LIGHT ISO Amend 2_11 June.pdf

INNOVATIVE SOLUTIONS OPENING

FOR

LYMPHATIC IMAGING, GENOMIC AND PHENOTYPING

TECHNOLOGIES (LIGHT)

HEALTH SCIENCE FUTURES

ARPA-H-SOL-24-102

April 30, 2024 Amended June 4, 2024 Amended June 11, 2024

Contents

1. INNOVATIVE SOLUTIONS OPENING OVERVIEW INFORMATION

1.1 ACQUISITION STRATEGY

1.2 SOLICITATION AND PROGRAM INFORMATION AVAILABILITY

1.3 AWARD INFORMATION

2. ELIGIBILITY INFORMATION

2.1 ELIGIBLE APPLICANTS (I.E., PROPOSERS)

2.1.1 FEDERALLY FUNDED RESEARCH AND DEVELOPMENT CENTERS (FFRDCs)

AND OTHER GOVERNMENT ENTITIES

2.1.2 NON-U.S. ENTITIES

2.2 SYSTEM FOR AWARD MANAGEMENT (SAM)

2.3. ORGANIZATIONAL CONFLICTS OF INTEREST (OCI)

3. THE PROGRAM

3.1 LIGHT OVERVIEW

3.2 TECHNICAL APPROACH AND STRUCTURE

3.2.1 TECHNICAL AREAS (TAs)

3.2.2 PROGRAM STRUCTURE

3.2.3 LIGHT GO/NO-GO PHASE I CHECKPOINT

3.2.4 DATA MANAGEMENT AND SHARING PLAN (DMSP)

3.3 TECHNICAL AREA METRICS AND OBJECTIVES

OVERALL LIGHT PROGRAM GOALS

3.3.1 TA1 METRICS AND OBJECTIVES

3.3.2 TA2 METRICS AND OBJECTIVES

3.3.3 TA3 METRICS AND OBJECTIVES

3.3.4 TECHNICAL REQUIREMENTS FOR ALL PERFORMERS

3.4 GENERAL REQUIREMENTS

3.4.1 PROPOSING TEAMS

3.4.2 LIGHT PROGRAM MEETINGS AND ATTENDANCE

3.4.3 DIVERSITY IN CLINICAL TRIAL POPULATIONS FOR LIGHT PHASE III

3.4.4 EQUITY REQUIREMENTS

4. SOLUTION SUMMARY AND PROPOSAL PREPARATION AND SUBMISSION

INFORMATION

4.1 SOLUTION SUMMARY PREPARATION INSTRUCTIONS

4.2 SOLUTION SUMMARY AND PROPOSAL SUBMISSION INFORMATION

4.3 SOLUTION SUMMARY AND PROPOSAL SUBMISSION DEADLINES

4.4 PROPRIETARY INFORMATION

5. SOLUTION SUMMARY REVIEW AND EVALUATION OF FULL PROPOSALS

5.1 CONFORMING SOLUTION SUMMARY AND PROPOSAL SUBMISSIONS

5.2 SOLUTION SUMMARY REVIEW PROCESS

5.3 FULL PROPOSAL EVALUATION CRITERIA FOR AWARD

5.3.1 CRITERIA 1: OVERALL SCIENTIFIC AND TECHNICAL MERIT

5.3.2 CRITERIA 2: PROPOSER’S CAPABILITIES AND/OR RELATED EXPERIENCE 33

5.3.3 CRITERIA 3: POTENTIAL CONTRIBUTION TO RELEVANCE TO THE ARPA-H

MISSION

5.3.4 CRITERIA 4: PRICE ANALYSIS

5.4 REVIEW, EVALUATION, AND SELECTION PROCESS

5.4.1 SELECTABLE OR NON-SELECTABLE DETERMINATION

5.4.2 RESERVED

5.4.3 REVIEW AND EVALUATION TIMELINES

5.5 HANDLING OF COMPETITIVE SENSITIVE INFORMATION

6. POLICY REQUIREMENTS AND AWARD ADMINISTRATION INFORMATION

6.1.1 INTELLECTUAL PROPERTY

6.1.2 HUMAN SUBJECTS RESEARCH

6.1.3 ANIMAL SUBJECTS RESEARCH

6.1.4 ELECTRONIC INVOICING AND PAYMENTS

6.1.5 GOVERNMENT-FURNISHED PROPERTY/EQUIPMENT/INFORMATION

7. ISO QUESTIONS AND ANSWERS

8. OTHER INFORMATION

APPENDIX A: SOLUTION SUMMARY FORMAT AND INSTRUCTIONS

APPENDIX B: FULL PROPOSAL FORMAT AND INSTRUCTIONS

APPENDIX C: ADMINISTRATIVE AND POLICY REQUIREMENTS

APPENDIX D: TARGET PRODUCT PROFILE (TPP) FOR TA1, TA2, TA3

1. INNOVATIVE SOLUTIONS OPENING OVERVIEW INFORMATION

FEDERAL AGENCY NAME: Advanced Research Projects Agency for Health (ARPA-H)

ISO SOLICITATION TITLE: Lymphatic Imaging, Genomic, and pHenotyping Technologies (LIGHT)

ANNOUNCEMENT TYPE: Solicitation

ISO SOLICITATION NUMBER: ARPA-H-SOL-24-102

DATES: (All times listed are Eastern Time)

Proposer’s Day: May 21, 2024 Questions & Answers (Q&A) due date: May 29, 2024, 11:00AM ET Closing Date (Solution Summaries Due): June 27, 2024, 2:00PM ET

ANTICIPATED INDIVIDUAL AWARDS: Multiple awards

TYPE OF AWARD INSTRUMENTS: Other Transaction Agreements (OTs) and Cooperative Agreements (CAs)

AGENCY CONTACT: LIGHT@ARPA-H.gov

Program Overview: LIGHT intends to shine a light on the lymphatic system, illuminating the unseen both literally via novel diagnostic approaches and figuratively through insight gained into the critical role the lymphatic system plays in health as well as its impacts when dysfunctional. LIGHT aims to improve the lives of tens of millions of Americans by creating agile tools that are scalable, accessible, accurate and clinically useful to detect lymphatic structure and function. Multiple diagnostic technologies will enable targeted interventions that result in better patient outcomes and reduced treatment costs, and will advance our understanding of lymphatic dysfunction, a key factor in the pathophysiology of many important diseases. Signs and symptoms of lymphatic dysfunction do not manifest until the disease has progressed, and current assessment tools neither adequately appraise lymphatic anatomy nor measure lymphatic function.

