A Solicitation of the National Institutes of Health (NIH) and The Centers for Disease Control and Prevention (CDC) for Small Business Innovation Research (SBIR) Contract Proprosals

(Fast-Track proposals will not be accepted. Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning.) Number of anticipated awards: 1 to 3 Budget (total costs, per award): Phase I: $325,000 for 9-12 months; Phase II: $2,000,000 for 2 years It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Summary: The objective of this contract is to develop a multi-modal virtual reality environment for remote use enabling physicians and healthcare providers to guide rare disease patient therapy while automatically obtaining crucial health metrics. Genetic and rare diseases are often chronic debilitating disorders for which patients require life-long individualized care, and which frequently require longer and more frequent visits with their physicians and healthcare providers than for typical patients. Given the small numbers of patients with each rare disease and few specialists with expert knowledge about these disorders, an understanding of the clinical characteristics and course of a rare disease often resides with patients and caregivers who are geographically scattered throughout the country. . Thus, there is a need for rare disease patients to receive active feedback pertaining to their health and disease progression, as well as to engage patients to positively enable the healing process. Engagement of rare disease physicians and healthcare providers can also be a challenge given the frequent lack of measurable outcome assessment tools to monitor patients over the long-term for both disease progression and the benefits of therapeutic intervention, and the need for seamless coordination with a multi-disciplinary care team. Additionally, rare diseases disproportionately affect children and adolescents, and the repetitive often boring nature of physical and occupational therapies can lead to disengagement and a lack of motivation to continue these interventions outside of the clinic. Rare disease patients may also be located far from expert medical centers, have difficulty with travel due to the severity of their conditions, and in the event of National emergencies (i.e. pandemics), many rare disease patients experience disproportionate interruptions in medical care. These issues are especially difficult for rare disease patients in rural or low-income communities (“medical deserts”). While current video-conferencing capabilities enable communication, they lack the interpersonal connections between healthcare providers and patients, and the ability to accurately assess functional measures over the course of treatment, such as joint mobility, forces/timing of physical movement, global activity, or accurate assessment of heart/respiratory rate. Thus, there is a critical need for rare disease patients to have the ability to remain home with continued access to high-quality teletherapy and remote monitoring. To address the needs for user engagement and remote metrics for rare disease patients, physicians, therapists and healthcare providers are collaborating to develop an immersive VR environment for physical and occupational therapy and rehabilitation. The experience provides a remote medium to monitor user pain, discomfort, mobility, and biometrics during a prescribed therapeutic exercise session. Research has indicated that immersion afforded by VR can reduce pain and discomfort in the physical medicine and rehabilitation context. However, perception of immersion is highly individualized and context-dependent to the patient. To address the needs for user engagement and remote metrics, physicians, therapists and healthcare providers are working with developers to advance an immersive VR environment for physical and occupational therapy and rehabilitation. Efforts in game design mechanics through multi-modal immersion such as haptic feedback vests, olfactory masks, and other emerging technologies are being investigated to understand how to best design healthcare experiences for emotional engagement and interpersonal connection. These metrics can provide a remote medium for physicians and therapists to understand patient movement and engagement in therapy protocols. Now, these efforts should evolve into an interactive environment so physicians and healthcare providers and rare disease patients can meet remotely and still receive quality care. Project Goals: The purpose of this project is to create a virtual reality therapy environment for remote use enabling physicians and healthcare providers to provide quality care for rare disease patients outside of their offices or clinic settings. Offerors will address the current limitations with teletherapy by creating features to guide patients and gather relevant metrics necessary for physicians and healthcare providers. We want to address the challenges of disengagement and frustration by creating a stimulating, enjoyable and easy to use virtual environment for rare disease patients. To this end, the goal of this project is to translate rare disease patient care into virtual reality through (1) automated health metrics utilizing an immersive virtual reality systems motion capture, (2) remote healthcare provider-patient interaction through virtual avatars in a 6 degrees of freedom (6-DoF) environment, and (3) a series of games that are customizable by the healthcare provider for physical, functional, cognitive, or behavioral exercises for the rare disease patient to be played independently. An optimal outcome would be the creation of a system for physicians and healthcare providers to adopt beyond shelter in place that would have the following benefits: ● Increase physician and healthcare provider accessibility to rare disease patients through virtual clinics and at-home meetings. ● Increase rare disease patient motivation and engagement to therapy protocol through gamification. ● Monitor and document compliance with therapy protocols through remote capture. ● Optimize healthcare provider time by automating analysis of patient specific health metrics. ● Personalize rare disease patient therapeutic exercises through a tunable environment for both the patient and physician. ● Provide real-time rare disease patient feedback through web-based analytic dashboards. ● Provide engagement through virtual environments to aid in physical, functional, cognitive or behavioral exercises. ● Enable a standardized platform for collecting remote health data. For this process to be possible several key components will be required as described in the Phase 1 Activities and Expected Deliverables section. Phase I Activities and Expected Deliverables: ● An immersive virtual reality environment with a minimum of the following capabilities: ○ An avatar representation for remote patient- healthcare provider interaction. ○ A WebXR instance of the experience through the Unity Game Engine to enable usage on any VR device through the world-wide web. ○ Sensing capabilities to perform runtime health analytics for physician observation. ● An analytics dashboard for patient- healthcare provider interpretation both in and outside of the virtual environment. ○ An algorithm for automated runtime health informatics to provide rare disease patient engagement, discomfort, kinematics, dynamics, and muscle force estimation. ○ Representations of functional assessment for the patient’s avatar in immersive virtual reality through force vectors and heatmaps. ○ A modular dashboard for representations of targeted health informatics. ○ Verification of secure and ethical data practices for remote data collection. ● A method of personalized gamification for physician prescribed exercises. ○ A customizable background environment to change the audio-visual stimuli of the user’s virtual health experience. ○ An adaptive input system to enable the addition of immersive peripherals such as haptic feedback vests, olfactory masks, gaze-based systems, and custom controllers for accessibility and variable immersion. ○ A physical exercise game for physicians to record desired movements and prescribe them to patients. ○ A mindfulness exercise game for healthcare providers to record desired breathing patterns and mediation lengths and prescribe them to patients. ● Assemble appropriate expertise in their teams to meet statement of work goals, which could include clinicians, occupational therapists, physical therapists and other appropriate subject matter experts depending on the deliverables of the contract. ● Provide NCATS with all data and materials resulting from Phase I Activities and Deliverables. Phase II Activities and Expected Deliverables: ● Build a prototype virtual experience that meets the Phase I specifications. ● Provide a test plan to evaluate every feature of the virtual experience. ● Provide NCATS with all data from each executed test to properly evaluate each test condition. ● Develop a robust web server for the virtual experience, using compliant secure components and minimizing expense where possible. ● Provide NCATS with all data resulting from Phase II Activities and Deliverables. ● Assemble appropriate team/expertise to perform deliverables of the contract ● Provide NCATS with all data and materials resulting from Phase II Activities and Deliverables.

(Fast-Track proposals will not be accepted. Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning.) Number of anticipated awards: 1 to 3 Budget (total costs, per award): Phase I: $325,000 for 9 months; Phase II: $2,000,000 for 2 years It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Summary: The unprecedented 2020 COVID-19 pandemic and subsequent physical distancing has led critical experimentation for developing novel diagnostic techniques and potential therapeutic interventions to nearly grind to a halt. This is due to the reliance on people to be physically present in a laboratory. The contract proposed here is to develop a next generation therapeutic discovery or diagnostic platform consisting of distributed, Artificial Intelligence (AI)-enabled, fully automated pieces of instrumentation that are capable of functioning in an autonomous fashion and directly linked to virtual cloud-based resources. The type of instrumentation required will depend upon the kind of experiment to be performed. Regardless of the experiment type, the instrumentation should be geared towards therapeutic discovery or a diagnostic technique such as an ELISA assay, the resultant experimental data could be ingested in real time to a cloud-based virtual research organization (VRO). The VRO model proposed would greatly improve safety with little or no loss of productivity. A key challenge for rapid development of diagnostics and therapeutics has been the inability to acquire, harmonize, store, analyze and share data generated during experimentation. Through this concept, a platform would be created to make data accessible to researchers anywhere on the globe in near real-time to help respond to a fast-changing pandemic or other healthcare crisis where time is of the essence. Project Goals: The goals of this project are to develop a platform comprised of three core components: 1. Distributed, modular, next generation autonomous laboratories that focus on areas such as high throughput screening (HTS) for drug discovery, next generation sequencing (NGS), high content imaging (HCI), polymerase chain reaction (PCR) diagnostics and others. 2. A cloud based VRO that each distributed automated laboratory is directly connected to. 3. Federated AI, potentially most critical, is the integration of the physical laboratories with the virtual cloud environment such that AI methods can be utilized to generate hypotheses based on previous experiments that could then be tested in the physical laboratory environment. This distributed and iterative approach would allow for the on demand initiation of a physical experiment, which could conceivably be a HTS run in one location along with NGS at another, the generation and analysis of data, with each experiment performed further expanding the available data to be used for more efficient and accurate AI models which can then initiate new experiments. It would be possible to compile and quickly perform a relational analysis of multiple relevant data types ingested into the cloud-based VRO from different distributed autonomous laboratories, as well as use AI generated hypotheses to trigger new experiments in order to broaden the dimension of discovery in a shorter time frame. The modular nature of this approach will also allow the entire platform to quickly add or scale up additional resources as required to respond to emerging pathogens or other biological scientific needs. Phase I Activities and Expected Deliverables: • Develop a prototype Platform for Rapidly Deployable Autonomous Laboratory comprised of three components: o Modular instrumentation with the following characteristics: • Must be used in typical laboratory operations such as HTS, NGS, HCI, PCR, etc. • Must use standard laboratory instrumentation communication protocols to communicate with other devices such as RS-232, TCP/IP, CAN bus, etc. • Must use ethernet based protocols to communicate with cloud-based environments such as TCP/IP, MQ Telemetry Transport (MQTT); commonly used for the Internet of Things (IoT); Advanced Message Queuing Protocol (AMQP), etc. • Must have a comprehensive application program interface (API) allowing for full control of the instrument, ranging from initiating the execution of an instrument specific protocol, to monitoring the status of the device, reporting results, reporting device faults with ability to recover, etc. • Must be able to communicate with other pieces of instrumentation to develop functional laboratory platforms. • Must include an instrument which generates data as the result from laboratory operations such as HTS, NGS, HCI, PCR, etc. • Must include consideration for a sample transport device. • Ideally will utilize modular components which are easily replaced when required. o A cloud based VRO that each distributed automated laboratory is directly connected to with the following core capabilities: • Infrastructure: • A scalable, cloud-based architecture residing in a major cloud service provider such as Amazon Web Services (AWS), Microsoft Azure, Google Cloud Platform (GCP), etc. The offeror should be able to demonstrate access (via an executed license) to the cloud service. • Data Storage, Access, and Catalog • Distributed data storage via services such as S3, Azure and Google storage etc. • Storage Class memory technology to be able to access data in real-time. • Data access API for simplified interface such as the use of 'PUT' and 'GET' requests. • A Data Catalog accessible via an API and keep tracks of all data sources and their respective metadata. • Data Extraction, Aggregation, Integration, and Harmonization: • Ability to integrate simultaneous data connections from multiple concurrent sources. • Enable connections to multiple types of databases and makes data available to users through a single access point. • Secure collaboration: • Multiple users should be able to visualize and work on the same data in a collaborative platform. • Remote Binding to ensure device control is handled securely and safely • Complaint with the following industry best-practice certifications, attestations, alignments, and frameworks such as: o SSAE18 SOC 2 Type II o ISAE 3000 SOC 2 Type II o FedRAMP Moderate (Ideally, but not required for Phase I) • Interoperability and Open Architecture • Store data in open source formats and expose REST APIs to interoperate with third-party and open source tools o Integration of the physical laboratories with the virtual cloud environment to allow for: • Federated AI and Machine Learning (ML) such that AI and ML methods can be utilized to generate hypotheses based on previous experiments that could then be tested in the physical laboratory environment. • Accessibility from external collaborator laboratories for use of the VRO and ability to remotely run experiments and process data into the VRO cloud environment • Adherence to appropriate safety protocols and procedures for physical control is mandatory of the above requirement within the VRO for anyone to be able to remotely control instrumentation. • Ability to scale, publish and share instrument services/functionality i.e. laboratory as a service (LaaS) • Provide cost estimates to develop a proof of concept platform capable of meeting the specifications listed above. • Provide NCATS with all data resulting from Phase I Activities and Deliverables. Phase II Activities and Expected Deliverables: • Build a prototype platform that meets the Phase I specifications. • Provide a test plan to evaluates all components of the platform, from the instrumentation performing some laboratory operation, to the data being sent securely to the VRO and finally with that data being used to propose and initiate a new experiment to be run on the platform. • Demonstrate that the platform is scalable to potentially hundreds of pieces of instrumentation in a distributed fashion. • Provide NCATS with all data resulting from Phase II Activities and Deliverables.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Tertiary lymphoid organs (TLOs) are lymph node-like structures that form in tissues in the presence of chronic inflammation in response to molecular and pathological damage from exposures (both internal and external). The purpose of their formation is an active area of study, but they likely form to fight damage at the tissue level while also collecting, processing, and delivering and presenting tissue- and tumor- antigens to primary and secondary lymphoid organs. TLOs are characterized by many of the same morphological features as lymph nodes. These morphological features include germinal center B-cell zones, T-cell follicles, and high endothelial venules (HEVs) through which immune cells traffic into/out of the TLO. TLOs are also populated with many of the same cell types as lymph nodes, including mesenchymal derived follicular dendritic cells that recruit lymphocytes and assist in the formation of the morphological features; and hematopoietic stem cell derived antigen presenting dendritic cells (DCs), macrophages, central and effector memory lymphocytes, etc. TLOs are found within almost all tumors and may play a critical gatekeeping role in the ability for T cells to access the tumor microenvironment and participate in immune surveillance. Recent studies show that intra-tumoral TLOs can sequester cytotoxic T cells, and ectopic TLO formation immediately adjacent to the tumor margin prevents the infiltration of T lymphocytes (TILs) into tumor. While TLOs are likely to play a critical role in the ability of the immune system to mount an immune response to tumor neoantigens, and also control effector cell access to tumor cells, TLO containing in vitro models do not exist and in vivo approaches to induce TLOs in animal models are extremely limited. Therefore, there is a need for more efforts to develop both intra and ectopic tumor associated TLO models to understand their role in the development of cancer, immune tolerance, tumor immune evasion, and antitumor immunity. Generating these 3D systems with TLOs that are viable for longer periods is challenging but once established using right elements that best represent the biology and pathology, they can be valuable tools for obtaining insights in basic and translational research in cancer, autoimmune diseases and chronic inflammatory and infectious diseases. Establishing TLO containing 3D systems that survive for a longer duration is not only important for understanding the immune system’s role in keeping cancers in check but also for unraveling how immune system may contribute ques for cell transformation, cancer development and progression, and all these processes require a longer interaction of the immune system with the tissue cells. Project Goals The goal is to advance the development of next generation 3D tissue/tumor cell culture systems that develop and maintain self-assembled TLOs for months. There are several potential research uses for 3D culture models that incorporate TLOs, including: 1) studying immune system’s role in clearing autophagy, apoptosis and/or necrosis mediated tissue damage; 2) studying immune system’s role in prevention, initiation and development of cancer as well as metastasis, 3) studying interactions among immune cells and tumor cells in the tumor microenvironment, 4) serving as an innovative and simple in vitro approach for identifying neoantigens that are collected, processed and displayed by the antigen presenting cells in the TLOs, 5) studying movements and interactions of TILs in tumors, and 6) facilitate development of personalized immunotherapy. The activities and deliverables in the solicitation will focus on the development of 3D tissue cultures that contain self- assembling TLOs with key morphological and functional characteristics. Critical morphological characteristics of the TLOs are B cell and T cell zones. Offerors will be required to interrogate the functional aspects of the TLOs including tumor antigen presentation by DCs within the TLO, and activation and expansion of T cells and B cells. This topic will require developers to establish a 3D culture system representing at least one tumor type and develop 3D cultures from multiple donors. Furthermore, the activities will require that the offerors evaluate the longevity of TLOs in vitro, and ideally demonstrating that a 3D culture systems containing TLOs can be maintained for a minimum of 2 months, with a preference for longer periods of 8-10 months, to allow testing the utility of the established systems, particularly for studying tumor microenvironment interactions. Responsive proposals must develop 3D culture systems containing TLOs using human tumor and immune tissue. Offerors must propose to use tumor tissue and immune cells from the same donor for each 3D system’s development. The immune cells must be differentiated and/or obtained using progenitors with tumor cells providing the cues for their differentiation and activation. The stromal-like cells, to improve structural organization and functionality of the TLOs, must be differentiated/obtained from mesenchymal stromal cells. Preference may be given to systems that use matrices from human sources. Systems that use matrices from non-human sources will be of low priority. Offerors will not be required to develop new 3D tissue culture systems to respond to the solicitation, and companies that have expertise in building 3D culture systems and previously built 3D culture systems through a previous NCI SBIR contract opportunity or other opportunities will be eligible to compete for this topic assuming their proposals meet all of the requirements laid out in this solicitation. Activities not responsive to announcement: 3D systems 1) without functional immune cells, 2) that are simply made by incubating the 3D systems with peripheral blood mononuclear cells (PBMCs) to allow infiltration of immune cells, 3) made using immune cells not properly allowed to mature, differentiate and activate using the cues from the tissue/tumor cells used for creating the 3D system, and 4) 3D systems with TLOs made using synthetic polymer-based dendritic cells Phase I Activities and Deliverables: • Project team: Establish a project team with proven expertise in development of 3D complex tissue models, immunology, clinicians with access to patient samples, including subject matter experts in the tumor(s) being studied • Identify appropriate cell types needed to create the 3D systems • Show resources and expertise needed to mature, differentiate and/or activate the cells needed for creating 3D systems containing TLOs • Create the 3D systems with TLOs representing at least one cancer type (such as pancreas, breast, prostate, lung, colon or liver) • Show that the 3D systems can be developed reproducibly, by showing that the developed systems maintain genotypic and phenotypic characteristics for at least a month. Determine growth and expansion of cells and continued maintenance of genotype and phenotype in different compartments of the 3D systems • Characterize the cells in the 3D system: Show that the mesenchymal derived follicular dendritic cells can recruit immune cells and form TLOs in the 3D systems. Determine antigen presenting capacity of dendritic cells, and central and effector memory cells divide, expand and maintain the TLOs. Analyze T cell receptor excision circles and kappa-deleting recombination excision circles to determine half-life of the T/B cell clonotypes and number of cell divisions, and T cell and B cell receptor sequencing to determine suitability of the T/B cells for forming TLOs that represent the TLOs present in tumor/tissue that is being created • Show access to samples needed to conduct comparative analysis in phase II • Establish workflows for creation and maintenance of 3D systems, and morphological and molecular characterization of the 3D systems and component cells • Submit a detailed statement of performance characteristics along with SOPs for establishing and characterizing the 3D systems to NCI. Phase II Activities and Deliverables: • Create 3D systems with intra and/or ectopic TLOs. • Improve viability and show that the 3D systems’ viability is for a minimum of 2 months with a preference for longer periods of 8-10 months and reproducibility is > 75%. • Characterize the interactions in the microenvironment - such as genotypic (chromatin accessibility, mutation, structural changes, etc.), epigenetic (methylation, histone modification, etc.) and phenotypic (gene expression, chemokines, cytokines, morphological, function, etc.) changes- among immune cells, endothelial cells and epithelial cells using physicochemical, biological, immunocytochemical/histochemical imaging methods. • Compare the 3D systems’ physicochemical and functional characteristics with the characteristics of TLO containing tissues/tumors from humans • Compare antigens displayed by the TLO-DCs in 3D systems with antigens displayed by the circulating migratory DCs in blood from experimental animals or cancer patients with respective cancer type(s) • Compare microenvironment interactions displayed by the 3D systems with the data from in vivo models • Demonstrate utility of the 3D systems for quickly collecting neoantigens in vitro: Identify antigens displayed by the dendritic cells (TLO resident or migratory dendritic cells) in the 3D system • Assess utility of the 3D systems for determining drug/immunotherapy response • Assess how the location and duration of TLO (intra or ectopic) alter infiltration and movement of TILs • Establish QC and QA parameters to increase reliability of the 3D systems and create a commercial prototype of the 3D tissue/tumor culture system • Submit final SOPs, QC/QA parameters, performance characteristics, and characterization and antigen data

