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

(Fast-Track proposals will not be accepted. Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning.) Number of anticipated awards: 1 to 4 Budget (total costs, per award): Phase I: $325,000 for 9 months; Phase II: $2,000,000 for 2 years It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Summary: The objective of this contract is to develop and validate digital health technologies for data capture that can be used to assess individuals with rare diseases in remote settings in a manner that is suitably sensitive and specific for use in clinical trials. Technologies should be reliable, secure, and easy to use to monitor study participants remotely. Conducting clinical trials for both rare and common diseases involve many challenges, some of the most frequent of which include the identification, enrollment, and retention of study participants. Most clinical research trials, regardless of disease area, are conducted at large academic medical centers, and patients who do not live near the research centers are often unable to participate due to health challenges, financial challenges, and the difficulty committing to long-term trials that requires regular travel. It is also difficult to recruit a diverse cohort of patients for study, resulting in many study populations being homogenous and not broadly representative of the US population. Additionally, because the individual rare diseases each have only a few patients with the condition, participation from patients at multiple national and international sites will often be needed, and rare disease research community often faces the added challenge of meeting regulatory requirements for more than one international regulatory agency. Virtual, decentralized, remote or site agnostic trials may be used to include individuals in studies that previously would have been excluded. In addition to these commonly encountered clinical trial challenges, rare diseases present additional complexities beyond those seen with many common conditions. For example, most rare diseases do not have clinical trial precedent and there are typically no validated outcome measures to assess treatment effects. Rare disease researchers often are, therefore, left to develop their own measures that have not been previously used or validated or they must modify existing measures developed for other disorders that may not provide the required sensitivity or specificity needed to accurately assess targeted outcomes. Data that is collected will also need to be seamlessly captured and integrated from multiple sources and be of sufficient quality to meet regulatory requirements. Page 64 Mobile technology offers the opportunity for remote participation and monitoring of study subjects, as well as remote and reliable data capture. This includes technologies that have not yet been widely incorporated into regulated clinical trials, such as wearables, ingestibles, implantables, and portables. Patient-reported outcomes (PROs), Observer-reported outcomes (ObsROs), Performance outcomes (PerfOs), Clinician-Reported outcomes (ClinROs) can also be collected using innovative technology. Development and use of these technologies have the potential to allow for broader and more diverse study populations for participation in clinical trials for rare diseases while simultaneously improving the quality of data capture and efficiency of the trials. The Clinical Trials Transformation Initiative (CTTI), (funded in part, by the Food and Drug Administration through grant R18FD005292 and cooperative agreement U19FD003800 - https://www.ctti-clinicaltrials.org/projects/digital-health-technologies ) has developed recommendations for the use of mobile technologies for data capture for use in clinical trials, and comprehensive guidelines for reducing barriers to participation. These recommendations, provided only for informational purposes, include mobile technology selection, data collection, analysis, and interpretation, data management, protocol design and execution, and FDA submission and inspection. In addition, CTTI recommendations state that as technologies are developed, it will be important to consider that end users will still need to 1) adhere to scientific principles currently in use across the clinical trials enterprise; 2) adhere to data quality principles, which are the same for clinical trials using mobile technologies for data capture and those using data collection approaches in the clinic; and 3) study participant engagement is critical in the design of trials that use mobile technologies for data capture. Goals and Specific Objectives: Technology developers, clinicians, researchers, and patients/patient groups will work collaboratively to develop validated digital health technologies specifically for outcomes data capture for clinical trials for rare diseases, and not for the purposes of recruitment, retention, or as the intervention itself. Digital health technologies may include clinical outcome assessments including new or modified: Patient-reported outcomes (PROs), Observer-reported outcomes (ObsROs), Performance outcomes (PerfOs), ClinicianReported outcomes (ClinROs) and devices for gathering physiological data. The technology must be reliable, secure, and easy to use to monitor study participants remotely, either in the home or while participating in activities of daily living. The technology should also be appropriate for use in three or more different rare diseases, (e.g., tool to assess movement in neurodegenerative diseases, PRO for reporting level of pain). Phase I Activities and Expected Deliverables: Develop prototype digital health technologies specifically for outcomes data capture for clinical trials 1. Intended population a. Describe intended population(s) i. Rare diseases ii. Age group 2. Measurement Property a. Target measure – describe purpose of measure i. Reliability – describe test re-test reliability ii. Validity – describe content and construct validity iii. Sensitivity – describe the ability to detect change iv. Specificity – describe the ability to measure target 3. Technical Performance – For the digital health technology prototype describe and demonstrate: a. Measurement Performance across multiple environments i. Accuracy – The digital health technology must have agreement between the measurement and a known standard in the field ii. Precision – Describe and demonstrate agreement across multiple measurements for the device such that it is evident that variability in assessment is due to the measuring technology iii. Calibration-Describe the process of calibration. iv. Sampling Frequency- Describe the sampling process v. Resolution- Describe the amount of measurable change vi. Reliability -Describe the ability to yield consistent, reproducible estimates of true treatment effects vii. Data Processing – Describe the operations performed on a given set of data to extract the required information in an appropriate form b. Metadata- Sufficient and appropriate metadata is required to provide context for the data captured by mobile technologies, allow it to be readily interpreted, and determine its clinical meaningfulness c. Mobile Technology Communication and Data Transfer Page 65 i. App Pairing – the connectivity and quality ii. Transfer to Data Gathering Platform – the transfer of individual participant data to a central server 4. Data Management Specifications a. Must be 21 CFR Part 11 Compliant b. Data Access i. Mobile Technology Manufacturer Access to Study Data – describe and demonstrate the process. Address security and consent issues ii. Sponsor Access to Study Data – describe and demonstrate what data will be provided to the end user (e.g., raw data, processed data, algorithms) and the data format. iii. Third Party Access to Study Data – describe procedures related to third party access to data (e.g., deidentified data from all users) 5. Safety Specifications a. Study Participant b. Data Security and Privacy i. Cybersecurity – describe and demonstrate steps taken to avert potential cybersecurity vulnerabilities ii. Privacy – describe and demonstrate policies, procedures, and technical approaches implemented to ensure Health Insurance Portability and Accountability Act (HIPAA) compliance 6. Human Factor Specifications a. Acceptability b. Tolerability c. Useability d. Appropriate for age of participant 7. Operational Specifications a. Firmware b. Failure Rate c. Battery life 8. Non-Performance specifications a. Cost b. Customer Service • Provide cost estimates to develop a proof-of-concept digital health tool capable of meeting the specifications listed above. • Present phase I findings and demonstrate the functional prototype system to an NCATS contracts and scientific team via webinar. • Provide NCATS with all data and materials resulting from Phase I Activities and Deliverables Phase II Activities and Expected Deliverables: • Build a prototype that meets the Phase I specifications. • Validate assessment method and technology in selected rare disease populations. • Provide a test plan to evaluates all components of the digital health technology • Demonstrate that the technology is scalable to potentially hundreds of pieces of instrumentation in a distributed fashion. • Present Phase II findings and demonstrate the software system to an NCATS contracts and scientific team via webinar. • 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. • Provide NCATS with all data and materials resulting from Phase II Activities and Deliverables.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 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 agerelated diseases is cellular senescence and its associated secretory phenotype (SASP). Senescence is a complex cellular state characterized by stress-induced replicative arrest, heterochromatization and transcriptional reprogramming. While senescence and the SASP play important short-term beneficial roles in orchestrating tumor suppression by blocking the proliferation of damaged cells, it also contributes to long-term detrimental effects if not readily removed. The oncogenic and tumor aggressive effects of senescence are driven by the SASP-associated anti-apoptotic, pro-inflammatory and invasive cytokines, growth factors and matrix-degrading enzymes. Aging tissues accumulate senescent cells; and the in vivo selective elimination of age-dependent/spontaneously emerging senescent cells is documented to delay tumor formation and deterioration of cardiac, renal and adipose tissue function. Furthermore, senescence is induced by a range of cancer treatments, including radiation, chemotherapy, and several targeted therapies. Therapy-induced senescence (TIS) and SASP-induced field cancerization may in turn promote invasive and metastatic phenotypes. In contrast, elimination of TIS cells is reported to reduce many side effects of cancer drugs in pre-clinical models, including bone marrow suppression, cardiac dysfunction, fatigue, and also reduce cancer recurrence. A number of research groups and companies are developing senotherapeutics, agents that exploit senescent cells for therapeutic benefit. Senotherapeutics include senolytics, pharmacologic agents that eliminate senescent cells, and senomorphics, agents that suppress senescent phenotype without cell-killing. A variety of agents have been reported to have senolytic activity and have demonstrated promising results in animal models. Despite the progress, senotherapeutic agents are not represented in the NCI’s SBIR portfolio and/or extensively tested as anti-cancer agents. Thus, the goal of this contract topic is to support small businesses developing senotherapeutics and catalyze the development of this class of drugs to improve outcomes for cancer patients Project Goals The purpose of this contract topic is to support the basic and pre-clinical development of senotherapeutic agents for use in research, neoadjuvant, adjuvant, or combination cancer therapy. Projects supported under this contract topic should extend the pre-clinical development of senotherapeutics as anticancer agent(s). Projects intending to enhance the efficacy of cancer therapies (including radiotherapy) or reduce the toxicities or the severity and duration of adverse effects by the use of senotherapeutics will also be supported. Such agents may include radiation-effect modulators and mitigators that reduce senescence associated side-effects. Responsive projects should have hit or lead compounds in hand, and offerors should use clearly defined parameters and accepted markers of senescence to define the population of senescent cells and senescent phenotypes being targeted by their agent(s). 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; animal efficacy testing; pharmacokinetic, pharmacodynamic, and toxicological studies. Phase I Activities and Deliverables: Phase I projects should focus on the optimization of the senotherapeutic agent(s), or combinations, and demonstrate proofof-concept by showing senolytic or senomorphic activity, and benefits in terms of efficacy and/or reduction of side effects when combined with appropriate cancer 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(s) 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. At the end of Phase I, in vivo efficacy should be demonstrated in an appropriate animal model. • Demonstrate in vitro efficacy for the agent(s) in human cancer-appropriate models. Appropriate endpoints Page 68 include demonstration of enhanced anticancer activity in combination with other therapeutic approaches (e.g. chemotherapy or radiotherapy), or the reduction of cancer therapy side-effects. • Conduct structure-activity relationship (SAR) studies, medicinal chemistry, and/or lead biologic optimization (as appropriate). • Optimize formulation of senotherapeutic agent(s) (as appropriate). • Perform animal efficacy studies in an appropriate and well-justified animal model of human cancer, for TIS, or aged mouse models that have accumulated senescent cells through aging and increased risk for cancer, and conduct experiments to determine whether senotherapeutic agent(s) confer benefits with respect to reduced side effects and/or cancer therapy efficacy. Phase II Activities and Deliverables: 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; animal efficacy testing; pharmacokinetic, pharmacodynamic, and toxicological studies. • Conduct structure-activity relationship (SAR) studies, medicinal chemistry, and/or lead biologic optimization (as appropriate). • Perform animal toxicology and 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 mitigation of adverse side effects to normal tissues and/or enhanced cancer therapy efficacy. • Perform other IND-enabling studies as appropriate for the agent(s) under development.

Fast-Track Proposal will be accepted Direct-to-Phase II proposal will be accepted Number of Anticipated Awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for 12 months Phase II: up to $2,000,000 for 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Cancer is a leading cause of premature death in low-resource settings globally. Nearly two-thirds of the 7.6 million cancer deaths worldwide occur in low- and middle-income countries (LMICs). Gaps in access to cancer treatment present significant challenges in many global health settings, especially in rural areas with limited infrastructure, where most of the LMIC population lives. Most of current cancer treatment technologies are not affordable in global low resource settings, and there is a need to develop cost-effective cancer treatment technologies. In addition, although treatment approaches exist in the US for most cancers, many examples of disparities in cancer outcomes exist for certain underserved populations, in both rural and urban settings. There are many factors thought to contribute to these disparate outcomes. We believe that novel treatment products that are affordable can improve cancer outcomes in LMICs and in underserved US populations. This solicitation will provide funding opportunities for small business concerns (SBCs) to develop cost-effective and affordable cancer treatment technologies that target low-resource settings, both internationally and within the US. It will allow applications to focus on any specific cancer type, however four cancer types (histologies) are highlighted that are of particular interest because they are highly amenable to cancer treatment in low-resource settings. The four cancer types of interest are: cancers of the cervix, colon/rectum, esophagus, and oral cavity. These four cancer types are given a high priority because the introduction of low-cost technologies for cancer treatment is likely to have an especially strong impact to reduce the burden of these cancers in low-resource settings. Project Goals The goal of this solicitation is to encourages applications from SBCs to develop or adapt, apply, and validate existing or emerging technologies into low-resource setting-appropriate technologies for cancer treatment. Page 69 Projects proposed for this contract topic will require multidisciplinary efforts to succeed, and, therefore, all applicant teams must include expertise in oncology, engineering, global health, and healthcare delivery in low-resource settings. Products addressing cancers of the cervix, colon/rectum, esophagus, and oral cavity are particularly encouraged for this solicitation. However, applications may address any cancer type and may benefit from LMICs collaborators. When appropriate, the proposed project may focus on a specific cancer type (histology). Scientific/Technical Scope Applications submitted to this solicitation must propose to develop or adapt technologies into user-friendly, affordable products for treatment of cancers in a low-resource setting. The proposed project must focus on a specific cancer type (histology) and must show preliminary evidence to deliver medical utility for improved cancer outcomes. Products addressing cancers of the cervix, colon/rectum, esophagus, and oral cavity are particularly encouraged for this solicitation. However, applications may address any single cancer type. The proposals must include quantitative milestones and a way to document the clinical utility of the propose product within the specific low-resource healthcare system of interest. The proposed product must comply with the regulations and international standards/guidelines applicable to investigational medical products in the low-resource setting where the product will be used (examples are World Health Organization guidelines and local regulations in LMICs, and Good Laboratory Practice, Good Manufacturing Practice, FDA Investigational New Drug, and Investigational Device Exemption for US settings). All applicants should demonstrate familiarity with applicable regulatory requirements, while Phase II applications require in the commercialization plan to include a detailed regulatory strategy matched to the low-resource setting of the study. Beyond the scope of this solicitation, it is anticipated (and encouraged) that the outcomes of successful SBIR projects will help attract strategic partners or investors to support the ultimate commercialization of the technology as a publicly available product or service. Projects funded by this solicitation may include patient enrollment in foreign countries. Per SBIR policy, when there are special circumstances justifying the conduct of the proposed research outside the US within time and budget constraints (e.g. a high disease incidence that makes clinical validation more feasible and timely), agencies may approve performance of a portion of the SBIR R&D work outside of the US. In this case, applicants are required to include a statement in their applications on why these resources are not available in the US. Technology areas of interest include, but are not limited to, the following: • Affordable guided surgery • Affordable immunotherapy • Affordable tumor-infiltrating lymphocytes or adaptive cell cancer therapies • Affordable photodynamic therapies • Affordable technology for eradication of H. pylori infection • Affordable and preferably mobile devices for cancer treatment such as tools that may facilitate standard minimally invasive cancer treatment modalities tools for cryotherapy, thermal ablation, radiofrequency ablation, laser therapy, low-power-density sonication, high-intensity focused ultrasound (HIFU) therapy that are appropriate to low-resource settings • Devices to aid in delivery of cancer drugs • Mobile "pop-up" cancer therapy lab • Oncolytic viruses’ therapies • Mobile radiotherapy treatments • Portable radiation equipment for therapy and assisting surgery • Tools for information and communications technologies to enhance cancer data collection, sharing, or analysis for treatment of cancer Technologies that are generally not appropriate for this solicitation include the following: • Devices that require extensive user training before they can be used • Drug screening • Experimental therapeutics modalities which are not approved in the US • Technologies not affordable or can’t be maintained in low resource settings Expected Activities and Deliverables Quantitative milestones are required for both Phase I and Phase II projects, regardless of whether they are combined in a Fast-Track application. It should be noted that LMICs have limited healthcare budgets and often struggle to prioritize healthcare needs. Because of Page 70 the variation in healthcare systems among LMICs and US regions with underserved populations, applicants will need to consult with local partners and organizations (beginning before they submit their application) to develop plans for product design and testing that are suitable to the low-resource setting, including strategies for regulatory approval and reimbursement (if applicable) for the proposed product. Examples of suitable consulting organizations are local hospitals, medical schools, charities, community groups, nongovernmental organizations, and local governmental offices with expertise in the setting. A portion of contract fund can go to these organizations, standard SBIR outsourcing requirements apply. Phase I Activities and Deliverables • Develop a working prototype based on adaptation of existing technology, or development of new technology. • Demonstrate the feasibility of the technological innovation for use in a low-resource setting (real or modeled), using a small number of biological samples or animals, where appropriate. • Deliver to NCI the SOPs of the system for cancer treatment • Develop a regulatory strategy/plan and timeline for seeking approval from the appropriate regulatory agency to market the product • Provide a brief business plan, which is likely to require partnering with healthcare staff local to the low-resource setting of interest Phase II Activities and Deliverables • Continue the consultation with local healthcare delivery experts in the low-resource setting of study • Adapt the prototype device or treatment technology developed in Phase I to the targeted low-resource setting • Validate the device or treatment technology in the low-resource setting with a statistically significant number of animal and/or human samples, live animals, or human subjects (if animal work or human subjects are involved) for the proposed product in the low-resource setting of interest. Animal studies are optional and may not be needed for many products supported by this solicitation. Animal studies need only be proposed for products where intermediate testing in animals is thought to be necessary for regulatory approval, or necessary before an IRB will approve a follow-on human study. • To the extent possible, benchmark the product against existing commercial products used to address the same healthcare need in developed countries and include a description of competitive landscape in the commercialization plan. • Engage with FDA or the local state regulatory agency to refine the regulatory strategy • 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, where appropriate. • By the end of Phase II, engage with the appropriate regulatory agency (e.g., US Food and Drug Administration, World Health Organization) to seek and/or obtain marketing approval for the product that was developed.

