ARPA-H-SOL-25-115 - OCULAB ISO FINAL DRAFT 11.4.24.pdf

ARPA-H-SOL-25-115, OCULAB

Ocular Laboratory for Analysis of Biomarkers (OCULAB) Health Science Futures (HSF) Office

Innovative Solutions Opening ARPA-H-SOL-25-115 November 4, 2024

Contents

PART I: OVERVIEW INFORMATION

PART II: FULL TEXT OF ANNOUNCEMENT

1. ISO Description

1.1. Program Overview

1.2. Technical Approach and Structure

1.3. Program Goals and Metrics

1.4. General Requirements

2. Award Strategy

3. Eligibility Information

3.1. Eligible Applicants

3.2. Non-U.S. Organizations

4. Submission Information

4.1. ISO Package

4.2. Content and Form of Submission

4.3. Funding Restrictions

4.4. Questions

5. Application Review Information

5.1. Evaluation Criteria

5.2. Review of Solution Summaries and Full Proposals

6. Award Administration Information

6.1. Selection Notices and Notifications

6.2. Reporting

6.3. Electronic Systems

7. Agency Contacts

8. Other Information

APPENDIX A: SOLUTION SUMMARY TEMPLATE

APPENDIX B: SUPPLEMENTARY TABLE

PART I: OVERVIEW INFORMATION

Federal Agency Name – Advanced Research Projects Agency for Health (ARPA-H), Health

Science Futures Office ISO Title – OCUlar Laboratory for Analysis of Biomarkers (OCULAB) Announcement Type – Initial Announcement ISO Number – ARPA-H-SOL-25-115 Dates o Posting Date: [November 4, 2024] o Proposers’ Day: [December 12, 2024, 9:00 AM to 5:00 PM ET] o Proposers’ Day Registration Deadline: [December 5, 2024, 5:00 PM ET] o Solution Summary Due Date and time: [January 27, 2025, 5:00 PM ET] o Proposal Due Date and Time: [April 14, 2025, 5:00 PM ET]

Concise description of the opportunity – The OCULAB program seeks to make diagnosis, monitoring, and treating ocular and systemic conditions like dry eye disease more precise, more efficient, and less invasive for patients. The program will build on advancements in continuous monitoring biosensor technologies, sustained-release ocular drug devices, and AI algorithms for therapeutic delivery to alleviate the burden of patient medication compliance, improve data collection for ocular and systemic disease, and ultimately improve patient outcomes. The OCULAB platform consists of two (2) primary components: a biosensor to continuously monitor tear biomarkers which must fit in the form factor of a punctal plug or comparable tear duct insert, and a disease-modifying therapeutic which will be automatically delivered via an AI-enabled closed-loop system from the same housing as the biosensor or from a separate periocular implant.

By utilizing validated disease biomarkers present in tears and employing AI algorithms to drive closed-loop delivery of a therapeutic, OCULAB has the potential to become the first in situ tear biomarker measurement system, the first continuous monitor of multiple systemic chemistry biomarkers, and the first AI-powered closed loop ultra-precise medication delivery system.

Anticipated individual awards – Multiple awards are anticipated.

Potential award instruments – Cooperative Agreements or Other Transaction (OT)

Agreements

Cost Sharing - Cost sharing is not required but may be proposed where appropriate.

Agency Contact – All inquiries shall be sent to OCULAB@arpa-h.gov.

mailto:ILAB@arpa-h.gov

PART II: FULL TEXT OF ANNOUNCEMENT

1. ISO Description

This publication constitutes a merit-based process in accordance with 42 U.S.C. § 290c. Any resultant award negotiations will follow all pertinent laws and regulations.

The mission of ARPA-H is to accelerate better health outcomes for everyone by advancing innovative research that addresses 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. ARPA-H seeks proposals to develop ocular-based technologies within the continuous monitoring biosensor and closed-loop therapeutic dosing space for use in treating dry eye disease and a range of other ocular, neurological, and systemic conditions. The focus will be on leveraging existing knowledge in the fields of tear biomarkers, nanoscale biosensors, drug-eluting extraocular devices, and AI-based wearable biosensors to achieve this goal.

It is important to note that specifically excluded are proposals that: 1) offer incremental improvements to the existing state-of-the-art, 2) propose rigid gas-permeable lens-based technologies, 3) do not address cost of goods, manufacturability, and product quality from the onset of the program, 4) do not address the objectives of the program, 5) direct policy changes, traditional education and training, or center coordination and construction of physical infrastructure, which are outside the scope of the ARPA-H mission.

1.1. Program Overview

In patients, the absence or presence of disease may be identified and inferred through quantification of biomarkers (e.g., glucose, hormones, enzymes, and others). Currently, blood tests remain the gold standard for quantifying most biomarkers, but there are multiple drawbacks to this approach. In-office blood draws only capture biomarker levels at one point in time, which presents an incomplete picture of health. Blood testing can also be highly distressing to patients who fear needles. As a result, non-invasive testing of clear fluids such as saliva, urine, and tears have gained popularity as alternative sources of biomarkers. Of these options, tears represent the most readily accessible source of biomarkers for continuous monitoring. Tears are produced by the lacrimal gland as a hypotonic ultrafiltrate of blood plasma, and therefore contain many of the same biomarkers seen in blood, including glucose, cytokines, hormones, and enzymes, without the formed elements which can promote sensor biofouling like red and white blood cells. Compared to paradigms that collect and analyze fluid biomarkers at only one timepoint (e.g. a blood or urine test), continuous monitoring allows for 24/7/365 collection of biomarker data which can provide a fuller picture of complete health status.

