Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

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

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

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

Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

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

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Key Terms, Definitions, and Uses in this NOFO

New Approach Methodologies (NAMs) - NAMs are laboratory (in vitro and in chemico) or computer-based (in silico) research approaches intended to more accurately model human biology, and when used alone, or in concert with others, enable improved disease models, including toxicology as well as complex human-relevant models, and as a result, complement animal models in biomedical research.

Combinatorial NAMs – The combination and integration of multiple NAMs elements into a synergistic approach that augments gaps and/or deficiencies in individual NAMs approaches, ultimately allowing for improved predictions of human clinical response.

Consortium – Describes the participants involved in the Complement-ARIE program. The consortium is comprised of members of the trans-NIH Complement-ARIE NIH Working Group, all award recipients of this NOFO for the Comprehensive NAMs Technology Development Centers (TDC), the NAMs Data Hub and Coordinating Center (NDHCC), partners within the Validation and Qualification Network (VQN), and other relevant parties.

Drug development tools (DDTs) - Methods, materials, or measures that can potentially facilitate drug development.

Medical device development tools (MDDTs) - Methods, materials, or measures that can potentially facilitate medical device development.

In chemico - Experiments performed in cell-free systems to study the interaction of drugs, toxicants and other biological molecules.

In silico – Experiments performed by computing platforms or custom hardware, encompassing mathematical modeling and simulation, data-driven machine learning approaches, synthetic data, digital twin, and other computational techniques.

In vitro – Experiments performed generally outside of living organisms, including various types of cell culture systems, organoids, and tissue culture techniques.

Population diversity refers to the distinctive health characteristics and attributes due to variability in the general population. This could include (but is not limited to) diversity across age ranges, sex, genetics, ancestry, or economic strata.

Technical characterization – A key aspect of demonstrating the scientific validity of a NAM is that the assay is sufficiently well-characterized from a technical and analytical perspective to ensure that it is robust, reliable, and reproducible. Technical characterization includes an assessment of sources of variability in the NAMs, and could include designing the assay to include relevant control measurements, evaluating the range of test substances for which the assay can be used (i.e., the applicability domain), and developing a suitable statistical data analysis approach.

Validation – Validation is a process of establishing documentary evidence demonstrating that a procedure, process, or activity carried out in production or testing maintains the desired level of compliance at all stages and will consistently produce the expected results (https://www.fda.gov/media/94074/download).

Context of use (CoU) - Clearly articulated description delineating the manner and purpose of use for a particular method or approach. Having a more specific CoU greatly aids the validation and/or qualification process.

Qualification - Within a stated context of use, qualification is a conclusion that the results of an assessment using a model or assay can be relied upon to have a specific interpretation and application in product development and regulatory decision making. Qualification must identify the boundaries of the available data that adequately justify the use of the tool. The qualification process evaluates the fitness of the model for a specific context of use (CoU), with characterization of the challenge agent(s) and exposure, primary and secondary endpoints, triggers for intervention, and key disease values to be replicated for quality assurance and control. Qualification does not encompass the use of a DDT outside the CoU specified through the qualification process. (https://www.fda.gov/science-research/about-science-research-fda/fdas-predictive-toxicology-roadmap)

Interested parties - Includes, but is not limited to, academic, industry, and contract research organizations, regulators, individuals and/or organizations representing community members or advocacy groups; health care providers and health care systems; research participants; and patients.

Purpose

This Notice of Funding Opportunity (NOFO) is to establish Comprehensive NAMs Technology Development Centers to support NIH Common Fund’s Complement Animal Research In Experimentation (Complement-ARIE) program. The goal of the Comprehensive NAMs Technology Development Centers is to stimulate the development of combinatorial NAMs to support scientific areas of need, with emphasis on increased biological complexity and throughput, innovative combinatorial approaches, and data sharing according to FAIR principles. Developing these NAMs will require multi-disciplinary expertise in disease research, personalized medicine, screening therapeutics for safety and effectiveness, and in regulatory science.

Background

The 21st century has been a time of accelerated technological advancement. New and evolving methodologies, including gene editing, machine learning, induced pluripotent stem cells (iPSCs), 3D bioprinting, organoids, and microphysiological systems are fundamentally changing the way biomedical science is done. These technologies and other advances have greatly enabled and contributed to the development and application of New Approach Methodologies (NAMs). NAMs can be defined as any in vitro, in chemico, or in silico method, that when used alone, or in concert with others, enables improved disease models, including toxicology as well as complex human-relevant models, and as a result, complement animal models in biomedical research. NAMs hold tremendous promise in understanding various biological processes leading to better assessment of disease risk and progression, and development of precision interventions in the context of personalized medicine.The recent passage into law of the FDA Modernization Act 2.0 enables drug registration without the absolute requirement for the use of animals in safety toxicology assessment where alternative risk assessment tools are available. Similarly, the Toxic Substances Control Act (TSCA) as amended by the Frank R. Lautenberg Chemical Safety for the 21st Century Act, directs EPA to promote the development and timely incorporation of alternative test methods or strategies that do not require new vertebrate animal testing.  While traditional animal models continue to be vital to advancing scientific knowledge, NAMs offer unique strengths that, when utilized strategically or in combination, can complement animal models in ways that enable researchers to answer previously difficult or unanswerable questions, especially in areas where in vivo models are lacking or have consistently underperformed. 

NAMs have proven to be valuable tools in basic, clinical, and toxicology research, and have been used to study the efficacy and toxicity of novel therapeutics. In chemico cell-free platforms use cell-free systems to study the interaction of drugs, toxicants, and other biological molecules. This method requires a prior knowledge about the interaction of the test agent with a biological substance, such as in skin-sensitization assessments. In vitro models are systems that are performed generally outside of living organisms, including various types of cell culture systems, organoids, and tissue culture techniques, such as microphysiological systems (MPS). In silico computational models incorporate biological data with mathematical and computer-based representations to construct models of human biology using methods such as data analyses, data mining, homology models, machine learning, pharmacophores, quantitative structure-activity relationships, and network analysis tools.

A trans-NIH working group (now referred to as the trans-NIH Complement-ARIE Working Group) engaged in robust strategic planning activities and collaborator outreach focused on developing a unifying vision for building on ongoing efforts to develop, standardize, validate, and use NAMs. This working group identified opportunities for innovation and coordination in a new NIH Common Fund program called Complement Animal Research In Experimentation (Complement-ARIE).The NIH conducted strategic planning activities to inform the Complement-ARIE program concept. These included hosting three public listening sessions that brought together key representatives from multiple sectors: 1) industry and academic partners; 2) non-government organization (NGO) representatives; and 3) United States government and international partners. Each listening session was designed to gain insight into current opportunities and roadblocks in NAMs development unique to their fields. The Common Fund additionally hosted an interagency retreat with federal partners to discuss high-priority areas for the NIH to focus on when developing the Complement-ARIE program and potential opportunities for partnership, collaboration, and coordination. To ensure that the Complement-ARIE program is focused on areas of science with greatest need and present the best opportunities for human-based model development, a landscape analysis was performed to collect and analyze information on ongoing efforts in the NAMs space. This analysis focused on describing existing efforts and identifying gaps, challenges, and opportunities in the development of human-based models of health and disease. In combination with these efforts, the Common Fund hosted the Complement-ARIE Prize Challenge, a crowdsourcing competition that asked the public to propose novel ideas using NAMs to conduct basic research, uncover disease, and translate knowledge into products and practice. The competition awarded $1,000,000 in total prize money to twenty teams that provided out-of-the box solutions across the competition areas of in silico, in vitro, in chemico, and combinatorial approaches. The challenge provided NIH with information about where innovation can be incorporated into NAMs and what types of new NAMs may benefit from further investment.

Simultaneous to early planning stages of the Complement-ARIE program, the NIH sought the assistance of the Advisory Committee to the Director (ACD) on catalyzing the development and use of Novel Alternative Methods to Advance Biomedical Research to identify areas in which the development and use of novel alternative methods will provide the most value to biomedical research. The working group consulted with experts in the field and reviewed input from the community to deliver its report to the ACD during the Dec. 14, 2023, meeting. This report, which the ACD conveyed to the agency, recommendations that NIH work with the community to:

• Prioritize the development and use of combinatorial NAMs.
• Establish resources, infrastructure, and collaborations to promote the use of interoperable, reliable, and well curated/high quality datasets produced from research using NAMs.
• Promote effective dissemination and interconnection of NAMs technologies.
• Invest in comprehensive training to bolster continuous advances in development and use of NAMs.
• Facilitate multidisciplinary teams with expertise across technologies and the lifecycle of NAMs development and use.
• Promote social responsibility in both the creation and deployment of NAMs across the research lifecycle.
• Support and maintain coordinated infrastructure to catalyze effective and responsible NAMs development and use.

The ACD working group recommendations are aligned with Complement-ARIE program goals and have been incorporated into the program planning structure.

The overarching goal of the Complement-ARIE program is to catalyze the development, standardization, validation, and use of human-based NAMs that will transform the way basic, translational, and clinical sciences are done. Specific program goals include:

• Develop better models and understand human health and disease outcomes representative of the impacted patient populations.
• Develop NAMs that provide insight into specific biological processes or disease states.
• Validate mature NAMs to support standardization and clinical use.
• Complement traditional models and make biomedical research more efficient and effective.