Fast-Track proposals will NOT be accepted. Direct Phase II proposal will be accepted Number of anticipated awards: 3 - 5 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Gene therapy has come of age over the past few years. One of the most promising anticancer approaches in the clinic is chimeric antigen receptor (CAR)-T cell therapy. However, the pioneering first-generation products now on the market for B-cell malignancies, that target a single cancer antigen, have major limitations. First, all normal B cells expressing CD19 are eliminated by the therapy meaning that normal B cell functions are lost. Second, patients may lose expression of the CD19 CAR-T target antigen, rendering the malignant tumor cells invisible to the immune system tasked with its Page 71 destruction. Third, the therapies can trigger toxicities that are hard to predict and control, such as cytokine release syndrome. By combining computer science logic with biology, scientists have developed synthetic gene circuit technologies to redirect genetic events within cells to enable the resulting therapies to sense and adapt to their environment, or be controlled to avoid the safety and efficacy pitfalls that limited first-generation products. For example, new CAR-T approaches involve the delivery to T cells of gene circuits based on Boolean logic that can produce tumor cell killing only when two (or more) cancer antigens are expressed on cancer cells but not on normal cells, preserving normal B cell function. These synthetic gene circuits are assembled of DNA encoding RNA or protein that enable individual cells to respond and interact with each other to perform a function at the desired locations (e.g. within the tumor vs. whole body), targets (e.g. cancer cells vs. healthy neighboring cells), amount (e.g. therapeutic vs. toxic doses) and duration (e.g. shut down before significant side effect occurs). Key components include sensors that detect user-defined inputs, processors that make decisions in response to the inputs, and actuators that produce the desired output activities (payloads). Synthetic gene circuits can be delivered into cells ex vivo as in the CAR-T case, or in vivo using any well-established gene transfer vectors. These gene circuit therapies can be programmed to distinguish cancer cells from normal cells and to activate therapeutic payload expression from inside tumors. Project Goals The goal of the topic is to stimulate the development of gene circuit therapies for cancer. Engineering of immune cells and/or cancer cells is encouraged, while other cell types are not excluded. The recent pioneering work in synthetic biology has shown the potential of overcoming current challenges in gene therapy by creating sophisticated gene circuits to distinguish between malignant and healthy cells and to efficiently kill the former without harming the latter. Unlike conventional small molecules or biologics, including most of the current gene therapies, gene circuit therapies can potentially sense multiple disease signals, integrate this information to make a decision to trigger sophisticated or combinatory therapeutic mechanisms. Alternatively, gene circuit therapies can also be controlled exogenously, therefore allowing precise control over timing, dose and location of the therapies. The activities that fall within the scope of this solicitation include the development of the gene circuits designed and created using synthetic biology approaches into cancer therapies through engineering immune cells ex vivo, or by delivering directly into cancer cells in patients using viral or non-viral gene transfer approaches/vectors, including engineering of bacteria to specifically target cancer. The approach should also allow precise control over timing, dose, and location of the therapies. Examples of appropriate activities include to demonstrate that the gene circuit can be expressed in cancer cells in vitro and in vivo, with increased efficacy and decreased toxicity compared to currently available similar therapies or to standard of care. A system that does not have the potential to allow precise control of the therapeutics over timing, dose, and location as needed will not be responsive. Methodologies to create gene circuits without delivery will not be responsive. Animal studies establishing proof-of-concept efficacy in well-validated in vitro and in vivo models should be completed in Phase I. In Phase II the contractor is expected to perform a large-scale in vivo efficacy study, as well as other studies required for FDA IND submission. Phase I Activities and Deliverables: Establishing proof-of-concept efficacy and/or toxicity: • Demonstrate in vitro sustained and controllable transgene expression with efficacy in appropriate cell lines and/or 3D models • Demonstrate in vivo sustained and controllable transgene expression with efficacy in appropriate small animal models • Conduct gene circuit optimization (as appropriate). • Perform (optional) animal toxicology and pharmacology studies as appropriate. • Demonstrate (optional) increased efficacy and/or decreased toxicity as compared with standard-of-care for the cancer indication in appropriate animal model(s). Phase II Activities and Deliverables: The offerors are encouraged, but not required, to meet FDA before the submission of a Phase II proposal. A detailed experimental plan necessary for filing an IND is expected in the Phase II proposal: • Conduct properly powered efficacy studies, demonstrating benefits with statistical significance. • Complete IND-enabling experiments and assessments according to the plan developed. The plan should be reevaluated and refined as appropriate. • Develop and execute an appropriate regulatory strategy. If warranted, provide sufficient data to file an IND or an exploratory IND for the candidate therapeutic agent. Page 72 • Demonstrate the ability to produce a sufficient amount of clinical grade material suitable for an early clinical trial.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 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 There is an urgent need to spur innovation in developing unbiased medical technologies to reduce disparities in cancer outcomes. Structural inequalities in health and medicine, including in cancer control, have garnered the attention of leading clinicians, researchers, and journals. One insidious symptom of, and contributor to, structural inequalities in cancer outcomes is biased medical technology. For example, existing pulse oximeters overestimate oxygen saturation when used by people with darker skin, and particularly women of color. This is consequential for cancer, given that pulse oximeters are an important prognostic tool for lung cancer. Similarly, Black, Indigenous, or other People of Color (BIPOC) individuals are at risk of getting inaccurate readings from smartwatches and fitness trackers that monitor heartbeat, due to increasing inaccuracy in darker skin. This is consequential for cancer because activity guidelines for cancer prevention recommend the use of heart rate monitors. Algorithms and machine learning-informed artificial intelligence (AI) used to guide clinical cancer decisions are often adjusted for race/ethnicity (with no explanation or explanations based on outdated/biased data); such algorithms guide decisions in ways that direct greater resources to white patients, compared to BIPOC patients. Similarly, computer-aided cancer diagnostic tools (e.g., for medical imaging) may be biased because the datasets they are developed on are imbalanced with respect to race/gender. If underlying data informing algorithms, AI, and imaging reflect structural inequalities, these will perpetuate bias and widen existing cancer disparities. As such, there is a critical need to develop unbiased medical technologies to improve cancer disparities. Project Goals The goal is to create scalable health IT-based informatics tools that measure care coordination in order to assess and improve quality of care and patient outcomes, assist the ongoing healthcare delivery system transformation and improve research efficiency. The tools will help managers and clinical teams realistically assess the effectiveness of existing care coordination and patient engagement processes and help identify areas for improvement, which will help their efforts to transform delivery systems to meet the triple aim objectives of improving patient experience, improving population health and reducing costs. The researchers will gain access to tools that measure the variability in cancer care coordination and patient engagement in diverse settings, which will help identify the characteristics of clinical teams, processes and health systems associated with delivery of high-quality care and to test interventions based on these characteristics. Proposals should identify existing, racially/ethnically biased medical technologies integral to cancer prevention and control; identify the mechanisms contributing to such bias (e.g., targeted development and testing, inability to work effectively with a variety of skin tones, biased data inputs or outcome measurements); and develop new, unbiased replacement technologies. Potentially biased technologies could be identified in the existing literature or by the applicant. Activities that fall within the scope of this solicitation include development of unbiased medical technologies to replace existing bias in technologies that contribute to disparities in cancer control outcomes. Proposals should target existing technologies integral to cancer control and with demonstrated bias, including (but not limited to): pulse oximeters or other measures of blood oxygen to be used at home or in clinical settings; heart rate monitors to be used at home to guide appropriate intensity exercise for weight loss and maintenance; and algorithms and artificial intelligence (AI) designed to inform clinician decision making individualized to the patient, such as those used for diagnosis, prognostic prediction, distribution of medical resources, and assessment of patient-reported outcomes (including pain). Projects could also involve integration of large biomedical data sets containing genomic, proteomic, histological, and clinical information to develop Page 73 new technologies or algorithms, as prioritized in the Cancer Moonshot Blue Ribbon Panel. Activities can involve the development of any medical technology that could complement or replace existing, racially/ethnically biased technologies that are widely employed in the medical care system or recommended for at home use. Phase I Activities and Deliverables: • Establish a project team including personnel with training and research experience in the specific type of medical technology targeted, knowledge of the relevant area of cancer prevention and control, and expertise in structural inequalities/health disparities; • Provide a report including a detailed description and/ or documentation of: o Existing racial/ethnic bias in the targeted medical technology; o The role of such biased technology in perpetuating or exacerbating disparities in cancer prevention and control; o Potential mechanisms underlying biases in the target medical technology; o Description of the technical strategy that would be used to correct the bias in the existing technology or develop a new technology that could replace the cancer prevention and control function of the target biased technology; o Analysis of the cost-effectiveness and ability to disseminate/ implement/ integrate technology into standard cancer prevention and control practices or healthcare settings; o A detailed plan of methods that will be used to validate and evaluate the acceptability of the new technology in performing requisite cancer prevention and control strategies among the racial/ ethnic group for whom the initially targeted technology produced biased results; o A detailed plan of methods that will be used to validate and evaluate the efficacy of the new technology in performing requisite cancer prevention and control strategies among the racial/ ethnic group for whom the initially targeted technology produced biased results; o A detailed plan of methods that will be used to examine the reliability of the new technology in performing requisite cancer prevention and control strategies among the racial/ ethnic group for whom the initially targeted technology produced biased results across time; o A plan for marketing and distribution of the novel medical technology after it has passed cost-effectiveness and efficacy/ acceptability tests described above; o Any original data collected to demonstrate the bias in the target technology; and o A list of all references and research informing the description and documentation outlined above. • Develop a functional prototype of the newly developed technology; • Provide preliminary evidence for potential efficacy for newly developed technology in reducing or eliminating bias; Phase II Activities and Deliverables: • Evaluate and document cost of and time to development of technology, compared to the existing biased technology; • Scale the production of the technology, if necessary, to accommodate efficacy/acceptability research as described in the plan requested above; • Conduct studies of acceptability, efficacy, and reliability, based on the detailed methodological plan outlined as described above; • Prepare a report describing the cost-effectiveness and acceptability/efficacy/reliability findings; • Execute marketing and dissemination/ implementation plan; • In the first year of the contract, provide the program and contract officers with a letter(s) of commercial interest; and • In the second year of the contract, provide the program and contract officers with a letter(s) of commercial commitment.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 2-3 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 months Page 74 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 An important development in the field of radiation oncology is demonstration that ultra-fast dose rate (also known as FLASH) radiation therapy at the same delivered dose has fewer side effects than regular radiation therapy. This finding is under intense investigation globally and a race is underway to understand and subsequently implement this methodology in the clinic. The current devices that measure radiation dose lack response times sufficient to adequately address ultra-fast dose rates of 40-120 Gy/second. This is especially problematic when the total prescribed dose may be only 8-20 Gy. Current medical practice dictates that radiation dose must be given within 20% of the prescription, or else be subject to a formal reportable medical event, as regulated by the United States Nuclear Regulatory Commission. In order to safely utilize FLASH radiobiology effects in the clinic, detectors need to be developed that can affordably extend dose rate capacities from 2-10 Gy/minute to 40-120 Gy/second. Additionally, the physical structure of the pulse must meet FLASH specifications. Project Goals The goal of this concept is to solicit proposals to advance the development and/or application of devices, to allow FLASH radiation therapy to be properly evaluated and ultimately translated into the clinic. In particular, ultra-fast radiation dose rate detectors, and related components are the focus of this topic solicitation. By prompting the development of new, commercialized, ultra-fast detectors and safety systems, this solicitation has the potential to facilitate validated translation of laboratory findings to patients in this new and exciting domain – that of FLASH radiation therapy. The supported projects will focus on various devices and technologies to allow for measurement and evaluation of FLASH radiation delivery. The examples of the products are: • Development of devices to measure and validate the time and pulse structure, fluence and other characteristics of the FLASH irradiation beam in both laboratory and clinic. • Systems to record delivery rapidly and precisely enough to measure over or under dose delivery, and stop dose delivery if needed quickly enough to prevent delivery of dose causing a medical event. Activities not responsive to announcement: Tools that don’t measure FLASH dose rate reproducibly; tools that cannot measure the time structure of flash radiation therapy; design approaches that don’t account for scalability, interoperability or the need to be tested for daily validation in a non-destructive fashion; approaches that don’t plan for using tools in diverse medical centers and IT systems; tools or devices unable to be validated and traced to NIST sources/dose definitions. For applications designing safety system, systems that cannot stop the beam fast enough to prevent more than 5% dose over/under the goal (prescribed) dose. Phase I Activities and Deliverables: • Project team: Establish a project team, including proven expertise in: sensor development, user-centered design, team communication and clinical workflows, ultra-high speed electronic safety systems, radiation hardening electronics engineering and testing, measurement and display of beam time structure in a FLASH environment for at least one and ideally multiple modalities (electron beam, proton beam, photon beam, and other hadron beams potentially), clinical radiation oncology and medical physics. Knowledge and design of medical electronic safety systems architecture, health IT interoperability, NIST traceability and related processes will be required. • Design and build proof-of-principle prototype system to measure the time structure of FLASH beam delivery than can both sum dose and collect time structure data and allow the analysis of such data to confirm if it is with 5% of planned beam delivery immediately after treatment (within seconds but ideally much faster to allow use in a safety feedback system that could stop a beam during treatment). Appropriate controls with poor beam structure and inadequate dose rate should be implemented in the testing process. If a system is designed to shut off a delivery device that capability must be designed and tested in the prototype system. • Demonstrate that the prototype has a high probability of development into a clinically-relevant radiation measurement tool and/or safety device component that has is able to work in the FLASH regime (40-120 Gy/s). • Provide a report on the results of the first round of usability testing and any resultant modifications of the platform based on this user feedback. • Present phase I findings and demonstrate the functional prototype system to an NCI evaluation panel via webinar to be summarized in a formal report. Phase II Activities and Deliverables: • Enhance, beta test, and finalize system, data standards and protocols for a platform that can measure FLASH beam deliveries with less than 1% variance between at least 5 prototype measurement devices by the end of year Page 75 1 of the Phase II contract. • Enhance, beta test, and finalize system for clinical implementation. • Provide a report that synthesizes feedback from all relevant categories of end-users (such as physicians, physicists, OEM engineers, and radiobiologists) and summarizes the modifications made to the platform after each round of usability testing. • Provide a report specifying lessons learned and recommended next steps to implement the components in a commercial capacity. • Provide a report detailing plans for implementation of technical assistance and delivery of the complete system including needed software and related API data, platform compatibility standards employed if any, and measures developed, including standard operating procedures for use, validation of measurements, and checking device performance. • Develop systems documentation and user guides to facilitate commercialization. • Present phase II findings and demonstrate the system via a webinar at a time convenient to the offeror and NCI program staff. • In the first year of the contract (Phase II), provide the program and contract officers with a letter(s) of commercial interest. • In the first year of the contract (Phase II), conduct a call with the FDA. • In the second year of the contract, provide the program and contract officers with a letter(s) of commercial commitment. Where cooperation with other equipment manufacturers is critical for implementation of proposed technology, company should provide evidence of such cooperation (through partnering arrangement, collaboration, or letters of intent) as part of the Phase II proposal.

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 12 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 Lymphedema is a clinical expression of an impaired lymphatic circulation. Acquired lymphedema is most often the consequence of regionalized injury to lymphatic vessels as a consequence of trauma, infection, neoplasia, radiation damage, or surgical interventions, especially those that include lymphadenectomy. Secondary lymphedema following axillary lymph node dissection during surgery to remove malignant tissue is the most common cause of lymphedema in United States. Lymphedema is commonly associated with treatment for several types of cancers including breast cancer, melanoma, sarcoma, and gynecological cancers among others. Early stage lymphedema begins as tissue swelling with sense of heaviness and discomfort in affected area. This is followed by transient non-tender pitting edema and development of leathery texture on the skin due to thickening and fibrosis. Without any interventions, non-pitting edema may develop which indicates irreversible stage of lymphedema. Skin in chronic lymphedema is prone to fissures, ulceration, and recurrent cellulitis. Lymphorrhea and Impetigo are also common at this stage. Frequency of acute inflammatory incidences, pain, skin deformities, and reduced hand usage in cases of lymphedema in the arm all lead to frustration, annoyance, anxiety, depression, poor psychological adjustment, and poor body image issues in patients suffering from secondary lymphedema. Lymphedema-related physical disabilities and psychological issues can cause severe limitations and negatively affect personal, work, and social lifestyles. Despite the debilitating physical, psychological, and financial consequences, little progress has been made for the treatment of lymphedema. Current lymphedema treatments mostly involve physiotherapeutic interventions such as massage to manually drain the lymph, multilayer bandaging, topical skincare, compression garments etc. with varying degree of success. Project Goals The goal of this contract topic is to support the development of technologies that prevent, reduce, or eliminate lymphedema Page 76 following removal or radiation of lymph nodes due to cancer in the upper body, i.e. neck, chest, arm(s), or thoracic cavity. These technologies will provide healthcare providers with solutions for preventing and treating lymphedema, which can cause a serious reduction in function and quality-of-life for patients following treatment for cancer. Examples of technologies considered responsive to this solicitation include, but are not limited to; implantable devices capable of modulating the movement of lymph fluid to prevent lymphedema; innovative mechanical devices that can provide real time monitoring and compression throughout daily activities or sleeping hours, or other wearable devices incorporating highly innovative solutions to substantially improve control of lymphedema. The proposed technologies should provide either significant prevention of lymphedema in patients at high-risk of developing it or a long-term solution that reduces/eliminates lymphedema in patients that have the condition. While proposed technologies can have monitoring capability, the technology should include an integrated solution for the prevention or control of lymphedema. Priority will be given to technologies that aim to eliminate or nearly eliminate lymphedema. Activities not responsive to announcement: Proposals for new surgical techniques for lymph node transplant surgery, standard rehabilitation procedures (e.g., massages, techniques, or exercises) for managing lymphedema, or new tools that improve patient education of current rehabilitation procedures will not be considered responsive. Phase I Activities and Deliverables: • Develop a prototype of a device with appropriate specifications. • Demonstrate preliminary proof-of-concept of the device in a suitable animal model or phantom model. • Specify the quantitative technical and commercially relevant milestones that will be used to evaluate the success of the technology. • Identify required specifications necessary to make the device clinic ready. • Develop a regulatory strategy/plan and timeline that is necessary to file a regulatory application for the device. • Implantable device specifications and regulatory plans must include a description of infection risk and plans to test and mitigate the risk of infection or spreading infection. • Present phase I findings and demonstrate the functional prototype system to an NCI evaluation panel via webinar. Phase II Activities and Deliverables: • Build a device according to the specifications developed in Phase I. • Optimize the device design and performance for a clinical setting, and demonstrate the feasibility of this novel device to function in the current clinical workflow and/or in a home setting for patient use. • Demonstrate the safety and efficacy of the device in relevant animal models as required by FDA. • Engage with FDA to refine and execute an appropriate regulatory strategy. If warranted, provide sufficient data to submit a regulatory application to obtain approval for clinical application. • For offerors that have completed advanced pre-clinical work, NCI will support pilot human trials. • 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: 2-3 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 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 Numerous studies over the last several decades have reported on extrachromosomal circular DNAs (eccDNAs) that appear alongside coiled linear chromosomes in the cells of normal tissues. These DNAs are found in many eukaryotic species and have been observed in various forms including telomeric circles, small polydispersed DNA elements, and microDNAs. New research has revealed that cancer cells contain large numbers of a specific type of extrachromosomal DNA known Page 77 simply as ‘ecDNA.’ As compared to the other forms of DNA listed above, ecDNAs are relatively large (1-3 MB) and contain multiple full genes and regulatory regions. Recently, ecDNA has been increasingly recognized as a potent source of driver oncogene copy number amplification events in human tumors. ecDNAs are subject to non-Mendelian inheritance and can multiply rapidly while maintaining intratumoral genetic heterogeneity, which likely plays an important role in helping cancers to adapt, evolve and become resistant to treatment. Driver “undruggable” oncogenic targets, such as NMyc, are subject to ecDNA driven amplifications, and other enzymes and oncogenic proteins responsible for drug resistance may also be transiently driven by such events. Recent interest in this emerging and important area of research is reflected in the latest round of Cancer Grand Challenges, a major collaborative funding initiative between the NCI and Cancer Research United Kingdom (CRUK), which identified as one of its new 2020 challenges, “Understand the biology of ecDNA generation and action, and develop approaches to target these mechanisms in cancer.” Unfortunately, little is known about the genomic organization of ecDNA or the mechanisms that drive their formation, due in part to the challenges involved in their detection. ecDNAs can reintegrate into the genome and are distributed unequally to daughter cells during cell division, both of which contribute to the difficulty in their detection. Although recent advances in commercially available long-read sequencing platforms may play a role in addressing some of these challenges, many technology gaps still exist for the reliable analysis of ecDNAs, especially if limited samples are available. To keep pace with our rapidly evolving understanding of ecDNAs and their role in cancer, this contract topic aims to develop new tools that are critically needed to analyze ecDNA sequence, structure and regulation. This topic is agnostic as to specific technological approaches, which could involve optimizing ecDNA enrichment and purification, improving existing sequencing technologies, and/or developing new informatics tools. In the near term, technologies developed under this topic are expected to enable important basic research on ecDNA and cancer. Ultimately, such tools may also play a key role in revealing new therapeutic vulnerabilities in cancers that are currently intractable. Project Goals The goal of this contract topic is to spur the development of new and/or advanced analytical approaches that can support research into the mechanisms giving rise to ecDNA formation and organization, and its role in cancer. This solicitation seeks both completely new approaches, as well as “better, faster, cheaper” versions of existing technologies, to advance this field. Responsive proposals may include novel methods and/or reagents to selectively enrich, isolate, detect, and/or visualize ecDNA targets. Possible approaches that would be considered responsive to this solicitation include (but are not necessarily limited to): • Biochemical approaches to selectively enrich or purify ecDNA • Sequencing approaches that distinguish ecDNA from other forms of DNA • Affinity reagents or other biochemical detection strategies specific for ecDNA • Imaging probes that are specific for ecDNA targets • IT approaches that allow novel data analysis to interpret/detect ecDNA Phase I projects must demonstrate that the proposed technology/approach is capable of selectively detecting, analyzing and/or characterizing ecDNA in cancer-relevant biological systems (e.g., cancer cell lines). Offerors should conduct feasibility studies in cancer models for which there exists a sufficient understanding of the ecDNA biology to reliably interpret the results of the novel assay or technique. Phase I activities should focus on characterizing the relevant analytical parameters of the technique and should include target performance measures for key analytical parameters. Phase II activities should demonstrate the assay throughput, as well as the ability to analyze ecDNA in systems of increasing biological complexity (e.g., patient-derived xenografts, tumor tissue sections, human plasma). Phase II activities should demonstrate the ability of the proposed approach to detect temporal changes in ecDNA that are biologically relevant in human cancers (e.g., ecDNA biogenesis, replication, genomic organization, distribution to daughter cells). Offerors are encouraged, but not required, to conduct experiments in which changes in ecDNA can be monitored in a cancer-relevant model(s) following drug treatment or some other biological perturbation. Phase II activities should include other necessary validation activities to advance the technology as a commercially available research tool. Activities not responsive to announcement: Activities involving the detection of ecDNAs in non-cancer biological systems will be considered non-responsive to this announcement. Phase I Activities and Deliverables: • Demonstrate the ability to selectively analyze (e.g., enrich, purify, isolate, detect, image) ecDNAs found in cancer-relevant biological systems • Provide a clear justification for the biological systems (e.g., cell lines) used for analytical validation; include a summary of what is currently known about the role of ecDNA in these systems and how this may impact the interpretation of the proposed validation experiments • Demonstrate the specificity of the assay/technique to distinguish ecDNA from all other forms of cellular DNA in Page 78 the chosen cancer cells • Fully characterize the relevant analytical parameters of the assay/technique including sensitivity, specificity, limit of detection, dynamic range, etc. (as appropriate) • Describe target performance measures (i.e., quantitative milestones) for key analytical parameters, including the methods by which they will be assessed Phase II Activities and Deliverables: • Demonstrate the maximum throughput of the approach, and define appropriate measures of performance reliability for large-scale screening of cancer samples • Demonstrate the ability to analyze ecDNA in systems of increasing biological complexity (e.g., patient-derived xenografts, tumor tissue sections, human plasma) • Demonstrate the ability to use the proposed approach to detect temporal changes in ecDNA that are biologically relevant in human cancers (e.g., ecDNA biogenesis, replication, genomic organization, distribution to daughter cells) • Offerors are encouraged, but not required, to demonstrate that the technique can be used to monitor biologically relevant ecDNA changes in a cancer-relevant model(s) following drug treatment or some other biological perturbation • Conduct additional validation studies to advance the technology as a commercially available research tool, including manufacturing scale up, commercial partnerships, beta testing, etc. (as appropriate).