The OCULAB program seeks to improve the diagnosis, monitoring, and treatment of ocular, systemic, and neurological conditions via the development of a platform for the sensing of disease biomarkers in tear fluid and the continuous controlled delivery of therapeutics to alter disease progression. The first target of the OCULAB platform will be dry eye disease (DED), an underdiagnosed condition affecting over 20 million Americans, with the greatest incidence occurring in patients over 50 years of age and women, and most particularly post-menopausal women. DED is a multifactorial condition characterized by a deficiency in the quantity or quality of tears, leading to ocular surface inflammation and damage. This chronic condition can cause symptoms ranging from ocular discomfort to fluctuating vision. The underlying causes of DED are diverse, including factors such as aging, environmental conditions, autoimmune diseases like Sjögren's syndrome, and the use of contact lenses or digital devices.

Currently, the diagnosis of DED involves:

• a comprehensive in-office evaluation that includes patient history, symptom assessment, and clinical testing

• questionnaires like the Ocular Surface Disease Index (OSDI) to quantify the severity of symptoms

• clinical tests to assess tear film stability, tear production, and ocular surface health

• quantitative in-office assessment of validated tear biomarkers for DED including, but not limited to:

o tear osmolarity o matrix metalloproteinase-9 (MMP-9) o lactoferrin

While DED is the first target of the OCULAB program, performers may also be tasked with creating a biosensor to detect tear-based biomarkers for a second disease state of their choosing which follows a similar justification to what was presented for DED above. The second disease state selected must be corroborated with evidence of multiple (≥ 2) validated, diagnostic disease biomarkers present in tears whose detection would preclude the need for drawing blood or other diagnostic fluid (Appendix B). Patients with the proposed second disease state should also benefit from biomarker testing that occurs continuously, or multiple times a day at the minimum. The use of the OCULAB biosensor should markedly improve a patient’s quality of life (QoL) in a second disease state.

Subsequent to diagnosing and monitoring, disease treatment must also be considered and will be incorporated into the OCULAB program. Treatment for chronic diseases is often reliant upon a patient’s compliance with their medication regimen, and patient compliance is often far poorer than what is reported. Many patients simply forget their medications, or they have anxiety about adverse effects. Chronic diseases also require multiple medications which can be cost-prohibitive for patients with lack of adequate medical coverage, and confusing for those who lack the social support to help them keep track of their prescriptions. For ophthalmic conditions like DED, currently available treatments simply reduce ocular surface inflammation and alleviate symptoms rather than modifying the course of the disease, resulting in patients feeling relief from their symptoms and ceasing to take their eyedrops. Many patients also dislike the sensation of receiving eye drops or miss the eye during application, and the drop often stings or burns upon application or causes redness later.

Another major drawback to topical ophthalmic drop application is systemic absorption. When drops are applied to the surface of the eye, only 5-10% penetrates the cornea, while approximately 50% gets absorbed by the skin or the mucus membranes of the nose and pharynx. Eye drops can be absorbed into the bloodstream within minutes, and plasma concentrations of ophthalmic medications often peak between 15 min-2 h. In fact, systemic absorption of eye drops has precluded innovation in the medical treatment of ophthalmic disease for decades (e.g., timolol, a potent topical ophthalmic glaucoma medication that is contraindicated in patients with heart or lung problems).

Jointly, these concerns about patient compliance and systemic absorption of medications have fueled innovation in the sustained ocular drug delivery space. Current implantable intra- or extra-ocular devices offer numerous benefits to patients, including removing the need for compliance to a medication regimen. Importantly, preclinical and clinical studies utilizing many of these devices have demonstrated no drug presence in plasma, indicating that smaller, more frequent doses enhance the therapeutic window of more potent therapeutics. Importantly, while these delivery devices hold therapeutic promise, current iterations are unresponsive to changing conditions such as levels of disease biomarkers, outside climate conditions, emotions, exercise, and the like.

Closed-loop systems represent a data-driven approach to medication delivery to ensure that interventions are personalized to the patient’s needs in real-time. One recent example is in the field of intravenous anesthesia, where algorithms are set by a clinician and trained on a patient’s vital signs to either add or maintain anesthetic dosage accordingly. Standard closed-loop systems operate in three (3) phases: data acquisition, processing, and dose adjustment in order to maintain the desired effect. The addition of AI to this system may allow for integration of additional/external data related to treatment (such as incorporating imaging data results to blood biomarker information in the case of closed-loop systems utilized in oncology) to further personalize medication delivery. However, to date, no such closed-loop system is available for the eye or for administering treatment in real-time in response to changes in tear biomarkers.

