MOU 225-25-012

MEMORANDUM OF UNDERSTANDING
BETWEEN
DEPARTMENT OF HEALTH AND HUMAN SERVICES 
NATIONAL INSTITUTES OF HEALTH
AND 
THE FOOD AND DRUG ADMINISTRATION
CONCERNING
Coordinated Efforts on NIH COMPLEMENT-ARIE PROGRAM ("PROJECT")

I. PURPOSE

This Memorandum of Understanding (MOU) sets forth an overarching framework of partnership between the National Institutes of Health (NIH) and the Food and Drug Administration (FDA; collectively referred to as the “Parties”). To effectuate this purpose, the Parties enter into a non-exclusive, non-binding Memorandum of Understanding to promote the advancement of New Approach Methodologies (NAMs), sometimes referred to as Novel Alternative Methods, New Alternative Methods, or Non-Animal Models. These Parties share common interests and goals in developing NAMs to complement animal research in experimentation and catalyze the development, standardization, validation, qualification and use of human-based NAMs that will transform the way basic, translational, and nonclinical sciences are done. To this extent, this MOU will focus on collaboration among the Parties to advance the goals of the NIH Common Fund’s Complement Animal Research in Experimentation (Complement-ARIE) Program. The purpose of Complement-ARIE is to accelerate the development, standardization, validation, and use of human-based NAMs to allow for insights into disease processes and susceptibility across different populations and implement validated NAMs into widespread use. Overall, Complement-ARIE will improve understanding of human health and disease pathways across various populations for the most pressing and complex biological issues, integrate innovative NAMs (in vitro, in chemico, and in silico) with artificial intelligence (AI) and data ecosystems according to findable, accessible, interoperable, and reusable (FAIR) principles to generate human-relevant, actionable insights. This will be done while coordinating across NIH Institutes, Centers, and Offices (ICOs), agencies, and public-private partnerships to mobilize collective scientific progress, and leveraging the full scientific toolbox to improve biomedical research.

Each Party, operating under its own authority, intends to have specific roles in promoting this shared interest. This MOU provides a framework between the NIH and the FDA for coordination and collaborative efforts between the Parties to maintain and enhance effectiveness. It also provides the principles and procedures by which the parties involved intend to manage and share expertise and information in order to increase collaboration and strategic planning.

II. BACKGROUND

The 21st century has seen numerous scientific advances in gene editing, machine learning, induced pluripotent stem cells (iPSCs), 3D bioprinting, organoids, and microphysiological systems (MPS), which are fundamentally changing the way biomedical science is done. These technologies and other advances have enabled and contributed to the development and application of NAMs. NAMs are lab or computer-based research approaches intended to more accurately model human biology, and complement, or in some cases, replace traditional research models. NAMs can be any in vitro, in chemico, or in silico methods that when used alone or in concert with others can enable improved disease models (including toxicology as well as complex human-relevant models). In many cases, animal models for human diseases and conditions are not available or inadequate to mimic human pathophysiology and so by being able to complement or replace animal models NAMs hold tremendous promise in biomedical research. NAMs have the potential to improve understanding of various biological processes which could lead to better assessment of disease risk and progression and the development of precision interventions in the context of personalized medicine.

NAMs have proven to be valuable tools in basic, nonclinical, and toxicology research, and have been used to study the efficacy and toxicity of novel therapeutics. In chemico platforms use cell-free systems to study the interaction of drugs, toxicants, and other biological molecules. This method requires 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 on cells outside of the body, including various types of cell culture systems, organoids, and tissue culture techniques, such as 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. While traditional animal models continue to be vital to advancing scientific knowledge, NAMs offer unique strengths that, when utilized individually or in combination, can enable researchers to answer previously difficult or unanswerable questions. This is especially true in areas where in vivo models are lacking or have consistently underperformed.

With the recent adoption of the FDA Modernization Act 2.0, which authorizes the use of certain alternatives to animal testing to obtain an exemption from the FDA to investigate the safety and effectiveness of a drug, and the April 2025 announcement of the FDA Roadmap to Reducing Animal Testing in Preclinical Safety Studies there is significant impetus being made towards incorporating NAMs as nonclinical tests to demonstrate safety and efficacy of therapeutics. NIH has similarly announced plans to make NAMs a top research priority.

Complement-ARIE will address current challenges in NAMs, which include validation and testing in complex systems, and the ability to generate nonclinical data needed for first-in-human trials; characterization of long-term, systemic and developmental health effects of environmental and drug exposures; and development of 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 FAIR datasets and AI-engines to generate testable predictions.
• 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 scientific and research needs, 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, adherence to FAIR principles of NAMs-relevant data, and create a searchable NAMs repository.

• Validation and Qualification Network (VQN) – support the generation of data packages consistent with validation/qualification frameworks, based on common data elements and standardized reporting, to accelerate deployment and facilitate regulatory qualification and implementation of NAMs. This builds upon recommendations in the 2024 The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) report which calls for the implementation of flexible, fit-for-purpose validation strategies that consider the intended application of each NAM.