Complement-ARIE will address current challenges in NAMs which include, validation and testing in complex systems, and the ability to generate preclinical data needed for first-in-human trials; characterize long-term, systemic and developmental health effects of environmental and drug exposures, and develop systems that better model the physiology and disease pathology of human diseases or conditions for which current experimental models are lacking (e.g. neuroscience and behavior research). Key focal areas of the NIH Common Fund investment include, but are not limited to:

• Complex in vitro models that emulate human organ structure, function, and response to study both normal physiology and disease pathology.
• In silico multi-scale systems simulating and modeling healthy/diseased individuals through computational approaches.
• In chemico cell-free systems that capture dynamic changes to assess chemical toxicity, chemical hazard and risk assessment, and inform adverse outcome pathways.
• Integrated findable, accessible, interoperable, and reusable (FAIR) datasets and artificial intelligence (AI)-engines to generate testable predictions (i.e., patient digital twins).
• Combinatorial approaches that combine two or more of the above approaches.

To achieve its goals, Complement-ARIE consists of the following key components and centers.

• Comprehensive NAMs Technology Development Centers (TDCs)  – stimulate the development of NAMs to address areas of greatest need, with emphasis on increased biological complexity and throughput, innovative combinatorial approaches, and data sharing.  
• NAMs Data Hub and Coordinating Center (NDHCC) – create integrated data structures, including standards for model credibility, improve FAIRness of NAMs-relevant data, and create a searchable NAMs repository. 
• Validation and Qualification Network (VQN) – establish common data elements and standardized reporting, apply validation/qualification frameworks, accelerate deployment and regulatory implementation of NAMs.

Within each of the three key program components, training and outreach activities are required to facilitate dissemination, capacity building, and adoption of NAMs. Complement-ARIE will participate in strategic engagement with key partners from other federal agencies including regulatory bodies, industry, non-profits, and other NGOs to advance emerging opportunities in the development and use of NAMs in basic, translational, and clinical research.

Complement-ARIE will play a pivotal role in advancing NAMs and our current understanding of human health and etiology of human disease. This program will have near-term application in fields such as mechanism elucidation, personalized precision medicine, safety pharmacology, predictive toxicology, and efficacy evaluation of candidate therapeutics.

Trans-NIH Complement-ARIE Working Group

The Complement-ARIE program is led by the trans-NIH Complement-ARIE Working Group, which is responsible for the stewardship of the Complement-ARIE program. The Complement-ARIE NIH Executive Committee consists of the Complement-ARIE Working Group Co-Chairs and Leadership Team, who are responsible for the overall management of Complement-ARIE.

The Complement-ARIE Consortium

The three key components, namely, the TDCs, NDHCC, and VQN, described above, participate in the overall Complement-ARIE Consortium. The Consortium structure is meant to effectively guide all the funded projects to meet the overall goals of the Complement-ARIE program. The Consortium is further comprised of members of the trans-NIH Complement-ARIE NIH Working Group, all award recipients of this Notice of Funding Opportunity (NOFO), the NDHCC, and the VQN, and other relevant scientists and groups. The Consortium is led by the Complement-ARIE Steering Committee (SC).  The SC will include a representative Program Director/Principal Investigator (PD/PI) from each awarded TDCs, a NIH Project Scientist, the PD/PI of the VQN, and the PD/PI of the NDHCC. Members of the SC will elect the SC co-chairs from among the Complement-ARIE PDs/PIs.  The SC Co-chairs will preside at all SC meetings and provide scientific leadership for the Consortium with significant input from NIH staff.

Award recipients agree to governance, through voting and decision making of the consortium through the SC. It is expected that most of the decisions on the activities of the SC will be reached by consensus. Other Consortium subcommittees may be formed as needed, and as deemed appropriate by the SC to further or achieve the goals of Complement-ARIE.

Complement-ARIE Consortium Data Sharing

A central goal of the Complement-ARIE program is the harmonization of NAMs data collection, metadata, and the standardization of NAMs validation frameworks for wider NAMs adoption and use. NIH expects that all projects funded under this NOFO will actively coordinate, collaborate, and share data with NDHCC. The NDHCC will provide a centralized data hub, build a searchable repository for NAMs, establish standards for data reporting and model credibility, develop strategies for interoperability, sustainable data reuse, and develop tools for data analytics, dissemination, and sharing. The TDCs will be expected to submit data to the central Complement-ARIE data hub and follow the framework for standards, metadata and common data elements (CDEs) established by the NDHCC. The NDHCC will be responsible for managing the data generated by the Complement-ARIE program in accordance with the data management and access policies established by the Consortium through the Steering Committee and in accordance with the Data Management and Sharing Plans approved by Consortium members. The NDHCC will assist TDCs in identifying existing repositories, provide guidance on data standards, and help integrate data from public sources as needed. The VQN will collaborate with the NDHCC to develop a framework for standards, metadata and CDEs that apply to all types of data generated to maximize potential for research, data integration, and NAMs benchmarking and evaluation for validation and qualification. The NDHCC and VQN will collectively create a mechanism to support data harmonization and will participate in trans-NIH efforts to support scientific collaboration and data sharing, partnership, and rapid dissemination of the NAMs produced by the Complement-ARIE program. The NDHCC and VQN will provide support and guidance to award recipients funded under this NOFO in the following areas: (1) administrative operations and logistics, (2) data collection, curation, and integration, (3) data standardization, metadata development, ontology use, and CDE implementation, and (4) data management, sharing, search and use.

Research Scope

This NOFO applies only to the Comprehensive NAMs Technology Development Centers.

Complement-ARIE NAMs Technology Development Centers

The Comprehensive NAMs Technology Development Centers will integrate research and training components dedicated to the development of combinatorial NAMs, with an emphasis on increased biological complexity and focused on applicability to high priority scientific areas identified below. Each TDC should be focused on a scientific area of need that can benefit from the development and application of NAMs. This program will develop a range of mature combinatorial NAMs, for a breadth of applications, from drugs, medical devices, diagnostics, and biologics, to chemical exposure and toxicology assessment tools.

NAMs should incorporate lifespan, population diversity (within the context of the disease/condition), sex as a biological variable, and other human variables as relevant models for the scientific area of focus. Applicants are strongly encouraged to leverage existing research resources for their studies whenever possible. Programs such as the All of Us Research Program can enable studies that are not feasible or easily done in other cohorts and can accelerate discoveries.

High priority scientific areas of focus for NAMs were identified through a number of strategic planning activities. These include the Advisory Committee to the Director (ACD) on catalyzing the development and use of Novel Alternative Methods to Advance Biomedical Research and their recommendations, feedback from the scientific community through the Complement-ARIE Challenge, NIH Common Fund strategic planning activities, and a NAMs landscape analysis, which have all informed the development of the Complement-ARIE program. 

High priority scientific needs identified include, but are not limited to:

• Chronicity (i.e. across the lifespan - characterizing long-term, systemic, and developmental health effects of environmental and drug exposures)​
• Neuroscience (e.g. neurodegenerative disease models, neuropsychiatry, ophthalmology, behavioral research)​
• Personalized Health (e.g. human-specific models to address the rapid growth in biological therapeutics, including monoclonal antibodies, human proteins, oligonucleotides, gene editing, and cell therapies, and incorporating population diversity and sex as a biological variable) ​
• Cross-disease Pathogenesis (e.g. developmental, metabolic, immune, reproductive health)​

Complement-ARIE NAMs Technology Development Center Application Structure

Each Complement-ARIE Comprehensive NAMs Technology Development Center application must include the following six Elements and the associated Modules:

• Element A: Center Overview 
• Element B: Strategic Management 
  • Module B1: Center Management 
  • Module B2: Consortium Liaison 
• Element C: Integrated NAMs Technology Development 
  • Module C1: Major NAMs Technology Development 
  • Module C2: Technology Pilot Projects 
• Element D: Center Core Facilities 
  • Module D1: Administration 
  • Module D2: Data Collection and Bioinformatics 
  • Module D3: ResourcesR#8239;
• Element E: Technical Characterization 
• Element F: Training & Outreach 
  • Module F1: Ethical, Legal and Social Implications (ELSI) 
  • Module F2: Workforce Development and Training 
  • Module F3: Community Engagement 

Element A: Center Overview

Each NAMs Technology Development Center will consist of a multi-disciplinary research team of investigators with complementary expertise in developing and using multiple NAMs platforms for pre-clinical and clinical applications. NAMs platform development should include combinations of in silico, in vitro, and in chemico approaches, while integrating at least two approaches to develop combinatorial NAMs. Each TDC will be composed of several core activities that address the many stages of NAMs technology development.

The Center Overview Element includes:

• The overall vision for the proposed TDC and the scientific area of focus. The vision should define the strategic goals and how these goals will be attained, incorporating unique strengths and activities that will facilitate the accomplishment of the goals.
• A description of the assembled team, including partners/collaborators.
• A description of the NAMs utilized and how the TDC scientific area of need can benefit from the development and application of combinatorial NAMs.
• A statement on how the applicant will incorporate population diversity, sex as a biological variable, and human variability into the TDC NAMs.
• A statement on limitations of the NAMs, and what models they would best complement.
• A dissemination plan for combinatorial NAMs.
• Goals for TDC training, outreach, and community engagement.
• Expected accomplishments, incorporating the scientific and public health impact.

Element B: Strategic Management

The goal of the TDCs is to stimulate the development of combinatorial NAMs to address areas of greatest need, with emphasis on increased biological complexity and throughput, innovative integrated approaches, and data sharing. The Strategic Management Element includes all activities related to the management of the TDC and its partners and collaborators to ensure the successful execution of the proposed TDC aims and milestones. The PD/PI is required to have a Strategic Management plan to administer:

• All activities within the TDC (Module B1: Center Management) and
• Its interactions within the Complement-ARIE Consortium, including the VQN and the NDHCC (Module B2: Consortium Liaisons). 

In addition, the PD/PI (the contact PI if a multi-PI application) must devote at least 2.4 person months (20%) of full-time calendar month effort to the program.