The OCULAB platform will build on these enabling technologies and integrate them into a combination tear duct-based sensor and therapeutic device (which may be housed together with the sensor or in a separate periocular device) designed to:

1. continuously monitor biomarkers for DED and other disease indications in tears

2. communicate with the cloud to store patient biomarker data

3. integrate biomarker levels with data collected from external wearable monitoring devices including, but not limited to, smart watches

4. apply a learning algorithm to trigger the closed-loop delivery of a micro-sized dose of a disease modifying therapeutic to the ocular surface

The goal of the OCULAB program is to make diagnosing, monitoring, and treating diseases like DED and other ocular, neurologic, or systemic conditions, more efficient and less invasive for patients, while simultaneously collecting, integrating and analyzing external biomarker data from common wearable devices to paint a fuller picture of patient health. The OCULAB program envisions a future where diagnosis and treatment occur noninvasively in a closed-loop system based around tear biomarkers, negating the need for frequent doctor visits, invasive blood testing, and compliance to complicated and expensive medication regimens.

1.2. Technical Approach and Structure

1.2.1. Technical Areas (TAs)

While blood sampling remains the gold standard for the diagnosis and monitoring of disease, there are some examples where diagnostic biomarkers are present at higher concentrations in tears compared to blood (e.g., Huntington’s Disease, cystic fibrosis). By comparison, there are some conditions where biomarker testing must occur continuously or multiple times a day (e.g., infertility), where a non-invasive test would significantly improve a patient’s quality of life. As a pervasive and costly disease with regularly fluctuating biomarker levels, DED fits both paradigms.

The current diagnostic and treatment regimens for patients with DED are insufficient due to:

• diagnosis being made on a point-in-time examination with clinical testing

• fluctuating biomarker levels as the result of environmental changes or circadian rhythms

• the lack of a potent and commercially available disease modifying therapeutic

• lack of patient compliance with their medications

The OCULAB platform seeks to revolutionize how dry eye, and other ocular, neurologic, and systemic diseases are diagnosed, monitored, and treated by:

• creating a permeable punctal plug (or comparable tear duct insert) housing a multiplex biosensor which can continuously monitor biomarkers in tears as they flow through

• utilizing a disease-modifying therapeutic either housed within the same casing as the biosensor, or in a separate device within the orbital/periorbital region, where therapeutic release is triggered in a closed-loop manner by detected changes in tear biomarker levels

Both devices must also be connected to the cloud for data storage, for the purposes of integrating data from the device and external wearable biosensors, and to enable a learning algorithm to detect and eventually predict biomarker changes and facilitate therapeutic release.

Figure 1. Components of the OCULAB platform

The OCULAB program is comprised of two (2) main technical areas (TAs) with three (3) track configurations detailed below. All performers must address both TAs. Each proposal must be milestone driven and must be structured in three (3) phases. See Sections 1.2.2 Program Structure and Options, and 1.3 Program Goals and Metrics for details.

Performers will pursue one of the following OCULAB program track configurations (Figure 2):

A. a single sensor (TA1) and closed-loop delivery device (TA2) for DED Note: This track requires participation in the Advanced Studies Track (see below)

B. a hybrid sensor (TA1) that can detect biomarkers for DED and a second disease indication of the performer’s choice, and a closed-loop delivery device for DED (TA2) Note: Performers choosing this track have the option to participate in the Advanced Studies Track (see below)

C. two separate sensors (TA1) for two disease indications (one of which must be DED) and a single closed-loop delivery device for DED (TA2) Note: Performers choosing this track have the option to participate in the Advanced Studies Track (see below)

Advanced Studies Track: This 18-month track begins at the conclusion of Phase 1 to enable future expanded sensor capabilities including, but not limited to, additional or multiple ocular, neurological, or systemic disease states, detection of infectious agents, greater sensor multiplexing capability (>15 analytes), or exploratory power sources or biomaterials. Proposals including this Advanced Studies track should provide the same details for capabilities as what is detailed in TA1 Phase 1 below. Participation in the Advanced Studies Track is required for Track A performers (above), and optional for performers who choose Tracks B or C (Figure 2). Track A performers may begin their Advanced Studies during Phase 1, provided they present their proposed studies for both DED and the Advanced Studies at the start of the program. They may refine their Advanced Studies proposal through Phase 1 until those studies begin.

Note: Teams may not utilize the Advanced Studies Track as means to refine their DED (primary track) plug to be within the required metrics. Importantly, participation in the Advanced Studies track will be dependent on Program Manager acceptance of the final proposal details submitted at the end of Phase I as well as performance against Phase I milestones.

Figure 2. Track Configurations

1.2.1.1. TA1: Continuously-monitoring nanosensor

Recent advances in continuous monitoring technology have been so widely accepted in everyday life that an estimated 25-33% of the US population owns a smart watch, and thus have continuous access to information about their heart rate, sleep cycles, blood oxygen levels, and other statistics.

Similarly, the first continuous glucose monitoring (CGM) device was recently commercialized to allow diabetics 24/7/365 information about their blood sugar. However, to date, no advancements have been made in the realm of ocular health, nor have tears been regularly utilized as the rich source of biomarkers that they are.

TA1 aims to develop multiplex nano-scale biosensors that can fit within the confines of a standard-sized (approx. 1 x 2 mm) permeable punctal plug or comparable tear duct insert. The sensor must be capable of detecting multiple (≥ 2) disease-related diagnostic biomarkers, be equipped with Bluetooth, Near Field Communication (NFC), or other capabilities in order to send collected information to the cloud for data storage and analysis and contain a power source. The punctal insert must also be hollow or permeable to allow for the free flow of tears through the sensor and into the physiological tear drainage system.