Today, patients with lymphatic disease may remain misdiagnosed or undiagnosed for years; some never get a diagnosis.

In the future, with a comprehensive set of tools, the journey to diagnose lymphatic dysfunction will be measured in minutes.

1.1 ACQUISITION STRATEGY

ARPA-H seeks proposals from all eligible entities (see Section 2 Eligibility Information) to accomplish the LIGHT Program goals as described in this solicitation package. Ultimately, ARPA-H intends to negotiate multiple Other Transaction agreements (OTs) and/or Cooperative Agreements (CAs) with proposers whose proposals are most advantageous to the Government and are poised to meet the goals of the LIGHT program.

Proposals are expected to use innovative approaches that may include both existing and novel technology, enabling revolutionary advances in medicine and healthcare. The LIGHT program aims to develop a comprehensive diagnostic toolkit to assess lymphatic structure and function, and potential performers should consider an approach to ensure the final technology includes an imaging modality plus biomarkers and/or genetic integration. Initially proposers should consider primary lymphatic diseases as the targeted disease state; however, consideration of other chronic conditions associated with lymphatic dysfunction is encouraged.

Specifically excluded are proposals that represent an evolutionary or incremental advance in the current state of the art, including clinical trials of an otherwise developed product. Additionally, proposals directed towards policy changes, traditional education and training, or center coordination, formation, or development, and construction of physical infrastructure are outside the scope of the ARPA-H mission.

1.2 SOLICITATION AND PROGRAM INFORMATION AVAILABILITY

This ISO will be solicited through the System for Award Management (SAM.gov) and posted on the ARPA-H website at https://arpa-h.gov/research-and-funding/programs. See Section 4 for Solution preparation and submission information.

1.3 AWARD INFORMATION

The Government reserves the right to select for negotiation all, some, one, or none of the proposals received in response to this ISO. If warranted, portions of resulting awards may be segregated into pre-priced options. In the event the Government desires to award only portions of a proposal, negotiations will commence upon selection notification. The Government reserves the right to fund proposals in phases with options for continued work, as applicable.

The Government reserves the right to request any additional, necessary documentation to support the negotiation and award process. The Government reserves the right to remove a proposal from award consideration should the parties fail to reach agreement on award terms, conditions, cost, and/or if the proposer fails to provide requested additional information in a timely manner.

In all cases, the Government will have sole discretion to negotiate all instrument terms and conditions with selectees. ARPA-H will apply publication or other restrictions, as necessary, if it is determined that the research resulting from the proposed effort will present a high likelihood of disclosing sensitive information including Personally Identifiable Information (PII), Protected Health Information (PHI), financial records, proprietary data, any information marked Sensitive but Unclassified (SBU), etc. Any award resulting from such a determination will include a requirement for ARPA-H concurrence before publishing any information or results on the effort.

2. ELIGIBILITY INFORMATION

2.1 ELIGIBLE APPLICANTS (I.E., PROPOSERS)

All responsible sources capable of satisfying the Government’s needs may submit a proposal to this ISO. Specifically, universities, non-profit organizations, small businesses and other than small businesses are eligible and encouraged to propose to this ISO.

2.1.1 FEDERALLY FUNDED RESEARCH AND DEVELOPMENT CENTERS (FFRDCs)

AND OTHER GOVERNMENT ENTITIES

Federally Funded Research and Development Centers (FFRDCS) are not permitted to respond to this solicitation in any role on a proposed team, to include prime/lead or subperformer.

Government entities may not submit proposals to this solicitation as prime/lead performers but may participate on performing teams as a subperformer. Be aware, though, ARPA-H will not facilitate the establishment of the relationship between the prime/lead performer, performing team and the government entity that wishes to participate. Government entities and the prime/lead performer are responsible for determining if the government entity is eligible to participate as a subperformer, prior to proposal submission. ARPA-H will not enter into a relationship directly with the government entity to facilitate performance on a specific team nor will ARPA-H reimburse the government entity directly for any participation. If the government entity wishes to be a subperformer, they must establish that relationship directly with the prime/lead performer to include receiving payment directly from the prime/lead performer.

Should a FFRDC or Government entity have a research idea that is within the technology area of this program, it should submit a statement of interest to LIGHT@ARPA-H.gov.

Individual government employees who wish to participate as part of a performing team should be aware that there may be significant statutory and/or regulatory ethical implications with such participation. Government employees contemplating such participation are highly encouraged to consult with their agency’s legal counsel for guidance. ARPA-H will not provide such guidance. If a performing team includes a government employee, the prime/lead will be expected to do their due diligence and maintain on file a letter from the government employee’s home agency that such participation is permissible. ARPA-H reserves the right to ask for a copy of this letter at any time during the evaluation or negotiation periods or during performance if selected.