Module B1: Center Management 

Center management involves managing proposed activities in Elements C-F within the TDC. Although all activities outlined as Elements and Modules in the application structure must be included in the application, the structure and organization of each of these activities may vary among applicants. The Strategic Management Element must clearly outline how the application Elements and Modules will be organized and managed within the TDC. This should also include how the TDC will facilitate interactions among each Element or Element Module to achieve the TDC’s goals and milestones. Applicants should provide a graphic representation of the TDC structure and leadership plan that includes:

• Center governance and organizational structure to achieve the TDC’s goals and milestones,
• Conflict resolution procedures,
• Decision process for scientific direction and allocating funds and resources.

Each TDC must establish an external advisory committee with at least an annual meeting to review the TDC’s overall scientific progress, targeted activities in each TDC Element and provide recommendations on how to achieve the proposed TDC objectives and milestones. The expertise of the external advisory committee members needs to be broad and include those with a range of perspectives from academia, industry, non-profits, non-governmental organizations, and other interested parties. 

In addition, the Center Management plan must include:

• Governance and succession planning.
• Fiscal management and coordination of resources.
• A communication plan (within and outside of the TDC).
• Relationships of the applicant institution and all participating partners and collaborators in each TDC Element, including
  • what each partner/collaborator will contribute and any tangible commitments,
  • how each partner/collaborator will have input and participate in decision making, and
  • how the partners/collaborators will maintain ongoing communication, including with the TDC’s Consortium Liaisons.
  • The participation of any partner/collaborator must be strongly justified with a well described anticipated role.
• Integration of the leadership team of each Element or Element Module into the overall TDC structure and their anticipated roles and responsibilities.
• Ongoing planning, monitoring, reporting, and assessment of all that is necessary for the TDC to meet its goals and objectives.
• Implementation of recommendations from the advisory committee and/or the Complement-ARIE Consortium Steering Committee.
• Oversight of dedicated Consortium Liaisons to the VQN and the NDHCC (described below).
• Conflict resolution and alternative approaches which may be scientific or administrative
• Publication and intellectual property policies.
• Interaction with other TDCs in the Consortium to share best practices and promote interconnection and integration of NAMs technologies.

Module B2: Consortium Liaison

To ensure successful interaction with the Complement-ARIE Consortium, the TDCs must also develop a Strategic management plan to outline how the TDC will interact with the VQN and with the NDHCC. Dedicated liaisons in each TDC to the Complement-ARIE Consortium are required and need to be identified at the time of the application. Together with the PD/PI, they function as an interface between the TDC and the Complement-ARIE Consortium to keep seamless communications and collaboration. The PD/PI will be responsible to manage communication between the TDC and the Consortium Steering Committee. 

• VQN: The Validation and Qualification Network (VQN) will work with regulatory authorities, industry partners, and other collaborators to develop a framework to evaluate use cases from the technology development centers and the collaborator community to encourage adoption for regulatory, industrial, and biomedical research use. Therefore, the Liaison to the VQN includes the following responsibilities:
• Working with the TDC’s leadership team to prioritize the NAM for validation and qualification.
• Participating in VQN’s activities of establishing common data elements and standardized reporting, apply validation/qualification frameworks, accelerate deployment and regulatory implementation of NAMs.
• Coordinating the TDC technologies with the VQN for validation and qualification.
• Communicating the needs of TDC to VQN and back
• Implementing VQN’s guidelines in each TDC.
• Facilitate interactions with relevant regulatory agencies and members of the VQN to ensure that NAMs are being developed to meet agency requirements.
• Collaborating with Consortium Liaisons from other TDCs to share best practices and promote interconnection of NAMs technologies
• Keeping the TDC updated on relevant procedures and/or policies from the VQN
• Collaborating with the Training & Outreach Lead (Element F) to promote effective dissemination of the TDC’s technology 
• NDHCC: The NAMs Data Hub & Coordinating Center (NDHCC) will coordinate consortium activities while managing the data generated by the consortium. Therefore, the Liaison to NDHCC includes the following responsibilities:
• Working with the TDC’s leadership team to develop and adopt NDHCC’s standards and promote the use of interoperable, reliable, and well curated/high quality datasets produced from research using NAMs.
• Participating in NDHCC’s activities to create integrated data structures, including standards for model credibility, improve FAIRness (Findability, Accessibility, Interoperability, and Reusability) of NAMs-relevant data, create searchable NAMs repository.
• Communicating the needs of TDC to NDHCC and back.
• Coordinating with Consortium Liaisons from other TDCs to share best practices and promote interconnection of NAMs technologies.
• Keeping TDC updated on relevant procedures and/or policies from the NDHCC

Element C: Integrated NAMs Technology Development

The TDCs are expected to include two arms of NAMs technology development to include:

• Major NAMs Technology Development (Module C1)
• Technology Pilot Projects (Module C2)

Module C1: Major NAMs Technology Development 

The goal of this NOFO is to establish a network of TDCs to stimulate the development of combinatorial NAMs to support scientific areas of need, with emphasis on increased biological complexity and throughput, innovative combinatorial approaches, and data sharing according to FAIR principles. Each TDC should be focused on the development and application of combinatorial NAMs that can be applied and benefit a high-priority area of scientific need, across multiple CoUs. NIH anticipates considerable variety among the TDC scientific areas of focus.

The development and application of novel and combinatorial human-based NAMs are expected to support the scientific area of focus for each TDC. TDCs will require embedded technology development projects on individual NAMs, and combinatorial NAMs approaches. TDC areas of focus supported by this program must be relevant for multiple contexts of use and focus on at least two of the defined NAMs strategies (in vitro, in chemico, and in silico). More sophisticated NAMs will be achieved by catalyzing approaches that integrate and combine different methods for increased efficiency, improved performance, or the development of entirely new tools. As such, combinatorial strategies integrating in vitro, in chemico, and in silico strategies are required. The development of NAMs and combinatorial NAMs for specific applications are anticipated to be the major driving technologies within each TDC.

Each Center should address anticipated regulatory barriers for the anticipated NAMs technology, particularly for new classes of NAMs for which there are no precedents for use. Consistent with these goals, product development plans, and regulatory strategies should be included in the application.

Each Center will consist of a multi-disciplinary research team of investigators with complementary expertise in developing and using NAMs platforms. Experience in pre-clinical studies and qualification as DDTs or MDDTs, complex in-vitro models, bioinformatics (or mathematics), materials science, pharmacology/toxicology, and engineering are encouraged.

Population diversity, sex as a biological variable, and human variability must be incorporated into the NAMs developed and the TDC, as a whole. NAMs must be developed with sufficient diversity in the sample group to capture variability in the larger population. This could include (but is not limited to) diversity across age ranges, sex, genetics, ancestry, or economic strata. Population diversity should be factored into research design, validation, analyses, and reporting. Population diversity should be factored into statistical power analyses and considerations around algorithmic biases in data collection, analysis, and interpretation, as well as the cultural considerations and potential for stigmatization, need to be addressed.

TDCs will be expected to develop at least one mature combinatorial NAMs that can be transferred to the VQN for validation and/or qualification for defined use cases, by the end of the project period. A mature NAMs will have completed a robust technical characterization process within the TDC as described in Element E, which includes internal technology characterization processes that demonstrates the functionality, accuracy reliability, robustness, replicability, and human relevance of the NAMs technologies. The VQN will then evaluate mature combinatorial NAMs from the TDCs for further validation and/or qualification using readiness criteria. Combinatorial NAMs selected for validation and/or qualification under the VQN will then be transferred to the appropriate site for further validation studies. The NAMs developer (i.e. the submitting TDC) is expected to collaborate with the VQN for validation and/or qualification activities. 

Module C2: Technology Pilot projects 

The Technology Pilot Projects Module is intended to support rolling short-term activities of 1-2 years for new and innovative research pilot projects relevant to the TDC. Pilot projects must be focused on novel NAMs development and integration, i.e., projects that can be integrated readily into the center activities as described in the C1 module for implementation. Projects are intended to: (1) support the development of novel NAMs; (2) provide support to establish proof of concept for new or improved NAMs; (3) enhance the driving NAMs technology described in Module C1; and (4) provide support to optimize early stage NAMs for validation or integration toward combinatorial NAMs.

Pilot projects should be feasible and readily integrated into the major NAMs technology within the proposed timeframe, have high methodological and scientific quality, and support both the scientific priority of the TDC, and the primary NAMs developed under Module C1. Pilot projects should be well defined and will be peer reviewed as part of the UM1 application. Pilot projects are expected to have their own milestones and timelines. Applicants should describe how the pilot projects will support the TDC mission and explain how the pilot projects will be integrated into the major NAMs technology as part of Complement-ARIE efforts to develop combinatorial NAMs.

TDCs should propose a minimum of 3 pilot projects to be completed over the 5-year project period. Pilot awards may be internal or external to the TDC including outside the primary applicant’s institution. Pilot project support is not intended for large projects by established investigators that would otherwise be submitted as separate research grant applications.

Examples of activities that may be proposed:

• Development of new technologies/tools/resources that will advance the mission of the TDC and thus increase the efficiency and effectiveness of the primary integrated NAMs (such as adding a third NAM type).
• Early-stage development of NAMs technology with applications in the TDC’s scientific area of focus.
• Demonstration in a particular use case(s) that the new methodology or technology advances NAMs capabilities by successfully making one or more steps of the integration process more effective or efficient.

Both Modules within Element C should include:

• Plans to incorporate representative population and patient diversity for the specific CoU in the NAMs proposed.
• How the approaches taken will provide innovative solutions in support of overall TDC research objectives and present a range of opportunities – scientific, regulatory, and operationally.

Element D: Center Core Facilities

NIH anticipates that activities outlined in Element D will be organized into Center Core facilities to create organization and structure within each TDC, however there is flexibility as to how these cores can be organized. As such, each TDC must include the following activities: Administration, Data Collection and Bioinformatics, and Resources. Each activity is detailed below.

