U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS), THE NATIONAL INSTITUTES OF HEALTH (NIH) AND THE CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC) SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM

Fast-Track proposals will not be accepted. Direct-to-Phase II proposals will not be accepted. Number of anticipated awards: 1-3 Budget (total costs, per award): Phase I: $225,000 for 9 months; Phase II: $1,500,000 for 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning. Summary There has been an increased focus in the life sciences industry on the use of more complex 3D cellular and tissue models to help provide physiologically relevant platforms to be used in in-vitro drug testing. Nearly all high throughput in-vitro drug testing experiments utilize multi-well microtiter plates to act as a vessel where individual reactions between the biological model and the sample under test occur. The use of these more complex 3D cellular models has driven the use of more complex microtiter plates, namely cell culture insert-plates (CCIP) with permeable membranes. There are several factors that make these CCIPs suitable for use in the creation of complex cellular models, including the ability to co-culture cells with or without cell-to-cell contact, allowing for either apical or basolateral feeding to promote cellular metabolic activities, and provide an anchorage point which is typically required for most mammalian cells to remain viable. All these factors are needed to support cell proliferation and function, as well as formation of complex tissues, making the choice of membrane available for use in CCIPs a critical one towards the production of a physiologically relevant tissue model. The current membranes used in CCIPs are made using a variety of materials with options in pore size, coatings and surface treatments that can be selected depending upon the type of cell model to be produced. Most of these models incorporate the use of biomaterials to be used as scaffolds for the cells to be functional and create a new tissue. Many of the biomaterials used are naturally occurring and readily available such as collagen, alginate, chitosan and others. In many cases, these biomaterials are present in the extracellular matrix (ECM) produced by cells, so their use helps to provide a natural environment for the cells until they are healthy and producing ECM of their own. Aside from the biocompatibility of these scaffolding biomaterials, another factor is controlled biodegradability. This rate of biodegradation is a key factor for certain tissue model types where an initial scaffold is necessary to promote structural integrity, cellular anchorage, viability and proliferation but where over time the desire is for the scaffold to degrade and be replaced by naturally produced ECM and promote cell to cell interaction in co-culture models. The need for biodegradation of certain tissue models presents an inherent challenge to commercially available CCIPs that for all their advantages have one key limitation: there are none available on the market that have a biodegradable membrane. To overcome this limitation researchers at NIH have developed a technique that utilizes a biocompatible adhesive to attach an electrospun biodegradable poly(lactic-co-glycolic acid) (PLGA) membrane to the bottom of a cell culture insert. The production of these parts has become a standard practice to develop several tissue types, but it has limitations in that the process is laborious, time consuming and not scalable beyond a 24-well plate density. Topic Goals The goal of this project is to identify potential new biodegradable membranes that can be used to create CCIPs. Equally important is to identify manufacturing techniques that allow for the attachment of these custom membranes to CCIPs in a reproducible and cost-effective fashion without toxic adhesives or other contaminants in scalable well density formats (6, 12, 24, 96+). The optimal outcome would be a commercially available off-the-shelf 96 well CCIP that utilizes a biodegradable membrane. The availability of such a plate would increase the capabilities of groups conducting research that use CCIPs by potentially increasing the overall quantity, quality and viability of complex cellular constructs. Increasing the well density up to 96 wells would also push closer to true high throughput screening for groups using advanced cell models for in-vitro drug discovery. Phase I Activities and Expected Deliverables Phase I proposals must specify clear, appropriate, measurable goals (milestones) to be achieved. Phase I activities and deliverables may include the following: • Develop a prototype CCIP that has the following features: o Adheres as closely as possible to current ANSI/SLAS Microplate Standards  ANSI/SLAS 1-2004 (R2012) Microplates – Footprint Dimensions (formerly ANSI/SBS 1-2004)  ANSI/SLAS 2-2004 (R2012) Microplates – Height Dimensions (formerly ANSI/SBS 2-2004)  ANSI/SLAS 3-2004 (R2012) Microplates – Bottom Outside Flange Dimensions (formerly ANSI/SBS 3-2004)  ANSI/SLAS 4-2004 (R2012) Microplates – Well Positions (formerly ANSI/SBS 4-2004) o Utilizes membranes that have the following properties:  Biocompatibility with tissue culture environments  Biodegradability within a time period between 2-6 weeks  Suitable for cellular health and function for long term experiments (1+ month)  Have a thickness of <10 μm  Have a pore size <1 μm  Ability to increase cell attachment without the need for additional coatings o Incorporates a ridge or a cap on the underside of the insert such that it extends below the bottom of the membrane and ideally matches the inner diameter of the well wall. This in effect creates an additional well on the underside of the insert that provides greater structural integrity for three-dimensional tissues added to that portion of the insert.  This ridge or cap should extend no greater than 1mm from the bottom of the membrane layer. Page 68  This ridge or cap should match the inner diameter of the well wall as closely as possible to maximize the membrane surface area available for cell placement on the underside of the plate. o Utilizes manufacturing techniques and materials that do not introduce artifacts when undergoing standard high throughput screening measurements such as fluorescent microscopy. • Has at a minimum a 6 well density as a proof of concept. • Identify a tissue model to use as a standard to validate the functionality of the produced part. o This model should incorporate standard fluorescent labels such as DAPI, GFP, mCherry or others to determine if any of the materials used introduce a measurement artifact. o We have encountered certain adhesives that are biocompatible, although when introduced to a measurement system such as fluorescent microscopy the adhesive itself auto-fluoresces at the same emission wavelength as a cellular label such as GFP. This introduces a high degree of background signal that makes quantification of cellular features difficult if not impossible. This should be taken into consideration with regards to the identification of a tissue model to act as a means of validation. • Cost estimates to manufacture a device 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 plate that meets the Phase I specifications with a 96 well density as a minimum. o This requires all of the necessary tooling and infrastructure necessary to manufacture the plate. • Provide a test plan to evaluate the Phase I validated tissue model in the 96 well density plate. o Provide NCATS with all data from each executed test to properly evaluate the model. • Develop a robust manufacturing plan for the plate, using off the shelf OEM components where possible to minimize expense. • 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: 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 Cancer immunotherapy is a therapeutic approach that directs a patient’s own immune system to eradicate their tumor cells. Past and current NCI investments in adoptive T cells, CAR-T cells, NK cells, and other cell-based cancer immunotherapies have resulted in the translation of many lab-specific approaches into early clinical trials. Importantly, reproducible and robust production methods are critical to ensure that advances in basic research result in successful translation of cell-based therapies. Clinical development of such therapies requires multi-center, randomized clinical trials that must be supported with high quality, consistent, and reproducible cell-based products. Patient-specific autologous or allogeneic lots must be adequately characterized to ensure that similar products are given to all patients. For non-patient specific cell-based therapies, large-scale and reproducible manufacturing technologies are needed to produce high-quality products with uniform identity and potency. Current limitations in cell manufacturing can increase both the cost and time required to bring a therapy to market and can result in missed opportunities to evaluate promising new cell-based therapies. Product failures can be attributed to poor product design and characterization, as well as inadequate scale-up and manufacturing processes; therefore, further investments are needed to develop state-of-the art manufacturing technologies and processes to advance cell-based cancer immunotherapies at the commercial-scale. Effective use of science and engineering principles during the early development phase of a cell-based therapy can improve both the efficiency and reliability of the manufacturing process and the quality of the final product. Moreover, it is anticipated that standardized approaches to manufacturing, process analytics, release testing, and product characterization will result in more rapid, cost-effective product development and a higher level of regulatory success. Achieving the desired level of standardization for current and future cell-based cancer immunotherapy products will require both pragmatic research to establish consistent manufacturing processes, as well as the development of new innovations and technologies. Project Goals The overall goal of this contract topic is to facilitate the development of innovative methods and technologies capable of improving and modernizing product manufacturing processes for cell-based cancer immunotherapies. This includes the use of autologous, allogeneic, or pluripotent cells. Offerors submitting proposals under this solicitation are strongly encouraged to establish collaborative relationships with clinical product development companies focused on the development of specific cell-based products. In all cases, it is expected that offerors will demonstrate the utility of their innovation(s) in the context of at least one cell-based product, which is representative of a particular class of cell-based cancer immunotherapies. Examples of manufacturing innovations/advancements might include, but are not limited to: • Automated closed systems for cell separation, genetic modification, differentiation, and/or expansion; • Low-cost, high-efficiency methods for genetic modification to support cell engineering; • Standardized assays and/or surrogates to evaluate cell attributes that ensure lot-to-lot consistency in terms of phenotype, functionality, quality, and potency; • Real-time, non-destructive test methods with sensors and/or imaging technologies to assess critical quality attributes (e.g., contamination); and/or • Process analytics capable of feedback control in response to real-time changes in critical attributes of the cell product. It is expected that Phase I proposals will focus on novel inventions related to innovations or improvements in cell manufacturing processes, including in-line or on-line (i.e., continuous) process analytics to support product consistency and safety, as well as GMP production of a particular class of cell therapies. Phase II proposals should demonstrate the scalability and validation of the production platform or process improvements developed in Phase I. Engineering and process solutions must be capable of regulatory compliance with FDA Guidelines. The long-term goal of this initiative is to provide the tools necessary for efficient, high-quality manufacturing of novel products in the emerging field of cell-based cancer immunotherapies. Phase I Activities and Deliverables • Develop a device/technology/process to support commercially-relevant manufacturing advancements or improvements for the production of a specific class of cell-based cancer immunotherapies (e.g., CAR-T cells, adoptive T-cells, NK cells) • Establish defined specifications, assays and/or metrics to interpret scientific data supporting the feasibility of the device/technology/process, with respect to reproducible product manufacturing, process analytics, and/or process controls Page 71 • Demonstrate the suitability of the device/technology/process to improve relevant manufacturing metrics (e.g., product uniformity, quality, efficiency, cost-effectiveness) for at least one cell-based product, which is representative of a particular class of cell-based cancer immunotherapies • Provide proof of collaboration or partnership with an entity that is developing a representative cell-based therapeutic agent OR otherwise demonstrate access to a representative cell-based therapeutic agent through other means (e.g., internal drug development program), that can be used for validation of the device/technology/process • Demonstrate pilot-scale beta-testing of the production process to demonstrate reproducible performance within appropriate specifications for identity, purity, potency, and/or other relevant metric for the chosen cell-based immunotherapy product Phase II Activities and Deliverables • Generate scientific data demonstrating the proposed scalability (e.g. scale-up, scale-out, point-of-use) of the production platform, process analytics and/or process controls • Develop an at-scale prototype of the device/technology/process with detailed specifications for hardware/software that supports the production platform or process analytics/process controls improvements • Validate the production innovation and/or process improvements, including standards for calibrating any novel process analytics or process controls that monitor production

Fast track proposals will be accepted. Direct-to-Phase II proposals will not be accepted. Number of anticipated awards: 3-4 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 Age is a well-recognized risk factor for cancer development, and older patients pose a growing healthcare challenge since they are prone to developing more aggressive and therapy-resistant tumors. A key biological contributor to aging and age-related diseases is cellular senescence - a complex state characterized by not only its role in wound healing and tumor suppressive function via stress-induced replicative arrest, but also in driving neoplastic transformation and tumor aggressiveness downstream of its anti-apoptotic effect and expression/secretion of wide-ranging pro-tumorigenic cytokines, growth factors, and matrix-degrading enzymes. Aging tissues accumulate senescent cells, and the in vivo selective elimination of spontaneously emerging, age-associated senescent cells has been documented to delay tumor formation and deterioration of cardiac, renal, and adipose tissue function. Furthermore, senescence is induced by a range of cancer therapies, including radiation, chemotherapy, and several targeted therapies. In certain cancer types, this therapy-induced senescence (TIS) promotes invasive and metastatic phenotypes. Eliminating TIS cells has been reported to reduce many side effects of cancer drugs, including bone marrow suppression, cardiac dysfunction, fatigue, and also to reduce cancer recurrence. For research purposes, several genetically encoded methods to eliminate senescent cells have been developed and have proved critical in understanding the biology of senescence. More recently, attention has turned to the development of pharmacologic agents that selectively kill senescent cells (i.e., senolytic agents). A variety of agents have been reported to have senolytic activity and have demonstrated promising results in animal models. Project Goals The purpose of this contract topic is to support the pre-clinical development of senolytic agents for use in neoadjuvant and/or adjuvant/combination cancer therapy. Projects supported under this contract topic should further the pre-clinical development of senolytic agent(s). To apply for this topic, offerors should: • Identify a molecular target(s) and provide a clear rationale for how the proposed senolytic agent, or combination, will induce selective elimination of either spontaneously emerging or therapy-induced senescent cells, which are induced by relevant anti-cancer treatments (e.g., chemotherapy, radiation, etc.). Offerors should use clearly defined parameters and accepted markers of senescence to define the population of senescent cells being targeted by their agent. • Provide preliminary data or cite literature to support the proposed mechanism of action. • Demonstrate ownership of, or license for, at least one lead agent (e.g., compound or antibody) with preliminary in vitro data demonstrating senolytic activity. • Select and provide clear rationale for a specific indication that the senolytic agent will address (cancer type and context of treatment induced senescence). • Identify and provide justification for the choice of human cancer-relevant in vitro assays and in vivo models. Phase I projects should focus on the optimization of the senolytic agent, or combinations, and demonstrate proof-of-concept by showing selective elimination of senescent cells and benefits in terms of efficacy and/or reduction of side effects when combined with appropriate treatments (e.g., chemotherapy or radiotherapy) in human cancer-relevant animal models. Offerors should provide a justification and rationale for their choice of animal model for the proof-of-concept studies. The scope of work proposed may include structure activity relationships (SAR); medicinal chemistry for small molecules; antibody and protein engineering for biologics; formulation; and in vivo efficacy testing. Phase II projects should focus on IND-enabling pre-clinical studies. The scope of work may include further work on structure activity relationships (SAR); formulation; in vivo efficacy testing; or pharmacokinetic, pharmacodynamic, and toxicological studies. Phase I Activities and Deliverables • Demonstrate in vitro efficacy for the agent(s) in human cancer-appropriate models. • Conduct structure-activity relationship (SAR) studies, medicinal chemistry, and/or lead biologic optimization (as appropriate). • Optimize formulation of senolytic agent(s) (as appropriate). • Perform animal efficacy studies in an appropriate, and well justified animal model, for cancer therapy-induced senescence, or aged mouse models that have accumulated senescent cells through aging, and conduct experiments to determine whether senolytic agent(s) confer benefits with respect to side effects and/or cancer therapy efficacy. Phase II Activities and Deliverables • Conduct structure-activity relationship (SAR) studies, medicinal chemistry, and/or lead biologic optimization (as appropriate). • Perform animal toxicology and/or pharmacology studies as appropriate for the agent(s) selected for development. • Expand upon initial animal efficacy studies in an appropriate model for cancer therapy-induced senescence and conduct experiments to determine whether senolytic agent(s) confer benefits with respect to side effects and/or cancer therapy efficacy. • Other research and development activities necessary to submit an IND application.