  For clarity, the VQN does not have any legal or regulatory authority and, therefore, cannot validate and/or qualify any specific NAMs with regulatory context(s) of use. U.S. federal agencies operate under statutes, regulations, and policies particular to each agency and, therefore, have different criteria for a NAM to be acceptable and applicable toward each agency's individual requirements. In some cases, even within an agency (e.g., different centers of FDA) there may be different needs depending on the area of regulation. Even though a NAM may be validated to address a specific endpoint for one (or multiple) context(s) of use under a particular guidance/regulation, it may not be considered acceptable under a different guidance/regulation among various agencies, regulatory jurisdictions, and countries. For further clarity, it should be noted that “validation” has a specific meaning associated with FDA’s medical product regulation, beyond the term’s common use related to “scientific validation.”

Within each of the three key program components, training and outreach activities will be aimed at facilitating dissemination, capacity building, and adoption of NAMs. Complement-ARIE Program staff will participate in strategic engagement with key partners, including but not limited to regulatory bodies, industry, non-profits, and other non-governmental organizations committed to advancing emerging opportunities in the development and use of NAMs in basic, translational, and nonclinical research.

The three key components described above participate in the overall Complement-ARIE Consortium. The Consortium structure is meant to effectively guide all the funded activities to meet the overall goals of the Complement-ARIE program.

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. This program will provide a range of ready and standardized methodologies and data for health and disease biology. This MOU provides an opportunity to coordinate scientific and regulatory efforts surrounding NAMs technologies, achieve mutual benefits, and facilitate technology advancements and further adoption of NAMs.

Ill. SCOPE/SUBSTANCE OF UNDERSTANDING

The NIH and FDA intend to collaborate and coordinate efforts that will promote and accelerate the translational use of NAMs (referred to as the “PROJECT”). These collaborative efforts include:

• Providing regulatory expertise (FDA) to help support, refine, and advance projects with regulatory potential within the Complement-ARIE Program.
• Holding regular joint NIH-FDA workshops and/or meetings to ensure progress in our goals and to develop new policies and initiatives as needed.
• Engaging in additional activities, where appropriate, to promote development, adoption, and uptake of NAMs that may have applicability for FDA regulatory use.

This MOU does not alter existing NIH and industry authorities, command relationships, or privacy, civil liberties, and other oversight relationships. In establishing a proposed framework to provide mutually beneficial logistical and operational support, this MOU is not intended to replicate or aggregate unnecessarily the unique organizational structures of the NIH and FDA in scientific research. NIH and FDA agree that before any specific, NAMs-related collaborative initiative or activity is initiated or implemented, the Parties shall identify priorities, topics of mutual interest, and develop separate, written agreements, such as a Letter of Agreement, to describe collaboration and sharing of resources. These agreements will incorporate by reference this MOU. NIH and FDA may enter into additional agreements to the extent authorized by law and available resources.

IV.  PROJECT ACTIVITIES AND RESPONSIBILITIES OF EACH PARTY

The NIH and the FDA intend to assume the following respective roles and responsibilities in the PROJECT, such as:

• NIH investigators are to assume respective roles and responsibilities set in the NIH Notices of Funding Opportunity (NOFOs).
• NIH intends to hold semi-annual program review meetings for the Complement-ARIE Program Consortium to which the FDA will be invited and encouraged to attend.
• Each Party may utilize the expertise and relationships of the other to increase its own capability and responsiveness to the PROJECT, and to explore opportunities for FDA-NIH regulatory science research collaborations.

V. GENERAL PROVISIONS

1. Effective Date and Term. This MOU becomes effective on the date of the last signature and shall remain in full force and effect for a period of 10 years, unless extended by written agreement of the Parties, modified or terminated.
2. Effect of Termination. Either Party may terminate this MOU by providing written notice to the other Party of its intent to terminate the MOU.
3. PROJECT Activities and Responsibilities. It is understood by the Parties that all PROJECT activities and responsibilities are described in this MOU, unless the Parties agree that another type of agreement will need to be executed to complete the PROJECT. Such agreements will refer to this MOU. This MOU is strictly for internal management purposes for each of the Parties. It is not legally enforceable and shall not be construed to create any legal obligation on the part of any of the Parties.
4. Resource Obligations. All activities undertaken pursuant to this MOU are subject to the availability of personnel, resources, and funds. The FDA and NIH will not exchange or transfer funds. This MOU does not affect or supersede any existing or future agreements or arrangements among the Parties. This MOU does not create binding, enforceable obligations against any Party. This MOU and associated agreements will be subject to the applicable policies, rules, regulations, and statutes under which FDA and NIH operate.
5. Entire Agreement; Amendment. This MOU incorporates all Exhibits and Schedules (if any) hereto and constitutes the entire agreement and understanding between the Parties in respect of the subject matter hereof and replaces in its entirety any prior discussions, negotiations, agreements or other arrangements in relation to the subject matter, whether written or oral, all of which are replaced by the terms of this MOU. No amendment or modification of this MOU shall be valid unless made in writing and signed by authorized representatives of both parties.
6. Intellectual Property. The Parties agree that inventorship of any patentable matter, created by any of the participants pursuant to the terms of this MOU, will be determined in accordance with U.S. patent laws.