Module D1: Administration 

The Administrative Coordination Module is responsible for providing overall leadership for the Center’s activities, including management, coordination, and oversight. The Administrative Coordination Module should ensure the efficient planning, implementation, and timely completion of all activities and include day-to-day oversight of the center, with clear mechanisms for decision-making, particularly in situations where consensus cannot be achieved.

The awards funded under this NOFO will be cooperative agreements (see Section VI. 2. Cooperative Agreement Terms and Conditions of Award). Close interactions among the awardee recipients and NIH will be required to ensure successful execution of the projects, aims, and milestones proposed within each TDC. It is anticipated that the Administrative Coordination Module will lead these efforts and provide updates to NIH staff. Within this Module, applicants should describe the proposed administration component within the TDC, including the administrative leads.

Module D2: Data Collection and Bioinformatics 

The Data Collection and Bioinformatics module specifically supports the TDC’s goals of advancing combinatorial NAMs strategies to mimic complex human systems ex vivo. The Module will include data -related activities that are relevant to the TDC NAMs and overall goals. The Data Collection and Bioinformatics Module should encompass a range of expertise and capabilities in the areas of data science, bioinformatics and biostatistics, and information technology. Newly found knowledge, datasets and tools that can be disseminated to a variety of end users, including IND/IDE enabling studies, are some of the end-products of these integrated efforts.

Examples of activities that may be supported:

• Education and technology support for users of research informatics and open science (e.g., data management and sharing, tools, analytics, software, computing resources and other capabilities)
• Utilization of common data elements and standards that will enhance the ability to seamlessly share data
• Data management, storage, organization, representation and data sharing resources
• Data mining, visualization, and analytics tools and platforms
• Data processing methods such as data compression, data provenance, and data wrangling to prepare AI readiness
• Data curation and annotation tools, including common data elements, and ontologies
• Data integration and workflow tools and platforms
• Development of data standards, metadata, data exchange formats, data quality assurance methods, and data security and privacy management tools
• Performance evaluation of software tools, algorithms, in-silico models, and data collection methods
• Data preservation and access
• Informatics, computing, and data resources
• Statistical methods, graph and network theory approaches, and machine learning methods
• Natural language processing and text mining approaches
• Platforms for research collaboration and algorithm performance evaluation
• Environments for interactive modeling and simulation

The Data Collection and Bioinformatics core is expected to collaborate with the NDHCC. The NDHCC will create a central NAMs data hub for Complement-ARIE to support consortium activities as outlined in the Complement-ARIE Consortium Data Sharing section. The TDCs will be expected to submit data to the central Complement-ARIE data hub and follow the framework for standards, metadata and common data elements (CDEs) established by the NDHCC. The TDCs are ultimately responsible for ensuring the long-term sustainability of the data they generate through Complement-ARIE by identifying and depositing the data in an established public repository, in keeping with NIH Data Management and Sharing Policy.

Module D3: Resources 

TDC Resources may encompass a range of expertise and capabilities in areas including (but are not limited to) biospecimens, reagents, engineering tools, and computational technologies. Services may include (but are not limited to) support for research study design, human clinical trial protocol development, and regulatory compliance. The activities proposed in the Resources Module should be relevant to the TDC’s scientific area of focus and associated NAMs and should contribute to the overall goals of the TDC. Biospecimens, cell lines, engineered tools, codes that can be disseminated to a variety of interested parties are some of the end-products.

The Resources Module is intended to provide discrete resources or services that fill an otherwise unsupported need and is separate from support for NAMs technology development and technology pilot projects, which is detailed under Element C: Integrated NAMs Technology Development; Resource activities (e.g., biostatistical support, research design) associated with these projects should be requested within Element C, as appropriate.

Examples of activities that may be supported include:

• Biostatistics, epidemiology, and research design support
• Regulatory support (e.g., consultations for IND/IDE application submission or other regulatory matters)
• Pathology services
• Biorepository and biobanking
• Biospecimen collection, processing, analyses (including pathology services and -omics)
• Human specimen or NAMs collections/repositories
• Computer science

Element E: Technical Characterization

Please see the Key Terms, Definitions, and Uses in this NOFO section for a reference to the definition of Technical Characterization as it applies to this NOFO. To differentiate between these activities, a definition in the above-mentioned section has also been provided for the terms “technical characterization,” “validation,” and “qualification,” respectively.

A Technical Characterization component for each Center is required and must include internal technology characterization processes that demonstrates the functionality, accuracy, reliability, robustness, replicability, and human relevance of the NAMs technologies across projects within a Center. In this context, technical characterization is defined as utilizing standardized methodologies and predefined reference standards (e.g., test compounds) to determine functionality, reproducibility, robustness, and reliability in each NAMs. This Element will build confidence in the performance, reproducibility, and reliability of each NAMs technology and deliver potential use cases to the VQN for adoption and implementation in both research and regulatory contexts. The VQN will select use cases for further validation and qualification efforts and share data/methodology with the Complement-ARIE Consortium. This is a required center component.

Within technical characterization the following best practices should be considered:

• Evaluation of the protocol, equipment, and any computational models being used for endpoint prediction and/or in vitro to in vivo extrapolation.
• As outlined in OECD GD34, assess and describe the intra-laboratory reproducibility, applicability domain, associated assay controls and reference chemicals that are appropriate for the model and context of use, and limits of detection and quantification.
• When relevant, assess and describe the accuracy of the NAMs. Evaluation of accuracy through comparisons to data from the traditional animal test method should not be the default; however, where data from the traditional animal test method are available, it may be useful to determine performance benchmarks for the NAMs on the basis of the reproducibility of the animal test method.

NAMs need to be technically characterized and validated for their predictive capabilities including, but not limited to, safety pharmacology assessments that measure drug or chemical toxicity, biodistribution, and/or pharmacokinetics and pharmacodynamics; for disease modeling and efficacy studies, such as for clinical studies of rare diseases or pediatric patient populations, and other human conditions for which animal models do not exist or are difficult to generate; and in the use of precision medicine that will address issues of pharmacokinetic variability or difficulties with setting pharmacodynamic endpoints for specific patient populations. Rigorous NAMs technical characterization/validation will demonstrate to potential end users and regulatory agencies that the NAMs provides information of equivalent or better quality and relevance for regulatory decision making as compared, qualitatively or quantitatively, to the information that is provided by the traditional animal test method.

Technical characterization of in vitro NAMs should be performed according to OECD Guidance 2018 on Good In Vitro Method Practices (GIVIMP), as well as appropriate guidance on validation of alternatives to animal methods from the FDA.

Technical characterization of in chemico NAMs should be performed according to OECD Guidelines for the Testing of Chemicals (OECD TG).

Technical characterization of in silico/computation NAMs should be performed according to OECD GD 69 and the associated proposed QSAR Model Re-Porting Format, OECD, 2014.

TDCs will be expected to develop at least one mature combinatorial NAMs that can be transferred to the VQN for validation for a variety of specific context-of-use, by the end of the project period.  Mature NAMs will have completed a robust technical characterization before moving to validation. This should include the development of Standard Operating Procedures (SOPs) with sufficient detail to allow for a naïve, independent lab to generate comparable data using the method.

Validation studies for mature NAMs will be developed in collaboration with the VQN. While TDCs should address validation plans for mature NAMs at a high level within the application, TDCs will be expected to collaborate with the VQN to develop appropriate and specific validation studies. Validation efforts should align with recommendations set forth by the appropriate regulatory agency, for the intended CoU, whether that be the FDA, EPA, OECD, or other agencies. Existing animal-based data may be permitted as part of the validation studies for appropriate NAMs. As per the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) guidance on the validation, qualification, and regulatory acceptance of NAMs, validation studies should include the following 6 elements:

1. Context of Use
2. Biological relevance
3. Technical characterization
4. Data integrity
5. Information transparency
6. Independent review

Intellectual Property

NAMs Developers will retain title to any patent or other intellectual property rights in inventions made in the course of the performance of the Complement-ARIE Program. If NAMs Developers in conjunction with VQN investigators make modifications of the NAMs platforms as a use case that significantly change performance and/or functionality, both parties are expected to discuss ownership interests where applicable and consistent with Licensing of US Government Owned Inventions regulations as specified in 37 CFR 404, and to negotiate in good faith the terms of a commercial license. Inventorship for a patent application or a commercialized product based on said inventions will be determined according to United States patent law.

Element F: Training and Outreach

The Training and Outreach Element of each TDC is intended to promote advances in NAMs development and deployment. A training and outreach Element is a required TDC component with a goal to facilitate development, dissemination, capacity building, deployment, and adoption of NAMs. TDCs should establish procedures to obtain feedback from participants to assess the effectiveness of the training and outreach activities. When possible and reasonable, it will maintain records of training and outreach initiatives for further dissemination. The Training & Outreach Element includes three modules: ethical, legal and social implications (ELSI), workforce development and training, and community engagement.

The activities proposed in the Training and Outreach Element should be relevant to the TDC’s scientific area of focus and associated NAMs and contribute to the overall goals of the TDC. Additional limited competition funding opportunities are anticipated to further support Consortium-wide ELSI, workforce development and training, and community engagement for selected TDCs.

Module F1: Ethical, legal and social implications (ELSI) 

Applicants should describe the ethical, legal and social implications associated with the NAMs they propose to develop and outline the key elements the Center proposes to address within an Ethical, Legal, and Social Impact Statement. The Statement should include plans for the activities and an approach to address concerns about how the NAMs will be used, and how individuals and society will be protected from potential harm. Possible elements of an Ethical, Legal, and Social Impact Statement could include, but are not limited to:

• Contributions to policy recommendations and guidelines to ensure that NAMs are introduced and implemented appropriately.
• Research to maximize responsible deployment, promote equity, and provide “return of value” to research participants and communities.
• Activities that foster equitable development and use of NAMs for research and public benefit.
• Efforts to define and help achieve equity in NAMs for individuals, groups, communities, or populations.
• Activities that address the use and direction of NAMs by a broad range of entities whose missions may vary.
• Responsible use/deployment of artificial intelligence and intellectual property considerations.
• Privacy and data sharing.

