75N91024R00006 ARPA-H FY24 SBIR SOLITICATION.pdf

THE ADVANCED RESEARCH PROJECTS AGENCY FOR HEALTH (ARPA-H) SMALL BUSINESS INNOVATION

RESEARCH (SBIR) PROGRAM SOLICITATION

IMPORTANT

Deadline for Questions: Solicitation questions must be received by February 15, 2024, 5:00 PM EDT. Please send questions to the ARPA-H SBIR/STTR Program mailbox (sbir@arpa-h.gov).

Deadline for Receipt: Proposals must be received by February 22, 2024, 5:00 PM EDT.

Please read the entire solicitation carefully prior to submitting your proposal.

IMPORTANT: All proposals must be submitted using the electronic contract proposal submission (eCPS) website. Paper proposals will not be accepted.

Please go to the following link to read the SBIR/STTR Policy Directive issued by the Small Business Administration for further information:

https://www.sbir.gov/sites/default/files/SBA%20SBIR_STTR_POLICY_DIRECTIVE_May2023.pdf

Attention is directed to the inclusion of a new proposal requirement: Section 9 – Disclosure of Foreign Relationships. Please read the document in full, and include a completed disclosure form within your business proposal.

Contracting Officer/Specialist Points of Contact:

• Mandie White Contracting Officer EMAIL: whitems@mail.nih.gov

PHONE: 301-624-8756

• Randy Cook Contract Specialist

EMAIL: randy.cook@nih.gov

PHONE: 240-276-6907

https://www.sbir.gov/sites/default/files/SBA%20SBIR_STTR_POLICY_DIRECTIVE_May2023.pdf

Table of Contents

SECTION 1: INTRODUCTION ........................................................................................................PAGE 2 SECTION 2: PROGRAM DESCRIPTION........................................................................................ PAGE 16 SECTION 3: METHOD OF EVALUATION ...................................................................................... PAGE 18 SECTION 4: PROPOSAL PREPARATION AND INSTRUCTIONS .................................................. PAGE 20 SECTION 5: PROPOSAL SUBMISSION ........................................................................................ PAGE 21 SECTION 6: PROPOSAL FUNDAMENTALS ...................................................................................PAGE 23 SECTIONS 7-8: CONTRACT REQUIREMENTS .............................................................................PAGE 37*

SECTION 9: DISCLOSURE OF FOREIGN RELATIONSHIPS……………………………………………..…..……..PAGE 72

SECTION 10: GENERAL DEFINITIONS…………………………………………………….…………………………….……PAGE 73

*If performing Human or Animal Research, please refer to Appendices A.1 and A.2

1 INTRODUCTION

The Advanced Research Projects Agency for Health (ARPA-H) invites small business concerns (SBCs) to submit research proposals under this Small Business Innovation Research (SBIR) Contract Solicitation. Firms with the capability to conduct research and development (R&D) in any of the health-related topic areas described in Section 1.1, and to commercialize the results of that R&D, are encouraged to participate.

This solicitation contains opportunities to submit a proposal under a variety of different Topics, which are summarized in Section 1.1 below. ARPA-H is under no obligation to fund any proposals or any specific number of proposals in a given topic. It may also elect to fund several or none of the proposed approaches to a given topic. All awards are subject to the availability of funds. HHS is not responsible for any monies expended by the offeror before award of any contract.

The mission of ARPA-H is to accelerate better health outcomes for everyone by supporting the development of high-impact solutions to society’s most challenging health problems. Awardees will develop groundbreaking new ways to tackle health-related challenges through high potential, high-impact biomedical and health research. With a scope spanning the molecular to the societal, ARPA-H seeks SBIR proposals that aim to rapidly achieve better health outcomes across patient populations, communities, disease, and health conditions, including in support of the Cancer Moonshot. Proposals are expected to use innovative approaches to enable revolutionary advances in science, technology, or systems. Specifically excluded are proposals that represent an evolutionary or incremental advance in the current state of the art. Additionally, proposals directed towards policy changes, traditional education and training, or center coordination and construction of physical infrastructure are outside the scope of the ARPA-H mission.

1.1 List of Topics

This solicitation invites proposals in the following areas. The detailed project descriptions can be found on the following pages.

• ARPA-H 01 - Inexpensive plant-based manufacturing of viral vectors for gene therapies

• ARPA-H 02 - LymphoLab ProDiscover Kit

• ARPA-H 03 - Continuous Monitoring of Vascular health using Smart Biomimetic Implantables

• ARPA-H 04 - Personalized medicine platform for predicting response to immunotherapy

• ARPA-H 05 - Saving Baby Hearts: Fully Autonomous Neonatal Echocardiography for the Diagnosis of

Critical Congenital Heart Disease

• ARPA-H 06 - Improving Identity and Access Management with Clinical Context

ARPA-H 01 - Inexpensive plant-based manufacturing of viral vectors for gene therapies

Only Direct to Phase II proposals will be accepted.