Fast-Track proposals will NOT be accepted. Direct-to-Phase II proposals will be accepted Number of anticipated awards: 3 - 5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Gene therapy has come of age over the past few years. One of the most promising anticancer approaches in the clinic is chimeric antigen receptor (CAR)-T cell therapy. However, the pioneering first-generation products now on the market for B- cell malignancies, that target a single cancer antigen, have major limitations. First, all normal B cells expressing CD19 are eliminated by the therapy meaning that normal B cell functions are lost. Second, patients may lose expression of the CD19 CAR-T target antigen, rendering the malignant tumor cells invisible to the immune system tasked with its destruction. Third, the therapies can trigger toxicities that are hard to predict and control, such as cytokine release syndrome. By combining computer science logic with biology, scientists have developed synthetic gene circuit technologies to redirect genetic events within cells to enable the resulting therapies to sense and adapt to their environment, or be controlled to avoid the safety and efficacy pitfalls that limited first-generation products. For example, new CAR-T approaches involve the delivery to T cells of gene circuits based on Boolean logic that can produce tumor cell killing only when two (or more) cancer antigens are expressed on cancer cells but not on normal cells, preserving normal B cell function. These synthetic gene circuits are assembled of DNA encoding RNA or protein that enable individual cells to respond and interact with each other to perform a function at the desired locations (e.g. within the tumor vs. whole body), targets (e.g. cancer cells vs. healthy neighboring cells), amount (e.g. therapeutic vs. toxic doses) and duration (e.g. shut down before significant side effect occurs). Key components include sensors that detect user-defined inputs, processors that make decisions in response to the inputs, and actuators that produce the desired output activities (payloads). Synthetic gene circuits can be delivered into cells ex vivo as in the CAR-T case, or in vivo using any well-established gene transfer vectors. These gene circuit therapies can be programmed to distinguish cancer cells from normal cells and to activate therapeutic payload expression from inside tumors. Project Goals The goal of the topic is to stimulate the development of gene circuit therapies for cancer. Engineering of immune cells and/or cancer cells is encouraged, while other cell types are not excluded. The recent pioneering work in synthetic biology has shown the potential of overcoming current challenges in gene therapy by creating sophisticated gene circuits to distinguish between malignant and healthy cells and to efficiently kill the former without harming the latter. Unlike conventional small molecules or biologics, including most of the current gene therapies, gene circuit therapies can potentially sense multiple disease signals, integrate this information to make a decision to trigger sophisticated or combinatory therapeutic mechanisms. Alternatively, gene circuit therapies can also be controlled exogenously, therefore allowing precise control over timing, dose and location of the therapies. The activities that fall within the scope of this solicitation include the development of the gene circuits designed and created using synthetic biology approaches into cancer therapies through engineering immune cells ex vivo, or by delivering directly into cancer cells in patients using viral or non-viral gene transfer approaches/vectors, including engineering of bacteria to specifically target cancer. The approach should also allow precise control over timing, dose, and location of the therapies. Examples of appropriate activities include to demonstrate that the gene circuit can be expressed in cancer cells in vitro and in vivo, with increased efficacy and decreased toxicity compared to currently available similar therapies or to standard of care. A system that does not have the potential to allow precise control of the therapeutics over timing, dose, and location as needed will not be responsive. Methodologies to create gene circuits without delivery will not be responsive. Animal studies establishing proof-of-concept efficacy in well-validated in vitro and in vivo models should be completed in Phase I. In Phase II the contractor is expected to perform a large-scale in vivo efficacy study, as well as other studies required for FDA IND submission. Phase I Activities and Deliverables: Establishing proof-of-concept efficacy and/or toxicity: • Demonstrate in vitro sustained and controllable transgene expression with efficacy in appropriate cell lines and/or 3D models • Demonstrate in vivo sustained and controllable transgene expression with efficacy in appropriate small animal models • Conduct gene circuit optimization (as appropriate). • Perform (optional) animal toxicology and pharmacology studies as appropriate. • Demonstrate (optional) increased efficacy and/or decreased toxicity as compared with standard-of-care for the cancer indication in appropriate animal model(s). Phase II Activities and Deliverables: The offerors are encouraged, but not required, to meet FDA before the submission of a Phase II proposal. A detailed experimental plan necessary for filing an IND is expected in the Phase II proposal: • Conduct properly powered efficacy studies, demonstrating benefits with statistical significance. • Complete IND-enabling experiments and assessments according to the plan developed. The plan should be re- evaluated and refined as appropriate. • Develop and execute an appropriate regulatory strategy. If warranted, provide sufficient data to file an IND or an exploratory IND for the candidate therapeutic agent. • Demonstrate the ability to produce a sufficient amount of clinical grade material suitable for an early clinical trial.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 1-3 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary This solicitation calls for the development of electronic devices to replace current radiation sources for use in the clinic allowing for implementation using existing high dose rate (HDR) applicators. The goal is to leverage the full, existing radiation therapy infrastructure (training and applicator set investment) to provide radioactive source-free (e.g., iridium) brachytherapy. Submissions will be responsive if the proposed electronic brachytherapy sources are substitutable for radioactive sources currently in use in the clinic via use with unmodified commercial applicator sets. Brachytherapy, in surface, intracavitary and interstitial forms, using small radioactive sources is a critical component of global radiation therapy and is a mainstay in the cure for diseases like cervical cancer, sarcoma, and recurrent cancer. It is used in both adult and pediatric patient populations. The methods used are proven, affordable, and offer unique advantages to patients in terms of dosimetry - even relative to particle therapy. However, the permanent radioactivity of sources creates issues and costs related to safety and security that electronic devices would not present. Turning an electronic device off causes the radiation emission to cease. In addition, electronic sources may present unique, new advantages for dosimetric control of radiation. To be responsive to this FOA submissions must develop and test devices that can be employed using existing brachytherapy infrastructure. In this context, the proposed devices must be compatible with the current applicators available on the market. Applicator set examples can have paths with small radii of curvature and include ring and ovoid sets and tandem and ovoid sets for cervical cancer, catheters for prostate cancer, head and neck cancer and sarcoma, and even devices allowing ocular, skin, and nasopharyngeal deployment. Use of these devices is critical so as to take advantage of infrastructure and established safety and efficacy data. Project Goals This contract solicitation seeks to stimulate research, development, and commercialization of innovative devices to replace and enhance the radiation space currently occupied by radioactive sources in brachytherapy. To apply for this topic, offerors should: • Develop an appropriate electronic device and control system to allow integration into the clinic. • Measure and define the radiation characteristics of the device: output spectrum, stability, dose rates possible, and similar capacities for modulation of dose. • Validate that the planned (final) device will be deployed in a clinical setting using existing brachytherapy devices (applicator sets). Devices must be able to move around curves and cannot depend on waveguides. Activities not responsive to announcement: 1. Approaches requiring new infrastructure (patient applicator modifications, treatment planning system standards changes, imaging protocol modifications) are not appropriate for this solicitation. 2. Penetration of radiation in tissue must be equal to or greater than 1 cm and energy of the beam produced must be equal or greater to 250 kV. Devices unable to achieve these energy output constraints or greater will be considered non- responsive. Phase I Activities and Deliverables: • Establishment of a project team that includes necessary expertise in: electronic devices capable of delivering radiation that are small in size (physics/engineering); software development for device control and operation, user- centered design for interface design, radiation/clinical oncology delivery and processes, medical devices regulations and manufacturing process expertise. Medical knowledge of brachytherapy practice and delivery is required. • Develop a fully functional prototype that can be used with existing HDR medical devices (tandems, rings, sarcoma catheters, partial breast devices). o Confirm (documentation to be reported) that the device delivers dose at an energy and dose rate required of this announcement (penetration of radiation in tissue must be equal to or greater than 1 cm and energy of the beam produced must be equal or greater to 250 kV). o Demonstrate device stability in a model (phantom) of clinical use (motion, temperature, normal handling, dose rate, energy, with repetition). The device needs to be able to tolerate a 30 cm drop onto a solid surface without measurable change to the radiation delivered by the device. o Develop standard operating procedures to confirm dose delivery/validation of device function and stability. These must allow NIST traceability to be achieved in phase II. • Perform in vitro efficacy studies in relevant cancer cell line(s) with normal tissue and standard brachytherapy source device controls. • Develop user documentation for use of the device. • Document a telephone call(s) and/or meeting(s) with the FDA discussing the process to achieve an IND and related approvals. Phase II Activities and Deliverables: • Develop a device/technology/process to scale up manufacture and calibration of devices centrally so that once produced and sold they are easy to deploy and utilize – test this via making multiple devices that may be calibrated to within 5% dose delivery of each other or better (ideally within 1%). • Refinement process development for construction of final product by o Data for the successful scale-up of production of device o Data documenting the completion of process analytics for production and calibration, including demonstrating the ability to be calibrated in a stable fashion to NIST standards at the factory and in the field, o Demonstrating the formal, finalized process to allow general production unit’s dosimetric verification o Documentation demonstrating the completion of safety interfaces and procedures for clinical implementation • Demonstrate the ability to use a commercial and/or in-house robust and standards-based treatment planning system (TPS) with this device. o Treatment plans should be able to be taken from the TPS and put into the delivery system so as to control the “delivery” of the plan to a patient in standard fashion. o If an in-house system is developed, appropriate FDA approval processes must take place and demonstration that this TPS can properly interact with at least two leading TPS systems must be documented (plan import and export). o Published interface data and standards compliance for all interfaces so that a commercial TPS vendor “could” provide services to the device with their TPS. • Demonstration of continued, close communication with the FDA in years one and two to initiate the trials and processes needed to achieve full IND approval. Trials should be at least in the process of IRB review. • In the second year of the contract, provide the program and contract officers with a letter(s) of commercial commitment.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted Number of anticipated awards: 3 - 5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary All currently recommended screening tests for cervical cancer require a clinic visit and a clinical provider (physician/nurse practitioner/physician assistant)-conducted per-speculum examination for sample collection for the screening method (HPV testing and/or Pap smear cytology). An alternative that has been explored is self-collection of samples (‘self-sampling’) by women themselves for HPV testing, an approach that offers several benefits including ease of collection at a time/place of women’s choosing and without a need for appointment or speculum examination. However, most current sampling devices have not incorporated consumer-friendly/user-centric design principles; therefore, it has been challenging to demonstrate acceptable accuracy given the variations in collection type and the expected decrement in yield of cellular material when performing self-sampling versus a clinician-collected sample from the cervix directly. Therefore, there exists a significant need for development and evaluation of novel devices for self-collection. The proposed contract topic solicitates the development and evaluation of novel self-collection devices, including activities leading to manufacturing and regulatory approval. Project Goals The overall goal of the contract solicitation is to facilitate the commercial development and regulatory approval pathway for novel self-sampling devices for HPV-testing-based cervical cancer screening. In particular, companies are expected to propose designing and manufacturing of devices for self-collection and transport/storage of cervicovaginal specimens and to demonstrate their clinical accuracy with a goal to seek FDA clearance via the 510(K) pathway (substantial equivalence with a predicate device for safety and efficacy; NCI will provide access to the predicate device that is being evaluated in an ongoing trial). The type of novel self-sampling devices that fall within the scope of this solicitation can be, but not be limited to, cytobrush-like, broom-like, or tampon-like devices and when applicable may include the following accessories: (i) Transport media (e.g., dry-swab, paper-based, fluid-based), independent or in conjunction with the collection devices, and (ii) shipment protection (with or without the transport media) to prevent contamination and maintain sample integrity during transport. Please note that technologies that involve collection approaches that are designed to be performed without patient participation are NOT considered appropriate for development under this contract topic. Phase I Activities and Deliverables: Offers must propose to conduct activities that lead to development of a working prototype device ready for clinical evaluation, including but not limited to: • Using user-centric design principles, develop the prototype self-sampling device, transport media and shipment kits for evaluation. • Conduct studies to establish analytical performance (analytical sensitivity, specificity) and other performance characteristics (e.g., limit of detection, consistency, reproducibility). • Conduct studies to evaluate and test user acceptability and feasibility in both intended use populations (i.e., women who are likely to miss regular cervical cancer screening and may therefore be appropriate candidates for home-based self-sampling) as well as average-risk populations. • Conduct initial clinical testing with at least one of the current FDA-approved HPV testing assays to determine the clinical performance measures (e.g., concordance with clinician-collected sample, clinical sensitivity and specificity). • Offerors may need to establish a collaboration or partnership with a research group or medical facility that can provide relevant patient access; offerors must provide a letter of support from the partnering organization(s) in the proposal. Phase II Activities and Deliverables: Offerors must propose activities leading to the manufacturing and regulatory approval of the device, including but not limited to: • Develop a well-defined self-sampling device under good laboratory practices (GLP) and/or good manufacturing practices (GMP). • Perform manufacturing scale-up and production for multi-site and multi-test evaluations • Demonstrate the clinical sensitivity and specificity of the device for self-sampling by performing multi-site and multi-test evaluations • Establish a strategy for FDA regulatory approval and insurance and/or CMS reimbursement

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted Number of anticipated awards: 2-3 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Quantitative imaging software tools developed in academic settings are typically developed for specific research purposes and are often validated only within the home institution. However, for such software tools to become widely useful in the clinical oncology community, the tools require rigorous validation at multiple sites, and with dynamic interplay between the tool developer and the clinician end users (radiologists, oncologists) to further refine, optimize, and validate the tool. The goal of this solicitation is to support commercial development by small businesses of new, or existing quantitative imaging (QI) software tools with utility to radiologists who rely on patient medical images for accurate cancer diagnosis and radiation treatment planning. QI tools can be developed de novo for commercial purposes under this solicitation. Alternatively, existing tools can be advanced toward commercialization, and candidates include several well developed tools produced by the NCI Quantitative Imaging Network (QIN; see https://imaging.cancer.gov/programs_resources/specialized_initiatives/qin/tools/default.htm) for the purpose of quantifying or predicting response to cancer therapy in human clinical trials. Within QIN, teams of academic researchers have been developing and optimizing tools of various functions for eventual deployment into clinical trials. Possible paths for commercialization of existing QIN tools include small business partnership (with a QIN team or other academic institution) to take the lead in translating an academic QI tool into clinical validation, or for the academic institution to form a new small business for the purpose of QI tool commercialization. Project Goals Commercialization by small businesses is expected to produce robust, well documented and well supported software tools after iterative optimization and validation through quality management controls. Furthermore, the software tool will function on several hardware vendor platforms for the common cancer medical imaging modalities (CT, MRI, ultrasound, PET). Under this solicitation, NCI will not support development of software usable on only one vendor platform. The QI tools are intended to have improved cancer detection capabilities, diagnostic accuracy, and utility for radiation treatment planning and cancer treatment decisions to provide the potential for widespread impact on the clinical community. The small business offeror will be required to specify a cancer imaging use case (e.g. an imaging modality, a specific cancer type, and cancer diagnosis versus monitoring versus radiation treatment planning) to focus on, and will need to clearly describe deidentified medical image data sets and their source for the purposes of conducting the proposed research. Quantitative milestones - with performance targets that define success – should be provided for each project objective. Phase I Activities and Deliverables: • Convene the project team with expertise in medical image software design, informatics, radiology, and medical oncology or radiation oncology to review and finalize the software design • Build Alpha software prototype • Evaluate Alpha software performance via retrospective analysis of deidentified medical image data sets • Refine software as needed, and repeat software evaluation via retrospective analysis of deidentified medical image data sets • Perform small-scale Usability testing, requiring a minimum of 10 end users at 5 different sites • Develop plans for a pre-regulatory submission dialogue with the FDA, to be completed before submission of a SBIR Phase II proposal, so that FDA requirements can be included in the SBIR Phase II research plan Phase II Activities and Deliverables: • Refine, and build the Beta version of the software based on Phase I results • Perform large-scale Usability testing, requiring a minimum of 30 end users at 15 sites • Refine software as needed • Evaluate software performance via retrospective analysis of deidentified, retrospective medical image data sets • Evaluate software performance with statistical significance via analysis of newly collected medical images in an IRB-approved, prospective clinical trial • File regulatory submission with FDA by the end of year-02, following either the 510k or PMA path (as required by FDA for the specific product use and claims sought by the contractor) • Secure two letters of commercial interest from potential customers at the end of year-01 • Secure two letters of commercial commitment to buy the product from customers at the end of year-02

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Public large-scale molecular-level datasets have facilitated sophisticated secondary data analysis leading to new biological discovery. These data sources provide rich, multi-omic molecular level data on bulk or single-cell populations, but most measurements do not preserve the spatial relationships between tumor cells and thus limit the ability to discover important and targetable cell-cell and cell-microenvironment interactions. To address this shortcoming, several programs supported by NIH, NCI and beyond have undertaken the construction of spatiotemporal single cell resolution atlases of normal and diseased tissues. Examples of technologies currently employed to build spatial atlases include multiplex microscopy and mass cytometry- based imaging modalities that provide information on multiple (10s-1000s) of biological molecules (genes, proteins, metabolites, etc.) in a single two-dimensional thin tissue section. While imaging of sequential tissue sections provides a way to re-construct the three-dimensional (3D) tumor microenvironment, most high content imaging modalities require multiple rounds of tissue staining and manipulation that can be destructive to any one tissue section making it difficult to reconstruct accurate 3D views. Therefore, technologies that provide imaging workflows that deliver cellular to sub-cellular resolution - omics level data in three dimensions (i.e. in thick tissue resections or whole biopsy samples) are likely to more faithfully conserve the architectural or structural components within the tumor microenvironment that could be destroyed or altered during multiple rounds of tissue processing. It is possible that approaches such as light sheet microscopy could fill this need, but the current protocols for tissue clearing, multiple rounds of target labeling to facilitate highly multiplexed omics measurement, and subsequent image processing make the overall workflow for an individual tissue prohibitively slow (days to weeks) and difficult to employ in atlas building activities where a large number of normal and tumor maps is required for a representative normal tissue or tumor atlas. Project Goals The goal is to advance the development and dissemination of imaging workflows capable of omics-level measurements in thick tissue resections or whole biopsy cores that can scale for use in atlas building initiatives. Proposals should enable interrogation in a manner that combines high resolution (preferably single-cell) -omics level data (i.e. genomics, transcriptomic, proteomic, metabolomic, etc.) with information about 3D native tumor architecture (i.e. extracellular matrix, vasculature, higher order structure, etc.). Proposals that are within scope of this solicitation may combine existing, new, or improved assay components into an improved imaging workflow. Examples of existing, new, or improved components include imaging technologies or modalities, tissue clearing methodologies, imaging probes and/or detection reagents, cyclic staining or targeting procedures, and/or unique combinations of imaging and multi-omic measurement platforms. A minimal workflow will provide a 3D view of multiplexed omics data without the need for reconstruction from 2D tissue slices. The ability to concurrently acquire additional information regarding native tumor architecture would be considered a strength (e.g. second harmonic imaging or alternative technology). Offerors should benchmark their proposed workflow against current state-of-the-art imaging workflows and demonstrate a decrease in overall assay time while maintaining a similar or increased capacity for omic-scale analysis. Activities not responsive to announcement: It is anticipated that proposals may include the development of new algorithms, visualization tools, and analysis software to facilitate data handling, analysis and visualization of results. However, applications that are solely software-based will be considered not responsive. Phase I Activities and Deliverables: • Establish a project team with proven expertise in development of high-resolution cellular imaging systems and multi-modal data analysis, including subject matter experts in the tumor(s) being imaged and the -omics measurements being proposed. • Define relevant use cases for the technology including, but not limited to, what tissues can be analyzed, what imaging resolution can be expected, what -omic measurement(s) will be completed, desired throughput of the system, and identification of benchmark technologies. • Prepare a report that specifies quantitative technical and commercially relevant milestones that can be used to evaluate the success of the technology versus current state-of-the-art 3D high resolution imaging platforms. Quantitative milestones may be relevant metrics (i.e. compared to benchmarks, alternative assays) or absolute metrics (i.e. minimum number of proteins or genes detected, metrics related to repeatability of the assay). Metrics regarding total assay time (including tissue preparation, cyclic staining (if relevant), and imaging processing/analysis) are expected. • Generate proof-of-concept dataset that addresses the use case above using resection tissue or biopsy cores from solid human cancers or from a generally accepted mammalian cancer model (i.e. PDX, xenograft, GEMM) that demonstrates the ability to capture and visualize molecular -omics measurements in 3D. • Prepare a report summarizing the performance of the system against the quantitative technical milestones indicated above. Include any plans to modify the platform based upon performance against stated milestones. • Develop and provide preliminary Standard Operating Procedures for system use, including a validated list of reagents addressing the use case identified above. • Present phase I findings and demonstrate the functional prototype system to an NCI evaluation panel via webinar. Phase II Activities and Deliverables: • Generate proof-of-concept dataset that demonstrates the ability to quantify the 3D native tumor architecture (i.e. extracellular matrix, vasculature, higher order structure, etc) in addition to the capabilities optimized in Phase I. • Generate datasets representative of at least three solid tumor types (thick resections or whole biopsies). • Provide a report that documents the reliability, robustness and usability of the system for the purpose of generating large scale molecular and cellular atlas building. • Provide a report to benchmark system performance (including total assay time) and functionality against the commercially relevant quantitative milestones proposed in Phase I. Report should demonstrate feasibility for scale up at a price point that is compatible with market success. • Provide Standard Operating Procedures for system use, including a validated list of reagents for each of the three demonstration tumor types. Include documentation for troubleshooting new tumor or tissue types to demonstrate the system can be utilized beyond the tumor types proposed. • Provide a roadmap for development of a turnkey system.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 2-3 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Next-generation sequencing (NGS)–based technology has lowered the cost of testing for genomic alterations in a patient's cancer and is now commercially available from many diagnostic laboratories and covered by an increasing number of insurers. Due to increasing numbers of approved or investigational targeted therapies for cancer, patients are more routinely undergoing tumor or somatic tissue NGS testing at the time of diagnosis or progression. Oncology providers, particularly in low resource settings, need tools to interpret, appropriately utilize, and communicate with patients about NGS somatic test results. Unfortunately, the uptake of NGS testing in cancer care has grown faster than the oncology field’s understanding of somatic and tumor testing, and the dire shortage of genetic counselors has only served to exacerbate the problem. Many oncologists and other cancer providers lack time or expertise to interpret the results of NGS testing, and to counsel patients meaningfully about test implications. Published data indicate that providers are often at a loss for how to interpret somatic testing and have few resources for assistance, especially in low resource community settings. Yet, patients’ decisions about whether to undergo NGS tumor testing, and understanding of their test results can have profound medical, psychological and familial implications. Furthermore, NGS testing creates added responsibilities for the patient’s health care provider team beyond interpretation and communication of results to patients, such as guiding follow-up management, and facilitating communication to family members. Oncology health care providers have traditionally not been trained in the use of tumor or somatic testing technologies; yet, they are increasingly advised by professional societies to consider NGS testing and determine how to inform patients about these tests and the generated results. Resources are needed to help providers: (i) evaluate the need for somatic/tumor testing for their individual patients, (ii) understand, interpret and explain test findings, and (iii) communicate with their patients both before testing (to obtain truly informed consent) and after testing (to explain results). The need is particularly acute in low-resource settings where patients are more often treated by primary care physicians or other providers without access to tumor boards or experts in Precision Oncology. In settings without access to genetic consultants, clinicians face unique challenges communicating with patients about tumor test results that are suggestive of incidental germline findings. Tools are needed to provide high quality information and interpretation of patient NGS test results to health care providers in communities with limited access to genetic counselors, to enhance utilization of NGS testing in such areas, and to assist with point of care decision-making by clinicians. Such tools must be integrated with current care models and be easily accessible to providers given time constraints and other realities of medical practice. These tools must also provide complex information in a clear format so that providers can facilitate patient understanding and improve patient engagement in informed decision-making about their health. Companies should incorporate field testing, including patient and provider input into the design of these tools, to ensure utility and uptake. Project Goals The goal is to design and develop tools, technologies, or products to: (i) inform oncologists and other health care providers treating cancer patients in settings with low access to genetic counselors about NGS testing and current NCCN guidelines, (ii) help such providers evaluate the need for NGS somatic testing for their cancer patients, (iii) assist providers with interpretation of NGS results (including distinguishing between somatic and incidental germline findings), and (iv) help providers communicate NGS results to their patients. Interpretation of NGS results must be personalized for individual patients. Tools that cater to settings with limited or no access to genetic counselors are encouraged. Tools should: (i) assist providers with communicating test results in a clear and lay-friendly manner, to aid patients’ treatment or life planning decisions; (ii) inform providers about genetic counseling resources for their patients; (iii) offer options for video and telephone guidance, especially for patients located in remote settings; (iv) incorporate perspectives of populations experiencing disparities in cancer outcomes, such as minority, underserved and rural communities; and (v) identify strategies for enhancing access to tools for understanding cancer genomic test results. In addition, contractors must evaluate, pilot and disseminate the tool. Some recommended practices for tool development include: 1. Including patients’ and families’ perspectives in deciding when, whether and how to communicate specific genetic findings, and when to offer genetic counseling and confirmatory testing based on counseling. This could be accomplished using the principles and elements of a design thinking approach focused on designing the communication strategies for oncology care providers from the perspective of the patients, in an agile, iterative way. 2. Considering a range of cancer treatment scenarios to elicit a broad range of provider needs that can inform tool development. This range includes pediatric, adolescent and young adult as well as adult cancer types. 3. Assembling trans-disciplinary teams that include but are not limited to geneticists, genetic counselors, behavioral researchers, psychologists, oncologists as well as patient navigators, patient advocates, and user experience designers to inform development and validation of tools. 4. Planning for pilot implementation testing of the tool in clinical or other applicable settings as the tool is developed. The following would be considered out of scope: 1. Methodologies of genetic counseling that do not focus on development of provider-facing tools 2. Methods, reports, and tools that include only germline genetics/genomics 3. Genetic testing services 4. Reports and tools requiring genetic testing services be conducted by offeror Phase I Activities and Deliverables • Establish a project team with expertise in the area of genetic counseling, software development, user-centric design, oncology, patient navigation as appropriate for this proposed project. • Conduct or utilize formative/exploratory research during the trial period to identify barriers and facilitators faced by oncology providers in staying up to date regarding genetic testing best practices and regulations, understanding test results (and evolution of results as more is known about impact of specific genetic variants/somatic mutations), and accessing counseling resources based on currently available platforms for genetic counseling. • Develop a prototype tool or technology based on formative research, to explain to oncology providers the basis for somatic testing and the meaning of test results. This could be a tool/technology for enhancing provider understanding, a communication tool for providers to use with patients, and/or a tool/technology to support remote genetic counseling or use of other educational resources. It should have an oncology provider and counselor interface to meet the goals of genetic testing and counseling while maintaining confidentiality. Prototype must include 1. The database structure for the proposed platform, user-interfaces, and metadata requirements; 2. Data visualization, data query functions, feedback and reporting systems; 3. Data adaptation for mobile or tablet application(s) if applicable; 4. Ability to generate lay-friendly reports of genetic testing results that health care providers may use and are understandable to patients; 5. Ability to continuously incorporate new information on genetic variants for oncology providers to update their patients as necessary (i.e. when it impacts clinical care or has familial implications). 6. Incorporate and adhere to current data privacy and security standards • Identify at least one clinical setting where the tool may be used and integrated within a research or practice setting and develop process maps and algorithms to set up appropriate data flows and ensure privacy protections. • Test the feasibility /usability of tool in a sample population of oncology care providers and patients and providing written report and recommendations on the best practices for use of the tool in research and practice settings. Deliverables for this Phase include: • Prototype design • Demonstration of the tool and practicality of use by end users • Provide technical specifications as well as an operations/user guide for the tool to NCI • Outline of metrics that can be used to assess the successful application of the tool Phase II Activities and Deliverables The goal of Phase II is to evaluate application of the tool as well as pilot and disseminate in an ongoing research project or community practice setting after procurement of needed human subjects and operational approvals. Finally, a plan for commercialization based on the pilot should be developed. In order to meet these goals, the offeror will • Outline a plan to use the tool, technology, or product in practice settings. • Enhance systems interoperability for deployment in diverse software environments and provider networks. Provide a report detailing communication systems architecture and capability for data reporting to healthcare providers, electronic health records, and health surveillance systems as appropriate for the proposed project. • Refine prototype and scale up. • Perform an evaluation of the interpretation of genetic results by comparing to gold standard guidelines for interpretation. • Design and conduct a validation study including specifying study aims, participant characteristics (providers and patients), recruiting plans, primary and secondary end points and data analysis plans. The validation study should evaluate oncology provider communication of results and patient understanding of information communicated by the oncology provider. • Prepare a tutorial session for presentation at NCI and/or via webinars describing and illustrating the technology, its intended use and results from the validation study. • In the first year of the contract, provide the project and contract officers with a letter(s) of commercial interest. • Provide the project and contract officers with a letter(s) of commercial commitment. Deliverables and activities include: • Validated tool, technology or product that has been successfully used in active research or community settings by oncology care providers. • Metrics demonstrating that oncology care providers understand information provided, and patients understand materials communicated by providers. • Finalized user guide and operations manual for use of tool within an active research study. This will include technical specifications, process guides/flow charts for how and by whom the tool will be used. • Finalized trouble shooting guide as well as frequently asked questions. • Analysis and discussions from exit interviews of study participants, oncology care providers and counselors to understand and improve utility and usability of tool in a practical setting. • A plan to develop the tool commercially and disseminate it to the wider research and practice communities.

