Complement-ARIE (Complement Animal Research In Experimentation) Challenge

Challenge Breakthrough

Seize this unprecedented opportunity to redefine biomedical research. Collaborate, innovate, and develop transformative methodologies that resonate with human biology, transcending traditional approaches. Your innovations will pave the way for human-based research solutions that can transform how safety and efficacy studies and human disease modeling can be conducted. Envision a future where multiscale mathematical models, AI-driven approaches, and intricate cell-based constructs coalesce to revolutionize our understanding of health and disease. With $1,000,000 in prizes, the NIH is seeking your ideas that will help demonstrate new ways of conducting basic research, uncovering disease mechanisms, and translating knowledge into products and eventually into practice.

Background

The 21st century has been a time of expeditious technological advancement, with increasing use of new and evolving methodologies including, but not limited to, gene editing approaches, artificial intelligence (AI), multiscale mathematical approaches, tissue engineering approaches, and novel chemistry, sensing, and imaging technologies that are enabling new ways to conduct science. These technologies and other advances hold tremendous promise in understanding fundamental biology and advancing human health. Additionally, these technologies drive innovation in scientific methodologies themselves, opening doors to new scientific approaches.

The NIH Common Fund recognizes the pivotal moment we are in, a juncture where rapid technological advancement meets the pressing need for New Approach Methodologies (NAMs). Twenty-first-century technological advancements have ushered in unparalleled scientific progress, not only transforming the way we approach scientific inquiries but broadening our horizons, offering tools that could potentially replace or complement traditional models in certain areas, expand research laboratory capabilities, and potentially translate into improving human health in new ways. While animal models currently remain indispensable for research, there is a growing realization that alternative models, such as microphysiological systems and digital models, could offer unique advantages. They could provide key insights into human biology and answer complex biomedical questions with greater precision. However, human-based NAMs are relatively young in the field of biomedical research and must advance to be truly transformative. Current in vitro models do not recapitulate or emulate all the complexity of physiologic and pathophysiologic processes and cellular networks in disease. The in silico and biophysical models are limited in accurately predicting complex biological processes and clinical symptoms. The journey towards realizing the full potential of these NAMs demands collaboration across disciplines. This is an endeavor where biologists, engineers, data scientists, and many other experts can unite their expertise to create innovative solutions with relevance to human biology.

The evolution from traditional to modern methodologies is not only about technological progression. It reflects a broader shift in the biomedical landscape influenced by economic and regulatory developments. The cost-effectiveness of new methods, combined with regulatory encouragement, has amplified the momentum toward innovative research approaches. Additionally, the fusion of diverse fields — from computational sciences to engineering — with biomedical research is enabling a more holistic approach, redefining the boundaries of what is possible. This interdisciplinary synergy is central to the promise of NAMs, underscoring the importance of collaboration in pioneering solutions that could redefine our understanding of human biology. Amid this transformation, the scientific community stands on the brink of a new era, driven not just by the quest for knowledge but by the aspiration to reshape the very fabric of biomedical research.

The NIH is embarking on the bold, difficult, and necessary mission to develop and deploy an integrated set of NAMs that is human-based and would ultimately enable their use in precision medicine across the lifespan. The NIH Common Fund is hosting this challenge as part of the strategic planning process. The NIH Common Fund has the goal of catalyzing the development, standardization, validation, and use of human-based NAMs that will transform basic, translational, and clinical sciences. The goals would be: 1) to model and understand human health and disease outcomes across diverse populations; 2) to develop NAMs that provide insight into disease and specific biological processes; 3) to validate the use of NAMs that will support standardization and regulatory acceptance, and 4) to complement or replace existing traditional models and enhance the efficiency and effectiveness of biomedical research.

The Challenge

This challenge seeks to propel the development and refinement of human-based NAMs.  While traditional models continue to be vital to advancing scientific knowledge, NAMs offer unique strengths that, when utilized correctly or in combination, can expand the toolbox for researchers to answer previously difficult or unanswerable biomedical research questions: https://grants.nih.gov/grants/policy/air/alternatives

Solutions must include next-generation innovation in in vitro, in silico, or in chemico approaches to emulate human biology or integrations thereof. Solutions must demonstrate substantial advancement from the current state-of-the-art technologies. For additional context please see Attachment 1 for definitions and references.