Number of anticipated awards: 1-2

Budget (total costs, per award): up to $3,500,000.00 for 1 to 3 years. It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

Objective:

Viral vectors have shown great promise in treating a variety of previously intractable diseases. Viruses for therapeutic applications include adeno-associated viral (AAV) vectors, lentiviral and retroviral vectors, adenoviral vectors, etc. Manufacturing of these vectors is expensive and is based on mammalian (HEK293) and insect (Sf9) cell production methods. Alternative methods of virus production should be developed to ensure competitive pricing pressures, affordability of vectors for research uses, and, most importantly, ensuring the ability of NIST to create a multi-year supply of vector standards. Vector standardization has not been accomplished to date due to prohibitively high costs of vector production.

This SBP contract should allow small businesses pursuing plant-based production of viral vectors to develop and validate their approaches for AAV and lentiviral vectors. If successful, this grant will allow for cost reductions that will fuel more research of potentially curative therapeutics and for creating standards to ensure that vector biosimilars are able to enter the market this decade.

Background:

The purpose is to create competitive and inexpensive production processes for viral vectors. There is an unmet need for affordable and scalable production of viral vectors to fuel viral vector drug candidate pipelines and to support vector standardization and the vector standard supply. Recently, several startups emerged to harness plant-based production methods for viral vectors for therapeutic applications.

Together, unprecedently low cost of plant virus manufacturing and plant-based production and isolation methods for several FDA approved biologics support SBP’s focus on plant-based viral production innovation.

Specific requirements:

1) To demonstrate that plant-produced AAV viral vectors are comparable to those produced in mammalian or insect cells. Comparability should be assessed in terms of tropism and safety.

2) To demonstrate that various vector types can be produced in plants.

3) To demonstrate cost of goods reduction by at least 10-fold as compared to the standard mammalian or insect cell-based processes.

The following aspects will NOT be supported under this topic:

1) IND-enabling studies of specific viral vector drug candidates (only necessary comparability studies are supported).

2) Major hydroponic plant growing facility build-outs will not be supported.

Phase II activities and deliverables:

1) Validated manufacturing and purification process for two types of viruses

2) Comparability testing certificate

Mid-term metrics:

1) Production process for one selected vector with COGS reduction of at least 10x as compared to a mammalian process.

2) Comparability studies showing similar safety profiles and tropism of the selected vector produced in plants and in mammalian cells. Comparability will be confirmed when no statistically significant differences in liver ALTs and % target cells are detected for plant- and mammalian-based batches.

Final-exam metrics:

1) Demonstration that the plant-based process can be leveraged for a different type of viral vector without major changes to the process workflow or purification steps.

2) A master production protocol is established and a successful CATT meeting with the FDA is completed.

ARPA-H 02 - LymphoLab ProDiscover Kit

Fast-Track or Direct to Phase II proposals will only be accepted.

Budget (total costs, per award): Phase I: up to $600,000.00 for 6 months to 2 years. Phase II: up to $3,500,000.00 for 1 to 3 years. It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

Objective:

To develop in-vitro lymphatic assays that is affordable, and modular, offering the ability of this tool kit to be implemented in any lab environment across the USA and beyond.

Proposals will be asked to consider incorporating various key aspects of the lymphatic microenvironment, such as relevant extracellular matrix (ECM) components, lumen formation, various lymphatic and immune cells, physiological flow rates and biomechanics, and imaging.

It is not a requirement that the in-vitro assay incorporated every aspect outlined but is well tailored to observe lymphatic function and response to stimuli or drugs.

The unmet need: Existing platforms are lab specific and not standardized - thereby impeding reproducibility of findings, the ability for researchers to quickly build on existing findings, and the ability to quickly test interventions on a widely accepted in-vitro model of lymphatic vasculature. There are numerous examples of tool-kits developed for a variety of conditions, and disease states that small businesses took on and have been successful in marketing.

And, Increasingly, organoids and other organ-on-a-chip platforms have demonstrated the usefulness of this technology in disease modeling preclinical drug development.

These technologies have the potential of providing high throughput screening of drugs in complex microenvironments that better recapitulate the in-vivo culture conditions.

In recent years, increased research has demonstrated ideal conditions for the culture or lymphatic endothelial cells (LECs) and the formation of lymphatic vasculature in a variety of 3D models.

The development of a standardized in-vitro lymphatic assay platform is clearly well positioned for commercial success due to the increasing interest in lymphatics and their potential as a novel therapeutic target. Several pharmaceutical companies are now interested in nanoparticle delivery of their therapeutics.

But we first need diagnostics to establish the therapeutics.

We will encourage applications to incorporate design elements from existing in-vitro vasculature models of both blood and lymphatic vasculature. This includes:

• Layered or 3D bioprinting

• Synthetic or natural hydrogels

• Lymphatic vessel isolations

Background:

The human lymphatic system is critical to maintaining fluid homeostasis throughout the body. In addition to actively pumping fluid from the interstitial tissue to the blood circulation, the lymphatic system is integral in transporting proteins, facilitating immune cell migration, and absorption of dietary lipids.

Further, the lymphatic system is increasingly being understood as integral to other chronic diseases and inflammatory states. There is increased interest to understand lymphatic biology both in the context of diseases in which lymphatic dysfunction has been shown to play an active role, such as dementia (Alzheimer's), chronic liver disease, or autoimmune conditions, inflammatory conditions - Crohn’s disease, congestive heart failure, type II diabetes and infectious diseases like HIV and COVID.

