CIRCLE Frequently Asked Questions (FAQs)

Learning about the CIRCLE program, asking questions and connecting with potential collaborators are the primary goals of the CIRCLE Proposers' Day. To learn more about the details of the Proposers' Day event, please consult the CIRCLE Proposers' Day Special Notice on SAM.gov

In-person participants have the opportunity to present a poster for other in-person participants to view, and all interested parties are encouraged to post a Teaming Profile to facilitate collaboration in crafting the best teams to respond to the CIRCLE ISO.

There will be no Sidebars at this event.

The restrictions on individuals "contributing" to more than one Type A (TA) proposal  (CIRCLE ISO section 1.6.1) are not meant to restrict institutions from submitting multiple Type A proposals if they are staffed by different teams. However, all things being equal, it is likely that ARPA-H will not choose to fund more than one proposal from the same institution if the same quality and diversity of effort can be achieved by funding multiple institutions. If an individual contributes to more than one Type A proposal, ARPA-H will not fund both. Additionally, as stated in the same section, to avoid conflicts of interest, no institution will be allowed to participate in both a Type A and a Type B proposal. If an institution submits proposals of both types, ARPA-H will not fund both.

ARPA-H policy for submissions from international proposers is detailed in Section 3.3 of the ISO: "Non-U.S. entities may participate to the extent that such participants comply with any necessary nondisclosure agreements, security regulations, export control laws, and other governing statutes applicable under the circumstances. However, non-U.S. entities are encouraged to collaborate with domestic U.S. entities. In no case will awards be made to entities organized under the laws of a covered foreign country (as defined in section 119C of the National Security Act of 1947 (50 U.S.C. § 3059)); a foreign entity of concern meeting any of the criteria in section 10638(3) of the CHIPS and Science Act of 2022; or an individual that is party to a Malign Foreign Talent Recruitment Program (MFTRP), as defined in Section 10638(4) of the CHIPS and Science Act of 2022. "

Additionally, in Section 1.6.5 of the CIRCLE ISO, covering Commercial Transition, it is mentioned that, "Throughout the program, performers are expected to work towards the goal of transitioning their technological advances into the marketplace for the purpose of delivering improved critical care to the American public". Similarly, in section 5.1 covering evaluation criteria for TA proposals, "The degree to which commercialization plans are complete, realistic and give confidence that the ARPA-H investment will result in transition to publicly available technology for the benefit of American patients." Proposers would thus be wise to justify how their efforts would directly impact American patients. Although not required, one way to address this criterion would be to include American partner or partners in the proposing team.

Section 4.2 of the CIRCLE ISO includes, "All solution summaries submitted in response to this ISO must comply with the content, page, and formatting requirements outlined in Attachment A." Section 4.3 details the requirements for full proposals, including Volume I (Attachments B and C), and Volume 2 (Attachment D), and Volume 3 (Attachments E and F). All attachment instructions, forms and templates can be found on the same SAM.gov page as the CIRCLE ISO.

The CIRCLE ISO does not specify a minimum effort for the Project Lead (PL). However, the allocation of effort among the proposed team to perform the necessary tasks is used in evaluating the proposals. In particular, each Technical Area proposal team is required to include a Team Integrator component (see ISO section 1.5.1), which states, "The Team Integrator component of the CIRCLE program represents and highlights the overarching focus on integrated delivery of both research & development as well as commercialization/transition inherent to the CIRCLE program; this component is expected to play a management role and thus must be led by the performing teams’ Program Leads (PLs)." Thus, in addition to any other activities of the PL, the PL must include explicit effort for leading this Team Integrator activity, and including insufficient overall PL effort might be regarded as a weakness in a proposal.

Individuals may contribute to more than one Solution Summary. If multiple Solution Summaries including an individual are encouraged, proposers are cautioned that ARPA-H will not fund multiple proposals including the same individuals, groups or teams. Contributing to multiple proposal solutions may put the effort of the rest of the team at risk.

We encourage all interested parties to register on the CIRCLE Teaming page, and to look there to see who else may be interested in the CIRCLE program. You may be able to leverage internal communications within your organization to announce your interest in submitting a CIRCLE proposal to find willing collaborators, and to see who else is interested.