Performers will also design an algorithm which will integrate tear biomarker data with information from other wearable biosensors and learn to decipher biomarker level deviations related to disease from deviations related to situational changes (e.g., exercise, sleep, reflex/emotional tears).

A proposal must consider and provide information on each of the following aspects.

Phase I (18 months)

• The proposal must detail a research plan to develop a multiplex nanosensor prototype that meets size restrictions of the lacrimal canal (approx. 1 x 2 mm or comparably sized tear duct insert). This insert must be hollow or permeable to allow for the free flow of tears through the sensor for biomarker detection.

o Track A: Performers will build one nanosensor, which must have the ability to detect multiple diagnostic DED biomarkers, one of which must be tear osmolarity (lower limit = 270 mOsm) o Track B: Performers will build one nanosensor, which must have the ability to detect multiple diagnostic biomarkers each for DED and a second disease indication. Quantification of tear osmolarity is required.

o Track C: Performers will build two multiplex nanosensor prototypes, each with the ability to detect multiple diagnostic disease-related biomarkers. The DED sensor must have the ability to detect tear osmolarity.

• Biomarker selection must be justified by preliminary data or a thorough review of the literature, prioritizing specific and diagnostic biomarkers with the greatest disease relevance.

• A clear rationale must also be included for the selected degree of multiplexing. Priority should only be given to the minimal required biomarkers which indicate disease presence, absence, and/or progression.

• The proposed devices must maintain ≥ 99.9% threshold of baseline performance with a longevity of at least one-month post-insertion during this phase.

• The proposal must include details about the sensor’s components, including biosensing mechanism(s), interface, signal transducer, mechanism of connectivity (Bluetooth, NFC or other), and power source.

• The proposal must detail the anti-fouling technology that will be employed to maintain bioassay performance over the required one-month longevity requirement.

• The sensor must respond to any change in analyte concentration within the relevant physiological range in ≤ 30 minutes.

• Sensor readings and related algorithms should demonstrate at least 85% sensitivity (true positives / (true positives + false negatives) in detection of all biomarkers at a clinically relevant concentration threshold by the end of this phase.

• Performers should determine the linear range of detection for each biomarker:

o Limits of detection (LOD) should be within 5% of the lowest physiologically relevant value of each analyte. Lowest values may occur in either healthy or diseased states.

• Safety mechanisms that would be triggered in the event of device failure or loss of connectivity.

• Details of algorithm including, but not limited to:

o Relevant external data to be collected from other wearable devices (e.g., heart rate, exercise status, sleep status, and others).

o Explain how the algorithm will be trained to distinguish between disease-related deviations in tear biomarkers and deviations caused by other situations. If or how the patient or their doctor will be alerted of disease-related changes in tear biomarkers o Storage requirements for collected data.

o How data will be stored locally and how/when information will be pulled.

o Frequency and timing of data uploads to the cloud.

o Data security considerations.

o Biomarker concentrations that would initiate or cease DED therapeutic delivery.

• Consideration of potential obstacles that could require a revision in the work plan or milestones with a discussion of alternative approaches.

• A detailed schedule or timeline for each milestone and the overall goal.

Examples of TA1 technologies include, but are not limited to: punctal plugs, intracanalicular implants, or similar tear duct inserts. TA1 devices can reside in either the superior or inferior punctum and should be placed in each eye experiencing symptoms. Technologies that are not in scope for TA1 include anything which does not reside in the punctum such as rigid gas-permeable lenses or conjunctival inserts, and technology which samples any fluid other than tears. Any sensor device which does not allow for the physiological flow of tears is also outside the scope of TA1.

Phase II (12 months)

• The proposal must detail a research plan to begin testing the nanosensor(s) in large animals (healthy or models of disease).

• Sensor ability to detect tear osmolarity (lower limit = 270 mOsm) and other applicable biomarkers in animals.

• Successful integration of the DED nanosensor and its therapeutic delivery device from TA2 should occur by the end of this Phase.

• The proposed device(s) must maintain ≥ 99.9% threshold of baseline performance with a longevity of at least three (3) months post-insertion during this Phase.

• The sensor’s components should be optimized in this Phase for first-in-human (FIH) clinical proof-of-concept testing during Phase III.

• Sensor anti-fouling mechanisms should be verified in preclinical (large animal) studies.

• Failure safety mechanisms in the event of device failure or loss of connectivity should be verified in this Phase.

• The sensor minimum sampling rate should be at least four (4) times per hour in large animals and increase in frequency if biomarker levels read outside the normal/healthy range.

• The sensor must be capable of responding to any change in analyte concentration within the relevant physiological range in 15 minutes or less (the effective response time) in this Phase and increase in frequency if biomarker levels read outside the normal/healthy range.

• Sensor outputs and related algorithms should demonstrate at least 95% sensitivity in detection of all biomarkers at a clinically relevant concentration threshold by the end of this phase. Sensor should be able to reliably detect biomarker concentrations within 5% of lowest physiologically relevant value in large animals.

o Linear range of detection should also be validated in large animals

• Validation of algorithm response to sensor outputs should take place in this Phase.

o Physiological baselines and therapeutic accuracy should also be validated.

• A detailed schedule or timeline for each milestone and the overall goal.