Module F2: Workforce Development and Training 

Biomedical research and the resulting scientific knowledge are increasingly complex and multidisciplinary in nature. Advances depend upon a workforce composed of individuals trained in multiple disciplines and from a range of backgrounds who can provide the breadth of creativity, and individual interests, perspectives and experiences needed to identify and address important and complex scientific problems, engage with increasingly diverse patient populations, and effectively serve as mentors to trainees who are pursuing biomedical research careers. Complement-ARIE aims to develop and/or enhance research training opportunities for individuals interested in the development and application of NAMs. Training and education activities are required within each Center to facilitate the development, dissemination, capacity building, deployment, and adoption of NAMs. Possible activities could include, but are not limited to:

• Training programs that will disseminate the developed NAMs and enhance their use and utility, through various training tools (i.e., on-site user hands-on training for the technologies and digital media training documentation on principles, elements, and step-by-step operations of the NAMs).
• The development of NAMs-focused educational modules (e.g., seminars, workshops, e-learning courses, practical experience).
• Plans to prioritize training opportunities to early career scholars.
• Plans to bolster training opportunities within the workforce populations, including junior and early-career researchers from diverse scientific backgrounds, geographic locations, and different types of institutions and organizations (e.g., undergraduate-focused; 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); emerging research institutions).
• Cross-training opportunities that could include training across scientific disciplines, animal to human approaches, and technologies, including across sectors and NAMs approaches (in vitro, in chemico, and/or in silico), and across the lifecycle of development and use of NAMs.
• Training strategies for reliable NAMs technology development and deployment.

Consistent with existing NIH practices and applicable law: (1) Funded programs may not use the race, ethnicity, or sex (including gender identity, sexual orientation, or transgender status) of a researcher, trainee, faculty candidate, or other program participants as an eligibility or selection criterion, and (2) NIH does not use the race, ethnicity, or sex of researchers, trainees, faculty, or other program participants in the application review process or funding decisions.  Applicants and award recipients are encouraged to consult with their General Counsel to ensure all applicable laws and regulations are being followed in program design and implementation.

Module F3: Community Engagement

There are a variety of communities and interested parties, including NAMs developers, academic, industry, and contract research organizations, regulators, individuals and/or organizations representing community members or advocacy groups; health care providers and health care systems; research participants; and patients, whose knowledge, perspectives and experiences can inform and improve the field of NAMs. NAMs developers must have a deep understanding of the end user and what they need, whether it be a physician, a patient, a researcher, or a pharmaceutical developer. This Module should promote an awareness and understanding of NAMs across a spectrum of possible audiences (such as patient advocacy groups and/or non-profits) as they align with project milestones, along with the evaluation of prioritized outreach goals.

Possible activities could include, but are not limited to:

• Create collaborations for researchers and clinicians to incorporate patient perspectives in NAMs development.
• Partnering research initiatives with public engagement to incorporate social norms and promote awareness of emerging technologies.
• Developing publicly available educational course modules and workshops covering the lifecycle of NAMs, from conceptualization to dissemination and use.
• Establishing and maintaining partnerships with patient advocacy groups to ensure the NAMs and associated data are grounded in patients' real-world needs and experiences.
• Addressing any concerns or misinformation making NAMs more accessible to everyone.
• Building community engagement so that there is strong support for dissemination and implementation.

Milestones and Timeline

All projects will be milestone-driven with clear go/no-go criteria that are quantifiable. Provide a timeline in the form of a Gantt chart and the set of milestones that quantitatively measures progress towards each of the proposed specific aims.

Milestones are deliverables with quantifiable success metrics for each specific aim of the project and include, at the minimum, annual and/or intermediate quantitative criteria with key success metrics specifically defined. Each Complement-ARIE award is expected to have yearly milestones for the overall and for each individual component over the course of the five-year award indicating validation of at least one NAMS platform, and engagement with the Complement-ARIE VQN and NDHCC.

Specific to applications involving clinical trials, a detailed description of the study timeline must be provided as well as contingency plans should there be delays in attaining the trial’s milestones.

Prior to funding an application, the Program Official will contact the applicant to discuss the proposed milestones and, where appropriate, study timeline, any changes recommended by peer review and additional feedback from NIH staff. The Program Official and the applicant will negotiate and agree on a final set of milestones, the final approved milestones will be specified in the Notice of Award.

Achievement of the current year milestones as indicated in the annual report will be the basis for evaluating satisfactory progress and release of funds for the following award year. Failure to meet one or more of the milestones must be justified. If justified, future year milestones may be revised based on data and information obtained during the previous year. Based on the progress report, if the project does not demonstrate satisfactory progress, funding for the project may be discontinued or restricted.

Data Sharing within the Complement-ARIE Consortium

Complement-ARIE NAMs Technology Development Centers and their partners are expected to adhere to a culture of Open Science and Data Sharing that promote the F.A.I.R. principles (see: NIH Strategic Plan for Data Science) and abide by the NIH Data Management and Sharing Policy. 

In addition, all funded projects under this NOFO are required to actively coordinate, collaborate, and share data with the NDHCC and the VQN during the project period. To the extent possible, data acquisition, collection, organization, representation, curation and data deposition strategies will be coordinated by the NDHCC. Award recipients will be required to develop a data deposition pipeline and submit data to the NDHCC according to Consortium guidelines. The VQN will provide guidance on standardization and common data elements, annotation and benchmarking of data, consent for data sharing, and implementation of the schemas proposed. The DTCs are ultimately responsible for ensuring the long-term sustainability of the data they generate through Complement-ARIE by identifying and depositing the data in an established public repository, in keeping with NIH Data Management and Sharing Policy.

Responsiveness

In order to be responsive to this NOFO, applicants must:

• Include development of combinatorial NAMs using two or more different NAM’s approaches (in vitro, in chemico, in silico).
• Include milestones and a timeline for project completion.
• Consider human variability and diversity in their projects, cores, and training programs.

Applications will be considered non-responsive and will not be reviewed if:

• Any Element or Module described in the application structure is missing.
• PD/PI (the contact PI if a multi-PI application) does not devote at least 2.4 person months (20%) of full-time calendar month effort to the program.
• New animal-based NAMs, NAMs developed with animal cells, animal-based research, or in vivo animal studies are proposed within the application.

Pre-application consultation with NIH Program staff is encouraged. Budget justifications should be broken down by Element and Module.

Plan for Enhancing Diverse Perspectives (PEDP)

The NIH recognizes that teams comprised of investigators with diverse perspectives working together and capitalizing on innovative ideas and distinct viewpoints outperform homogeneous teams. There are many benefits that flow from a scientific workforce rich with diverse perspectives, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH encourages inclusivity in research guided by the consideration of diverse perspectives. Broadly, diverse perspectives can include but are not limited to the educational background and scientific expertise of the people who perform the research; the populations who participate as human subjects in research studies; and the places where research is done.

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation.  Assessment of applications containing a PEDP are based on the scientific and technical merit of the proposed project. Consistent with federal law, the race, ethnicity, or sex (including gender identity, sexual orientation, or transgender status) of a researcher, award participant, or trainee will not be considered during the application review process or when making funding decisions.  Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

The PEDP will be submitted as Other Project Information as an attachment (see Section IV).  Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP Guidance materials.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

All organizations administering an eligible parent award may apply for a supplement under this NOFO.

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

• Eligible Agencies of the Federal Government, including the NIH, FDA, and EPA intramural programs
• U.S. Territory or Possession

Other

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

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

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information. 

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including individuals from underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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

The PD/PI (the contact PI if a multi-PI application) must devote at least 2.4 person months (20%) of full-time calendar month effort to the program.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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:

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

The letter of intent should be sent to:

Danilo A. Tagle, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Email: [email protected]

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed,with the following exceptions or additional requirements:

Specific Aims. Briefly summarize the aims for the entire application, including all Elements and Modules. 1 page

Research Strategy. The Research Strategy must consist of the following sections with the indicated page limits:

• Element A. Overview; one required, 5 pages
• Element B. Strategic Management; one required, 3 pages
• Element C. Integrated NAM Technology Development; one required, 10 pages
• Element D. Center Core Facilities; one required, 10 pages
• Element E. Technical Characterization; one required, 6 pages
• Element F. Training & Outreach; one required, 5 pages

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

Other Attachments: 

Milestone Plan: The filename "Milestone Plan.pdf" should be used.

The applicant is required to provide detailed information and timelines for completing all proposed activities according to the specific aims. Applicants must include specific yearly milestones that will need to be met in order to accomplish the work set out in a five-year period. Milestones that reflect progress in each specific aim should be easily measurable and realistic. Project milestones that quantitatively measures progress towards each of the proposed specific aims are required. A timeline to achieve the proposed milestones, in the form of a Gantt chart, is also required.

Plan for Enhancing Diverse Perspectives (PEDP)

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of actionable strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity. 
• Applicants should align their proposed strategies for PEDP with the research strategy section, providing a holistic and integrated view of how enhancing diverse perspectives and inclusivity are buoyed throughout the application.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• The PEDP may be no more than 2 pages in length and should include:
  • Actionable strategies using defined approaches for the inclusion of diverse perspectives in the project;
  • Description of how the PEDP will advance the scientific and technical merit of the proposed project;
  • Anticipated timeline of proposed PEDP activities;
  • Evaluation methods for assessing the progress and success of PEDP activities.