Fast-Track proposals will NOT be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary This proposal is for the development of high-throughput, single-cell, unbiased (i.e. untargeted) discovery proteomic technologies to advance our knowledge in cancer development and progression, to enable robust cancer biomarker discovery and clinical application. So far, the identification of genomic changes in cancer has led to successful therapy-biomarker matches. It has also become integral to the design of clinical trials of molecularly targeted agents. However, it has only succeeded in identifying “actionable” abnormalities in a minority of cancer patients, and robust predictive biomarkers are still lacking for key targeted therapeutics. Since proteins are the targets of most anti-cancer therapies, and potentially meaningful changes at the proteomic level are not always present at the genomic level, it is becoming increasingly clear that the cancer proteome is an underexplored domain with significant potential for novel biomarker discovery. To date, the contribution of cancer tissue proteomics to biomarker discovery has been hampered by the requirement for substantial amounts of tissue and the need for more sensitive and high-throughput techniques. The current bulk proteomic analysis does not account for the heterogeneity within a tumor, or the proteomic profiling of rare or low-abundance cells. Single-cell proteomic technologies will have this capacity and will facilitate the development of better diagnosis and more efficient, individualized treatment. Although it is too early to predict the ultimate form and potential of such technology, some initial steps towards high- throughput single-cell proteomic approaches have already been taken. For example, researchers in the mass spectrometry field are rethinking sample preparation (cell lysis, protein purification, digestion and clean-up) and separation approaches to reduce sample losses during processing, to be able to quantify over a thousand proteins in single cells. New innovative proteomic approaches that use the principles of parallel-in-space fluorescence imaging (developed for next-generation DNA sequencing) are also being developed. Project Goals The short-term goal of this concept is to stimulate the development of unbiased (i.e. untargeted) discovery proteomic technologies with the capacity to identify proteins in a single cell with a typical size (~10 μm in diameter). The mid-term goal is to provide efficient research tools with the ability to generate more complete and accurate human cancer proteome information without relying on antibodies or inferring proteomes from mRNA sequencing. Protein sequencing at the single-cell level will allow a better understanding of tumor heterogeneity and microenvironment. Single-cell proteomics will also enable capturing proteomic information from rare and low-abundant cells such as circulating tumor cells and migratory dendritic cells. This will open the door to new biomarker and therapeutic target discoveries in cancers. The long-term goals also include providing efficient clinical tools for precision medicine by matching patients to therapies based on their proteomic results from clinically relevant samples; earlier cancer detection with the ability to better differentiate healthy normal cells from cancerous cells by adding proteomic information to the genomic and transcriptomic data; and better assessment of treatment response and monitoring with the capacity to get more precise clonal information. Activities not responsive to announcement: • Technologies that are solely based on computational approaches • Bulk proteomic technologies using bioinformatic approaches to deconvolve different cell and clone types in the bulk tumor sample • Targeted methods for identifying and quantifying proteins including, but not limited to, antibody-based methods • Technologies incapable to identify and quantify at least 500 proteins in a single cell Phase I Activities and Deliverables: Phase I activities should generate proof-of-concept data that demonstrates the capability of the technology to identify and quantify, at least, 500 proteins in a single cell with a typical size (i.e. ~10 μm in diameter): • Benchmark the new technology against existing approaches. • Provide an analytical validation report that describes the studies performed for analytical validation of your technology and its performance characteristics including: o Accuracy o Reproducibility o Repeatability o Sensitivity for low and high abundance protein o Specificity for low and high abundance protein o Single-cell proteome depth of coverage. • Address signal-to-noise issues by evaluating and interpreting “noise” of the measurements. • Deliver detailed SOPs related to the sample preparation and sequencing protocols used for your single-cell proteomic technology to NCI for evaluation. Note: SOPs for isolation of single cells are not required. • Describe the potential pitfalls of the experimental measurements. • Develop a proof-of-principle prototype. • Present assay performance and validation results and demonstrate the workflow of the technology during NCI SBIR site visit. Phase II Activities and Deliverables: Phase II activities should support establishing commercial prototype of the technology, including but not limited by the following activities: • Demonstrate that the technology is identifying and quantifying at least 500 proteins in a single cell with a typical size (i.e.~10 μm in diameter) • Demonstrate system performance and functionality by adopting commercially relevant quantitative milestones: o Offerors should specify quantitative technical and commercially-relevant milestones that can be used to evaluate the success of the tool or technology being developed. o Offerors should also provide appropriate justification relevant to both the development and commercialization of these technologies. o Quantitative milestones may be relative metrics (e.g. compared to benchmarks, alternative assays or minimization of the pitfalls of the experimental measurements described in phase I) or absolute metrics (e.g. minimum level of detection in a clinically meaningful indication). • Demonstrate that the technology can analyze the proteomes from the routinely collected cancer samples (fresh, frozen, fixed tissue and/or blood samples). • Report the throughput of the technology and the cost of the proteomic analysis of a single cell • Show feasibility to scale up the technology at a throughput compatible with widespread adoption by the clinical research community. • Establish QA/QC parameters at every step of the process to ensure reliability of results generated by your technology. • Develop a working prototype kit/tool/device for the single-cell proteomic technology (e.g. a sample preparation product and/or a protein sequencing product) and/or establish a marketing partnership/alliance with an established strategic business partner (e.g. diagnostic or device company)

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Oncologists are reliant on patient imaging to support clinical decision making and treatment planning for many types of cancer. Therefore, there is a constant need to develop, optimize, and validate new quantitative imaging and dosimetry tools and methods to improve and better inform diagnosis and treatment. Phantoms are widely used in medical imaging for instrument tuning, quality control, and scientific research. Traditional phantoms are vessels manufactured from man-made materials (e.g., acrylic, resins, etc.) that are filled with solutions containing an agent or tracer compound used in a modality-specific imaging application (e.g., MRI, SPECT, CT, PET systems). Due to their bulk, phantoms are typically not concurrently scanned with the patient. Recent technologies in the tissue engineering and biomimetics sector offer opportunities for construction of phantoms from tissue-equivalent materials with formulations that better represent the unique characteristics of organs commonly afflicted with cancers (e.g., brain, liver, breast, skin, bone, pancreas). Unique physical and chemical features can be engineered into tissue biomimetic systems with high precision, such as calibrated patches, zones, or gradients of varying stiffness, density, oxygenation, pH, temperature, etc. Bio-engineered matrixes may also incorporate fiducials and imaging agent(s) at known concentrations that can serve as a standardized reference from which quantitative dosimetry data in a tissue-equivalent context can be compared to data obtained by imaging these agents in the patient. Proper calibration and inter-comparison of scanners and imaging devices located in different institutions is crucial for clinical research rigor. Project Goals The goal of this concept is to stimulate growth in development of scalable quantitative tissue-equivalent technologies that would benefit patients who rely on cancer imaging modalities for diagnosis, dosimetry, and treatment. By prompting availability of new commercialized “smart-phantoms,” the solicitation has potential to catalyze scientific discovery in the broader cancer community wherein these commercialized devices could be used by researchers traditionally without access to tissue engineering biomimetic technologies. Small business development of Quantitative Biomimetic Phantoms (QBP) as organ-specific surrogates have potential to accelerate computational testing of sequences and algorithms to derive new quantitative radiomic and dosimetric data from cancer patients. The activities that fall within the scope of this solicitation include development and application of QBP devices that represent or simulate specific tissue types or organ sites. QBP devices are to provide the means to objectively detect, measure, and spatially resolve imaging probe(s) in the context of the QBP device’s tissue-equivalent environment(s) using either single- or multi-modal cancer imaging scanner systems. Examples of appropriate activities include pre-clinical feasibility and durability studies of the QBP device as a calibrated quantitative analysis tool that can improve quantitative accuracy and precision in imaging data obtained from the corresponding tissue type(s) or organ site(s) the QBP is intended to simulate. Phase I activities should generate data to confirm the feasibility and potential of the QBP technology(ies) to provide quantitative measurements of probes from cancer imaging systems. Phase I Activities and Deliverables • Define the cancer imaging modality or application(s) the QBP device(s) or combined device-computational approaches addresses (such as MRI, SPECT, CT, PET). Multimodal applications are suitable, but not required; • Define the tissue type(s) or organ site(s) the QBP device is intended to simulate. Offerors may propose to deliver a QBP device that represents only one distinct tissue/organ site, or one that has representation of multiple distinct tissues or organs; • Define the key tissue type or organ specific physical characteristics the QBP device is intended to simulate; • Generate proof-of-concept data that demonstrate the means to objectively detect, measure, and spatially resolve imaging probe(s) in the context of the QBP device’s tissue-equivalent environment(s) using the respective cancer imaging scanner(s); • Demonstrate feasibility of the QBP device as a calibrated quantitative analysis tool to improve quantitative accuracy and precision in imaging and/or dosimetry data obtained from the corresponding tissue type(s) or organ site(s) the QBP is intended to simulate. o Offerors should specify quantitative technical and commercially-relevant milestones, that can be used to evaluate the success of the tool or technology being developed. Offerors should also provide appropriate justification relevant to both the development and commercialization of these technologies. o Quantitative milestones may be relative metrics (e.g. compared to benchmarks, assays and/or algorithms to detect and measure the probe analyte), and/or absolute metrics (e.g. minimum level of detection). Phase II Activities and Deliverables • Demonstrate reliability, robustness, and usability in clinical and/or basic cancer research, dosimetry, and/or treatment planning; • Demonstrate system performance and functionality against commercially relevant quantitative milestones. o Offerors should specify quantitative technical and commercially-relevant milestones, that can be used to evaluate the success of the tool or technology being developed; o Offerors should also provide appropriate justification relevant to both the development and scalable commercialization of these technologies; o Quantitative assessment milestones may be relative metrics (e.g. compared to benchmarks, assays and/or algorithms to detect and measure the probe analyte), and/or absolute metrics (e.g. minimum level of detection); • Demonstrate rigor and reproducibility in benchmark experiments using relevant cancer imaging scanners or systems; • Demonstrate the QBP device and associated computational tools provide a calibrated and quantitative reference to assess radiometric characteristics relevant to cancer imaging and/or dosimetry of the tissue type(s) or organ site(s) the QBP device is intended to simulate; • Show feasibility to be scaled up at a price point that is compatible with market success and widespread adoption by the cancer research community; • In the first year of the contract, provide the Program and Contract officers with a letter(s) of commercial interest; • In the second year of the contract, provide the Program and Contract officers with a letter(s) of commercial commitment

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: $400,000 for 9 months Phase II: $2,000,000 for 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary It is commonly viewed that cancer originates from an accumulation of mutations in oncogenes and tumor suppressors such that cell growth becomes unregulated and invasive. The identification of genomic, epigenomic, and transcriptomic changes in cancer has led to precise classification, biomarker discovery, and mechanical understanding of cancer, and has played an essential part in cancer diagnosis, monitoring, and treatment. However, the up-to-now bulk sequencing without spatial information has limitations on the understanding of the tumor cells with neighbor cells and the tumor microenvironment. For example, limitations on detecting the heterogeneity within a tumor. This limitation has important clinical consequences. For example, cancer is often composed of multiple clones, and the most aggressive clone is difficult to identify and target, and it may not be the one that metastasizes. New sequencing techniques adding spatial resolution to the molecular information could provide a deeper understanding of the relationship between a cell's genotype or gene expression program and its morphology and interaction with local environment, therefore further our knowledge in cancer development and progression for better diagnosis and more efficient, individualized treatment. Project Goals The short-term goal of this concept is to stimulate the development of technologies that generate sequence information from slides without losing the histological context of the targets. These technologies must have the capability to identify thousands of genes in a tissue sample and must be able to select, visualize and compare sequences in areas of interest. The long-term goal is to provide research and/or clinical tools to improve cancer early detection, diagnosis, prognosis for precision medicine. Such tools can be used to identify location of aggressive/mutated clones within the tumor; differentiate between the center and infiltrating edges of the tumor; find correlation between molecular changes and cytology or atypia; evaluate molecular changes in the stroma infiltrated by the tumor verse stroma outside the tumor; and discover epithelial mesenchymal transition. The activities that fall within the scope of this solicitation include the development of technologies that can sequence the DNA or the RNA within fresh frozen or fixed normal and tumor cells without destroying their spatial context, and it can be used to directly link spatial features to particular genetic elements in native tissue or organoid specimens; integration of image modalities with cellular sequencing data; cellular mapping and characterization of tumor sequence with the spatial distribution of the original microenvironment including the complex organization of different cell types that are tightly regulated by the interplay of the individual cells. Contractors are not required to obtain whole genome/transcriptome data for all the cells on the entire slide but are required to demonstrate improved capabilities of the technology compared with existing special sequencing technologies. Activities not responsive to announcement: Technologies that are solely based in computational development are not appropriated for this solicitation. In situ and single cell technologies that do not have the capability of discovering new sequence variation in intact tissues would also not be considered as responsive. Phase I Activities and Deliverables: Phase I activities should generate data to confirm the feasibility and potential of the technology to obtain unbiased sequence (DNA and/or RNA) information directly from fixed or fresh tissue sections preserving the spatial distribution of the oligonucleotides in the tissue sample. • Demonstrate sensitivity, resolution, reliability, robustness and usability in basic and/or clinical cancer research. • If it is for RNA sequencing, it should be able to reveal RNA splicing and post-transcriptional modifications (e.g. methylation) while preserving their spatial context. • For DNA sequencing it should indicate how the sequence information is being used to determine Single Nucleotide Variation (SNV), Copy Number Variation (CNV), Methylation patterns, Gene rearrangements/translocations, Microsatellite Instability etc. while preserving the spatial context • Develop a computational platform to visualize spatial sequencing information (if applicable). • Provide the technology workflow and a working protocol, including the instrumentation, reagents and time needed for running samples, as well as estimations on speed of data generation and analysis. Phase II Activities and Deliverables: Phase II activities should support the commercialization of the proposed technology, including but not limited by the following activities: • Demonstrate system performance and functionality against commercially relevant quantitative milestones: o Offerors should specify quantitative technical and commercially relevant milestones that can be used to evaluate the success of the tool or technology being developed. o Offerors should also provide appropriate justification relevant to both the development and commercialization of these technologies. o Quantitative milestones may be relative metrics (e.g. compared to published benchmarks, alternative assays), or absolute metrics (e.g. minimum level of detection in a clinically meaningful indication) • Demonstrate the utility of the technology with benchmark experiments obtained across a range of generally accepted patient cancer tissues and/or cell types (as appropriate). • Show feasibility to scale production of the technology at a price point that is compatible with market success and widespread adoption by the basic research community and or clinical labs (as appropriate).