Participation in the Advanced Studies Track (if applicable) will also begin at the end of Phase 1 or during Phase 2. Proposals including this Advanced Studies track should provide the same details for sensor capabilities as what is detailed in TA1 Phase 1 above, but expanded to enable future expanded sensor capabilities including, but not limited to, additional or multiple ocular, neurological, or systemic disease states, detection of chemical or biological threats, greater sensor multiplexing capability (>15 analytes), or exploratory power sources or biomaterials.

Phase III (18 months)

• The proposal should detail a plan to commence manufacturing and a detailed research plan for FIH clinical trials with the integrated optimized OCULAB DED sensor and therapeutic delivery device.

• Sensor ability to detect tear osmolarity (lower limit = 270 mOsm) and all biomarker choices in humans must be demonstrated.

• The proposed device(s) must maintain ≥ 99.9% threshold of baseline performance with a longevity of at least six (6) months post-insertion during this phase.

• Sensor anti-fouling mechanisms should be verified in proof-of-concept clinical studies.

• Failure safety mechanisms in the event of device failure or loss of connectivity should be validated in patients in this Phase.

• The sensor must be capable of responding to any change in analyte concentration within the relevant physiological range in 10 minutes or less (the effective response time) in this Phase and increase in frequency if biomarker levels read outside the normal/healthy range.

• Sensor readings and related algorithms should demonstrate at least 98% sensitivity in detection of all biomarkers at a clinically relevant concentration threshold by the end of this phase. Detection range should meet or exceed previous phase target in patients.

• Finalize algorithm response to sensor readings.

• Validate physiological baselines and demonstrate accuracy in therapeutic dose delivery.

• A detailed schedule or timeline for each milestone and the overall goal.

• Performers should generate a TPP for their device(s) for further clinical development and commercialization after the conclusion of this program.

Proposers must provide the following information in the proposal for TA1:

• Any preliminary data that has already been generated in support of this proposal. List of patents (see Section 4.2.3 “Intellectual Property”).

• Include plans for any utilization of United States Government infrastructures.

• Gantt chart timeline.

• Risk mitigation (contingency plans) and alternative approaches.

• Accessibility plan.

1.2.1.2. TA2: Closed-Loop Therapeutic Dosing

Current therapeutic options to treat DED include over-the-counter topical rewetting drops such as artificial tears, lifestyle modifications (i.e., reducing screen time, omega-3 supplementation, humidifier use), prescription anti-inflammatory therapies to reduce inflammation and potentially enhance tear production, or surgical options (e.g., blocking tear drainage with a solid punctal plug).

With the exception of surgical interventions, successful management of DED is reliant upon a patient’s compliance with their medication regimen, which is typically poor in the eyedrop space.

Many eyedrops require multiple applications a day and/or can cause side effects such as stinging and redness. Patients may also miss their eye when applying their drops or forgo the medication entirely if they are averse to drops hitting their eye, or (more commonly) patients will cease taking their drops once their symptoms are alleviated which may restart disease pathology.

TA2 aims to establish a disease-modifying therapeutic for the treatment of DED. Choice of disease-modifying therapeutic must be accompanied with backing literature and/or preliminary data and may include (but is not limited to) androgens or specific anti-inflammatory/immune-modifying therapeutics. Examples of therapeutics which would be considered unsuitable include current commercialized dry eye therapies, rewetting drops or other similar symptom-treating options, corticosteroids which lack a specific disease-targeting mechanism of action, or therapeutics with known severe side effects even at very low doses.

The performers will also consider the form factor for housing and delivering their choice of therapeutic in response to a signal from the sensor developed in TA1. Examples of form factors to deliver the therapeutic in TA2 include but are not limited to the same device as the TA1 sensor, a separate permeable punctal insert or other intracanalicular implant, a conjunctival insert, or another extraocular device. TA2 devices must reside within the orbital or periorbital region and may be placed in either one or both eyes experiencing dry eye symptoms. Preclinical data is required to indicate good disease control if only one device is being used to treat both eyes. Technologies that are not in scope for TA2 include rigid gas-permeable lenses, and anything residing outside the orbital or periorbital region.

A proposal must consider and provide information on each of the following aspects.

Phase I (18 months)

• The proposal must include strategies to:

o Produce at least one (1) disease-modifying therapeutic for DED.

o Produce at least one (1) therapeutic device prototype to reside around the eye (i.e., same device as TA1, another permeable tear duct insert, a conjunctival insert, or other) for delivery of disease modifying therapy for DED.

o Demonstrate communication between the therapeutic delivery unit and the multiplex nanosensor.

• The proposers should establish concentrations of biomarkers of interest which will inform the therapeutic dosage and/or frequency determination.

• The proposal should detail proposed specifications for the therapeutic device, including, but not limited to, size, form factor, and placement.

• The proposal should detail plans for a response time of at least fifteen (15) minutes from the time of biosensing to therapeutic dosage delivery.

• The proposal should demonstrate plans for device longevity of at least one (1) month post-insertion.

• The proposal should detail the anti-fouling technology that will be employed to maintain bioassay performance over the required one-month longevity requirement.

• The proposal must detail plans for preclinical studies in Phase II and must utilize animal models that possess anatomically comparable puncta and globe size to humans.

