication and screening capabilities and the extramural investigators own internal capabilities for:
This funding opportunity includes activities in both intramural and extramural laboratories. Active engagement with open communication channels is expected between the extramural researchers and intramural researchers at the NCATS 3-D Tissue Bioprinting Laboratory. To promote collaborative efforts from the outset, the partnering intramural and extramural investigators must work jointly in developing the application for this FOA. The collaborations in this FOA will sustain an innovative and collaborative ecosystem where the NCATS 3-D Tissue Bioprinting Laboratory provides access to capabilities that may be beyond the capabilities of extramural investigators. In turn, the extramural investigators will provide access to disease expertise and the latest cutting-edge techniques for potential integration.
Specifically, this FOA is seeking extramural collaborators or teams of extramural collaborators with:
Phased Innovation Awards
This FOA will use the UH2/UH3 bi-phasic, innovation award mechanism of funding. During the UH2 phase, support will be provided for biofabrication of morphologically and physiologically validated 3D disease tissue models and corresponding screening assays in low to medium throughput format.
During the UH2 phase, applicants are expected to:
The use of spheroids (cell aggregates from differentiated cells) and/or organoids (cell aggregates differentiated from stem cell) are within scope if included in the context of a biofabricated tissue (e.g., neurospheroid connected to a muscle for a neuromuscular junction model). Tissue-in-a-chip devices in a microtiter plate format can be included if they have open access to include additional 3-D cellular layers and are commercially available and amenable to detection endpoints commonly used at NCATS for HTS (https://ncats.nih.gov/bioprinting).
The above activities will be primarily performed in the laboratory of the extramural investigator(s). The role of NCATS 3-D Tissue Bioprinting Laboratory during the UH2 phase will be to provide additional expertise relevant to biofabrication, assay development and drug screening.
UH2 projects that have met the scientific milestones and the technical readiness (see below) will be eligible for transition to the UH3 Phase after NIH administrative review (NCATS will support up to two projects for the UH3 phase). The criteria to determine whether a UH2 project will be continued into the UH3 phase will be negotiated between the NIH and the applicant institution prior to funding, and include the following:
The UH3 phase involves activities in both intramural and extramural laboratories. NCATS intramural investigators will work towards the adaptation of the 3-D tissue models and endpoint assays to a drug screening platform and implementation of screens of up to 1000 compounds. Extramural investigator(s) will work towards validation of any active compounds from the screens in additional in vitro and in vivo assays.
Activities supported during the UH3 phase may include, but are not limited to:
The goal of the UH3 phase is to be able to screen up to 1000 compounds at one compound dose per assay to pharmacologically, validate the 3-D disease tissue models (establish effect of known modulators), and to identify compounds that modulate the relevant disease phenotypes. The libraries screened will include compounds with annotated target and mechanism of action and approved drugs for drug repurposing screening (https://ncats.nih.gov/preclinical/core/compound). NCATS is also interested in exploring the screening of diversity collections and using artificial intelligence (AI) approaches for lead identification and structure activity relationship (SAR) studies using medicinal chemistry. NCATS has the capability to select and assemble a customized library of compounds for screening.
Technical readiness of the 3-D disease tissue model assays.
It is expected that 3-D tissue disease model assays will have been configured and characterized in a multi-well plate format (at least 6-well plate) by extramural investigator(s) with advice from NCATS scientists and can be rapidly adapted to the biofabrication and screening capabilities at NCATS. Technical readiness of the 3-D tissue models and detection readouts for drug screening will be demonstrated by:
Assays that require manual tissue processing and transferring to a different platform for assaying (e.g., histology) are not HTS compatible but should be discussed with the investigators at the NCATS 3-D Tissue Bioprinting Laboratory before submission for alternative options. Clearing protocols for high content screening are acceptable if needed and should also be discussed with the investigators at the NCATS 3-D Tissue Bioprinting Laboratory before submission for advice.