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary This solicitation builds on work performed in response to previous solicitations that developed information technology to support financial hardship, patient navigation, informal caregiving and care coordination. These areas of research remain NCI priorities; small business researchers who want to conduct research in these areas are encouraged to apply to the omnibus SBIR solicitation: https://sbir.cancer.gov/funding/opportunities/SBIR-STTR-omnibus-solicitation. Social determinants of health (SDH) are the health-affecting circumstances in which people are born, grow up, live and work. Examples of SDH that adversely affect health include food insecurity, financial strain, housing instability, social isolation, and transportation-related barriers. Addressing SDH within healthcare improves access to preventive care and improves treatment adherence. Accountable care organizations and other hospital systems have saved over $4.5 million by addressing food insecurity, reduced healthcare costs by 40% after establishing housing partnerships, and reduced inpatient and outpatient spending by 53% and 23%, respectively. Several large organizations, including CMS, CDC, HRSA and Kaiser Permanente, have invested in programs to address SDH. These programs are aimed at addressing SDH in primary care, not in oncology practices. Cancer patients are more likely to worry about their standard of living and experience food insecurity compared to individuals without cancer; these patients are less likely to receive appropriate and timely cancer treatment and have poorer survival. Recently, the American Cancer Society published a blueprint to understand and address SDH in cancer patients. The first step in addressing SDH is to conduct a patient assessment. The National Academy of Medicine (NAM) has identified several domains and validated measures of SDH that can be used in electronic health records (EHRs). For example, for the domain of social connections and social isolation, NAM identified the NHANES III measure (consisting of four questions) and for the domain of financial resource strain, it identified the measure of overall financial resource strain (consisting of one question). Another relevant activity is the Protocol for Responding to and Assessing Patients’ Assets, Risks, and Experiences (PRAPARE) assessment tool that includes16 core measures and 4 optional measures; this tool can be used in EHRs. The next step after conducting a systematic patient assessment is to address the relevant SDH need(s) in a timely manner. Because most interventions to address SDH are delivered by community-based social service providers (e.g. food banks), a clinician’s role is typically limited to referral and appropriate follow-up. A recent market analysis by NORC showed high variability in the level of sophistication of SDH-related systems and their functionalities; this analysis identified several needs, including better patient engagement, better analytic tools, improved collaboration with behavioral health professionals, and scalability of approaches to share data among healthcare providers and community organizations. There is a need for well-designed IT that supports systematic SDH assessment, appropriate referral, and follow-up of cancer patients in oncology practices in a manner that reduces the burden on patients, clinicians, and practices. Project Goals The goal of this concept is to solicit proposals that develop and evaluate software to address SDH in oncology practices. The software will be cancer-specific and developed in close collaboration with oncology practices. The software should be designed to support and enhance existing clinical workflows and reduce the burden of SDH data collection and synthesis in care settings. It will support appropriate evidence-based clinical actions, including referral, to address identified patient needs. The software will meet current IT interoperability standards, using FHIR (Fast Healthcare Interoperability Resources) when feasible, and privacy standards. The activities that fall within the scope of this solicitation include assessment of the current landscape of electronic SDH screening instruments and clinical decision support (including referrals to community-based social service providers); collaboration with oncology practices to understand existing workflows and IT architecture (including existing strategies for collection and use of SDH data); develop software with at least 5 existing, valid SDH measures; conduct usability studies of end-users: clinicians, patients, and community-based service providers; conduct an impact evaluation of the software on clinical workflows, care delivery processes, use of community resources, user satisfaction, and patient outcomes; and, identify an approach to scale the software beyond the initial set of oncology practices and SDH measures. Activities not responsive to announcement: Developing software that only screens for SDH without supporting appropriate clinical actions triggered by the screening (including referral to relevant community resources); software that does not work with validated SDH screening instruments; software that is either not integrated into the workflow or the existing IT architecture; software that does not incorporate the current standards and requirements of interoperability, cybersecurity and patient privacy; not working in partnership with oncology practices to identify the most relevant SDH measures and related clinical tasks; software not designed to reduce the patient- and clinician-level burden of performing SDH-related tasks. Phase I Activities and Deliverables • Establish a project team with expertise in the areas of software development, cybersecurity, user-centered design, SDH screening and implementation, oncology, health services and disparities research, community-based social services, community engagement and/or patient advocacy, as appropriate for the proposed project. • Conduct a focused environmental scan of existing software to screen and address SDH, as well as a targeted literature review on the accuracy of screening instruments and effectiveness of interventions for identified patients. The new software should screen for at least 5 SDH measures and use FHIR standards. • Conduct key informant interviews with members of at least two oncology practices to understand what is currently being done to address SDH, how IT systems are currently configured, how SDH data are collected and analyzed, and how new software would help. • Develop a prototype of the software. The design requirements of the software should ensure it can be used in a variety of cancer care delivery sites, ranging from academic clinics to community oncology practices, which care for diverse patient populations, including under-served cancer patients. Further, the design requirements should include compatibility with diverse IT architectures and the ability to work across IT systems. • Conduct pilot usability testing of the prototype with at least 25 persons who represent the end-users including but not limited to: oncology care team members, patients and community-based service providers. • Propose an approach to modify the software based on user feedback prior to implementation in Phase II. • Present Phase I findings and demonstrate prototype to an NCI Evaluation Panel via webinar. Phase II Activities and Deliverables • Establish a project team with expertise in the areas of software development, cybersecurity, user-centered design, SDH screening and implementation, oncology, health services and disparities research, implementation science, and statistical methods for validation/evaluation, as appropriate for the proposed project. • Provide a report detailing the approach to integrate the software in existing workflows and IT systems, and to evaluate the software, while considering the requirements of inter-operability, cybersecurity and patient privacy protection. • Develop appropriate human subjects protection/IRB submission packages and document approval of research plan. • Develop final study design including aims, participant characteristics (e.g. end users), recruiting plans, inclusion and exclusion criteria, measures, primary and secondary endpoints, design and comparison conditions (if appropriate), power analyses and sample size, and data analysis plan. • Implement and evaluate the software in at least three oncology practices. The evaluation includes user satisfaction with software, impact of software on care delivery processes and patient outcomes, lessons learned, and recommended modifications to the software, as appropriate. • Provide a report documenting the results of the software evaluation. • Identify an approach to scale the software beyond the initial set of oncology practices and SDH measures. • Provide study progress reports quarterly, documenting recruitment and enrollment, retention, data quality assurance and control measures, and relevant study specific milestones. • Develop user support documentation to support all applicable potential users of the technology, including but not limited to clinicians, patients, and healthcare systems. • Prepare a tutorial session for presentation via webinars describing and illustrating the technology and intended use. • In the first year of the contract, provide the program and contract officers with a letter(s) of commercial interest. • In the second year of the contract, provide the program and contract officers with a letter(s) of commercial commitment. • Present Phase II findings and demonstrate the validated software to an NCI Evaluation Panel via webinar.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 2-4 Budget (total costs, per award): Phase I: up to $252,131 for up to 9 months Phase II: up to $1,680,879 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary An estimated 11,060 new cases of cancer were expected to be diagnosed among children ages 0 to 14 years and approximately 70,000 among adolescent and young adults (AYAs) between ages 15 and 39 in 2019. Advances in diagnostic capabilities and treatment have resulted in increased survival rates, with more than 80% of children and AYAs surviving 5 years or more after their cancer diagnosis. This has led to exponential growth in the number of survivors of pediatric cancers. However, survival often comes at the cost of many life-altering late and long-term effects and other unique challenges including the following: • Adverse long-term and late effects including higher risk of secondary cancers, premature/accelerated aging, cardiotoxicity, endocrine dysfunction, reproductive and developmental issues like infertility, neurocognitive defects (e.g. learning disabilities), and psychosocial issues (e.g. anxiety and depression), poor mental and physical health (e.g. impaired stress management), poor health habits (e.g. alcohol use, physical activity levels), developmental issues, impaired/delayed social development • Challenges in coordinating care across multiple clinical teams, especially the transition from pediatric to adult care providers • Need for better care models to improve monitoring for recurrence of primary cancer and screening for early detection of secondary tumors and • Need for better care models to improve monitoring and management of symptoms arising from long-term adverse effects of cancer treatments Childhood cancer survivorship care is complex and improved care models are urgently needed. The increased use of digital tools in medical care can be leveraged to improve health outcomes and survivorship in these cancer survivors. This contract topic encourages innovative approaches to improve the quality of health outcomes for long-term childhood and adolescent cancer survivors. Project Goals The goal of this solicitation is to stimulate the development and evaluation of innovative digital tools (software, database systems, digital platforms and/or mobile applications) that are integrated with existing EHRs or other clinical IT systems and that support delivery of patient-centered, coordinated, high-quality care to pediatric cancer survivors. To accomplish these goals, the offerors should build a system/tool/app with one of the following two capabilities: • Creation and implementation of survivorship care plans including integration of National Academy of Medicine, Children’s Oncology Group and other relevant long- term follow-up and care guidelines for survivors of childhood and adolescent cancer, OR • Integration of accountability tools, checklists, and reminders that improve follow-up care adherence and clinical workflow Additionally, the following capabilities will also be required: • Seamless coordination of care across healthcare systems either from oncology-based practice to primary care setting or from pediatric to adult care setting • Remote collection of data from a patient to support and reinforce remote screening and monitoring, symptoms management and disease prevention, behavior modification and personalized intervention patient-reported outcomes • Secure bi-directional communication between clinical teams and the patients and caregivers that meets HIPAA requirements • Adopting current interoperability standards such as FHIR • Integration of technology into clinical workflows The tools can optionally be integrated with wearables and other devices for cancer recurrence screening and early detection of secondary tumors, monitoring symptoms and adverse effects, and support behavior or other lifestyle modifications needed to improve patient outcomes. The tool must support bi-directional communication; it may be focused on either patient/caregiver tasks or clinical team tasks. The design requirements must include protection of patient privacy and adherence to all relevant regulations. Activities not responsive to announcement: This solicitation is focused on development of integrated tools including software, database systems, digital platforms and/or mobile applications-based approaches. The following topic areas are not supported: • Drug development • New in vitro, in vivo, or ex vivo diagnostics for symptoms and cancer monitoring • Digital tools focused on adult cancer survivors Phase I Activities and Deliverables • Establish a project team with expertise in the areas of software development and implementation, human-centered design, health communication, pediatric oncology, pediatric cancer survivorship, primary care, behavioral science, health services, care delivery and clinical workflows. • Perform an environmental scan of relevant, existing software systems and apps designed to support the delivery of pediatric survivorship care, especially during the transitions of care, and identify major gaps that need to be addressed. • Conduct a small number of key informant interviews with childhood and adolescent cancer survivors, adult caregivers, pediatric oncology providers, and primary care providers to further refine and prioritize areas of unmet needs. • Develop a functional prototype of the tool with at least one of the following system capabilities and specifications: o Creation and implementation of survivorship care plans including integration of National Academy of Medicine, Children’s Oncology Group and other relevant long- term follow-up and care guidelines for survivors of childhood and adolescent cancer. Potential features for this type of tool may include:  A personal healthcare information management tool (dashboard or other innovative tool) on treatment summary, individualized survivorship care plan including associated risk factors and screening recommendations, key symptom indicators, and prompt survivor to share critical information with their care provider  Support module to educate patients and their adult caregivers about the disease, treatments and the potential impact of disease and treatments on a patient’s life. This module will also list the relevant clinicians, their contact information, and their roles in managing the patient’s care.  Seamless coordination of care across healthcare systems such as from oncology-based practice to primary care setting or from pediatric to adult care setting o Integration of accountability tools, checklists, and reminders that improve follow-up care adherence and clinical workflow. Potential features of this type of tool include:  A personal healthcare information management tool (dashboard or other innovative tool) with all these features  A psycho-social health information management tool (dashboard or other innovative tool) to track key factors associated with Quality of Life (QOL) outcomes in cancer survivors  Front-end mobile application(s) to facilitate scheduling, tracking and monitoring of care delivery processes, including referrals and the outcome of a referral; communications between patients and clinicians or between clinicians; and survivor support  Interfaces with healthcare delivery systems to facilitate remote patient monitoring, communications, and resource provisions (e.g. content management for tailored caregiver support). • In addition, all tools should include all the following capabilities and specifications: o Seamless coordination of care across healthcare systems from oncology-based practice to primary care setting or from pediatric to adult care setting o Remote collection of individual health data to support and reinforce efficacious remote screening and monitoring, symptoms management and disease prevention, behavior modification and personalized intervention patient-reported outcomes. o Secure bi-directional communication between clinical teams and the patients and caregivers o Adopt current interoperability standards such as FIHR o Integration into clinical workflows • The information management tool (dashboard or other innovative tool) needs to have a either patient/caregiver- facing and/or clinician-facing interface and the ability to download and upload relevant information as it becomes available. • The tool must adhere to relevant data and security standards for collection, transmission, and storage of data that ensure patient and caregiver privacy as required by relevant federal and state laws and regulations. • Data adaptation for mobile application(s) as needed. • Conduct a pilot usability testing of the protype tool with at least 25 potential users. • Present Phase I findings and demonstrate functional prototype to an NCI Evaluation Panel. Phase II Activities and Deliverables • Establish a project team for Phase II activities and outcomes. This team should include personnel with training and research experience in chronic disease patient clinical trial or intervention design, implementation, and statistical methods for validation/evaluation as appropriate for the proposed project. Provide a report outlining team member credentials, specific project roles, and timelines for performance. • Evaluate specific IT customization requirements to support hardware, software, or communications system integration of the technology into the target clinical, health system or service, or other relevant software environment in preparation for validation. Provide a report documenting the specific IT customization requirements and timelines for implementation. • Evaluate, enhance as necessary and provide documentation that the technology and communications systems maintain compliance with HIPAA, data security, privacy, and consent management protocols as required for the proposed project. • Enhance systems interoperability for deployment in diverse software environments and provider networks. Provide a report detailing communication systems architecture and capability for data reporting as appropriate for the proposed project. • Test the integration of the technology into the target clinical, health system or service, or other relevant software environment in preparation for validation. Provide a report documenting the results of system testing and timelines for troubleshooting. • Develop user support documentation to support all applicable potential users of the technology. Provide a report documenting user support resources, including but not limited to, links to online resources and copies of electronic or paper user support resources as appropriate. • Design and conduct a validation and evaluation study, including: o specify study aims, participant characteristics, recruiting plans, inclusion and exclusion criteria, measures, primary and secondary endpoints, design and comparison conditions (if appropriate), power analyses and sample size, and data analysis plan; o develop appropriate human subjects protection / IRB submission packages and documentation of approval for the research plan; and o provide study progress reports quarterly, documenting recruitment and enrollment, retention, data quality assurance and control measures, and relevant study specific milestones. • Present finding and demonstrate functional product to NCI evaluation panel in a webinar. • In the first year of the contract, provide the program and contract officers with a letter(s) of commercial commitment.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary The exponential rise in availability of digital still and video imagery has created enormous opportunities for health researchers. However, software tools for automated image analysis in health are lacking. The goal of this topic is to stimulate development of software for automated analysis of physical activity, performance, and behavior in still and video images for clinical, home monitoring and public health applications. Physical activity refers to movement and postures such as ’walking’, ‘sitting’ or ‘standing up'. Performance refers to quantitative measures of function such as walking speed or timing of a sit stand test. Behavior refers to identification of specific actions such as ‘taking a pill’ or ‘playing soccer’. Existing software tools emphasize counting and tracking customers (e.g. TraxSales), monitoring transportation behavior (e.g. TRAF-SYS), and security concerns in the private and defense sectors (e.g. DARPA Minds Eye Program). Additionally, emerging research is attempting to develop automated tools to assess sports performance and human performance capture for entertainment applications. In contrast, health-oriented applications are poorly developed, limited to a few publicly available image management and annotation tools. While larger companies are entering this sector (e.g. Microsoft AZURE), they also lack focus on health applications. Finally, advances in machine learning and AI research further support the potential for new products in this area. Project Goals This SBIR contract topic is designed to attract proposals for new and innovative image analysis tools to extract information concerning physical activity, performance and behavior. Each of these interrelated elements of human action have distinct associations with health and health monitoring needs. Examples include but are not limited to: 1) Automated assessments of gait, walking speed, and other medically-relevant performance parameters in the clinic; 2) Enabling in-home monitoring of compliance with medication and physical therapy regimens; and 3) Improved evaluation of physical activity in transportation or park settings. Potential image sources include, but are not limited to: wearable cameras, stationary cameras, smart phones, social media, Photovoice projects, and archives of street images from Google Street View or Gigapan. Applicants will be asked to specify the use case for their project and identify the source of images. Images may be from pre-existing sources or may be collected as part of the project. Collaboration with relevant subject matter experts and computer vision specialists is required to insure use of best possible analytical approaches. The tools developed must provide solutions for protecting sensitive or personally identifiable information available in the images. The long-term goal of the project is to develop software that can automatically extract data from images concerning people and their activities. Advances in security, loss prevention, assessment of human behavior in retail environments, and automated measurement of human performance in sport and animation domains along with growing capacity of computers to identify and count objects via advances in artificial intelligence and machine learning suggest that algorithms are available that could be applied to health questions. Data from these algorithms could help multiple aspects of cancer prevention and control from primary prevention such as improved evaluation of interventions to encourage physical activity, to enhanced epidemiological studies, to automation in monitoring of symptoms and response to treatment for disease affecting physical performance, to improved compliance with cancer treatments or physical rehabilitation regimens. This interplay could advance health research and lead to improved commercial products for diverse applications. Proposals addressing biomedical images such as MRIs, microscopy, or DEXA will not be deemed responsive to the call. Phase I Activities and Deliverables: • Establish a project team including proven expertise in: image analysis, including recognizing human actions and event segmentation; algorithms for data extraction, e.g. machine learning or neural networks; image data storage and manipulation; secure transmission of health data (if needed); user interface development; and topic-specific expertise in the appropriate behavioral science and public health domains. • Develop a precis of the proposed tool and carry out structured interviews or one or more focus groups aimed at defining specific subject matter needs. • Create or identify an open access image data source. Examples include, but are not limited to, cell phone images, SenseCam data, the AMOS archive of webcam images, Photovoice collected image libraries, and security video. • Develop a functional prototype system from planned Phase I characteristics that includes: • Capacity to extract data from at least one image type involving human physical activity, performance or behavior, • Capacity to combine both automatic and manual detection and counting of intended aspects of physical activity, performance and behavior via a graphical user interface on a desktop computer, laptop computer, and/or tablet. • Conduct a usability study with at least 15 users not affiliated with the study team and in several distinct user groups • Provide a report including a detailed description and/or technical documentation of the proposed tool including plans for managing large numbers of image files, specific data resources and file formats targeted, details of the algorithmic approaches to be used and an assessment of potential bias in training image data sets, and approaches to be used to assess performance of the software tools. Comparison with gold standard measures such as human data extraction is an important part of validating the approach. • Describe hardware and any additional software required for use of the tool. • Present phase I findings and demonstrate the functional prototype system to an NCI evaluation panel via webinar. Phase II Activities and Deliverables: • Describe and document protocols and guidance for investigators working with imaging to insure appropriate informed consent, risk assessment, and data management. • Present Phase II findings and demonstrate the software system to an NCI evaluation panel via webinar • Improve and expand the capacity of the software to identify aspects of physical activity, performance, and behavior • Develop or refine data extraction algorithms • Further test reliability and validity of data extraction via new methods or new image file sources; • Create a library of open access test images for additional algorithm training efforts; • Propose and implement a cycle of usability testing incorporating user center design principles to enhance software ease and efficiency of use; • Develop systems documentation where applicable to support the software and bioinformatic methods. • In the first year of the contract, provide the program and contract officers with a letter(s) of commercial interest. • In the second year of the contract, provide the program and contract officers with a letter(s) of commercial commitment.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Emerging single-cell and in situ technologies are facilitating the characterization of normal, diseased, stromal, and immune cells in human tissues. Coupling these data with imaging modalities that provide information about tissue composition, gross organ structure, and metabolism while incorporating longitudinal clinical data can improve our understanding of the development and evolution of disease. Several recent initiatives have focused on generating ‘atlases’ that integrate multi- scale maps to facilitate our understanding of health and disease. These include the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the Human BioMolecular Atlas Program (HuBMAP), the Human Cell Atlas (HCA) initiative, and the Human Tumor Atlas Network (HTAN). Additionally, the rapid advancement of single-cell genomic- and imaging-based technologies has expanded the use of these tools in individual research projects supported by the NIH and NCI. Spatial atlas mapping efforts seek to analyze and integrate multi-scale and multi-modal data sets to generate cohesive multi- dimensional maps of normal and diseased tissues and provide them in a user-friendly environment for the research and clinical communities. Tumor atlases may include single-cell resolution data describing the tumor itself, the tumor microenvironment, and the immune milieu. A major challenge to realizing the full potential of tumor atlases is the lack of tools for the visualization of data across scales and modalities. The purpose of this contract topic is to incentivize small businesses to develop technologies that allow integrative multi-scale data visualization to facilitate building and sharing of atlases. Project Goals The goal of this project is to promote integrative visualization of multi-scale data. Potential tools or technologies would include, but are not limited to: • Web-based or containerized visualization tools that allow seamless traversal across scales of heterogenous or integrated datasets from genetic to molecular to cellular to tissue scales • Virtual Reality / Augmented Reality systems that let users interact with and manipulate multi-scale data in novel ways, using efficient interaction paradigms • Visualization tools and methods for intuitive display of high-dimensional multi-scale data and metadata in context, such as integration of cell and tissue image data with accessible genomic profile information • Visualization tools and methods that display and / or capture the heterogenous quality, uncertainty, or provenance of integrated data sets • Tools that combine existing visualization sources to facilitate and construct multi-scale visualizations For this project, data scales are defined as: 1. Genomic (e.g., DNA sequence, epigenetic state) 2. Molecular/subcellular (e.g., RNA abundance, protein abundance, intracellular structures) 3. Cellular (e.g., cell-state, cell-type) 4. Tissue (e.g., tissue morphology, histology, metabolic state) 5. Individual patient (e.g., clinical data, exposure, microbiome) 6. Population (e.g., epidemiological) Activities not responsive to announcement: Work that would not fall under this topic include: (1) approaches for visualization at a single scale and (2) approaches that focus on analysis and do not include data visualization as the major component. Phase I Activities and Deliverables: The goal of Phase I is to develop proof-of-concept or prototype tools, technologies, or products for visualizing multi-scale biomedical data. Activities and deliverables include: • Identify and define at least three scales of data (as defined above) that will be part of the Phase I visualization tool. • Identify relevant use cases for the proposed tool. • Identify one or more user communities this visualization tool will support. Communities include: (1) basic researchers, (2) computational researcher, (3) clinicians / clinical researchers, and (4) the public. • Identify and justify development of a tool or technology for visualization of multi-scale data, including the rationale for the selection of data scales and user communities. • Describe the current state of the art technologies, if any, for visualizing the selected data scales. • Develop a minimal viable product for visualizing multi-scale data capable of ingesting and visualizing the relevant data types. • Carryout initial alpha-testing by the appropriate user communities to solicit user feedback. • Specify and justify quantitative milestones that can be used to evaluate the success of the tool or technology being developed. Phase II Activities and Deliverables: The goal of Phase II is an optimized commercial tool or technology for visualizing multi-scale biomedical data. Deliverables and activities include: • Revise the minimal viable product based on user feedback to add features or functionalities and increase the use- ability and stability of the tool or technology. • Expand the tool or technology to support the integrative multi-scale visualization of at least four scales of data defined above. • Make the tool or technology compatible with a wide-range of web browsers and / or operating systems as applicable. • Carryout beta-testing by the appropriate user communities to solicit additional user feedback. • Further revise the visualization tool or technology based on user feedback focusing on the transitions between data scales and preserving the relationship of data across scales. • Develop SOPs and user documentation.

Fast-Track proposals will NOT be accepted. Direct-to-Phase II proposal will NOT be accepted Number of Anticipated Awards: 3-5 Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Imaging data is a core component in the development of the National Cancer Data Ecosystem, important in areas from basic research to diagnostics and surveillance. Sharing of any data collected from patients, however, requires first the removal of Protected Health Information (PHI) and personally identifiable information (PII) which can be used to identify the individual from whom the data were collected. Image de-identification, or anonymization, refers to the removal of PHI /PII from imaging data. In digital pathology PHI can be found in the label slide as well as the file header. In clinical imaging, where images are commonly in the DICOM (Digital Imaging and Communication in Medicine) format, PHI is contained in the header of each image file and at times PHI may be embedded in the image itself. For example, the imaging acquisition software may insert PHI in the image field, or the patient may be wearing identifiable jewelry or a personal tag that may be captured in an image. Both the file header and the image field itself must be examined for information that could link the file to a specific individual. In headers, PHI is found in patient identifier fields, such as patient name, patient number, date of birth, etc., and at times in fields not intended to contain such information. In addition, in certain instances, individuals may be identifiable by PII obtained through 3D reconstruction of the face or body surface from tomographic data such as computed tomography or magnetic resonance imaging (MRI). The complexity of the de-identification problem dictates that a substantial amount of human curation is required to ensure proper and complete removal of PHI from images. The need for extensive human participation in the de-identification process impedes the generation of anonymized image collections suitable for public distribution and sharing, including deposition into components of the National Cancer Data Ecosystem like The Cancer Imaging Archive (TCIA) (https://cancerimagingarchive.net) and the Imaging Data Commons of the Cancer Research Data Commons. The goal of this concept is to support the development of software tools that comprehensively de- identify images by removing PHI and PII from image files generated by clinical imaging and/or WSI modalities while retaining metadata relevant to providing interoperability. Project Goals While multiple tools exist to remove protected data from image files, particularly DICOM radiology files (https://link.springer.com/article/10.1007/s00330-015-3794-0), they may not thoroughly remove PHI from unexpected DICOM fields or from the image field itself. In addition, other image formats such as proprietary WSI files and other microscope image formats also contain PHI. Proper de-identification of patient imaging files requires careful analysis and remediation of two components of those files: the header and the image field. The goal of this contract topic is to support development and sustainment of software tools and pipelines for image de-identification, specifically for images produced by radiologic and pathology imaging modalities. Within that goal, the following objectives should be met: 1) Removal of PHI from expected fields in multiple imaging formats, 2) Scanning for PHI in fields not designed for their insertion, identification and subsequent removal, 3) Scanning of imaging data for PHI and PII, identification, labeling and subsequent resolution, and 4) Produce processed images that meet a threshold level of de-identification. Brute force methods for de-identification (e.g., erasing of all header information) are not acceptable. A successful de-identification algorithm would not simply remove data from all elements, but simultaneously remove PHI while retaining information required for research studies. While fully automated image de-identification tools are desired, the proposed solutions should provide a capability to flag suspicious cases that require human intervention for human-in-the-loop remediation. Furthermore, in order to broaden the community of users and developers, offerors are encouraged to consider leveraging open standards to the degree that is possible and does not prevent from the development of commercial solutions. Moreover, the de-identification algorithms should be vendor agnostic particularly for WSI file type, where each vendor has their proprietary format. In addition, development of cloud-ready solutions is also encouraged. To build upon existing resources in medical image de-identification, , the TCIA de-identification knowledge base (https://wiki.cancerimagingarchive.net/x/ZwA2) could serve as a foundation.. The final delivery in each phase would require the vendor providing their de-identification tool to NCI for a final validation. For this purpose, NCI, possibly in collaboration with TCIA or another contractor, will need to run the tool on selected validation datasets that would include PHI in various places in the header and the image field and confirm that the developed tool has successfully de-identified the collection. Offerors must identify the eventual customers for this tool. While NCI may be a potential future customer, this is not assured or certain. Offerors are expected to get their own datasets. NIH or the TCIA will not provide data with PHI to the offeror. The TCIA database has free downloadable imaging and digital pathology collections that provide examples of the final product. In general, NCI encourages the development of deidentification tools for developing imaging or digital pathology databases. This contract is not meant to be a service contract to the NCI to deidentify images for TCIA or NCI. Successful companies must provide a version of the software developed as part of this contract along with a user manual to NCI for user acceptability testing. A user acceptance testing (UAT) report will be provided back to the company. Phase I Activities and Deliverables: • Identify different clinical imaging or WSI file types and the fields that contain PHI (i.e. conduct landscape analysis) • Ability to recognize and open multiple clinical imaging or WSI file formats • Display PHI field variable values • Remove or alter PHI field values • Produce a log of removed and altered PHI and PII parameters • Delivery of tool along with required software documentation and user manual to NCI for acceptance testing/validation study • Include funds in budget ($15K) to present phase I findings and for NCI to complete User Acceptance Testing/validation study. Phase II Activities and Deliverables: • Detect PHI in non-PHI fields (e.g., comment fields that may contain PHI) • Alert user, allow user to edit detected field • Detection of PHI within image • Masking of PHI and PII within image • Masking of PII that may be obtained through 3D reconstruction or other manipulation of the image collection • Generation of de-identified images with provenance of process • Flag and report suspicious cases and allow for human-in-the-loop remediation • Validation with a test data set should demonstrate successful PHI/PII removal from image and image file meta data for ≥95% test files • Include funds in budget ($20K) to present phase I findings and for NCI to complete User Acceptance Testing/validation study. • Statistical analysis of validation testing will be provided to NCI • In the first year of the contract, provide the Program and Contract officers with a letter(s) of commercial interest