Fast-Track proposals will NOT be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Public large-scale molecular-level datasets have facilitated sophisticated secondary data analysis leading to new biological discovery. These data sources provide rich, multi-omic data on bulk or single-cell populations, but most measurements do not preserve the spatial relationships between tumor cells and thus limit the ability to discover important and targetable cellcell and cell-microenvironment interactions. To address this shortcoming, several programs supported by NIH, NCI and beyond have undertaken the construction of spatiotemporal single cell resolution atlases of normal and diseased tissues. Examples of technologies currently employed to build spatial atlases include multiplex microscopy and mass cytometrybased imaging modalities that provide information on multiple (10s-1000s) of biological molecules (genes, proteins, metabolites, etc) in a single two-dimensional thin tissue section. While imaging of sequential tissue sections provides a way to re-construct the three-dimensional (3D) tumor microenvironment, most high content imaging modalities require multiple rounds of tissue staining and manipulation that can be destructive to any one tissue section making it difficult to reconstruct accurate 3D views. Therefore, technologies that provide imaging workflows that deliver cellular to sub-cellular resolution omic-level data in three dimensions (i.e. in thick tissue resections or whole biopsy samples) are likely to more faithfully conserve the architectural or structural components within the tumor microenvironment that could be destroyed or altered during multiple rounds of tissue processing. It is possible that approaches such as light sheet microscopy could fill this need, but the current protocols for tissue clearing, multiple rounds of target labeling to facilitate highly multiplexed omics measurement, and subsequent image processing make the overall workflow for an individual tissue prohibitively slow (days to weeks) and difficult to employ in atlas building activities where a large number of normal and tumor maps is required for a representative normal tissue or tumor atlas. Project Goals The goal of this concept is to solicit proposals to advance the development and dissemination of imaging workflows capable of omics-level measurements in thick tissue resections or whole biopsy cores. Proposals should enable interrogation Page 79 in a manner that combines high resolution (preferably single-cell) omics level data (i.e. genomic, transcriptomic, proteomic, metabolomic, etc) with information about 3D native tumor architecture (i.e. extracellular matrix, vasculature, higher order structure, etc). Proposals that are within scope of this solicitation may combine existing, new, or improved assay components into an improved imaging workflow. Examples of existing, new, or improved components include imaging technologies or modalities, tissue clearing methodologies, imaging probes and/or detection reagents, cyclic staining or targeting procedures, and/or unique combinations of imaging and multi-omic measurement platforms. A minimal workflow will provide a 3D view of multiplexed omics data without the need for reconstruction from 2D tissue slices. The ability to concurrently acquire additional information regarding native tumor architecture would be considered a strength (eg. second harmonic imaging or alternative technology). Offerors should benchmark their proposed workflow against current state-of-the-art imaging workflows and demonstrate a decrease in overall assay time while maintaining a similar or increased capacity for omic-scale analysis. Cellular or sub-cellular resolution imaging is a requirement. It is anticipated that proposals may include the development of new algorithms, visualization tools, and analysis software to facilitate data handling, analysis and visualization of results. However, applications that are solely software-based are not within the scope of this solicitation. Phase I Activities and Deliverables: Phase I activities should generate data to confirm feasibility and potential of the technology(ies) to provide 3D images of high-resolution omics-level data in thick resections or whole biopsy cores by completing the following deliverables: • Define the relevant use cases for the technology (i.e. what tissues can be used, what imaging resolution can be expected, what -omic measurement(s) will be completed). • Generate proof-of-concept dataset using resection tissue or biopsy cores from solid human cancers or from a generally accepted mammalian cancer model (i.e. PDX, xenograft, GEMM) that demonstrates the ability to capture and visualize molecular omics measurements in 3D. o Offerors should specify quantitative technical and commercially-relevant milestones that can be used to evaluate the success of the technology versus current state-of-the-art 3D high resolution imaging platforms (i.e. light sheet microscopy). o Quantitative milestones may be relevant metrics (i.e. compared to benchmarks, alternative assays) or absolute metrics (i.e. minimum number of proteins or genes detected, metrics related to repeatability of the assay). o Metrics regarding total assay time (including tissue preparation, cyclic staining (if relevant), and imaging processing/analysis) should be included. • Development of preliminary Standard Operating Procedures for system use, including a validated list of reagents for a specific tumor type. Phase II Activities and Deliverables: Phase II activities should support the commercialization of the system developed in Phase I and include the additional activities and deliverables: • Demonstrate the ability to quantify the 3D native tumor architecture (i.e. extracellular matrix, vasculature, higher order structure, etc) in addition to the capabilities optimized in Phase I. • Demonstrate reliability, robustness and usability for the purpose of generating large scale datasets for atlas building. • Benchmark system performance (including total assay time) and functionality against commercially relevant quantitative milestones. • Demonstrate utility across at least three solid tumor types (thick resections or whole biopsies). • Show feasibility to be scaled up at a price point that is compatible with market success and will facilitate largescale atlas-building activities. • Publication of Standard Operating Procedures for system use, including a validated list of reagents for each of the three tumor types. Documentation for troubleshooting new tumor or tissue types to demonstrate the system can be utilized beyond the tumor types proposed. • Provide a roadmap for development of a turnkey system

Fast-Track proposals will NOT 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 12 months Phase II: up to $2,000,000 for up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Next-generation sequencing (NGS)–based technology has lowered the cost of testing for genomic alterations in a patient's cancer and is now commercially available from many diagnostic laboratories. Due to increasing numbers of approved or investigational targeted therapies, cancer patients are more routinely undergoing tumor/somatic genetic testing at the time of diagnosis or progression. Although the decision to undergo tumor/somatic testing can have profound medical implications for patients, oncology providers traditionally have not been trained to interpret and communicate NGS results. Yet, they are increasingly advised by professional societies to consider NGS testing, and thus face the need to counsel patients about generated results. Published data indicate that the growing uptake of NGS in cancer care has left many oncology providers inadequately prepared to discuss the complex and potentially hereditary implications of such testing. Often, clinicians lack not only the expertise but also the time needed to counsel cancer patients about whether to undergo tumor/somatic testing, and the layered implications of test results. Tumor/somatic testing creates several added responsibilities for oncology providers such as guiding follow-up care - including clinical trial options - and facilitating communication within families. The need for assistance is particularly acute in low-resourced settings that lack access to geneticists, genetic counselors, tumor boards, or other such consultation. Indeed, clinicians in such lower resourced oncology settings face unique challenges discussing NGS testing with cancer patients. Tools, technologies and/or services are needed to help providers: (i) evaluate the benefits of somatic/tumor testing for their individual patients, (ii) understand and interpret test findings, including potential familial implications for suspected inherited cancer and (iii) communicate findings with their patients both before testing (to obtain truly informed consent) and after testing (to explain results). Such products must be integrated with current care models and be easily accessible to oncology providers given the time constraints of medical practice. These tools or technologies must distill complex genomic data so that oncology providers appropriately implement tumor/somatic genomic testing in the context of evolving National Comprehensive Cancer Network (NCCN) guidelines. They should also provide information in a legible format to facilitate patient comprehension and engagement in decision-making. Companies should incorporate provider and community input into the design of these products, to ensure utility and uptake. Project Goals The goal is to design and develop products such as tools, technologies, and/or services to: (i) inform oncology providers about tumor/somatic testing and current NCCN guidelines, (ii) help oncology providers evaluate the need for tumor/somatic testing for specific cancer patients, (iii) assist oncology providers with interpretation of tumor/somatic test results, including the impact of incidental germline findings, and (iv) help oncology providers communicate NGS results to their patients. Interpretation of NGS results must be personalized for individual patients. Products that cater to settings with limited or no access to genetic counselors, or on-site tumor boards, are encouraged. Products should: (i) identify strategies for enhancing provider understanding of cancer genomic test results; (ii) assist with provider communication of test results in a clear and lay-friendly manner, to aid both treatment and life planning decisions; (iii) inform providers about genetic counseling and clinical trial resources for their patients; (iv) offer remote technology applications such as video and telephone guidance; and (v) incorporate perspectives of populations experiencing disparities in cancer outcomes, such as minority and rural communities. In addition, contractors must evaluate, pilot and disseminate the product. The product(s) should aim to accomplish as many of the following as primary goals: • provide a resource for improving knowledge of somatic genetic testing for oncology health care providers; • assist health care providers to evaluate patients and determine need of genetic testing; • facilitate interpretation of somatic genetic test results (include noting germline findings vs. somatic findings and flagging germline variants for possible follow-up), using existing clinical guidelines, available resources and established standards to help health care providers understand medical and familial implications of test results; Page 81 • promote communication of genetic test results in a clear and lay-friendly manner, to assist with treatment or life planning decisions; • explain to health care providers how and why information on variants of unknown significance may evolve over time and provide guidance about how to communicate this information to patients; • provide a discussion guide to facilitate communications regarding genetic results with providers and related family; • inform health care providers about genetic counseling resources they may provide to their patients; • offer options for video and telephone guidance if a patient is located in a remote setting; and • include and incorporate perspectives of populations experiencing disparities in cancer outcomes, such as minority, underserved and rural communities as well as identify and meet needs that would improve use and access for understanding cancer genomic test results. Some recommended practices for product development include: • Including patients’ and families’ perspectives in deciding when, whether and how to communicate specific genetic findings, and when to offer genetic counseling and confirmatory testing based on counseling. This could be accomplished using the principles and elements of a design thinking approach focused on designing the communication strategies for oncology care providers from the perspective of the patients, in an agile, iterative way. • Considering a range of cancer treatment scenarios to elicit a broad range of provider needs that can inform tool development. This range includes pediatric, adolescent and young adult as well as adult cancer types. • Assembling trans-disciplinary teams that include but are not limited to geneticists, genetic counselors, behavioral researchers, psychologists, oncologists as well as patient navigators, patient advocates, and user experience designers to inform development and validation of tools. • Planning for pilot implementation testing of the tool in clinical or other applicable settings as the tool is developed. The following would be considered out of scope: • Methodologies of genetic counseling that do not focus on development of provider-facing tools • Methods, reports, and tools that include only germline genetics/genomics • Genetic testing services • Reports and tools requiring genetic testing services be conducted by offeror Phase I Activities and Deliverables: The goal of Phase I is to design and develop tools, technologies, or products to 1) inform the user about the role of tumor (somatic) genetic testing and counseling in cancer research and treatment 2) aid understanding and interpretation of somatic genetic findings; 3) aid in effective communication of tumor (somatic) genetic test results. • Establish a project team with expertise in the area of genetic counselling, software development, user-centric design, oncology, patient navigation as appropriate for this proposed project. • Conduct or utilize formative/exploratory research during the trial period to identify barriers and facilitators faced by physicians in staying up to date regarding genetic testing best practices and regulations, understanding test results (and evolution of results as more is known about impact of specific genetic variants/somatic mutations), and accessing counseling resources based on currently available platforms for genetic counselling. • Develop a prototype tool or technology based on formative research, to explain genetic tests and test result to physicians for them to provide to their patients. This could be a tool/technology for physicians, a communication tool for physicians to use, and/or a tool/technology to support remote genetic counseling or use of other educational resources. It should have a physician and counselor interface to meet the goals of genetic testing and counseling while maintaining confidentiality. Prototype must include - o The database structure for the proposed platform, user-interfaces, and metadata requirements; o Data visualization, data query functions, feedback and reporting systems; o Data adaptation for mobile application(s) if applicable; o Ability to generate lay-friendly reports of genetic testing results that health care providers may use and are understandable to patients; o Ability to continuously incorporate new information on genetic variants for physicians to update their patients as necessary (i.e. when it impacts clinical care or has familial implications). • Identify at least one clinical setting where the tool may be used and integrated within a research or practice setting and develop process maps and algorithms to set up appropriate data flows and ensure privacy protections. • Test the feasibility /usability of tool in a sample population of physicians and patients and providing written report and recommendations on the best practices for use of the tool in research and practice settings. Deliverables for this Phase include: Page 82 • Prototype design • Demonstration of the tool and practicality of use by patients, counselors and providers • Provision of technical specifications as well as an operations/user guide for the tool • Outline of metrics that can be used to assess the successful application of the tool Phase II Activities and Deliverables The goal of Phase II is to evaluate application of the tool as well as pilot and disseminate in an ongoing research project or community practice setting after procurement of needed human subjects and operational approvals. Finally, a plan for commercialization based on the pilot should be developed. In order to meet these goals, the offeror will • Outline a plan to use the tool, technology, or product in practice settings. • Enhance systems interoperability for deployment in diverse software environments and provider networks. Provide a report detailing communication systems architecture and capability for data reporting to healthcare providers, electronic health records, and health surveillance systems as appropriate for the proposed project. • Refine prototype and scale up. • Perform an evaluation of the interpretation of genetic results by comparing to gold standard guidelines for interpretation. • Design and conduct a validation study including specifying study aims, participant characteristics (physicians and patients), recruiting plans, primary and secondary end points and data analysis plans. The validation study should evaluate physician communication of results and patient understanding of information communicated by the physician. • Prepare a tutorial session for presentation at NCI and/or via webinars describing and illustrating the technology, its intended use and results from the validation study. • In the first year of the contract, provide the project and contract officers with a letter(s) of commercial interest. • Provide the project and contract officers with a letter(s) of commercial commitment. Deliverables and activities include: • Validated tool, technology or product that has been successfully used in active research or community settings by physicians or health care providers. • Metrics demonstrating that physicians/health care providers understand information provided, and patients understand materials communicated by physicians. • Finalized user guide and operations manual for use of tool within an active research study. This will include technical specifications, process guides/flow charts for how and by whom the tool will be used. • Finalized trouble shooting guide as well as frequently asked questions. • Analysis and discussions from exit interviews of study participants, physicians and counselors to understand and improve utility and usability of tool in a practical setting. • A plan to develop the tool commercially and disseminate it to the wider research and practice communities.

Fast-Track proposals will NOT be accepted. Direct Phase II proposal will be accepted Number of anticipated awards: 3 - 5 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 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 Single cell multimodal omics (scMulti-omics) technologies by integrating different readouts, such as DNA, RNA and protein expression, can provide greater value than the sum of the parts making these technologies powerful to characterize the cell in-depth. Isolation of unique cell populations, and simultaneous and selective extraction of different macromolecules can enable further experimental analyses to answer critical questions in basic science and clinical research and empower observational and therapeutic studies. For example, in cancer, scMulti-omic technologies will enable us to identify rare cell types and their characteristics with unprecedented accuracy, to better understand the mechanisms related Page 83 to tumorigenesis, metastasis, tumor heterogeneity, tumor immune response and immune evasion, and to improve the accuracy of tumor diagnosis, treatment, and prognosis. By 2025, the global scMulti-omics market is anticipated to be $5.32 billion, mainly driven by the increasing need for noninvasive or minimally invasive diagnosis and personalized medicine. Recent advances have significantly improved multi-omic analysis; however, the sample processing technologies for tumors, in particular solid tumors for multi-omic analysis are lagging behind. The existing technologies are associated with low throughput, high cost, and sub-optimal processing affecting data quality, which hamper their widespread use in biology and ultimately in medicine. There is a need for robust sample processing technologies that are compatible with downstream analysis and can be easily integrated in the preanalytical workflow. In this contract topic, we will focus on improving the preanalytical workflow consisting of several steps to make the biomolecules ready for multi-omic analysis: cell isolation and enrichment for the population of interest followed by cell lysis to release biological materials and then processing of the materials, such as gDNA, mRNA, or expressed proteins, tailored for the downstream target analysis, since biomolecules from single cells are usually extremely low in quantity. Improving the preanalytical workflow may be done at different steps in the workflow such as processing of tissues to maintain integrity of biomolecules, isolation and enrichment of a cell population including unique/rare cell population, biomolecular isolation and enrichment, conversion of the molecular target species into a readable format, while ensuring reagent compatibility in the workflow for downstream analysis and also including quality control (QC) methods to assess capture, isolation and enrichment, QC tools that integrate cellular phenotypic information with the omics information to distinguish cell-to-cell variability from technical noise, and also tools that assess cell viability early on in the workflow to prevent processing of inadequate samples through costly multi-omic analysis. Project Goals The offerors are encouraged to integrate the preanalytical workflow from tumor cell dissociation/isolation, enrichment, tracking, cell lysis, to biomolecular isolation on a single platform to enable single cell multimodal-omic analysis. This approach should provide smoother transitions between functional components thereby leading to shorter analysis time and thus higher throughput. In addition, by omitting human intervention, workflow with higher degree of automation should ultimately translate into greater experimental reproducibility. Novel micropillar-based microfluidic platforms that are capable of providing high efficiency separation, isolation and enrichment of single cells and molecules instead of relying on a single-compartment design (e.g. droplet microfluidics, microwell technologies, valved and chambered microchannels, tube-based kits, etc.) for cell and biomolecular processing may be explored. Micropillar arrays within microfluidic channels may serve to physically size-separate genomic DNA from proteins and RNA during cell lysis in a manner compatible with the downstream target analysis. Overall, at the end of the contract an offeror is expected to provide a robust sample processing platform that easily integrates with scMulti-omic analysis and allow better understanding of heterogeneity in solid tumors and the microenvironment, and also that enable analysis of rare and low-abundant cells such as circulating tumor cells and antigen presenting cells, to potentially open the door to new biomarker and therapeutic targets discoveries in cancer. The activities that fall within the scope of this solicitation include development of technologies to improve single-cell multi-omic preanalytical microfluidic platforms that integrate steps of the preanalytical workflow such as sample processing, single-cell separation or isolation and enrichment, technologies for solid tumor dissociation/isolation, enrichment and tracking of cancer cells and/or biomolecules for scMulti-omics. Technology proposals focused on developing new or improved molecular analysis will be considered non-responsive to this contract topic. Phase I Activities and Deliverables Phase I activities should demonstrate the feasibility of a technology to improve single-cell multi-omic preanalytical platforms. • Develop an early/proof-of-principle prototype, single-cell multi-omic preanalytical device/platform or technology for at least one improved step of the scMulti-omic preanalytical workflow • If the technology developed is a novel technology for at least one step of the scMulti-omic preanalytical workflow, describe its capability for integration with other steps in the scMulti-omic workflow into a device/platform • Establish assays and/or metrics, especially functional comparability and quality attributes, and benchmark the approach against current methods used in single-cell analysis preanalytical workflows using at least two tumor types. • Define the target for analysis and demonstrate compatibility with the downstream analytical step (at least two downstream readouts for example DNA and RNA sequencing technologies) • Present assay performance and validation results and demonstrate the workflow of the technology during a Page 84 potential NCI SBIR site visit. Phase II Activities and Deliverables Phase II activities should support establishing commercial prototype of the technology, including but not limited by the following activities: • Demonstrate system performance and functionality by adopting commercially relevant quantitative milestones: o Offerors should specify quantitative technical and commercially-relevant milestones that can be used to evaluate the success of the tool or technology being developed. o Offerors should also provide appropriate justification relevant to both the development and commercialization of these technologies. o Quantitative milestones may be relative metrics (e.g. comparison to benchmarks, alternative assays or minimization of the pitfalls of the experimental measurements described in phase I) or absolute metrics (e.g. minimum level of detection in a clinically meaningful indication). • Show potential/feasibility to scale up the technology at a throughput compatible with widespread adoption by the research and clinical community. • Develop a working, commercial prototype device/platform for the single-cell preanalytical workflow and perform pre-market evaluation at multiple sites. • Report throughput capacity and cost of the device/platform