Yet the lymphatic system has been ignored and lags far behind in research compared to our other body systems.

However, our dedicated researchers within the lymphatic community have successfully created a variety of in-vitro assays to study factors that influence lymphangiogensis, lymphatic sprouting, permeability, and other lymphatic functions in physiological and pathological conditions.

The problem is that these assays have largely remained unique to each lab and narrowly tailored to specific disease states or pathological conditions.

This heterogeneity of the existing platforms impedes reproducibility of findings, the ability for researchers to quickly build on existing findings, and the ability to quickly test interventions on a widely accepted in-vitro model of lymphatic vasculature. Explaining why research lags far behind and why only small incremental advances are achieved.

This SBP topic is designed to encourage the development of a commercially available lymphatic vasculature assay kit - The LymphoLab ProDiscover Kit. This kit will facilitate a relatively rapid and standardized platform to test the effect of drugs, cells, and factors of the microenvironment on the function and formation of lymphatic vasculature.

Currently to test a drug we use either an animal model or cells. But 9 out of 10 drugs that work in these models fail in humans. We need better tool kits most importantly for the lymphatic system.

Activities and Deliverables:

Phase I: Prototype development

• Devices should adhere to the following design principles.

o Fabrication with biocompatible materials o Suitable for use by researchers with minimal training. The kit should not require advanced dissection and surgical skillsets.

o Operable in a lab with relatively typical biomedical research equipment (biosafety cabinet, cell culture flasks and well plates, incubators) outside of provided components.

• Design choices should reflect a strong fit to a specific lymphatic anatomy and regional microenvironment.

• The platform should facilitate tracking of lymphatic vascular formation. Easy integration with at least one imaging modality to track growth and function is required.

• Strong proposals should allow for some level of modularity or customization.

o Altering extracellular matrix component or biomechanics to mimic various physiological and pathological states.

o Ability to integrate closely associated cells and tissues (immune cells, blood vasculature, fibroblasts).

o Facilitates flow to recapitulate interstitial fluid flow or lymph flow.

• The design should facilitate the study of at least one phenotypic marker below:

o Protein or expression o Genomic, proteomic, or other transcriptomic based analysis o Cellular proliferation

• Applications should be responsive to at least on design consideration, although we encourage models to incorporate aspects from more than one “track” below:

Track Design Considerations

Lymphatic endothelial cell (LEC) communication o Culture with LECs and at least one additional cell type o Facilitates cell collection post experimental duration

Lymphatic capillary o Facilitates intraluminal flow at physiological flow rates.

Lymphatic Collecting Vessel o Facilitates intraluminal flow at physiological flow rates.

o Application of cyclic strain (at least

0.1 Hz and 5% elongation)

Phase II: Testing and scaling o Based on the selected track the proposal should demonstrate effectiveness of the platform at recapitulating the following:

Track Minimum functionality

Lymphatic endothelial cell (LEC) communication o Measurable lymphangiogenic response to VEGFC

Lymphatic capillary o Drainage of common lymph components o Staining or visualization of capillary junctions

Lymphatic Collecting Vessel o Measurable response to common vasoconstrictors o Staining or visualization of cellular junctions o Scaling the platform to allow for the studying of at least two experiment conditions in triplicate.

Conduct studies to validate the platforms sensitivity to well established stimulation, for example to VEGFC exposure.

ARPA-H 03 - Continuous Monitoring of Vascular health using Smart Biomimetic Implantables

Budget (total costs, per award): Phase I: up to $600,000.00 for 6 months to 2 years. Phase II: up to $3,500,000.00 for 1 to 3 years. It is strongly suggested that proposals adhere to the above budget amounts

The SBP program will support the development of a medical device prototype that aims to create a smart implantable stent or vascular graft that will both structurally correct for a vessel blockage and become a cardiovascular (CV) health monitoring tool with each biomarker (hemodynamics, troponin) normalized to the specific user’s baseline(s) and accurately measure biomarkers throughout the lifespan of the patient. The stent will be powered by and transmit data to a health app wirelessly, and continuously monitor CV biomarkers including vessel occlusion, flow, arterial pressure, and troponin levels. Even moderate success in detecting biomarkers early has demonstrated significant improvement in health outcomes. Early detection of troponin has resulted in a 55% reduction in death or myocardial infarction and continuous hemodynamic monitoring has been shown to reduce hospitalization by 28%. The program represents the gateway toward long-term continuous implantable biosensors through development of core biomimetic materials that enabling monitoring of any measurable biomarker in any tissue.

The purpose is to accelerate the development of the first commercially available smart stent or vascular graft. The Phase I SBP will aim to generate an initial prototype capable of making flow and occlusion measurements wirelessly and Phase II will include the measurement of troponin, an integrated data hub, and initial testing in a large animal model. There is a window of opportunity for a small business uniquely positioned to disrupt this space prior to new entrants challenging the status quo.

Specific requirements include:

• Similar safety profile to existing solutions, including biocompatibility (minimal cytotoxicity less than 15%) and mechanical properties (hydrodynamic pulsatile loading).

• Utilization of new or existing materials for optimized intervention (stent, graft) design.

• Optimization to maximize the necessary efficiency of wireless charging/power and data transfer.