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 Systemic administration of therapeutic agents for cancer treatment is common practice; however, drug exposure in normal tissues often leads to adverse toxicities thereby limiting the administered dose and treatment efficacy. The use of heat or ultrasound to achieve local activation or release of therapeutic agents has been an active area of research for many years, and approaches involving thermal release of drugs from liposomes has been used in clinical practice. In addition to these approaches, toxicity in off-target tissues might also be avoided if the agent remained encapsulated or inactive until exposed to external radiation within a well-defined target volume. Using external radiation for local drug activation or release may provide unique opportunities and benefits compared to previous strategies. For example, X-rays could be used with nanoscintillators to generate visible photons in vivo, which could then activate photosensitizers for photodynamic therapy (PDT). Such a strategy could extend the range of PDT to deep-seated tumors that are currently intractable with existing PDT. Using external radiation to remotely trigger therapeutic agents could also be used to carefully control the timing of drug release to achieve the appropriate therapeutic drug concentrations within a specific target volume at the right time. Successful treatment using this approach would require delivering safe doses of external radiation to quantitatively control the localized activation or release of the therapeutic agent. Toward achieving these goals, this solicitation is intended to develop combinatory treatment modalities utilizing external ionizing radiation to locally activate or release systemically or intratumorally delivered therapeutics, including high-atomic number elements that emit auger electrons. Remote release triggering mechanisms could include X rays or particle (e.g. proton) beams currently used for radiation therapy of cancer. The goal of this topic is to leverage existing radiation therapy infrastructure that is readily available in many clinical centers. In the future, such therapeutic approaches could be implemented as an addition to the current standard of care involving radiation therapy to achieve improved clinical outcomes. Project Goals This contract solicitation seeks to stimulate research, development, and commercialization of innovative techniques that could synergistically improve the effectiveness of radiation therapy and therapeutic agents or auger emitters to reduce toxicity to normal tissues. Proposals addressing the following technology areas are encouraged: • New treatment strategies • Design, synthesis, and evaluation of innovative therapeutic agents • Development of new drug formulations (e.g., nanoformulations) The short-term goal of the project is to perform feasibility studies for the development and use of combinatory treatment modalities for the treatment of cancer. The long-term goal of the project is to enable small businesses to advance fully developed combinatory treatment modalities to the clinic and eventually to the market. To apply for this topic, offerors should: • Identify or develop an appropriate therapeutic agent that could be activated in vivo by radiation • Develop a drug formulation that could be triggered to release a therapeutic agent by radiation in vivo • Define the mechanism(s) of action for the proposed therapeutic agent • Identify the patient population(s) likely to be impacted by this technology While modification of the radiation delivery device for eventual use with the therapeutic agent in the clinic is acceptable, it must not be the focus of the proposal. Please note that the following are NOT considered appropriate for development under this solicitation: • Development of agents that act as radiation sensitizers • New instrumentation for triggering the release of the therapeutic agent • Combinatory treatment strategies that do not involve the delivery of external radiation Phase I Activities and Deliverables • Demonstrate that the expected release/activation action with a proper amplitude can be induced in vitro and in vivo by safe doses of radiation • Demonstrate (if appropriate) tumor-specific targeting and localization of the therapeutic agent and activation of the therapeutic agent only after exposure to radiation • Carry out a pilot animal pharmacokinetic/pharmacodynamic studies utilizing an appropriate animal model • Significantly characterize the chemistry and purity of the therapeutic agent and chemistry of the reaction Phase II Activities and Deliverables • Demonstrate an improved therapeutic efficacy and improved therapeutic index, assessment of toxicity to normal tissues in vivo • Development of the manufacturing and scale-up scheme • IND-enabling studies carried out in a suitable pre-clinical environment for PK/PD, preclinical efficacy, and safety assessment When appropriate, demonstration of similar or higher efficacy of the proposed strategy when compared to current therapies.

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 Treatment planning for radiation therapy is becoming increasingly complex with the advent of image-guided radiation therapy (IGRT) and charged particle therapy (CPT). Fundamental to treatment planning is dose. The goal of any treatment plan is optimization of dose distribution. In the vast majority of planning this is the physical dose – energy delivery in Joules per kilogram of body mass, or units of Gray (Gy). Simply stated, we engage in creating a complex plan using advanced technology so that we can deliver dose to areas of tumor and avoid delivering dose to areas of normal tissue. To this end, a large portion of the treatment team’s time and effort is allocated to reproducibly positioning, locating, and contouring key tumor and normal tissue structures, to optimize physical dose distribution. Even upon successful efforts to optimize physical dose delivery, tumor control and toxicity vary. Variation in biologic dose (biologic response to a given physical dose) may make even perfect physical dose delivery systems unable to properly deliver expected therapeutic dose to tumor in the patient. Biologic response and therefore optimal dose prescription may vary in the same patient across time and across location even at the same time. Tools are needed to measure biologic response to delivered physical dose in host systems, ideally that are volumetric – hence our focus on miniature and integrated sensors. Contemporary engineering and device miniaturization (including nanotechnology) offer many compelling approaches that could enable a new generation of measurement tools to measure biological response directly and/or indirectly. Examples include: nanoparticle systems that self-assemble upon interaction with endogenous biomolecules, nanoparticles that target and allow direct imaging assessment of the tumor and its microenvironment, sensor systems that respond to local cues of biological damage and are excreted for ex vivo assessment, among many others. Standard dosimeters, even implantable dosimeters, cannot address biology in this context. Implantable dosimeters are much larger in scale. For this reason, integrated sensor solutions for measurement of biological response will be the focus of this contract solicitation. These systems can be used alone or in combination and can be utilized both in the body (in vivo) to allow volumetric assessment and extracorporeally (in vitro) to allow rapid, lab-test style measurements. Project Goals The purpose of this solicitation is to develop in vivo or in vitro sensor tools to measure biologic response to radiation, specifically, to help to redefine dose from solely the traditional physical dose to include the additional dimension of biological response. The resulting new, multidimensional definition of dose may allow more refined treatment planning and clinical trial development, avoidance of toxicity from overdosing, avoidance of tumor escape from biological under-dosing, and hopefully allow truly personalized medicine to be performed in the combined modality space where chemotherapy, surgery, immunotherapy, and radiation are used in combination to treat patients. The overarching goal of this solicitation is to produce a toolbox of sensor tools that will be used to improve the outcome for patients with cancer. By developing biologic response measurement tools, it will ultimately be possible to design and interpret biologically optimized treatment. These newly developed sensors are to allow study of the biological effects of radiation and combination therapies. These sensors should facilitate the development and study of precision radiation oncology. The sensors can be used alone, in combination, in the body, or outside of the body. A sensor would report temporal and spatial information about, for example, one biologic pathway, molecule’s activity, or a complex’s formation/function. Ideally, these sensors should be able to generate response via CT or MRI to allow non-invasive dynamic and real-time data collection. As such, the development and evaluation of sensor systems that can measure in a validated fashion biologic response to physical dose from radiation therapy will be preferred. Nanotechnology-based sensors are encouraged. Overall scope: Such systems are diverse (e.g. surface chemistries, material properties) as noted in the above examples, and thus this request does not limit the scope of the technical methodologies allowed. The work requested in this announcement includes any type of systems (including but not limited to nanotechnology) that can convey biological information and that can be correlated with radiation therapy physical dose delivery in treated and untreated human tissue. Thus, sensors should measure biological status in collected liquid or solid samples and/or should evaluate biologic signals in situ that are correlated with tumor control, tumor survival, and toxicity. Mechanisms that involve conjugation and / or chemistry to monitor property changes to nanoparticles (e.g., self-assembly, emission changes, reporter release, etc.) are other examples of methods that fall into the scope of this solicitation. Furthermore, it is desired that sensors be able to be used serially and in combinations in patients before, during, and after treatment. Such biologic response sensors should function with combination therapy (radiation with chemotherapy or other biologic therapy). Sensors that can be imaged via 4D techniques already utilized in radiation therapy are also of particular interest so that spatial biological data can be collected over time to measure spatial changes correlated to treatment. As noted above, mixtures of these agents that can be differentiated via signal characteristics would be of a high priority as well because it may be true that a combination of markers offers unique biologic insights such as toxicity fingerprints or treatment failure fingerprints. Robust combinatorial analysis capabilities of new agents will be a key goal of this project and should be addressed in applications. Prior to the start of the project a multidisciplinary team must be constructed. This needs to be outlined in submissions for this award. Creation of a multidisciplinary team to design and evaluate the sensor’s design parameters and goals in terms of biology, chemistry, human toxicity, and reporting capabilities is critical. Examples of desired team members will be radiobiologists, imaging scientists, radiation oncologists, chemists, small animal model specialists, and molecular biologists. Failure to outline such a team in the proposal will be considered non-responsive to the FOA. Projects that may be supported: Devices/agents that can measure tumor biological change caused by radiation therapy that are injectable or otherwise distributed into in vitro or in vivo models of cancer and normal tissue. Work toward use in humans is of particular interest. The Phase I application must provide a detailed experimental strategy to develop and deliver the biologic response sensor and identify an appropriate cancer biologic signal for the sensor. Activities not responsive to announcement: Systems or tools that measure physical dose delivery only. Devices meant to interact with radiation and either potentiate its effects or mitigate its effects. Software solutions to model these effects without actual particle development would also be considered non-responsive. Phase I Activities and Deliverables • Development of the sensor to measure biologic response to radiation • Demonstrate sensor stability in vitro • Perform in vitro efficacy studies in the relevant cancer cell line(s) and in normal tissue(s): measurement of the target gene/enzyme/other signal • Establish specificity of the construct and conduct validation studies • Perform a small in vivo efficacy study in animal model systems to evaluate appropriate correlative endpoints Activities and deliverables that will be used to evaluate whether the project should continue to be funded for Phase II include: • Successful measurement of a biologic signal with the construct designed and produced. • Concordance between known tissue signaling and sensor response (testing for false positive and false negatives). • Establishment of partnerships for potential validation. Phase II Activities and Deliverables • Consultation with FDA regarding development of a regulatory strategy and timeline for an IND submission • Refinement process development of construction and purification process to allow GMP production • Demonstrations of sensor use serially in samples at a minimum that are relevant in a pathology/diagnostic capacity but preferably in vivo (properly powered studies) • Evaluation of tissue with testing in the context of causing toxicity and evaluation of sensor use to predict and/or measure the degree of this toxicity with a goal to taking these agents to clinical use in humans, in vitro and in vivo • 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 • By the end of Phase II, submit an IND to FDA

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 patient care for many types of cancer. Therefore, there is a constant need to develop, optimize, and validate new quantitative imaging 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 data in a tissue-equivalent context can be compared to data obtained by imaging these agents in the patient. 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 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 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 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 • 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. 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 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: 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 Tremendous progress has been made in cancer imaging in the last decade, and much of this is due to computers that have revolutionized imaging protocols and image analysis. Magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), ultrasound, optical imaging, and other modalities have become fundamental tools for cancer research and clinical applications. While these medical imaging modalities are the workhorses of cancer prevention, diagnosis, and monitoring, there is increasing evidence that the accuracy of pattern recognition, predictions, and clinical decision making can be improved by the use of machine learning (artificial intelligence; AI) in image analysis. For example, retrospective review of false negative cases indicates that missed cancer diagnosis is often due to misinterpretation of perceived abnormality. In addition, the amount of imaging data has increased tremendously. Rich data have empowered physicians but also challenged them with computational complexity. As imaging data are continually growing and readily available, they offer an incredibly abundant resource for scientific and medical discovery, particularly in the application of AI for medical imaging. AI, which is defined as an area of computer science that mimics cognitive functions, such as learning and problem solving, has been progressing rapidly over the past decade. More and more physicians have started to recognize that AI-aided imaging tools (e.g. machine learning, or deep learning based on learning data) could help them with clinical decision making and improve imaging efficiency that would otherwise not be possible. Project Goals The goal of this solicitation is to call for development of AI-aided imaging software for cancer prevention, diagnostics, prognostics, and/or response to therapy. The system that will be developed can be used either as a stand-alone package for clinical applications or a tool for facilitating clinical decision making. The AI-based system may also be used to provide a better mechanistic understanding of tumor development and progress with the idea that this knowledge may lead to better therapeutic targets and improve patient outcome. The data sources for cancer imaging can be from conventional X-ray, MRI, PET, CT, ultrasound, optical imaging, and/or other imaging modalities or imaging devices. Since a single imaging modality may not be sufficient to quantitatively process, reconstruct, and analyze specific cancer imaging, integration of images from multi-imaging modalities or imaging devices that could make the system more robust for their technology development is permitted. The sensitivity and specificity for the cancer prevention, diagnosis, and/or monitoring will depend on the clinical question and unmet need that the tool is attempting to answer. Products addressing cancers of the brain, cervix, colon, head and neck, lung, prostate, and rare cancers as well as childhood cancers are particularly encouraged for this topic. However, proposals may be focused on any single cancer type. Cloud-based AI-aided imaging systems are also encouraged. To apply for this topic, offerors must outline and indicate the clinical question and unmet clinical need in the areas of cancer prevention, diagnosis, and/or monitoring that their AI-aided imaging system will address. Proposals focused on sharing and archiving imaging information, radiation therapy treatment planning, or mammography will not be considered responsive to this solicitation. Phase I Activities and Deliverables • Select one modality, or a set of imaging modalities (e.g., MRI, PET, CT, ultrasound and/or optical imaging, etc.), and data sources that are associated with the modalities for the AI-aided imaging software that will be developed for cancer prevention, diagnosis, and/or monitoring • Perform a software usability study for the prototype software with at least 25 users • Demonstrate in a small-scale, proof-of-concept study with animal or human medical image data the feasibility of an algorithm and software package for an AI-aided imaging system for cancer prevention, diagnosis, and/or monitoring. This study should be designed to assess the sensitivity and cancer specificity of the prototype software • Deliver to NCI the SOPs of the system for cancer prevention, diagnosis, and/or monitoring • Develop a regulatory strategy/plan and timeline for seeking approval from FDA to market the AI-aided imaging software Phase II Activities and Deliverables • Engage with FDA to refine the regulatory strategy • Refine and modify the software based on usability and feasibility data from Phase I • Perform a large-scale usability study with at least 100 users • Perform a large-scale validation study with human medical image data. The study should be designed to show a statistically significant improvement in the performance of the AI-aided image software • 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 • By the end of Phase II, submit a regulatory application to FDA to obtain marketing approval for the AI-aided software for cancer prevention, diagnosis, and/or monitoring

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 Page 79 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 micro environment, 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 its local environment; therefore, this information could 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 tools to improve cancer early detection, diagnosis, and prognosis for precision medicine. Such tools could be used to identify the 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 versus 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 DNA or RNA within fresh frozen or fixed normal and tumor cells without destroying their spatial context, and 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 information without losing 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 within it. Activities outside the scope of this Topic: Technologies that are solely based in computational development are not appropriate 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, such as single cell fluorescence in situ hybridization (FISH) based technologies. Projects that propose to integrate image modalities with orthogonal -omics measurement other than sequencing information should respond to Topic for “Subcellular Microscopy and -Omics in Cancer Cell Biology”. Phase I Activities and Deliverables • Demonstrate sensitivity, resolution, reliability, robustness, and usability in basic and/or clinical cancer research. • If the technology 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, the proposal 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. • 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 benchmarks, alternative assays) or absolute metrics (e.g. minimum level of detection in a clinically meaningful indication). • Demonstrate utility with benchmark experiments obtained across a range of generally accepted cancer indications. • Show feasibility to be scaled up at a price point that is compatible with market success and widespread adoption by the basic and/or clinical research community.