Fast-Track Proposal will be accepted Direct-to-Phase II proposal will be accepted Number of Anticipated Awards: 4-6 (3 for HPV diagnostics) Budget (total costs, per award): Phase I: up $400,000 for 12 months Phase II: up $2,000,000 for 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Summary Cancer is a leading cause of premature death in low-resource settings globally, where gaps in access to cancer prevention, screening, early detection, and diagnosis present significant challenges. For example, cervical cancer is the fourth most common cancer in women. When pre-cancer or early-stage cancer is diagnosed, it is one of the most preventable or treatable forms of cancer, respectively. As a result of complex and expensive cytology-based programs in high-income countries, cervical cancer has become a cancer that defines health disparity populations and one that is still a major cause of morbidity and mortality in low-resource settings globally, where building out a cytology-based screening program may not be realizable. Realization of that goal given the current commercially available human papillomavirus (HPV) tests is unlikely without newer, lower-cost tests coming to market. The purpose of this solicitation is to provide funding opportunities for small business concerns (SBCs) to develop cost effective and affordable technologies for cancer prevention, early detection and/or diagnosis that target low-resource settings, both internationally and within the US. It will allow applications to any specific cancer type, however four cancer types (tissues) are of particularly interest because they are highly amenable to prevention, early detection, and diagnosis in low-resource settings. The four cancer types of interest are: cancers of the cervix, colon/rectum, esophagus, and oral cavity. These four cancer types are given a high priority because the introduction of affordable and cost-effective technologies for cancer prevention early detection and diagnosis is likely to have an especially strong impact to reduce the burden of these cancers in low-resource settings. For cervical cancer, one of the goals for this initiative is to support the development of new alternatives to standard labbased HPV testing to the market that are both in a form factor as well as price point that will enable primary screening paradigms based on self-collected cervicovaginal specimens to be established globally. Specifically, at- or near-patient nucleic acid amplification approaches are needed that enable rapid detection and genotyping for HPV. Project Goals The goal of this solicitation is to encourages applications from SBCs to develop or adapt, apply, and validate existing or Page 85 emerging technologies into low-resource setting-appropriate technologies for cancer prevention early detection and/or diagnosis. Investigators must explicitly consider potential for adoption and scale-up in the local context as design criteria for technologies proposed in applications responding to this solicitation. Projects proposed for this contract topic will require multidisciplinary efforts to succeed, and, therefore, all applicant teams must include expertise in oncology, engineering, global health, and healthcare delivery in low-resource settings. Products addressing cancers of the cervix, colon/rectum, esophagus, and oral cavity are highly encouraged for this solicitation. However, applications may address any single cancer type. For cervical cancer, this solicitation is particularly focused on the development of rapid HPV diagnostics at the point-ofneed suitable for taking to scale (e.g., a portable loop-mediated isothermal amplification (LAMP) based assays). Scientific/Technical Scope Applications submitted to this solicitation must propose to develop or adapt technologies into user-friendly, affordable products for prevention, early detection, and diagnosis of cancers in a low-resource setting. The proposed project must focus on a specific cancer type (histology) and must show preliminary evidence to deliver medical utility for improved cancer outcomes. Products addressing cancers of the cervix, colon/rectum, esophagus, and oral cavity are particularly encouraged for this solicitation. However, applications may address any single cancer type. The proposals must include quantitative milestones and a way to document the clinical utility of the propose product within the specific low-resource healthcare system of interest. The proposed product must comply with the regulations and international standards/guidelines applicable to investigational medical products in the low-resource setting where the product will be used (examples are World Health Organization guidelines and local regulations in LMICs, and Good Laboratory Practice, Good Manufacturing Practice, FDA Investigational New Drug, and Investigational Device Exemption for US settings). All applicants should demonstrate familiarity with applicable regulatory requirements, while Phase II applications require in the commercialization plan to include a detailed regulatory strategy matched to the low-resource setting of the study. Beyond the scope of this solicitation, it is anticipated (and encouraged) that the outcomes of successful SBIR projects will help attract strategic partners or investors to support the ultimate commercialization of the technology as a publicly available product or service. Projects funded by this solicitation may include patient enrollment in foreign countries. Per SBIR policy, when there are special circumstances justifying the conduct of the proposed research outside the US within time and budget constraints (e.g. a high disease incidence that makes clinical validation more feasible and timely), agencies may approve performance of a portion of the SBIR R&D work outside of the US. In this case, applicants are required to include a statement in their applications on why these resources are not available in the US. Technology areas of interest for cancer prevention, early detection and diagnosis include, but are not limited to, the following: • Delivery technologies to improve reliability, effectiveness, and/or safety of vaccines at the point of use (e.g., needle-free delivery methods, intradermal delivery, or oral delivery) • Diagnostic microarrays • High-throughput cancer screening, cytology, or imaging-based screening • In vitro diagnostic assays such as point-of-care (POC) analytical tools for exfoliated epithelial specimens (e.g., cervical Pap specimens), blood, saliva, or urine (e.g. lab-on-a-chip biosensors that allow remote performance of chemical and/or biological assays outside of a laboratory environment) • Machine learning algorithms to identify precancer and cancer in optical images captured with simple devices (e.g., smart phones) • Portable imaging devices for cancer diagnosis (e.g., optical imaging, diffuse optical tomography, endoscopy, or ultrasound) • "pop-up" labs for cancer screening and diagnosis • Smartphone-based technologies for cancer prevention, detection and/or diagnosis • Software tools for cancer prevention, such as tools for screening, vaccine dissemination, or tools to improve vaccine supply chains • Tele-oncology (e.g., tele-diagnosis, tele-screening, tele-cytology, or tele-colonoscopy) • Tests to predict the potential effectiveness of chemotherapy • Tools for information and communications technologies to enhance cancer data collection, sharing, or analysis Technologies that are generally not appropriate for this solicitation include the following: • Companion diagnostics for high-cost drugs that are not affordable in low-resource settings Page 86 • Devices that involve highly invasive interventions • Devices that require extensive user training before they can be used (e.g., FDA definitions moderate and high complexity devices) • Experimental diagnosis modalities that are not approved in the US • Technologies not affordable or cannot be maintained in lower-resource settings (e.g., World Bank definitions of low-income and lower middle-income countries) Expected Activities and Deliverables Quantitative milestones are required for both Phase I and Phase II projects, regardless of whether they are combined in a Fast-Track application. It should be noted that low-resource settings have limited healthcare budgets and often struggle to prioritize healthcare needs. Because of the variation in healthcare systems among LMICs and US regions with underserved populations, applicants will need to consult with local partners and organizations (beginning before they submit their application) to develop plans for product design and testing that are suitable to the low-resource setting, including strategies for regulatory approval and reimbursement (if applicable) for the proposed product. Examples of suitable consulting organizations are local hospitals, medical schools, charities, community groups, nongovernmental organizations, and local governmental offices with expertise in the setting. A portion of contract fund can go to these organizations, standard SBIR outsourcing requirements apply. Phase I Activities and Deliverables • Develop a working prototype based on adaptation of existing technology, or development of new technology • Demonstrate the feasibility of the technological innovation for use in a low-resource setting (real or modeled), using a small number of biological samples or animals, where appropriate • For software/IT tool development, applicants are required to conduct a pilot usability study with at least 25 users • Deliver to NCI the SOPs of the system for cancer prevention, and/or diagnosis. • Develop a regulatory strategy/plan and timeline for seeking approval from the appropriate regulatory agency to market the product • Provide a brief business plan, which is likely to require partnering with healthcare staff local to the low-resource setting of interest Specific activities and deliverables for applications focused on HPV diagnostics: o Using end-user design principles, develop the prototype diagnostic device with the following characteristics:  Ease of use: the device must be suitable for use by local caregivers with minimal training in its operation and maintenance  Operable in locations with limited clinical infrastructure (i.e., design for use outside of laboratory settings)  Designed for use at the community level and in non-traditional healthcare settings.  Intended for use with self-collected cervicovaginal specimens obtained with one of the current commercially available kits o Demonstrate a working relationship with the site(s) where the clinical validation study will take place. o Conduct studies to establish analytical performance (analytical sensitivity, specificity) and other performance characteristics (e.g., limit of detection, consistency, reproducibility) with self-collected samples. o Conduct studies to evaluate and test user acceptability and feasibility in both average-risk and high-risk (e.g., women living with HIV) populations. o Conduct initial cross-validation with at least one of the current FDA-approved HPV testing assays to determine the clinical performance measures. Phase II Activities and Deliverables • Continue the consultation with local healthcare delivery experts in the low-resource setting of study • Adapt the prototype device developed in Phase I to the targeted low-resource setting • Validate the device in the low-resource setting(s) with a statistically significant number of animal and/or human samples, live animals, or human subjects (if animal work or human subjects are involved) for the proposed product. Animal studies are optional and may not be needed for many products supported by this solicitation. Animal studies need only be proposed for products where intermediate testing in animals is thought to be necessary for regulatory approval, or necessary before an IRB will approve a follow-on human study • Validate the product with a large-scale validation/usability study with at least 100 users if a software/IT tool is developed • To the extent possible, benchmark the product against existing commercial products used to address the same healthcare need in developed countries and include a description of competitive landscape in the Page 87 commercialization plan • Engage with local state regulatory agency to refine the regulatory strategy • 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, where appropriate • By the end of Phase II, engage with the appropriate regulatory agency (e.g., US Food and Drug Administration, World Health Organization) to seek and/or obtain marketing approval for the product that was developed. Specific activities and deliverables for applications focused on HPV diagnostics: o Develop a well-defined diagnostic device under good laboratory practices (GLP) and/or good manufacturing practices (GMP) o Perform manufacturing scale-up and production for multi-site and multi-test evaluations, including sites both in the U.S. and at a site in a resource-limited setting o Demonstrate the clinical sensitivity and specificity of the device for self-sampling by performing multi-site and multi-test evaluations o Develop a training plan for healthcare delivery users, to help assure progression toward clinical utility and benefit from the validated technology. o Report on the sustainability/durability of the device/assay

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 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 Hepatitis C virus (HCV) causes both acute and chronic hepatitis, liver cirrhosis, and is a major cause of liver cancer. An estimated 71 million people worldwide have chronic HCV infection and approximately 400,000 people die annually from HCV-related cirrhosis and liver cancer. In the US, approximately 2.4 million people are currently living with HCV and the last decade has seen a 5-fold increase in new HCV infections primarily due to increases in intravenous injections of opioids. The greatest increases in new HCV infections has been in people aged 20-39 years. Highly effective and increasingly affordable direct-acting antiviral (DAA) therapies are now available. Currently, HCV can be diagnosed with a blood test and is curable. The CDC estimated that 50,300 acute hepatitis C cases occurred in 2018 but only 3,621 were reported to them due to under-ascertainment and under-reporting. In 2020, the US Preventive Services Task Force (USPSTF) recommended HCV screening for people aged 18-79 years, which expands on the previous USPSTF recommendation of HCV screening born between 1945 and 1965. The current screening modality includes screening for anti-HCV antibody serology testing followed by reverse transcriptase-polymerase chain reaction (RT-PCR) testing for HCV RNA and is accurate for identifying patients with chronic HCV infection. Given the large size of the target population for HCV screening, including populations who cannot or will not undergo clinic-based screening and marginalized high-risk populations, new strategies are needed to increase access and democratize HCV screening. A non-invasive, accurate screening test for HCV exposure or infection would allow initial screening to occur in non-clinical settings including at-home testing. A rapid test for anti-HCV antibodies is FDA approved but not for home use. A recent meta-analysis reported that oral specimens used with current anti-HCV antibody serology tests, including a rapid test, are almost as sensitive for anti-HCV antibodies as using blood. None of these tests have been optimized for use of oral specimens and only one is a rapid test. The development of a rapid and accurate at-home test for HCV antibodies for HCV exposure or HCV antigens or RNA for active HCV infection will provide a readily acceptable and accessible modality that can eventually reduce the burden of liver disease and HCC cancer morbidity and mortality. Project Goals The purpose of this solicitation is to develop and validate a rapid, sample-to-answer, point-of-care test for HCV exposure or Page 88 active infection that has the following required specifications: 1) can be used as a self-test in non-clinical settings including at home; 2) testing requires only the use of non-invasive specimens that can be safely collected at home such as (but not limited to) blood via finger prick, oral samples (e.g., saliva or buccal cells collections), or urine; and 3) achieves the same analytic performance as predicate tests that use blood for the detection of anti-HCV antibodies as a measure of exposure or HCV RNA or proteins as a measure of active infection. Activities not responsive to announcement: HCV diagnostics that do not meet the specifications in the Project Goals will be considered non-responsive. For example, tests that cannot be used at the point-of-care or as a self-test in the home setting will be considered non-responsive. Phase I Activities and Deliverables: Offers must propose to conduct activities that lead to development of a working prototype device ready for clinical evaluation, including but not limited to: • Develop a working diagnostic assay and/or prototype point-of-care diagnostic device that can identify people exposed to or have an infection by HCV using oral salivary specimens, urine, or sample of blood that can be collected using a lancet (i.e., specimens that can self-collected). • Demonstrate that the prototype diagnostic assay can be operated as a self-test by the target population. • Determine the sensitivity, specificity, and other performance characteristics (e.g. limit of detection, cross reactivity with other infectious agents, reproducibility, feasibility for newly infected, chronically infected, and resolved infected clinical samples, test stability) of the diagnostic test for HCV. • Conduct initial testing using samples from animal models and/or preferably on patient isolates to demonstrate feasibility. • Offerors may need to establish a collaboration or partnership with a medical facility or research group in the US that can provide relevant positive control and patient samples; offerors must provide a letter of support from the partnering organization(s) in the proposal. Phase II Activities and Deliverables: • Develop a well-defined test platform under good laboratory practices (GLP) and/or good manufacturing practices (GMP). • Perform scale-up and production for multi-site evaluations (with at least one independent CLIA-certified laboratory) using clinical isolates. • Demonstrate suitability and operability of the test for use in non-clinical laboratory settings including self-test (with self-collection of the specimen) at home by target population. • Establish a product development strategy for FDA regulatory approval (as appropriate).

Fast-Track proposals will NOT 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 12 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 For existing and novel cancer therapies, there is an unmet need for quantitative biomarkers for selecting patients for targeted therapeutic products as well as for evaluating and predicting therapeutic outcomes faster and with greater precision. These biomarker reference tools are also needed to address challenges associated with heterogeneous or difficult to biopsy tumors. Such biomarkers tests may be considered for qualification by the FDA Medical Device Development Tools (MDDT) Program. FDA’s mission is to protect and promote public health by helping to speed innovations that make medical products safer and effective for the public. The FDA MDDT Program is a mechanism for FDA to qualify tools that companies can use in the development and evaluation of medical devices subject to regulatory decision-making by the Center of Devices and Page 89 Radiological Health (CDRH). MDDTs can have a variety of uses/roles in a device clinical study such as patient selection, study population enrichment, monitoring treatment response, predicting or identifying safety problems related to treatment with a medical device, or identifying patients who are or are not candidates for certain forms of therapy. Learn more about the FDA’s MDDT Program here. FDA’s MDDT Program collaboration with the NCI SBIR Development Center can help incentivize the small business community to develop these innovative tools in oncology-related regulatory decision-making and disseminate them by selling to industry or academia who are developing new device technologies, or users such as device developers that would benefit from using the MDDT in their regulatory submission. Given these similar areas of interest, FDA CDRH and NCI SBIR have developed this joint contract topic to stimulate and support innovation across our overlapping communities. Potential examples that could be MDDTs include new/high resolution multimodal imaging as biomarkers for detection of various melanomas or difficult to biopsy tumors, or laboratory-based biomarker tests to be used to help regulatory evaluation of diagnostic and therapeutic medical products. Project Goals The goal of this contract topic is to stimulate the participation of small businesses in the FDA's MDDT Program to develop quantitative biomarker tests. An MDDT is a method, material, or measurement used to assess the effectiveness, safety, or performance of a medical device. MDDTs can accelerate the device development process by providing developers with measurements and tools qualified by FDA that do not need to be re-evaluated within the context of use which helps streamline/speed device development and FDA regulatory decision-making. Offerors are expected to have identified biomarkers and tools with the potential to serve in the evaluation of newly developed similar reference tests for patient selection or device safety/effectiveness evaluation by CDRH. Biomarker-based assays that may serve as reference tools and qualify as an MDDT include tests or instruments used to detect or measure a biomarker. Categories of biomarkers that could be used in clinical or nonclinical trials evaluating devices include: susceptibility/risk biomarker, diagnostic biomarker, monitoring biomarker, prognostic biomarker, predictive biomarker, pharmacodynamic/response biomarker, and safety biomarker. CDRH also intends to consider characteristics derived from medical imaging to be biomarker tests. Activities that fall within the scope of this solicitation include development and optimization of a biomarker-based assay that meets the criteria defined by the FDA MDDT Program. Examples of technologies considered responsive to this solicitation include quantitative biomarker tests for checkpoint inhibitors to enhance cancer patient selection, quantitative imaging methods for assessing therapeutic outcomes, or an algorithm combining various biomarkers to make a comprehensive assessment in therapeutic or safety outcomes in cancer patients. Phase I Activities and Deliverables: • Develop a working biomarker-based assay that meets the criteria defined by the FDA MDDT program. • Prepare an MDDT proposal using the MDDT Qualification Plan Submission Template which includes specific requirements and activities with respect to the proposed MDDT. For additional details review ‘Qualification of Medical Device Development Tools - Guidance for Industry, Tool Developers, and Food and Drug Administration Staff.’ • Demonstrate the suitability of the assay for use in a regulatory setting. • Submit a complete Qualification Plan to the FDA’s MDDT Program. It should include description of the MDDT, context of use, and a detailed plan to collect evidence based on the context of use for qualification of the tool. Use the MDDT Qualification Plan Submission Template for this submission. • Specify the quantitative technical and commercially relevant milestones that will be used to evaluate the success of the biomarker-based assay. • Develop a regulatory strategy/plan and timeline to file a regulatory application for an MDDT. Phase II Activities and Deliverables: • Build the biomarker-based assay according to the specifications developed in Phase I. • Optimize and demonstrate regulatory/clinical utility and value by testing sufficient numbers of patients from multiple sites to unequivocally prove statistical significance with regards to patient selection. • Prepare a Full MDDT Qualification Package Submission Template which includes specific requirements and activities with respect to the proposed MDDT. • Demonstrate the safety and efficacy of the biomarker-based assay in relevant animal models if required by FDA. • Engage with FDA to refine and execute an appropriate regulatory strategy. If warranted, provide sufficient data to submit a regulatory application to obtain approval for clinical application. Page 90 • Submit a Full Qualification Package to the FDA’s MDDT Program including the data collected according to the FDA-accepted Qualification Plan. Use the MDDT Qualification Package Submission Template for this submission. Frequently Asked Questions 1. Who are the potential customers for an MDDT? MDDTs can be used by other developers, researchers, small businesses, and other industry and research groups who are working to develop technologies in the same space as the MDDT technology. These tools will facilitate the regulatory decision-making process and expedite the development of new technologies, benefiting both FDA and companies with technologies under FDA review. 2. Will FDA or NCI purchase the MDDT? Offerors must identify the eventual customers for their tool. NCI and the FDA are not potential customers for this product. 3. Are there examples of MDDTs? Yes, the MDDT page (https://www.fda.gov/medical-devices/science-and-research-medical-devices/medical-devicedevelopment-tools-mddt) lists some examples of MDDTs. There are no examples in the biomarker or the dataset spaces, which is one reason that the FDA and NCI are interested in supporting offerors working in these areas. 4. What happens if my tool is not qualified as an MDDT? You must submit your qualification plan to the FDA by the end of the Phase I contract. CDRH will review Full Qualification Packages submitted at the end of the Phase II contract and make a qualification decision regarding the tool’s acceptance as an FDA-qualified MDDT. This risk is mitigated by a company developing their Qualification Plan in accordance with CDRH feedback prior to submitting their final Qualification Plan to FDA. If awarded, companies are highly encouraged to engage FDA early on when developing their Qualification Plan for the MDDT Program.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 2-4 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 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 use of computer-aided detection and diagnosis systems with endoscopic procedures has the potential to improve the detection of hard-to-find colonic polyps and esophageal lesions and to differentiate high-risk adenomas and dysplasia from lower risk lesions. Recent data indicate that machine learning, and artificial intelligence can help improve the detection and diagnosis of imaged precancerous lesions in the colon, liver, lung, prostate, and other organs. Because most imaging-aided diagnosis examinations are operator-dependent and thus are limited by operator experience and human error, there is a demonstrable need for systematic, unbiased quantitative approaches to improve detection and diagnostic decision-making and during preventative screening and surveillance. Computer-aided detection and diagnosis systems for endoscopy are designed to capture all abnormalities including flat or diminutive adenomas and those hidden in poorly visualized areas of the intestine, that are commonly missed with standard endoscopic instruments. However, AI software diagnostic tools are underrepresented at present or have yet to reach their Page 91 full potential in the clinical practices. Likewise, the solicited algorithms would detect small foci of dysplasia that often go unrecognized in heterogenous Barrett’s esophagus lesions. Thus, these algorithms have the potential to identify characteristics that indicate clinical relevance and cancer risk level of precisely visualized lesions, thereby helping medical professionals perform more effectively and efficiently. Some companies are currently developing these areas of artificial intelligence and machine learning however, small business and academic institutions can provide an impetus for the development of these technologies and provide important pilot data to determine feasibility that can be further validated either in phase II or independently funded research projects (R21/R01). Project Goals The goal of this topic is to solicit proposals to advance the development and application of artificial intelligence-based algorithms to improve the visual human-based determination of precancerous lesions examined through visual inspection of upper and lower endoscopies. The technology should be designed for effective detection and characterization of endoscopic images to properly help decide clinically relevant next steps and to provide physicians with the diagnostic confidence that comes with AI-support. The activities that fall within the scope of this solicitation include the development and application of algorithms for computer-aided diagnosis of Barrett’s esophagus and dysplasia and colorectal polyps and adenomas. Examples of appropriate activities include the development of computer-aided algorithms that can distinguish between low-grade and high-grade dysplasia, precancerous and cancerous lesions of the upper and lower gastrointestinal tract. The offeror may develop only an upper or lower endoscopy computer aided algorithm. Adequate justification for the appropriateness of including multiple diseases or organs (upper and lower GI tract) must be provided if the same algorithm is to be used. Adenoma and dysplasia detection rates are validated quality measures for endoscopy. However, these rates vary based on several factors, endoscopy indication (surveillance vs screening and anatomical location, distal vs proximal colon). A successful computer-aided algorithm shall demonstrate statistically significant improvement of detection rates for each modality compared to standard endoscopy lesion detection rates. Phase I Activities and Deliverables: • Establish a multidisciplinary project team with expertise in computer-aided diagnosis, medical imaging software design, informatics, and gastroenterology or medical oncology to oversee the development of software. • Develop tools for an artificial intelligence-based system that can analyze cell nuclei, crypt structure, and microvessels in endoscopic images, for the identification of esophageal or colon neoplasms (including polyps, precancers, dysplasia, and metaplasia). • Develop an algorithm for evaluating endoscopic images for prediction of progression to more advanced disease and / or response to cancer interception intervention. • Develop a system where the primary outcome is accurate differentiation between normal tissue, precancers, and cancers. • Design and build a computer-aided diagnosis (CAD) tool as a prototype. • Evaluate CAD performance via available (retrospective) image data sets. • Refine CAD tool as needed to improve performance and sensitivity and specificity. • Perform small scale usability testing (5-10 end users) at multiple sites. • Finalize discussion with FDA for regulatory requirements to be completed in the SBIR Phase II. Phase II Activities and Deliverables: Offerors must propose activities leading to the manufacturing and regulatory approval of the computer-aided diagnosis (CAD) tool, including but not limited to: • Validate tools developed in Phase I for an artificial intelligence-based system that can analyze neoplastic and non-neoplastic lesions including polyps, precancers, dysplasia, and metaplasia. • Clinical validation of the algorithm/AI system for evaluating endoscopic images for prediction of the progression to more advanced disease and / or response to cancer preventive intervention. • Include all requirements from FDA to be completed in Phase II. • Build the final version of CAD tool and test with 5-10 end users. • Design a prospective trial to evaluate CAD tool’s ability to distinguish premalignant lesions from high-risk neoplasia at statistical significance level. • File regulatory submission with FDA for the CAD product for the specific use. • Develop and implement a commercialization plan for the CAD tool with customers.