2.1.2 NON-U.S. ENTITIES

Non-U.S. entities may participate to the extent that such participants comply with any necessary nondisclosure agreements, security regulations, export control laws, and other governing statutes applicable under the circumstances. However, non-U.S. entities are encouraged to collaborate with domestic U.S. entities. In no case will awards be made to entities organized under the laws of a covered foreign country (as defined in section 119C of the National Security Act of 1947 (50 U.S.C. § 3059)) or entities suspended or debarred from business with the Government.

2.2 SYSTEM FOR AWARD MANAGEMENT (SAM)

All proposers must have an active registration in SAM.gov in order for their proposal to be found conforming. Proposers must maintain an active registration in SAM.gov with current information at all times during which a proposal is under consideration or a current award from ARPA-H is held.

Information on SAM.gov registration is available at SAM.gov.

NOTE: New registrations as well as renewals may take more than 14 business days to process in SAM.gov. SAM.gov is independent of ARPA-H and thus ARPA-H representatives have no influence over processing timeframes.

2.3. ORGANIZATIONAL CONFLICTS OF INTEREST (OCI)

Proposers are required to identify and disclose all facts relevant to potential or actual OCIs involving the proposer’s organization and any proposed team member (proposed sub-awardee). Although the FAR does not apply to OTs, ARPA-H requires OCIs be addressed in the same manner prescribed in FAR subpart 9.5. Regardless of whether the proposer has identified potential or actual OCIs under this section, the proposer is responsible for providing a disclosure with its proposal. If a potential or actual OCI has been identified, the disclosure must include the proposers’, and as applicable, proposed team members’ OCI mitigation plans. The OCI mitigation plan(s) must include a description of the actions the proposer has taken, or intends to take, to prevent the existence of conflicting roles that might bias the proposer’s judgment and to prevent the proposer from having unfair competitive advantage. The OCI mitigation plan will specifically discuss the disclosed OCI in the context of each of the OCI limitations outlined in FAR 9.505-1 through FAR 9.505-4. The disclosure and mitigation plan(s) do not count toward the page limit.

2.3.1. Agency Supplemental OCI Policy

In addition, ARPA-H restricts performers from concurrently providing professional support services, or similar support services, and being a technical performer. Therefore, as part of the FAR 9.5 disclosure requirement above, a proposer must affirm whether the proposer or any proposed team member (proposed sub-awardee, etc.) is providing professional support services to any ARPA-H office(s) under: (a) a current award or subaward; or (b) a past award or subaward that ended within one calendar year prior to the proposal’s submission date.

Proposers shall follow the instructions in, and complete, Volume III (see Appendix C) to address the requirements of this ISO Section.

Note: An OCI based on a proposer currently providing professional support services, as described above, cannot be mitigated.

GOVERNMENT PROCEDURES

The Government will evaluate OCI mitigation plans to avoid, neutralize, or mitigate potential OCI issues before award and to determine whether it is in the Government’s interest to grant a waiver. The Government will only evaluate OCI mitigation plans for proposals selected for potential award based on the evaluation criteria and funding availability.

The Government may require proposers to provide additional information to assist the Government in evaluating the OCI mitigation plan.

If the Government determines a proposer failed to fully disclose an OCI; or failed to provide the affirmation of ARPA-H support as described above; or failed to reasonably provide additional information requested by the Government to assist in evaluating the proposer’s OCI mitigation plan, the Government may reject the proposal and withdraw it from consideration for award.

3. THE PROGRAM

3.1 LIGHT OVERVIEW

The lymphatic system (LS) is an indispensable body system without which we could not survive. It consists of a complex network of lymphatic vessels, lymph nodes, and lymphatic organs that play a critical role in fluid balance, immune cell surveillance, and macromolecule homeostasis in almost every tissue of the human body. In contrast to the tools available for assessment of cardiovascular health (blood pressure, electrocardiography, echocardiography, etc.) there exist few means of assessing the structure and function of the LS. Lymphatic vessels are translucent, tiny, and fragile; additionally, they have low flow rates and pressures, making them difficult to visualize or assess using traditional tools such as blood pressure, visual inspection, or ultrasound. Today, clinicians have no easy-to-use, widely accessible, and safe tools to assess the health of the LS. As a result, the human LS has been largely ignored in the minds of clinicians and researchers alike and patients with primary lymphatic diseases are often undiagnosed or misdiagnosed, leading to avoidable morbidity and mortality. Further, patients whose lymphatic dysfunction underlies their chronic disease miss out on the benefit of early diagnosis and treatment.

The current, limited methods for the assessment of lymphatic anatomy and function include:

1. Physical exam and assessment for pitting and non-pitting edema (Stemmer Sign) and measurement of arm and leg circumference. The physical exam is rudimentary, non-quantitative, poorly standardized, and operator dependent. Additionally, it measures neither lymphatic anatomy nor lymphatic function.

2. Biomarkers are in development but are not yet standardized or in widespread clinical use.

3. Imaging – non-invasive imaging with bioimpedance, magnetic resonance imaging (MRI) or ultrasound (US), or invasive imaging via lymphoscintigraphy (LSG), dynamic contrast-enhanced MRI lymphangiography (DCMRL), intranodal CT lymphangiography (ICTL), conventional lymphangiography, and near-infrared (NIR) indocyanine green (ICG) lymphography. These imaging techniques lack deep tissue penetration, are unable to visualize small vessels due to limited resolution and lack organ specificity and dynamic functionality.

Access is limited as they require a high level of expertise and expensive equipment.

Importantly for the patient, many require risky invasive techniques.

4. Detection of genetic mutations (both inherited and somatic) are difficult and genomic approaches have not been fully explored.