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 Advances in microscopy have improved the ability to resolve, describe, and quantify subcellular anatomic structures, organization, and dynamics. Concurrently, single-cell molecular ‘omics technologies have revolutionized our understanding of intracellular processes and intercellular communication. Our understanding of basic cancer mechanisms is informed by multiple orthogonal perspectives, including employment of technologies such as high-resolution microscopy and multiscale ‘omics. However, experimental or computational methods that facilitate true integration of advanced high-resolution cellular and subcellular microscopy and multi-scale molecular ‘omics technologies are not readily available to the broader research community. Technologies that offer such integration will facilitate multidimensional and spatially preserved mapping of the tumor ecosystem, leading to a broader understanding of tumor heterogeneity, and the role of cell-cell and/or cell-matrix interactions in response to cancer therapy, and will provide data for building predictive computational models of cancer initiation, progression, metastasis, and response to treatment. Recommendations of the Cancer Moonshot Blue Ribbon Panel call for enabling technologies that combine approaches from disparate fields, such as imaging at the cellular to subcellular scales with single cell “-omics” approaches. It is anticipated that the innovation in the small business sector can provide instrumentation and enabling technologies to serve the basic cancer biology research needs, in particular, technologies that directly link cellular phenotypes measured through high-resolution cellular and sub-cellular imaging in combination with multi-scale ‘omics measurements. Project Goals The main objective of this contract topic is to support the broader goal of developing an infrastructure to accelerate the microscopy-omics community and enable transformative research in cancer cell biology, diagnostics, or monitoring strategies. The short-term goal of this contract topic will be to stimulate innovation that integrates cellular imaging modalities with technologies that provide single cell -omic level data (e.g. proteomic, transcriptomic, etc.) that are relevant to cellular processes and are disabled or exploited in cancer. Projects supported by this contract topic should enable multidimensional interrogation of cancer cell biology in a manner that combines the spatial-temporal strengths of imaging modalities with complementary orthogonal measurements achieved through -omics and physicochemical approaches. This solicitation seeks to encourage the development of new imaging platforms, probes, or a unique combination of platforms with image-based approaches that leverage a multidimensional perspective of cancer cell biology. It is anticipated that that projects may include the development of new algorithms or software that facilitates image analysis or multimodal data analysis to render an understanding of cancer cell biology from a multidimensional perspective; however, proposals that are solely software based will not be responsive. The focus of this topic is on non-sequencing based -omic technologies. Proposals to integrate single cell sequencing technologies with imaging should respond to the contract solicitation for the “Spatial Sequencing Technologies with Single Cell Resolution for Cancer Research”. Phase I Activities and Deliverables Phase I activities should generate data to confirm the feasibility and potential of the technology(ies) to combine microscopy at the subcellular scale with orthogonal cell “-omics” and physicochemical measurement approaches. Activities and deliverables include: • Define the cancer biology application the device(s) or combined device-computational approaches addresses. • Generate proof-of-concept data in a generally accepted cancer cell model system that demonstrates the ability to sense, interrogate, detect or resolve and map spatial cellular anatomy and/or dynamics using microscopy or other imaging modalities with nano- to micro-scale resolution. • Demonstrate feasibility of combining the imaging modality(ies) in Phase I Deliverable #2 with orthogonal assessments at the molecular scale (such as genomic, proteomic, metabolomic, or epigenomic analyses), physicochemical scale (such as redox, pH, force/stiffness), and/or functional scale (such as proliferation, transformation, motility, invasion, resistance, or cell death) to generate multidimensional data. • 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. • Quantitative milestones may be relative metrics (e.g. compared to benchmarks, alternative assays) or absolute metrics (e.g. minimum level of detection). Phase II Activities and Deliverables Phase II activities should support the commercialization of the proposed technology and include the following activities: • Demonstrate reliability, robustness and usability in basic and/or clinical cancer research. • Demonstrate system performance and functionality against commercially relevant quantitative milestones. • 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. • Quantitative milestones may be relative metrics (e.g. compared to benchmarks, alternative assays) or absolute metrics (e.g. minimum level of detection). • Demonstrate utility with benchmark experiments obtained across a range of generally accepted cancer cell model systems. • Show feasibility to be scaled up at a price point that is compatible with market success and widespread adoption by the basic research community.

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 Determining the best treatment for each individual cancer patient can be a difficult task. To make that decision, clinicians rely on information such as the tumor type and stage, the presence of certain prognostic markers, and specific genetic characteristics of the tumor. Nevertheless, it is not always possible to determine whether a patient will respond to a specific therapeutic agent; and in some cases, several rounds of varied treatments are required to find one that is effective in a given patient. An emerging possibility identified by the Cancer Moonshot Blue Ribbon Panel (BRP) is to use the patient’s own tumor to safely and simultaneously test sub-therapeutic doses of multiple candidate drugs to more efficiently determine the most effective therapeutic agent(s). A major advantage of this strategy is that it can be personalized to each individual patient, thus allowing clinicians to more rapidly determine whether a patient will respond to a specific agent or drug combination. This capability would allow clinicians to optimize treatment decisions not only at the early stages of treatment, but also during later stages of treatment to address acquired resistance to initial therapies. In the future, such technologies might be used to generate pharmacotyping data that would accompany genotyping data in databases from large numbers of patients, which could be further mined to predict sensitivity to certain drugs and drug combinations. The BRP identified several emerging technologies that might contribute to such a “pharmaco-typing” capability; however, further development and validation of these technologies is needed before they are ready to be deployed in a clinical setting. Project Goals The primary goal of this topic is to expand the capabilities that can enable these emerging pharmaco-typing approaches by developing intra-tumoral sensing technologies. Proposals under this topic must involve the in vivo measurement of specific intra-tumoral markers of anti-cancer activity that are triggered in response to the delivery of sub-therapeutic doses of candidate therapeutic agents. Responsive proposals must offer approaches that can eventually report on patient-specific efficacy from a variety of potential treatment options while maintaining patient safety. To demonstrate the sensing capabilities of their technologies, offerors may utilize any route of administration to deliver candidate therapeutic agents (e.g., intratumoral administration, multiple/sequential rounds of systemic dosing, or other delivery strategies). However, the proposed sensing technology and/or process must enable sufficient throughput to evaluate an appropriate number of therapeutic agents that would be needed to inform clinical decision-making within a relevant timeframe. For Phase I projects, offerors must demonstrate intra-tumoral sensing capabilities using at least one solid tumor animal model; however, technologies that are capable of intra-tumoral sensing in multiple solid tumors are preferred. In all cases, offerors must provide a scientific justification for the methods, assays, and metrics that will be used to identify the optimal therapeutic agent or combinations that will be tested in their chosen tumor model(s). For Phase II projects, offerors will be expected to further develop the technology and/or process for use in human patients. Small businesses developing more mature technologies may advance far enough during Phase I to propose clinical trials during their Phase II projects; therefore, clinical trials will be allowed for Phase II SBIR contracts but will not be required. Phase I Activities and Deliverables • Demonstrate intra-tumoral sensing capabilities using at least one solid tumor animal model • Conduct proof-of-concept experiments using an appropriate number of anti-cancer agents, combinations, and/or doses (at least four) to demonstrate throughput capability that would eventually support clinical decision-making for the chosen tumor(s) • Conduct preliminary safety studies in the chosen animal model (animal safety studies may be limited in scope, but they should provide early evidence that the technology is likely to support human testing without compromising patient safety or interfering with standard of care) Phase II Activities and Deliverables • Perform testing in multiple solid tumor models and/or PDX models to advance the technology for clinical testing in specific solid tumors • Conduct preclinical studies as required for regulatory approval of the device and/or a specific clinical test • Conduct clinical trials in animals (as appropriate) • Conduct human clinical trials (as appropriate) • Complete other activities required for regulatory approval and/or marketing of the technology or test