Challenge participants will submit a 15-page whitepaper demonstrating:

Innovation in In Vitro Modeling: Develop advanced human-derived, cell-, or tissue-based models that represent human physiological and pathophysiologic processes across the lifespan. These models should replicate intricate biological reactions and architectural structures, thereby serving as effective platforms for testing, analysis, and prediction. Some capabilities of these solutions are (but are not limited to):

• Demonstrate the ability to model the complexities of human population diversity.
• Catalyze the development of NAMs of sufficient complexity to address a more complicated context of use that is not attainable by current NAM models, such as vascular, neural, immune, and/or microbiome components.
• Incorporate complex immune function in microphysiological Systems (MPS) for emulating immune-related pathways and environmental triggers in inflammatory and autoimmune conditions.
• Standardize functional assays to assess the physiological relevance of the models.
• Utilize patient-derived cells or tissues to develop personalized models. 
• Use gene-editing techniques like CRISPR to introduce specific mutations into your in vitro models to study disease mechanisms.

Powering In Silico Models and Simulations: Harness the capabilities of computational tools to create models that can simulate biological responses. These in silico models, backed by robust algorithms, should be capable of analyzing complex datasets, predicting possible outcomes, and aiding in decision-making processes in biomedical research. Some capabilities of these solutions are (but are not limited to):

• Simulate health and model key disease states or pathological changes (e.g., chronic inflammation, mitochondrial dysfunction, mutation accumulation, etc.)
• Develop the ability for real-time incorporation of real-world clinical data and insights to fine-tune simulations, improving their predictive accuracy.
• Utilize generative models to design synthetic biological systems or pathways for robust testing and validation.
• Demonstrate the ability to model the diversities of the human population.
• Develop computational models that can accurately simulate metabolic reactions in cells, providing insights into disease pathways.
• Develop virtual clinical trial approaches that use simulations to predict how human populations might respond to a new drug or treatment, enabling informed clinical trial designs.

Exploration of In Chemico Systems: Venture into the realm of cell-free systems that allow researchers to study molecular interactions outside the confines of cellular environments. These systems should provide a clear window into the intricate interactions of molecules, enabling precise studies without cellular interference. Some capabilities of these solutions are (but are not limited to):

• Ability to capture and control dynamic epigenetic, biochemical, and genetic changes.
• High-throughput assays to query biologically relevant molecular properties.
• Incorporate advanced analytical methods to assess the full range of metabolic and proteomic changes in reaction conditions.
• Include cell-free expression systems as alternatives to production of biologics including those with non-natural functionalities.
• Implement nanotechnology to manipulate molecular interactions at an incredibly small scale.

NAM Integration: The challenge emphasizes integration of NAMs, either across models or into other platforms. The idea is to create a cohesive solution that leverages multiple methodologies for a comprehensive insight into human biology. Some examples of these solutions are (but are not limited to):

• Development of patient or population-level digital twins with other NAMs
• Integration of NAMs with diagnostic platforms for informed decision-making in the clinical setting (i.e., learning healthcare systems)
• Integration of AI/machine learning (ML) with other NAMs to develop predictive models
• Integrated AI and in chemico NAMs that can capture the vast complexities (e.g., socioeconomic status, diet, chemical exposure, social media interactions, etc.) in the environment around individuals and populations (i.e., exposome). 
• Multi-tissue MPS coupled with AI-based governing tools and in chemico monitoring components to rapidly evaluate and adjust MPS parameters to model an individuals’ unique physiology and pathophysiology.
• Implement AI-based decision support systems that can perform real-time analysis of data from various NAMs to assist clinicians and researchers in making more informed decisions.

Each submission should contain a detailed explanation of the proposed methodology's design, its potential applications, and most importantly, the rationale for its effectiveness. It is crucial to elucidate the challenges that could be encountered during the development phase, the strategies employed to overcome them, and the innovations introduced. Any datasets included should align with  FAIR principles, ensuring they are easily findable, accessible, interoperable, and reusable. If AI or ML models are employed, their design, accuracy metrics, and utility should be clearly detailed. To address these hurdles, the transformative NAMs proposed under this initiative must demonstrate substantial advancement compared to current approaches in challenge areas by developing innovative and integrative approaches that, for example, emulate/mimic complex biological structures/processes. Solutions should further enable the study of human-based NAMs to advance human relevance in biomedical research. For this challenge competition, solutions that include small animal models and other non-mammalian species will be considered out of scope.