UH2/UH3 Milestones
All projects must be milestone-driven with clear go/no-go criteria that are quantifiable. Prior to funding an application, the NCATS Program Official will contact the applicant to discuss the proposed UH2 and UH3 milestones and any changes suggested by NIH staff . The NCATS Program Official and the applicant will negotiate and agree on a final set of approved UH2 milestones that will be specified in the Notice of Award. These milestones will be the basis for judging the successful completion of the work proposed in the UH2 stage and progress towards interim milestones in the UH3 stage. Only projects that meet their UH2 milestones will have an opportunity to move to the UH3 phase. UH3 milestones will be the basis for judging progress towards and completion of the UH3 phase (please see Section VI below).
Additional Considerations
Subject Matter Experts:
Extramural investigator(s) are advised to recruit all the expertise that is needed for the development of the specific module of interest and leverage it with the existing NCATS expertise.
Cells:
The availability and use of human primary cells, or pluripotent stem cells, e.g., iPSC, are strongly encouraged. Multipotent or unipotent stem cells also may be utilized where appropriate. The current NIH guidance on stem cell usage can be found at https://stemcells.nih.gov/policy/2009-guidelines.htm. All normal and pathologically relevant, as well as any reporter iPSC lines required for the project must be established and validated prior to submission. Differentiation protocols from iPSC to relevant cells needed for the tissues must be demonstrated as preliminary data. For primary cells, the extramural investigators will have to demonstrate availability of the cells in large quantities for subsequent utilization in drug screening platforms.
Visiting investigator(s) at NCATS:
Following consultations with the NCATS 3-D Tissue Bioprinting Laboratory, extramural teams may identify a visiting investigator who will spend time at NCATS during the UH3 phase of the project. The role of the visiting investigator(s) at NCATS will be to ensure adaptation of the 3-D tissue assay to HTS format and the extent of visit will vary depending upon the project.
Collaboration Plan:
Applications for this program will be submitted by the extramural institution with the NCATS intramural investigator(s) integrated into the application as described in the Collaboration Plan (please see below). For successful applicants, annual progress reports will be prepared and submitted by the extramural institutions, with the participation and input of the intramural investigator(s) and should include the project findings, publications, data and resource-sharing and impact of the collaborative project. This collaborative translational research between NCATS intramural investigators and extramural investigators will involve either a Cooperative Research and Development Agreement (CRADA) or Research Collaboration Agreement (RCA), which will need to be executed for projects deemed scientifically meritorious by peer review and prior to funding. NCATS will provide CRADA or RCA template documents to help streamline the interaction between NCATS intramural investigators and extramural investigators. These template agreements can be found on https://ncats.nih.gov/alliances/forms. Questions regarding any of these agreements can be referred to the NCATS Office of Strategic Alliances at NCATSPartnerships@mail.nih.gov. Applicants should review this document and consult with their institutes about their willingness to agree to the conditions well in advance of applying to this FOA. The CRADA or RCA will need to be executed after the application has been identified for funding. While the CRADA or RCA may not be in place prior to application submission, a statement from the applicant’s Sponsored Research Office that they agree, in principle, to the conditions of the CRADA/RCA should be included in the application.
Important: As indicated above, potential applicants are required to consult with the Director of the NCATS 3-D Tissue Bioprinting Laboratory (see https://ncats.nih.gov/bioprinting/work). Early contact provides an opportunity for NCATS staff to discuss the program scope and goals and to provide information and guidance. Applications submitted without prior consultation with the NCATS 3-D Bioprinting Laboratory’s staff or without a Letter of Support from the NCATS Director of Preclinical Innovation (see NCATS Intramural Program contacts below) will not be reviewed.
See Section VIII. Other Information for award authorities and regulations.
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.
Not Allowed: Only accepting applications that do not propose clinical trials.
Need help determining whether you are doing a clinical trial?
NCATS intends to commit $1,500,000 in FY 2022 to fund 2-3 awards. Future year amounts will depend on annual appropriations.