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 Cancer care delivery systems are complex and difficult to navigate. Patient navigators (PNs) help patients navigate these systems. PNs facilitate timely cancer screening, diagnosis and treatment by decreasing barriers to care. Navigation programs have successfully reduced time from detection to diagnosis, and from diagnosis to start of treatment, in cervical, breast, and colorectal cancers, and have reduced disparities in cancer outcomes due to differences in income or employment. Page 83 Nurses, social workers, and lay persons may serve as PNs. PNs work with patients to overcome health system barriers, provide health education, and psychosocial support. Common tasks of PNs include patient education and communication, scheduling and coordinating appointments, communication with clinicians, connecting patients and caregivers with community resources, and assistance with medical paperwork. Patient navigation services are mandated by the Commission on Cancer. There is an increasing demand for expanding the use of PNs in all phases of the cancer care continuum. A National Academy of Medicine (NAM) report has identified several challenges faced by PNs, including: care coordination, tracking patients through their trajectory of care with different clinicians and facilities, supporting patients throughout the cancer care continuum, and addressing communication, transportation, and financial barriers. It takes significant time for PNs to collate information across different information systems, from patients and their caregivers, and from the relevant clinicians. It can be cognitively burdensome for navigators to synthesize this information, triage key tasks, and address patient needs in a timely manner. Projected increases in cancer survivors will further strain the capacity of the existing professional PN workforce, accelerating the need for new approaches to support and extend the work of both professional and lay PNs. Information technology (IT) has the potential to increase the reach and effectiveness of patient navigation programs by supporting the day-to-day work of PNs. IT-based tools can provide education, support communication and coordination, curate information, assist decision-making, reduce cognitive burden by improving information synthesis or decision support, and adaptively meet patients’ needs. However, the lack of user-centered design and sub-optimal integration of navigation related IT tools into existing IT systems are significant barriers. User-friendly IT tools are needed to reduce the cognitive and time burden of performing navigation tasks. User-friendly IT tools that are integrated in the workflow of PNs can improve cancer care delivery and patient outcomes. Project Goals The long-term goal is to provide timely cancer care and improve patient outcomes by developing new software tools that support patient navigation. The short-term goals are to develop, deploy and evaluate IT tools that: 1) reduce the cognitive or time burden (or both) of navigation-related tasks performed by either PNs or patients; 2) are well-integrated in the work flow of PNs and existing IT architecture; 3) securely transmit information across a variety of IT systems. The technical scope includes the development, deployment and evaluation of IT tools that support patient navigation. The tool design approach must account for integration within existing IT systems, interoperability, cyber-security and protecting patient’s privacy. Activities outside the scope of this Topic: Not using a human-centered design process to understand and meet the users’ needs; development of tools that do not use current best practices for inter-operability, cybersecurity and patient privacy; development of tools that are either not integrated in the work flow or in the existing IT architecture; merely increasing access to patient data (e.g. increasing access to data within a patient portal) without synthesis and presentation of data in a manner that reduces the user’s cognitive burden. Phase I Activities and Deliverables • Project team: Establish a project team with expertise in: cancer patient navigation; software development and evaluation; user-centered design; health services research; and the design, deployment and use of health IT in a healthcare delivery organization. Knowledge and design of systems architecture, health IT interoperability, cybersecurity, and HIPAA and other laws and regulations to protect privacy and confidentiality of patient information will be required. • Perform a targeted literature review to inform the needs assessment of PNs and the approach to be used to design, develop and evaluate the IT tool(s). • Conduct a needs assessment of PNs and cancer patients in at least one cancer care delivery site. • Develop prototype software tool(s) to support two or more patient navigation tasks. Tasks include, but are not limited to, providing education to patients, scheduling or coordinating appointments, communicating with clinicians, coordination care planning, referring patients to appropriate resources to meet their financial or transportation needs. • Conduct at least one usability study of the IT tool(s) with the participation of a minimum of 25 users. • Submit a report specifying approach taken to design and evaluate the IT tool(s), usability study findings and the plans and approach to be taken to improve the tool(s) usability. • Submit a report detailing plans for implementation of IT tool(s), including technical assistance and a review of technical specifications for systems interoperability, within existing EHR and other health IT systems, cybersecurity and patient privacy. • Present Phase I findings and demonstrate the functional prototype system to an NCI evaluation panel via webinar. Phase II Activities and Deliverables Phase II activities should support the commercialization of the proposed technology, including but not limited by the following activities: • Deploy the IT tool(s) in at least one cancer care delivery site. • Conduct a study to evaluate the usability and effectiveness of the deployed IT tool(s) in supporting two or more patient navigation tasks. The specific aims, approach, outcomes and analysis plan of the evaluation study should be explicitly stated. A minimum of 100 users should participate in this evaluation study, and the human subjects protection plan (including IRB review and patient consent) should be in place before the start of the study. • Refine the IT tool(s) based on the evaluation of the usability and effectiveness. • Evaluate the interoperability of the IT tool(s), the effectiveness of the cybersecurity design and the protection of patient privacy. • Submit a report that details the aims, approach, data analysis, and conclusions of the evaluation of usability, effectiveness, interoperability, cybersecurity and protection of patient privacy. • Submit a report that details the future approach to modify the tool(s) to support additional PN tasks and to support patients across the cancer care continuum. This report should include a plan to commercialize the IT tool(s). • Present Phase II findings and demonstrate the system via a webinar at a time convenient to the contractor and NCI Program and Contracting staff. • 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 $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 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), Therapeutically Applicable Research to Generate Effective Treatment (TARGET), and Clinical Proteomic Tumor Atlas Consortium (CPTAC) to generate a wealth of 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, population, and clinical data, 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 Moonshot 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 analytic tools that can be disseminated and sustained within the cancer research community. The SBIR contract funding mechanism will offer small businesses the opportunity to contribute solutions to address unmet challenges of big data analysis that are not currently provided by the 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 by offering enhanced data analysis capabilities, visualization tools, and data access and sharing platforms. This topic is relevant to the BRP recommendation to develop a national cancer data ecosystem for sharing and analysis. 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 that operate across the CRDC and other data commons such as Gabriella Miller’s Kids First for multi-domain 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 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 datasets stored in CRDC such as TCGA 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 outside the scope of this Topic: Proposals for the development of big data analysis tools without consideration for integration with the CRDC will not be considered for award under this Topic. Phase I Activities and Deliverables The proposed Phase I research is expected to clearly demonstrate at minimum a ‘proof of concept’ feasibility of adaption of the offeror’s informatics tool(s) to the CRDC through the Data Commons Framework. The proposal should 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, project management, team communication, and user-centered design. • Design the specifications for the development/extension of cloud-based informatics tools to operate in the Cancer Research Data Commons. • Develop an early software prototype. • Demonstrate the feasibility of CRDC integration through the DCF. Examples of feasibility qualification include, but are not limited to, user authentication using Fence to access datasets stored in at least one CRDC node such as the Genomic Data Commons (which exists now) and providing authorization to datasets the user has access to. More nodes, such as the Proteomic Data Commons, are expected to be available for feasibility testing by the end of 2019. • Conduct a pilot software usability study with the participation of 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 a 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 detailed 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 data analysis using the offeror’s tools or resources. Examples of large-scale data analysis include, but are not limited to, demonstration of integration of user-provided data with available datasets such as TCGA from CRDC to perform comparative analyses. • Conduct usability testing with the participation of at least 100 users. • Provide a report that synthesizes feedback from all relevant categories of end-users (minimum of 100 users and end users include biomedical researchers and computational scientists) and summarizes the modifications made to the platform after each round of usability testing. • Develop systems documentation and user guides to facilitate commercialization. • Develop and implement a business process for broader adoption of their tools and resources by actively engaging with the user communities. • Develop business process that includes business plans for marketing and long-term sustainability, such as sustained hosting of tools, training and associated resources. • Conduct outreach and training activities. • Present Phase II findings and demonstrate the system to NCI program staff. • In the first year of the contract, provide the Program and Contracting 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: 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 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: • Establish 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) 3) Cellular (e.g., cell-state, cell-type) 4) Tissue (e.g., tissue morphology, metabolic state) 5) Individual patient (e.g., clinical data, exposure, microbiome) 6) Population (e.g., epidemiological) Activities outside the scope of this Topic: Work that would not fall under this Topic includes: (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 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 the 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. This work builds on developments in 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 is required. 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 environment, and automated measurement of human performance in sport and animation domains along with growing capacity of computers to identify and count objects 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. Activities outside the scope of this Topic: Proposals addressing medical images such as MRI scans, microscopy, or DEXA scans will not be considered for award under this Topic. 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 software 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: o Capacity to extract data from at least one image type involving human physical activity, performance or behavior. o 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. • 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. Phase II usability testing should include the participation of at least 100 users. • 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: 3-4 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 A large number of NCI funded clinical trials fail to meet their accrual goals which leads to delays, early termination, or inability to draw conclusions at trial completion due to loss of statistical power. A study in 2014 reported that 1 in 4 cancer clinical trials were terminated early with 1 in 10 being terminated for poor accrual. There are no easy solutions to solving accrual challenges. Retention of subjects enrolled in trials can also be a challenge. NCI provides various educational resources and tools to support and enhance participant accrual through portals like AccrualNet. However, most of these resources are limited to educating the study team on good practices to enhance accrual. Tools that could be either clinic-facing or participant-facing or both and that are based on empirical evidence and have been shown to increase participant accrual and retention are mostly lacking. This solicitation has the potential to enhance clinical trials recruitment and retention by developing tools that could be used across NCI clinical trials networks and beyond. The goal of these tools is to enhance communication between participants and study staff and reduce the participant burden of traveling to the clinic when virtual communication is sufficient. Project Goals The goal is to solicit proposals to advance the development of tools for clinical trials recruitment, retention, or both. The tool could be clinic-facing or participant-facing or both. If clinic-facing for recruitment, it should help identify protocol barriers to recruitment and present options for addressing the challenge(s), effective recruitment strategies, potentially integrate with electronic medical records, and allow for tracking of screening efforts. If clinic-facing for retention, it should enhance patient engagement, potentially integrate with electronic medical records, and allow for tracking of retention efforts. If participant-facing for recruitment, it should be designed to engage potential participants, help them understand details of a given trial, and be easily adaptable for different trials. If participant-facing for retention, it should be designed to engage enrolled participants, help them adhere to protocol requirements and communicate with clinic staff in an effective and efficient manner, and be easily adaptable for different trials. Preference will be given to projects that are easily adaptable between trials. The best practices for recruitment and retention that are relevant to tool development include [Denicoff AM et al. (2013) J Oncol Pract. 9(6): 267-76]: 1) Consider the patient point of view of potential research, including potential barriers, when reviewing and implementing trials. Patient advocates could support this effort. 2) Identify and address reasons why eligible patients decline trial participation. 3) Simplify informed consent documents and enhance personal communication during the informed consent process, including clarifying possible financial liability the patient may incur by participating in the trial. 4) Educate patients and the community, including community providers, about clinical trials, using culturally appropriate material. 5) Use smart devices, social media, patient registries, and electronic databases to identify potential participants, notify providers, and enhance recruitment and retention to prevention, treatment, quality-of-life, survivorship, and rare-cancer studies. 6) Provide access to peer mentors (other patients who have participated in a clinical trial) and patient navigators for those patients identified as in need of additional support. 7) Increase awareness and provide easy access to information on all ongoing clinical trials. The tools should incorporate these best practices and should • Develop and test culturally sensitive participant educational tools/interventions that support varied communication preferences (e.g. written, visual etc.). • Develop and test provider-based tools to facilitate discussion with potential participants. • Facilitate understanding costs associated with clinical trials participation. • Integrate with smart devices, social media, patient registries, and electronic medical records. • Enhance the consenting process. • Enhance study adherence through interactive participant and/ or study-team engagement (gamification). • For retention, provide a platform for participant communication to study team and provide information to the study participants. Phase I Activities and Deliverables The goal of Phase I is to develop proof-of-concept or prototype tools, technologies, or products for monitoring and enhancing cancer prevention, treatment, and control clinical trials recruitment and retention. Activities and deliverables include: • Develop and characterize a prototype tool/technology and demonstrate that the tool addresses specific recruitment and/or retention concern(s). • Specify and justify quantitative milestones that can be used to evaluate the success of the tool or technology being developed. • Provide a proof-of-concept SOP for the tool or technology. • Consider human subjects protection compliance. • Demonstrate feasibility and usability with a pilot user testing. Provide a report on the results of the first round of usability testing and the approach to modify the platform based on this user feedback. Offerors shall provide a technical evaluation and quality assurance plan with specific detail required for use. • Demonstration that the tool, technology, or product can be adapted to multiple clinical trials at a price point that is compatible with market success and widespread adoption by the clinical research community. • Present Phase I findings and demonstrate the functional prototype system to an NCI evaluation panel via webinar. Phase II Activities and Deliverables The goal of Phase II is an optimized commercial resource, product, or tool for cancer prevention, treatment, and control clinical trials recruitment and retention. Deliverables and activities include: • Enhance, test and finalize the tool with refinement of SOPs to allow for user friendly implementation of the tool, technology, or product by the target market including human subjects protection compliance. • Provide a report that synthesizes feedback from all relevant categories of end-users (such as physicians, oncologists, nurses, patients, and patient navigators) and summarizes the modifications made to the platform after each round of usability testing. • Validate scaled up tool, technology, or product. Specifically, demonstrate the utility, of the tool, technology, or product across clinical trials. • Develop systems documentation and user guides to facilitate commercialization, including citation and details of how systems align with current regulations and best practices in user-centered design, interoperability, and protection of privacy and confidentiality of information. • Present Phase II findings and demonstrate the system via a webinar at a time convenient to the offeror and NCI program staff.