Phase II (12 months)

• The proposal must include strategies to:

o Verify ≥ 1 ocular therapeutic device prototype (i.e., tear duct inserts or other) in large animals for delivery of disease modifying therapy for DED.

• Proposers must detail a plan to develop, characterize and verify methodologies for restoration of tear osmolarity and biomarkers of interest to physiological baselines in large animals.

• The proposal should detail plans for manufacturing of a device that can be utilized for FIH proof of concept trials in Phase III.

• The proposal should detail plans for a response time ≤ 5 minutes from the time of biosensing to therapeutic dosage delivery.

• The proposal should demonstrate plans for device longevity ≥ 3 months post-insertion.

• Anti-fouling mechanisms must be verified in preclinical (large animal) studies.

• Proposers must develop a strong metric for disease indication and biomarker that will inform dosage accuracy and demonstrate ≥ 80% of the target dosage in large animals.

Phase III (18 months)

• The proposal must include strategies to:

o Verify ≥ 1 ocular therapeutic device prototype (i.e., punctal plug or other) in humans for delivery of disease modifying therapy for DED.

• Proposers must detail a plan to develop, characterize and validate methodologies for restoration of tear osmolarity and biomarker of interest to physiological baselines in humans.

• The proposal should detail plans for human studies and management of clinical trials according to accepted standards.

• The proposal should detail plans for a response time ≤ 5 minutes from the time of biosensing to therapeutic dosage delivery.

• The proposal should demonstrate plans for device longevity ≥ 6 months post-insertion.

• Anti-fouling mechanisms must be verified in proof-of-concept clinical studies.

• Proposers must develop a strong metric for disease indication and biomarker that will inform dosage accuracy and demonstrate ≥ 98% of the target dosage in large animals.

In addition to Phase specific guidelines, proposers must provide the following information in the proposal for TA2:

• Any preliminary data that has already been generated in support of this proposal.

• List of patents (see section 4.2.3.3 “Intellectual Property”).

• Include plans for any utilization of United States Government infrastructures.

• Methodological redundancies for a “multiple shots on goal” approach.

• Consideration of potential obstacles that could require a revision in the work plan or milestones with a discussion of alternative approaches.

• A detailed schedule or timeline for each milestone and the overall goal.

• Gantt chart timeline.

• Risk mitigation (contingency plans) and alternative approaches.

• Accessibility plan.

TA2 metrics and timelines are outlined in Table 2 and will increase in difficulty and complexity over the course of the OCULAB program. Monthly technical and financial status reports will be required and discussed with the ARPA-H Program Manager Team at monthly meetings. ARPA- H may request performer data as deemed necessary throughout the program to validate progress toward achieving the program goals.

Performance reporting will be required throughout the program:

• Monthly technical and financial status reports will be required and discussed with the ARPA-H Program Manager team.

• More frequent interactions to discuss underlying science, project challenges, and other project-related topics are recommended but not required.

• End-of-Phase project

• ARPA-H may request performer data as deemed necessary throughout the program to validate technical progress.

1.2.2. Program Structure and Options

The OCULAB program is structured as a 4-year effort consisting of three (3) phases, as shown in Figure 2.

Phase I = (18) Months Phase II = (12) Months

Phase III = (18) Months

Figure 3. Program structure by phase and year.

Phase 1 is designated for research and development of the multiplex sensor and the closed-loop therapeutic device. This also includes checkpoints at the transition between phases. Progression to Phase II of the project is designed to occur upon meeting specified metrics and having (1) validated biomarkers for dry eye disease (Track A) or validated biomarkers for DED and a second indication (Tracks B and C), (2) a nanosensor prototype against the biomarkers of interest, (3) a disease modifying therapeutic, and (4) a delivery device prototype.

Phase 2 will involve the incorporation of the sensor and delivery device technology to animal models, and Phase 3 will initiate the clinical (Phase 1) use of OCULAB in patients. To progress towards OCULAB proof-of-concept human studies, performers must demonstrate successful integration of the sensor and therapeutic device in a closed-loop mechanism, and utilize the resources provided by ARPA-H's Project Accelerator Transition Innovation Office (PATIO) to develop equitable and accessible clinical programs.

1.2.3. Accessibility Requirements

ARPA-H is committed to equitable healthcare access irrespective of race, ethnicity, gender/gender identity, sexual orientation, disability, geography, employment, insurance, and socioeconomic status. Patients of any background, gender, sex, socioeconomic status, religion, or ethnicity will benefit from the development of inexpensive scalable diagnostic and therapeutic delivery technologies in order to reduce disparities in healthcare. To ensure accessibility, OCULAB will ensure that all performers follow the FDA’s guidance titled “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials”. In accordance with current ARPA-H and Department of Health and Human Services (HHS) guidance, all proposals will describe the composition of any proposed clinical trial subject population in terms of sex or gender, racial, and ethnic groups. Proposing institutions should also plan for outreach programs to recruit and retain the proposed clinical trial population consistent with the goals of the research project.

1.2.4. Data Sharing Plan and Teaming

Proposers must agree to share deidentified/sanitized data acquired during the period of performance directly with OCULAB program management team.