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary The cancer research field has become intensely focused on the generation of high-throughput datasets to better understand cancer and ultimately to inform the development of better treatment and prevention tools. NIH and NCI have supported numerous programs including The Cancer Genome Atlas (TCGA), The Cancer Imaging Archive (TCIA), Therapeutically Applicable Research to Generate Effective Treatment (TARGET), and Clinical Proteomic Tumor Atlas Consortium (CPTAC) to generate a wealth of multi-modal data to be leveraged by the cancer research community. However, we are still limited in our ability to draw insights and meaningful interpretations from these datasets, which include multi-omics, imaging, and clinical data, and by challenges in integration across disparate datasets. To address these challenges, NCI has created the Cancer Research Data Commons (CRDC) as part of the National Cancer Data Ecosystem recommended by the Cancer MoonshotSM Blue Ribbon Panel (BRP). The CRDC brings together data with cloud computing infrastructure to provide secure access to various data types across scientific domains, allowing users to analyze, share, and store results by leveraging the storage and elastic compute of the cloud. The primary goal of this contract topic is to solicit commercial sector participation in the CRDC to develop strong commercial cloud-based analytic tools, specifically on multi-omics and/or imaging analysis, that can be disseminated and sustained within the cancer research community. To that end, leveraging of open standards to the extent that is possible is highly encouraged. The SBIR contract funding mechanism will offer the opportunity for small business participants to contribute solutions to address unmet challenges of big data analysis that are not currently provided by existing tools in the CRDC by developing and extending tools and resources to integrate into the rapidly evolving CRDC. Through this contract topic, NCI seeks to enable wider engagement of the CRDC community which includes researchers, and clinicians by offering enhanced data analysis capabilities, visualization tools, and data access and sharing platforms. Project Goals The goal of this contract topic is to provide support for development and implementation of innovative solutions for continued advancement and evolution of cloud-based informatics tools to integrate with the CRDC for broader user community engagement. Unmet challenges that should be addressed through this solicitation include, but are not limited to: 1. Integration of existing tools widely utilized by the cancer research community with the CRDC through adoption of the Data Commons Framework (DCF), and extension of these tools to support unique data analysis opportunities of this platform; 2. Development of novel tools to perform multi-omics and/or imaging analysis; 3. Collaboration with academic developers of popular tools to integrate them with the CRDC and support commercialization. Development and adaptation of tools that support innovative, integrative data analysis (particularly machine learning algorithms and models), interoperable across the CRDC are of particular interest. The activities that fall within the scope of this contract topic include delivery of design specification for the development/extension of informatics tools and demonstration of early phase prototype that shows successful integration with CRDC. Examples of effective integration with CRDC through DCF include execution of the offeror’s pre-existing or new informatics tools on multi-omics and/or imaging datasets stored in CRDC such as CPTAC and performing co-analysis with user-provided data. Successful offerors are expected to develop and implement a business process for broad adoption of their tools and resources by actively engaging with the user communities and conducting outreach and training activities as well as providing appropriate system documentation. The business process should also include business plans for marketing and long-term sustainability, such as sustained hosting of tools, training, and associated resources. Activities not responsive to announcement: Proposals for the development of big data analysis tools without consideration for integration with the CRDC will not be responsive to this solicitation. Phase I Activities and Deliverables: Phase I proposal is expected to clearly demonstrate at minimum a ‘proof of concept’ feasibility of adaption of the offeror’s informatics tool(s) or development of new tool(s) to the CRDC through the Data Commons Framework. The proposal should also identify potential barriers for commercial translation and plans to overcome those barriers. Phase I work should include software system specifications of cloud-based platforms for phase II deployment of the proposed tools and resources. Key activities and deliverables include: • Establish a project team composed of experts in software development, cloud infrastructure, big data informatics (e.g. proteogenomics, imaging), project management, team communication, and user-centered design. • Design specification for the development/extension of cloud-based informatics tools to operate in the Cancer Research Data Commons. • Develop an early phase prototype. • Demonstrate the feasibility of CRDC integration through DCF. Example of feasibility qualification include, but not limited to, user authentication using Fence to access datasets stored in at least one CRDC repository such as Genomic Data Commons and Proteomic Data Commons, which exist now and providing authorization to datasets the user has access to. More nodes, such as Imaging Data Commons, are expected to be available for feasibility testing by the end of 2020. • Conduct a pilot usability testing by at least 25 users • Provide a report on the results of the first round of usability testing and the approach to modify the prototype based on this user feedback. • Present Phase I results and future system development plan to NCI staff. Phase II Activities and Deliverables: Phase II projects will be expected to implement requirements identified in all phase I deliverables and launch a prototype that demonstrates successful integration with CRDC and, as appropriate, other data commons. The system design process should encourage interactions between users and developers for evaluation and further advancement of the tools and resources. Key activities and deliverables include: • Enhance, beta test, and finalize prototype development. • Provide detail plans for implementation of technical assistance and delivery of tool(s) within CRDC. • Demonstrate CRDC integration through DCF by successfully providing access to data within CRDC and performing large-scale multi-omics and/or imaging data analysis using offeror’s tools or resources. Examples of large-scale data analysis include, but are not limited to, demonstration of integration and interoperability of user-provided data with available datasets such as CPTAC from CRDC to perform comparative analyses. • Conduct usability testing using at least 100 users

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 2-4 Budget (total costs, per award): Phase I: up to $400,000 for up to 9 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Current manufacturing processes for autologous cell-based cancer therapies are complex, slow, labor intensive, and expensive. These involve highly personalized methods requiring leukapheresis followed by ex vivo manipulation of cells before a therapy can be administered to the patient. While autologous cell-based therapies offer great promise for cancer treatment, there is growing concern that current manufacturing methods are unable to support the delivery of these treatments to the large numbers of patients eligible to receive them. In particular, the cell processing period between cell isolation and therapeutic administration, referred to as ‘vein-to-vein’ time, currently takes from 3-8 weeks. Using current methods, medical center laboratories that provide cell-based therapy often have the capacity to treat only 2-8 patients per month, which is insufficient to meet the high demand of clinical trials. Moreover, given that cell-based cancer therapy is still in its nascent stages, higher patient throughput is likely to accelerate the iterative bench-to-bedside-to-bench research that will be needed to improve and mature this treatment modality. Advanced manufacturing approaches that can process multiple cell therapies for several patients in parallel could substantially improve the availability of emerging autologous cell-based therapies. Achieving this complex, multi-step, parallel processing is likely to require automated systems that can continuously control and monitor critical quality attributes of the engineered cells. Such systems must also be capable of optimizing and maintaining the desired physiological and immunological status of the expanded cells in a multiplexed fashion, while overcoming issues of cell senescence and exhaustion. A further challenge may involve miniaturization of cell culturing processes to achieve greater efficiency and higher throughput as compared to current approaches. It is expected that advanced manufacturing technologies will decrease both the cost and time required to deliver emerging autologous cell-based therapies to a greater number of patients, including those patients with rapidly progressing disease for whom autologous therapies may not currently be feasible. Project Goals The overall goal of this solicitation is to stimulate the development of advanced manufacturing technologies that substantially improve the speed and cost of producing autologous cell-based therapies. Technical solutions are expected to involve parallel processing (i.e., multiplexing) of individual cell-based therapies, although other approaches are encouraged. New technologies must produce cell-based products of equal or superior quality as compared to current manufacturing methods. In addition, the NCI encourages system design features that enable rapid and iterative customization to support bench-to- bedside-to-bench research. For example, technologies may involve a modular engineering approach in which the system can be readily adapted as the critical quality attributes of cell-based products are refined over time based on new clinical research. Proposals submitted under this topic must involve a collaboration between technology developers and clinical researchers with experience developing and treating patients with autologous cell-based cancer therapies. Phase I projects will be expected to involve feasibility testing of the proposed advanced manufacturing technology. A key activity during the Phase I project is to benchmark the novel advanced manufacturing approach against the current manufacturing method for a specific autologous cell-based product. More specifically, the research plan must include validating the proposed novel manufacturing approach against a process that has been used to produce product for clinical trials by demonstrating comparability of products with respect to specific critical quality attributes. Phase II projects will be expected to conduct full-scale parallel processing to demonstrate a substantial increase in the speed and cost of producing autologous cell-based therapies. It is anticipated that most offerors will propose to study T-cell-based immunotherapy products, although other cell types are also encouraged (e.g., NK cells). Advanced manufacturing approaches may involve genetic engineering and optimization as appropriate for the cell-based therapy product, but the primary goal is to achieve substantial cost and throughput improvements for the overall vein-to-vein process. Projects proposing to use allogeneic cell-based therapies for technology validation will not be considered responsive under this solicitation. Phase I Activities and Deliverables: • Provide proof of collaboration with an engineer(s), immunologist(s) and clinician(s) that has experience developing high throughput systems and/or treating patients with autologous cell-based cancer therapies; • Establish assays and/or metrics, especially functional comparability and quality attributes, for benchmarking the approach against current manufacturing methods; • Establish defined specifications to enable integrated high throughput parallel manufacturing at faster speed and lower cost than current manufacturing methods; • Develop an early prototype device or technology for integrated high throughput autologous-cell manufacturing that include specifications designed to substantially reducing the speed, as well as any cost savings based on the new manufacturing approach; • Demonstrate the suitability of the approach to manufacture a minimum of two cell products in parallel • Demonstrate pilot-scale beta-testing of the approach comparing it against appropriate benchmarking technology • Demonstrate the immunological functionality of the cells based on the previously identified functional comparability assays and/or metrics, and compare cell function to appropriate benchmarking technology; • Establish cell culturing technology compatible with high throughput production and technology to monitor the cells Phase II Activities and Deliverables: • Develop an at-scale prototype of the approach with detailed specifications for hardware/software that supports the manufacturing of multiple cell products simultaneously • Generate scientific data demonstrating the proposed scalability (e.g. scale-out, point-of-use) of the technology and demonstrate cost and time improvements over current clinical standard • Demonstrate comparable quality between the current manufacturing standard and cell-products manufactured at scale with the proposed approach

Budget and number of awards: Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted Number of anticipated awards: 2 Phase I, 1 Phase II Budget (total costs per award): Phase I: $300,000 for 12 months; Phase II: $2,000,000 for 2 years It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Summary The Portable Oxygen Concentrators (POCs) currently on the market do not meet the needs of the advanced stage lung disease population or those trying to participate in routine activities for a higher quality of life. The majority of POCs deliver a pulsed oxygen flow up to 3 liters per minute, synchronized with the breathing cycle, but at higher levels of oxygen needs, the pulsed mode is insufficient for routine exertion such as housework or tending to children. Current POCs that deliver a higher, continuous flow of oxygen (up to 10 liters per minute) are too heavy to carry in a shoulder bag or backpack; the user cannot carry a bag or child while also toting a heavy POC around. Also, most of the currently available POCs are not designed to easily or remotely adjust the oxygen flow-based on need. Different modes of remote access are needed to allow for flexibility in adjusting the oxygen flow of the device. This solicitation aims to support the development and commercialization of a light weight continuous flow Portable Oxygen Device that is available for clinical and investigational care of patients. Project Goals The goal of this project is to develop a lightweight, Portable Oxygen Device, with a continuous flow of oxygen of at least 5 liters per minute, and provide pulsed oxygen at a rate equivalent to 5 liters per minute of continuous flow. Remote control of the device to allow adjustments without taking the POC off and allow for use on domestic and international travel. The final device features should include but are not limited to: • The flow rate must be adjustable between 1 and 5 liters per minute, both for continuous and pulsed flow options. • The oxygen delivery system must be light, with a maximum total weight of 5 pounds, so the user can easily carry it hands-free. • If powered by a battery, the battery must last a minimum of 2 hours at the continuous flow rate of 5 liters per minute. • The POC system must provide a means to remotely control the flow of oxygen during activity at least 30 feet away. The remote control must enable adjustment easily, without having to remove it from the backpack or bag. • The POC system must include functional means for the user to control flow rate via a wired or wireless (e.g., Bluetooth, WiFi) connection, as the user needs. The wired controller may be a device attached to a shoulder/waist strap positioned for easy, one-hand access, or on a smart wearable device like a wristband. The wireless controller may be an app residing on a cell phone (e.g., iPhone, Android) or on a smart wearable (e.g., FitBit, iWatch). The app must utilize open source code or otherwise be publicly accessible to ensure it can be maintained by others in the event the awardee ceases to do so. Miscellaneous Requirements: • The oxygen delivery system shall sound an alarm when running low in battery, oxygen or if other types of malfunction occurs. • The oxygen delivery system must operate at the minimum performance level up to 10,000 feet of elevation. Ideally, the oxygen delivery system will be FAA approved for use on commercial airlines for domestic and international travel. • The oxygen delivery system must comply with all applicable FDA medical device product regulations based on its device class. Offerors are encouraged to include concrete milestones in their proposals, along with detailed research and development plans, risk analysis, and contingency plans, both for Phase I and Phase II. Phase I Activities and Expected Deliverables A Phase I awardee must develop at least one working prototype demonstrating proof of concept for the design. The awardee must perform a formal risk analysis, design a feasible concept, develop a prototype, and demonstrate it has the potential to meet the ultimate requirements of the NHLBI intramural lab. Below is a list of specific milestones: • Conception and ideation. Identify POC subsystems and determine areas of potential improvement based on user needs, come up with engineering concepts. • Risk assessment. Narrow down ideas based on a detailed risk matrix to objectively compare the ideas based on numerically rated cost, performance, and technology characteristics. • Engineering Analysis. Do mathematical and technical analysis of proposed POC subsystems. Create a report detailing the concepts and hypotheses. Make 3D-CAD conceptual models. • Minimum Viable Prototype Design. Create physical mockups, software, or electronic breadboard to get data and determine real-world feasibility. Create lean prototypes to validate key performance metrics. An example would be making a breadboard of a wireless communication system that could detect a button being switched on and off from 50 feet away. • Engineering Design. Use MVPs and initial data to design final prototype that should meet all functional requirements. • Prototype. Build a prototype according to the engineering design. Design and run a series of tests to determine if prototype achieved the functional requirements. Write final report detailing the development and prototype results, with details regarding outlook, key learnings, remaining technology risks, user assessments, and potential impact of the project on state of the art POC technology moving into Phase II. Offerors are advised to plan travel to NHLBI in Bethesda Maryland. Offerors are expected to plan meetings at project initiation, at mid-project to determine what iteration is necessary, and at project completion. Consideration for transition to Phase II funding will include progress toward regulatory clearance. Consideration may include the status of the contractor’s interactions with the Food and Drug Administration (FDA); therefore, contractors are encouraged to provide a detailed report of pre-IDE interactions with the FDA identifying requirements for IDE development under Phase II, including the summary of mutual understanding, if available. Phase II Activities and Expected Deliverables Phase II will move past the prototype stage to production grade product development and subsequent FDA approval/compliance and manufacturing. The timeline shall be detailed and allow for the completion and validation of the product development and engineering design controls within 24 months. In addition to meeting all requirements for Phase I, a Phase II award would allow commercial introduction of the device(s) together or independently as 510(k) devices substantially equivalent to marketed predicate devices, or under a de novo designation of lower risk. If this is not feasible, the Phase II deliverable would be all testing and regulatory development for the device to be used in human investigation in the United States, under Investigational Device Exemption (IDE), along with devices sufficient to test on 30 human subjects. All communications with FDA related to the device must be recorded and provided to NHLBI. This Phase II development will likely require specialized engineering, regulatory, and manufacturing expertise related to engineering design controls, fluid control, electric motors, electromechanical engineering, pneumatics, zeolite adsorbents, chemical engineering, firmware/embedded software development, power electronics, battery systems, quality engineering, medical device development, FDA compliance, and/or wireless communication electronics. Any recipients of this NIH grant should be well versed in these areas of engineering or have identified subcontractors who have the requisite industry experience. Below is a list of specific milestones: • Ensure stakeholder feedback is incorporated into any Phase I prototypes that are developed. Meet with NHLBI DIR lab to review all elements and finalize design documentation. • Refine and generate final 3D-CAD model. Iteratively build a model from custom-manufactured goods, test, update risk assessments, adapt software, and improve the 3D-CAD model. Prepare Design Master Record documentation • Assess required standards test; perform altitude test; confirm software verification; send prototypes to 3rd-party testing houses; select initial sources and production tooling; design verification reports; perform a design review and audit. • Complete all final documentation requirements, including Quality Plan, Mfg. Assembly Procedures, and Supplier QAs. The output will be three things: a documentation package, secured production sources, and manufacturing infrastructure; together, they must allow the product to be officially produced. • To ensure that the device conforms to defined user needs and intended uses, test production units under actual or simulated use conditions. Offerors are advised to plan travel to NHLBI in Bethesda Maryland. Offerors are expected to plan meetings at project initiation, at mid-project to determine what iteration is necessary, and at project completion. The contracting DIR lab offers to perform a clinical trial at no cost to the awardee.

Budget and number of awards: Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 1 Phase I, 1 Phase II Budget (total costs): Phase I: $400,000 for 12 months; Phase II: $3,000,000 for 3 years: It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Summary: Tricuspid valve regurgitation is a common malignant disease with few attractive mechanical treatment options. Secondary tricuspid regurgitation frequently accompanies secondary mitral valve regurgitation and confers a worse prognosis. NHLBI has developed the Suture via Coronary sinus with Interstitial myocardial navigation for MItral and Tricuspid Annular Reduction (SCIMITAR) procedure to accomplish dual-valve annuloplasty via interstitial navigation of heart muscles entered through heart veins. Clinical evaluation will require the development of purpose-built SCIMITAR devices. This contract solicitation aims to support the development and commercialization of an transcatheter SCIMITAR system. Project Goals: The project goal is to develop a SCIMITAR (Suture via Coronary sinus with Interstitial Myocardial navIgation for MItral and Tricuspid Annular Reduction) system implants and delivery catheters. SCIMITAR creates a figure-of-eight loop around the left ventricular myocardial base and inside the right ventricular myocardial wall that narrows both mitral and tricuspid annulis. SCIMITAR implantation requires device or guidewire traversal sequentially from the coronary sinus, through the basal interventricular septum, into the wall of the posterior right ventricle at the base, and through the basal right ventricular free wall to its anterior extent. A tension element is implanted along the SCIMITAR trajectory and countertraction is applied from the free limbs in the coronary sinus and right heart re-entry point near the anteroseptal commissure of the tricuspid valve. The goals are to develop and commercialize specific catheter tools to accomplish a SCIMITAR annuloplasty. The tools work together as a suite of catheters. Offerors are encouraged to include concrete milestones in their proposals, along with detailed research and development plans, risk analysis, and contingency plans, both for Phase I and Phase II. Phase I Activities and Expected Deliverables A phase I award would develop and test a suite of working prototypes in swine. The contracting intramural laboratory wishes to test the final prototype in vivo, and offers an earlier stage test to the contractor at no cost. Below is a list of required characteristics for the specified device system. The system presupposes that an off-the-shelf or purpose-built guidewire has navigated the intramyocardial SCIMITAR trajectory. • Able to exchange the SCIMITAR guidewire for a permanent tension element, without contributing to or precipitating centripetal (cameral) pull-through • Incorporating a coronary artery protection element, to protect entrapped (circumflex) coronary artery branches from extrinsic compression. • Able to deliver a tension countertraction element through the coronary sinus on one limb and the right atrial or right ventricular reentry site on the other limb • Incorporating an adjustable intravascular lock • Allowing early removal or at least tension interruption using transcatheter techniques as an emergency bail-out • Preferred embodiments allow late transcatheter tension adjustment (days to months after the first implantation procedure) • Incorporating radiopaque markers. Preferred embodiments indicate the perimeter of the implant as a reflection of applied tension • Preferred embodiments incorporate elements to protect entrapped coronary sinus (“left ventricular”) pacemaker or cardiac resynchronization therapy leads from damage • Safe for body and brain MRI at a minimum 1.5T field strength according to contemporary FDA guidelines Offerors are advised to plan travel to NHLBI in Bethesda Maryland, and are expected to plan meeting at project initiation, mid-project to determine what iteration is necessary, and at project completion. Consideration for transition to Phase II funding will include progress toward regulatory clearance. Consideration may include the status of the contractor’s interactions with the Food and Drug Administration (FDA); therefore, contractors are encouraged to provide a detailed report of pre-IDE interactions with the FDA identifying requirements for IDE development under Phase II, including the summary of mutual understanding, if available. NHLBI encourages contractors to consider requesting designation to the FDA’s Expedited Access for PMA Devices (EAP) program (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM393978.pdf) during the Phase I award period. Phase II Activities and Expected Deliverables In addition to meeting all requirements for Phase I, a phase II award would allow commercial introduction of the device(s) together or independently as PMA devices or 510(k) devices substantially equivalent to marketed predicate devices. If this is not feasible, the phase II deliverable would be all testing and regulatory development for the device to be used in human investigation in the United States, under Investigational Device Exemption, along with devices sufficient to test in 30 human subjects. All communications with FDA related to the contracted device must be recorded and provided to NHLBI. The contracting DIR lab offers to perform an IDE clinical trial at no cost to the awardee. Complete IDE documentation and license and a suitable supply of clinical materials would constitute the deliverable.