• Data transfer must be secure and with minimal threat to privacy (e.g., only transfer meta data)

• Manufacturing methods to enable practical, scalable, and cost considerations.

• Demonstration of sensor performance using a vessel phantom.

Non-responsive approaches include:

• Modeling and simulation tools that do not result in an actual prototype.

• Using materials that are cytotoxic or have low biocompatibility.

• Hardware that requires standard battery power only (no wireless component), plugs/wires, or is lacking a wireless data transfer capability. Namely, the medical device should be an implantable with no external hardware required to be on the body to function (except for the external data/power hub to be placed in the home).

Background:

Cardiovascular disease (CVD) is one of the most prevalent diseases in the US with over 17 million deaths annually comprising one of every 4 deaths that occur. The most common CVD condition is coronary artery disease which results from the build-up of unwanted debris in blood vessels or arthrosclerosis (ASVD). Over time, these arteries can become narrow, limiting oxygen and nutrient exchange and can lead to health complications including heart attack, stroke, and even death. Treatment of ASVD is typically conducted by balloon angioplasty, stent (small wire mesh tubes) placement, or through surgical bypass graft. Balloon angioplasty works by inserting a catheter with a balloon inside the narrowed vessel and inflating the balloon to reopen the vessel (and place a stent in most cases), release the blockage, and restore blood flow. Once blood flow is restored the balloon is removed leaving the stent in situ to hold the vessel open. Alternatively, a healthy vessel from another part of the body or synthetic vessel can be grafted to restore blood flow by circumventing the blockage. Over 3 million vascular graft and stent procedures are performed in the US each year, yet 30-50% of patients experience vessel re-narrowing in the first year and the 30-day mortality rate for thrombosis is 25%. Typical post-procedure or post-surgical follow up includes physical exam, imaging, and blood testing including serum lipid levels at 1 month, 6 months, and annually thereafter. Imaging is costly ($100 - $400, CT scan), can have artefacts and only provides a snapshot of existing health. And while biomarkers such as troponin, a protein found in heart muscle cells which is elevated for 4 days post cardiac damage is a sign of significant complications such as acute coronary syndrome it can be missed. Thus, post procedure gaps in monitoring the early detection on restenonsis and/or thrombosis following cardiac stent or bypass grafts remain a significant morbidity and mortality. Other challenges are long-term biocompatibility issues and mechanical properties to avoid collapse/failure.

Activities and Deliverables:

The Phase I deliverables will be a prototype (smart stent or vascular graft) which is: (1) biocompatible, (2) mechanically feasible for human use, (3), wireless power and data transfer, and (4) capable of hemodynamic measurement. The Phase II deliverables will also include the addition of (1) a troponin biosensor, (2) anti-biofouling mechanism, (3) smart phone app, and (4) initial in vivo testing.

Phase I Midterm exams

1. Should only use biocompatible materials

2. Hydrodynamic pulsative loading equivalent to 72 beats per min for 380 million cycles

3. Powering output >1 dBm at 1m

4. Hemodynamic sensor (e.g., capacitive) pressure and flow accuracy >60%

Final exams

1. Demonstrate >85% biocompatibility via MTT assay

2. Optimized design for smart implantable completed, pass a comprehensive design review

3. Power output > 5 dBm and data transfer rate > 200nkbps at 1m

4. Hemodynamic sensor >75% accuracy for flow and occlusion in phantom

Phase II Midterm exams

1. Troponin sensor demonstrates 75% in vitro sensitivity and specificity

2. Demonstration of anti-biofouling sensor coating/filter with no more than 10% loss of sensitivity after 6 months in human serum

3. Smart phone app to display data readouts for user and integration with the EHR for physician viewing

Final exams

1. Smart phone app flags significant changes with 20% variance from baseline

2. Test in large animal model with 85% biocompatibility and accuracy for all biomarkers

ARPA-H 04 - Personalized medicine platform for predicting response to immunotherapy

Budget (total costs, per award): Phase I: up to $600,000.00 for 6 months to 2 years. Phase II: up to $3,500,000.00 for 1 to 3 years. It is strongly suggested that proposals adhere to the above budget amounts

To address the problems listed below, there is a pressing need for clinical platforms/approaches capable of guiding clinicians in selecting the most appropriate immunotherapeutic strategy for each patient. For this, we envision a method capable of capturing the intricate molecular and immune landscape of tumors to extract predictive biomarkers for use in robust models that will facilitate improved cancer prognosis. Hence, the goal of this topic is to catalyze innovative developments in personalized medicine that address the complexities of immunotherapy response prediction in a clinically employable manner.

Due to the urgency of this public health need, projects supporting the validation of an already existing approach will be prioritized. Background data may include rigorous preclinical testing (e.g., known responder syngeneic mice models), or preliminary results from observational clinical trials. Applications focusing solely on basic science research such as: biomarker identification in in vitro and/or animal models, generation of new animal models and/or mechanistic studies, are not considered responsive. The platform must be capable of providing response prediction prior to the patient undergoing initial treatment – hence, not include any markers measured past treatment start. In addition, platforms that would take an unreasonable amount of time to deliver a clinically actionable prediction or submissions that do not aim to successfully predict response across a range of cancer types will not be considered. Proposers should recognize that neoadjuvant therapy (i.e., chemotherapy in combination with ICI) is the current standard of care in the United States.