For the UH2 phase, the direct cost is limited to $275,000 per year.
For the UH3 phase, the direct cost is limited to $150,000 per year.
Application budgets need to reflect the actual needs of the proposed project.
The proposed project period for the initial development phase (UH2) must not exceed 2 years.
The proposed project period for the subsequent drug screening and validation phase (UH3) must not exceed 4 years.
The total project period is limited to a maximum of 5 years.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For-Profit Organizations
Local Governments
Federal Governments
Other
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.
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.
Important: This program requires the full collaboration of the extramural PD/PI of the applicant institution and the intramural investigator(s). In order to be eligible for this program, the application must include at least one intramural investigator as a co-investigator. Intramural investigators whose involvement would not be classified as substantial should be assigned a collaborator role.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
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.
Letter of Intent
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
Carol Lambert, Ph.D.
Telephone: 301-435-0814
Email: lambert@mail.nih.gov
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.
Other Attachments:
The following attachments must be included, as applicable.
Collaboration Plan:
Applications must include a Collaboration Plan, describing how the proposed collaboration will be maintained throughout the duration of the award.
The following areas should be addressed:
The filename "Collaboration Plan-PI-NAME.pdf" should be used, must not exceed 50 characters, and will be reflected in the final image bookmarking for easy access by reviewers. The Collaboration Plan is limited to 5 pages. Applications that do not include the Collaboration Plan will be considered incomplete and will not be reviewed.
Milestone Plan:
Applications must include a Milestone Plan. The Milestone plan should:
The filename "Milestone Plan-PI-NAME.pdf" should be used, must not exceed 50 characters, and will be reflected in the final image bookmarking for easy access by reviewers. The Milestone Plan is limited to 3 pages. Applications that do not include the Milestone Plan will be considered incomplete and will not be reviewed.
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.
Budget Justification:
Because of the anticipated complexity of the budget information and the need to clearly delineate costs for the extramural applicant, a detailed R&R budget must be submitted. Submission of a Modular Budget is not allowed for this FOA.
The budget request for this FOA must distinguish between extramural costs and the NIH intramural investigator costs. Extramural costs are associated with the extramural investigator and the applicant organization. NIH intramural investigator costs are those required by the intramural investigator for carrying out the proposed work and which are specifically identified with the project.
During the UH2 phase, it is anticipated that most of the work will be performed at the extramural laboratory, while during the UH3 phase work will be primarily performed at NCATS. The extramural budget needs to be scientifically justified and reflect the work that will be carried by the extramural lab.
Extramural Grantee Costs:
Extramural costs of up to $275,000/year (UH2 phase) and $150,000/year (UH3 phase) may include such items as salary support for the extramural PD/PI and staff at the applicant organization, supplies, laboratory animals, data analysis, and other allowable costs for work performed at the (extramural) applicant organization, as well as travel costs for the extramural investigator(s).
F&A (Indirect) Costs: Applicant organizations are reminded that Facilities and Administrative (F&A) or indirect costs are allowable for only the allowable extramural costs of the project.
For profit institutions are reminded that the SBIR/STTR F&A (Indirect) Costs do not apply to this program. For profit institutions that do not have an approved F&A rate agreement may opt to include all applicable costs as direct costs, if the organization appropriately and consistently treats all costs as direct costs.
Intramural Investigator Costs:
The requests by NIH intramural investigator(s) will be limited to the incremental costs required for participation. Intramural investigator costs may include salary for contract staff to be specifically hired under a temporary appointment for the project, consultant costs, supplies, and other items typically listed under Other Expenses. Budget requests from the NIH intramural program may not include any salary and related fringe benefits for career, career conditional or other federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative costs). Although the budget request may not include salary support for such individuals, it should indicate person months for any key personnel. Resources required need to be determined before the research protocol can be approved by NCATS. Prospective applicants are strongly encouraged to contact NCATS staff to discuss intramural investigator costs.