Fast Track proposals will be accepted. Direct to Phase II will not be accepted. Number of anticipated awards: 5 Budget (total costs): Phase I: $300,000 for up to 1 year; Phase II: $2,000,000 for up to 3 years. Background A new initiative by the US Government (https://www.hiv.gov/federal-response/ending-the-hiv-epidemic/overview) seeks to reduce the number of new HIV infections in the United States by 75 percent within five years, and then by at least 90 percent within 10 years. Most new infections occur in a limited number of counties and among specific populations. One of the necessities to reduce HIV incidence in the US are point-of-care assays to assist People Living with HIV (PLWH) or people at high risk of HIV infection manage their condition and prevent HIV transmissions among the US population. The solicitation would support two of the four pillars: 1. Treat people with HIV rapidly and effectively to reach sustained viral suppression, and 2. Prevent new HIV transmissions by using proven interventions, including pre-exposure prophylaxis. The small business innovation program is uniquely suited to reduce the HIV incidence in the US because funds can only be spent domestically and not abroad. Project Goals The long-term goal is to propose novel, low-cost, real-time point-of-care (POC) assays for 1. HIV Viral Load Monitoring - The assays should be designed as a home-test or for use in local clinics to detect HIV from finger-stick blood or other biospecimens at the earliest possible time after initial infection or after loss of viral suppression. For assays to be used at home, the design should be user-driven. The technology should include the capacity to connect results to healthcare providers. - The assays should be designed for use by People Living With HIV (PLWH) on/off antiretroviral therapy or on PrEP to detect viral spikes during ART therapy, viral rebound during analytical treatment interruption, HIV breakthrough infection during PrEP, or in the presence of an HIV vaccine-induced immune sero-reactivity. - Assays should be capable of detecting infection in at least one of the following groups: acutely infected people who may have no antibody response and low viral loads; Pre-Exposure Prophylaxis (PrEP) users who may have a very low viral load and a delayed antibody response; vaccine-induced sero-reactive people who will have antibody present even during acute infection; and/or ART-treated people after loss of viral suppression. - The method should be semiquantitative and should detect HIV RNA or other biomarkers, such as p24, immune markers, etc., with a qualitative sensitivity of at least 98% and specificity of at least 98%. - The assays should o have a minimum sensitivity of <500 RNA copies per mL of HIV-1 or equivalent if a biomarker is used. o at a minimum be able to detect HIV strains circulating in the US but detection can be extended to other HIV-1 subtypes. o have a short diagnostic time to the final result (optimally 20 minutes or less but no longer than 1 hour). o be culture-independent, easy to use, and cost-effective. - Proposals can include the development of a small handheld unit to be used with individual test strips or cartridges, but device-free, disposable units are preferred. Test units may require refrigeration, but stability at room temperature is preferable. - All necessary materials should be supplied with the test and no additional materials should be required. - The amount of handling required by the operator should be suitable for home testing by untrained individuals. 2. HIV Drug Resistance Monitoring - Develop an inexpensive, easy to use, POC assay that will detect the presence or absence of five common HIV drug resistance mutations in blood samples from patients failing HAART regimens. - Must detect HIV resistant variants in blood specimens from HIV-infected individuals with HIV RNA viral loads above 500 copies/mL. - Methods that detect a set of relevant point mutations and methods that collect full sequences are both acceptable, but the method must be developed for POC testing by trained professionals in clinics. - For methods that detect point mutations, a set of relevant mutations should be proposed in the application but will be finalized in cooperation with DAIDS program staff. - The method must be appropriate for use in clinics with a target turn-around-time of less than 2 hours and an initial target cost of $100 or less. 3. Pharmacological Adherence Monitoring - Rapid point-of-care methods that measure long-term (> 7 days) adherence to antiretrovirals. - Need to be able to measure drug levels in various biological matrices, e.g., urine, hair, dried blood spots, etc. - Need to be able to monitor o PrEP adherence o ART adherence to trigger adherence interventions o The long-tail associated with long-acting ART or PrEP o Blood donations for PrEP or ART drug levels (as a risk indicator of HIV exposure or infection) All three assays will assist with monitoring HIV viral loads, HIV drug resistance, and adherence to antiretrovirals. The ultimate goal is to increase viral suppression under combination ART and to monitor the effectiveness of PrEP. Phase I activities: • Develop prototype assays considering specificity, sensitivity, dynamic range, interference, robustness, reproducibility, accuracy (precision), and analysis of assay performance • Demonstrate that the assays can detect the analyte in various matrices, such as blood, dried blood spots, urine, saliva, hair (for drugs) dependent on the application • Preliminary studies to determine the assay feasibility • Define process controls • Establish potential for commercialization Phase II activities: • Further development of the prototype point-of-care diagnostic products • Further determination of the sensitivity, specificity and other performance characteristics (e.g., time to result, limit of detection, test stability) of the assay • Final validation testing and scale-up manufacturing of test kits • Development of quality control program to enable longitudinal measurements in compliance with Good Clinical Laboratory Practice • Finalization of the commercialization plan This SBIR contract topic will not support: • The conduct of clinical trials

Fast Track Proposals will be accepted. Direct to Phase II will not be accepted. Number of anticipated awards: 2 Budget (total costs): Phase I: $300,000 for up to one year; Phase II: $2,000,000 for up to 3 years. Background During the HIV life-cycle, multiple viral nucleic acids and proteins are expressed inside the infected cell. All are critical to support assembly, release, and maturation of the virus. Considering each HIV gene product has a defined role in the life- cycle, therapeutically targeting one or more may be an effective strategy to obtain a sustained viral remission. Small molecule inhibitors have been approved for the inhibition of reverse transcriptase, protease, and integrase. Attempts to develop small molecule inhibitors to other intracellular HIV proteins have not been successful since these proteins lack an active site to be targeted for binding, which renders them as “undruggable”. Therapeutic targeting of intracellular HIV proteins or nucleic acids may be an effective strategy for shutting down viral replication, preventing cellular transmission, and may ultimately lead to sustained viral remission. Recent advances in chemoproteomic platforms have resulted in the discovery of druggable hotspots on proteins previously considered to be undruggable. These hotspots can be targeted with small-molecule compounds with the goal of inhibiting protein function. Macromolecules have been developed as therapeutics, which are effective at targeting intracellular proteins. This class of drugs, which include intracellular antibodies, antibody fragments, disordered peptides, and stapled peptides are capable of inhibiting protein function and disrupting protein-protein interactions. The selective targeting of intracellular proteins for ubiquitination and degradation in the proteasome is an effective strategy for removing a protein from the cell and provides an approach, which is different from inhibition. Therapeutic targeting of HIV structural and regulatory proteins may be an effective strategy for inhibiting viral replication and assembly. Alternatively, targeting HIV accessory proteins may restore host anti-viral activities. The identification of detailed RNA structures (mRNA, noncoding RNAs, and micro RNAs) now allows the design of drugs, which are capable of binding to RNA with high selectivity and specificity or otherwise influence RNA biology resulting in disruption of the HIV life cycle. This strategy has the potential to expand the use of drugs beyond inhibiting functional activity, by preventing the translation of mRNAs, so that the targeted HIV protein is never expressed. In addition, HIV RNA can also be modified by tagging RNA nucleotides with side chains (adducts), especially at the hairpin loop where nucleotides are free. Project Goals The goal of this contract solicitation is to support the development of therapeutics which target intracellular HIV proteins or nucleic acids (DNA, RNA) with the goal of inhibiting their function and ultimately HIV replication. Phase I activities may include: • Designing, optimizing, and testing strategies for the development of therapeutics, which target intracellular HIV proteins or HIV nucleic acids • Performing proof-of-concept studies to demonstrate that therapeutics target intracellular HIV proteins or HIV nucleic acids • Evaluating the ability of the proposed therapeutics to inhibit HIV proteins/nucleic acids and disrupt HIV host protein/RNA interactions in relevant cell lines and primary cells • Exploring off-target effects • Performing proof-of-concept studies in small animal models Phase II activities may include: • Optimizing delivery to target HIV-infected cells with minimal off-target effects • Evaluating organ toxicity, immune responses/adverse events, and pharmacokinetic/pharmacodynamic parameters in nonhuman primates • Performing IND-enabling studies in consultation with the FDA The SBIR contract topic will not support: • Development of small molecules to inhibit HIV enzyme activity • Molecules that enhance latency reversal • Therapeutic targeting of HIV surface proteins, such as HIV Envelope

Fast Track Proposals will be accepted. Direct to Phase II will not be accepted. Number of anticipated awards: 2-4 Budget (total costs): Phase I: $300,000 for up to 1 year; Phase II: $2,000,000 for up to 3 years. Background A major focus of HIV vaccine research has been the development of immunogens that elicit broadly neutralizing antibody responses targeting the envelope protein (Env). While the field has predominantly focused on immunogen design and soluble antigens, the targeted and controlled delivery of antigens and optimal antigen-adjuvant formulations has not received much attention and is a gap in the HIV field that needs to be addressed. Lipid- and polymer-based nanoparticle platforms have been shown to induce HIV-specific antibody and cellular immune responses in animal studies. HIV immunogens delivered via particle-based modalities may elicit better and improved humoral and cellular immune responses. Specifically, multivalent/repetitive antigenic display on particle-based carriers may allow for higher avidity interactions and stimulate a diverse set of B cells. Consequently, such multivalent antigen display may mediate efficient engagement and activation of B cells, promoting stimulation of lower avidity cells from the germline antibody repertoire thereby enhancing affinity maturation resulting in superior antibody responses characterized by improved breadth, potency, and durability. Additionally, the ability of nanoparticles to target specific cells and release antigens in a controlled and sustained manner without the complications of viral vector toxicity and anti-vector immune responses makes nanoparticles a promising alternative to viral vectors. Altogether, for elicitation of potent, protective and durable immune responses, HIV immunogen design and particulate delivery of antigens should remain mutually inclusive and should converge for the development of HIV vaccine candidates capable of effectively inducing B/T-cell activation. Project Goal Tailored immunogens (such as Envs, monomers, native and/or native-like trimers, nucleic acids/RNA such as mRNAs, self- amplifying RNAs) combined with an effective multivalent antigenic display on nanoparticles for delivery may provide a strategy to promote strong and long-lived neutralizing antibody responses against HIV and direct affinity maturation toward HIV neutralizing antibodies. The primary goal of this SBIR is to solicit proposals that cover the following activities. Phase I activities may include, but are not limited to: • Engineering, fabricating nanoparticle platforms/systems and approaches (such as synthetic and/or self-assembling particles and/or conjugating technologies to attach antigen to nanoparticles and/or immunogens to adjuvants and/or encapsulating antigens) for delivering existing and/or novel HIV immunogens (such as Envs, monomers, native and/or native-like trimers, nucleic acids/mRNA/self-amplifying RNAs) that can enhance formulation codelivery, stability and scalability. • Augmenting HIV vaccine development by enhanced presentation, trafficking and targeting the antigen presentation for the induction of broad humoral and cellular immune responses. • Developing and evaluating particulate systems (such as synthetic and/or self-assembling and/or covalent chemical attachment and/or encapsulation/condensation of an antigen) that can facilitate co-delivery and/or co-formulation of HIV antigens (such as Envs, monomers, native and/or native-like trimers, nucleic acids/RNA) with adjuvants (such as existing, licensed, biosimilar novel adjuvants/TLR agonists). • Developing optimal parameters/conditions for incorporation of HIV antigen(s) in nanoparticulate formulation. • Assessing the effects of modulating particle size, shape, surface properties, composition and modulus/elastic properties of particulate delivery system components on immune responses. • Conducting pre-formulation/formulation studies on particulate antigen combinations to understand the interactions and compatibility of components (excipients, buffers, pH) and effect on antigen epitope integrity and its performance. • Developing assays and test methods to analyze and characterize molecular properties of the particulate-antigen formulations through in vitro (biophysical, physicochemical, binding assays) and/or in vivo testing (small animal studies). • Developing assays to quantify encapsulation efficiency, immunogen release and expression. • Studying conditions for controlling particle size and size distribution, charge, composition, and aggregation. • Conducting mixing, compatibility, studies and short-term stability studies on antigen-adjuvanted formulations. • Evaluating particulated formulation technologies for fabrication and development of HIV vaccine development. • Testing for batch-to-batch reproducibility and consistency of particulate formulations for manufacturing, impact of changes in scale, size of the batches. • Conducting studies whether the particulated formulations can be subjected to sterile filtration and assessing the composition of components after sterilization. • Developing an efficient process for early-stage/pre-clinical studies, which could be adapted to scale-up studies and which can subsequently lead to the production of clinical-grade material in conformance with current good manufacturing practices (cGMP). • Evaluating the immunogenicity and effectiveness of particle-based HIV protein and nucleic acid/RNA vaccine candidates using different co-delivery strategies such as, but not limited to, co-administration, colocalization, encapsulation, surface adsorption of antigens (vs. soluble antigen) in animal models. • Investigating the influence of heterologous prime-boost vaccination strategies on targeting B cell activation and maturation. • Investigating the effects of route of immunization, dose, dosage form, and dose-sparing capacity of particulate formulations on the particle distribution and kinetics of immunogen immune response. Phase II activities may include, but are not limited to: • Developing lead nanoparticle antigen formulation into an efficient, stable and reproducible process. • Generating a pilot lot and/or scale-up studies based on optimized conditions that can subsequently lead to the production of clinical-grade material in conformance with current Good Manufacturing Practices (cGMP). • Developing cGMP manufacturing processes for developing nanoparticle formulations. • Translating into in vitro studies to proof of concept studies in NHPs, as warranted. • Developing methods to evaluate compositional quality on critical components in nanoparticles, for example, but not limited to, quality, manufacturability and stability/degradation of lipids and related components. • Evaluating the performance, effectiveness, and toxicity of particulated HIV vaccine candidates vs. soluble antigen in small animal models. • Establishing quality assurance and quality control, methodology and development protocols for generation of HIV antigen-adjuvanted formulations for co-delivery.

Fast Track Proposals will be accepted. Direct to Phase II will not be accepted. Number of anticipated awards: 1-2 Budget (total costs): Phase I: $300,000 for up to 1 year; Phase II: $2,000,000 for up to 3 years. Background Despite effective antiretroviral therapy (ART), HIV-1 persists in all infected individuals as proviral DNA within long-lived memory CD4+ T cells. Early studies on PBMC from HIV-infected donors on suppressive ART demonstrated that a subset of proviruses could be induced to replicate in tissue culture. This replication-competent HIV reservoir constitutes the primary barrier for curing HIV infection. In this context, the number of full-length (intact) HIV proviruses represents the upper limit of the replication-competent HIV reservoir whereas infectious units per million (IUPM) measured by the Quantitative Viral Outgrowth Assay constitute the lower limit of this reservoir of interest. To measure success, the design of HIV cure strategies should be accompanied by the development of fast and reliable assays that accurately measure changes in the replication-competent HIV reservoir. In addition, for practical reasons, HIV reservoir assays should only require small sample sizes, either a few million cells or a tissue biopsy. Recently, several assays have been developed to replace the time-consuming Quantitative Viral Outgrowth Assay, but validation for clinical applications and commercial purposes is lagging behind. Project Goal The overall goal of this project is to develop and commercialize sequence-based HIV reservoir assays for clinical HIV cure interventions. Specifically, the assay should be designed as an analytical tool to monitor the size of the replication-competent HIV reservoir in clinical research and if successful, in prospective clinical trials. Essential characteristics for commercially applicable HIV reservoir assays are reproducibility, low labor intensity, medium-to-high throughput performance, and correlation with the replication-competent HIV reservoir. When designing the requested assays, it needs to be also taken into consideration that besides internal sequence deletions, lethal mutagenesis, such as G-A hypermutations, stop codons within the HIV open reading frames and nonfunctional LTR promoters could also present blockades in the HIV replication cycle. An additional goal of this project is to develop secondary assays that are not tissue culture-based and discriminate between actively transcribed and latent full-length proviruses. Applicants also need to provide a plan for evaluation how their assay correlates with the Quantitative Viral Outgrowth Assay and other recently developed HIV reservoir assays, such as the Tat/Rev Induced Limiting Dilution Assay (TILDA), and why their assay is superior to similar reservoir assays. The ultimate goal of this project is to develop an assay that accurately measures the size of the HIV reservoir defined as the “barrier” to the HIV cure, which needs to be eliminated to prevent viral rebound. Phase I activities may include, but are not limited to: • Developing medium-to-high throughput sequence-based assays that accurately reflect the size of the replication- competent reservoir. • Developing standardized controls for the sequence-based assays. • Confirming that the sequences detected correspond to full-length HIV proviruses. • Determining the following assay parameters: o Specificity: Will the assay only detect full-length proviruses? o Sensitivity: Will the assay detect small levels of full-length proviruses? What is the dynamic range and is it adequate? o Interference: will components in the assay sample interfere with the assay (for example, blood anticoagulants, such as heparin)? o Robustness: Can the assay cope with small changes in the assay sample/equipment/operator? o Accuracy: Is the assay capable of accurately determining the absolute number of full-length proviruses? Phase II activities may include, but are not limited to: • Determining the utility of the assay for clinical samples. • Testing clinical samples from diverse cohorts of HIV+ individuals with varying levels of residual viral reservoirs. • Validating the developed assays under CLIA and ICH harmonized Good Clinical Practices. • Determining that the assays qualify for FDA regulatory submissions. • Determining assay performance for different HIV subtypes and drug-resistant strains. • Determining assay performance in tissues versus blood. • Demonstrating that the assay can measure changes in the size of the latent HIV reservoir in response to an intervention.

Fast-Track proposals will be accepted. Direct-to-phase II proposals will be accepted. Number of anticipated awards: 1-3 Budget (total costs): Phase I: $300,000/year for up to 2 years; Phase II: $1,000,000/year with appropriate justification by the applicant for up to 3 years. Background The goal of this program is to support the preclinical development of novel vaccine adjuvant candidates against infectious diseases or of tolerogenic adjuvants for immune-mediated diseases. For the purpose of this SBIR, vaccine adjuvants are defined according to the U.S. Food and Drug Administration (FDA) as “agents added to, or used in conjunction with, vaccine antigens to augment or potentiate, and possibly target, the specific immune response to the antigen”. Tolerogenic adjuvants are defined as compounds that promote immunoregulatory or immunosuppressive signals to induce non-responsiveness to self-antigens in autoimmune diseases, or environmental antigens in allergic diseases. Currently, only a few adjuvants other than aluminum salts (“Alum”) have been licensed as components of vaccines in the United States (U.S.): 4’-monophosphoryl lipid A (MPL), adsorbed to alum as an adjuvant for an HPV vaccine; CpG Oligodinucleotide as an adjuvant for a recombinant Hepatitis B vaccine; MPL and QS-21 combined in a liposomal formulation for a varicella vaccine; and the oil-in-water emulsion MF59 as part of an influenza vaccine for people age 65 years and older. Additional efforts are needed to develop promising novel adjuvants, particularly for vulnerable populations such as the young, elderly and immune-compromised. In addition, adjuvants may facilitate the development of immunotherapeutics for immune-mediated diseases (e.g., allergic rhinitis, asthma, food allergy, autoimmunity, transplant rejection). The field of tolerogenic adjuvants is still in its infancy. No compounds have been licensed yet in the U.S. and immune-mediated diseases are treated mostly with broadly immunosuppressive drugs or long-term single- or multi-allergen immunotherapy. In contrast to drugs, tolerogenic or immunomodulatory adjuvants may regulate immune responses to specific antigens through a variety of mechanisms, including induction of regulatory T cells or alterations in the profile of the pathogenic lymphocyte response (e.g., Th1 to Th2 or vice versa). For tolerogenic and immune modifying adjuvants, the antigens may originate from environmental (allergy) or endogenous (autoimmunity) sources and may not need to be supplied exogenously together with the adjuvant. When using this approach, the proposal must describe a compelling mechanism by which the adjuvant would modulate an antigen- specific response, and include studies demonstrating altered or suppressed responses against the allergen or autoantigen. Adjuvanticity may be obtained with a single immunostimulatory (or immunoregulatory/tolerizing) compound or formulation, or with a combination adjuvant. For this solicitation, a combination-adjuvant is defined as a complex exhibiting synergy between individual adjuvants, such as: overall enhancement or tolerization of the immune response depending on the focus and nature of the vaccine antigen; potential for adjuvant-dose sparing to reduce reactogenicity while preserving immunogenicity or tolerizing effects; or broadening of effector responses, such as through target-epitope spreading or enhanced antibody avidity. Project Goal The goal of each project will be to accelerate the pre-clinical development and optimization of a single lead adjuvant candidate or a select combination-adjuvant for prevention of human disease caused by non-HIV infectious pathogens, for the treatment of autoimmune or allergic diseases, or transplantation. The adjuvant products supported by this program must be studied and further developed toward human licensure with currently licensed or new investigational vaccines and may not be developed as stand-alone agents. Phase I Activities: Depending on the developmental stage at which an adjuvant is entered into the program, the offeror may choose to perform one or more of the following: • Optimization of one candidate compound for enhanced safety and efficacy. Studies may include: o Structural alterations of the adjuvant o Formulation modifications (adjuvant alone or in combination with antigen(s)) o Optimization of immunization regimens • Development of novel combinations of previously described individual adjuvants, including the further characterization of an adjuvant combination previously shown to enhance or tolerize immune responses synergistically • Preliminary studies in a suitable animal model to evaluate: immunologic profile of activity; immunotoxicity and safety profile; protective or tolerizing efficacy of a lead adjuvant:antigen/vaccine combination Phase II Activities: Extended pre-clinical studies that may include IND-enabling studies such as: • Additional animal testing of the lead adjuvant:vaccine combination to evaluate immunogenicity or tolerance induction, protective efficacy, and immune mechanisms of protection • Pilot lot or cGMP manufacturing of adjuvant or adjuvant:vaccine • Advanced formulation and stability studies • Toxicology testing • Pharmacokinetics/absorption, distribution, metabolism and excretion studies • Establishment and implementation of quality assurance and quality control protocols Areas of Interest: • Adjuvants to improve the efficacy of vaccines to protect against infectious disease, particularly for vaccines targeted towards vulnerable populations • Novel combination adjuvants • Tolerogenic or immune deviating adjuvants for allergen immunotherapy This SBIR will not support: • The further development of an adjuvant that has been previously licensed for use with any vaccine unless such an adjuvant is use as a component of a novel combination adjuvant as defined above • The conduct of clinical trials (see https://osp.od.nih.gov/wp- content/uploads/2014/11/NIH%20Definition%20of%20Clinical%20Trial%2010-23-2014-UPDATED_0.pdf for the NIH definition of a clinical trial) • The discovery and initial characterization of adjuvant candidates • The development of adjuvants or vaccines to prevent or treat cancer • Development of platforms, such as vehicles, or delivery systems that have no immunostimulatory or tolerogenic activity themselves • The development of the vaccine’s antigen component • The development of immunostimulatory compounds or formulations as stand-alone immunotherapeutics (i.e., without a specific antigen/pathogen-specific vaccine component) unless the adjuvant is used to modulate or suppress the response against an allergen or autoantigen. In this case, the proposal must include assays to demonstrate the effect of the treatment with an adjuvant on specific allergens or autoantigens.