Background:

Cancer immunotherapy is a transformative approach to cancer treatment that harnesses the body's native immune system to recognize and eliminate cancer cells. Importantly, therapies such as immune checkpoint inhibitors (ICI) have demonstrated curative potential in a subset of patients across a variety of malignancies.

Despite these achievements, significant challenges remain – particularly in predicting response to ICI on an individual basis prior to treatment inception. Unfortunately, only 15-20% of patients achieve durable results in response to ICI at present. Indeed, the efficacy of immunotherapy is influenced by a complex interplay of factors such as tumor heterogeneity, the immune microenvironment, and a myriad of other patient-specific characteristics. Hence, identifying biomarkers and developing predictive models that can reliably forecast an individual patient's response before therapy begins is a critical unmet need.

Current clinical practice often relies on trial-and-error approaches, where patients undergo immunotherapy without knowing whether they will respond favorably. Dedicated effort has been directed towards improving this standard of care – such as by employing multiplexed IHC of fixed biopsy tissue to derive phenotypic biomarkers (e.g., cytotoxic T cell density, antigen expression of tumor cells, etc.) for subsequent use in predictive models, but the clinical utility of these developments is demonstrably inadequate. Altogether, this unpredictability not only hinders treatment optimization but oftentimes leads to unnecessary side effects, as well as significant financial burdens on the healthcare system.

Activities and Deliverables:

Phase I activities and deliverables:

• Optimization of platform and/or workflow for clinical use

• Identification of predictive biomarkers and their weighted importance (i.e., cannot be a “black box”).

o Specifically, the proposers must have a plan in place for interpretable/explainable AI if their approach calls for it.

• Validation of predictive utility in relevant animal models (e.g., patient-derived xenograft models) using two ICI antibodies (e.g., vehicle vs. PD-1 vs. CTLA-4 vs. PD-1 & CTLA-4 combination).

• Identification of metrics that will be used to reflect immune response ground-truth in human population (e.g., quantitative changes in tumor burden, symptomatic surveys, etc.).

• Proposers must identify an appropriate number of clinical partners able to collect data in patients treated with neoadjuvant immunotherapy alone (as opposed to the standard of care chemotherapy + immunotherapy) o Alternative solutions could be proposed that would disentangle the effect of chemotherapy and immunotherapy, if the two are given concomitantly.

• IRB submission and approval (pilot study in adult population)

• Interviews with immunologists, oncologists and/or other relevant clinical staff to ensure the acceptability of the proposed solution.

• Development of action plan for collecting ground-truth response in human population

• Finalization of predictive model for feasibility testing in at least two cancer types (human)

• Run prospective observational trial with markers deemed important from phase I activities.

o Highly directed population studies should be considered to ensure sufficient pool of responders (e.g., microsatellite instability high (MSI-H) colorectal cancer population)

• Rigorous comparison with known response rates are required

• Collect user feedback, implement quality improvement initiatives based on the findings

• Workflow and algorithm adjustment, if necessary, to account for potentially critical biomarkers

• Regulatory submissions in preparation for 510k.

ARPA-H 05 - Saving Baby Hearts: Fully Autonomous Neonatal Echocardiography for the Diagnosis of Critical Congenital Heart Disease

Only Direct to Phase II proposals will be accepted.

Budget (total costs, per award): up to $3,500,000.00 for 1 to 3 years. It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

Objective:

Develop the first-in-class fully autonomous, simple-to-use, low-cost, universally accessible complete echocardiography device for neonates at risk of cyanotic (fatal) congenital heart disease

Potential performers must develop:

1. A fully autonomous, reusable, low-cost simple multisensory ultrasound probe with at least 12 mHz resolution with pulse wave/continuous and color Doppler and 2-D imaging

2. The device must be able to be used without any training and require placement in only a single anatomical location (e.g. below the xiphoid process) and obtain all images without further operator intervention (i.e. fully autonomous), within 5 minutes of scanning.

3. The probe must allow for complete collection and transmission of all data with DICOMM or appropriate format for integration via standard informational exchange programs to standard cardiac imaging software via wireless technology

4. The device must also include software interpretation or at-least augmented autonomous reading to indicate low- or high-risk for congenital heart defects, with clinical grade performance for positive and negative predictive value

5. The device should be tested in clinical settings on at least 500 live human newborns to feasibility of image capture

6. The device should be validated with echocardiography on at least 100 known newborns with CCHD to establish capability to detect anomalies

7. The device ideally will interface with commonly available smartphone technology to allow for ease of viewing and sharing of imaging data in settings lacking point-of-care echocardiography hardware

Background:

The Centers for Disease Control and Prevention reported that the infant mortality rate in the United States was 6.71 per 1,000 live births, which was widely reported as being higher than other developed countries.

Birth defects, especially involving the heart, are an important cause of these deaths.

Traditionally, prospective mothers have prenatal sonograms to look for birth defects. But the quality of these scans varies widely, depending on the skill of the technician and the supervising doctor. In addition, past guidelines supported by the American College of Obstetricians and Gynecologists mandate only a limited “four-chamber view” of the heart. As a result, only one-quarter of major heart defects are identified prenatally by routine obstetrical ultrasounds.