LIGHT will address these limitations by extending and combining existing modalities to develop two important capabilities in the assessment of the lymphatic system:

1. The ability to image lymphatic structure in individual organs.

The LS provides a one-way transport system from multiple organ-based subsystems (brain, eyes, lung, heart, gut, spleen, liver, skin, and soft tissue). To appreciate the entire lymphatic anatomy each lymphatic subsystem must be imaged.

A variety of approaches may address this, including the identification of novel tracers through biomarker and genetic discovery that are specific to organ tissues and absorbed directly into the LS, combination of existing imaging modalities, and discovery of non-invasive imaging technologies. Additionally, the application of promising technologies used for other body systems has yet to be tried in the diagnosis of Lymphatic disease (LD). Examples may include but are not limited to microbubbles, small gas-filled lipid microspheres that are easily absorbed into the lymphatics and have acoustic properties suitable for use as an ultrasound contrast agent, and novel CT technologies such as high-resolution dual-energy CT that can visualize peristalsis of individual lymphatic vessels, enabling calculation of lymphatic flow and assessment of thoracic duct obstruction.

2. The ability to measure lymphatic function.

Assessment of fluid dynamics and flow, permeability, pressure, and valvular function is an essential part of the evaluation of any vascular system. Administration of agents that accumulate in the tissue beds of different organs and are cleared via the LS could enable visualization and measurement of lymphatic flow in each organ. Development of such breakthrough methods would allow assessment of both lymph production and drainage via the LS, both of which can be causes and consequences of disease. Further, recent technological breakthroughs and computational approaches have revolutionized medical imaging and other diagnostic tools, and these approaches may be applied to the LS, unlocking meaningful measurement of lymphatic function.

3.2 TECHNICAL APPROACH AND STRUCTURE

3.2.1 TECHNICAL AREAS (TAs)

LIGHT performers will develop a comprehensive diagnostic toolkit to assess lymphatic structure and function. Potential performers must consider a revolutionary BIG (biomarkers, imaging, and genetic) approach to ensure the final diagnostic toolkit includes an imaging modality plus biomarkers and/or genetic integration. Performers should consider primary lymphatic diseases as the targeted disease state; however, consideration of other chronic conditions such as cancer, chronic heart, lung, kidney, liver, gastrointestinal, autoimmune (i.e., inflammatory bowel disease, rheumatoid arthritis), infectious diseases or transplantation, associated with lymphatic dysfunction is encouraged. To accomplish these goals LIGHT is structured into three technical areas (TAs), two tracks, and three phases. Phase 1 will encompass proof-of concept research (24 months), Phase 2 – Pre-clinical research (24 months), and Phase III – clinical validation (12 months). See Table 1. List of Primary Lymphatic Diseases and Chronic Diseases with Underlying Lymphatic Dysfunction.

Table 1.

Primary lymphatic diseases* Chronic disease with underlying lymphatic dysfunction*

Lymphedema o Primary o Secondary (injury, trauma, infection, and surgery) Lymphatic anomalies o Tumors o Malformations (microcystic and macrocystic) Lipedema

Lipedema Chronic kidney diseases Chronic liver diseases Inflammatory Bowel Disease (e.g. Chron’s disease) Cardiovascular diseases (e.g. heart failure and atherosclerosis) Chronic lung disease Metastatic cancer Obesity Infectious disease Ocular diseases Tissue transplantation Autoimmune disease

*Performers may propose an alternative disease with justification. However, neurodegenerative diseases and other brain related disorders are outside the scope of LIGHT and should not be proposed.

Technical Area 1 (TA1): Diagnostics and Monitoring – through biomarker development.

TA1 focuses on the identification and development of specific biomarkers capable of diagnosing and monitoring lymphatic dysfunction. Approaches may include evaluation of novel biospecimens using traditional methodologies and implementation of innovative high throughput approaches. Biomarkers may consist of cells, proteins, peptides, metabolites, and nucleic acids, as well as physiologic measurements, such as bioimpedance. Additionally, LIGHT is supportive of proposals looking to mine existing data sets, such as public single-cell RNA-seq databases and patient registries, to identify novel markers of lymphatic phenotypes and disease indicators.

TA1 has three broad objectives:

Objective a: Discover and intelligently monitor biomarkers specific to lymphatic physiology, function, and LD. Performers may apply highly sensitive biomarker discovery methodologies to assess lymphatic dysfunction (i.e., nanosensors or aptamer scRNA-seq approaches) or use traditional methodologies to explore lymphatic biospecimens (i.e., interstitial fluid and lymph). Further, performers are encouraged to identify biological biomarkers that may inform the development of new tracers and contrast agents enabling novel imaging modalities (see Technical Area 2).

Objective b: Correlate biomarker expression with lymphatic function and dysfunction. Novel biomarkers could be used in conjunction with imaging of the LS to yield a new understanding of lymphatic pathophysiology. Performers are encouraged to carefully assess the fit of their novel biomarker(s) with the following categories: susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, and safety.

TA1 will enable rapid and reliable diagnosis and accurate monitoring of LD using highly specific and sensitive biomarkers.

Technical Area 2 (TA2): Imaging Technologies

Advancing clinical care for lymphatic diseases is dependent on imaging systems capable of visualizing and measuring the LS of individual organs reliably and accessibly. New imaging technologies and approaches should represent a significant leap forward in capabilities compared to the current state-of-the-art in lymphatic imaging. Performers are encouraged to be bold while developing imaging technologies and may consider unorthodox approaches to understanding lymphatic anatomy, for example, cadaveric or novel humanized models. Performers are encouraged to choose from three potential approaches, below, but may suggest an alternative approach.

Potential Approach A.: Imaging tracer/contrast agent development and delivery. Performers will develop an imaging contrast agent in combination with an imaging modality that is specific to the LS and provides enhanced lymphatic imaging. Performers must carefully justify how the contrast agent will be delivered to minimize undesirable off target outcomes and improve patient experience.