Fast-Track proposals will be accepted. Direct-to-phase II proposals will be accepted. Number of anticipated awards: 1-3 Budget (total costs): Phase I: $300,000/year for up to 2 years; Phase II: $1,000,000/year with appropriate justification by the applicant for up to 3 years. Background The goal of this program is to support the screening for new vaccine adjuvant candidates against infectious diseases or for tolerogenic adjuvants for autoimmune or allergic diseases. For the purpose of this SBIR, the definition of vaccine adjuvants follows that of the U.S. Food and Drug Administration (FDA): “Agents added to, or used in conjunction with, vaccine antigens to augment or potentiate and possibly target the specific immune response to the antigen.” Tolerogenic adjuvants are defined as compounds that promote immunoregulatory or immunosuppressive signals to induce non-responsiveness to self- antigens in autoimmune diseases or transplantation, or environmental antigens in allergic diseases. Currently, only a few adjuvants other than aluminum salts (“Alum”) have been licensed as components of vaccines in the United States (U.S.): 4’-monophosphoryl lipid A (MPL), adsorbed to alum as an adjuvant for an HPV vaccine; MPL and QS- 21 combined in a liposomal formulation for a varicella vaccine; CpG Oligodinucleotide as an adjuvant for a recombinant Hepatitis B vaccine; and the oil-in-water emulsion MF59 as part of an influenza vaccine for people age 65 years and older. In addition, adjuvants may facilitate the development of immunotherapeutics for immune-mediated diseases (e.g., allergic rhinitis, asthma, food allergy, autoimmunity, transplant rejection). The field of tolerogenic adjuvants is still in its infancy. No compounds have been licensed yet in the U.S. and immune-mediated diseases are treated mostly with broadly immunosuppressive drugs or long-term single- or multi-allergen immunotherapy. In contrast to drugs, tolerogenic or immunomodulatory adjuvants may regulate immune responses to specific antigens through a variety of mechanisms, including induction of regulatory T cells or alterations in the profile of the pathogenic lymphocyte response (e.g., Th1 to Th2 or vice versa). For tolerogenic and immune modifying adjuvants, the antigens may originate from environmental (allergy) or endogenous (autoimmunity) sources and may not need to be supplied exogenously together with the adjuvant. When pursuing this approach, the proposal must describe a compelling mechanism by which the adjuvant would modulate an antigen-specific response, and include studies demonstrating altered or suppressed responses against the allergen or autoantigen. Recent advances in understanding of innate immune mechanisms have led to new putative targets for vaccine adjuvants and for immunotherapy. Simultaneously, progress is being made in the identification of in vitro correlates of clinical adjuvanticity, which allows the design of in vitro screening assays to discover novel adjuvant candidates in a systematic manner. The gaps that need to be addressed by new adjuvants include improvements to existing vaccines (e.g., the acellular pertussis vaccine, influenza, etc), and development of vaccines for: emerging threats (e.g., Ebola outbreaks); special populations that respond poorly to existing vaccines (e.g., elderly, newborns/infants, immunosuppressed patients); or treatment/prevention of immune-mediated diseases (e.g., allergic rhinitis, asthma, food allergy, autoimmunity, transplant rejection). For example, the combination of putative tolerogenic adjuvants with allergen immunotherapy should aim at accelerating tolerance induction, increasing the magnitude of tolerance and decreasing treatment duration. For transplantation, donor-derived major and minor histocompatibility molecules that are not matched between donor and recipient may be formulated with novel tolerogenic adjuvants and used to induce transplant tolerance in the recipient. Program Goal The objective of this program is to support the screening for new adjuvant candidates for vaccines against infectious diseases, or for autoimmune and allergic diseases, or transplantation; their characterization; and early-stage optimization. Phase I Activities include, but are not limited to: • Optimize and scale-up screening assays to identify new potential vaccine- or tolerogenic adjuvant candidates • Create targeted libraries of putative ligands of innate immune receptors • Conduct pilot screening assays to validate high-throughput screening (HTS) approaches for identifying adjuvant candidates • Develop or conduct in silico screening approaches to pre-select adjuvant candidates for subsequent in vitro screens and validation Phase II Activities include, but are not limited to: • HTS of compound libraries and confirmation of adjuvant activity of lead compounds • Confirmatory in vitro screening of hits identified by HTS or in silico prediction algorithms • Optimization of lead candidates identified through screening campaigns through medicinal chemistry or formulation • Screening of adjuvant candidates for their usefulness in vulnerable populations, such as the use of cells from cord blood of infants or elderly/frail humans • Screening of adjuvant candidates in animal models representing vulnerable human populations This SBIR will not support • The development of immunostimulatory compounds or formulations as stand-alone immunotherapeutics (i.e., without a specific antigen/pathogen-specific vaccine component) unless the putative adjuvant is used to modulate or suppress the response against an allergen or autoantigen. In this case, the proposal must include assays to demonstrate the effect of the treatment with an adjuvant on specific allergens or autoantigens. • The testing of newly identified immunomodulatory compounds or formulations in cancer models • The further development of previously identified adjuvant • The conduct of clinical trials (see https://osp.od.nih.gov/wp- content/uploads/2014/11/NIH%20Definition%20of%20Clinical%20Trial%2010-23-2014-UPDATED_0.pdf for the NIH definition of a clinical trial)

Fast-Track proposals will be accepted. Direct-to-phase II proposals will be accepted. Number of anticipated awards: 3-5 Budget (total costs): Phase I: $300,000/year for up to 2 years; Phase II: $1,000,000/year with appropriate justification by the applicant for up to 3 years. Background Many experimental and licensed vaccines depend on adjuvants to exert their protective effect. While several immunostimulatory compounds and formulations are available commercially for use in preclinical studies, these compounds generally cannot be advanced into clinical trials. Furthermore, head-to-head comparisons of novel experimental and existing adjuvants is hampered by limited availability of such reagents. NIAID supports the discovery and development of novel adjuvants through different mechanisms; and this Funding Opportunity Announcement (FOA) is intended to address the limited availability of adjuvants that: mimic those with a favorable clinical track record; or show high potential in late pre- clinical testing. Program Goal Development, validation and production of adjuvants that are based on, or similar to, compounds or formulations previously successfully used in clinical trials, for use by the broader research community, either as commercial products or through licensing agreements. Phase I Activities must include at least the following 2 activities: • Development of one or more adjuvant/adjuvant formulations that is based on or similar to an adjuvant with a proven clinical track record of high adjuvanticity • Preclinical testing to assure immune potency and safety Phase II Activities include, but are not limited to: • Establishment of an immunological profile of the lead product • Pharmacological and toxicological studies in appropriate animal models • Validation of product • Scale-up production • Development of a marketing plan This SBIR will not support • Development of aluminum-based adjuvants as marketable products, unless the aluminum-component is used as a co- adjuvant or carrier • Discovery of novel immunostimulatory compounds • Commercial development of adjuvants that do not have the ability or potential to activate human immune cells • Development of adjuvant mimics that would violate existing patents

Fast-Track proposals will be accepted. Direct-to-phase II proposals will be accepted. Number of anticipated awards: 3-5 Budget (total costs): Phase I: $300,000/year for up to 2 years; Phase II: $1,500,000 with appropriate justification by the applicant for up to 3 years. Background This Funding Opportunity Announcement (FOA) addresses the limited availability of reagents (e.g., antibodies, proteins, ligands) for the identification and discrimination of immune cells and the characterization of immune responses in non- mammalian models (arthropods, amphibians, fish (e.g., jawless, sharks, zebrafish), nematodes, marine echinoids) or in specific underrepresented mammalian models (guinea pig, ferret, cotton rat, pig (including minipigs), rabbit and marmoset). Non-mammalian models are easily tractable model systems to study basic, conserved immune defense pathways and mechanisms. For example, characterization of the Drosophila Toll signaling pathway facilitated the discovery of mammalian Toll-Like Receptors (TLR), which significantly accelerated progress made in the field of innate immunity. Non-mammalian models can be much more easily adapted to high-throughput screening formats than mammalian organisms. Caenorhabditis elegans has been used for whole organism high-throughput screening assays to identify developmental and immune response genes, as well as for drug screening. Many non-mammalian species are natural hosts for human pathogens and share many conserved innate immune pathways with humans, such as the Nf-B pathway in mosquitoes, the intermediate hosts for Plasmodia parasites. However, studies to better understand immune regulation within non-mammalian models have been constrained by the limited availability of antibodies and other immune-based reagents for use in scientific studies. Certain mammalian models display many features of human immunity but are similarly underutilized due to the limitations noted above. For example, the progression of disease that follows infection of guinea pigs with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), displays many features of human TB. While this model has been used for more than 100 years as a research tool to understand and describe disease mechanisms, immunologic analyses are constrained by the limited availability of immunological reagents specific for the guinea pig. Another example is the ferret model, one of the best animal models of human influenza infection, where immunologic studies also have been limited by the lack of immunological reagents. Project Goal Development and validation of reliable antibodies and reagents for the identification and tracking of primary immune cells or the analysis of immune function/responses (e.g., cytokines, chemokines, intracellular signaling) in non-mammalian models or underrepresented mammalian models. Non-mammalian models are limited to arthropods, amphibians, fish (e.g., jawless, sharks, zebrafish), nematodes, and marine echinoids. Underrepresented mammalian models are limited to guinea pig, ferret, cotton rat, pig (including minipigs), rabbit and marmoset. Phase I Activities must include the following activities: • Selection of targets, which may include: immune cell markers; receptors with immune function; or other molecules important for immune function • Development of antibodies or other reagents against these targets o If polycloncal antibodies are being developed, the plan also must include the development of monoclonal antibodies • Characterization of antibodies or reagents developed (e.g. confirmation of binding to intended antigen/immunogen) Phase II Activities must include, but are not limited to: • Comprehensive evaluation of specificity and functional utility of antibodies/reagents, which must minimally include: evaluation of non-specific binding to cells or unrelated molecules and utility of antibodies/reagents for Western blotting (denatured and native protein), immunoprecipitation, immunohistochemistry and flow cytometry. In addition, Phase II Activities may include, but are not limited to: • Screening for cross-reactivity with related molecules on other non-mammalian species or mammalian immune cells • Optimization (e.g., secondary modifications/conjugations) of the antibodies/reagents for use in different assays and platforms • Scale-up production of the reagents This SBIR will not support: • Identification of immune target molecules and development of antibodies/reagents against immune markers or molecules for animal models not listed in the solicitation • Development of antibodies/reagents for molecules or mechanisms not involved in immune responses • Development of novel or refined animal models

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will not be accepted. Number of anticipated awards: 2-3 Budget (total costs): Phase I: $300,000 for up to one year; Phase II: $1,500,000 for up to 3 years. Background The rapid emergence of antibiotic resistance in both Gram-positive and Gram-negative bacteria has limited our ability to treat certain infections, leading to an urgent need for new antimicrobial agents and the development of novel approaches to combat bacterial infections. In recent years, there has been an increasing number of reports in which bacteriophages (phages) have been used in a clinical setting to treat infections caused by drug resistant bacteria. However, the use of phage has been largely limited to eIND or compassionate use situations, making it difficult to make definitive conclusions regarding their clinical efficacy. In addition, there are significant roadblocks to testing phage therapy in a clinical setting, including: • Absence of generalizable procedures to manufacture high titer phage stocks suitable for use in clinical studies. • Knowledge gaps related to the stability and formulation for specific phages and combinations thereof. Project Goal The goal of this solicitation is to develop generalizable procedures and necessary tools to manufacture and purify stable high titer phage stocks suitable for use in clinical trials. The tools and methods should be applicable to phage that could be used to treat mycobacteria or one of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). Phase 1 activities may include, but are not limited to: • Identification and development of robust tools and methods to produce and purify high titer phage stocks suitable for use in clinical trials. • Development of methods to ensure the stability of high titer phage stocks. • Investigation and development of novel formulations and methodologies that advance the use of high titer phages. Phase 2 activities may include, but are not limited to: • Demonstration that methods developed in Phase 1 are not limited to particular types of phages or phages which grow on specific bacterial pathogens. • Demonstration that stability methods developed in Phase 1 will be suitable for use with phage cocktails in addition to be suitable for use with single phages. This SBIR will not support: • Clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial for the NIH definition of a clinical trial).

Fast-Track proposals will be accepted. Direct to Phase II will not be accepted. Number of anticipated awards: 2-3 Budget (total costs): Phase I: $300,000 for up to one year; Phase II: $1,500,000 for up to 3 years Background Chagas disease (CD) is endemic in Latin America and is a growing public health concern in the U.S. where there are an estimated 300,000 cases. CD progresses from a brief acute phase to a prolonged asymptomatic chronic phase, with 20-30% of those infected developing serious cardiac or gastrointestinal complications. Early diagnosis is important, as the two drugs used to treat CD, benznidazole and nifurtimox, are highly effective if given early but show uncertain efficacy and increasing toxicity with increasing duration of infection and patient age. Currently available diagnostic assays have suboptimal sensitivity and specificity, and a positive diagnosis can require multiple confirmatory tests. The extensive genetic diversity of Trypanosoma cruzi, the parasite responsible for CD, likely contributes to this assay discordance. A reliable clinical test of cure (ToC) to gauge treatment efficacy is also lacking, as there are currently no known biomarkers that would provide an early indication of treatment success. Project Goal The purpose of this solicitation is to develop one of the following: i) a rapid point-of-care diagnostic assay with sensitivity greater than standard serological tests, and appropriate for use during both the acute and chronic phases; or ii) a biomarker- based ToC to evaluate treatment outcome during the chronic phase of infection that does not require months or years to definitive results. Both assays should be able to detect all circulating strains of T. cruzi. Additionally, there should be no cross-reactivity with other parasites (i.e. Leishmania, T. rangeli). Offerors may need to establish a collaboration or partnership with a medical facility or research group in the US or overseas that can provide relevant positive control and patient samples; offerors must provide a letter of support from the partnering organization(s) in the proposal. Phase 1 activities may include but are not limited to: • Identification of appropriate biomarkers for prototype diagnostic test. • Determination of sensitivity, specificity and other performance characteristics (e.g. time to result, limit of detection, cross reactivity, test stability, feasibility for newly infected, chronically infected, and resolved infected clinical samples) of the diagnostic test. • Performance of initial testing on laboratory isolates. • Performance of further testing on isolates from across the geographic range of the parasite. Phase 2 activities may include, but are not limited to: • Further characterization of appropriate biomarkers for a prototype diagnostic. • Further optimization of the assay platform technology and validation of assay reproducibility. • Testing of de-identified clinical samples from diverse cohorts with varying levels of infection. • Final validation testing and scale-up manufacturing of test kits. This SBIR will not support: • The design and conduct of clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial for the NIH definition of a clinical trial). • Development of assays and/or technologies for research use only. • Development of diagnostic assays that only identify one or a small subset of circulating strains of T. cruzi.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 2-3 Budget (total costs): Phase I: $300,000 for up to one year; Phase II: $1,500,000 for up to 3 years. Background Tuberculosis (TB) is the world’s leading infectious killer and rates of multi and extensively drug resistant TB (MDR/XDR TB) are increasing. In 2018, an estimated 1.1 million children became ill with TB and an estimated 234,000 children died from the disease. Current TB drug dosing and administration for pediatric TB cases is inadequate, leading to poor adherence, potentially suboptimal drug levels and the development of drug resistant TB. Pediatric formulations of first line TB drugs Isoniazid, Rifampicin (rifampin), Pyrazinamide and Ethambutol are currently available or under development. Treatment of MDR/XDR requires the use of second line TB drugs. However, for many of these drugs, pediatric friendly formulations do not exist. Adult tablets are often cut and administered to children in juice or other palatable substances such as food, which may inactivate these drugs. For MDR and XDR TB, long term treatment is required (18-24 months) and for rapidly growing children frequent dose adjustments may be required, so flexible dose formulations which allow personalization based on weight, age and nutritional status are particularly desirable. Additionally, formulations stable under ambient conditions and suitable for use in resource-limited countries are desirable. Project Goal The purpose of this solicitation is to develop innovative, pediatric-friendly, oral formulations for select second line drugs that are approved for treatment of TB. This solicitation specifically targets the development of pediatric formulations for the oxazolidinones (e.g. linezolid), clofazimine, fluoroquinolones, para-aminosalicylic acid (PAS), cycloserine, and the nitroimidazoles Delaminid and Pretomanid. Examples of the types of oral formulations that may address these needs include but are not limited to: oral thin films; porous, chewable matrix systems (scorable “taffy” based on patient weight); candy-like formulations, including gummies and jellybeans; inhaled formulations and easy to dissolve tablets. Ideally, the final product should be stable at room temperature and ready for testing in bioequivalence and pharmacokinetic/pharmacodynamic studies. Phase I activities may include, but are not limited to: • Develop prototype formulations for one or more of the following second line TB drugs: the oxazolidinones (e.g. linezolid), clofazimine, fluoroquinolones, para-aminosalicylic acid (PAS), cycloserine, and the nitroimidazoles Delamanid and Pretomanid. • Develop analytical assays to characterize chemical composition, purity and stability of prototype formulations • Assess the pharmacokinetic profile and safety of the formulations in appropriate systems or animal models • Conduct or develop drug potency assays for bioequivalence studies Phase II Activities may include, but are not limited to: • Scale-up formulations for further preclinical studies • Conduct additional pharmacology and toxicology evaluations of the formulations in appropriate systems or animal models • Conduct bioequivalence studies This SBIR will not support: • The design and conduct of clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial for the NIH definition of a clinical trial). • Proposals that include formulation of first line TB drugs (Isoniazid, Rifampicin (rifampin), Pyrazinamide and Ethambutol).

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 1-3 Budget (total costs): Phase I: $300,000 for up to one year; Phase II: $2,500,000 for up to 3 years. Background Group A Streptococcus (GAS) infection is a global health threat due to its high morbidity and mortality. No licensed GAS vaccines are available, and few candidates have been evaluated clinically. There is a critical need for the development of a safe and effective GAS vaccine. While recent advances in the field of GAS vaccine development have led to many important vaccine candidates, most are at the stages of basic research and early preclinical development. Project Goals The overall goal of this solicitation is to develop safe and effective GAS candidate vaccines that are suitable for future product and clinical development. Proposals should establish proof-of-concept for and/or support preclinical development of a candidate vaccine to combat GAS, as well as standardize methods to evaluate immunity, protection, and safety of the candidate vaccine(s). Proposals that significantly advance a candidate vaccine toward clinical development are highly encouraged. Phase I activities may include but are not limited to: • Identification and evaluation of novel or improved vaccine candidate(s)/formulation(s) using in vitro and/or in vivo studies • Development and standardization of in vitro surrogate assays to evaluate induction of immunity and protection • Development and validation of in vivo proof-of-concept studies to demonstrate protection in animal models • Development, standardization and validation of assays to evaluate the safety of the vaccine candidate(s) Phase II activities may include but are not limited to: • Additional testing and process development of the lead vaccine candidate(s) in the product development pathway leading to IND-enabling studies, including but not limited to testing to improve safety, efficacy, and quality assurance/quality control • Preclinical testing in animal, including non-human primate, models • Pilot lot cGMP manufacturing, as appropriate, for further refinement of the vaccine candidate(s) • Stability and toxicology studies, as appropriate, for later stages of the vaccine product development pathway This SBIR will not support: • The design and conduct of clinical trials (see https://osp.od.nih.gov/wp-content/uploads/2014/11/NIH%20Definition%20of%20Clinical%20Trial%2010-23-2014- UPDATED_0.pdf for the NIH definition of a clinical trial).

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will not be accepted. Number of anticipated awards: 2-3 Budget (total costs): Phase I: $300,000 for up to one year; Phase II: $1,500,000 for up to 3 years. Background Infection rates of hepatitis C virus (HCV) in the USA have steadily risen since 2010. There are approximately 2 million people chronically infected with HCV in the USA, and it is estimated that up to 45,000 acute infections occur annually. Spontaneous clearance of HCV occurs in 15-47% of acutely infected individuals; the remaining will develop chronic HCV (defined as viremic for 6 months or greater). Globally, there are an estimated 71 million people with chronic HCV; it is estimated that as many as 50% may be unaware of their infection. In 2016, the World Health Organization established a goal for eliminating HCV infection as a major public health threat by 2030, defined by reductions in incidence (by 90%) and mortality (by 65%). In order to achieve these goals, a new point-of- care (POC) diagnostic that is sensitive, specific, simple, rapid, and cost-effective is critical to more readily connect infected individuals with treatment and case management efforts. While the current HCV diagnostic process utilizes assays that are highly sensitive and specific, it requires at least two tests that can take up to a week or more for results. An initial positive point-of-care screen for anti-HCV antibodies in blood is followed by a viral load test performed in a centralized laboratory. Either the same sample is reflex tested, or the patient must supply an additional sample. The delay in diagnosis can have a significant impact on follow-up care, initiation of treatment, and potential transmission of the virus in at-risk groups (such as persons who inject drugs). Simplified POC testing for active, viremic HCV infections would allow patients to receive their result in a single visit and allow for rapid care planning and management with their physician. Project Goal The purpose of this solicitation is to develop a POC diagnostic for primary health-care settings to detect active, viremic HCV infections in a single visit and to confirm cure following treatment. The diagnostic should be rapid (e.g. results ideally in 1 hour or less), simple (require minimal equipment or training to perform), cost-effective, and have the same or better sensitivity and specificity characteristics as similar FDA-approved diagnostic tests currently available for HCV. Additionally, the diagnostic should be able to detect all HCV genotypes, exhibit no cross-reactivity with endogenous substances or exogenous factors, and ideally utilize sample types that are minimally invasive (such as capillary whole blood). Offerors may need to establish a collaboration or partnership with a medical facility or research group in the US that can provide relevant positive control and patient samples; offerors must provide a letter of support from any partnering organization(s) in the proposal. Phase 1 activities may include, but are not limited to: • Identification of appropriate diagnostic targets (antigen, biomarkers, nucleic acid sequences, etc.) for a POC diagnostic to detect active, viremic HCV infections. • Development of the prototype POC diagnostic platform (lateral flow system, instrument, etc.) to detect active, viremic HCV infections. • Determination and/or optimization of the sensitivity, specificity and other performance characteristics (e.g. time to result, limit of detection, test stability) of the prototype POC diagnostic. • Initial testing using clinical laboratory isolates with multiple genotypes. • Initial testing using HCV clinical samples or matrices spiked with known quantities of HCV. Phase 2 activities may include, but are not limited to: • Further characterization of diagnostic targets for the POC diagnostic to detect active, viremic HCV infections. • Advanced development of the prototype POC diagnostic platform to detect active, viremic HCV infections. • Optimization of the sensitivity, specificity, and other performance characteristics (e.g. time to result, limit of detection, test stability). • Validation of assay reproducibility. • Testing clinical samples from diverse cohorts with varying infecting genotypes and varying case history (acute or chronic). • GMP manufacturing of test components and final validation studies. This SBIR will not support: • The design and conduct of clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial for the NIH definition of a clinical trial). • Proposals that are focused on serological assays that solely detect antibodies against HCV. • Proposals that do not have the ultimate goal of detecting and identifying an active, viremic HCV infection in human clinical samples.