Unfortunately, when heart defects are missed by prenatal ultrasounds, pediatricians also have a hard time telling if critical cardiac problems are present. Normally, doctors examining newborns suspect heart defects if they hear a loud rushing noise (a “murmur”) with a stethoscope, notice the child has a bluish color, or lacks a pulse in the lower extremities. But in 1999, British researchers found that half of serious heart defects were missed by routine exams after birth—especially in babies with dark skin. If sent home, these newborns become seriously ill and can die.

To address this need, in 2011, the U.S. Secretary of Health and Human Services recommended that all newborns receive pulse-oximetry screening before hospital discharge. If abnormal, complete echocardiography would be performed prior to hospital discharge for the neonate. While this has been a key advance to save some babies, infants who screen positive are still subject to (in many areas such as rural locations or specialty care deserts) emergency transport far from home for diagnosis echocardiography, which can be extremely disruptive for false positives. Further, it’s estimated pulse oximetry still misses 30-50% of major congenital heart disease. We need a far better test.

Year 1: Completion of hardware prototype with complete high quality image capture performed on at least 5 human newborns and full integration with standard smartphone and electronic-health-record data transfer.

Year 2: Development of autonomous image classification technology stack to correctly identify the following CCHD conditions: d-TGA, Tetralogy of Fallot, hypoplastic right and left heart syndromes, and severe pulmonary or aortic stenosis.

https://www.ncbi.nlm.nih.gov/pubmed/9892769?dopt=Abstract https://fn.bmjjournals.com/cgi/content/abstract/80/1/F49 https://fn.bmjjournals.com/cgi/content/abstract/80/1/F49 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4892233/

Year 3: Enrollment and clinical validation in cohorts of at least 500 human newborns (normal) and 100 newborns with CCHD, culminating in device go-to-market strategy.

ARPA-H 06 - Improving Identity and Access Management with Clinical Context

Only Phase I proposals will be accepted.

Budget (total costs, per award): Phase I: up to $600,000.00 for 6 months to 2 years. It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

Objective:

The overall purpose of this topic area is to create novel IAM systems for healthcare that:

• Prevent data exposure and reduce potential breach blast radius by enabling unified control execution in a federated environment.

• Streamline access authorization, allowing clinicians and administrators to focus on providing better health outcomes.

• Leverage artificial intelligence to detect misconfigurations and other risks not visible while managing access at the individual asset level.

• Reduce the cost burden of IAM operations in complex hospital systems.

There has not been significant research into vendor-agnostic unification of enterprise controls (e.g., Active Directory) and clinical applications. Industry leaders in these domains have little incentive to create interoperable solutions. A small group of experienced security experts and developers could create a prototype system and potentially engage industry leaders without being viewed as a threat to their market share. Some vendors in the medical space have attempted this on a nano scale allowing multiple medical device access to be managed centrally in a middleware application. These attempts have been positively received in industry, but no attempts at larger scale unification have been done.

Some specific requirements for this topic area would include:

• Compatibility/mapping of Application Programming Interfaces (APIs) across access control layers and products

• Vendor-agnostic workflow automation for I.T. administrators

• Automation that can sense where insecure IAM configurations exist and flag for administrator review The following would be out of scope for this topic:

• Solutions that rely on endpoint detection and response (EDR) deployment or custom agents

• Approaches requiring hypervisor or embedded micro-kernel (e.g., Intel Management Engine) access.

• Hospital operational technology (OT).

Background:

This effort will improve the resiliency of Information Technology (I.T.) in healthcare by using the clinical context of an entity (e.g., device, user account, software service, etc.) to inform Identity and Access Management (IAM) policies and decisions. Hospitals face challenges in meeting IAM industry best practices, as highlighted in HHS 405(d) Program’s “Hospital Cyber Resiliency Initiative Landscape Analysis,” as an “Urgent Need for Improvement.”

By exploring the feasibility and creating prototypes of integrated IAM systems, future large-scale development efforts will be deployed at significantly lower risk, improving patient safety and securing access to care for rural communities.

Today, healthcare I.T. environments have minimal connectivity between all the layers of the access control “stack”, from network access controls (NAC) up through clinical application-specific permissions. Each layer makes decisions without any regard to the state of the others. This leads to inefficient use of resources and preventable security issues. Unified, automated IAM processes will enable new, resilient controls that adapt based on changes in the clinical context of an entity.

Phase I activities and deliverables:

Deliver a working prototype of a successful, limited overhead IAM model working in a simulated small-scale medical environment.

Provide a clear road map on how this effort can be scaled up to larger environments that approach the scale and IT complexity of a twenty-five (25) bed critical access hospital where IAM staff support is lacking.

Present this model to small, rural hospitals to for feedback, approval, and support.