Examples of items that advance inclusivity in research and may be appropriate for a PEDP can include, but are not limited to:

• Partnerships with different types of institutions and organizations (e.g., research-intensive; undergraduate-focused; HBCUs; emerging research institutions; community-based organizations).
• Project frameworks that enable communities and researchers to work collaboratively as equal partners in all phases of the research process.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as human subjects in clinical trials, including those from underrepresented backgrounds.
• Description of planned partnerships that may enhance geographic and regional diversity.
• Outreach and recruiting activities intended to diversify the pool of applicants for research training programs, such as outreach to prospective applicants from groups underrepresented in the biomedical sciences, for example, individuals from underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Plans to utilize the project infrastructure (i.e., research and structure) to enhance the research environment and support career-advancing opportunities for junior, early- and mid-career researchers.
• Transdisciplinary research projects and collaborations among researchers from fields beyond the biological sciences, such as physics, engineering, mathematics, computational biology, computer and data sciences, as well as bioethics.

Examples of items that are not appropriate in a PEDP include, but are not limited to:

• Selection or hiring of personnel for a research team based on their race, ethnicity, or sex (including gender identity, sexual orientation, or transgender status).
• A training or mentorship program limited to certain researchers based on their race, ethnicity, or sex (including gender identity, sexual orientation, or transgender status).

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see PEDP Guidance materials.

All instructions in the How to Apply - Application Guide must be followed.

R&R Budget

All instructions in the How to Apply - Application Guide must be followed.

A single budget is required; include funds requested, as per notes below. Budget justifications must be broken out by Element and Module. Subaward budgets should follow the same format.

Applicants are reminded that although Cost Share is not required; if these types of costs are included in the research application and peer reviewed, it is expected that these costs will not be covered by NIH.

Element A: Overview

Do not include a budget request for this element.

Element B: Strategic Management

Include funds for personnel, administration, and other expenses, as appropriate. Because administrative structures will differ, carefully explain and justify requested support.

Notes:

• PD/PI (the contact PI if a multi-PI application) must devote at least 2.4 person months (20%) of full-time calendar month effort to the program.
• There will be two annual in-person Complement-ARIE Consortium meetings in the Washington, DC area, or relevant scientific conference as designated by NIH. The contact PD/PIs must include travel to attend such meetings in their budgets.

Element C: Integrated NAMs Technology Development

Include funds for personnel, research, and other expenses, as appropriate.

Element D: Center Core Facilities

For each of the Modules in this Element, include support for Module Leaders, Co-Leaders, personnel and other expenses, as appropriate.

Element E: Technical Characterization

Include funds for personnel, research, and other expenses, as appropriate.

Element F: Training & Outreach

Include funds for personnel, research, and other expenses, as appropriate.

PEDP implementation costs:

Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7): https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm.

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Specific Aims and Research Strategy apply to the entire TDC Center application.

All projects will be milestone-driven with clear go/no-go criteria that are quantifiable. Project milestones that quantitatively measure progress towards each of the proposed specific aims are required. A timeline to achieve the proposed milestones, in the form of a Gantt chart, is also required. The milestone plan should be submitted as a separate attachment.

Although all activities outlined as Elements and Modules in the application structure must be included in the application, the structure and organization of each of these activities may vary among applicants.

Element A: Overview

The Center Overview Element includes:

• The overall vision for the proposed TDC and the scientific area of focus. The vision should define the strategic goals and how these goals will be attained, incorporating unique strengths and activities that will facilitate the accomplishment of the goals and overall alignment with Complement-ARIE program objectives.
• A description of the assembled team, including partners and collaborators.
• A description of the combinatorial NAMs utilized and how the TDC scientific area of need can benefit from the development and application of combinatorial NAMs.
• A statement on how the applicant will incorporate population diversity and human variability into the TDC NAMs.
• A dissemination plan for combinatorial NAMs. Applicant should describe how the proposed NAMs, research protocols, and results will be disseminated and made accessible to the broader research community.
• Goals for TDC training, outreach, and community engagement.
• Expected accomplishments, incorporating the scientific and public health impact.

This Element should describe and justify a strategic vision to innovate combinatorial NAMs and further the Complement-ARIE program goals.

Element B: Strategic Management

The Strategic Management Element includes all activities related to the management of the TDC and its partners and collaborators to ensure the successful execution of the proposed TDC aims and milestones. These complex, multi-component centers will require dedicated expertise and multi-disciplinary teams.

The applicant is required to have a Strategic Management plan to manage:

• All activities within the TDC (Module B1: Center Management) and
• Its interactions within the Complement-ARIE Consortium, including the Steering Committee, the Validation and Qualification Network (VQN) and with the NAMs Data Hub and Coordinating Center (NDHCC) (Module B2: Consortium Liaisons). 

The Strategic Management Element must clearly outline how application Elements C-F will be organized and managed within the TDC. Applicants should provide an organizational chart of the TDC structure and a leadership plan that includes:

• Team governance and organizational structure, including how there will be coordination, interrelationships, cohesiveness, and synergy among the Elements
• Conflict resolution procedures
• Decision process for scientific direction and allocating funds and resources

Contributions of each partner and collaborator should be well justified and integrated into the TDC structure. Applicants should describe how the TDC will commit to a culture of open science and to sharing and implementing resources across the Complement-ARIE consortium and the biomedical research community.

Element C: Integrated NAMs Technology Development

The TDCs are expected to include two arms of NAMs technology development to include:

• Major NAMs Technology Development (Module C1)
• Technology Pilot Projects (Module C2)

Population diversity, sex as a biological variable, and human variability must be incorporated into the NAMs developed and the TDC, as a whole. NAMs must be developed with sufficient diversity in the sample group to capture variability in the larger population. This could include (but is not limited to) diversity across age ranges, sex, genetics, ancestry, or economic strata. Population diversity should be factored into research design, validation, analyses, and reporting. Population diversity should be factored into statistical power analyses and considerations around algorithmic biases in data collection, analysis, and interpretation, as well as the cultural considerations and potential for stigmatization, need to be addressed.

Module C1: The development of NAMs and combinatorial NAMs for specific applications are anticipated to be the major driving technologies within each TDC. The TDC area of focus supported by this program must be relevant for multiple CoUs and focus on at least two of the defined NAMs strategies (in vitro, in chemico, and/or in silico). Combinatorial strategies integrating in vitro, in chemico, and in silico strategies are required. More sophisticated NAMs will be achieved by catalyzing approaches that integrate and combine different methods for increased efficiency, improved performance, or the development of entirely new tools. TDCs will be expected to develop at least one mature combinatorial NAMs that can be transferred to the VQN for validation or qualification within a specific context-of-use, by the end of the project period. Applicant should include how the proposed NAMs open new ways towards regulatory acceptance and broad use.

Population diversity and human variability must be incorporated into the NAMs developed and the TDC, as a whole. NAMs must be developed with sufficient diversity in the sample group to capture variability in the larger population. This could include (but is not limited to) diversity across age ranges, sex, genetics, ancestry, or economic strata. Population diversity should be factored into research design, validation, analyses, and reporting.

Module C2: Pilot projects should be completed in approximately 1-2 years. Projects must be feasible within the proposed timeframe, have high methodological and scientific quality, and support both the scientific priority of the TDC, and the primary NAMs developed under Module C1. Pilot projects are expected to have their own milestones and timelines. Applicants should describe how the pilot projects will support the TDC mission and explain how the pilot projects will be integrated into the major driving NAMs as part of Complement-ARIE efforts to develop combinatorial NAMs. Pilot projects are required and TDCs must propose a minimum of 3 pilot projects to be completed over the 5-year project period. Pilot awards may be internal or external to the TDC including outside the primary applicant’s institution and should be responsive to emerging scientific opportunities and technological innovations.

Both Modules within this Element should include:

• Plans to incorporate representative populations and patient diversity for specific CoU in the NAMs proposed. This plan should not duplicate the Plan for the Inclusion of Women and Minorities and the Plan for Inclusion of Individuals Across the Lifespan provided in the PHS Human Subjects and Clinical Trials Information Form.
• How the approaches taken will provide innovative solutions in support of overall TDC research objectives and present a range of opportunities – scientific, regulatory, and operationally.

Animal studies and/or the generation of animal-based data is not permitted as part of activities proposed under Element C.

Element D: Center Core Facilities

Each TDC must include the following activities: Administration, Data Collection and Bioinformatics, and Resources. For each activity (Module), applicants should describe the proposed organizational structure within the TDC, and identify project leads and key personnel for each Module within Element D. Proposed resources should address important needs or critical barriers for NAMs developers and other research teams, including planning, conduct, analysis, and dissemination of NAMs. Explain how the scientific expertise of the project leads and key personnel will facilitate the project goals.

Module D1: The Administrative Coordination Module should ensure the efficient planning, implementation, and timely completion of all activities, including coordination of ongoing activities, and day-to-day oversight of the center with clear mechanisms for decision-making, particularly in situations where consensus cannot be achieved.

Module D2: The TDC Data Collection and Bioinformatics core is expected to collaborate with the NDHCC. The TDCs will be required to submit data to the central Complement-ARIE data hub and follow the framework for standards, metadata and common data elements (CDEs) established by the NDHCC in a timely manner. Applicants should develop a data deposition pipeline and address plans for data submission to the NDHCC within the application.

Module D3: TDC Resources may include (but are not limited to) biospecimens, reagents, engineering tools, and computational technologies. Services may include (but are not limited to) support for research study design, human clinical trial protocol development, and regulatory compliance. The application should clearly outline the activities included in this Module. The activities proposed in the Resources Module should be relevant to the TDC’s scientific area of focus and associated NAMs and should contribute to the overall goals of the TDC.