Fast-Track proposals will NOT be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 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 Oncology data science and analytics is a burgeoning area of machine learning (ML) and artificial intelligence (AI) technologies that have fueled unprecedented levels of interest across the industrial and academic sectors. The past few years have witnessed many startups and large companies focusing on ML/AI technologies with the aim of reducing complexities in clinical workflow or increasing accuracy in detection, diagnosis, and treatment of cancer. To that end large, wellcharacterized datasets with the best available ground truth/reference standard and relevant metadata are essential for developing machine-based applications in cancer. While tremendous amounts of data are generated through clinical practice, significant gaps remain to leveraging the data for device development and evaluation, including: 1) generation/acquisition of patient outcome data; 2) truthing of images by clinicians; 3) correlation of combined imaging, comprehensive clinical, and genomic data in common repositories for developers; 4) extraction of information from unstructured electronic health records (EHR) data; and 5) availability of infrequent, but clinically relevant, variants. The goal of this topic is to promote and support an unmet need for the development of large, well-curated, and statistically robust datasets that can be used for the evaluation of cancer medical devices subjected to regulation by Center for Devices and Radiological Health (CDRH). Such datasets may be used in scientific research, to develop new devices as a measure of device performance, and have a regulatory use appropriate for the FDA Medical Device Development Tool program. A tool eligible for consideration by the MDDT Program is one that reduces the regulatory burden of industry and the FDA. FDA’s mission is to protect and promote public health by helping to speed innovations that make medical products safer and effective for the public. To qualify a dataset as an MDDT, the FDA evaluates the dataset and concurs with the available supporting evidence that the dataset produces scientifically plausible measurements and works as intended within the specified context of use. More information about the FDA’s MDDT Program can be found here. FDA’s MDDT program collaboration with the NCI SBIR Development Center can help incentivize the small business community to develop and qualify innovative tools for oncology-related regulatory decision-making. These tools can be sold to industry or academia developing new device technologies that would benefit from using the MDDT in their regulatory submission thus stimulating and supporting translation of innovative devices to the clinic. Given these similar areas of interest, FDA CDRH and NCI SBIR have developed this joint contract topic to stimulate and support innovation across our overlapping communities. Project Goals The goal of this contract topic is to stimulate the participation of small businesses in the FDA's MDDT program to develop and demonstrate the utility of qualified datasets as MDDTs to assess medical devices subject to regulation by CDRH. An MDDT can be a method, material, or measurement used to assess the effectiveness, safety, or performance of a medical device. The functionalities of such medical devices run the gamut in the cancer care continuum including prevention, detection, diagnosis, treatment planning etc. Datatypes of interest cover a broad range of data produced by those devices, and include, but are not limited to, imaging (radiology and pathology), cancer genomics, proteomics, structured data extracted from unstructured EHR, and treatment outcome data. In order to achieve the goal of developing datasets as MDDTs for a specified context of use, each dataset may have the following technical characteristics: • Focused on a specific cancer (i.e., disease site), a specific clinical application (e.g., diagnosis, therapy), and a specific modality (e.g., radiologic imaging systems, microscopy, spectroscopy, genomics, proteomics, laboratory testing, therapeutic or surgical devices, etc.). • Structured and well-characterized, to include the best available ground truth or reference standard and the relevant metadata and data model to help in device development and evaluation. The truthing process must be clearly described and include an appropriate number of qualified experts. • Contain a diverse patient demography and an appropriately broad range of data acquisition systems, follow well- Page 93 described reconstruction and processing methods, include full details of the imaging systems, protocols, reconstruction methods, etc., and be presented in formats that follow the latest standards, when available. • Anonymized with respect to the protected health information (PHI) and patient-identifying information (PII). • Stored and tabulated as an organized collection of data and metadata electronically accessible and searchable by a computer system, and include a concise data descriptor, covering the above requirements. Offerors are expected to follow the above requirements and conform to the two phases of the MDDT process. Please note that the MDDT process phases are separate from the SBIR phases. Proposal Phase: The goal is to determine if the MDDT is suitable for qualification consideration through the MDDT Program by submitting a Qualification Plan that includes MDDT description, context of use, and an appropriate plan for collecting evidence to support qualification of the tool for the defined context of use. The FDA makes a decision on whether to advance the tool to the qualification phase. Qualification Phase: The goal is to determine whether, for a specific context of use, the tool is qualified based on the evidence and justifications provided. The data collected according to the Qualification Plan is submitted as the Full Qualification Package and reviewed by FDA for qualification decision. During the NCI Phase I contract time period, companies will engage with FDA in the proposal phase and develop their Qualification Plan for the MDDT. By the end of the Phase I contract, companies will submit their Qualification Plan to FDA, and FDA review will determine if the tool is accepted into the MDDT Program. During the NCI Phase II contract time period, companies will complete activities in the qualification phase. Examples of technologies considered responsive to this solicitation include, cancer diagnostics (e.g., laboratory in vitro, imaging in vivo) and therapeutics (e.g., chemo, radiation, surgery, and immunotherapy). Activities that would not be responsive under this announcement include datasets solely for the purpose of algorithm training and acquired without proper statistical considerations, or datasets that are applicable to assessing performance of only a single manufacturer’s device design. Expected Activities and Deliverables Phase I Activities and Deliverables • Develop a pilot dataset that demonstrates how the data will be collected and what it will look like. In addition to truth data (from the clinician, an alternate modality, or patient outcome), include important patient sub-group information (demographics, disease type and stage, therapies) and information about the source of the data (site, date, sample prep, imaging device make and model, imaging protocol, and post-acquisition image processing, like reconstruction methods). • Develop an algorithm-assessment plan and corresponding software. Use the pilot dataset to demonstrate the algorithm-assessment plan: performance metric, uncertainty estimation, hypothesis test. This may require simulation or modeling of the dataset and a hypothetical algorithm. This should explore different levels of hypothetical algorithm performance, sources of variability from the algorithm, sources of variability from the dataset, and expected missing data. • If truth data is from a clinician or alternate modality, characterize the related uncertainty and account for it in all analyses. Multiple clinicians or multiple replicates are needed. • Identify precision and performance-level parameters necessary for the dataset to become a clinically relevant tool that can be used for testing and evaluation of novel medical devices. This includes a sizing analysis to determine the size of a pivotal dataset following the algorithm-assessment plan. Develop a dataset and a statistical analysis plan for algorithm assessment. The plan should estimate the expected uncertainty of the algorithm assessment results for a range of algorithm performance levels using modeling and simulation. • Prepare an MDDT Qualification Plan Submission Template using the MDDT Qualification Plan Submission Template which includes specific requirements and activities with respect to the proposed MDDT. For additional details review ‘Qualification of Medical Device Development Tools - Guidance for Industry, Tool Developers, and Food and Drug Administration Staff.’ • Demonstrate suitability of the dataset for the targeted test population and planned reference standard(s). • Submit a complete Qualification Plan to the FDA’s MDDT Program. The plan to collect evidence for qualification of the dataset should include details on the data source and planned patient population for the specified context of use. Use the MDDT Qualification Plan Submission Template for this submission. • Specify the quantitative technical and commercially relevant milestones that will be used to evaluate the success of the dataset. Page 94 Phase II Activities and Deliverables • Collect the pivotal dataset and prepare it for sharing: plan, establish, and demonstrate the sharing platform and methods. Fully document the data. • Characterize the precision and performance-level parameters of the dataset. If truth data is from a clinician or alternate modality, characterize the related uncertainty and account for it in all analyses. Multiple clinicians or multiple replicates are needed. • Compare and contrast the pivotal dataset against the simulated and modeled results related to the algorithmassessment plan and sizing analysis from Phase I. • Demonstrate clinical utility and value of the dataset for use in testing and assessing novel medical devices. • Validate the dataset according to the specifications approved by the MDDT program. • Prepare a Full MDDT Qualification Package Submission Template which includes specific requirements and activities with respect to the proposed MDDT. • Submit a Full Qualification Package to the FDA’s MDDT Program including the data collected according to the FDA-approved Qualification Plan. Use the MDDT Qualification Package Submission Template for this submission. Frequently Asked Questions 1. Who are the potential customers for an MDDT? MDDTs can be used by other developers, researchers, small businesses, and other industry and research groups who are working to develop technologies in the same space as the MDDT technology. These tools will facilitate the regulatory decision-making process and expedite the development of new technologies, benefiting both FDA and companies with technologies under FDA review. 2. Will FDA or NCI purchase the MDDT? Offerors must identify the eventual customers for their tool. NCI and the FDA are not potential customers for this product. 3. Are there examples of MDDTs? Yes, the MDDT page (https://www.fda.gov/medical-devices/science-and-research-medical-devices/medical-devicedevelopment-tools-mddt) lists some examples of MDDTs. There are no examples in the biomarker or the dataset spaces, which is one reason that the FDA and NCI are interested in supporting offerors working in these areas. 4. What happens if my tool is not qualified as an MDDT? You must submit your qualification plan to the FDA by the end of the Phase I contract. CDRH will review Full Qualification Packages submitted at the end of the Phase II contract and make a qualification decision regarding the tool’s acceptance as an FDA-qualified MDDT. This risk is mitigated by a company developing their Qualification Plan in accordance with CDRH feedback prior to submitting their final Qualification Plan to FDA. If awarded, companies are highly encouraged to engage FDA early on when developing their Qualification Plan for the MDDT Program.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will be accepted. Number of anticipated awards: 2-4 Budget (total costs, per award): Phase I: up to $400,000 for up to 12 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 Page 95 Current manufacturing processes for autologous cell-based cancer therapies are complex, slow, labor intensive, and expensive. These involve highly personalized methods requiring leukapheresis followed by ex vivo manipulation of cells before a therapy can be administered to the patient. While autologous cell-based therapies offer great promise for cancer treatment, there is growing concern that current manufacturing methods are unable to support the delivery of these treatments to the large numbers of patients eligible to receive them. In particular, the cell processing period between cell isolation and therapeutic administration, referred to as ‘vein-to-vein’ time, currently takes from 3-8 weeks. Using current methods, medical center laboratories that provide cell-based therapy often have the capacity to treat only 2-8 patients per month, which is insufficient to meet the high demand of clinical trials. Moreover, given that cell-based cancer therapy is still in its nascent stages, higher patient throughput is likely to accelerate the iterative bench-to-bedside-to-bench research that will be needed to improve and mature this treatment modality. There are several areas where innovation could improve the speed of autologous cell manufacturing, therefore reducing vein to vein time and increasing the number of patients that can be treated. Innovative solutions must propose a key bottleneck in the current system. Responsive proposals could develop systems capable of processing multiple patient samples simultaneously, modify current methods or systems to become novel point of care solutions, or address known release time bottlenecks such as developing rapid QC assays for sterility and potency. Ideal solutions will decrease both the time and cost required to deliver emerging autologous cell-based therapies to a greater number of patients, including those patients with rapidly progressing disease for whom autologous therapies may not currently be feasible. Proposed systems must be capable of optimizing and maintaining the desired physiological and immunological status of the expanded cells, while overcoming issues of cell senescence and exhaustion. Project Goals The overall goal of this solicitation is to stimulate the development of advanced manufacturing technologies that substantially improve the speed and cost of producing autologous cell-based therapies. Technical solutions are expected to address a key bottleneck in the current manufacturing process for individual cell-based therapies. Ideal solutions will involve parallel processing, rapid release testing, or point of care technology development, although other approaches may also be considered responsive. New technologies must produce cell-based products of equal or superior quality as compared to current manufacturing methods. The development of scalable systems capable of changing the number of cell products produced simultaneously, is strongly encouraged. For example, technologies may involve a modular engineering approach in which the system can be readily adapted as the demand for autologous cell therapies changes. To achieve the goals of the solicitation, offerors must be improving upon an existing end to end process that they have experience with, rather than developing end to end processes as part of the project. To be responsive, proposals must involve a collaboration between technology developers and clinical researchers with experience developing and treating patients with autologous cell-based cancer therapies. Projects also including an immunologist on the team will be prioritized. Phase I projects will be expected to involve feasibility testing of the proposed advanced manufacturing technology. A key activity during the Phase I project is to benchmark the novel advanced manufacturing approach against the current manufacturing method for a specific autologous cell-based product. More specifically, the research plan must include validating the proposed novel manufacturing approach against a process that has been used to produce product for clinical trials by demonstrating comparability of products with respect to specific critical quality attributes. Phase II projects will be expected to conduct full-scale processing to demonstrate a substantial increase in the speed and cost of producing autologous cell-based therapies. It is anticipated that most offerors will propose to study T-cell-based immunotherapy products, although other cell types are also encouraged (e.g., NK cells). Advanced manufacturing approaches may involve genetic engineering and optimization as appropriate for the cell-based therapy product, but the primary goal is to achieve substantial cost and throughput improvements for the overall vein-to-vein process. Activities not responsive to announcement: Projects proposing to use allogeneic cell-based therapies for technology validation will not be considered responsive under this solicitation. Projects improving a key part of the cell manufacturing process, but not being tested in an end to end process will be considered incomplete proposals and therefore not responsive to the topic. Phase I Activities and Deliverables: • Provide proof of collaboration with an immunologist(s), clinician(s), and an engineer(s) if device development activities are proposed. All collaborators must have experience developing high throughput systems and/or treating patients with autologous cell-based cancer therapies; • Establish assays and/or metrics, especially functional comparability and quality attributes, for benchmarking the approach against current manufacturing methods; • Establish defined specifications to enable integrated high throughput parallel manufacturing at faster speed and lower cost than current manufacturing methods; • Develop an early prototype device or technology for integrated high throughput autologous-cell manufacturing Page 96 that include specifications designed to substantially reducing the speed, as well as any cost savings based on the new manufacturing approach; • Demonstrate the suitability of the approach within the cell manufacturing process; • Demonstrate pilot-scale beta-testing of the approach comparing it against appropriate benchmarking technology; • Demonstrate the immunological functionality of the cells based on the previously identified functional comparability assays and/or metrics, and compare cell function to appropriate benchmarking technology; • Establish cell culturing technology compatible with high throughput production and technology to monitor the cells. Phase II Activities and Deliverables: • Develop an at-scale prototype of the approach with detailed specifications for hardware/software that supports the manufacturing of autologous cell therapies; • Generate scientific data demonstrating the proposed scalability (e.g. scale-out, point-of-use) of the technology and demonstrate cost and time improvements over current clinical standard; • Demonstrate comparable quality between the current manufacturing standard and cell-products manufactured at scale with the proposed approach.

Fast- Track proposals will be accepted. Direct-to-Phase II proposals will be accepted for companies that have already demonstrated feasibility and rigorously achieved the deliverables in described for Phase Number of anticipated awards: 2 to 5 Budget (total costs, per award): Phase I: $500,000 for 12 months; Phase II: $2,500,000 for 2 years It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Summary: To improve, diversify, and reinvigorate the AD/ADRD drug development pipeline, the NIA has spearheaded several innovative programs including the Accelerating Medicines Partnership-Alzheimer’s Disease (AMP- AD), aimed at identifying the next generation of therapeutic targets. These target discovery programs have identified and made publicly available more than 500 novel candidate targets (to view the list of targets and supporting evidence see the open-source platform Agora) . Detailed assessment of these nascent targets using a standard biopharma target tractability evaluation has revealed that a significant number of them have low small-molecule druggability. Therefore, an expanded tool- kit of therapeutic modalities to include traditional biotherapeutics (i.e. genome editing, gene silencing, and proteins) will be required to integrate many of the next generation targets into drug discovery campaigns. This contract focuses on gene therapy, which has the advantage over protein therapy to target specific cells for gene transduction leading to production or deduction of proteins precisely where therapy is needed. For gene delivery, adeno-associated virus (AAV)-vectors are widely used gene delivery vectors for gene therapy due to features such as tissue tropism, potential of gene transfer to non-dividing cells, and long-term expression. However, vectors have several challenges including low biodistribution and brain delivery, high immunogenicity, and limited payload size. Therefore, this contract proposal focuses on gene delivery system optimization to be used for AD/ADRD gene therapy development. Project goals: Drug delivery systems are engineered technologies to help with the transport of therapeutic agents to a therapeutic target. This can involve movement through the circulatory system and further through cells of the blood-brain-barrier (BBB). The BBB is the biggest limiting hurdle to deliver a drug to the brain, and this is especially true in the case of gene delivery. The current mode of administration that is typically used for brain delivery for gene therapy is the highly invasive intrathecal administration, while other methods such as intravenous injection would provide less physical burden on the patients. AAV-vectors are currently known as the most advanced gene delivery vector and are used to transduce therapeutic genes to the CNS site for treatment of neurodegenerative disorders. Many AAV serotypes have been developed using capsid modification strategies, but each serotype has various limitations associated with brain delivery, cell-type targeting, immunogenicity, biodistribution, and payload size. Novel gene delivery systems can strive to overcome these challenges by providing safer and more flexible routes to gene delivery. By engineering new delivery vehicles using novel biomaterials or delivery modalities, gene therapy can have enhanced stability and bioavailability, decreased immunogenicity, increased brain delivery, and improved cell-type targeting. Novel delivery vehicles can include (but are not limited Page 98 to) nanoparticles, liposomes, micelles, and Trojan horse approaches; examples of novel delivery modalities can include ultrasound, electroporation, and implantable pumps. The short-term goals of this contract proposal are development of a gene delivery system and proof of concept in vivo testing for Phase I, and long-term goals are further development leading to IND submission to the FDA for Phase II. Phase I Activities and Expected Deliverables: • Details concerning special formulations or technologies (i.e., slow release, liposomes, nanoparticles, etc.). • Perform in vitro efficacy studies in the relevant cell line(s) • In vivo study results that include assessment of pharmacokinetics and bioavailability at the relevant site of action. • Rigorous evidence that the agent is blood-brain-barrier penetrant. • Immunogenicity evaluations • Evaluation of metabolism. Phase II Activities and Expected Deliverables: • PK evaluations in species relevant for toxicology or human dose-prediction • Efficacy of gene therapy in a disease-relevant model • Testing delivery to target cells in a large animal species, as appropriate • Preliminary safety such as safety pharmacology and/or dose-range finding toxicology • IND-enabling toxicology, with toxicokinetics, if applicable • Tumorigenicity evaluations • Chemistry, Manufacturing, and Control (CMC) activities (e.g., master and working cell banks development, purification development, CMC analytical development, formulation development, scale-up manufacturing or cGMP manufacturing) for INDenabling pharmacology/toxicology tests, as appropriate • IND document preparation and/or pre-IND meeting • GMP manufacturing of material for phase I clinical testing, if applicable