2 PROGRAM DESCRIPTION

2.1 Background

The basic design of the ARPA-H SBIR program is in accordance with the Small Business Administration (SBA) SBIR Program Policy Directive dated May 3, 2023. This SBIR contract solicitation strives to encourage scientific and technical innovation in areas specifically identified by ARPA-H. The potential contributions of the proposed effort are relevant to health outcomes for all Americans. Specifically, ARPA-H’s mission is to benefit the health of all Americans by catalyzing health breakthroughs that cannot readily be accomplished through traditional research or commercial activity. The guidelines presented in this solicitation reflect the flexibility provided in the Policy Directive to encourage proposals based on scientific and technical approaches most likely to yield results important to ARPA-H and to the private sector.

2.2 Phased Program

The SBIR program consists of separate phases. Note: At this time, ARPA-H is only accepting Phase I, Direct to Phase II, and Fast-Track proposals for this solicitation. Please refer to the individual topics above for more information.

Phase I: Feasibility The objective of Phase I is to determine the scientific or technical feasibility and commercial merit of the proposed research or R&D efforts.

Phase II: Full R/R&D Effort The objective of Phase II is to further develop the research or R&D efforts initiated in Phase I. If your project has already demonstrated feasibility, you may prepare a Direct-to-Phase II proposal and begin your Federal SBIR award at Phase II.

Phase III: Commercialization stage without SBIR funds Phase III refers to work that derives from, extends, or completes an effort made under prior SBIR/STTR Funding Agreements, but is funded by sources other than the SBIR/STTR programs. Each of the following types of activity constitutes SBIR/STTR Phase III work:

(i) Commercial application of SBIR/STTR funded R/R&D that is financed by non-Federal sources of capital.

(ii) SBIR/STTR derived products or services intended for use by the Federal Government, funded by non- SBIR/STTR sources of Federal funding.

(iii) Continuation of SBIR/STTR work, funded by non-SBIR/STTR sources of Federal funding including R/R&D. For HHS SBIR/STTR projects, Phase III is primary financed by non-Federal sources of capital.

The competition for SBIR Phase I and Phase II awards satisfies the competition requirements of the Competition in Contracting Act. Therefore, for an agency that wishes to fund an SBIR project beyond the Phase II, it is sufficient to state for purposes of a Justification and Approval pursuant to FAR 6.302-5 that the project is derived from, extends, or logically concludes efforts performed under prior SBIR funding agreements and is authorized under 10 U.S.C. 2304(b)(2) or 41 U.S.C. 253(b)(2).

2.2 Direct to Phase II Proposals

If your project has already demonstrated feasibility, but you have not received a Phase I SBIR or STTR award, you can apply for a Direct to Phase II award and bypass Phase I. Small business concerns applying for Direct to Phase II awards must have already built a technology prototype and tested its technical feasibility (i.e., completed Phase I type R&D or another effort). Phase II type R&D tests the functional viability of the prototype according to scientific methods and potential for commercial development. Refer to Section 1.1 List of Topics for notation of Topics allowing Direct to Phase II proposals.

2.3 Fast Track Proposals

A Fast Track submission may result in an initial award for Phase I with a contractual option that the Government may exercise to continue the award on to Phase II. The Government is not obligated to fund the Phase II portion unless and until ARPA-H exercises that option. This mechanism allows for streamlined processes that have the potential to significantly minimize the funding gap between Phase I and Phase II.

If a Topic notes that Fast Track proposals will be accepted, a Phase I proposal and a Phase II proposal may be submitted simultaneously. As described in Section 4.2 “Proposal Instructions,” a Fast Track submission consists of one complete Phase I proposal and one complete Phase II proposal, separately paginated. The Phase I proposal and Phase II proposal will be separately evaluated as set forth in Section 3.3 “Technical Evaluation Criteria.”

3 METHOD OF EVALUATION

All proposals will be evaluated on a competitive basis. Each proposal will be judged on its own merit. ARPA-H is under no obligation to fund any proposals or any specific number of proposals in each topic. It may also elect to fund several or none of the proposed approaches to a given topic.

3.1 Evaluation Process

ARPA-H will conduct a preliminary (initial) review of each proposal, followed by a full (final) scientific/technical review of conforming proposals as described below. Conforming proposals must comply with all requirements detailed in this solicitation; proposals that fail to do so may be deemed non-conforming and may be removed from consideration.

Initial Review - Proposals shall undergo a preliminary review process in which only those proposals deemed to have the highest non-priced technical criteria stated in Section 3.3 will be discussed and assigned an overall impact/preliminary confidence rating as defined under Section 3.3 Technical Evaluation Criteria.

Given this, the lowest rated applications will not be considered for a full scientific/technical review.

Final Review - Proposals will be evaluated based on their individual merits rather than against each other since they are not submitted in accordance with a common work statement. Award(s) will be made to proposers whose proposals are determined to be the most advantageous to the Government, consistent with instructions and Sections 3.2 and 3.3 herein, and availability of funding.

The scientific/technical review members will determine whether each proposal is technically acceptable, meaning that it demonstrates sufficient technical understanding and capabilities to perform the technical objectives set forth in the solicitation.

3.2 Award Decisions

To receive an award, offerors must be eligible according to the requirements defined in SECTION 6 – PROPOSAL FUNDAMENTALS, Section 6.2 Offeror Eligibility and Performance Requirements. ARPA-H will make awards to the offerors who provide the best overall value to the Government, considering the below:

• Ratings resulting from the technical evaluation.