Potential Approach B.: Combining multiple imaging modalities. Current lymphatic imaging approaches each have unique strengths and limitations. However, if the approaches were combined, it could significantly improve the current capabilities in lymphatic imaging. Performers will combine multiple imaging technologies or approaches to significantly improve their assessment of lymphatic function and/or provide earlier detection of dysfunction.

Potential Approach C.: Advancement of non-invasive imaging technology. Performers will apply emerging advancements in non-invasive imaging approaches, coupled with state-of-the-art computational approaches to image the LS without a contrast agent or dye. Examples of non-invasive imaging approaches that have been identified for potential application to lymphatic imaging are ultrasound imaging, non-invasive MRI, and optical coherence tomography.

TA2 will develop novel imaging technologies to assess whole-body lymphatic structure and function qualitatively and quantitatively at a cost and user-friendliness that will encourage widespread adoption.

Technical Area 3 (TA3): Prevention, Prediction & Diagnostic Confirmation – through genetics, epigenetics, and models of lymphatic dysfunction.

The various genetic and epigenetic variants of lymphatic disease (LD) and lymphatic dysfunction have yet to be fully explored; however, this discovery effort could revolutionize how we predict, diagnose, and treat LD. Performers must discover novel disease-causing genetic variants and develop accompanying models to enable prediction, prognosis, and risk assessment for personalized patient care.

TA3 has four broad objectives:

Objective a. Establish large scale databases. Performers will develop large databases and implement data sharing strategies to adequately address lymphatic diseases which are often relatively rare and may have somatic mutations with low allele frequency. Further, LIGHT encourages performers to apply state-of-the-art computational approaches to mine existing data sets for novel genetic variants associated with LD.

Objective b. Apply cutting edge approaches in discovering genetic or epigenetic variants to lymphatic disease and dysfunction. Performers will utilize emerging technologies to predict or discover genetic variants that have not been applied to lymphatic diseases on a wide scale. Performers will then explore the expression in both lymphatic diseases and in chronic disease with noted lymphatic dysfunction.

Objective c. Validate genetic targets with novel models of lymphatic dysfunction and disease.

Performers will validate novel genetic and epigenetic variants identified in patients with LD with novel in-vivo, in-vitro, and ex-vivo models able to recreate key aspects of the LD. Models should focus on clinical and pre-clinical utility for translating novel diagnostic technologies.

Objective d. Apply radiogenomic (imaging genomics) or similar, methodologies to predict variant expression via imaging phenotype. Utilizing imaging technologies developed in TA2, performers must identify imaging features that can serve as a predictive surrogate for genetic testing and variant expression.

TA3 will identify genetic and epigenetic variants causing lymphatic dysfunction, allowing in combination with biomarkers and imaging for early and definitive diagnosis, prevention, prediction and refinement of prognosis and therapy.

Technical Requirements for All Performers:

All performers, regardless of technical area, must adhere to the following technical requirements:

A. Tissue Bed and LD Selection

In Phase I, performers must specify the organ/tissue bed and the LD for which their technology is best suited to address. Performers may propose a wide range of organs and tissue beds except for brain related lymphatics (i.e. meningeal lymphatics and the “glymphatic system”).

In Phase II, performers must test the technology developed in Phase I in a relevant preclinical model to enable its clinical translation. Additionally, performers must conduct appropriate studies to test the technology in an alternative tissue bed, biofluid, or disease model. For example, a biomarker identified in the interstitial fluid could be explored in blood or urine, or an imaging approach developed for central lymphatic imaging should be tested in an organ-specific lymphatic network.

B. Leveraging Computational Intelligence and Big Data Management

All performers should clearly outline how they are utilizing the latest, state-of-the-art, approaches in Artificial Intelligence (AI) and machine learning (ML) in order to increase the speed, efficiency, or predictiveness of their diagnostic technology in Phase I and Phase II of LIGHT. Additionally, across all phases of LIGHT, performers must leverage and share data in a smart and collaborative way using FAIR Data Principles (Findable, Accessible, Interoperable and Reusable) with the shared goal to advance lymphatic diagnostic technology and achieve commercial viability.

C. Product Development and Regulatory Science

At proposal submission, performers must identify a product development team (regulatory, reimbursement, and commercialization experts) as consultants or subcontractors for the award.

Additionally, performers must include a brief commercialization plan to outline how their technology compares to current clinical options. Within the first 18 months of the award, performers, led by the product development team, must meet with appropriate regulatory bodies, such as the FDA, to develop and validate pre-clinical milestones for success. This will culminate in a full commercialization plan (≤ 8 pages) outlining a path for successful commercialization of their technology, including a market analysis, funding plan, pre-clinical testing, regulatory and reimbursement strategy, etc. LIGHT requires performers to revise the pre-clinical studies proposed at the time of submission to align with these regulatory findings. As appropriate for each Technical Area, the performer’s commercialization plan should include a submission strategy to a relevant FDA approval program. For example:

The Biomarker Qualification Program (BQP) for novel biomarkers

A De Novo/510k/Premarket Approval (PMA) submission for imaging technologies

An Investigation New Drug (IND) submission for injectable tracers and contrast agents

In Phase II, performers will implement the commercialization plan, and continue with regular engagement with intellectual property, reimbursement, and regulatory experts.

Proposals that fail to address the required technical areas and phase requirements may be deemed non-conforming and be rejected without further review.

Proposing teams must include data access plans and commercialization plans including FDA meeting milestones, technology transfer milestones to contract manufacturing organization (CMO) partners, preclinical proof of concept objectives, and market analysis and partnership models for commercialization. The proposed technology for TA1, TA2 and TA3 should meet the specifications listed in Section 3.3 Technical Area Metrics and Objectives.