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 Imaging data are a core component in the development of the National Cancer Data Ecosystem and are important in areas from basic research to diagnostics and surveillance. Sharing of any data collected from patients, however, requires that information that can connect that data to the individual from which the data were collected must be removed, or anonymized to the extent possible. Removal of Protected Health Information (PHI) from imaging data files is a twofold problem. 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, this information is often found in fields not intended to contain such information. In the image field itself, PHI can be found in different forms, inserted into the image by the imaging system, or by the presence of identifying jewelry in the image (in the case of radiological images). 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. This need for human participation in the de-identification process is a significant bottleneck; it impedes the generation of 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 proposed Imaging Data Commons of the Cancer Research Data Commons. For example, on a TCIA data curation team, one person manually reviews files for PHI. Improved tools would shift a large portion of the de-identification burden to software, improving data throughput and increasing data accessibility. Currently, tools do not exist to properly remove PHI from proprietary file formats (e.g. digital pathology images) while retaining other data that maybe be useful to researchers. Project Goals The goal of this contract solicitation is to support development and sustainment of software tools and pipelines for image de-identification, especially for but not exclusive to CT patient data sets and images produced by whole slide imagers (WSI) for digital pathology applications. These tools will selectively remove PHI while retaining other metadata fields that help provide interoperability with other image formats and other data types, such as genomic data and proteomic data. The following tasks/objectives should be met by the software tool: 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 (e.g., comment fields that may contain PHI) 3) Scanning of images for PHI, identification, labeling, and subsequent resolution 4) Production of processed images that meet a threshold level of de-identification 5) Validation algorithm to confirm images within the processed dataset are de-identified 6) Identification (e.g., flagging) of processed data files that may require manual resolution to remove PHI Brute force methods for de-identification (e.g., erasing of all header information) are not acceptable. Retention of data and metadata necessary for downstream applications (population studies, segmentation training) is required. Solutions should not compromise the biomedical use of data files. To build upon previous work for field retention, removal, and alteration, the TCIA de-identification knowledge base (https://wiki.cancerimagingarchive.net/display/Public/De-identification+Knowledge+Base) may serve as a foundation for determining and prioritizing similar attributes in digital pathology images. Phase I Activities and Deliverables • In addressing WSI datasets, identify different WSI vendor file types and the fields that contain PHI (i.e., conduct landscape analysis) • Ability to recognize and open multiple WSI file formats • Provide data set(s) for Phase I activities • Display PHI field variable values • Remove or alter PHI field values from fields labeled with PHI • Identify the data sets and file types required to demonstrate software capability in Phase II o WSI data sets should include at least 1000 differentiated case files (i.e., one image per patient case) from across various imager systems as identified from the performed landscape analysis o CT data sets should include at least 1000 difference case files (e.g., 100 images per patient case) from across at least 5 distinct research institutions o Requests to use NCI data sets from the TCIA database or similar may be directed to the NCI Contracting contact person listed for this solicitation. Requests will be granted at the discretion of NCI. 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 fields • Detection of PHI within image • Masking of PHI within image • Generation of de-identified images with provenance of process • Validation with a test data set should demonstrate successful PHI removal from image and image file meta data for ≥95% test files • Statistical analysis of validation testing will be provided to NCI • The software tool should identify and flag any cases that are less than fully verified for PHI removal • For any dataset where 5% or less of files are not fully verified with successful PHI removal, such files should be flagged for manual correction • 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: 2-3 Budget (total costs, per award): Phase I: up to $400,000 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 The rapid adoption of wearable, cyber-physical, and ambient sensing platforms since 2015 by the consumer health market have begun to pave the way for similar platforms to act as objective measures for continuous, out-of-clinic cancer research and patient assessment. They collectively will be a key component of the perceived future for Smart and Connected communities via a continually linked internet of health sensors. The passive, continuously measured data streams generated by current or future physical and chemical/biological sensors will allow direct/indirect measures of cancer progression and its symptoms. Increased out-of-clinic patient and clinician engagement via these tools will allow more precise delivery of cancer care after as well as during cancer remission. Ultimately, these passive sensing platforms’ data for digital biomarkers will afford clinicians: 1) more objective metrics of response to therapeutics; 2) control and auto-reporting of symptoms and their fluctuations; 3) monitoring of side-effects of experimental or standard of care therapies; and 4) more ecologically valid clinical endpoints, all decreasing assessment burden via increased continuity of physiological measurement sampling and patient context in the ambulatory setting. Near real-time analytical capability such as what these devices offer represents an opportunity to measure population-based statistics from large cohorts of cancer patients by way of the myriad of devices currently available or being developed. From vital signs, physical activity, or non-invasive patch based measures of biochemistry from bodily fluids to external monitoring of environment, these tools will offer a more complete picture of patient performance status, fatigue, other symptoms, cachexia, and patient monitoring (e.g., drug metabolism, toxicity, adherence, adverse events or side effects) during clinical trials, in convenient small form factors with the ability to auto-report these data for research purposes or informed clinical assessment of patients outside of the clinic. In order to ascertain the potential of these tools for more precise delivery of cancer care and patient monitoring, much clinical cancer research must be performed to understand sensor measurement versus cancer progression and patient context outside of the clinic. As much of the power of these technologies lie in their ability to offer a granularity not seen before in patient-specific data, the research to advance this to the clinical setting will rely on tools already commercialized or of research grade platforms not yet translated. Moreover, as any one wearable sensor-specific parameter will unlikely allow for both patient physiology and context in which the measurement was taken, multiple devices and subsequent parameters will be necessary to enable commercialization of more targeted and specific devices for clinical cancer care or assessment. There is a considerable need for scalable informatics tools that allow automated data aggregation, integration and machine learning/artificial intelligence (AI)/predictive analytics that can pull from disparate data sets across device vendors and have the flexibility to add new measures as they are developed. Furthermore, a central software platform that could obtain wearable, implantable, or external device data and uniformly compare/contrast/couple data streams to understand physiology versus patient context with respect to time will advance this unique approach to aid cancer patients, clinician assessment and clinical trial design. Project Goals The goal is in development, and subsequent commercialization, of scalable informatics tools and resources for their broad adoption across the burgeoning clinical cancer research applications that continuous, passive monitoring of multiple biological parameters via wearable platform technologies are beginning to be used. A limitation to their current use in cancer research, to more objectively understand cancer patient progression or cancer-specific symptoms, is that device manufacturers and platform technology developers do not utilize identical data sets / standards and no resources are available to easily assess large multiparameter data sets via traditional bioinformatics methods. As such, the primary focus of this contract topic is on data agnostic informatics tools and resources that can be easily adopted in the cancer research communities for cohort studies involving their monitoring platform(s) of choice to understand their specific research problem / patient cohort of choice. Informatics tools include mobile apps for sensor data retrieval; computer software tools and platforms to aggregate, integrate and organize data streams from multiple devices; and machine/deep learning or predictive analytic informatics ‘AI’ platforms for subsequent interpretation of integrated data streams derived from a myriad of continuous passive monitoring devices that could be used by cancer researchers. The informatics resources include sensor and patient data repositories and platforms that provide data, workflow, and a workspace for online research collaboration, evaluation as well as dissemination of informatics tools and resources, and support for population-based research. The overall scope of proposed funding approach includes the entire spectrum of passive continuous monitoring devices being commercialized or developed, extending from wearable sensor platforms and implantable devices to external monitoring devices for all phases of cancer clinical research. Offerors will be expected to formulate and execute well- designed project plans with clearly defined milestones that will eventually lead to commercially viable solutions for: 1) sustained development and evolution of passive continuous monitoring platform informatics tools and resources; and 2) their broad adoption in clinical cancer research. Activities outside the scope of this Topic: Tools that do not allow the integration and subsequent interpretation of a myriad of current wearable sensor platforms simultaneously, or that use only data from inertial sensing wearables; tools that are not scalable to future wearable, implantable or external out of clinic monitoring; tools that do not incorporate safeguards to protect privacy and confidentiality of information; design approaches that don’t account for scalability, interoperability or user-centered design; approaches that don’t plan for using tools in diverse sites and IT systems. Phase I Activities and Deliverables • Establish a project team including proven expertise in: sensor technology for physiological monitoring, wireless sensor integration with mobile devices, secure wireless transport of health data using standards based protocols, secure cloud computing models, bioanalytical technologies, epidemiology, biostatistics/bioinformatics, and systems architecture • Provide a report including a detailed description and/or technical documentation of the proposed: o Development of bioinformatic methods or algorithms (e.g., machine/deep learning, etc.) for wearable sensor data integration across data inputs from diverse wearable bio-/sensor platforms, including harmonization of data of the same biometric from different vendor device platforms o Evaluation of a wide range of wearable, implantable, and external sensor platforms that would be of legitimate use for out of clinic patient monitoring and / or understanding disease / symptom progression (e.g., therapy-induced fatigue, patient performance status, cachexia, experimental therapeutic side effects, toxicity, etc.) vs. the myriad of potential physical and / or physiological factors o Development of the database structure for the proposed system's chem-/bio-/physical sensor-based data inputs and metadata requirements o Database formats that support the import and export of individual datasets and coalesced datasets, store structured data from different sources of wearable sensor data, and are readily used for data integration and Quality Control (QC) protocols o Specific approach to QC o Technology compatibility matrix for Phase I and Phase II wearable sensor data sources by platform, sensor type, sensor technology, and differing device data streams as well as and back-end server systems to be developed o Data visualization, feedback, and reporting systems for population or clinical monitoring and research applications o Data integration approaches to leverage multiple data input streams o Data types for exchange of physiological-metrics between mobile platforms and secure servers o Data standards for transfer and importation of individual wearable sensor data and storage of individual and coalesced wearable sensor data o Transparent, documented, and non-proprietary bio-/informatic methods o Description of additional software and hardware required for use of the tool. • Provide wireframes and user workflows for proposed Graphical User Interface (GUI) and software functions that: o Support the import and export of individual datasets and coalesced datasets o Implement, script or automate all features and functions of the data integration tool(s) o Conduct QC of coalesced datasets • Develop a functional prototype system from the planned Phase I compatibility matrix that includes: o Front-end mobile applications to facilitate and control the collection and transport of multiple wearable chem-/bio-/physical sensor data inputs and any associated metadata used within the system o Integration with several wearable chem-/bio-/physical sensor o Automated data screening algorithms and importation protocols for data transferred from the mobile application to the back-end server systems o Software systems GUI (web- or computer-based) o Software tools as mobile and web applications o Back-end user-interface controls for custom data integration and visualization for individual or group-level data o Finalize database formats and structure, data collection, transport, and importation methods for targeted data inputs • Include funds in the budget to present Phase I findings in a detailed report and demonstrate the final prototype to an NCI evaluation panel. Phase II Activities and Deliverables • Expand the informatic methods to include other research grade sensor data points or streams, in addition to already identified commercialized wearable sensor data, and demonstrate data integration across inputs from diverse sensor platforms • Demonstrate database integration capability to collect data from four different parameters and collected from three distinct wearable device platforms, as well as to be adaptable to at least 20 more current or future platforms designed for physiological or objective measurements of patients outside of the clinic • Participate in validation and scale-up between the contractor, NCI, and / or contractor-identified third party sources to access relevant input data types for the proposed project. Validation within established cohort studies with wearable sensor data (e.g., pre-identified analytes of use to monitoring of syndrome-specific therapeutics, patient fatigue, or similar cancer cachexia-specific physiological metric, etc.) will serve to: 1) train and validate the expanded bioinformatic methods; and 2) demonstrate the application of these methods through scalable software to automate complex data integration tasks for wearable sensor data sources • Beta-test and finalize front-end mobile applications developed in Phase I • Beta-test and finalize automated file transfer, screening, and database importation protocols and systems • Perform regression testing for both front-end and back-end system functions • Demonstrate usability of scalable software through the following: o Beta-test and finalize automated file transfer, database importation protocols, wearable biosensor data integration applications and reporting tools developed in Phase I o Develop beta-test, finalize, and demonstrate the GUI o Demonstrate the software systems ability to integrate data from planned Phase II technology compatibility matrix data sources using automated algorithms and analytic methods • Conduct usability testing of the GUI elements of the sensor-specific data integration tool(s) • Conduct usability testing of consumer/patient-facing mobile applications and any associated web portals and care team/researcher-facing user interface features including system management, analyses, and reporting applications • Develop systems documentation to support the software and informatic 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

Direct to Phase II proposals will be accepted Fast-Track proposals will be accepted. Number of anticipated awards: 2 Budget (total costs): Phase I: $400,000 for up to 12 months; Phase II: $3,000,000 for 36 months PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Primary and secondary tricuspid valve regurgitation can cause disabling right heart failure, hepatic dysfunction, cardiorenal syndrome, and death. Primary surgical repair or replacement is highly morbid especially at the advanced stage of typical clinical presentation. Transcatheter repair using marketed and investigational clip-type devices is poorly suited for the trileaflet tricuspid valve. There is substantial unmet need. This solicitation aims to support the development of an Transcatheter trileaflet tricuspid suture repair system for commercial clinical application. Project Goals The goal of this project is to develop a catheter system to achieve a non-surgical off-pump tricuspid valve LEAFLET repair that allows 3 or more sutures to reappose 3 or more tricuspid valve leaflets to repair secondary or primary tricuspid valve regurgitation, sometimes described as “clover-leaf repair.” This project should generate an Early Feasibility Study (EFS) IDE for clinical evaluation in the United States, towards commercialization through a mechanism such as Phase IIb bridge-to-commercialization. Phase I Activities and Expected Deliverables A phase I award would develop and test working prototypes in swine. The contracting intramural laboratory wishes to test the final prototypes in vivo, and offers one earlier no-cost testing round to the contractor if desired. The offeror should provide a complete transcatheter solution to effect suture apposition repair of three or more tricuspid leaflets. Elements of a complete system would typically include • Low profile transvenous access • Multi-axial deflectable guiding sheaths • Leaflet traversal tools such as radiofrequency or mechanical energy transmission • Retrieval tools to use in tandem with traversal tools • Radiopaque tension elements such as sutures • Force-redistribution elements that are radiopaque, such as pledgets, to prevent tension-induced leaflet injury • Features to accomplish real-time image guidance including visibility under ultrasound and visibility under X-ray fluoroscopy • Biocompatibility required of permanent endovascular clinical implants • Capabilities to accomplish three or more points of apposition Proposals that include novel image guidance and catheter navigation assistance in 3-dimensional space are welcomed. A phase I award would develop and test functioning prototype system, including accessories, in vivo. At the conclusion of the Phase I award, the contractor should provide a detailed report of pre-IDE interactions with the Food and Drug Administration to identify clear requirements for human testing, including the summary of mutual understanding. The contracting NHLBI DIR lab is willing to provide feedback about design at all stages of development. The contracting NHLBI DIR lab will test the final deliverable device for success in vivo in swine. Phase II Activities and Expected Deliverables In addition to meeting all requirements for Phase I, a phase II award would support testing and regulatory development for the device to be used in human investigation in the United States, under Investigational Device Exemption or other mutually agreed pathway. All FDA communications regarding the device should be shared with NHLBI. The contracting DIR lab offers to perform an IDE clinical trial at no cost to the awardee. A complete Early Feasibility Study IDE application short of device verification and validation testing would constitute the deliverable. A plan for separate Bridge-to-Commercialization funding support is invited to complete the Early Feasibility IDE licensed clinical study. Offers are encouraged to supply a detailed milestone plan. The offeror should have a proven track record of safe and compliant early-phase clinical testing of structural heart cardiovascular implants in the United States.

Direct to Phase II proposals will be accepted Fast-Track proposals will be accepted. Number of anticipated awards: 2 Budget (total costs): Phase I: $400,000 for up to 12 months; Phase II: $3,000,000 for 24-36 months 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 Endomyocardial biopsies are performed approximately 10,000 times each year worldwide. The procedure suffers large anatomic sampling error because of no current appropriate image guidance. Endomyocardial biopsy is currently performed without targeting, whether under X-ray or ultrasound guidance. This may account for the known low diagnostic yield and high sampling error. MRI operation affords exquisite imaging and delineation of soft tissue beyond what is afforded by X-ray fluoroscopy, CT, and ultrasound guidance. Image-guided myocardial biopsy using MRI might enhance the diagnostic utility and safety of myocardial biopsy in inflammatory or infiltrative cardiomyopathies. This solution would be especially attractive in pediatrics, where the risk of and need for biopsy is higher than in adults, yet the need more frequent. This solicitation aims to support the development of an MRI myocardial biopsy forceps and accessories for commercial clinical availability. Project Goals The goal of the project is to develop a myocardial biopsy catheter of materials safe for MRI operation yet sufficiently sharp to extract myocardial tissue effectively. First a prototype would be developed and tested in animals, and ultimately a clinical-grade device would undergo regulatory development for clinical testing. This project should generate an Early Feasibility Study (EFS) IDE for clinical evaluation at NIH or another suitable medical center, towards commercialization through a mechanism such as Phase IIb bridge-to-commercialization. Alternatively it is possible that 510(k) market clearance can be achieved depending on the selected technologies. Phase I Activities and Expected Deliverables A phase I award would develop and test a bioptome prototype along with necessary accessories. The awardee deliverable would be tested in vivo at NHLBI DIR. The specific deliverable would be: • Myocardial biopsy forceps catheter with an outer diameter 6-7 French • Bioptome sharpness equivalent or superior to commercially available stainless steel myocardial biopsy forceps catheters • Able successfully to cut endomyocardial biopsy specimens 1-2mm x 2-3mm each • Deflectable curve or shapable to impart a curve analogous to Stanford-style endomyocardial bioptome • Suitable for transjugular or transfemoral venous biopsy of the right ventricle or transfemoral arterial retrograde aortic biopsy of the left ventricle • Free from clinically-important heating (2oC at 1W/kg SAR) during MRI at 0.55T-1.5T • Visibility during MRI. If visible using magnetic susceptibility phenomena, the tip should be distinctly visible, and at least the distal 40cm of the shaft should also be visible. In general, susceptibility markers should be > 3mm in diameter using commonly used steady state free precession or fast gradient echo MRI techniques. • There should be a characteristic imaging signature that distinguishes the “open” from the “closed” position of the biopsy forceps, using MRI • The deliverable includes all accessories necessary to perform right and left ventricular biopsy under real-time MRI guidance via a pre-positioned vascular introducer sheath. This specifically includes MRI-conspicuous guiding catheters or sheaths, whether pre-shaped or deflectable. • Proposals for alternative visualization strategies, such as “active” or “inductively-coupled” receiver coils, are welcomed. A phase I award would develop and test functioning MRI myocardial biopsy forceps system, including accessories, in vivo. The contractor should provide a detailed report of pre-IDE interactions with the Food and Drug Administration to identify requirements for premarket notification [510(K)] under Phase II, including the summary of mutual understanding. The contracting DIR lab is willing to provide feedback about design at all stages of development. The contracting DIR lab will test the final deliverable device for success in vivo in swine. This may require tailored hardware compatibility with the NIH investigational MRI system, or the test can be performed by NHLBI DIR staff at an outside facility. Phase II Activities and Expected Deliverables A phase II award would allow mechanical and safety testing and regulatory development for the device to be used in human investigation, whether under Investigational Device Exemption or under 510(k) marketing clearance. The contracting DIR lab offers to perform a IDE clinical trial at no cost to the awardee. Proposals should include key milestone for contract review including FDA presubmission meeting(s), design lock, DFEA creation and completion, GLP experiments, etc. IDE license or 510(k) clearance and 10 functioning clinical devices would constitute the deliverable.