Fast- Track proposals will NOT be accepted. Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 1 to 2 Budget (total costs, per award): Phase I: $350,000 for 12 months; Phase II: $2,500,000 for 2 years It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Summary: Ulcerative wounds, including venous leg ulcers, diabetic foot ulcers and pressure ulcers, occur more commonly in older adults and their impaired healing is associated with underlying and comorbid diseases of aging, and defects of wound repair. The incidence of chronic wounds, those that are difficult to heal or do not follow a normal healing process, increases with age from the sixth to the ninth decades. Chronic wounds rarely occur in persons without multiple chronic conditions, and specific comorbid conditions exacerbate them, notably malnutrition and metabolic syndrome. Delayed wound healing increases the risk of recurrent infection and tissue necrosis. This results in substantial morbidity, disability, hospitalization, and even mortality among older adults. Using just one clinical example, an older person with diabetes can develop a foot ulcer, it may progress and fail to heal, necessitate a foot or toe amputation, and ultimately increases the risk of death. Until recently, approaches to chronic wound treatment have been primarily mechanical barriers and frequent dressing changes, including skin substitutes (such as acellular dermal substitutes, cellular dermal substitutes, and cellular epidermal and dermal substitutes), medical devices, and care processes such as surgery. These products are not regulated based on demonstrating Page 99 effectiveness, and comparative studies have been rare without identified superior approaches. Recent advances in the understanding of the wound-healing process have led to innovative clinical approaches to wound care including the use of stem cells, growth factors and bioactive materials to support the body’s own regenerative capacity, but these approaches have not yet obtained regulatory clearance or approval by the Food and Drug Administration (FDA). Project goals: This initiative proposes to fund development of a new geroscience-based approach to treating chronic wounds. Novel gerosciencebased approaches may target relevant mechanisms of wound healing including stem cell therapies, cell senescence, inflammation, adaptation to stress, epigenetics, metabolism, macromolecular damage and/or proteostasis. Cellular senescence was initially described by Hayflick and Morehead in 1961, and more recent work has shown that senescent cells can negatively affect their local tissue environments through multiple pathways. The inflammatory response following tissue injury has important roles in both normal and pathological healing. Inflammatory cells, cytokines and growth factors all play key regulatory roles in the complex series of events during wound healing. Among potential inflammatory targets for wound healing therapeutics, the macrophage may be an attractive target, both in terms of reducing fibrosis and scarring, and to improve healing of chronic wounds. Vascular responses to stress may be adaptive in the wound healing process. Several epigenetic regulatory factors, such as the endogenous non-coding microRNAs, have been demonstrated to be drivers of the wound healing response. Metabolic considerations relevant to wound healing are also important and include the collagen metabolism requirements, and impairments from neuropathy and metabolic disruption in diabetes. The goal of this solicitation is to call for the development of a geroscience-based wound healing product which may include but are not limited to: cellular products and therapies, immune modulation, microbiome-modifying therapy, human tissue, animal-derived tissue, and biosynthetic products. The product would be developed for clinical application to chronic non-healing wounds, in conjunction with current standard therapies. Proposals should establish proof-of-concept for and/or support preclinical development of a candidate geroscience-based wound healing product, as well as standardize methods to evaluate wound healing and safety of the candidate product(s). Proposals that significantly advance a candidate product toward clinical development are highly encouraged. Offerors must outline in their proposal the preliminary data supporting selection of the geroscience-based product for wound healing, specific clinical question and unmet clinical need in the areas of chronic wound healing that their product will address. This RFA would solicit a Phase I project for a small business to advance development of their geroscience-based wound healing product. The activities could include pre-clinical development and feasibility testing in Phase I and might involve developing the design of a comparative clinical trial that might comprise a subsequent Phase II for treating older adults with chronic wounds to induce healing. Activities not responsive to announcement: Proposals that are limited to existing FDA approved or cleared therapies for wound healing or their equivalent (dressings, barriers, skin substitutes, etc.) would be considered non- responsive. Phase I Activities and Expected Deliverables: • Select one geroscience-based potential wound healing product (drug, cellular product or drug-device) and develop and test the prototype. • Show differentiation of this product relative to other wound care products in terms cost, ease of use, efficacy, side effects, etc. • Conduct non-clinical toxicology studies (e.g., sensitization, immunogenicity) (optional) • Complete adequately powered animal trial with appropriate wound-healing endpoints (as appropriate for stage of development) • Complete preparatory steps for human studies (as appropriate: e.g., finalize protocol, data and safety monitoring plan, obtain IRB approval). (if applicable) • Perform human usability studies for the prototype with at least 10 subjects (ideally, but not required) • Develop regulatory strategy/plan and timeline for seeking approval from FDA to conduct human trials or market the product (as appropriate). Phase II Activities and Expected Deliverables (Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning): • Conduct sterility and pharmaceutical testing • Perform in vitro studies of product release over time • Perform in vivo pharmacokinetic and biodistribution (PK /BD) studies Page 100 • Complete adequately powered human trial with appropriate wound-healing endpoints (ideally, but not required) • Complete preparatory steps for human studies (e.g., finalize protocol, data and safety monitoring plan, obtain IRB approval). • Develop commercialization plan that includes a go-to-market strategy and include comparable reimbursements, manufacturing, and distribution

Fast- Track proposals will be accepted. Direct-to-Phase II proposals will NOT be accepted. Number of anticipated awards: 1 to 2 Budget (total costs, per award): Phase I: $350,000 for 12 months; Phase II: $2,000,000 for 2 years It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Summary: Americans are living longer than ever before. Life expectancy nearly doubled during the 20th century with a 10- fold increase in the number of Americans age 65 or older. As life expectancy increases, diseases and conditions that are associated with older age have become a major health burden. A major risk factor for the development and progression of some of the most prevalent late onset declines in function and health, such as wound healing, osteoporosis, sarcopenia, joint soft tissue deterioration and others are thought to be contributed by depletion or dysfunction of stem cells. Stem cell rejuvenation via heterochronic parabiosis in mice has demonstrated blood stem cells and their factors from young mice contribute to improved wound repair and motor function in old mice. It has also been demonstrated by the ability to generate “youthful” induced pluripotent stem cells derived from aging tissues. In addition, the development of novel adult stem cell-based therapies is on the rise and include the use of adult stem cells or biologics that facilitate healthy repair after orthopedic surgeries and in wound repair. However, the majority of these studies have based their efficacy and mode of action using young animal models despite the need and market pressure to treat older people. Thus, a better understanding of how aging stem cells or tissue environments respond to potential treatments is needed. The goal of the SBIR contract topic is to support small businesses that are in the early to mid-developmental stages testing adult stem cell or related biologics in aging animal or aging human tissue models to develop novel adult stem cell treatments. The impetus of this SBIR contract solicitation is to promote full use of the base of knowledge of stem cell biology for adult stem cellrelated target validation and drug discovery and development for treatment and prevention of age-related afflictions. This initiative is intended to encourage and support young, upstart biotechnology companies and also more established firms to direct their efforts into new ventures in stem cell therapeutics that target the increasing aging population. Great advances have been made in the past decade in our understanding of adult stem cells in health and in aging. Many molecular processes that have gone awry during cellular aging have been identified, and new information on the difference between a young and aged stem cell continues to be added to this wealth of knowledge. It is now incumbent that this knowledge be used to mount a new direction that targets the use of this knowledge to facilitate tissue regeneration and rejuvenation of aged stem cells and to use stem cell technologies to target treatments that afflict the aging population. While the empiric approaches of stem cell therapies are on the rise, this new paradigm demands a more reasoned and knowledge-based approach. The search for molecules or agents with translational potential that will rejuvenate or subvert the deleterious effect of aging on adult stem cells or the study of biologics and the pursuit of knowledge of the molecular mechanisms that they target which facilitate the regeneration of aging tissues will be an important component of this SBIR contract solicitation. These agents could be chemical or biological, manmade or naturally occurring, but well characterized or subject to characterization as potential therapeutic agents for age-related afflictions. Areas of focus may include improved tools, methods, standards, or applied science that support a better understanding and improved evaluation of in-depth product characterization, manufacturing, potency, identity, quality, safety, in vivo function and integration, or effectiveness. The development and utilization of modern tools for target validation and drug discovery, including combinatorial libraries and high throughput screening, would be appropriate. However, the development of new assays and innovative technologies for monitoring stem cell maintenance and differentiation will not be sufficient; their development in conjunction with molecular target identification and validation, and drug discovery and development will be appropriate. Page 101 Applicable research may also include developing biologics (e.g., growth factors, cytokines) and biomaterials (e.g., extracellular matrix, scaffolds) that stimulate an older adult’s stem cell self-renewal, proliferation, differentiation, and/or function or otherwise directly act upon adult stems cells to support innate host healing mechanisms, treat disease, and/or restore function. Funding could also be used for the appropriate chemistry, manufacturing, and controls development to support the production of such products for aging clinical trials using current good manufacturing practices (cGMP). Project goals: This contract will support research directed toward developing therapeutics with clearly established proof of mechanisms to facilitate aging tissue regeneration at the molecular, cellular, tissue organism level. The goal is to provide evidence for a stem cell-based product with defined direct and/or indirect alterations of cellular and/or molecular processes (senescence, inflammation, metabolism, DNA repair, etc.) that contributes to its therapeutic use for the aging community. Projects will include in-depth aging stem cell characterization (RNA-seq, proteomics, metabolomics, etc.) including responses in senescence and inflammation using cells, tissues, or animals. Appropriate applications will span a diverse range of technical and methodological approaches in an effort to generate adult stem-cell based therapies that can facilitate regeneration and repair for aging, mechanisms of their action, and how this knowledge may be exploited for the identification and development of novel therapeutic targets. Emphasis will be given to projects that focus on developing stem cell-based strategies and to define their molecular and/or cellular mechanisms that promote healthy stem cell aging or treatment of age-related diseases. Research projects responsive to this FOA are expected to involve aging models which may include human and nonhuman aging cells and tissues and may include human or nonhuman adult stem cells. Research projects involving human or animal induced pluripotent stem (iPS) cells may be supported, as long as the cells used to generate the iPS cells were not of fetal or embryonic origin. Offerors must outline in their proposal the product, the molecular or cellular mechanism of action, and detailed characterization of the biologic and/or adult stem cells involved in the therapy-based approach as well as the unmet needs required to treat the aging population with stem cell-based strategies. Inclusion: The emphasis to study the role of stem cell-based therapies in the aging population will help fulfill the commitment NIH solidified in 2020 for inclusion across the lifespan by expanding the importance and relevance of this research in an aging body. Special Note: This initiative also supports the 21st Century Act for the Regenerative Medicine Initiative to facilitating getting these therapies into the clinic. These awards started four years ago with no further allotted support from the original allotment of $20 Million. Activities not responsive to announcement: The following will not be supported under this FOA and will not proceed to review: • Research that does not utilize aging cells, tissues, or animal models • Any research using embryonic or fetal stem cells. Such projects are non-responsive. Phase I Activities and Expected Deliverables: • Product testing of adult stem cells and related biologics in the aging body • Product testing may include autologous adult stem cell transplants in animal species, exosomes, metabolites, non-translating RNAs, blood components including but not limited to exosomes and non=translating RNA • Physiological, molecular and cell characterization of the mechanism of action for adult stem cell-based treatment for repair or regeneration of aging tissues. Included are changes in stem cell or hose tissue replication, maintenance, differentiation, senescence and inflammatory responses • Preclinical studies that contribute to conducting clinical trials that address specific clinical indications • Development of methods, standards and cGMP for adult stem cell-based RM products for using in aging • Phenotypic assay development, including stem cell technology platforms for stem cell “Aging-in-a-dish" applications and the evaluation of toxicity • Identification and validation of specific biological markers or biosignatures for aged adult stem cells including stem cell characterization and deep fingerprinting • Demonstrate in a small-scare, proof-of-concept study with in vivo animal studies or ex vivo human cells or tissue assays the feasibility of the product as potential treatment for age-related affliction. Feasibility assays including proper controls should provide Page 102 insight into whether the product can either accelerate or enhance standardized treatment pricated or provide treatment where there are no currently effective treatment options. This study should be designed to assess the sensitivity and specificity of the molecular mechanisms involved in the repair or regeneration of aging tissue • Deliver to NIA the Standard Operating Procedures of the system for treating the aging dysfunction • Develop a regulatory strategy/plan and timeline for seeking approval from FDA to market the stem-cell based product Phase II Activities and Expected Deliverables: • Refinement or modification of tools, methods, standards, or applied science that support a better understanding and improved evaluation of in-depth product characterization, manufacturing, potency, identity, quality, safety, in vivo function and integration, or effectiveness for treating the aging population • Emphasis will be given to projects that address critical issues needed for product development relevant for regulatory submissions • Demonstrates readiness of regenerative medicine products with well- characterized quality attributes for advancement into clinical trials under an IND/IDE application to treat aging patients • Addresses critical issues relevant to clinical research and regulatory submissions, including those related to improved evaluation of product quality for aging • Helps to significantly advance the field of regenerative medicine for the aging population by addressing well-recognized challenges in clinical development to treat the aging population, including the development and evaluation of safe and effective RM products • Perform a large-scale usability study with at least 100 in vivo animal studies or 500 ex vivo human cells or tissue assays. • Perform a large-scale validation study in in vivo animal studies or ex vivo human cells or tissue assays. The study should be designed to show a statistically significant improvement in the performance of the treatment • Optimally, by the end of Phase II the offeror will be able to both demonstrate commercial partnering/investment interest and submission of a regulatory application to FDA

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 Efforts towards the development of an efficacious HIV vaccine have focused on improvements in the design of the HIV envelope (Env) immunogen for induction and generation of broadly neutralizing antibody (bNAb) responses and novel platforms for immunogen delivery. One major hurdle for the induction of bnAbs is that the B cell lineages for these antibodies are found at extremely low frequencies; further, the naïve B cell receptors of these lineages may only recognize an HIV envelope from the transmitted infecting virus. Therefore, considerable efforts have focused on HIV envelope design to target these rare germline B-cells receptors including minimal epitopes and modified stabilized Env trimers. Once these naïve, germline B-cell receptors have been triggered, more native-like HIV Env immunogens may be designed to drive B cell maturation and evolution towards Ab breadth. Additionally, effective activation of rare B cell lineages will probably require an alternative delivery platform of immunogens compared to vaccination with just soluble Env immunogens. Improvements to the delivery system of these next-generation HIV Env immunogens could include multivalent antigen presentation, targeted delivery to lymph nodes, sustained antigen release, coupled co-delivery of adjuvants, etc. It is expected that the improvements to Env design coupled to improved delivery methods may increase the probability of engaging rare bNAb B cell precursors, enhance affinity maturation, and improve antibody magnitude and durability. This topic will selectively focus on the development of platforms for the delivery of HIV immunogens; immunogens may be either based on protein or nucleic acid-based design. Co-delivery of adjuvants can be included with the vaccine delivery platform. Project Goal The goal of this project is to develop an HIV vaccine platform for delivery of HIV Env immunogens that induce bnAbs. The platforms may include, but not be limited to: lipid- or polymer-based nanoparticles (NP) or equivalent multimeric antigen display platform and may contain immune-stimulators, such as adjuvants; the immunogen may either be recombinant protein (minimal epitopes, optimized trimers, etc.) or nucleic acids (RNA or DNA) expressing HIV Env proteins and/or Env proteins covalently linked to NP or multimerization domains. The goal will be to demonstrate that the vaccine platform/immunogen proposed will elicit a strong and durable NAb HIV Env response. Phase I activities may include, but are not limited to: • Engineering and fabricating nanoparticle platforms/systems and approaches (such as synthetic, self-assembling particles, conjugating technologies to attach HIV antigen to nanoparticles, lipid encapsulating technologies, etc.) for delivering existing and/or novel HIV Env immunogens (minimal epitope, native and/or native-like trimers either as a recombinant protein or expressed by nucleic acids/mRNA/self-amplifying RNAs). Page 104 • Developing and evaluating particulate systems (described above) that can facilitate co-delivery and/or co-formulation of HIV antigens (described above) with adjuvants (such as existing, licensed, biosimilar novel adjuvants/TLR agonists). • Developing optimal parameters/conditions for incorporation of HIV Env antigen(s) into nanoparticulate formulation. • 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). • Studying conditions for controlling particle size and size distribution, charge, composition, and aggregation. • Evaluating particulated formulation technologies for fabrication and development of HIV vaccine development. • 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 the Current Good Manufacturing Practice (cGMP) regulations. • Evaluating the delivery, immunogenicity, and effectiveness of particle-based HIV vector platforms in small animal models. • Investigating the effects of route of immunization, dose, dosage form, and dose-sparing capacity of particulate formulations on the particle distribution and kinetics of the immune response to the immunogen. Phase II activities may include, but are not limited to: • Developing lead vaccine 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 the cGMP regulation. • Developing cGMP manufacturing processes for developing nanoparticle formulations. • Translating in vitro studies into proof-of-concept studies in nonhuman primates, 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 compared to soluble antigen in small animal models. • Establishing quality assurance and quality control, methodology, and development protocols for the 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: 1-3 Budget (total costs): Phase I: $300,000 for up to 1 year; Phase II: $2,000,000 for up to 3 years. Background The development of novel HIV candidate vaccines generally requires preclinical testing in animal models before proceeding to Phase I clinical trials. Multiple efforts have focused on developing and evaluating innovative platforms and formulations of HIV envelope (Env) immunogens for the induction and generation of a durable and broadly neutralizing antibody (bNAb) response. Progress has been hampered, in part, due to the lack of an iterative, physiologically relevant, small animal model to test novel HIV vaccine candidates, concepts, and formulations that elicit bnAbs. Human immunoglobulin (IgG) gene knockin (KI) technology has been used to engineer mice with relevant pre-rearranged V(D)J exons of mature bnAbs or unrearranged human V, D, and J segments to generate the desired bNAb lineage. There is a need for methodological improvements of existing KI models and creation of new lines using current state-of-the-art, e.g., genome editing technologies. Several limitations due to immune tolerance mechanisms in mice need to be overcome. Humanized mice may express B cell precursors of the desired bNAb germline lineage at more variable frequencies than found in humans; other germline genes may not be functionally expressed due to the inability to overcome B cell tolerance mechanisms, yet others may be lethal to the mouse line. Existing mouse lines and novel improved second-generation human immunoglobulin KI mice or those generated by crossbreeding to other transgenic mice expressing relevant immunological receptors may Page 105 expedite translation of HIV vaccine concepts. Such strains could be used to rapidly test, for instance, HIV vaccination strategies, contribution of B cell precursor frequencies to elicit a robust bNAb response, factors that modulate B cell dominance and sub-dominance, affinity maturation (AM), somatic hypermutations (SHM), and factors that drive germinal center responses. This topic will focus on evaluating proof-of-concept HIV vaccine strategies in existing KI models or in newly created next-generation KI and transgenic mice to accelerate translation of HIV vaccine candidates for testing in Phase I clinical trials. Project Goal The goal of this project is to utilize genetically engineered mouse models, such as human immunoglobulin KI or other transgenic mice expressing relevant human genes, to accelerate testing and development of HIV vaccine candidates. Genetically engineered mice expressing human genes, for example, V(D)J immunoglobulin genes, Fc receptors, and/or other protein receptors on diverse cell types and further modified with gene-editing technologies, such as CRISPR-Cas, should offer an iterative, robust, small animal platform for rapidly testing HIV vaccine immunogens and formulations. Such models may lead to the generation of a flexible preclinical model that more accurately reflects the human humoral immune response. Ultimately, development of a predictive in vivo small animal model could accelerate testing of novel HIV vaccine concepts into Phase I clinical trials. Phase I activities may include, but are not limited to: • Investigation of proof-of-concept HIV vaccine studies in existing KI models that express human IgG germline genes of bnAbs, e.g., unmutated common ancestors of HIV bnAbs lineage • Modulation of the human B cell repertoire in existing KI models to elicit a bNAb response to HIV vaccine immunogens and particle-based HIV vector platforms • Determination of mechanism(s) required to elicit a bNAb response to HIV vaccine candidates • Determination of in vivo factors contributing to a weak humoral response, e.g., B cell tolerance, anergy, clonal deletion, sub-dominance • Identification of immunogen platforms that will elicit a rapid, robust, and durable humoral response in the mouse model • Measurement of neutralizing bnAbs of B cell lineages and other functions (e.g., non-neutralizing) of antibodies in response to HIV immunogens • Testing antibody-antigen and adjuvant formulations that promote successful B cell responses during vaccination • Evaluating the performance, effectiveness, and toxicity of particulate HIV vaccine candidates versus soluble antigens in KI models • Investigating the effects of route of immunization, dose, dosage form, and dose-sparing capacity of particulate formulations on the particle distribution and kinetics of the immune response to the immunogen Phase II activities may include, but are not limited to: • Creation and development of next-generation pre-clinical genetically engineered mouse model(s) for the rapid evaluation of HIV vaccine candidates and testing immunogen-guided bNAb lineage HIV vaccine concepts • Rapid creation of novel lines of human IgG KI models by crossbreeding with other transgenic mice expressing relevant human genes to enhance bnAbs to HIV immunogens • Testing proof of concept studies, outlined as Phase I activities, in next-generation, novel KI models • Characterization, genotyping, and detailed phenotyping of new mouse models associated with existing mouse strains and made publicly available, if applicable • Ensure availability of the newly created mouse models to academic, government, and private sector scientists, for example through NIH-supported mouse repositories • Creation of the cryopreserved archive for all new strains of mice, to enable storage of strains, for which there is no immediate need and serve as a backup supply of pathogen-free and genetically stable genetically engineered strains • Establishment of a live, specific pathogen-free colony for research use and distribution for a mouse strain upon request (Animal genotype should be verified, and health and disease status should be assessed.) • Maintenance of the breeding colonies to be conducted using standard breeding schemes appropriate to the strain, with maintenance of pedigree records • Maintenance as a live breeding colony for several months, if needed, after which it is retired to the cryopreserved archive if no further use or interest is expressed or if no orders are received. This SBIR will not support: • The design and conduct of clinical trials (see http://www.grants.nih.gov/policy/clinical-trials/definition.htm for the NIH definition of a clinical trial) • Testing non-HIV immunogens or studies unrelated to HIV vaccine development efforts • Humanized mouse models engrafted with human cells or human fetal tissue (such as hu-PBL, hu-CD34, and BLT mice) Page 106 • Investigation of transplantation, autoimmune diseases, allergic diseases, other immune-mediated diseases, and cancer

Fast Track Proposals will be accepted. Direct-to-Phase II will not be accepted. Number of anticipated awards: 1-3 Budget (total costs): Phase I: $ 300,000 for up to 1 year; Phase II: $ 2 million for up to 3 years. Background HIV/AIDS continues to be a major health problem throughout the world, with the greatest impact on vulnerable and underserved populations. A safe and effective HIV vaccine has been pursued for several decades. Ongoing efficacy trials with the latest HIV vaccine candidates can change this scenario and may lead the way to approval of a licensed vaccine in the near future. Several years of clinical trials have revealed that some HIV vaccines can elicit long-lasting (>15 years) serological immune responses that can be confused with HIV infection in common diagnostic tests. This phenomenon, known as vaccineinduced sero-reactivity or sero-positivity (VISR/VISP), can severely impact several life aspects of clinical trial participants: immigration, marriage, military service, blood/organ donation and employment, among others. VISR/VISP seems to be more prevalent with vaccines that incorporate (completely or partially) the gp41 region of the HIV envelope. Although a VISP result can be differentiated, most of the time, from a true HIV infection by nucleic acid tests (NAT) (e.g. RT-PCR), these are more expensive and technically challenging tests, and not always readily available. Furthermore, deployment of NATs might not be the single solution to VISP. In fact, the use of highly active antiretroviral therapy (HAART) or pre-exposure prophylaxis (PrEP) therapies can cause false-negative NAT results due to undetectable viral load. Previous attempts to develop a serological test agnostic to responses elicited by HIV vaccine candidates failed to reach the high sensitivity and specificity demanded by the regulatory agency (>99% sensitivity and specificity). The parallel detection and/or quantification of IgM and IgG antibodies against antigens absent in HIV vaccines, such as peptides of gp41, and systemically circulating HIV antigens, such as p24, are promising approaches. In order to prepare for the deployment of an HIV vaccine, after FDA registration and approval, companion diagnostic tests must be in place to avoid the problems associated with VISR/VISP in vaccine recipients. Project Goal The overarching goal of this project is to support the development of new serological and nucleic acid assays that can identify HIV infection while avoiding false-positive results due to VISP, with high sensitivity and specificity. These nextgeneration assays should be developed to address one or all applications/indications of HIV tests, namely: (1) laboratorybased tests; (2) point-of-care and clinical practices; and (3) self-testing. Ideally, these assays should be scalable and adaptable for manual performance (point-of-care, medical practices and selftesting) as well as fully or partially automated for high throughput (medical laboratories). They can be developed for performance in already existing, commercially available platforms and automated equipment or for performance using new devices. The newly developed assays should accept different biological samples, such as serum/plasma, whole blood, and saliva, although the specific application/indication might dictate the best sample collection method to reach the highest assay performance. During the development and qualification of the new assays, the proper algorithm for each application/indication should be defined. Since test(s) will also be deployed in low-to-middle-income countries and remote areas, dependency on refrigeration and electricity must be kept to a minimum and shelf life should be maximized. Special attention must be given to how results are obtained or communicated in order to protect confidentiality and privacy. Finally, production and operating costs should be Page 107 as low as possible to make it affordable to individuals and institutions, and practical for repeated testing by the end-user. Phase I activities may include, but are not limited to: • Development of Target Product Profile to address applications and assay performance indicators; • Development of assay concept/methodology and assessment of feasibility; • Generation/procurement of critical reagents and controls; • Pilot studies with prototype methodologies and antigens and/or nucleic-acid targets/sequences to determine feasibility; • Development of SOPs for the assay(s); • Primary assessment of sensitivity, specificity, low limit of detection, and linearity; and • Small scale screening of biological samples. Phase II activities may include, but are not limited to: • Market assessment and cost analysis; • Development of testing workflow for a specific product application/indication; • Adaptation of methodologies to equipment (different degrees of automation); • Large scale testing of biological samples and assessment of equivalence; • Assay validation (establishment of sensitivity, specificity, low limit of detection, and linearity and precision); and • Submission for FDA approval. This SBIR contract topic will NOT support: • The design and operation of clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial for the NIH definition of a clinical trial); and • Testing non-HIV immunogens or studies unrelated to HIV vaccine development efforts.