3.2.2 PROGRAM STRUCTURE

Figure 1. Program Structure and Timeline

LS: Lymphatic System LD: Lymphatic Disease FDA: Food and Drug Administration IND: Investigation New Drug IDE: Investigational Device Exemption

NDA: New Drug Application BLA: Biologics License Application PMA: Premarket Approval AI/ML: Artificial Intelligence/Machine Learning

Integrative Engineering:

1. Identify a Track One team with whom there is mutual interest to integrate; or.

2. Identify one or more Track Two performers with which to form a new performer team capable of addressing TA2 and at least one other TA.

LIGHT will be accomplished over three sequential phases: Phase I – proof-of concept research (24 months), Phase II – Pre-clinical research (24 months), and Phase III – clinical validation (12 months).

Further, LIGHT has been structured to allow performers to choose from one of two tracks which will dictate the number of TAs and period of performance.

To encourage optimal collaboration and positive competition, all performers in both Track One and Track Two will be required to meet semiannually for Meeting of the Minds (M&M) virtual forum.

Further, all performers from Track One and Track Two are required to present their discoveries at an internal innovations workshop hosted by LIGHT during Phase I at ~21 months. Guests from the NIH and the National Lymphatic Commission, FDA and other government agencies may be invited with the intended purpose of gathering insight into possible transition partners, commercialization strategies and importantly “shining a light” on the LS. See all LIGHT meeting descriptions in Section 3.4.2 LIGHT Program Meetings and Attendance.

Description of Tracks:

Track One: Integrated Technical Areas (60 months)

Proposers applying to Track One will enter Phase I (24 months) as an integrated team with a 5-year plan that must address at least two of three TAs: TA2 (Imaging technologies) is required, and proposers can choose between TA1 (Diagnostics and Monitoring) and/or TA3 (Prediction and Prevention).

Track Two: Individual Technical Areas (24 months)

Cutting edge technical discovery approaches have yet to be applied to the LS. Many of these approaches appear promising but it is unclear which will most quickly produce translational clinical findings in the underexplored field of lymphatics. Track Two provides an option for individual performers who can contribute a piece of the puzzle to an integrated solution.

Proposers applying to Track Two will enter Phase I to address one technical area: TA1 (Diagnosis & Monitoring – through biomarker discovery), or TA2 (Imaging technologies), or TA3 (Prevention, Prediction & Diagnostic Confirmation – through genetic, epigenetic and models of lymphatic dysfunction).

If a performer enters Track Two it is important to be aware this track ends at 24 months. Proposals for Track Two should be 24-month proposals that are responsive to the metrics and milestones outlined in Phase I of LIGHT. See below for additional information.

3.2.3 LIGHT GO/NO-GO PHASE I CHECKPOINT

By the end of Phase I, Track Two will end and LIGHT will down-select ensuring that the remaining performing teams develop the strongest diagnostic tools by the end of the program.

Selection Process:

In the last quarter of Phase I, there will be a down selection of teams based on performance against LIGHT Phase I metrics and milestones as described in the TA metrics and objectives tables (Section 3.3). Successful completion of Phase I metrics does not guarantee a Track One or Two team will continue to subsequent phases. Progression into future phases via exercise of Options 1 and 2 is determined by the ARPA-H PM and is based on performer progress toward current phase metrics and probability of success in future phases.

Track Two performers who remain in the program must meet all the minimal required metrics for Phase I of their specific TA. Assuming successful completion of Phase I metrics, Track Two performers may proceed through one of the two options below. LIGHT has coined this process:

Integrative Engineering – Integrate or Terminate.

1. Identify a Track One team with whom there is mutual interest to integrate; or.

2. Identify one or more Track Two performers with which to form a new performer team capable of addressing TA2 and at least one other TA. This new Track One team must submit a Statement of Work (SOW) by month 22 of Phase I, to describe plans for Phase II and Phase III. The ultimate move from Track Two to Track One will be negotiated with ARPA-H.

Additionally, any performer that does not meet the equity, product development and attendance requirements may not progress to the subsequent phases.

3.2.4 DATA MANAGEMENT AND SHARING PLAN (DMSP)

LIGHT encourages all teams to consider the importance of data sharing opportunities that may be possible during the LIGHT program. All proposals are required to include a data management and sharing plan, that address the following points:

1. What type of data will be generated? Explain rationale for what scientific data will be preserved and what will be shared.

2. Will specialized tools, software, or code be needed to access or manipulate shared data, and if so, provide the purpose and rationale?

3. What are the common data standards that apply to scientific data and metadata to enable interoperability and safety?

4. What is the timeline for data preservation and access.

5. Outline your plan for data access, distribution, reuse, and privacy considerations.

6. Describe activities and individuals to ensure compliance and oversight.

Unless an exception is approved by the LIGHT PM, proposers will openly share deidentified/sanitized data acquired during the period of performance with the scientific community. Any member of the scientific community may have access to the deidentified/sanitized data; registration to a specific repository website is acceptable, but approval needs to be automatic. The specific repository where data will be deposited will be chosen in agreement with the ARPA-H Program Manager. The proposers will need to present explicit solutions to address the significant data storage and computing challenges presented by the program, with the understanding that the plans and repository may change later in the program. The DMSP must address any instances where open sharing of data may jeopardize the technology’s commercial potential. With PM approval, proposers may restrict access to even the sanitized/deidentified data generated during the period of performance for up to 20 years following the award.