Continuation into subsequent phases will be determined by the Program Manager based on successful completion of previous phase goals, ability to meet future goals, and funding availability which may result. If a performer is unwilling or unable to work with another team, the OCULAB management team will consider other teaming formations to successfully meet the program’s goals. The purpose of this process is to successfully bring together the highest performing teams to meet all the technical metrics and to successfully achieve the medical breakthroughs for OCULAB. Each performer will be responsible for data-sharing, technology transfer, personnel management, and communication within their performer teams in each phase of the program.

1.3. Program Goals and Metrics

To evaluate the effectiveness of a proposed solution in achieving the stated program objectives, the following program metrics will serve as the basis for determination of satisfactory progress to warrant continued funding. Although the program metrics are specified below, proposers should note that the Government has identified these goals with the intention of bounding the scope of effort while affording maximum flexibility, creativity, and innovation of proposed solutions to the goals. Proposals must cite the quantitative and qualitative success criteria that the effort will achieve at each program milestone phase, as well as the measurement of intermediary metrics. If the metrics are not meaningful for a particular case, proposing teams are expected to provide their own metrics and describe the quantitative improvement that those metrics represent over the state-of-the-art.

1.3.1. Overall Program Goals

The overall OCULAB goal timeline is shown in Table 1. The overall program goals are listed in Table 1. The expected metrics are listed in Table 2 (for TA1) and Table 3 (for TA2). In addition to frequent performance reviews throughout the phases, performers must provide an end-of-phase final report that summarizes all efforts and data for each completed Phase.

Table 1. Overall Program Goals

Sensor Device Produce 1 sensor (Tracks A & B) or 2 sensors (Track C) with dimensions that meet size restrictions of the lacrimal canal. Device longevity at the conclusion of the program should be ≥ 6 months.

Multiplexing Capability Ensure that sensor(s) are capable of continuously detecting multiple diagnostic biomarkers, including tear osmolarity, for DED alone (Track A) or with a second disease state (Tracks B and C).

Sensitivity, Specificity, Timing, Limits

Device(s) should detect biomarkers of choice multiple times per hour with ≥ 98% specificity and sensitivity, with lower limit of detection within 5% of lowest physiologically relevant value.

Algorithm Create customizable algorithm establishing personalized biomarker baselines for each patient and demonstrate accuracy in therapeutic dose delivery where applicable.

Therapeutic Device, Efficacy, and Longevity

Produce ≥ 1 ocular therapeutic delivery device capable of residing around the eye for ≥ 6 months. Therapeutic should restore tear osmolarity and biomarker of interest to physiological baselines.

Device Accuracy and Response Time

Dosage at conclusion of the program should meet or exceed 98% of what is needed to restore biomarker levels to physiological baselines. Response time to changes in biomarker levels should be ≤ 5 minutes.

Accessibility Requirements

Performers account for health inequalities with respect to cost and accessibility of care, protection regardless of socioeconomic status of ethnicity. Develop solutions with equity in mind at the start.

Inclusion in patient recruitment and clinical trials participation (both investigators and subjects).

1.3.2. TA1 Metrics

Table 2. TA1 Metrics by Phase

Phase 1

Device Produce ≥ 1 ocular nanosensor device prototype (i.e., punctal plug or comparable tear duct insert). Device dimensions must meet physiological size restrictions of the lacrimal canal and must be hollow or permeable to allow for the free flow of tears through the sensor.

Track A performers will create a single sensor for DED and participate in the Advanced Studies Track (below).

Track B performers will create a hybrid sensor for biomarkers for DED and a second disease indication of the performers’ choice.

Track C performers will create two separate sensors for two disease indications, one of which must be DED.

Longevity Demonstrate ≥ 99.9% threshold of baseline performance with a device longevity ≥ 1-month post-insertion.

Sampling Rate Minimum of twice per hour (approx. every ≤ 30 minutes).

Multiplexing Capability

Minimum requirement of 2-plex. Multiplexing decision should be based on the minimum number of biomarkers required for accurate disease monitoring (justification required).

Limit of Detection

(LOD)

Within 5% of the lowest physiologically relevant value of each analyte and establish linear range of detection.

Lowest values may occur in either healthy or diseased states.

Sensitivity (true positives/true positives + false negatives) ≥ 85% for biomarker detection Specificity ≥ 85% for each analyte of interest

Algorithm

Produce framework for algorithm using any platform.

Establish boundaries and thresholds for biomarker of interest based on disease indication.

Validate algorithm performance and accuracy against biomarker of interest.

Produce plan for data privacy and security.

Advanced Studies Track

At the conclusion of Phase 1 or beginning of Phase 2, Track A performers will begin creating a second exploratory sensor using the metrics described above. Options for this sensor include, but are not limited to, detection of additional ocular, neurological, or systemic disease states or chemical/biological threats, sensor multiplexing >15, or use of exploratory power sources or biomaterials.

This is optional for performers on Tracks B and C.

Phase 2

Device Validate 1 ocular nanosensor device prototype (Tracks A & B) or 2 sensors (Track C) in large animals.

Longevity Demonstrate device longevity ≥ 3 months post-insertion in large animals

Sampling Rate Minimum of four times per hour (approx. every ≤ 15 minutes) in large animals, increasing in frequency if biomarker levels read outside the normal/healthy range.

Multiplexing Capability

Minimum 2-plex device in large animals.