Element E: Technical Characterization

A Technical Characterization component for each Center is required and must include internal technology characterization processes that demonstrates the functionality, accuracy reliability, robustness, replicability, and human relevance of the NAMs technologies across projects within a Center. Within technical characterization, best practices should be considered:

• Evaluation of the protocol, equipment, and any computational models being used for endpoint prediction and/or in vitro to in vivo extrapolation.
• As outlined in OECD GD34, assess and describe the intra-laboratory reproducibility, applicability domain, associated assay controls and reference chemicals that are appropriate for the model and context of use, and limits of detection and quantification.
• When relevant, assess and describe the accuracy of the NAMs. Evaluation of accuracy through comparisons to data from the traditional animal test method should not be the default; however, where data from the traditional animal test method are available, it may be useful to determine performance benchmarks for the NAMs on the basis of the reproducibility of the animal test method.

Technical characterization of in vitro NAMs should be performed according to OECD Guidance 2018 on Good In Vitro Method Practices (GIVIMP), as well as appropriate guidance on validation of alternatives to animal methods from the FDA.

Technical characterization of in chemico NAMs should be performed according to OECD Guidelines for the Testing of Chemicals (OECD TG).

Technical characterization of in silico/computation NAMs should be performed according to OECD GD 69 and the associated proposed QSAR Model Re-Porting Format, OECD, 2014.

TDCs will be expected to develop at least one mature combinatorial NAMs that can be transferred to the VQN for validation for a variety of specific CoU, by the end of the project period.  Mature NAMs will have completed a robust technical characterization before moving to validation. This should include the development of SOPs with sufficient detail to allow for a naïve, independent lab to generate comparable data using the method.

Validation studies for mature NAMs will be developed in collaboration with the VQN. While TDCs should address validation plans for mature NAMs at a high level within the application, TDCs will be expected to collaborate with the VQN to develop appropriate and specific validation studies. Validation efforts should align with recommendations set forth by the appropriate regulatory agency, for the intended CoU.

Animal data is only permitted within Element E as part of validation studies to benchmark newly developed NAMs (i.e. demonstrating equal or superior performance to existing animal models) and only existing animal data may be used for validation purposes. No new animal-based research or data may be proposed as part of the application.

Element F: Training & Outreach

A Training and Outreach Element is a required TDC component with a goal to facilitate development, dissemination, capacity building, deployment, and adoption of NAMs. The Training & Outreach Element includes three Modules, ethical, legal and social implications (ELSI), workforce development and training, and community and stakeholder engagement. Activities within each Module should be relevant to the major NAMs and the scientific area of interest of the TDC. Activities that address important needs or critical barriers for NAMs and dissemination are encouraged.

Module F1: Applicants should describe the ethical, legal and social implications associated with the NAMs they propose to develop and outline the key elements the TDC proposes to address within an Ethical, Legal, and Social Impact Statement. The Statement should include plans for the activities and an approach to address concerns about how the NAMs will be used, and how individuals and society will be protected from potential harm.

Module F2: Training and education activities are required within each Center to facilitate the development, dissemination, capacity building, deployment, and adoption of NAMs. Applicants should describe planned workforce development and training activities within the TDC and outline the capabilities, expertise, and unique resources within the TDC that will ensure the successful execution of the workforce development and training plan. Applicants should also outline how the proposed workforce development and training efforts impact both the project, and the development, dissemination, capacity building, deployment, and adoption of the TDC’s major NAMs. 

Module F3: There are a variety of communities and interested parties whose knowledge, perspectives and experiences can inform and improve the field of NAMs. This Module should promote an awareness and understanding of NAMs across a spectrum of possible audiences. Applicants should outline community engagement efforts, potential partners or collaborators, and the projected impact to the field with respect to the dissemination of the major NAMs and the scientific area of interest of the TDC.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide. 

Other Plan(s):

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
• All project resources, tools, and methods developed from the project are expected to be made broadly available (e.g., putting into the public domain) or made accessible to the research community according to the NIH-approved data management and sharing plan submitted for each project. Applicants are expected to outline plans to make any project resources, tools, and methods developed broadly available. 

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

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 How to Apply - 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 How to Apply - Application Guide must be followed.

Delayed Onset Study

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 How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

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

See Part 2. 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. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply - 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 form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide.

See more tips for avoiding common errors.

Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by Office of Strategic Coordination (OSC), NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will 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 or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this NOFO. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above and, in the NIH, Intramural Source Book.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected]. 

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

Section V. Application Review Information

1. Criteria

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

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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). As part of the overall impact score, reviewers should consider and indicate how the Plan for Enhancing Diverse Perspectives affects the scientific merit of the project.

.

Scored Review Criteria

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

Significance

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

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific to this NOFO:

To what extent will the proposed TDC contribute to the overall Complement-ARIE program goals, i.e. will the TDC be able to develop, demonstrate and quickly disseminate advances in combinatorial NAMs that will lead to validation and qualification? To what extent is the plan for dissemination and the proposed impact statement appropriate for the stated TDC activities? Will there be coordination, interrelationships, cohesiveness, and synergy among the Elements as they relate to the stated research focus of the TDC? How will the governance, collaboration, communication, and succession planning result in successful management of the proposed TDC?

To what extent do the proposed resources, elements, and training/outreach activities address important needs or critical barriers for NAMs developers and other research teams, including planning, conduct, analysis, and dissemination, and will they enable investigators to achieve their research goals? To what extent have the applicants articulated plans to lay the foundation of high-quality research by creating and maintaining a skillful and multidisciplinarytranslational workforce? To what extent does the TDC support a commitment to a culture of open science and to sharing and implementing resources across the Complement-ARIE Consortium and the biomedical research community? To what extent will the project(s) proposed be able to address a truly significant roadblock in NAMs development and dissemination, that if successful would have generalizable application?

Investigator(s)

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

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Specific to this NOFO:

To what degree do the applicant and any partner(s) and/or collaborator(s) have a strong record of NAMs research and development with high impact achievements in useful methods and procedures leading to improved diagnoses, treatments, and strategies for model development? Have the contributions of each partner and collaborator been well justified and integrated into the UM1 structure?

Are the qualifications, experience, and commitment of the Module and Project Leaders/Co-Leaders, management committees, and other personnel appropriate and sufficient? To what extent are the roles of partners well described and is their participation justified? To what extent do the staff have sufficient breadth and depth of technical and/or scientific knowledge to cover a wide range of NAMs research activities and address the various educational and training needs of investigators or teams?

Innovation

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

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Specific to this NOFO:

To what extent does the UM1 application clearly describe and justify a strategic vision to innovate NAMs and further Complement-ARIE goals; to what extent do applicants provide a plan to measure these innovations and progress towards the goals? How compelling is the transformative potential of the proposed NAM(s)? To what degree will the proposed combinatorial NAM(s) innovate human-relevant basic, translational, or clinical sciences?  What is the potential of the proposed NAM(s) to open new ways towards regulatory acceptance and broad use? To what degree do the plans include not only developing innovations but also using those made by others to demonstrate utility and to ultimately disseminate successful solutions?

To what extent are innovative methods evident, such as experimental approaches to identify best practices in translational research; workforce education and training; and stakeholder outreach? To what extent does the TDC encourage continued innovation towards an integrated and combinatorial NAMs through the proposed Pilot Module? To what extent do the applicants propose innovative solutions in support of the TDC proposed research activities? To what extent does the Elements C1 and C2 project(s) utilize innovative approaches to accomplish the stated aims?

Approach

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

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 or 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?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, sex, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex or gender and race or ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this NOFO:

Are the proposed administrative organization and management plans appropriate and adequate for the following: (a) effective day-to-day management of the TDC; (b) coordination of ongoing research activities, including mechanisms for internal monitoring; (c) establishment and maintenance of internal communication and cooperation amongst the TDC investigators; (d) mechanisms for selecting and replacing staff; and (e) responses to emerging scientific opportunities and technological innovations? How do the Milestones and Timeline developed for the overall and individual components provide a framework for the successful completion of the proposed aims? What is the likelihood that the yearly Milestones and Timelines will be met to accomplish the work set out above in a five-year time frame?

To what extent do the plans describe a range of opportunities (e.g., scientific, regulatory, and operational) for the proposed TDC activities? To what extent is the application focused on human-based NAMs development, as well as combinatorial NAM development?  Is there adequate consideration to NAMs incorporating lifespan, population diversity, sex as a biological variable, and other human variables for generalizability of the NAMs as relevant models for the diseases studied? To what extent have the applicants set forth an appropriate plan to establish a TDC Liaison towards robust interactions with other Complement-ARIE consortium members, including NHDCC and VQN? To what extent has the applicant described a comprehensive plan for internal TDC evaluation and for continuous operational and scientific improvement? To what degree will the proposed NAMs, research protocols, and results be accessible to the broader research community?

To what extent have the applicants developed plans for patient or patient advocacy engagement and partnership, professional development, outreach, and training? To what extent are the plans to support the pilot projects well integrated into the activities of the main technology driver in the UM1? Is there adequate assurance that the activities are not duplicative? 

Environment

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

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Specific to this NOFO:

Is there evidence that the environment is conducive to operating a Center of the complexity and scope of the program? How will the TDC demonstrate its commitment to participating in the larger Complement-ARIE Consortium, including capabilities to engage with NHDCC and VQN members?

How will this TDC benefit from unique institutional strengths such as human capital and infrastructure in the support of Complement-ARIE goals in advancing research and education in NAMs? To what extent does various activities across the TDC integrates well with overall TDC aims; how might this integrated structure assist in establishing NAMs feasibility and lead to widespread adoption and use of NAMs in an efficient and ethical manner?

Additional Review Criteria

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.

Study Timeline

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

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 or 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 three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals 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.

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 Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review, in accordance with NIH peer review policies and practices, 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 NOFO.