7. Data Sharing. Proprietary data from the Complement-ARIE program components and centers, namely, the TDCs, VQN, and NDHCC may be shared by those components and centers with FDA representatives, subject to separate confidentiality agreements setting forth terms specific to needs of all the involved entities. FDA does not intend to share nonpublic information under this MOU. Exchange of non-public information between FDA and NIH shall be governed by separate Confidentiality Agreements in which the Parties will agree and certify in writing that they shall not further release, publish or disclose such information and that they shall protect such information in accordance with the provisions of 21 U.S.C. § 331;18 U.S.C. § 1905; 21 C.F.R. Parts 20 and 21; 45 C.F.R. Parts 5 and 5b; 42 U.S.C. § 242m, 42 U.S.C. § 241(d), and other pertinent laws and regulations governing the confidentiality of such information.

   Additionally, the Parties will ensure that staff will comply with their respective policies and procedures for Conflict of Interest management.

8. Counterparts. This MOU may be executed in counterparts, each of which shall be deemed to be an original and all of which together shall constitute a single document. The Parties acknowledge and agree that the exchange of electronic or fax signatures will have the same legal validity as the Parties' signatures would have if signed in hard copy form.
9. Authority. FDA has authority to enter into this agreement pursuant to 21 U.S.C. §393(b) and (c). NIH has the authority to enter into this agreement pursuant to Section 402 of Public Health Service (PHS) Act, 42 U.S.C. §282; Section 301 of the PHS Act, 42 U.S.C. §241.
10. Notices and Meetings. All notices pertaining to this MOU will be in writing, signed by an authorized representative of the notifying Party, and delivered by email, registered or certified mail, or an express/overnight delivery service and sent to the other Party at the address designated below.

11. Points of Contact. The following individuals are designated points of contact for the MOU:

    The names of NIH ICO and FDA staff listed below represent the current persons in these assigned roles at the date of signing of this MOU. Additional NIH and FDA staff may be drawn to provide scientific expertise as needed.

    NATIONAL INSTITUTES OF HEALTH CONTACTS

    Margaret Ochocinska, PhD
    Program Leader 
    Office of Strategic Coordination – The Common Fund 
    Division of Program Coordination, Planning, and Strategic Initiatives 
    Office of the Director, 
    National Institutes of Health 
    (p): 301-435-6801 
    (e): Margaret.Ochocinska@nih.gov

    Nicole C. Kleinstreuer, PhD 
    Acting NIH Deputy Director for Program Coordination, Planning, and Strategic Initiatives (DPCPSI)
    Office of the Director
    National Institutes of Health
    (p): 301-402-9852
    (e): Nicole.Kleinstreuer@nih.gov

    Danilo A. Tagle, PhD
    Director, Office for Special Initiatives
    National Center for Advancing Translational Sciences
    National Institutes of Health
    (p): 301-594-8064
    (e): Danilo.Tagle@nih.gov

    FOOD AND DRUG ADMINISTRATION CONTACTS

    Tracy Chen, PhD, DABT
    Senior Science Advisor
    Office of the Chief Scientist
    Office of the Commissioner, FDA
    (p): 301-796-3597
    (e): Tracy.Chen@fda.hhs.gov

    Tracy Beth Høeg, MD, PhD
    Senior Advisor for Clinical Sciences
    Office of the Commissioner (OC) & Center for Biologics Evaluation and Research (CBER)
    (p): 240-461-0179
    (e): TracyBeth.Hoeg@fda.hhs.gov

    Dorn Carranza, PhD, MBA
    Senior Science Advisor
    Office of the Commissioner
    (p): 301-796 8338
    (e): Dorn.Carranza@fda.hhs.gov

    Scott Steele, PhD
    Senior Advisor for Translational Science 
    Center for Biologics Evaluation and Research (CBER)
    (p) 301-796-2209
    (e) Scott.Steele@fda.hhs.gov

12. Use of Name; Public Statements. By entering into this MOU, neither Party directly or indirectly endorses any product or service that is or will be provided to the other, whether directly or indirectly related to this MOU. Neither Party will in any way state or imply that the other Party or any of its organizational units or employees endorses its product or service. Each Party agrees to provide proposed public statements that reference or rely upon the work under this MOU to the other Party for review and comment at least seven (7) days prior to publication.

APPROVED AND ACCEPTED BY
National Institutes of Health

/s/
Jayanta Bhattacharya, MD, PhD    
Director
Date: 08/26/2025

APPROVED AND ACCEPTED BY
Food and Drug Administration

/s/
Martin A. Makary, MD, MPH
Commissioner
Date: 08/12/2025