Fast-Track and Direct to Phase II proposals will be accepted. Number of anticipated awards: 1-3 Budget (total costs, per award): Phase I: up to $500,000 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. Background The National Institute on Alcohol Abuse and Alcoholism (NIAAA) seeks a wearable or otherwise discreet device capable of measuring, recording and storing blood alcohol levels in real time. Alcohol biosensors that are unnoticeable by the user and provide continuous alcohol use monitoring will advance the mission of NIAAA in the arenas of research, treatment, rehabilitation, and recovery. For example, research that seeks to understand the progression of medical conditions exacerbated by alcohol to discover treatments depends on the ability to accurately measure and record alcohol consumption continuously over time. Alcohol biosensors will simplify the process of determining close to real time alcohol consumption for both the scientists and the participants by providing an objective, biomedical measure of alcohol consumption; allowing participants to avoid the inconvenience and discomfort of having blood drawn at regular intervals. Likewise, during treatment of individuals with alcohol use disorder (AUD), and especially in clinical trials designed to identify the most effective treatments for AUD, it is essential to know accurately the extent of alcohol consumption of trial participants to determine the effectiveness of the intervention being studied. The current method of determining alcohol consumption (Time-Line Followback (TLFB)) is cumbersome, time-consuming, relies on retrospective recall and can be highly variable from one interviewer to another. Alcohol biosensors in contact with the human body will decrease the assessment variability experienced with the TLFB and increase the rigor and reproducibility of measuring alcohol consumption in clinical trials. Current technological developments in electronics, miniaturization, wireless technology, and biophysical techniques of alcohol detection in humans increase the likelihood of successful development of a useful alcohol biosensor in the short term. Objectives NIAAA seeks the design and production of a discreet device to measure, record, and store blood alcohol levels in real time (or close to real-time). The device should be inconspicuous, low profile, and appealing to the wearer. The design can take the form of jewelry, clothing, or any other format located in contact with the human body. The detection of alcohol should be passive, close to real time, and accurate. Alcohol biosensors that detect consumed alcohol in sweat or sweat vapor have been used in criminal justice settings for a decade or more. More recently, advances in more discreet wearable alcohol sensing devices has been made; however, these still depend on detection of alcohol in the sweat, rather than in blood. It is important to note that there is a forty-minute to two-hour lag in detection of alcohol in sweat relative to actual blood alcohol levels. Under certain circumstances, this can have significant consequences. For this reason, this solicitation seeks the development of techniques that are not sweat-based. Only advances in alcohol detection that depart from measuring alcohol in sweat or sweat vapor will be responsive to this solicitation. Offerors are encouraged to pursue any technology - including but not limited to- biophysical, optical, wave, or other novel approaches that passively quantify blood alcohol in human subjects... NIAAA recognizes that there are other technologies that also offer promise; so innovative, original approaches to alcohol quantification as well as the adaptation and miniaturization of existing technologies are welcome. The device should be able to quantitate blood alcohol level, interpret, and store the data or transmit it to a smartphone or other device by wireless transmission. The device should have the ability to verify standardization at regular intervals and to indicate loss of functionality. The power source should be dependable and rechargeable. Data storage and transmission must be completely secure for the protection of the privacy of the individual. A form of subject identification would be an added benefit. If the device is removable by the user, the ability to record the exact time the device is removed is preferred. Ideally, the device will be stable, with expectation of long-term function. The design should be acceptable to the wearer from comfort, privacy, financial, and convenience standpoints. It is envisioned that subject alcohol monitoring will serve useful purposes in research, clinical, and treatment settings, may play a role in public safety, and will be of interest in the consumer market to individuals interested in tracking personal health parameters. Designs may emphasize any of these potential market subsets or may seek to be broadly marketable. While achievable lower limits of detection remain to be demonstrated, devices capable of detecting 0.02% BAC would be of value to NIAAA. To apply for this topic, offerors should: Include a description of the technology by which the device will quantitate blood alcohol level. Provide preliminary data or cite literature to support the rationale for the underlying approach. If modifying an existing technology to wearable scale, describe the potential for success of the miniaturization process. Explanations of data handling should discuss how the device will collect, interpret, store and protect the data or transmit it to a smartphone or other device by wireless transmission and address data security measures. The approach should address the ability to verify standardization at regular intervals and to alert a loss of functionality. The power source, charging duration, and battery life (if applicable) should be addressed. Since alcohol biosensors may be of great benefit to treatment professionals, clinicians, researchers, and individuals, designs may emphasize any of these potential market subsets or may seek to be broadly marketable. Proposals should identify the intended target audience(s) and provide the rationale for their design decisions regarding both technology and form factor. This SBIR will not support: Development or improvement of biosensors that detect alcohol exuded through the skin in sweat or vapor. Phase I activities and expected deliverables • Demonstration of the ability of the technology to detect alcohol. • Demonstration that the detection signal is proportional to amount or concentration of alcohol. • Demonstration of the specificity of alcohol detection in blood or a solution approximating the physiological mixture. • Demonstration of the limit of detection (sensitivity). While not required, if validation of new or existing technology in human subjects is proposed in the Phase II portion, evidence of the availability of existing clinical infrastructure and knowledge and familiarity with NIH and FDA regulations on human protections must be provided before progression to the Phase II. As the development of a wearable alcohol biosensor is a priority for NIAAA ((https://www.niaaa.nih.gov/sites/default/files/StrategicPlan_NIAAA_optimized_2017-2020.pdf) and NIH (https://www.nih.gov/sites/default/files/about-nih/strategic-plan-fy2016-2020-508.pdf), NIAAA envisions that the Phase I milestones will be quickly met, leading to rapid advancement to the Phase II period. Phase II activities and expected deliverables • Incorporation the alcohol sensor into a discreet device in a form factor in contact with the human body. • Refinements of functionality, accuracy, security, and integration of data collection, data transmission and data storage. • Further refinement of accuracy of quantitation of blood alcohol concentration. Development of an algorithm that accurately converts the detection signal to blood alcohol concentration. • Demonstration that the detection of alcohol is passive, not requiring action on the part of the wearer. • Demonstration of frequency of measurement. • Demonstration that the device shows the time of detection and that the BAC value corresponds to the time of measurement. • Summary of human testing completed. • Plans for process of manufacture. • Evidence of a functional, marketable, alcohol biosensor is the specific deliverable of the Phase II portion of the contract.

Fast-Track proposals will not be accepted. Number of anticipated awards: 1-2 Budget (total costs, per award): Phase I: up to $225,000 for 6-12 months. Summary NIAAA supported studies in genomics, imaging, electrophysiology and optogenetics, electronic health records, and personal wearable devices presents new challenges in analyses and interpretations and opportunities for discovery. The NIAAA data sharing policy (NOT-AA-18-101), effective January 25, 2019, expects that investigators and their institutions will submit their grant-related human subjects data to an NIAAA-sponsored data repository. The future data sources will be combined with significant current data repositories and archives, including: database of Genotypes and Phenotype, dbGaP, https://www.ncbi.nlm.nih.gov/gap, Collaborative Studies on Genetics of Alcoholism (COGA), https://niaaagenetics.org/, National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III), and the NIMH Data Archive, NDA, https://data-archive.nimh.nih.gov/ to form a large and rich source for analysis of alcohol use, suitable for analysis by data science methods. Examples of electronic health records (EHRs) include: (NIH-funded) Health Care Systems Research Collaboratory, https://commonfund.nih.gov/hcscollaboratory, (NIH-funded) Clinical and Translational Science Awards (CTSA) Program, https://ncats.nih.gov/ctsa/about/hubs, Health Care Systems Research Network, http://www.hcsrn.org/en/. Data science includes and extends beyond bioinformatics and computational neuroscience to discover new relationships and pathways for complex systems of normal human function and during adaptations due to disorders or disease. However, many of the tools needed to answer questions in alcohol research require specific applications, algorithms or toolkits that are not currently available. User-friendly methods and applications program interfaces (APIs) for retrieving metadata and data from the repositories for secondary analyses are not currently available. Alcohol researchers require assistance from data scientists to appreciate the power of tools such as machine learning, deep learning and artificial intelligence and the skills for programmers to implement analysis methods to answer key questions about alcohol use. NIAAA is interested in analytical approaches and tools that can integrate data (i.e. genetic, social, economic, EHR, treatment approaches) to predict the development of alcohol use disorder, or the effectiveness of interventions that reduce or delay the onset or progression of alcohol use disorder, or guide effective treatment and management strategies for alcohol use disorder, including recovery and relapse. One possible example is a tool that assists researchers in developing a risk algorithm for alcohol use disorder when researchers combine multiple existing data sets. The tool could parse out age, sex, race/ethnicity, with alcohol use measures (quantity/frequency/binge episodes), consequences and other risk factors. Project Goal The goal is to develop data science analysis algorithms, mathematical models, and software tools for use in alcohol research, integrating data across disciplines and clinical and basic sciences realms. Phase I Activities and Deliverables Specific deliverables may include any of the following: • New algorithms for integrative analysis of current NIAAA and public ‘big data’ sets, including machine learning, deep learning, artificial intelligence, data mining and other model based and model-free approaches. • Software applications for data interfaces for aggregation, imputation, harmonization, or visualization of data from multiple sources, including current and future NIH data systems (i.e. NCBI (National Center for Biotechnology Information), dbGaP (database of Genotypes and Phenotypes), National Institute of Mental Health Data Archive), or other studies of alcohol research. • Algorithms and/or software tools for improving data collection, i.e. smart phone apps, extraction of specific alcohol research parameters from existing large databases and established public health studies, biological sensors or wearable devices, natural language processing for analysis of survey data. • Generation and validation of computational and/or systems biology models of alcohol exposure and use on cellular, organ, network, or organism scales. Multiscale models are appropriate, along with models that include data from clinical and basic science research. Activities and deliverables are expected to use currently available data sets and databases. Offerors should discuss potential deliverables with NIAAA-supported researchers to determine research needs and goals. All funded NIAAA studies can be found in the public database, NIH RePORTER, https://projectreporter.nih.gov/reporter.cfm. The generation of new primary data is not supported by this topic.

Fast Track proposals will be accepted. Direct to Phase II will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: $300,000 for up to 1 year; Phase II: $2,000,000 for up to 3 years. Background The RV144 Phase III Thai trial, which tested the heterologous prime-boost combination of two vaccines: ALVAC® HIV vaccine (prime) and AIDSVAX® B/E vaccine adjuvanted with Alum (boost), showed limited 31% protective efficacy and revealed the need for novel and more potent vaccine formulations. Co-delivery of adjuvant/immunomodulators with HIV antigens has the potential to modulate the type, quality, and durability of antigen-specific immune responses through a variety of mechanisms that include the induction of regulatory T cells or by altering the profile of the pathogenic lymphocyte response (e.g., Th1 to Th2 or vice versa). Significantly, induction of protective and long-lasting durable immune responses, activation of germline B cells along with enhanced magnitude and breadth of antibodies that can be harnessed by optimal HIV antigen-adjuvant/immunomodulators/Toll-like receptor agonists (TLR) formulations would aid in the rational design of a safe and effective preventive HIV vaccine. More recent efforts have focused on testing adjuvant formulations that can boost the immune response and generate broadly neutralizing antibodies to HIV-1 Env. Despite these efforts, significant challenges remain towards achieving optimal and effective immunogen/adjuvant formulations for an efficacious HIV vaccine. While ongoing new strategies and efforts for developing an effective HIV vaccine have predominantly focused on design of new HIV immunogens and targets, an understudied area of investigation are studies involving co-delivery and formulation of HIV immunogens with adjuvants. As such, several challenges remain, including poorly understood and variable humoral and cellular immune responses in preclinical and clinical setting, lack of consistent tier 2 broadly neutralizing antibodies (nAbs), maintenance of Env immunogenicity, selection of optimal inoculation sites and trafficking to lymphatics, stability of the incorporated and/or co-delivered antigens and Env neutralizing epitopes in select adjuvant formulations, and induction of mucosal immunity and long-term maintenance/durability of the immune response. Moreover, access to promising new/proprietary adjuvant systems developed by commercial organizations, development of effective combinations of adjuvant formulations and public-private partnerships are highly desirable and warranted for HIV vaccine development. While alum-based adjuvants and variations of oil-in-water approaches have been tested with other non-HIV recombinant protein immunogens, the results obtained from other immunogens, which are generally more stable and less glycosylated than Env protein, have been difficult to extrapolate to HIV vaccines. Finally, the empirical basis of studies and the large inter-laboratory variations in antigen/adjuvant mixture formulations and protein stability assays used to characterize these mixtures further limits the usefulness of these data for HIV vaccine research. Project Goal Co-delivery of adjuvants with HIV antigens combined with HIV immunogen design is not mutually exclusive and should converge to accelerate the development of safe and effective adjuvanted HIV vaccine candidates that are capable of effective B/T-cell activation, enhanced antibody avidity or broadening of effector immune responses while minimizing reactogenicity and preserving the protective immune responses against HIV. The primary goal of this SBIR solicitation is to support, accelerate and advance early stage and/or pre-clinical development and optimization of a promising HIV antigen-adjuvant formulation or select combination-adjuvant(s) for co-delivery/co-administration for a preventative HIV vaccine. Phase 1 activities may include, but are not limited to: • Developing optimal parameters/conditions for HIV protein antigen(s) and adjuvant co-formulations; developing conjugating technologies to attach immunogens to adjuvants. • Developing and evaluating particulate adjuvant systems 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, biosimilars and/or novel adjuvants/TLR agonists. • Evaluating formulations with immunomodulatory agents such as mineral salts, microbial products, emulsions, cytokines, chemokines, polymers, liposomes, lipid nanoparticles, saponins, carbohydrate adjuvants, TLR agonists, etc. • Developing and harmonizing all relevant analytical assays and testing methods for physicochemical, biophysical and functional/potency characterization of antigen-adjuvant formulations and its individual components, as applicable. • Evaluating and screening compatibility of excipients, buffers, pH on adjuvanted antigen formulations and its performance. • Measuring the effects of these interactions using critical in vitro performance metrics and quality attributes related to vaccine adsorption, desorption, potency, antigen integrity, and stability. • Developing and optimizing novel adjuvant combinations by admixing previously known individual adjuvants, including characterization of adjuvant combinations previously shown to enhance immune responses synergistically and/or additively. • Evaluating conditions for vaccine presentation as a two-vial system with bedside mixing and/or one vial co-formulation of adjuvanted antigen. • As appropriate, evaluating and comparing different adjuvanted formulations in small animal models, assess the influence of route of administration, delivery and dose-sparing capacity of HIV antigen-adjuvanted vaccines on the kinetics of immune response. • Conducting short term stability studies on antigen-adjuvant formulations. • Testing for batch-to-batch reproducibility and consistency of adjuvanted formulations for manufacturing. Phase II activities may include, but are not limited to: • Developing lead antigen-adjuvant formulation into an efficient, stable and reproducible formulation 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). • cGMP manufacturing processes for developing adjuvanted formulations. • Evaluating the performance, effectiveness, and toxicity of adjuvanted HIV vaccine candidates vs. soluble antigen in small animal models. • Evaluating adjuvants in NHP studies. • Establishing quality assurance and quality control, methodology and development protocols for generation of HIV antigen-adjuvanted formulations for co-delivery. As appropriate, collaborating and/or partnering with different labs to harmonize inter-laboratory variations in antigen/adjuvant mixture formulations and for characterization and protein stability assays.