• Areas of high program relevance to the ARPA-H Mission. The ARPA-H mission is to accelerate better health outcomes for everyone by supporting the development of high-impact solutions to society’s most challenging health problems. Therefore, an award decision will be made to the extent proposals align to and further ARPA-H’s mission.

• Program balance (i.e., balance among areas of research).

• Availability of funds and cost/price reasonableness

3.3 Technical Evaluation Criteria

The Government will assess its level of confidence that the Contractor will successfully perform the requirements based on the below criteria. The technical evaluation criteria are of equal importance and confidence ratings will be assigned as defined below. Offerors shall provide sufficient information for the Government to determine its level of confidence in the ability of the Offeror to perform the requirements of the solicitation.

High Confidence The Government has high confidence that the Offeror understands the requirement, proposes a sound approach, and will be successful in performing the contract with little or no Government intervention.

Some Confidence The Government has some confidence that the Offeror understands the requirement, proposes a sound approach, and will be successful in performing the contract with some Government intervention.

Low Confidence The Government has low confidence that the Offeror understands the requirement, proposes a sound approach, or will be successful in performing the contract even with Government intervention.

Non-price Factors:

1. The soundness and technical merit of the proposed approach. Identification of clear, measurable goals (i.e., milestones) that have a reasonable chance of meeting the topic objectives.

2. The potential of the proposed research for technological innovation – whether the end product or technology proposed would offer significant advantages over existing approaches, methodologies, instrumentation, or interventions currently utilized in research or clinical practice.

3. The potential of the proposed research for commercial application - whether the outcome of the proposed research activity will likely lead to a marketable product or process considering the offeror’s proposed methods of overcoming potential barriers to entry in the competitive market landscape.

4. The qualifications of the proposed Principal Investigators, Project Directors, supporting staff and consultants, and the appropriateness of the leadership approach (including the designated roles and responsibilities, governance, and organizational structure).

3.4 Price Factor

Price:

A price evaluation will be conducted to ensure that the proposed price is reasonable. The Government may use various price evaluation techniques and methodologies to ensure the proposed price is reasonable. An assessment that the proposal price is not reasonable may result in the proposal being non-selectable for award.

4 PROPOSAL PREPARATION AND INSTRUCTIONS

4.1 Introduction

It is important to read and follow the proposal preparation instructions carefully, which are outlined below.

Pay special attention to the requirements concerning Human Subjects and use of Vertebrate Animals if your project will encompass either item.

4.2 Proposal Instructions

A complete Phase I proposal consists of a Technical Proposal (Appendix A) and a Business Proposal (Appendix B). A complete Phase II proposal consists of a Technical Proposal (Appendix C) and a Business Proposal (Appendix D). Each proposal will be submitted via the application template in the corresponding Appendix.

For Fast-Track submissions, both a complete Phase I proposal and a separate, complete Phase II proposal must be submitted. To identify the submission as a Fast Track proposal, check the box marked “Yes,” next to the words “Fast Track Proposal” shown on the Phase I and Phase II applications. The Phase I proposal and the Phase II proposal in a Fast Track submission will be evaluated and scored individually. However, if a Phase I proposal is evaluated and found to be unacceptable, the corresponding Phase II Fast Track proposal will not be evaluated.

Please see below for additional proposal submission instructions.

Human Subjects and Clinical Trials Information Form and Attachments

Appendix A.1. is required for every proposal submission. If your proposal does not involve Human Subjects or Clinical Trials, you must still note this on the form and submit the form. If applicable, Appendix A.2. – Study Record must be attached to Appendix A.1.

• APPENDIX A.1 — HUMAN SUBJECTS AND CLINICAL TRIALS INFORMATION FORM

Instructions to complete this form can be found at:

https://grants.nih.gov/grants/funding/SBIRContract/ContractAppendixH.1.pdf

• APPENDIX A.2. — STUDY RECORD, ATTACHMENT TO HUMAN SUBJECTS AND CLINICAL TRIALS

INFORMATION FORM

For SBIR Phase I and II Technical Proposals, the Human Subjects and Clinical Trials Information form and its attachments (Appendix A.1., and, if applicable, Appendix A.2.) are excluded from Appendix A and are to be submitted as a separate document from the Technical Proposal. There is a field in the eCPS proposal submission website that is specifically identified for upload of the Human Subjects and Clinical Trials Information Form and its attachments, separate from the Technical Proposal.

Business Proposal

The award will result in a Firm-Fixed Price (FFP) contract type. The Business Proposal includes the Pricing Proposal and Summary of Related Activities, as well as the following:

1. SBIR Application VCOC Certification, if applicable. See SECTION 6 – PROPOSAL FUNDAMENTALS to determine if this applies to your organization. If applicable, please complete this form in Appendix B

- Business Proposal.

2. Proof of Registration in the SBA Company Registry is required at proposal submission. Refer to SECTION 6 – PROPOSAL FUNDAMENTALS for directions. All applicants to the SBIR and STTR programs are required to register at the SBA Company Registry prior to proposal submission and attach proof of registration to the Business Proposal.

5 PROPOSAL SUBMISSION

5.1 How-to-Submit

Offerors are responsible for submitting proposals to the electronic Contract Proposal Submission (eCPS) website…