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

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

Please note that reviewers will not consider race, ethnicity, age, or gender (including gender identity, sexual orientation or transgender status) of the researcher, award participant, or trainee, even in part, in providing critiques, scores, or funding recommendations. NIH will not consider such factors in making its funding decisions.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website. 
  • HHS recognizes that NIH 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 NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations. NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

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 (HHS) grant administration regulations at 2 CFR Part 200, 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 recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

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

• Negotiate and agree on a final set of milestones, the final negotiated and approved milestones will be specified in the Notice of Award.
• Participating in regular (monthly) conference calls with the NIH Program Official.
• Accepting and fully participating in the cooperative nature of the Complement-ARIE Consortium, including participation in the semi-annual consortium meetings organized by NIH and NDHCC.
• Coordinating efforts with other recipients, especially in circumstances where synergy of efforts and resources is beneficial to the overall goals of the Complement-ARIE program.
• Adhere to the NIH policies regarding intellectual property, data release and other policies that might be established during the course of this activity.
• Working with, cooperatively interacting with, and actively seeking input from NIH.
• Identifying and maintaining infrastructure and collaborations needed to support the development of the proposed NAMs.
• Working with the NIH, FDA, EPA, and industry partners, when appropriate, to establish context of use, validation and qualification of NAM technologies.
• Sharing data, materials, informatics tools, methods, information and unique resources that are generated by the project, as appropriate, and in accordance with NIH policies to facilitate progress and consistent with achieving the goals of Complement-ARIE.
• Sharing data and NAMs technology with the broader scientific community. Data should be submitted to an appropriate public data repository.
• Ensuring that for activities that involve academic and/or industry collaborations within and outside the Complement-ARIE Consortium there are appropriate research collaboration agreements (e.g., CRA, CDA, MTA etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement terms of award as well as any additional applicable NIH policies and procedures.
• In-Kind contributions or Cost share is not a requirement for this program; however, if cost share is proposed, peer reviewed, and accepted by NIH, it will become a Special Award Condition in the NoA. Third Party involvement or support involving the proposed research activity must be reviewed and concurred by NIH staff and/or their designee(s). If the support involves financial or material aid necessary for the completion of the project, and the support is no longer available and/or is not replaceable in a timely fashion and it will negatively impact the success or progress of the study, then NIH staff may negotiate phasing out the award.
• Coordinate data collection and data submission activities with the New Approach Methodologies (NAMs) Data Hub and Coordinating Center.
• Working with the VQN to establish agreements that address the following issues: (1) adherence to NIH and Complement-ARIE Consortium data sharing policies as approved by Program staff prior to award. This includes data sharing with Complement-ARIE consortium members, as appropriate; (2) procedures for safeguarding confidential information, including without limitation, any data generated by the Complement-ARIE consortium as well as information and/or data received from external collaborators; (3) procedures for addressing ownership of intellectual property that result from aggregate multi-party data; (4) procedures for reviewing publications, determining authorship, and industry access to publications.
• Upon completion or termination of the project, ensure all project resources, tools, and methods 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 data management and sharing plan submitted for each project.
• Provide updates at least annually on progress in PEDP implementation.

Publications

The contact Program Director/Principal Investigator (PD/PI) 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. The PD/PI and Project Leaders are requested to submit manuscripts to the NIH Program Official within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained. Publications and oral presentations of work conducted under the Cooperative Agreement are the responsibility of the Principal Investigator and will require appropriate acknowledgement of NIH support. Timely publication of major findings is encouraged.

Intellectual Property

The successful development of NAMs and the integration of these microsystems may require either substantial investment and support by private sector industries, and/or may involve collaborations with other organizations such as academic, other government agencies, and/or non-profit research institutions not directly involved in the Complement-ARIE program. NIH recognizes that intellectual property rights are likely to play an important role in achieving the goals of this program.

To this end, all award recipients shall understand and acknowledge the following:

• The award recipient is solely responsible for the timely acquisition of all appropriate proprietary rights, including intellectual property rights, and all materials needed for the applicant to perform the project.
• Before, during, and subsequent to the award, the U.S. Government is not required to obtain for the recipient any proprietary rights, including intellectual property rights, or any materials needed by the recipient to perform the project.
• The award recipient is required to report to the U.S. Government all inventions made in the performance of the project, as specified by 35 U.S.C. Sect. 202 (Bayh-Dole Act).
• Recipients 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.
• All rights, title and interest in and to any inventions or technologies of NAMs Developers or of VQN investigators, respectively, existing prior to receiving NIH grant funds will be the exclusive property of the respective party. Furthermore, all rights, title and interest in and to any inventions or technologies developed by NAMs Developers or VQN investigators not directly arising from the project plan described in the collaboration agreement will be the exclusive property of the respective party. NAMs Developers must agree to disclose developed intellectual property promptly and fully to VQN investigators.

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

NIH Program Staff

An NIH Program Official will be responsible for the normal programmatic stewardship of the award and will be named in the award notice. The program official(s) will:

• Provide stewardship and administrative oversight of the cooperative agreement;
• Assist in enforcing general statutory, regulatory or administrative assistance policy requirements;
• Negotiate and agree on a final set of milestones, the final negotiated and approved milestones will be specified in the Notice of Award;
• Evaluate progress by reviews of technical or fiscal reports or by site visits to determine that performance is consistent with objectives, terms and conditions of the award;
• Ensure that activities proposed for development or implementation do not overlap or duplicate activities supported by other peer reviewed funding mechanisms;
• Review all requests for prior approval as required by the NIH Grants Policy Statement;
• Retain the option to recommend the withholding or reduction of support from any cooperative agreement that either substantially fails to achieve its goals according to the milestones agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award.

NIH Project Scientist(s) will have substantial scientific involvement during the conduct of this activity, through technical assistance, advice, and coordination. NIH Project Scientist(s) will: 

• Participate in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols, project milestones or approaches as warranted. The Project Scientists will assist and facilitate the group process but not direct it;
• Monitor progress on the agreed upon milestones and help identify recourses, if needed;
• Provide advice on project management and technical performance;
• Serve as a liaison between the recipients, and participating NIH Institutes and Centers, and the larger scientific community;
• Coordinate and manage trans-NIH Complement-ARIE Working Group and Complement-ARIE NIH Executive Committee efforts.
• Coordinate the efforts of the recipient with others engaged in Complement-ARIE;
• Attend Steering Committee meetings and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action;
• Periodically report progress to the Directors of NIH Institutes and Centers involved in the Complement-ARIE program;
• Serve on subcommittees/working groups of the Steering Committee as appropriate;
• Provide advice in the management and technical performance of the investigation;
• Assist in promoting the availability of data and resources developed in the course of this project to the scientific community at large;
• Assist recipients in the development, if needed, of policies for dealing with situations that require coordinated action;
• Enlist additional scientific experts as necessary from within the NIH and other government agencies, such as the FDA, to assist the recipients in carrying out the goals and aims of the approved studies.

Areas of Joint Responsibility include:

• Participate in recurring monthly meetings to discuss progress, obstacles and any other Complement-ARIE related issues and/or activities.
• The NIH will enlist additional scientific experts as necessary from within the NIH, other government agencies, such as the FDA, and from industry partners, whose function will be to assist the PD(s)/PI(s) in carrying out the goals and aims of the approved studies.

Communication Plan

• Participate and present findings at the semi-annual Complement-ARIE Consortium meetings convened by the Complement-ARIE Data Hub and Coordinating Center.
• Coordinate or jointly publish findings in a timely manner, and as to have the broadest impact.
• Make new information and materials known to the research community in a timely manner through publications, web announcements, reports to the NIH.

Performance Requirements

• Meet yearly milestones as defined by investigators and NIH program officials and referenced in the Notice of Award.
• Actively coordinate, collaborate, and share data with the NAMs Data Hub and Coordinating Center, as allowed, and with considerations under tribal IRB processes, as appropriate.
• Work with the NAMs Data Hub and Coordinating Center to submit NAMs evaluation metrics and data.

Complement-ARIE Consortium

Recipients agree to governance, through voting and decision making, of the Complement-ARIE consortium through a Steering Committee (SC). The Steering Committee membership will include a representative PD/PI from each awarded Cooperative Agreement, a NIH Project Scientist, the PD/PI of the Validation and Qualification Network (VQN) and the PD/PI of NAMs Data Hub and Coordinating Center (NDHCC) PD/PI. The PD/PI of each award (or designee) will have one vote on the SC. A NIH Project Scientist will represent NIH Project Staff and will have a single vote. The Steering Committee Chairs will not be NIH staff members. Award recipients will be required to accept and implement policies approved by the SC. Other government staff may attend the Steering Committee meetings if their expertise is required for specific discussions. The Steering Committee will:

• Discuss progress in meeting the goals of Complement-ARIE projects;
• Develop recommendations for uniform procedures and policies necessary to meet the goals of Complement-ARIE;
• The SC will also serve as a venue for coordination for collaborative efforts across the  Complement-ARIE consortium;
• The SC will consider the collective program goals for Complement-ARIE activities.

Dispute Resolution:

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

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting.  To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

• Recipients will provide updates at least annually on implementation of the PEDP.

The Federal Funding Accountability and Transparency Act of 2006 as amended (FFATA), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients 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 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, 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 (Responsibility/Qualification in SAM.gov, formerly 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 2 CFR Part 200 – Award Term and Conditions for Recipient Integrity and Performance Matters.

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 Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

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

Finding Help Online: https://www.era.nih.gov/need-help (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: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Danilo A. Tagle, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 240-418-5017
Email: [email protected]

Christine Happel, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 240-472-7550
Email: [email protected]

Center for Scientific Review (CSR)
Email: [email protected]

Elizabeth E. Conklin
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-496-7480
Email: [email protected] 

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.