Once the intramural investigator costs are known, the extramural applicant will enter this amount as a "subaward" budget in the application, and attach appropriate justification and documentation, including any spreadsheets as appropriate. The intramural investigator's costs will not be included in the award paid to the grantee. Support for intramural participation will be provided by a budget allocation within the NIH.
Peer reviewers will evaluate the appropriateness of the Intramural Research Program staff and budget request for the work proposed and will therefore need to know the level of effort being proposed to conduct the work.
Additional Guidance on Budget Preparation:
Initial cooperative agreement awards for up to 2 years will be granted in the UH2 phase for developing of tissue constructs and appropriate assays that are deemed to be compatible for high-throughput screening. If the project meets the metrics described for the UH2 phase, then the project will proceed to the UH3 phase pending review and availability of funds. The UH2 phase will focus on development and demonstration of physiologically relevant human cells and tissues that can model the mechanisms relevant to the disease of choice and/or its respective therapies and treatments. It is anticipated that during the UH2 phase, the majority of the funds will be dedicated to the work in the extramural laboratory. The intramural NCATS 3-D Tissue Bioprinting Laboratory will provide consultation regarding biofabrication of tissue constructs and assay development. During the UH3 phase, high density screening platforms on microplates seeded with the tissue constructs developed during the UH2 phase will be developed and coupled to relevant assays for screening novel therapeutics. This work will be primarily performed at the NCATS intramural 3-D Tissue Bioprinting Laboratory. The extramural team can choose to identify an extramural lab member who may spend time at NCATS during the UH3 phase to facilitate the success of the project Once screening is performed and hits are identified, extramural investigators will be provided with compounds and perform validation of hits identified in screening in their laboratories. The application budget should reflect actual needs of the proposed project and align with the distribution of the work during the two-phase project.
The budget requests for this FOA are more complex and will require more coordination than those of other programs. Therefore, extramural investigators are encouraged to begin discussions about logistics and budget issues with their intramural collaborators and with NIH staff in the early phases of application preparation.
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:
Letters of Support:
Applications submitted in response to this FOA must include a current (i.e., within 2 months of application due date) letter from the Scientific Director of the NCATS Division of Preclinical Innovation to confirm that the NCATS 3-D Tissue Bioprinting Laboratory will be able to accommodate the proposed research and that the NCATS intramural investigators will be able to collaborate on the project. Applications submitted without this letter of support will be considered incomplete and will not be reviewed.
The application must include a statement from the applicant’s Sponsored Research Office (or equivalent) that they agree, in principle, to the conditions of the CRADA/RCA. For more details, please see Collaboration Plan in Additional Considerations Section above.
Letter(s) from other collaborators/consultants confirming participation should also be included.
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:
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.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit 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 components of participating organizations, NIH. 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. Any instructions provided here are in addition to the instructions in the policy.
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 UH2/UH3 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. A UH2/UH3 grant application is not required to have extensive preliminary data, background material or preliminary information, but these may be included if available. Appropriate justification for the proposed work can also be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will focus their evaluation on 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 the UH2 and UH3 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.
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:
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Specific to this FOA:
Collaboration Plan
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?
Specific to this FOA:
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?
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?
Specific to this FOA:
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.
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
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
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
Not Applicable
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.
Milestones:
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; and (3) Genomic Data Sharing Plan (GDS).
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.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCATS, 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.
Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.
Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate NCATS Advisory Council or Board. The following will be considered in making funding decisions:
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient'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.
Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
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, Recipients, 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.
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.
The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75, and other HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.
The Extramural Project Director(s)/Principal Investigator [PD(s)/PI(s)] will have the primary responsibility for:
Upon completion or termination of the project, ensuring all study materials, tools, databases, and procedures developed from the project are broadly available (e.g., putting into the public domain) or made accessible to the research community according to the NIH-approved plan submitted for each project, for making data and materials available to the scientific community and the NIH for the conduct of research. The data sharing plan should include a plan to accomplish this within 90 days of the end of the study.