Fast Track proposals will be accepted. Direct to Phase II will be accepted. Number of anticipated awards: 1-3 Budget (total costs): Phase I: $300,000 for up to 1 year; Phase II: $1,000,000 for up to 3 years. Background Data intense infectious, immune, and allergic basic and clinical research projects are generating unprecedented amounts of complex and diverse data sets and beginning to accelerate research in infectious, immune, and allergic diseases ranging from basic understanding of the pathogen and disease to developing new and improved therapeutic interventions and diagnostics and identifying precise, molecular signatures for clinical application. Yet, increasing the use and re- use of these diverse and complex data sets by basic and clinical scientists studying infectious, immune and allergic diseases remains challenging. Challenges include the availability of innovative, user focused data ready environments that co- locates data and computational tools for managing, sharing, accessing, integrating, visualizing and analyzing diverse and complex data sets generated or collected across NIAID extramural and intramural projects from multiple sources and platforms. Critical to this data ready environment is the continuous development, enhancement and adaptation of informatic tools (machine learning algorithms, computational and software tools, and mathematical modeling methods) which will extract knowledge from these data sets and drive discovery. This project builds up NIAID’s significant investment in bioinformatics capacity and data science and most recent NIAID’s data science activities that are directed to enhancing a data ready environment and leveraging data science activities also across NIH. Examples include piloting a NIAID Data Ecosystem Prototype, enhancing the interoperability of currently supported NIAID data repositories, participating with other ICs in a trans-NIH FOA on Database Repositories that has the potential to increase interoperability across NIH data repositories and trans-NIH FOA focused on developing training modules for rigor and reproducibility of data, key to equipping basic and clinical scientists with skills for generating high quality reproducible data sets. Project Goals The project goal is to support the development, enhancement or adaptation of innovative, robust, user focused informatic tools (machine learning algorithms, computational and software tools, and mathematical modeling methods) for use in infectious, immune, and allergic diseases basic and clinical research to improve the management, visualization, integration and analysisof large, complex and diverse data sets from multiple sources, platforms and environments including publicly available data repositories. Integrative analysis of data sets (genomic and other omics data, clinical as EHR and clinical trial, surveillance, social, environmental, etc.) and performing advanced and predictive analytics are powerful approaches to begin to extract knowledge from data sets that can catalyze discovery in basic and clinical research and improve the development of therapeutic interventions. Development of user-focused tools that meet the informatic needs of the infectious, immune, and allergic diseases basic and clinical research community is of high priority. Therefore, it is expected that user focused documentation as user guides, SOPs, and training materials also be developed along with the informatics tool for broad use beyond the developer. Phase I activities: • Provide an overall product development plan for the informatic tool and identify the specific set of milestones proposed in this application related to the overall product development plan. • Provide justification for the development, adaptation or enhancement of this specific informatic tool in light of the currently available informatic tools. • Develop, significantly enhance, modify, improve, or adapt existing informatic tools for visualization and integrative analysis of multi-scale data from multiple sources and platforms including publicly available data repositories for infectious, immune and allergic diseases research. • Develop, significantly enhance, modify, improve, or adapt existing informatic methods for systems level modeling of multiple scale diverse data sets and from multiple sources. • Develop an (early) prototype for the informatics tool, perform alpha testing, and address issues from testing and evaluate with appropriate user community to solicit user feedback. Describe the potential user(s) communities and provide two relevant use cases. Phase II activities: • Further development, enhancement, adaptation, and optimization of the prototype informatic tool. • Beta test the informatic tool with the appropriate user communities and use cases, demonstrating the usability of the tool by the infectious, immune or allergic community. • Document and implement feedback, address issues and feedback, modify the informatic tool, if appropriate, and finalize the prototype for the informatics tool • Develop user focused documentation, user guides, SOPs and training materials This SBIR contract topic will not support: • Projects proposing significant data generation and analysis for validation and testing of informatics tool. • Projects developing wet-laboratory, experimental methods, research or technologies • Projects that are not focused on developing informatic tools directly applicable to infectious, immune or allergic basic and clinical research.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Maintaining the integrity of clinical and laboratory specimens from the collection (self-collected or collected by a healthcare professional) to analysis is critical. As such, the performance of any laboratory test is dependent on several pre-analytical phases, including using suitable containers and applying appropriate packaging methods to avoid any possible leakage. During specimen packaging, it is critical to account for various transit factors to ensure shipping personnel and laboratory staff are not exposed to hazardous material. Transit challenges that may result in leaky specimens may also result in rejection for testing, which would require the recollection of clinical specimens thereby delaying timely diagnosis and patient management. During emergencies, opportunities to re-collect specimens may not be available due to potential health risks, inaccessibility, or death among affected individuals. Though smaller leak-proof specimen containers utilize O-rings to prevent leakage, the COVID-19 pandemic has highlighted potential operational challenges with maintaining specimen integrity resulting from underlying environmental or human- related factors on larger specimen volumes. Some polypropylene specimen tubes (e.g. Viral Universal Transport Medium tubes used for swab collections) are not currently designed to withstand increased cabin pressure that may occur during transportation by air. As air cabin pressure changes, gases expand, including, the trapped air inside a specimen tube. The expanded air may result in the loosening of the screw cap that alleviates the internal pressure. This may result in specimen leakage. Currently, the United Nations packaging recommendations for Category A or B infectious materials suggest the use of parafilm as a layered barrier on screw caps to reduce the risk of leakage. However, for parafilm to serve as a leak-proof seal it must be stretched around the container cap in the same direction as it closes. This introduces the possibility of additional human error into the specimen processing workflow. Second, based on the principles of application torque the overtightening of a container cap may strip the threaded closure leading to unintended leaks. Similarly, loosely tightening a cap may render the same result. Currently, re-training healthcare staff on specimen handling is a traditional intervention method used to prevent packaging-related issues and improve quality assurance practices. However, constantly rotating staff (as experienced during emergencies) increases the prevalence of human error, further impacting aspects of the quality management cycle on preserving specimen integrity. As such, overcoming environmental and/or human-prone challenges are critical to facilitate timely patient care, enable a rapid public health response, prevent loss of valuable and sometimes irreplaceable specimens, and protect the handling personals from exposure to hazardous materials. Project Goals The primary goal of this proposal is to develop a technical capability that improves the integrity of specimen packaging through transit. Like a ‘tamper-proof’ cap on prescription pill bottles, the innovation must provide a physical or visual indication to the handling personnel, re-assuring that the specimen is secure from leakage. The innovation may also consider the principles of torque and develop approaches that prevent the handler from over-tightening or loosely tightening a cap for both small and large volume specimen collection containers. The innovation should not increase the physical efforts needed to close specimen containers. This innovation may offer a low-cost advanced safety capability to current specimen collection containers or provide new specimen container alternatives to promote safe packaging of various specimen types. Further, a successful proposal must take into consideration the dependability on supply chain processes to support commercialization potential. Phase I Activities and Expected Deliverables During the Phase I period, the activities can include, but are not limited to: 1. Conduct a technical assessment of currently used specimen collection containers in various transport environments to determine physical or functional properties that may result in leaks and other specimen challenges associated with containers (e.g., material of container, external pressure, external vibration, torque, temperature changes, etc.). 2. Identify functional gaps and provide specific technical improvements that may be applied to existing specimen collection containers or for the development of new specimen containers to promote safe packaging of different clinical and laboratory specimen types (e.g., cerebral spinal fluid, OP/NP wash, swabs, serum, whole blood, urine, culture) and prevent leakage and other challenges through various transport environments. 3. Develop a technical prototype for existing or new specimen collection containers that includes a safety feature to prevent leakage through various modes of transportation. Impact The Institute of Medicine report “To Err Is Human: Building a Safer Health System,” among others, highlights the impact logistical, laboratory, or medical errors may have on public health and patient care. Specimen leakages pose increased health risks to shipping and laboratory personnel, further raising public health concerns on the spread of disease. Improving safety measures on specimen collection containers may promote public health safety, ensure specimen integrity to enable accurate laboratory result reporting, and supports the timely diagnosis for critical patient management during emergencies. The impact of this innovation on public health may be evaluated both during non-emergent and emergency scenarios to measure its effectiveness in preventing disease spread and patient outcome. Commercialization Potential This innovation has the potential of commercialization as an ‘add-on’ custom packaging safety feature to existing specimen collection products or a new specimen container alternative. Like the development of the ‘tamper-proof’ safety cap on prescription pill bottles, this capability offers a mechanism to prevent specimen leakage and unintentional exposure during transit resulting from poor packaging practices or environmental factors.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Surfaces touched by patients and healthcare workers, such as bedrails, tables, medical equipment and toilet sites, are not often cleaned properly and can contribute to the spread of organisms such as Clostridioides difficile, Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus (MRSA) and other antibiotic resistant organisms. When infections repeatedly occur in healthcare settings, epidemiologists and hospital staff typically investigate and search for a potential source of the infection by sampling with swabs (for small surfaces; 4in2) and wipes or sponges (for larger surfaces; 100 – 200 in2), sending them to a laboratory to extract the organisms from the sampling device, and for detection of the organisms by culture or by a direct molecular detection assay such as polymerase chain reaction (PCR) or whole genome sequencing. Laboratory extraction methods are often labor intensive and require expensive equipment and time. With the advent of rapid detection instruments such as the MinION for metagenomic sequencing, microfluidic devices, and “Lab on a Chip” portable detection instruments, the detection of microbes in the field will soon be routinely possible. However, direct detection of target organisms in the field is challenged by low bioburden environmental samples, thus requiring the need for samples to be concentrated and tested in the laboratory using culture-dependent methods. Novel strategies are needed that can elute and concentrate samples from the environmental sampling tool for direct detection of target organisms while at the field location. All manipulations need to be completed while maintaining integrity of the sample, i.e., aseptically and without cross-contamination of samples. Responders investigating the potential release of a biothreat agent also face the same concerns and, in a bio-terrorism event, rapid detection guides decisions to protect public health and safety. This research topic aims at development of a novel device for environmental sampling of a large area and direct elution and concentration in the field for detection of target organisms and/or broader delineation of microbial populations with either molecular assays or culture assays. Project Goals The goal of this project is to develop a novel sampling device that can efficiently collect microorganisms from a solid surface and to extract and concentrate the organisms from the device and into a vial or tube in the field. The extracted sample will be used to detect organisms with both culture and culture-free assays. Since organisms in healthcare settings are typically found in low numbers, the sampling devices must be efficient at recovering vegetative cells and spores from surfaces and able to sample a large surface area (100 in2 to 200 in2 or greater) without drying out. Wipes or sponges that are pre-moistened with a wetting agent containing a surfactant or disinfectant neutralizer recover organisms better than if dry, therefore the device should be made available pre-moistened and able to maintain stability and shelf life for at least 1 year or, be available dry and able to be pre-moistened easily prior to sampling on-site. Recommended criteria for the device include: easily operated; packaged as sterile and pre-moistened OR be easily pre- moistened aseptically at the sampling site; the device can be sealed aseptically to prevent contamination; able to easily extract the collected organisms from the sampling device without need for a laboratory (i.e., at the sampling site) into a vial or tube for storage until detection is available; final extraction volume must not exceed 2-3 mL. (if the sample can be concentrated to a smaller volume without losing sensitivity, this would be optimum); effective at collecting and eluting organisms, recovering the same log10 level of organisms known to be present on a surface; and, low cost (<$15 each device). Phase I Activities and Expected Deliverables Develop prototype sampling, elution and concentration device. Test efficiency of recovery by placing known quantities of Staphylococcus aureus, and Acinetobacter baumannii cells and Clostridioides difficile spores (or Bacillus spp. Spores, if anaerobe chamber is not available) onto surfaces, then use the device to recover the cells and spores. Efficiency will be determined by a quantitative microbial culture and qPCR, then compared to number of cells and spores placed on surface Impact A successful novel sampling and extracting device will enable rapid response during a public health investigation resulting from transmission of infections due to contaminated environmental surfaces, whether from drug resistant bacteria in a healthcare facility or as the result of an intentional release of a bio-threat agent. This device, coupled with a field deployable rapid detection device, will eliminate the need to ship samples to a laboratory for analysis, thereby allowing for detection of target organisms in hours rather than days. Reduced sample analysis time will enable faster public health decisions, saving lives. Commercialization Potential The commercialization potential is high. A successful device may be used for detection of multiple organisms in a variety of field settings, whether in a healthcare setting, a biothreat public health scenario, or a pharmaceutical manufacturing facility requiring environmental monitoring. A successful device could be used for traditional culture detection, as well as for next generation molecular detection. The device would save money and time for rapid detection of organisms by enabling field detection or readying and optimizing samples for laboratory detection methods.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1-2 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Antimicrobial susceptibility testing relies on standardized microbiological techniques assessing growth of pure cultures on either solid or liquid media with various concentrations of antibiotics. The inhibition of growth is predictive of treatment success and reported by the clinical laboratory to guide therapy. Although this has been the standard for decades, such testing often fails to estimate treatment outcome when an infection is caused by multiple strains or species of bacteria or yeast (i.e., mixed infection), especially if the infection involves a community of microorganisms growing on a surface (i.e., biofilm). Examples of such infections include lung infections in patients with cystic fibrosis, mixed wound or bone infections, and mixed infections involving implanted prosthetic material. In such infections traditional antibiotic susceptibility testing fails to account for the impact of an antibiotic on overall microbial community. Microbial communities can involve cooperative (or antagonistic) communication between members, recruitment of secondary pathogens, and biofilm matrix effects – all of which can impact inherent drug resistance that is not reflected in traditional susceptibility testing methods and results. Project Goals The specific goals of this project are to develop a standardized diagnostic platform for use in a clinical laboratory for taking primary clinical specimens (e.g., sputum, stool) and determining the microbial community-level susceptibility/antibiogram of an infection. The second goal is to construct laboratory-developed test methodologies/models or significantly adapt commercial platforms for use in parallel and in comparative assessments with standard clinical isolate-level antibiotic susceptibility testing (AST) analysis. All should have the potential to be validated for use in the clinical setting for treatment decisions. Phase I Activities and Expected Deliverables It is anticipated that such development will require dedicated and highly refined approaches specific to primary specimen and pathogen combinations. The technical merit or feasibility of the proposed methodology should be assessed through initial bench-top (in vitro) studies with focus on one such specimen-pathogen combination and associated/community and matrix attributes. These studies should be designed to provide a proof-of-concept, and expected deliverables would include a determination of the efficacy of the approach by monitoring community dynamics in the process as well as testing comparative panels of such pathogens in parallel by standard reference methodologies. a) Produce data useful for informing clinical treatment decisions b) Document the in vitro kinetics being used as a marker of susceptibility c) Define medium/matrix composition d) Define potential host factors that affect microbial growth or antibiotic activity in vivo e) Define metabolites of microbial communities that affect microbial growth or antibiotic activity in vivo f) Establish standard methodologies to arrive at a quantitative measurement of minimum inhibitory concentration g) Establish back-end detection/verification of target pathogen activity h) Incorporate appropriate methods for specimen processing. Impact This project has the potential to impact antibiotic stewardship and therapy practice using available primary specimens to produce a rapid, more clinically relevant estimation of potential drug efficacy including reduction in potential resistance development. Generation of such a system or model may also identify and highlight the relative disparities that exist with reference-based testing and help redefine clinical practice. The broad use of such a system also may have profound impact on directing future drug-specific design by incorporating such considerations (and associated underlying mechanisms thereof) during the drug development phase. Commercialization Potential The commercialization potential of such technology is high with a potential for wide-scale use including patenting of processes, universal enrichment/growth media, matrix inhibitors and/or community parameterization. If the design involves laboratory-developed test protocols, kitting of reagents, developed controls, and/or mock communities, these may also provide additional avenues for commercialization. Development of such tools may be employed as front-end, value-added adaptation for commercial platforms. Regardless, this SBIR has potential to impact other settings involving intellectual property rights extended to preserving microbial community strata formulations for modeling biological interactions.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Although just a handful of deaths occur each year in North America and Europe, the barriers to access life-saving rabies vaccines are evident by the estimated 59,000 human deaths in the developing world every year. Exposures to rabid animals are frequent worldwide, but cost, remote locations, lack of cold chain, and other cultural and social factors remain obstacles to vaccination in most high-risk rabies regions. With proper post-exposure prophylaxis (PEP) almost all rabies deaths are preventable. The majority of these deaths occur in Africa and Asia where canine rabies remains enzootic and availability of rabies biologics for PEP is limited. New, cost-effective strategies are required to overcome the current challenges in rabies prevention. Currently, human rabies vaccine is delivered in a 1 ml intramuscular (IM) dose. This necessitates using a needle by a trained professional, bulky packaging, and maintenance of cold-chain. We propose a SBIR topic to deliver human rabies vaccine via the intradermal (ID) route using dissolvable microneedles. Microneedles can be administered directly by the patient eliminating the need for trained medical personnel, needles and sharps disposal, as well as flat packaging. Numerous studies have indicated that intradermal delivery of rabies vaccine is dose sparing and more effective than intramuscular delivery. In addition, the current ACIP-recommended regimen for rabies pre- and post-exposure prophylaxis is complex, requiring multiple boosters over a one-month period. Ensuring multiple boosters is especially difficult to achieve in remote settings where human rabies exposures often occur. Other regimens exist for both IM and ID, further confounding the situation, especially in developing countries where governments are hesitant to approve new vaccines. By simplifying the regimen using a microneedle patch, vaccine delivery will be dose sparing and save lives by reaching more people in need of rabies PEP. Project Goals The goal of this project is to develop dissolvable microneedles to deliver human rabies vaccine that can induce protective immunity. Phase I Activities and Expected Deliverables 1. Formulation of rabies vaccine suitable for dissolvable microneedle delivery 2. Development of a dissolvable microneedle device containing rabies virus vaccine i. Selection of microneedle material ii. Optimization of micromolding iii. In vitro analysis of antigen dose present in the final device Impact An intradermal rabies immunization by dissolvable microneedles will not only simplify mass pre-exposure prophylaxis (pediatric vaccination in remote areas such as the Amazon jungle or pre-exposure vaccination of soldiers deployed to rabies endemic countries) but will also potentially simplify regimens and reduce time for post-exposure vaccine administration. Adaptation of microneedle technology to rabies vaccine will simplify the administration of human rabies vaccine currently provided mostly via intramuscular administration and will exclude necessity of trained personnel to perform vaccination. A microneedle patch will eliminate injuries associated with vaccination using sharp needles and will eliminate re-use of needles and potential for spread of blood-borne pathogens. Rabies vaccine dissolvable microneedle administration with a continuous release vaccine formulation, will represent a paradigm shift in rabies pre- and post-exposure prophylaxis, ultimately allowing for one microneedle administration to stimulate adequate immune response in recipients. Commercialization Potential Intradermal delivery Human Rabies Vaccine using dissolvable microneedles will generates a novel delivery method for human rabies vaccine allowing for results analysis and to make recommendations for further work toward licensing, IND submission, and manufacturing.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Hand hygiene is one of the simplest, most effective interventions to limit the spread of communicable disease such as gastrointestinal or respiratory illness. As part of the response to the COVID-19 pandemic, a range of non-pharmaceutical interventions are being promoted as key prevention strategies. This includes frequent handwashing with soap and water and frequent use of hand sanitizers. Engagement in frequent handwashing is being promoted among multiple populations as part of the coronavirus response. Polling conducted over the course of the coronavirus response has indicated that the general public is engaging in handwashing behavior and perceive handwashing to be an effective strategy for coronavirus prevention. A range of factors can influence whether an individual engages in handwashing. This can include knowledge of the benefits, perceptions of risk for illness, access to supplies or infrastructure to engage in handwashing, norms, and hygiene related habits. Interventions to promote community handwashing behavior have targeted these drivers through social marketing or health communication campaigns, or educational interventions. Several of these interventions have been focused on promoting handwashing behavior among youth and children. Children and youth have been prioritized for interventions aimed at promoting handwashing behavior because children often engage in inadequate hygiene related behaviors and are often in congregate settings where there is potential to spread infection easily. Additionally, if children are educated early about the importance of handwashing, and this behavior becomes a life-long habit, it could result in future health benefits. To date, however, few interventions focused on promoting handwashing behavior have utilized “gamification” as an approach. Gamification has been used broadly in public health to promote a range of health promotion behaviors in both adults and children. Games can make learning about a health behavior more fun, can keep individuals more engaged with a health promoting behavior, and can allow for behavioral monitoring and feedback that can further reinforce the behavior into routine activities. Games have been used, for example, to promote exercise behavior among children. Games work by going beyond increasing knowledge, and incorporate strategies to incentivize health promotion behavior, provide opportunities for feedback, can allow for monitoring, and can utilize video and animation to provide real-time feedback on behaviors. Developing an innovative, interactive, phone-based game to promote handwashing behavior could be used as an innovative strategy to promote handwashing behavior among children and to help sustain frequent handwashing behavior over the lifespan. Project Goals The purpose of this project is to develop an interactive, phone-based game to promote handwashing behavior among children. Phase I Activities and Expected Deliverables It is expected that the development of a complete, functional, prototype of the video game would be accomplished during this project period. This would include the game story line, the graphics, the scientific content, and all other functionalities to make the game compelling and fun for the user. As part of the development of the functional prototype, aspects of human- centered design strategies will be used to assess and improve the usability of the game. Impact As handwashing is one of the key non-pharmaceutical interventions being promoted during the coronavirus response, it is critical to identify innovative strategies to promote this behavior and to encourage sustained engagement in these behaviors. The impact of this game could result in increases in handwashing behavior which could result in decreases in infection of not just respiratory illness associated with coronavirus, but also for a wider range of other communicable diseases. Commercialization Potential Educational games for children are widely promoted through phone-based app stores and educational games for children are also available through a range of toy companies. As more and more children are using tablets as part of their school-work activities, this educational game could be marketed toward school districts to be included on these tablets and incorporate the game into routine activities children complete on their school tablets. The game could also be marketed toward a range of parent groups, such as PTAs, as an educational tool parents can utilize within the home to promote handwashing behavior among children. As many of the games developed to promote healthy behaviors among children allow for real-time monitoring by an administrator, this functionality would be of interest to parents and educators who can monitor child engagement with the materials as well as monitor their completed handwashing behavior. The game could also be marketed to pediatrician offices which could load it on waiting room tablets allowing children to utilize the game to learn about proper handwashing behavior, and could give pediatricians real-time feedback to follow-up on information learned from the game to provide directed health education to both parents and children about handwashing.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Molecular and serological surveillance for infectious diseases often involves high sample throughput and reproducibility. High volume sample processing is also very frequently associated with a higher end user risk of exposure and human error. Automated solutions significantly reduce exposure and human error, while increasing sample throughput and performance. Fully automated, walk-away (load-and-go) platforms are usually designed to further limit the end user exposure by limiting the hands-on requirements for the initial setup. End user errors can still happen at the load stage when working with highly, or even moderately, integrated solutions due to densely labware-populated setups. Developing an agnostic, vendor cross- over, computer vision approach that could validate the initial labware, reagents and sample setup during runtime, is likely to eliminate human errors in reference and clinical laboratories. Project Goals The specific goals of this project include the following: 1. Develop an agnostic deck verification tool for use with robotic platforms by different vendors 2. Develop a cross-over solution for validation of integrated devices in complex automated platforms 3. The solution should be sufficiently portable to be included in a single installer package 4. The solution should be easily scalable to add multiple high definition cameras 5. The solution should have recording capabilities for spinning/moving devices 6. The recording capabilities should be able to record during runtime to monitor run progress 7. The solution should be easily trainable to accommodate newly developed methods 8. The solution should log records per run/process 9. The solution should provide optical volume verification 10. User facial recognition is highly desirable but not indispensable 11. The solution should be Windows compatible (7 or higher) Phase I Activities and Expected Deliverables 1. Hardware specifications (cameras and accessory drives, if applicable) 2. Schematic representation of the workflow for deck and integrated devices setup validation 3. Specifications for training set for new workflows 4. Schematic diagram of the training module and learning approach used by the solution to incorporate new workflows 5. Minimal requirements for device controller Impact This solution is expected to significantly reduce errors during setup/runtime by de facto preventing run failures and hardware crashes. As a result, minimal disruption in production environments for molecular and serological testing would be experienced. The deck verification piece expected for this solution should be easily implemented in small automated units, allowing small labs to validate the initial setup and preventing major runtime failures. Commercialization Potential This solution will likely have a large spectrum of users including reference and clinical laboratories as well as core facilities.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Timely identification of incident cases is critical for the detection of hepatitis C virus (HCV) transmission networks. In addition, detection of serological markers for viral hepatitis aids to establish high risk individuals who are often positive for multiple markers. Identification of high-risk individuals and their corresponding contacts improves outbreak investigations, molecular surveillance and patient’s linkage to care. However, identification of all necessary serological markers and simultaneous genetic characterization of hepatotropic viruses requires multiple diagnostic tools. Implementation of all these diagnostic tools is time consuming, cumbersome and requires highly trained laboratory personnel. Thus, development of a "universal" platform for both genetic characterization and serological marker detection for viral hepatitis will simplify and improve identification of incident and high-risk cases. CITE-SEQ coupled to amplicon deep sequencing is a viable alternative for simultaneous identification of serological markers and viral characterization. Advanced molecular characterization of infectious agents often relies on next-generation sequencing (NGS) approaches to accurately obtain DNA fingerprints required to establish genetic relatedness among viral strains. Generation of DNA libraries suitable for NGS involves several lengthy, cumbersome and error-prone lab processes. Often, standard operating procedures (SOPs) are devised for manual library preps, leading to small sample throughput, cross contamination and delay in reporting. Automated solutions for DNA library preps are commercially available. However, such automated approaches are expensive and require expertise to implement custom workflows. Microfluidic chips are an alternative to complex automated laboratory methods without the initial investment required for conventional automated solutions. Microfluidic chips are also small and user friendly allowing easy implementation and requiring minimal training. There are no commercially available microfluidic chips capable of performing all laboratory steps required to generate DNA libraries suitable for Illumina sequencers, including CITE-SEQ for detection of serological markers. This project aims to develop a microfluidic chip capable of extracting nucleic acids and generating Illumina DNA libraries from clinical samples, suitable for advanced genetic and serological characterization, relying on a CITE-Amplicon SEQ approach for detection of hepatitis C virus infection. Project Goals The specific goals of this project include the following: 1. Develop a CITE-SEQ approach for the identification of serological HCV markers (IgM, IgG and core antigen) 2. Develop a microfluidic chip for genetic characterization of HCV using deep amplicon sequencing 3. Develop a microfluidic chip suitable for the HCV CITE-SEQ approach Phase I Activities and Expected Deliverables 1. An engineering model for the corresponding microfluidic chip(s) is required 2. Draft protocols for the CITE-SEQ approach suitable for microfluidics is required 3. Draft protocol for HCV deep sequencing genetic characterization for microfluidics is required Impact Availability of commercial microfluidic solutions for HCV genetic and serological characterization is likely to shorten reporting time and increase sample processing capacity. Additionally, microfluidic approaches significantly reduce risk of exposure and end user error and require minimal training for the operator. As a result, outbreak investigations and molecular surveillance should considerably improve. Commercialization Potential Microfluidic approaches for HCV characterization will aid state and reference laboratories conducting outbreak investigations, contributing to a better understanding of transmission networks.