3.3 TECHNICAL AREA METRICS AND OBJECTIVES

ARPA-H will meet with LIGHT performers at least monthly to review progress towards the metrics and milestones defined below. Achievement of all metrics as agreed to by ARPA-H is part of the basis for initiation of moving to the next Phase. Key overall program metrics and milestones are listed in this section below. Performers may propose additional quantitative metrics and milestones for the Program Manager to consider that may be better suited for their specific technology. However, the performers must provide a justification for these additions to the metrics and milestones as specified below. A full target product profile (TPP), outlining the minimum and ideal functionality of the technology developed in each TA can be found in Appendix D.

OVERALL LIGHT PROGRAM GOALS

TA1: Diagnosis & Monitoring – through biomarker discovery

Biomarkers will aid in early detection, monitoring of lymphatic dysfunction (providing real-time information about disease status and response to treatment (i.e., clinical trials: as companion diagnostics), inform treatment selection and decision making.

Identify or develop a biomarker capable of detecting lymphatic disease (a lymphatic anomaly or primary or secondary lymphedema) Biomarkers will be correlated with specific lymphatic functions or modes of lymphatic dysfunction informing imaging diagnostic tools.

TA2: Imaging Technologies

Doctors will have imaging modalities that allow organ specific assessment of lymphatic structure and function and the ability to monitor treatment response.

Develop an imaging modality that enables mapping of the local LS and measuring of LS functionality.

TA3: Prevention, Prediction & Diagnostic Confirmation – through genetics, epigenetics, and models of lymphatic dysfunction

Genetics /epigenetics inform early diagnosis, prediction, targeted therapies, treatment response, and in combination with biomarkers and imaging confirms diagnosis.

Identification of new genetic variants strongly associated with LD.

Novel approaches and initiation of consortiums to identify genetic variants in patient samples.

Create a model of LD that represents greater physiological relevance to the human LS - to accelerate the development of novel diagnostic tools or interventions.

Tissue Bed and Disease Model Selection

Performers will have developed a suite of diagnostic tools that allows for a more nuanced and comprehensive understanding of underlying disease mechanisms, differential diagnosis approaches and development of targeted therapeutic strategies.

Tools developed will be reliable, accessible, and affordable for assessing lymphatic structure and function in at least one tissue bed and/or for a specific LD.

Additionally, performers must translate their diagnostic tool to at least one alternative tissue bed and/or disease model.

Leveraging Computational Intelligence and Big Data Management

Gather and mine large databases from multiple research centers (s.a.

NIH HubMAP and All of Us Initiative) to determine novel insight into lymphatic physiology and pathology.

All performers must leverage and share data in a smart and collaborative way using FAIR Data Principles (Findable, Accessible, Interoperable and Reusable).

Apply current state-of-the-art approaches to leveraging Artificial Intelligence (AI) and machine learning (ML) approaches to increase speed, efficiency, or predictiveness of the team’s diagnostic technology.

Leveraging computational intelligence with imaging, genetics and biomarkers will transform the diagnosis of lymphatic dysfunction using “the rising star” in cancer detection – Radiogenomics.

Product Development and Regulatory Science

FDA evaluated and approved diagnostic tools to assess lymphatic structure and function.

Detailed commercialization plan for translating a diagnostic tool.

Igniting a market for a comprehensive toolkit used by clinicians across the world to assist when the differential diagnosis includes lymphatic dysfunction.

Equity Requirements Performers must adhere to all equity requirements outlined in Section

3.4.3. This includes the following key milestones:

Identify a “Discovery Duo”, consisting of a patient advocate and junior investigator, to join LIGHT’s equity taskforce (aka OWL EASE taskforce).

Adhere to the key performance indicators developed by the equity taskforce and report back to the performing team.

Adhere to feedback from LIGHT’s OWL EASE taskforce.

Dissemination Disseminate new technology, models, documents, and other findings to the public and stakeholders through appropriate collaborations with private and government organizations (i.e., patient advocacy groups, and academic institutions).

Attendance and Participation

A collaborative environment, where all members are accountable and bring value-added contributions to drive Program success (as a result of the Mandatory Attendance Policy)

3.3.1 TA1 METRICS AND OBJECTIVES

The expected metrics per phase in TA1 are listed in the table below.

TABLE 1A. TA1 METRICS

Phase I

Sample Collection and Discovery

Identify 10+ candidate biomarkers that are statistically correlated with LD.

Develop a methodology for reliable collection for healthy and LD samples.

Performers are strongly encouraged to gather and mine large databases from multiple research centers (i.e. patient repositories and NIH All of Us Initiative).

Validation and Standardizing

Establish normal to pathological ranges for the candidate biomarkers, as well as the most cost effective, reliable, and reproducible methodology for biomarker quantification.

Target Reproducibility:

Minimal Acceptable Result: >90% of patients receive same diagnosis when evaluated twice in the same day.

Ideal Result: 100% of patients receive the same diagnosis when evaluated twice in the same day.

Target Stability (for molecular and biological biomarkers):

Minimal Acceptable Result: 8hrs (20-22 oC) / 72hrs (4-8 oC) Ideal Result: 72hrs (20-22 oC) / 1 week (4-8 oC)

Specificity and Sensitivity

Develop an ROC curve to assess the specificity and sensitivity of the biomarkers.

Minimal Acceptable Result: >1 biomarker in alternative biospecimen achieves Area Under the Curve (AUC) of > 0.85 ±

0.05 (95% CI)

Ideal Result: >1 biomarker with an AUC > 0.90 ± 0.03(95%

CI)

Phase II

Alternate Biospecimen Testing

Reassess biomarkers identified in Phase I in at least one additional dataset/biospecimen.

Minimal Acceptable Result: >1 biomarker in alternative biospecimen achieves AUC > 0.85 ±0.05 (95% CI)

Alternate Lymphatic Disease Testing

Assess candidate biomarkers expression in at least one additional model of LD.

