The Advanced Research Projects Agency for Health (ARPA-H), through its Resilient Systems Office (RSO), has released an Innovative Solutions Opening (ISO) titled Critical Illness Immunological Reprogramming and Control Point Learning Engine (CIRCLE), ARPA-H-SOL-26-139 . This solicitation reflects ARPA-H’s mandate to pursue bold, high-impact biomedical innovations that can transform patient outcomes at scale. With CIRCLE, ARPA-H is targeting one of the most persistent and costly challenges in modern healthcare: critical illness in the intensive care unit (ICU). The overarching goal is to shift critical care from a purely reactive, organ-support paradigm to a model that integrates organ support with targeted treatment of dysregulated immuno-inflammation, thereby reducing ICU length of stay, lowering costs, and improving long-term patient outcomes.
Solicitation Overview: From Organ Support to Immune Reprogramming
Critical illness, as defined in the ISO, involves multi-organ dysfunction driven by dysregulated inflammation and immune responses. Despite advances in supportive care, there are currently no Food and Drug Administration (FDA)-approved therapies that directly treat the underlying immune dysfunction responsible for most forms of critical illness. ARPA-H’s CIRCLE program seeks to address this gap by developing an integrated “measure-model-modulate” approach capable of identifying and therapeutically targeting immune control points before organ failure progresses.
CIRCLE is structured around three integrated Technical Areas (TAs):
- TA1: Measure: Dynamic Immune Descriptor
Development of rapid, tissue-informed biomarker platforms capable of capturing dynamic immuno-inflammatory states in near real time. - TA2: Model: Digital Twin Generator
Creation of mechanistic, patient-specific computational “digital twin” models that incorporate biomarker data, electronic health records (EHRs), and ICU data streams to identify actionable immune control points. - TA3: Modulate: Rational Immune Reprogrammer
Validation and deployment of immune-modulating interventions, initially focused on repurposing FDA-approved therapies, to alter disease trajectories based on digital twin outputs.
Each TA team must be integrated under a Team Integrator function responsible for cross-TA coordination, regulatory alignment, and commercialization strategy. In parallel, three Acceleration Platforms (APs) will provide independent verification and validation (IV&V), regulatory guidance, shared data infrastructure, and adaptive clinical trial support. These include:
- AP1: Critical Illness Clinical Data and Analysis Platform
- AP2: FDA-compliant Digital Twin Platform
- AP3: Critical Illness Clinical Trials Platform
The program is designed as a five-year, three-phase effort. Phase I (three years) focuses on prototyping and validation. Phase II (one year, optional) advances in silico and early clinical validation and requires at least five percent commercialization partner funding. Phase III (one year, optional) emphasizes regulatory filings, clinical trials, and transition activities, requiring at least twenty-five percent commercialization co-investment. Notably, performers are expected to achieve a 25 percent reduction in ICU length of stay through validated immune control point modulation.
Key Dates and Submission Milestones
ARPA-H has outlined the following critical deadlines (all times Eastern):
- Proposers’ Day: March 11, 2026
- Solution Summary Submission: March 30, 2026, 1:00 PM
- Questions and Answers (Q&A) Submission Deadline: May 22, 2026, 1:00 PM
- Full Proposal Submission: May 28, 2026, 1:00 PM
Solution summaries are required prior to full proposal submission. Deadlines will be strictly enforced.
Award Structure
The period of performance is structured for up to five years across three phases. While specific award sizes are not prescribed in the overview, proposals must present cost structures commensurate with the scale, integration, and commercialization expectations of a multi-disciplinary ICU platform effort. Down-selects may occur at the end of Phase I based on milestone and metric performance.
Advancing Human Health Through Precision Immune Control
CIRCLE represents a paradigm shift in critical care. By integrating rapid biomarker measurement, mechanistic digital twin modeling, and precision immune modulation, ARPA-H is seeking to reduce ICU duration, prevent downstream morbidity, and curb the development of chronic conditions that often follow critical illness. A validated 25 percent reduction in ICU stay would not only improve survival and recovery but also reduce billions in annual healthcare expenditures.
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