This policy is detailed in Section 3.2 of the CIRCLE ISO, and incudes, "FFRDCs and U.S. Government entities, including federal Government employees, are not permitted to respond to this ISO as a prime or sub-performer on a proposed performer team."

As indicated in section 1.5.1 of the CIRCLE ISO, the Team Integrator is a component of the TA performer team. The Team integrator "must be led" by the performing teams' Program Leads (PLs). If the proposing team elects to have the Team Integrator component consist of only the PL, that is an option. They may alternatively opt to establish a larger group including and led by the PL.

Section 4.2 of the CIRCLE ISO states, "ARPA-H will provide written feedback to all solution summary submissions. Feedback at a minimum will provide an encourage or discourage recommendation in submitting a proposal submission. Feedback will be sent to the administrative and technical points of contact noted on the solution summary cover sheet." Submitted full proposals will go directly to formal review. Proposals that are selected for potential funding will enter into a contract negotiations phase which will refine the final statement of work (Task Description Document).

The CIRCLE ISO contains this text (Section 1.3 Program Scope): "The primary focus of the CIRCLE program is on critical illness in adults. Due to the differences in the immuno-inflammatory mechanisms between adults and neonates or pediatric populations as well as the difficulty in obtaining sufficient data in these groups, proposers are strongly encouraged to focus on adult populations to strengthen the generalizability if CIRCLE therapeutic targets."

So no, focusing on pediatric populations is not strictly out of scope, but requires significant additional justification that the deliverables from the proposed effort will be generalizable to non-pediatric populations.

There is a preference in the CIRCLE program for the application of FDA approved therapies: (CIRCLE ISO, Section 1.3) "CIRCLE will focus initially on repurposing FDA-approved therapies that can effect immuno-inflammatory reprogramming, ideally with tissue-specific precision. If justified, CIRCLE will support the development of novel immune-modulating approaches as a means of validating specific predictions derived from digital twin models and/or as novel therapeutics." Additionally, Section 1.5.3, under TA3 states: "In the case of non-FDA approved therapies, TA3 performers may engage in activities advancing novel therapeutics to the pre-IND (investigational new drug/device) stage". While not explicitly mandated, any TA3 effort that can be connected to an existing or in-process IND would likely greatly strengthen a proposal.

AP2 will not be creating a specification to which TA2 performers must adhere. However AP2 performers are responsible for coordinating TA2 performer compliance with "standard ontologies and nomenclatures for objects in their models and [compliance] with relevant regulatory standards and best practices" as indicated in the CIRCLE ISO section 1.7.4. Ideally, the AP2 performer will have the capabilities to evaluate and test all TA2 products fairly within the AP2 performer's framework (which is also expected to ultimately be capable of supporting regulatory submissions based on digital twin models developed by TA2 performers), and thereby to compare them to each other to the greatest extent possible. Capabilities to integrate multiple TA2 products into a single system would be looked upon as a strength of an AP2 proposal. AP2 required tasks are detailed in the CIRCLE ISO, Section 1.6.4.

Proposers are free to include whatever evaluation studies are most cost, time and effort efficient to achieve the goals of the CIRCLE program. Evaluations in human subjects, or any non-human modality are allowable. Note that the CIRCLE ISO (section 1.4) states: " To the greatest extent practical, data should come from patients as opposed to animal models (although the use of clinically realistic animal models for verification and validation of model predictions, for the evaluation of therapeutics, and the safety and effectiveness of new sampling methods is appropriate, as are data obtained from other experimental systems if justified).", and "Proposed interventions should be tested under the most patient-realistic conditions practical, whether in simulations, large animal/non-human primate trials, and/or human studies." Section 1.5.2 states, for TA3, "If novel therapeutic approaches are used as a means of validating model predictions, performers will clearly establish the feasibility of the methods for testing their effectiveness and specificity for the desired target(s) through appropriate in vitro, ex vivo/micro-physiological devices, and/or animal studies. " Section 1.6 states that in Phase II of the program, "Validation of computational model simulations and predictions may involve either animal models or human subjects, or both." All studies in animals or humans must be supported by the appropriate ethical board certifications and follow accepted best-practices (see Section 6.3.4, and 6.3.5).