Minimal Acceptable Result: >1 biomarker of additional LD achieves an AUC > 0.85 ±0.05 (95% CI)

Integration with TA2

Correlate candidate biomarkers with imaging assessment of lymphatic structure and function.

Ideal Result: Rsq > 0.5 between at least one biomarker and one imaging based lymphatic functional metric.

Phase III

Clinical Validation

Develop or participate in a patient study where the biomarker’s effectiveness will be further evaluated alongside an imaging technology in TA2.

Demonstrate that efficacy and accuracy in, matches or exceed Phase I/II metrics in patient study.

Earliest Clinical Detection (in comparison to reference test):

Minimal Acceptable Result: Detection following initial reporting of symptoms.

Ideal Result: Pre-clinical detection of lymphatic dysfunction

Transition and Adoption Successfully transition to the clinic or larger commercial entities.

Develop workshops and showcases of technology for key stakeholders.

Scope and Equity Targets Product Target Minimal Acceptable Result Ideal Result

Intended Use Detect and monitor primary lymphatic diseases (lymphedema and complex lymphatic anomalies)

Detect, monitor, and inform treatment of lymphatic dysfunction that is driving or contributing to a chronic disease.

Target User

Populations with primary lymphatic disease (performers must be able to accurately detect lymphatic disease in the presence of comorbid conditions and differentiate lymphatic disease from other comorbid conditions).

Populations with primary lymphatic diseases and general lymphatic dysfunction

Accessibility Results in ≤ 1 week Results in ≤ 3 days

Affordability <$100 to customer Full coverage by healthcare insurance

TABLE 1B. TA1 MILESTONES & TIMELINE

3.3.2 TA2 METRICS AND OBJECTIVES

The expected metrics per phase in TA2 are listed in the table below.

Specific metrics for potential approaches are identified in the table below with the following designated letters:

A. Imaging tracer or contrast agent development and delivery B. Combining multiple imaging modalities C. Advancement of non-invasive imaging technology

Table 2A. TA2 Metrics

Phase I Selection and Development

Outline a specific LD and/or tissue bed that your solution is optimized for.

Demonstrate that your approach will achieve or exceed at least 5 of the six metrics:

Minimal Acceptable Result:

1. Field of view (FOV) >12cm x 12cm

2. Spatial resolution: <1.0mm

3. Temporal resolution >1 scan of FOV/min

4. Depth of imaging >2.0cm

5. Total procedure time <2 hours

6. Affordability <$1,200 per scan (cost to patient)

Ideal Result:

1. Field of view (FOV) > 1m x 15cm

2. Spatial resolution: <100μm

3. Temporal resolution >20 scans of FOV/min

4. Depth of imaging >6cm

5. Total procedure time <30 minutes

6. Affordability <$500 per scan (cost to patient)

Specificity and Sensitivity

Month 9 to 12: Submit project work record - demonstrate maintenance of a design history file (DHF) demonstrating capability of imaging LS >90% of patients, 90% specificity to the LS.

Minimal Acceptable Result:

A. Detection of LD with ≥ 90% accuracy in small animal models.

B. Detection of LD with ≥ 80% accuracy in small animal models or ≥

60% accuracy in human data.

C. Detection of LD with ≥ 60% accuracy in human data.

Initial Performance Test

Resolution of LS anatomical structure in a tissue bed (in alignment with development targets above).

Additionally, performers must develop imaging-based functional metrics (i.e. imaging biomarkers):

A. At least 1 functional metrics of the LS B. At least 2 functional metrics of the LS C. At least 1 functional metrics of the LS Functional metrics for the LS include, but are not limited to: Lymph generation rate, transport rate to thoracic duct, vessel permeability, luminal pressure, flow rate, contractility, valve competence. Functional metrics must correlate with a performer determined reference (Target: r > 0.7)

Phase II

Quantification of function

Quantification of at least two additional imaging-based functional metrics.

Minimal Acceptable Result:

Imaging based functional metrics should be correlated with LD state with a sensitivity of 75% and specificity of 90% in initial models.

Risk Reduction

Evaluate and mitigate barriers to adoption: Affordability, ease of use and integration into clinical workflow, size.

If appropriate, further validate AI/ML approaches used for detection or functional measurement with additional testing and training sets.

Additionally:

A. Toxicology and PK/PD studies.

Alternative Strategies

Implement the imaging tool in an alternative tissue bed or LD to assess efficacy and universality of approach.

Performance targets should align with the Phase I development goals for the six performance categories outlined.

Additionally:

A. Assess efficacy of a secondary delivery method to target the LS in the Phase I tissue bed.

Organ/Tissue Targeting

Minimal Acceptable Result: ≥ 2 organs/tissues Ideal Result: ≥ All organs / whole body

Performance Test

Detection of LD, or lymphatic associated tissue disease, with >95% accuracy in a large animal model or human data (in combination with diagnostic tools from TA1 and TA3)

Phase III

Clinical Trial or Clinical Validation

Develop or participate in a phase I clinical trial (A) or patient study for clinical validation (B & C).

Validate efficacy and accuracy in patient study.

Transition and Adoption

Successfully transition to the clinic or larger commercial entities.

Develop workshops and showcases of technology for key stakeholders.

Scope and Equity Targets: Imaging Technology

Intended Use Detect and monitor primary lymphatic diseases (lymphedema and complex lymphatic anomalies)

Detect, monitor, and inform treatment of lymphatic dysfunction that is driving or contributing to disease.

Target User

Populations with primary lymphatic disease (i.e., ability to accurately detect LD in the presence of comorbid conditions and differentiate LD from other comorbid conditions).

Populations with primary lymphatic diseases and general lymphatic dysfunction.

Safety Radiation Limit: <15mSV No radiation

Accessibility Available for use in suburban community hospitals

Available for use in rural and…