Examples of general challenge areas for all NAMs in need of testable and feasible solutions include, but are not limited to:

• Representing diversity in human populations in modeling disease or health outcomes (e.g., diverse genetic ancestries, age groups, sex as a biological variable [SABV], socioeconomic status, health disparities, social determinants of health [SDOH])
• Modeling complex human physiology (e.g., pregnancy, development, metabolic, immune, neurosensory, age-related changes) and characterizing long-term, systemic, and developmental health effects of environmental and drug exposures (i.e., DOHaD)
• Areas of high need for alternative models (e.g., rare diseases, rare cancers, psychiatric disorders, ophthalmology, pediatrics, aging, reproductive health, infectious diseases, neuroscience, and behavior research)
• Testing in complex systems for non-clinical data needed for first-in-human or first-in-population trials (e.g., dose-ranging, toxicology)
• Developing, standardizing, and manufacturing of platforms for in vitro, in chemico, and in silico approaches and the integration of such platforms for advancing NAMs for regulatory acceptance
• Validation and standardization of NAMs to enable robust, reliable, and reproducible research
• Global harmonization across the many stakeholders (e.g., academia, industry, regulatory agencies) for widespread use and adoption of NAMs

While the introduction of a novel methodology is a significant advance, this challenge seeks more than just innovation. It aims to find solutions that bridge existing gaps in biomedical research to improve human health. Winning entries will not only showcase a novel approach but will also support its potential impact in the real world. A thorough understanding of human biology, the relevance of the innovation in the current research landscape, and its scalability are factors that will be pivotal in the evaluation process. In essence, the challenge is not just about proposing a solution, but about influencing the foreseeable future of biomedical research.

Timeline

Prize

Up to twenty proposals that are judged to best meet the requirements will be awarded up to $50,000 each. The total prize purse for this challenge is $1,000,000.

Rules

• Eligibility rules:
  • To be eligible to win a prize under this Challenge, a Participant (whether a Team or an Entity) — 

a. Shall have registered to participate in the Challenge under the rules promulgated by the National Institutes of Health (NIH) as published in this announcement.

b. Shall have complied with all the requirements set forth in this announcement.

c. In the case of an Entity, shall be incorporated in and maintain a primary place of business in the United States. In the case of a Team, the Team Leader shall be a citizen or permanent resident of the United States. However, non-U.S. citizens and non-permanent residents can participate as a member of a Team or Entity that otherwise satisfies the eligibility criteria. Non-U.S. citizens and non-permanent residents are not eligible to win a monetary prize (in whole or in part). Their participation as part of a winning Team or Entity, if applicable, may be recognized when the results are announced.

d. Shall not be a federal entity or federal employee acting within the scope of their employment.

e. Shall not be an employee of the Department of Health and Human Services (HHS, or any other component of HHS) acting in their personal capacity.

f. Who is employed by a federal agency or entity other than HHS (or any component of HHS), should consult with an agency ethics official to determine whether the federal ethics rules will limit or prohibit the acceptance of a prize under this Challenge.

g. Shall not be a judge of the Challenge, or any other party involved with the design, production, execution, or distribution of the Challenge or the immediate family of such a party (i.e., spouse, parent, stepparent, child, or stepchild).

h. Shall be 18 years of age or older at the time of submission.

• Participation Rules:

(1) Federal grantees and recipients of cooperative agreements or other transaction (OT) awards are eligible to participate in the Challenge but may not use Federal funds from a grant award, cooperative agreement, or OT award to develop their Challenge submission or to fund efforts in support of their Challenge submission unless use of such funds is consistent with the purpose, terms, and conditions of the grant award, cooperative agreement, or OT award. Each Participant (whether participating as a Team or Entity) intending to use Federal grant, cooperative agreement, or OT award funds must register for and participate in the Challenge as an entity on behalf of the awardee institution, organization, or entity. If a winning Participant uses Federal grant, cooperative agreement, or OT award funds to participate in the Challenge, the prize must be treated as program income for purposes of the original grant, cooperative agreement, or OT award in accordance with applicable Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards [2 CFR § 200]. Participants using Federal grant, cooperative agreement, or OT award funds to participate and/or report prize funding as program income (for winning Participants) should coordinate with the awarding official at the federal awarding agency.