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. Page 107 • 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 codelivery.

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 will not be accepted. Number of anticipated awards: 1-2 Budget (total costs): Phase I: $300,000 for up to one year; Phase II: $2,000,000 for up to 3 years. Background Therapeutic targeting of RNA may be a strategy which could inhibit the translation of one or more disease-associated proteins. Antisense technologies have been highly effective; however, these technologies rely on derivatized oligonucleotide structures which have poor cell permeability and biodistribution which limits their effectiveness as a therapeutic. The identification of detailed RNA structures now allows the design of small molecules which are capable of binding to RNA with high selectivity and specificity. This strategy has the potential to expand the use of small molecules beyond inhibiting functional activity, by preventing the translation of mRNAs, so that the targeted protein is never expressed. Small molecule drugs have been developed that successfully inhibit several HIV intracellular proteins. However, a number of HIV proteins have not been successfully inhibited since they lack a reactive site that can bind a small molecule. By developing small molecules to selectively bind to key sites on transcribed HIV RNA the translation of RNA to protein may be inhibited for any HIV intracellular protein. Targeting one or more HIV RNA sequences with small molecules may be an effective way of shutting down viral replication, preventing cellular transmission and ultimately leading to sustained viral remission. Project Goal The goal of this SBIR solicitation is to support the discovery and design of RNA-targeted small molecules which specifically bind to HIV RNA transcripts to prevent RNA processing and translation into protein. Phase I activities may include, but are not limited to: • Designing, optimizing and testing strategies for the targeting of small molecules to key sites on HIV RNA. • Performing proof-of-concept studies to demonstrate that small molecule binding to HIV RNA can prevent processing and translation into proteins in relevant cell lines and primary cells. • Evaluating off-target effects. • Performing proof-of-concept studies in an HIV animal model. Phase II activities may include, but are not limited to: • 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.

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 immune-mediated 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. The field of tolerogenic adjuvants is still in its infancy. No compounds have been licensed yet in the U.S. and immune-mediated diseases continue to be treated mostly with broadly immunosuppressive drugs or long-term single or multi-allergen immunotherapy. In contrast to drugs, tolerogenic or immunomodulatory adjuvants would interfere with immune responses to specific antigens through a variety of mechanisms including the induction of regulatory T cells, or by changing the profile of the pathogenic lymphocyte response (e.g., Th1/Th2/Th17, etc). 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 for 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., 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). Examples of applications of tolerogenic adjuvants include: combination with allergen immunotherapy to accelerate tolerance induction, increase the magnitude of tolerance and decrease treatment duration; and combination with self- or donor-derived antigens to induce tolerance in the recipient. Project Goal The objective of this program is to support the screening for new adjuvant candidates for vaccines against infectious diseases or for immune-mediated diseases (autoimmune and allergic diseases or transplant tolerance); adjuvant 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 testing of newly identified immunomodulatory compounds or formulations as stand-alone immunotherapeutics (i.e., without a specific antigen) • The testing of newly identified immunomodulatory compounds or formulations in cancer models • The further development of previously identified adjuvants, if being used for the original indication (i.e., in vaccines against infectious diseases or as a tolerogenic 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: 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 (i.e., autoimmunity, organ/tissue transplant rejection, allergic diseases and asthma). 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, donor-specific-antigens in transplant rejection, 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). 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, or for autoimmune or allergic diseases, or organ/tissue transplantation tolerance. The adjuvant products supported by this program must be studied and further developed toward human licensure with currently licensed or new investigational vaccines and cannot be developed as stand-alone agents. Phase I Activities Depending on the developmental stage at which an adjuvant is entered 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 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 • Discovery of the vaccine’s antigen component, though further development as part of adjuvant/antigen formulation is acceptable • The development of immunostimulatory compounds or formulations as stand-alone immunotherapeutics (i.e., without a specific antigen/pathogen-specific vaccine component)

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 adjuvants with those used in licensed vaccines or at late stages of clinical development is hampered by limited access to such reagents. NIAID supports the discovery and development of novel adjuvants through different mechanisms; and this topic is intended to address the limited availability of adjuvants that mimic the functionality of those with a favorable clinical track record. This topic also supports the development of formulations with immunostimulatory components that are functionally, but not necessarily chemically, similar to those used in licensed vaccines or at late stages of development Project Goal Development, validation and production of adjuvants that are based on, or similar to, compounds or formulations successfully used (i.e., efficacious) in clinical trials or part of licensed vaccines, 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 are 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 • 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) • Intellectual Property: The awardee is solely responsible for the timely acquisition of all appropriate proprietary rights, including intellectual property rights, and all materials needed for the awardee to perform the project. Before, during, and subsequent to the award, the U.S. Government is not required to obtain for the awardee any proprietary rights, including intellectual property rights, or any materials needed by the awardee to perform the project. .

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 specific 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-κB 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 specific non-mammalian models or underrepresented mammalian models. Justification should be provided for the selection of proposed targets which may include immune cell markers, receptors with immune function and or other molecules important for immune function. 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: • 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 MAY include, but are not limited to: • Comprehensive evaluation of specificity and functional utility of the reagent(s), such as evaluation of non-specific binding to cells or unrelated molecules and utility of antibodies/reagents for specific indications (e.g., Western blotting, immunoprecipitation, immunohistochemistry, flow cytometry) • 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 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 Chronic infection with hepatitis B virus (HBV) leads to serious and often fatal liver diseases like cirrhosis and hepatocellular carcinoma. Current therapy uses potent antiviral drugs that significantly lower viral replication in patients. However, all the currently used small molecule drugs - nucleoside/nucleotide analogs - target the function of a single HBV protein, the polymerase (reverse transcriptase), and none achieves complete and permanent cure. Thus, these drugs are used for many years, even lifelong, at the risk of inducing toxicity and drug resistance. With the elucidation of new viral and cellular targets and pathways involved in HBV infection and replication, novel antiviral drugs may be within reach. Novel drugs may potentially be used as monotherapies or in combination with existing therapies. It is imperative that the pace of development of new drugs be measurably accelerated to lower the very substantial global burden of HBV. Project Goal The purpose of this solicitation is to invite research on candidate drugs and mechanisms of action different from that of existing licensed drugs, and pre-clinical development of such candidates, with the express purpose of advancing them commercially. The objective is to obtain functional cure of HBV - defined as loss of virus, loss of hepatitis B surface antigen (HBsAg) and seroconversion, which rarely occurs with current regimens. As the intent of this project is to obtain potentially curative drugs, it may be necessary to develop, in parallel, additional determinants of post-treatment efficacy (both short- and intermediate-term). Phase 1 activities may include, but are not limited to: • Selection of lead compounds that efficiently target viral or cellular products or pathways with potent anti-HBV effects and low cell toxicities. • Studies on mechanisms of action of potent inhibitors of HBV and/or host cellular pathways that support HBV infection, replication, and persistence. Phase 2 activities may include, but are not limited to: • Developing promising selected lead compounds characterized in phase I studies, including investigating structure activity relationships (SARs) for optimization of lead compounds. • Studying efficacy parameters of new anti-HBV drug candidates in an animal model of HBV replication, as envisioned in the project goals. • Optimizing absorption, distribution, metabolism, and excretion (ADME); pharmacokinetics (PK); and minimizing cytotoxicity. • Examining potential synergistic activity of candidate drug with currently used standard of care HBV drug(s). 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). For SBIR phase II clinical trial support, see the NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement program announcement.

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 Human enterovirus (HEV) infections can cause a variety of conditions including conjunctivitis, hand-foot-mouth disease (HFMD), viral meningitis, viral encephalitis, pericarditis, acute flaccid paralysis (AFP), myocarditis, and possibly type 1 diabetes. While HEV infections are common and generally mild, in some patients HEV infections can cause severe symptoms, including sepsis in neonates, aseptic meningitis in children, and meningitis in adults. EV-D68, EV-71, and coxsackie viruses have been implicated in causing acute flaccid myelitis (AFM) in recent years. Currently, there are no therapeutics available to treat enterovirus infections. There are seven HEV species, each of which includes multiple members, and many of them are known to cause disease. Non-pathogenic strains can evolve to acquire pathogenic potential as well, which can cause difficulty for therapeutic development. One way to address this problem is to focus on broad-spectrum therapeutics, specifically monoclonal antibodies. Project Goal The goal of this topic is to develop broad spectrum prophylactic and therapeutic monoclonal antibody therapeutics against human enteroviruses. The final product can be monoclonal antibodies specific to multiple enteroviruses, a combination of multiple monoclonal antibodies with a narrow specificity, or both. The final product should target different strains of a single family, for example, multiple EV-D68 strains, multiple members in one species (for example Enterovirus A species), or members in multiple species (for example, coxsackie viruses in A and B species). The choice of strains should be medically relevant. Phase 1 activities may include, but are not limited to: • Develop multi-spectrum monoclonal antibodies. • Demonstrate neutralizing activity in vitro against target enteroviruses. • Humanize antibodies if applicable. Phase 2 activities may include, but are not limited to: • Further improve multi-spectrum humanized monoclonal antibodies including but not limited to humanizing monoclonal antibodies and improve potency. • Demonstrate therapeutic potential in animal models. • Develop an efficient delivery system. This SBIR will not support: • Products primarily focused on poliovirus. 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). For SBIR phase II clinical trial support, see the NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement program announcement.

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 Timely recognition and treatment of invasive fungal diseases (IFDs) is necessary to reduce the morbidity, mortality and inappropriate antibiotic usage commonly associated with IFDs. Recent medical advances in the management of cancer patients and hematopoietic stem cell and organ transplantation, in addition to immunocompromising diseases, such as AIDS, have created an expanding population at risk for IFDs. Unfortunately, the management of patients with suspected IFDs often involves empiric, prophylactic antifungal therapy until the results of time-consuming, culture-based and/or highly technical assays are made available. The prophylactic use of antifungal agents is associated with an increase in resistance to the available antifungal therapies and a rise in fatal IFDs by previously rare fungal organisms such as the Mucorales and Fusarium spp. Assays that rapidly diagnose fungal infections will preserve the utility of the available antifungal therapies and reduce the inappropriate use of antibiotics. Project Goal The purpose of this project is to support the development of rapid, sensitive, specific, simple, and cost-effective diagnostics for primary health-care settings (hospitals and point-of-care (POC)) to detect IFDs. Phase 1 activities may include, but are not limited to: • Identification of appropriate biomarkers for a prototype POC diagnostic for invasive fungal diseases. • Development of the prototype POC diagnostic product for detection of invasive fungal diseases. • Determination of the sensitivity, specificity and other performance characteristics (e.g. time to result, limit of detection, test stability) of the prototype POC diagnostic. Phase 2 activities may include, but are not limited to: • Further characterization of appropriate biomarkers for a prototype POC diagnostic for invasive fungal diseases. • Further development of the prototype POC diagnostic product for detection of invasive fungal diseases. • Further determination of the sensitivity, specificity and other performance characteristics (e.g. time to result, limit of detection, test stability) of the product. • 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). For clinical trial support, please refer to the NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement program announcement or the NIAID Investigator-Initiated Clinical Trial Resources webpage. • Proposals that do not include the identification of at least one of the following dimorphic fungi: Coccidioides spp, Histoplasma spp, Blastomyces spp, Paracoccidioides spp, Talaromyces spp, and Sporothrix spp.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $150,000 for up to 6 months PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Reflective of the larger opioid epidemic, the number of newborns dependent on opioids has increased dramatically, from 2,920 in 2000 to 31,904 in 2014, the latest year of published data. These newborns experience withdrawal symptoms after birth, which can include: high-pitched and excessive crying, increased muscle tone, uncontrollable shaking (tremors), sweating or fever, rapid breathing rate, frequent yawning, and poor feeding and growth. Newborns born dependent to opioids have longer birth hospitalizations (17 days versus 2 days mean length of stay for a healthy newborn) and higher hospitalization costs ($19,340 versus $3,700 for a healthy newborn). Assessment of withdrawal symptoms depends on the judgement and experience of clinical staff, which may vary and can result in inadequate treatment. For example, assessment of a high-pitch and excessive cry can vary between nurses. Different observations can result in incorrect treatment. Additionally, it may be difficult for staff to distinguish whether observed symptoms are due to withdrawal or simply waking a sleeping newborn at set times. Using technology to standardize symptom measurement would reduce variation in diagnosis and quality of care; however, no such device exists. Creating a device that objectively measures withdrawal symptoms in a continuous manner could greatly improve the care of these newborns. Project Goals The goal of this project is to create a wearable device that objectively measures a newborn’s withdrawal symptoms, including: 1. tremors (frequency and duration, start and stop time); 2. muscle tone (degree of rigidity); 3. crying (frequency, duration, pitch); 4. body temperature (fluctuations); and, 5. sleep (duration, frequency of sleep cycles). The device will have the following characteristics: 1. small and unnoticeable for newborn wear; 2. humidity-resistant; 3. bacteria-resistant (infection-controlled); 4. single use; 5. wireless; 6. able to capture data for 12-hours without interruption; and, 7. user-friendly interface for clinicians to view symptoms. Phase I Activities and Expected Deliverables The expected deliverable for Phase I is a functional prototype with the above mentioned specifications. Wearable technology is capable of capturing body temperature, movement, and sleep cycles for adults. It is anticipated that this technology could be adapted or developed for newborns. Activities for Phase I include: 1. Build upon existing technology to create a device that not only captures body temperature, movement, and sleep, but also sound (crying frequency, duration, pitch) and muscle tone (degree of rigidity); 2. Ensure the device is small enough and safe for newborn wear; 3. Create a user-friendly interface to view symptoms and guide diagnosis, treatment, and management of opioid withdrawal in newborns. Impact The number of newborns with opioid withdrawal has increased dramatically from only 2,920 newborns in 2000 to 31,904 newborns in 2014. In 2011-2014, newborns with opioid withdrawal cost Medicaid$462 million. A device that assists clinicians in accurate assessment of withdrawal symptoms in newborns could lead to improved diagnosis and management along with shorter lengths of stay (and lower costs). Exposure to medication-assisted treatment can also lead to newborns with opioid withdrawal. Initiatives to improve the care of these newborns, supplemented by devices that can objectively monitor symptoms, is key to improving quality and standards of care. To be successful, the awardee will have to demonstrate ability to design a safe, functional device (as described above) and navigate Institutional Review Board approval for any potential clinical research or requirements necessary for FDA approval. Compliance requirements for FDA approval may vary depending on how the device is developed. Commercialization Potential This technology could greatly improve the diagnosis and management of newborns with opioid withdrawal in hospitals and neonatal intensive care units. In 2014, over 31,904 U.S. newborns had opioid withdrawal and stayed an average of 15 days in the hospital longer than newborns without withdrawal. Estimates of newborns with opioid withdrawal are expected to increase with the ongoing opioid epidemic. This technology could be used across the U.S. in all hospitals and neonatal intensive care units that care for newborns with withdrawal.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $150,000 for up to 6 months PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background The number of extreme flooding events that have been declared as “Billion Dollar Disasters” by federal agencies have increased in the last decade. Projections are that such events will become more widespread, as well as increase in frequency and intensity in the years to come. The direct impact of these flooding events cause disruptions in the provision of healthcare by affecting the operations of critical health infrastructure (such as hospitals) as well as impede access to care when roads become flooded. The lack of robust information on potential risk of flooding for healthcare facilities (e.g., hospitals, urgent care centers, and pharmacies) and real-time information on flooding that impedes patients’ access to care affects preparedness planning before and during flooding events. There are no existing online platforms or websites that link flooding and hospital data to aid healthcare resiliency and protect public health during floods. Project Goals The goals of this project are to (i) prepare a national database that assesses the risk of flooding to health facilities (e.g., hospitals, urgent care centers, and pharmacies); and (ii) disseminate information via a web-based platform or app on baseline risk and real-time information on inundation zones through mobile technology to stakeholders (e.g., facility managers, patients, emergency responders) that would facilitate preparedness planning. The ultimate goal of this project is the launch of an online data portal or platform, providing high-resolution spatial information on baseline flood risk and real-time inundation information. The proposed data platform, intended to receive updated data feeds from federal agencies and private partners, can protect human health during flooding disasters by facilitating access to healthcare and emergency care. Phase I Activities and Expected Deliverables The expected deliverables are the: 1. Collection and synthesis of publicly available baseline flood risk information from sources such as the Environmental Protection Agency (EPA) and the Federal Emergency Management Association (FEMA). 2. Creation of a national dataset of critical healthcare facilities using data from sources such as the American Hospital Association, Urgent Care Association, and "Healthcare Ready." Software developers must attend to privacy concerns associated with these data systems (e.g., protected health and law enforcement data). 3. Merging of two datasets into a single pilot web-based platform that overlays flooding maps with healthcare facilities, demonstrating potential facilities at risk from flooding. Software must be user-friendly, and accompanied by guidance for effective utilizations of the platform. Impact This project will provide scientifically robust risk information that will facilitate healthcare agencies development of preparedness plans to improve resiliency to extreme weather events. Individual patients seeking emergency and/or regular healthcare services can use the mobile app to seek alternatives, if normal services are disrupted due to an extreme weather event. This can improve the resiliency of the healthcare system and access to care. Commercialization Potential The resulting platform or app could be seen as a unique innovation and beneficial to hospitals, long-term care facilities, other healthcare facility managers, healthcare transportation-related companies (e.g. ambulance contractors and others that may travel roads to healthcare facilities that could be impeded by flood waters), and other relevant user