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 the treatment of autoimmune or allergic diseases. For the purpose of this SBIR, the definition of vaccine adjuvants follows that of the U.S. Food and Drug Administration (FDA): “Agents added to, or used in conjunction with, vaccine antigens to augment or potentiate and possibly target the specific immune response to the antigen.” Tolerogenic adjuvants are defined as compounds that promote immunoregulatory or immunosuppressive signals to induce non-responsiveness to self-antigens in autoimmune diseases or transplantation, or environmental antigens in allergic diseases. Currently, only a few adjuvants other than aluminum salts (“Alum”) have been licensed as components of vaccines in the United States (U.S.): 4’-monophosphoryl lipid A (MPL), adsorbed to alum as an adjuvant for an HPV vaccine; MPL and QS-21 combined in a liposomal formulation for a varicella vaccine; CpG Oligodinucleotide as an adjuvant for a recombinant Hepatitis B vaccine; and the oil-in-water emulsion MF59 as part of an influenza vaccine for people age 65 years and older. In addition, adjuvants may facilitate the development of immunotherapeutics for immune-mediated diseases (e.g., allergic rhinitis, asthma, food allergy, autoimmunity, transplant rejection). The field of tolerogenic adjuvants is still in its infancy. No compounds have been licensed yet in the U.S. and immune-mediated diseases are treated mostly with broadly immunosuppressive drugs or long-term single- or multi-allergen immunotherapy. In contrast to drugs, tolerogenic or immunomodulatory adjuvants may regulate immune responses to specific antigens through a variety of mechanisms, Page 108 including induction of regulatory T cells or alterations in the profile of the pathogenic lymphocyte response (e.g., Th1 to Th2 or vice versa). For tolerogenic and immune modifying adjuvants, the antigens may originate from environmental (allergy) or endogenous (autoimmunity) sources and may not need to be supplied exogenously together with the adjuvant. When pursuing this approach, the proposal must describe a compelling mechanism by which the adjuvant would modulate an antigen-specific response, and include studies demonstrating altered or suppressed responses against the allergen or autoantigen. Recent advances in understanding of innate immune mechanisms have led to new putative targets for vaccine adjuvants and for immunotherapy. Simultaneously, progress is being made in the identification of in vitro correlates of clinical adjuvanticity, which allows the design of in vitro screening assays to discover novel adjuvant candidates in a systematic manner. The gaps that need to be addressed by new adjuvants include improvements to existing vaccines (e.g., the acellular pertussis vaccine, influenza, etc), and development of vaccines for: emerging and re-emerging threats (e.g., Coronaviruses, Enteroviruses, MRSE); special populations that respond poorly to existing vaccines (e.g., elderly, newborns/infants, immunosuppressed patients); or treatment/prevention of immune-mediated diseases (e.g., allergic rhinitis, asthma, food allergy, autoimmunity, transplant rejection). For example, the combination of putative tolerogenic adjuvants with allergen immunotherapy should aim at accelerating tolerance induction, increasing the magnitude of tolerance and decreasing treatment duration. For transplantation, donor-derived major and minor histocompatibility molecules that are not matched between donor and recipient may be formulated with novel tolerogenic adjuvants and used to induce transplant tolerance in the recipient. Program Goal The objective of this program is to support the screening for new adjuvant candidates for vaccines against infectious diseases, or for autoimmune and allergic diseases, or transplantation; their characterization; and early-stage optimization. Phase I Activities may 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 may include, but are not limited to: • HTS of compound libraries and confirmation of adjuvant activity of lead compounds • Confirmatory in vitro screening of hits identified by HTS or in silico prediction algorithms • Optimization of lead candidates identified through screening campaigns through medicinal chemistry or formulation • Screening of adjuvant candidates for their usefulness in vulnerable populations, such as the use of cells from cord blood of infants or elderly/frail humans • Screening of adjuvant candidates in animal models representing vulnerable human populations This SBIR will not support: • The development of immunostimulatory compounds or formulations as stand-alone immunotherapeutics (i.e., without a specific antigen/pathogen-specific vaccine component) unless the putative adjuvant is used to modulate or suppress the response against an allergen or autoantigen. In this case, the proposal must include assays to demonstrate the effect of the treatment with an adjuvant on specific allergens or autoantigens. • The testing of newly identified immunomodulatory compounds or formulations in cancer models • The further development of previously identified adjuvants • The conduct of clinical trials (see https://grants.nih.gov/policy/clinical-trials/definition.htm for the NIH definition of a clinical trial)

Fast-Track proposals will be accepted. Direct-to-phase II proposals will be accepted. Page 109 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 adjuvants for use in vaccines against infectious diseases or of tolerogenic adjuvants for the treatment of immune-mediated diseases. For the purpose of this SBIR, vaccine adjuvants are defined according to the U.S. Food and Drug Administration (FDA) as “agents added to, or used in conjunction with, vaccine antigens to augment or potentiate, and possibly target, the specific immune response to the antigen”. Tolerogenic adjuvants are defined as compounds that promote immunoregulatory or immunosuppressive signals to induce non-responsiveness to self-antigens in autoimmune diseases, or environmental antigens in allergic diseases. Currently, only a few adjuvants other than aluminum salts (“Alum”) have been licensed as components of vaccines in the United States (U.S.): 4’-monophosphoryl lipid A (MPL), adsorbed to alum as an adjuvant for an HPV vaccine; CpG Oligodinucleotide as an adjuvant for a recombinant Hepatitis B vaccine; MPL and QS-21 combined in a liposomal formulation for a varicella vaccine; and the oil-in-water emulsion MF59 as part of an influenza vaccine for people age 65 years and older. Additional efforts are needed to develop promising novel adjuvants, particularly for vulnerable populations such as the young, elderly and immune-compromised. In addition, adjuvants may facilitate the development of immunotherapeutics for immune-mediated diseases (e.g., allergic rhinitis, asthma, food allergy, autoimmunity, transplant rejection). The field of tolerogenic adjuvants is still in its infancy. No compounds have been licensed yet in the U.S. and immune-mediated diseases are treated mostly with broadly immunosuppressive drugs or long-term single- or multi-allergen immunotherapy. In contrast to drugs, tolerogenic or immunomodulatory adjuvants may regulate immune responses to specific antigens through a variety of mechanisms, including induction of regulatory T cells or alterations in the profile of the pathogenic lymphocyte response (e.g., Th1 to Th2 or vice versa). For tolerogenic and immune modifying adjuvants, the antigens may originate from environmental (allergy) or endogenous (autoimmunity) sources and may not need to be supplied exogenously together with the adjuvant. When using this approach, the proposal must describe a compelling mechanism by which the adjuvant would modulate an antigenspecific response, and include studies demonstrating altered or suppressed responses against the allergen or autoantigen. Adjuvanticity may be obtained with a single immunostimulatory (or immunoregulatory/tolerizing) compound or formulation, or with a combination adjuvant. For this solicitation, a combination-adjuvant is defined as a complex exhibiting synergy between individual adjuvants, such as: overall enhancement or tolerization of the immune response depending on the focus and nature of the vaccine antigen; potential for adjuvant-dose sparing to reduce reactogenicity while preserving immunogenicity or tolerizing effects; or broadening of effector responses, such as through target-epitope spreading or enhanced antibody avidity. Project Goal The goal of the project must be the pre-clinical development and optimization of a single lead adjuvant candidate or a selected combination-adjuvant for prevention of human disease caused by non-HIV infectious pathogens, or for the treatment of autoimmune or allergic diseases, or induction/maintenance of organ transplant 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 may not be developed as stand-alone agents unless the adjuvant is used to modulate or suppress immune responses against an allergen. In response to this topic, offerors must include the following information in the proposal: • A clear description of the single lead adjuvant or selected combination-adjuvant; • Data demonstrating that the adjuvant has adjuvant activity; o For Phase I proposals, that data may be within any context (e.g., in combination with a different antigen than used in the proposal, etc.); o For Phase II proposals, preliminary data from in vivo studies must support the utility of the selected adjuvant with the proposed vaccine candidate; • Evidence that the offeror has guaranteed access to the adjuvant to be used in the project (e.g., is the IP holder, or has an agreement in place with the IP holder); • Narrative describing that the offeror has the appropriate intellectual property protections or agreements in place and/or proprietary freedom to commercially develop the adjuvant. Page 110 Phase I activities may include, but are not limited to: • 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 may include, but are not limited to: • Additional animal testing of the lead adjuvant:vaccine combination to evaluate immunogenicity; or tolerance induction, protective efficacy, and immune mechanisms of protection; • Pilot lot or cGMP manufacturing of adjuvant or adjuvant:vaccine; • Advanced formulation and stability studies; • Toxicology testing; • Pharmacokinetics/absorption, distribution, metabolism and excretion studies; • Establishment and implementation of quality assurance and quality control protocols. Areas of Interest: • Adjuvants to improve the efficacy of vaccines to protect against infectious disease, particularly for vaccines targeted towards vulnerable populations; • Novel combination adjuvants; • Tolerogenic or immune deviating adjuvants for allergen immunotherapy. This SBIR will not support: • Projects that are not focused on a single lead adjuvant candidate or a selected combination-adjuvant; • The discovery or initial characterization of an adjuvant; • Further development of an adjuvant that has been previously used with any FDA licensed vaccine, unless such an adjuvant is used as a component of a novel combination adjuvant as defined above; • The conduct of clinical trials (see https://grants.nih.gov/policy/clinical-trials/definition.htm for the NIH definition of a clinical trial); • The development of adjuvants within the context of vaccines to prevent or treat cancer or HIV; • Development of platforms technologies or delivery systems that have no immunostimulatory or tolerogenic activity themselves; • The development of the vaccine’s antigen component; • The development of immunostimulatory compounds or formulations as stand-alone immunotherapeutics (i.e., without a specific antigen/pathogen-specific vaccine component) unless the adjuvant is used to modulate or suppress the response against an allergen. In this case, the proposal must include assays to demonstrate the effect of the treatment with an adjuvant on specific allergens; • The development of adjuvants where the offeror has not demonstrated intellectual property (IP) protection and/or proprietary freedom to commercially develop the adjuvant.

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. Page 111 Background Many experimental and licensed vaccines depend on adjuvants to exert their protective effect. While several immunostimulatory compounds and formulations are available commercially for use in preclinical studies, these compounds generally cannot be advanced into clinical trials. Furthermore, head-to-head comparisons of novel experimental and existing adjuvants is hampered by limited availability of such reagents. NIAID supports the discovery and development of novel adjuvants through different mechanisms, and this Funding Opportunity Announcement (FOA) is intended to address the limited availability of adjuvants that: mimic those with a favorable clinical track record; or show high potential in late preclinical testing. Program Goal Development, validation and production of adjuvants that are based on, or similar to, compounds or formulations previously successfully used in clinical trials, for use by the broader research community, either as commercial products or through licensing agreements. Phase I Activities must include at least the following 2 activities: • Development of one or more adjuvants (or adjuvant combinations)/adjuvant formulations that are based on, or similar to, an adjuvant with a proven clinical track record of high adjuvanticity; and • Preclinical testing to assure immune potency and safety. Immune potency studies shall include comparison to at least one well-established reference adjuvant that is expected to be effective in the disease model under study. 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; • Product validation, that includes in vitro and in vivo approaches using a relevant disease model; • Production scale-up; and • 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 coadjuvant or carrier; • Discovery of novel immunostimulatory compounds; • Commercial development of adjuvants that do not have the ability or potential to activate human immune cells; • Development of adjuvant mimics that would violate existing patents; • Data analyses, pattern discovery from aggregated datasets; or • Development of AS01 biosimilars without previous consultation with NIAID. 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: 3-6 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. Page 112 Background This program addresses the limited availability of reagents (e.g., antibodies, proteins, ligands) for the identification and discrimination of immune cells and the characterization of immune responses in non-mammalian models or in specific underrepresented mammalian models. Non-mammalian and under-represented mammalian models of interest include: arthropods, amphibians, fish (e.g., jawless fish, sharks, zebrafish), nematodes, marine echinoids; and guinea pig, ferret, bat, mink, hamster, bird, cotton rat, pig (including minipigs), cat, rabbit and marmoset, respectively. 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. In addition, minks and cats are highly susceptible to SARS-CoV-2 infection with potential for zoonotic pathogen transmission. However, there are almost no reagents available for immunological studies in these species. Lastly, although bats are the natural reservoir and vector for several major zoonotic diseases that cause severe human diseases, the lack of reagents has impeded studies of how bat adaptive or innate immune responses control these pathogens. Project Goal This program supports the development and validation of reliable antibodies and reagents for the identification and tracking of immune cells or the analysis of immune function/responses (e.g., cytokines, chemokines, intracellular signaling) in nonmammalian models or underrepresented mammalian models. Non-mammalian models are limited to arthropods, amphibians, fish (e.g., jawless fish, sharks, zebrafish), nematodes, and marine echinoids. Underrepresented mammalian models are limited to guinea pig, ferret, bat, mink, hamster, cotton rat, pig (including minipigs), cat, rabbit and marmoset. Phase I Activities must include the following activities: • Selection of targets, which may include: immune cell markers; receptors with immune function; or other molecules important for immune function; • Development of antibodies or other reagents against these targets, o If polyclonal antibodies are being developed, the plan also must include the development of monoclonal antibodies; • Characterization of antibodies or reagents developed, o Initial determination of affinity/avidity and specificity o Confirmation of binding to the intended native antigen/immunogen by flow cytometry and/or other assays. Phase II Activities must include but are not limited to: • Comprehensive evaluation of specificity and sensitivity, functional utility, and cross-reactivity/off-target binding of antibodies/reagents by Western blotting (denatured and native protein); immunoprecipitation; immunohistochemistry; and flow cytometry. o The functional studies must minimally include analysis of primary cells or target antigens from host species; o The off-target binding must minimally include evaluation of non-specific binding to other cells or unrelated molecules from host species; o The cross-reactivity must at least contain a screening of binding to related cells or molecules from other species. • Optimization (e.g., secondary modifications/conjugations) of the antibodies/reagents for the intended application. • Development of well-established protocols by: o setting up working concentrations, assay linearity, assay validation, and functional activity test; Page 113 o determining quantitative criteria such as binding kinetics and signal versus background, and quality control acceptance criteria (e.g., purity requirement, endotoxin testing, specificity and activity(titer) threshold, molecular mass confirmation, multiple freeze-thaw stability) in assay performance and manufacturing. • Scale-up production of the reagents, batch to batch comparison, and backup plan(s) to guard against loss of source material (e.g., hybridoma cells). • A commercialization plan for distribution and marketing of the reagents. This SBIR will not support: • Identification of immune target molecules and development of antibodies/reagents against immune markers or molecules for animal models not listed in the solicitation; • Development of antibodies/reagents for molecules or mechanisms not involved in immune responses; • Development of novel or refined animal models

Fast-Track proposals will be accepted. Direct to Phase II proposals will not be accepted. Number of anticipated awards: 1-2 Budget (total costs): Phase I: up to $300,000 for up to 1 year; Phase II: up to $1,500,000 for up to 3 years. Background Cases of syphilis, caused by the pathogen T. pallidum, are increasing in the US and globally. In 2018, the total number of syphilis cases (all stages) in the U.S. was the highest it had been in over 25 years. From 2017 to 2018, syphilis cases increased 13.3%, and congenital syphilis cases increased by 39.7% (CDC’s 2018 STD Surveillance Report). Current diagnostics for syphilis are inefficient, cumbersome to use, and outdated. Attempts to control or eradicate syphilis will require the development of straightforward, easy-to-use diagnostics that take advantage of modern molecular technology. Project goal The goal of this project is to develop a rapid (≤ one hour), point-of-care diagnostic capable of detecting T. pallidum directly from patient specimens. Phase I activities may include: • Development of a prototype assay that demonstrates the rapid (less than 60 minutes) detection of T. pallidum from clinical specimens • Integration of platform and assay to rapidly identify T. pallidum • Development of sample preparation methods consistent with the product platform Phase II activities may include: • Development of sample preparation methods consistent with the product platform • Further development of the prototype product to determine performance characteristics • Final validation testing and scale-up manufacturing of test kits This SBIR will not support: • The design or conduct of clinical trials; please see https://grants.nih.gov/policy/clinical-trials/definition.htm 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.

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will not be accepted. Number of anticipated awards: 1-3 Budget (total costs): Phase I: up to $300,000 for up to 1 year; Phase II: up to $1,500,000 for up to 3 years. Background According to the World Malaria Report 2020, progress towards malaria control and elimination appears to be slowing in recent years. Although a moderately efficacious vaccine (RTS,S/AS01 [MosquiRix®] has been made available for pilot implementation in selected African countries, novel immunization approaches to combat malaria are still urgently needed. It has been demonstrated previously that polyclonal sera from malaria-exposed individuals could be used to confer protection against malaria in recipients. Research in animal models has also shown that passive transfer of monoclonal antibodies (mAbs) can protect against malaria infection. Recently, passive immunization using mAbs either as immunotherapy or preexposure prophylaxis has been explored for other infectious diseases, such as SARS-CoV-2, HIV or RSV, and has demonstrated promising feasibility both preclinically and clinically. If passive immunization with mAbs or mAb-based interventions against malaria similarly demonstrates promising clinical feasibility, it could be incorporated into public health program strategies, such as for seasonal malaria prophylaxis, prophylaxis for pregnant women or for migrant workers entering malarious areas, or outbreak control, thus enhancing global malaria control and elimination efforts. The availability of well-characterized and appropriately designed mAbs will not only support development of mAb-based immune prophylaxis or immunotherapy strategies but could also provide credentialing of vaccine antigen(s) and necessary tools for rational immunogen design for active immunization approaches. Project Goals The overall goal of this solicitation is to develop mAb or mAb-based candidates for malaria prevention or treatment. The scope of the research can range from product candidate discovery or optimization to preclinical process development leading to IND filing. Applicants may propose to establish initial proof-of-concept data in animals, conduct preclinical process development or production of mAb(s) or mAb-based candidates to combat Plasmodium falciparum or P. vivax malaria by targeting one or more life cycle stages (i.e., pre-erythrocytic, asexual blood, or sexual stages). Proposals to address innovative potential uses for novel indications (e.g., prevention of malaria relapse, overcoming or prevention of emergence or spread of antimalarial drug resistance, etc.) are also encouraged. Phase I activities may include but are not limited to: • Identification, construction, optimization/refinement, and/or evaluation (e.g., biophysical, epitope mapping, etc.) of novel mAbs and mAb-based product candidates (e.g., mAb-conjugates), and technology platforms (e.g., viral vectorencoded mAb); • Establishment of preliminary process development to demonstrate technical feasibility; • Demonstration of potential efficacy and/or safety of the proposed candidates either by in vitro functional assays or in animal models; Phase II activities may include but are not limited to: • Preclinical process development leading to IND filing; activities may include formulation studies, process scale up, stability studies, analytical assay development, cGMP production, or GLP safety assessment; • Further preclinical assessment in animal models, including non-human primates; • Stability testing to support product stability program for later stages of product development. This SBIR will not support: • The design and conduct of clinical trials (see https://grants.nih.gov/policy/clinical-trials/definition.htm for the NIH definition of a clinical trial).