(2) Federal contractors may not use federal funds from a contract to develop their Challenge submissions or to fund efforts in support of their Challenge submissions. 

(3) By participating in this Challenge, each Participant (whether participating as a Team or an Entity) agrees to assume any and all risks and waive claims against the federal government and its related entities, except in the case of willful misconduct, for any injury, death, damage, or loss of property, revenue, or profits, whether direct, indirect, or consequential, arising from participation in this Challenge, whether the injury, death, damage, or loss arises through negligence or otherwise. 

(4) Based on the subject matter of the Challenge, the type of work that it will possibly require, as well as an analysis of the likelihood of any claims for death, bodily injury, property damage, or loss potentially resulting from Challenge participation, no Participant (whether participating as a Team or an Entity) participating in the Challenge is required to obtain liability insurance, or demonstrate financial responsibility, or agree to indemnify the federal government against third party claims for damages arising from or related to Challenge activities in order to participate in this Challenge.

(5) A Participant (whether participating as a Team or an Entity) shall not be deemed ineligible because the Participant used federal facilities or consulted with federal employees during the Challenge if the facilities and employees are made available to all Participants participating in the Challenge on an equitable basis.

(6) By participating in this Challenge, each Participant (whether participating as a Team or an Entity) warrants that they are sole author or owner of, or has the right to use, any copyrightable works that the submission comprises, that the works are wholly original with the Participant (or is an improved version of an existing work that the Participant has sufficient rights to use and improve), and that the submission does not infringe any copyright or any other rights of any third party of which the Participant is aware. 

(7) By participating in this Challenge, each Participant (whether participating as a Team or an Entity) grants to the NIH a nonexclusive, nontransferable, irrevocable, paid-up license to utilize the full contents of the submission for the purposes of informing the design of ongoing or future programs or activities supported by NIH. Additionally, each Participant selected to win a prize award under this Challenge grants to the NIH an irrevocable, paid-up, royalty-free nonexclusive worldwide license to reproduce, publish, post, link to, share, and display publicly the Title, Executive Summary, and Plain Language Summary components of the submission on the web or elsewhere. Each Participant will retain all other intellectual property rights in their submissions, as applicable. To participate in the Challenge, each Participant must warrant that there are no legal obstacles to providing the above-referenced nonexclusive licenses of the Participant’s rights to the federal government. To receive an award, Participants will not be required to transfer their intellectual property rights to NIH, but Participants must grant to the federal government the nonexclusive licenses recited herein.

(8) Each Participant (whether participating as a Team or an Entity) agrees to follow all applicable federal, state, and local laws, regulations, and policies. 

(9) Each Participant (whether participating as a Team or an Entity) participating in this Challenge must comply with all terms and conditions of these rules, and participation in this Challenge constitutes each such Participant’s full and unconditional agreement to abide by these rules. Winning is contingent upon fulfilling all requirements herein.

(10) As a condition for winning a cash prize in this Challenge, each Participant (whether participating as a Team or an Entity) that has been selected as a winner must complete and submit all requested winner verification and payment documents to NIH within 7 business days of formal notification. Failure to return all required verification documents by the date specified in the notification may be a basis for disqualification of a cash prize winning submission.

(11) By participating in this Challenge, each Participant (whether participating as a Team or an Entity) irrevocably grants to NIH the right to the use of their name, affiliation, city and state, and likeness or image for the purposes of publicity releases and any other promotion of this Challenge. 

Judging Criteria

How do I Win?

Challenge participants should consist of multidisciplinary teams of experts who are appropriate for their proposed solution. Submit an entry describing the specific challenge area(s), what their proposed solution will address, why a novel or improved NAM is needed, and how it will address the challenge area(s). Submissions will also consist of detailed descriptions of the particpant’s team composition and expertise, efficacy of the proposed new approach methodology, scientific rationale, novelty of the idea, and its potential impact. Participants may submit proposed solutions to more than one NAM but must do so with separate proposals that independently address each of the NAMs challenges.

To be eligible for an award, your submission must, at minimum:

• Sufficiently satisfy the minimum Judging Criteria requirements.
• Thoughtfully address the Submission Form questions.
• Be scored higher than your competitors!

See the Rules section for specific team/entity eligibility information.

Submission Form