Limit of Detection Reliably detect (within 5%) lowest physiologically relevant value in large animals. Validate linear range of detection.

Sensitivity ≥ 95% for biomarker detection Specificity ≥ 95% for each analyte of interest

Algorithm Validate algorithm response to sensor readings. Establish physiological baselines and demonstrate accuracy in therapeutic dose delivery.

Phase 3

Device Validate 1 ocular nanosensor device prototype (Tracks A & B) or 2 sensors (Track C) in humans.

Longevity Demonstrate device longevity ≥ 6 months post-insertion in humans

Sampling Rate Minimum of six times per hour in humans (approx. every ≤ 10 minutes), increasing in frequency if biomarker levels read outside the normal/healthy range.

Multiplexing Capability

Minimum 2-plex device in humans

Limit of Detection Reliably detect (within 5%) lowest physiologically relevant value in humans.

Sensitivity ≥ 98% for biomarker detection Specificity ≥ 98% for each analyte of interest

Algorithm Finalize algorithm response to sensor readings. Validate physiological baselines and demonstrate accuracy in therapeutic dose delivery.

1.3.3. TA2 Metrics

Table 3. TA2 Metrics by Phase.

Phase 1

Device and Therapeutic

Produce ≥ 1 disease-modifying therapeutic for DED.

Produce ≥ 1 ocular therapeutic device prototype (i.e., same device as TA1, other lacrimal canal insert, conjunctival insert, or other extraocular device) for delivery of disease modifying therapy for

DED.

Therapeutic Efficacy N/A Response Time ≤ 15 minutes Longevity Demonstrate device longevity ≥ 1-month post-insertion Dosage Accuracy Performer set metric for disease indication and biomarker

Phase 2 Device and Therapeutic Validate ≥ 1 ocular therapeutic device prototype in large animals

Therapeutic Efficacy Restoration of tear osmolarity and biomarkers of interest to physiological baselines in large animals

Response Time ≤ 5 minutes in large animals

Longevity Demonstrate device longevity ≥ 3 months post-insertion in large animals

Dosage Accuracy ≥ 80% target in large animals Phase 3

Device and Therapeutic Validate ≥ 1 ocular therapeutic device prototype in humans

Therapeutic Efficacy Restoration of tear osmolarity and biomarkers of interest to physiological baselines in humans

Response Time ≤ 5 minutes in large animals

Longevity Demonstrate device longevity ≥ 6 months post-insertion in large animals

Dosage Accuracy ≥ 98% target in humans

1.4. General Requirements

1.4.1. Proposing Teams

Proposals are expected to involve diverse teams with the expertise needed to collectively achieve the goals of both TA1 and TA2. Specific content, communications, networking, and team formation are the sole responsibility of the proposer1. Proposers must submit a single, integrated proposal led by a Principal Investigator (PI), under a single prime awardee2 that addresses all program phases, as applicable. Proposers may only submit one (1) proposal as the prime proposer and may be listed as a co-investigator on two (2) other proposals if applicable.

While ARPA-H expects proposer teams to encompass a variety of organizational types (e.g., commercial organizations, academic institutions, non-profits, etc.), to ensure future commercialization success and adherence to project timelines, academic and/or nonprofit performers are encouraged to partner with a commercial organization3 with expertise in punctal plug or tear duct insert technology (e.g., biotech/biopharma or another for-profit company).

ARPA-H will hold a Proposers’ Day (see Section 8, Other Information) to facilitate the formation of proposer teams and enable sharing of information among interested proposers.

2. Award Strategy The ISO constitutes a merit-based solicitation, and the number of awards made will depend on the quality of the proposals received and the availability of funds. Proposals are expected to use innovative approaches that include novel technology, enabling revolutionary advances in medicine and healthcare. The ISO uses merit-based competitive procedures to the maximum extent practicable. It is highly encouraged that commercial organizations propose as the prime on teams (teams may comprise a wide variety of organizations, including academic institutions and other non-profit entities). ARPA-H has determined, based on extensive market intelligence and the nature of the OCULAB program, that this approach will be most effective in increasing the likelihood of programmatic success.

1 Proposer refers to all respondents to this Broad Agency Announcement, regardless of resulting award instrument 2 Awardee is synonymous with performer and in this announcement refers to any entity entering into an award with the Government. Prime awardee is thus synonymous with prime performer. Subawardees refer to entities performing in support of a Government award, without a direct award from the Government (i.e., support is provided directly to the prime performer or other tier subawardee).

3. Commercial organization means an organization, institution, corporation, or other legal entity, including, but not limited to, partnerships, sole proprietorships, and limited liability companies, that is organized or operated for the profit or benefit of its shareholders or other owners. The term includes small and large businesses and may be used interchangeably with “for-profit organization.”

The Government reserves the right to select for negotiation all, some, one, or none of the proposals received in response to this ISO and to make awards without negotiations with proposers. The Government also reserves the right to conduct negotiations if it is later determined to be necessary.

Additionally, ARPA-H reserves the right to accept proposals in their entirety or to select only portions of proposals for negotiation and award. The Government reserves the right to fund proposals in phases, including as optional phases, as applicable. ARPA-H reserves the right to make multiple awards, a single award, or no awards. Multiple awards are anticipated.

Proposals identified for negotiation are expected to result in Cooperative Agreements or Other Transactions (OTs).