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will be accepted. Number of anticipated awards: 1-2 Budget (total costs): Phase I: up to $150,000 for up to 6 months PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Current methods for detecting and quantifying E. coli in water samples do not detect E. coli O157 or other related Shiga toxin-producing E. coli (STEC) strains. There are several commercially available assays to quantify E. coli in water samples; however, they rely on detection of the beta-glucuronidase enzyme, which is not present in STEC strains. Food Safety and Modernization Act (FSMA) regulations now require food producers to ensure that all water used for irrigation meet the standards for recreational water, which sets a maximum value at 126 cfu/100 ml. Despite this regulation, a multistate outbreak of E. coli O157 was linked to contaminated irrigation water used for romaine lettuce production. The outbreak strain was isolated from three irrigation water samples. Importantly, all three of these samples were below the FSMA-required E. coli levels, suggesting that even water that passes standard water quality metrics can harbor dangerous levels of E. coli O157. Project Goals The goal of the proposed research is to develop an assay that can detect and quantify E. coli O157 in water samples. This assay must be amenable to on-site use by stakeholders, such as farm managers, environmental health consultants, water managers, and packing shed managers. The assay can use molecular or non-molecular methods to detect and quantify E. coli, but must not require an advanced molecular laboratory. The assay will provide a quantitative measure of E. coli O157 present in the sample and must be able to detect 1 cfu/100 ml. Phase I Activities and Expected Deliverables The expected deliverables are: 1. Develop or adapt a method to detect and quantify E. coli O157 in water samples; the assay must be able to detect 1 cfu/100 ml. 2. Determine the sensitivity and specificity of the test against E. coli O157, other STEC serotypes, and non-STEC E. coli. 3. Conduct matrix evaluation to understand the assay performance using different water types (e.g., varied mineral or chemical composition, pH, etc. of the water source being tested). Impact The product of this proposed research will allow food producers to monitor their water supplies for E. coli O157, which is currently not possible. Once monitoring is available, control processes can be implemented to protect food products and ultimately reduce the burden of E. coli O157 infections. Commercialization Potential This research will lead to the development of a new water quality test method that can be implemented by stakeholders at every point in the supply chain from the farm to the packing shed operators. Potential products include assay kits, assay reagents, and water sampling devices. These products could be used by farm managers, water managers, and packing shed operators, as well as federal, state, and local public and environmental health agencies

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will be accepted. Number of anticipated awards: 1-2 Budget (total costs): Phase I: up to $150,000 for up to 6 months PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Sampling surfaces to investigate disease transmission is a common practice. Surfaces touched by patients and healthcare workers, such as bedrails, tables, and 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 metagenomics 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 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 bio threat 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 is able to 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. The criteria for a successful device are: 1) Easy to use. 2) Packaged as sterile and pre-moistened OR be easily pre-moistened aseptically at the sampling site. 3) Sterile gloves are not required by the person using the device to collect organisms from a surface. 4) After sampling, the device can be sealed aseptically to prevent contamination. 5) 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. 6) The 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. 7) Effective at collecting and eluting organisms, recovering the same log10 level of organisms known to be present on a surface. 8) Low cost (<$15 for each device). Phase I Activities and Expected Deliverables The expected deliverables are: 1) Develop prototype sampling, elution and concentration device. 2) 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, and 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 bio threat 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 be accepted. Number of anticipated awards: 1-2 Budget (total costs): Phase I: up to $150,000 for up to 6 months PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Each year approximately 1,000 new cases of cystic fibrosis (CF) are diagnosed, with over 30,000 living with CF in the United States. Over half of the CF patient population is now over the age of 18; these patients are living longer and, consequently, are exposed to more and more antibiotics over time, often as part of the daily care regimen. Critically important for their care, these chronic and repeated antibiotic treatments can have unintended consequences, such as the development and spread of antibiotic resistance and multidrug-resistant organisms, including Pseudomonas aeruginosa. More than other patients, those with CF have suffered longest under the threat of untreatable pan-resistant infections Antimicrobial susceptibility testing (AST) relies on standardized microbiological techniques assessing growth of pure cultures using either solid or liquid media and various concentrations of antibiotics. The inhibition of growth is predictive of treatment success and is 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). Lung infections in cystic fibrosis patients is one example of such infections; traditional antibiotic susceptibility testing fails to account for the impact of an antibiotic on the 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 goal of this project is to support the development of a standardized diagnostic platform for use in a clinical laboratory to determine the microbial community susceptibility/antibiogram of an infection using primary cystic fibrosis (CF) clinical specimens (i.e., sputum). This test should produce data useful for informing clinical treatment decisions. The proposal should incorporate appropriate methods for specimen management and processing, medium composition, including potential host factors that affect microbial growth or antibiotic activity in vivo, standard methodologies to arrive at a quantitative measurement of minimum inhibitory concentration, and back end detection/verification of target pathogen activity. Such work may involve laboratory-developed test methodologies/models or significantly adapted commercial platforms for use in parallel and in comparative assessments with standard clinical isolate-level 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 diagnostic test development will require dedicated and highly refined approaches specific to primary specimen and pathogen combination. The technical merit or feasibility of the proposed methodology should be assessed through initial bench-top (in vitro) studies of sputum, with the focus on a single pathogen and associated/community and matrix attributes. For these efforts, an existing set or bank of clinical sputum specimens from CF patients, collected longitudinally before, during, and after antibiotic treatment, and with complete data available (antibiotic treatment, single pathogen antimicrobial susceptibility testing results, clinical indicators and outcomes) is needed. These studies should be designed to provide a proof-of-concept. Expected deliverables would include: 1. Establish a laboratory-developed in vitro test methodology/model, or significantly adapt an existing commercial platform, that can test clinical sputum specimens for microbial community-susceptibilities or yield a microbial community-antibiogram. 2. Apply the method/model from deliverable #1 to sputum from an existing set or bank of clinical specimens (described above), to track sequential sputum community composition (or changes in sputum community) following treatment with one or more antibiotics (same antibiotics as the patient received). Microbial community composition would be defined using next generation sequencing. 3. Proof of concept: Compare these in vitro community changes to microbial community changes observed in clinical sputum specimens from the same patient during/following antibiotic treatment. Demonstrate whether the in vitro microbial communities are or are not significantly different from the sequential clinical sputum specimens from the same patient. Microbial community composition would be defined using next generation sequencing. Impact This project has the potential to impact antibiotic stewardship and therapeutic practice using available primary sputum 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. The results of this project have the 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 be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $150,000 for up to 6 months PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Legionnaires’ disease is a severe pneumonia typically caused by inhalation of aerosolized water containing Legionella bacteria. In the United States, more than 8,000 illnesses are reported annually, though this likely underestimates the true burden of disease. This represents an increase of more than 500% since 2000. When complex building water systems are not well maintained, Legionella bacteria can grow and spread, creating a risk for infection. Common sources of exposure to Legionella include showers, hot tubs, water misters, and large air conditioning devices known as cooling towers. During outbreak investigations, public health professionals often collect environmental samples from these and other devices to identify potential sources of exposure. Testing for Legionella bacteria is time-consuming, requires specific expertise, and typical takes between 7-14 days before results are available. Recently, PCR-based technologies have been introduced that have the potential speed up the testing process. Unfortunately, current tests that rely solely on detecting Legionella genetic material cannot distinguish between live and dead bacteria, limiting their usefulness. A test that could rapidly identify viable Legionella in environmental water samples has the potential to accelerate detection of exposure sources. This would significantly improve the ability of public health professionals to halt outbreaks of Legionnaires’ disease when they occur. Project Goals The goal of this research is to develop a test that can rapidly detect viable Legionella bacteria in water samples collected from environmental sources. Ideally, this test would be simple to perform, have the ability to detect and identify all species of Legionella in a sample, and require minimal processing of the sample. The true innovation of this research would be shortening the time to detection and quantification of Legionella bacteria. A true breakthrough would require this time to be shortened considerably from the current 7-14 day requirement for traditional Legionella culture. A successful test would not need to be purely culture-independent if other project goals were met. This test would also not need to generate Legionella isolates. Phase I Activities and Expected Deliverables The expected deliverables are: 1. Develop a laboratory assay that detects viable Legionella bacteria in environmental (water) samples. The approach may use molecular, serological, or chemical procedures singly or in combination. Minimum performance criteria are: • Time to result less than 72 hours • Discrimination of strains of clinical interest (i.e., Legionella pneumophila serogroup 1.) • Detailed typing information is not necessary, but at minimum, the procedure must be able to differentiate between Legionella pneumophila and all other Legionella spp. 2. Demonstrate proof of principle by comparing results with traditional Legionella culture methods. This could be accomplished using laboratory-generated, Legionella-containing water samples using multiple water sample sources (e.g. potable water, cooling tower basin water, utility distribution system water, etc.). 3. Determine ranges of sensitivity and specificity for all water sample sources tested. If the procedure provides quantification of viable Legionella, the limit of detection and precision should also be determined. 4. Develop a protocol to validate the assay in the field. Impact The development of a rapid assay would significantly advance public health response. The current 7-14 day wait time associated with Legionella culture testing can lead to additional cases of disease, limits the ability of public health to identify the exposure source, and delay recommendations that could protect the public. Shortening this time can speed up the response to cases and outbreaks of Legionnaires’ disease. It could also lead to more widespread testing to identify risky exposure sources before they cause disease. The wait for testing results can delay the time before action can be taken to eliminate any risk that might be present. A more rapid test with actionable results could solve this problem. Finally, successful completion of this project could expand environmental Legionella testing to more public health, academic, hospital, and private labs. Currently Legionella culture testing is difficult to perform and requires significant expertise. A simpler test could lead to adoption of Legionella testing in more labs, increasing the ability for healthcare facilities, hotel owners, cooling tower operators, and state and local public health jurisdictions to obtain results during outbreak investigations or for routine testing purposes. Commercialization Potential A test developed as part of this research proposal has significant commercialization potential. Cases and outbreaks of Legionnaires’ disease have increased significantly over the past 10 years. This has resulted in more investigations, which typically require testing of environmental samples. A product that simplified and sped up this process would be useful to both public health labs and private consulting companies. Recently, the Centers for Medicare & Medicaid Services (CMS) released a memorandum stating that all acute care facilities must implement a water management program to prevent the growth and spread of Legionella bacteria. While not required, many of these facilities may choose to begin routinely testing their water systems for presence of Legionella. A rapid, easy to administer, reliable test to detect Legionella could prove very useful for these facilities. Recent reports have estimated that the market for Legionella testing eclipsed $180 million in 2016. This number is expected to increase to nearly $400 million by 2025. The advent of a Legionella test that solves many of the problems associated with the current technologies could prove extremely lucrative from a commercial standpoint.