Proposals covering only one of the CIRCLE TAs are out of scope. TA1 sensor systems must be included within a comprehensive TA1-TA2-TA3 proposal that can produce a workable integrated Measure-Model-Modulate system by the indicated timepoints. The CIRCLE program is not proscriptive with respect to the types of technologies to be applied within complete TA (Type A) proposals, so long as the specific metrics and milestones listed in the CIRCLE ISO can be reached. Proposers with in-development technology should particularly reference the "Technological Readiness" metric.

TA2 is intended to cover the development of Digital Twins (computational models) that process repeated inputs of patient data, and deliver useful information directing therapeutic delivery. If an organ-on-a-chip/organoid can fill this role in an integrated TA proposal that can meet all of CIRCLE's metrics and milestones, than it would be in scope, but most likely in the context of TA3, not TA2.

While the Government cannot tell you exactly how to price your proposal, it is important that your proposed budget is realistic and thorough, covering all aspects needed to achieve your technical and management goals. Your budget narrative should include enough explanation and supporting information to justify the costs listed in your budget spreadsheet.

The milestones for the CIRCLE program are indicated in Table 1 (and elaborated in Appendix A) of the ISO. These include completion of a platform trial assessment of selected control point modulations and initiating a first-in-human adaptive clinical trial of the [performer's] integrated CIRCLE system, in concert with the AP3 performer, by 4.5 years after award.

The Regulatory Submission milestone at 4.5 years is described in Appendix A as, "Performer teams will make documentary submissions to regulatory bodies appropriate to the level of development for each TA technology product, and each combined partial and complete integrated system instance." The level of technological development must be sufficient to achieve other milestones, such as those for carrying out Platform Trials on specific interventions, and the integrated system.

The CIRCLE ISO does not specify that proposals must address at least two causes of inflammation-mediated critical illness. Rather, the program requires that the focus not be "relevant to only one specific cause of critical illness, e.g., sepsis" (section 1.3). In other words, the solutions provided by CIRCLE performers are expected to be generalizable to multiple initiating causes, acting on the underlying immuno-inflammatory processes of critical illness, and not solely address specific initiating causes. Any validation in pre-clinical animal or other models in the context of TA3 should at the very minimum validate specific predictions or assumptions of the digital twin models with regards to the underlying immuno-inflammatory processes of critical illness. If the predictions of the models are specific to a particular initiating stimulus for critical illness then it is likely that the validation strategy would need to encompass multiple etiologies of critical illness to demonstrate model generalizability.

AP performers will only have access to TA performers work products for the expressed purposes of sharing data within the team, and testing, evaluating, validating and comparing work products. All access by AP providers to TA performers' data and work products are governed by the indicated text in Section 1.6.4. As indicated in Section 1.4, data generated by performers as part of the CIRCLE program will be incorporated (by the AP1 performer) into a common database "that will ultimately become a public resource". The AP2 performer will investigate the possibility of creating "meta" digital twins by integrating digital twin models from multiple CIRCLE performers. Policies and process for handling data and IP rights are discussed in section 1.7.3 and 1.7.6 of the CIRCLE ISO.

Type A (Technical Area) proposals must be integrated, stand-alone TA1/TA2/TA3 teams that incorporate data collection, modeling and pre-clinical/clinical evaluation. These teams are expected to be capable of meeting all CIRCLE metrics and milestones. The AP1 performer is responsible for incorporating all data from the TA teams into a CIRCLE-wide database that is available to all performers. AP1 is responsible for providing additional datasets, which will be made available to performers for use. The CIRCLE program will not be requiring a unity of approach across different TA teams, nor will it specify any particular evaluation platforms.

Thank you for identifying that typo. You are correct that the TA2 metrics begin with "Model Response Time". This will be corrected in the next Amendment of the CIRCLE ISO.

We apologize for the poor separation of the text between columns in Table 1. The correct parsing of this Milestone is:
 Milestone: "Demonstrate the possibility of 15%, 25% reduction in ICU stay (directly in pre-clinical model and/or simulation)" 
 Deadline: "3.5, 4.5 years"
This means that we expect to see 15% reduction demonstrated at 3.5 years, and 25% reduction demonstrated by 4.5 years. "Directly" means in a real pre-clinical model, as opposed to a simulation, which we would regard in contrast as "Indirectly".