Publications
The Extramural PD(s)/PI(s)will be responsible for the timely submission of all abstracts, manuscripts, and reviews (co)authored by project investigators and supported in whole or in part under this Cooperative Agreement. Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the Extramural PD(s)/PI(s) and will require appropriate acknowledgement of NIH support. Timely publication of major findings is encouraged.
Communication Plans
The extramural PD(s)/PI(s)) will be responsible for participating in regular monthly conference calls with NCATS intramural investigator(s) involved in the project and NCATS program staff; coordinating efforts with other awardees, especially in circumstances where synergy of efforts and resources is beneficial to the overall goals of the NCATS 3-D Tissue Bioprinting program; anticipating and presenting findings at the semi-annual in-person or virtual meetings convened by the NIH; and coordinating or jointly publishing findings in a timely manner through publications, web announcements, reports to the NCATS Program Official, and other mechanisms.
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.
NCATS will assign a staff member to serve as NCATS Project Scientist. The Project Scientist will have substantial scientific involvement during the conduct of this activity, through technical assistance, advice, and coordination.
The NCATS Project Scientist will be primarily responsible for:
Additionally, an IC program director acting as the NCATS Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
The NCATS Program Official will be primarily responsible for:
The NCATS Intramural Investigator(s)will be primary responsible for:
The NCATS Intramural Investigator(s) are subject to the same publication/authorship policies as the official NIH publication policy.
The NIH reserves the right to phase out or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable protocol, (b) substantial shortfall in subject recruitment, consortium participation and collaboration with other awardees, (c) substantive changes in the agreed-upon methodologies and tools with which NIH cannot concur, (d) human subject ethical issues that may dictate a premature termination, or (e) results that substantially diminish the scientific value of study continuation.
Areas of Joint Responsibilities:
Since the purpose of this FOA is to establish and/or further develop collaborative arrangements between extramural and intramural investigator(s), many responsibilities are shared between awardees and NIH staff and will require close coordination. Responsibilities will be divided between awardees and NIH staff, as described above.
Awardees will participate in monthly calls with the NCATS staff and semi-annual meetings to discuss progress, obstacles and any other program-related issues and/or activities. Annual progress reports will be prepared and submitted by the extramural institutions, with the participation and input of the NCATS intramural investigator(s)and should include the project findings, publications, impact of the project, a description of what NCATS 3-D Tissue Bioprinting Laboratory unique resources were utilized and the new intramural-extramural partnerships that developed. This will be evaluated by the NCATS Program Official.
Data
Awardees will retain custody of and have primary rights to the data and resources developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.
Intellectual Property
Dispute Resolution
Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the awardee, and NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.
T&C Inclusions and Modifications
The Terms and Conditions of Award will include references to the currently approved versions of the Collaboration Plan and the Sharing Plans for Resources and Data. Before the initial award is made, NIH and the awardees may negotiate changes or additions to the versions of these plans in the application. Future changes or additions to these plans may be developed by the NIH and the PD(s)/PI(s) and negotiated with the awardee. Changes will be documented by an exchange of correspondence and the updated plans will become part of the Terms and Conditions of a revised Notice of Award.
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.
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: 301-945-7573
Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov
NCATS Extramural Program
Dobrila D. Rudnicki, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-2080
Email: dobrila.rudnicki@nih.gov
Danilo A. Tagle, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-8064
Email: danilo.tagle@nih.gov
NCATS Intramural Program:
Marc Ferrer, Ph.D.
Director, NCATS 3-D Tissue Bioprinting Laboratory
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-217-5722
Email: marc.ferrer@nih.gov
Anton Simeonov, Ph.D.
Director, NCATS Division of Preclinical Innovation
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-217-5721
Email: asimeono@mail.nih.gov
Carol Lambert, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0814
Email:lambert@mail.nih.gov
Katie Matthews
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-827-7060
Email: katie.matthews@nih.gov
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.
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