Fast-Track proposals will be accepted. Direct-to-Phase II proposals will not be accepted. Number of anticipated awards: 3-4 Budget (total costs): Phase I: up to $300,000 for up to 1 year; Phase II: up to $1,500,000 for up to 3 years. Background Diarrheal diseases are the 5th leading cause of mortality in children less than 5 years of age (Lancet Infect Dis 2018; 18: 1211–28) and antimicrobial resistance in the causative agents is increasingly problematic (CDC report: Antibiotic Threats in the United States 2019). Recent technological advances may facilitate the development of simple, rapid and inexpensive point-of-care diagnostics for the detection of enteric bacterial and parasitic pathogens in children under five years of age with moderate to severe diarrheal disease. Rapid identification of the pathogen(s) and associated antimicrobial resistance profile(s) are needed to determine treatment options, especially for infants under 12 months of age for whom persistent diarrheal disease is particularly risky. Project Goal The goal is to develop a rapid (≤ one hour) point-of-care diagnostic capable of detecting infectious enteric pathogens (≥ two) and associated antimicrobial resistance profile(s) directly from patient specimens (e.g., stool samples). The end product must identify antimicrobial resistance profiles; detection of both bacterial and parasitic pathogens in the same device is strongly encouraged where feasible. Diagnostic devices and associated methodologies, e.g., microfluidic PCR, should be designed for use in clinical or field settings, such as physician’s offices or in the field during outbreaks of diarrheal disease that impact the population across all ages. Diagnostics that focus on multiple enteric bacterial pathogens with known drug resistance, as well as parasitic pathogens, such as Giardia and Cryptosporidium, would be considered responsive. Phase 1 activities may include, but are not limited to: • Define the targets for pathogen identification • Identify the antimicrobial resistance markers • Demonstrate assay feasibility for rapid detection of enteric pathogens and their antimicrobial resistance profiles • Develop sample preparation methods consistent with the product platform • Conduct validation testing of true clinical specimens Phase 2 activities may include, but are not limited to: • Integrate platform and assay for rapid detection of enteric pathogens and antibiotic resistance profiles • Conduct final analytical validation testing and scale-up manufacturing of test kits • Complete development of the final prototype product up to, but not including, verification This SBIR will not support: • The design or conduct of clinical trials; please see https://grants.nih.gov/policy/clinical-trials/definition.htm for the NIH definition of a clinical trial.

Fast Track proposals will be accepted. Direct to Phase II proposals will not be accepted. Number of anticipated awards: 1-3 Page 116 Budget (total costs): Phase I: $300,000 for up to 1 year; Phase II: $1,000,000 for up to 3 years. Background Data intense infectious and immune-mediated research projects are generating unprecedented amounts of complex and diverse basic research and clinical data sets. Increasing the use and re-use of these data by basic and clinical scientists studying infectious, immune and allergic diseases will drive discovery and accelerate the development of diagnostic, preventative and therapeutic interventions. Yet, managing, preserving, sharing, finding, accessing, integrating, visualizing, and analyzing these data sets from multiple sources and platforms remains challenging. Innovation in optimal search and discovery of biomedical data is still lacking. Moreover, non-interoperable data impedes the ability to answer sophisticated biological questions across diverse data types without significant harmonization. Although there is considerable effort in developing standards and data curation programs to address these challenges, they are mostly manual, expensive, and not scalable. Visualization tools that integrate new and emerging 3D technologies to visualize and communicate research data are also needed. This broad topic includes investments in data resources and repositories, development of computational tools, their use, and tools to enhance timely data sharing and adherence to FAIR Data Principles (Findable, Accessible, Interoperable, and Reusable). Tools that can enhance privacy in an environment that maximizes sharing are also sought. This includes novel approaches to share de-identified individual patient level data while maintaining the complexity of the original data. If developed, they have the potential to confirm reproducibility, promote transparency of clinical studies, increase confidence in therapeutic interventions, and inform and accelerate new clinical research and trials. Project Goal The goal is to support the new development of innovative, robust informatics/data science tools, or enhancement or adaptation of existing tools for use in infectious, immune, and allergic diseases. These tools should be appropriate for, but not limited to, data from natural history studies, biomarkers, in vitro assays, correlates of vaccine protection, animal models and non-human primates. The tools can aim to improve data management, or the FAIR-ness of data, or can focus on data visualization, integration, or analysis. Potential projects relevant but not limited to this topic include the development, enhancement, modification, or adaptation of existing informatics and data science tools for • Increase the findability of data by utilizing information that includes, but is not limited to data, metadata, associated literature, and text; • Improve indexing by popular search engines and recommend or discover relevant data sets beyond the original search; • Visualize and integrate analysis of “big”, multi-scale, complex data from multiple sources and their dissemination; • Perform automated curation and quality control; • increase data interoperability and query-ability across multiple resources by application and adoption of community standards and ontologies that may include software pipelines or platforms to automate annotation, markup, or curate datasets not compatible with community standards, formats, or controlled vocabularies; • Harmonize clinical data via customized data harmonization pipelines which among other features could combine data sets or un-merge combined data sets; • Standardize the de-identification, and other privacy-preserving approaches, of individual patient level data and allow the timely sharing of human clinical research data including tools that can assess and minimize the risk of re-identification. Phase I Activities: • Establish a project team composed of experts in software development and as appropriate to the project include but not limited to expertise in statistics, infectious and immune mediated diseases, or clinical research. • Provide an overall development plan with milestones and deliverables for the proposed tool. • Provide justification and unique value proposition for the development, adaptation or enhancement of this specific tool in light of the currently available tools. • Describe the potential user communities and provide relevant use cases. Page 117 • Develop an (early) prototype for the tool, perform alpha testing, and address issues from testing and solicit feedback from the appropriate user community. Phase II Activities: • Enhance and optimize the prototype developed in phase I. • Improve robustness, scalability, and usability of the tool. • Conduct beta tests for the software tool with the appropriate user communities and use cases, demonstrate the usability of the tool by the infectious, immune or allergic community. • Gather feedback from the beta testing by the research community. • Add functionalities and capabilities based on feedback and deploy a production version. • Develop documentation, user guides, SOPs and training materials. The SBIR will not support: • Projects proposing significant data generation and analysis for validation and testing of the tool. • Projects developing wet-laboratory, experimental methods, research or technologies. • Projects that are not focused on developing tools directly applicable to infectious, immune or allergic basic and clinical research.

Fast Track proposals will be accepted. Direct to Phase II proposals will not be accepted. Number of anticipated awards: 1-2 Budget (total costs): Phase I: $300,000 for up to 1 year; Phase II: $1,000,000 for up to 3 years. Background: It has been estimated that as many as 40% of the US population choose not get certain established and newly approved vaccines (e.g., HPV, flu) and recently, there has been hesitancy about receiving the SARS-CoV-2 vaccines. In many cases, the underlying reasons for this decision can be traced back to widespread dissemination of misinformation about the vaccine itself or about the process used to test and obtain regulatory approval for these vaccines. Similarly, despite the overwhelming scientific body of evidence supporting the safety of other vaccines, like measles, mumps and rubella (MMR), there is a notinsignificant proportion of the population that continues to be skeptical and cite misinformation about vaccine adverse events, which have been discredited. Research has shown that much of this misinformation is disseminated through digital platforms and social media, where this type of misinformation can spread widely – like a virus. During the COVID-19 pandemic, many other falsehoods about the spread (or lack of spread) of the virus, the severity of the disease, and whether interventions were effective or not were widely disseminated among social and popular media. Therefore, it is critically important to develop digital tools to rapidly identify misinformation and minimize the effects of this unintended or malicious information to ensure effectiveness of public health measures and eliminate vaccine hesitancy and increase effectiveness of vaccinations, including but not limited to vaccination programs. Project Goal: The goal of this solicitation is to develop digital tools to identify and combat malicious digital bots that spread misinformation about infectious disease treatments and vaccines. The proposed digital tools could be specific to a single digital platform or social media outlet. The tools could either identify or combat misinformation, or it could be a holistic solution that both identifies and combats misinformation. The solicitation will support efforts to implement and test proposed solutions. Page 118 Phase 1 activities may include, but are not limited to: • Development of digital tools and/or methods to identify and/or combat malicious digital spread of misinformation and bots related to diagnosis, prevention and treatment of infectious diseases directly from digital platforms or social media. • Provide justification and unique value proposition for the development, adaptation or enhancement of this specific software tool and pipeline. • Describe the potential user(s) communities and provide two relevant use cases. • Development and/or improvement of sensitivity, specificity and other performance characteristics (e.g., time to identify, limit of detection, feasibility for implementation) of the digital tool or solution. • Development of methods to ensure the usability of the tool or solution in various scenarios, including but not limited to implementing routine vaccine recommendations, new and re-emerging outbreaks, epidemics, pandemics, rapidly spreading vs. sporadic or endemic infections • Develop an (early) prototype for the tool, perform alpha testing, and address issues from testing and evaluate with appropriate user community to solicit user feedback. Phase 2 activities may include, but are not limited to: • Further optimization of the methods and protocols and validation of reproducibility. • Final validation testing and scale-up for deployment on a specific platform. • Demonstration that methods developed in Phase I are applicable to a broader range of platforms • Enhancement and optimization of the prototype developed in phase I • Improve robustness, scalability, and usability of the tool • Conduct beta tests with the appropriate user communities and use cases, demonstrating the usability of the tool by the infectious, immune or allergic community • Gather feedback from the beta testing by the research community • Add functionalities and capabilities based on feedback and deploy a production version • Develop user documentation, user guides, SOPs and training materials. This SBIR will not support: • Clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial for the NIH definition of a clinical trial). • Projects proposing significant data generation and analysis for validation and testing of informatics tool.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Page 120 Background Record linkage (or de-duplication) is an essential component of many CDC-supported projects and programs. If an individual is reported as a case by more than one data source, or reported at multiple times, it is vital to link records so that an individual will not be counted as multiple incident cases. There are powerful algorithms that can automatically detect matches in many situations. However, these software tools are often proprietary or require programming/coding skills that may not be available in every state or jurisdiction. A free and easy-to-use solution would strengthen public health expertise, as the same tools could be used across programs, and users who cannot write code could use the same underlying packages and algorithms as more technically inclined users. Motivating example: CDC’s Autism and Developmental Disabilities Monitoring (ADDM) Network currently supports autism surveillance in different states. States receive information from various medical and educational providers, and states must link records to ensure each child is counted once and that all critical data elements are linked to the child’s record. The ADDM surveillance program uses “The Link King”, a SAS-based record linkage program, for data linkages. There are several beneficial attributes of this tool: it uses high-performing algorithms, is free (but requires a paid SAS subscription), and it has a graphical user interface that allows easy use by non-coders. However, it is no longer actively supported or developed (the team received permission to host an archival copy at www.the-link-king.party). Future updates to SAS, Microsoft Windows, or any dependency could jeopardize the functioning of the tool, and therefore the surveillance program. Project Goals Short term project goals – • Understand basic needs and use cases for record linkage in public health applications • Develop an R package that provides an R Shiny front-end to a high-performance record linkage package (such as fastLink, RecordLinkage, or csvdedupe) ○ Functionality should include the ability to facilitate linkage parameters (select variables used for linkages), identify data sets to be used, manually verify and review results, and export the resulting matched and non-matched data. ○ Create documentation to instruct users on its use (such as a “getting started” vignette) ○ Create a public GitHub repository for the code, as well as for tracking issues and feature requests from end-users Phase I Activities and Expected Deliverables During the Phase I period, the activities can include, but are not limited to: The following deliverables should be produced by the end of the project period: - R Package providing interface to record linkage/de-duplication program(s) - Includes documentation (built into package, and vignette) - Package and materials hosted on CRAN - Source code maintained on a public GitHub repository - Demonstration to CDC/public health community - Summary of potential enhancements and community feedback/requests Impact This project could have both long- and short-term impact on CDC surveillance programs and other projects. Most immediately, it will provide a sustainable solution for the ADDM Network, as the current record linkage software is effectively “abandonware” and requires SAS licenses. Other “free options” (summarized here and here) often lack easy-to-use interfaces, are not updated, or are only available in programming languages that would add complexity to (or be incompatible with) a public health program. Commercial tools could be expensive (as shown here) or require uploading sensitive data to a cloud-based service, which might violate public health data privacy requirements. Proprietary software could also be custom-tailored to each surveillance system and include this functionality. For example, the ADDM Network discontinued a $500,000 annual contract to build and maintain a proprietary data system that included rudimentary record linkage functionality. Other customizable products have linkage/de-duplication functionality, such as Conduent’s Maven software, but can be expensive and encourage fragmentation between different systems by virtue of requiring software licenses/contracts. Page 121 More broadly, this tool could fill similar gaps in functionality in other CDC and public health programs without having to resort to custom-developed software. There are already thousands of R users at CDC, and they would be able to easily integrate this tool into other systems that could benefit, such as during Epi Aids, when simple tools are needed immediately. When we designed our current data system, we spoke with other surveillance programs and often heard that record linkage / de-duplication processes were lacking in performance (such as when a basic matching algorithm is integrated into custom software) or were deemed responsibilities that were “left up to the states” to complete without explicit support from CDC. If selected, this project would have a high likelihood of success, as the core record linkage algorithms are already available – this project would make them easier to use by non-programmers and better integrate them into typical public health / surveillance workflows. Commercialization Potential Many open source software projects have successful commercial models through selling professional services, including enhanced support, customized features, consultation, training, or analytic capacity. This record linkage tool could become part of a suite of widely-used data management and analytic tools that are commonly deployed in the public health community. The developer would be well-positioned to offer premium support and technical services to programs that use the tools or need custom solutions built upon an open-source platform.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Improving nutrition and reducing obesity are key objectives for Healthy People 2030. In addition, reducing consumption of calories from added sugars by persons aged 2 years and over is a leading 2030 health indicator for the nation. As part of the effort to encourage availability of healthier food and beverage options, numerous business industry standards and practice guidelines have been developed. For example, the US federal government has developed food service guidelines that include nutrition standards based on Dietary Guidelines for Americans. Food service guidelines, such as the Food Service Guidelines for Federal Facilities, are used widely by institutional purchasers including government facilities, worksites, hospitals, universities, and schools. Notably, these guidelines provide desired food standards but do not list specific food products meeting the guidelines. The difficulty in identifying qualifying packaged products is a major obstacle in using food service guidelines, particularly when guideline specifications may differ slightly from one jurisdiction to another. For example, New York City’s and Los Angeles County’s food service operations, which serve 25 million people combined, have reported difficulty meeting their own food service guidelines because their primary suppliers do not have the resources (i.e., time, staff) to determine which of their products meet guidelines. The problem faced by these large purchasers led to creation of an excel list tool, but the current format and its databases are not automatized and require users to hand search product lists to determine which foods meet guidelines. We are aware of static PDF versions such as on the Costco website and the Business to Business section for ordering on Amazon. However, non-automated paper type methods quickly become outdated as products and their ingredients change frequently and excel sheets need input from the product by a person. An algorithmic processing tool that creates a database of foods and beverages meeting nutrition standards within food service guidelines can increase the ease of operationalizing food service guidelines by food service operators, retail, or the charitable food system (food banks/pantries). Identifying foods that meet food service guidelines is crucial for food service operators to fulfill contractual requirement to institutional clients. Easy identification of foods that meet guidelines is also helpful for retailers who want to market specific products to personal or demographic interests. Project Goals The goal of this project is to create a mobile and desktop computer software tool that enables food service, retail, and charitable food sectors to identify food and beverage products that align with various food service guidelines. Phase I Activities and Expected Deliverables During the Phase I period, the activities can include, but are not limited to: Page 123 The deliverable is an easy-to-use web-based application that is able to import food databases, determine which foods meet guidelines by comparing the individual food records with particular food service guidelines and export the results as a list. The tool must be easy to use by food service operators, retailers, charitable food systems, manufacturers, and distributors. Expected key activities include: Phase 1 (6 months) • Create computer program with algorithms that identify foods and beverages meeting food service guidelines. The program must be able to process large food databases, incorporate nutritional and other information into algorithms and provide output of foods that meet guidelines. o Provide ability to import individual or groups of food items from food databases or other sources and determine if they meet guidelines. o Program must be able to process and translate input from primary computer database software (i.e., MS Access, MS Excel) and food management software (i.e., Computrition Hospitality Suite, Foodservice Suite, etc.). o Include algorithms representing the major public food service guidelines, including but not limited to: Food Service Guidelines for Federal Facilities, Smart Snacks guidelines, NYC’s Food Standards, LA County’s food procurement initiative, Philadelphia’s Comprehensive Nutrition Standards, and Department of Defense’s food service guidelines. Use programing infrastructure that enables the addition of further sets of guidelines that may be of interest by the private or public sectors. o Ability to analyze products against several different sets of guidelines or standards simultaneously. o Output must create a list of products that meet guidelines that is usable in ordering and meal planning software. o Algorithm results need to include foods that fail to meet guidelines and the reasons they fail. o Ability to assess product costs to determine most affordable products meeting guidelines. • User Interface (UI) features need to include: ○ Easy to use UI for the target audience. ○ Operator-end and supplier-end interfaces. ○ Enable user to input available list of products from a company database and generate a formatted list of foods that comply with customer’s food service guidelines. ○ Secure user account. ○ Account and login system. ○ Functionally easy to use. ○ Overall aesthetic experience. ○ User training. • Conduct concept and feasibility testing to identify any issues with user experience, algorithm guidelines processing, or outputs. • Collect data and modify application based on operability, acceptability, efficiency, and sustainability. • Test on most potential users, including manufacturers/producers, distributors, wholesale clubs, and food service operators. NOTE that testing can only be done on 9 or less persons. • The proof-of-concept can be tested and refined with a selected industry partner (manufacture, distributor, etc) and a single set of guidelines, such as the Food Service Guidelines for Federal Facilities. • Business Plan Page 124 ○ The offeror needs to provide an assessment of the tool’s commercial potential, including methods to remain solvent by both making profit and expanding reach, while supporting a public health mission. Impact Operationalizing nutrition guidelines in institutional settings has the potential to improve dietary intake by aligning available dietary options with dietary requirements. This tool will assist institutional food operators to align their offerings more efficiently with food and nutrition guidelines by providing lists of products that meet guidelines. It will also assist retail and charitable food operations to procure and provide food items that align with guidelines and, in turn, are healthier. We envision that program recipients funded by CDC such as State Physical Activity and Nutrition (SPAN), Racial and Ethnic Approaches to Community Health (REACH), and High Obesity Program (HOP) would be able to use such a tool via their partners to support organizational purchasing efforts. This tool will enable manufactures and distributors to provide more easily to their customers (e.g., food service operators) products that meet specific jurisdictional guidelines or standards included in food service contracts. The tool will also enable food service operators to quickly identify and select products that align with guidelines or that appeal to specific health-conscious market segments. In areas with difficulty accessing healthier foods (e.g. rural areas and inner cities), this tool can incentivize broader distribution and easier access of those foods, thereby enabling greater prominence of heathier foods and beverages in the supply chain. Furthermore, food banks might use this tool to purchase food for donation that meets dietary guidelines. Commercialization Potential Currently, public health departments and other organizations responsible for procurement of food service contracts must use scarce resources to develop one-time lists of products that meet guidelines or spend time adding nutrition facts label information into excel macros. Current tools are static PDFs or excel sheets. This creates an attributable time and cost burden and does not provide a consistent tool for the user. Placing the ability to determine foods that meet guidelines within the hands of suppliers, eliminates the burden of developing these lists. It also helps suppliers use a new type of tool to enhance their business model and advances competition in the marketplace.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Candida auris is an emerging multidrug resistant fungal pathogen that has spread rapidly through networked healthcare facilities in the United States since it was first identified in 2016. C. auris heavily colonizes patients’ skin and extensively contaminates the healthcare environment, making this pathogen highly transmissible and hard to control. The admission of just a single colonized patient can lead to sustained outbreaks in facilities caring for highly vulnerable populations. Colonization is an established risk factor for subsequent C. auris infections, which have high associated morbidity and mortality, and are difficult to treat. Rapid identification of C. auris is therefore essential for the timely implementation of infection control measures. Currently, C. auris colonization screening is primarily performed by specialized regional public health laboratories when validated as lab-developed tests (LDT). The dependency on highly specialized laboratories limits the total capacity for C. auris colonization screening, and is not ideal for admission screening, which is best implemented at the point of care. Because C. auris impacts many healthcare facilities that do not have laboratories, efficient admission screening is not feasible with existing technologies. A simple, fast, and portable test that could be performed at the point of care in resource limited settings, without requiring specialized laboratory equipment, would greatly improve testing capacity and broader C. auris response efforts. The purpose of this work is to support development of such a test. Project Goals The goal is to develop a simple, fast and highly portable test that could be performed at the point of care, even in resource-limited settings, without a laboratory. Dipsticks and Lateral Flow Assays are examples of how such a test could be achieved. The test should detect an analyte directly indicative of C. auris rather than an associated antibody or other immune response indicator of exposure. The test should generate results that can be interpreted without the requirement of sophisticated equipment, such as a visually observable color change, or appearance of a positive indicator, as commonly seen in CLIA-waved test platforms. Each individual test should include an internal positive control sensitive to inhibitors. External positive and negative controls should also be provided, which could be accomplished through inclusion in a kit of multiple tests, or as otherwise appropriate, to sufficiently control for the associated production lot. Phase I Activities and Expected Deliverables Phase 1 deliverables should include a functional prototype and preliminary data indicating potential for further development. Expected Phase I deliverables include: 1. A physical prototype suitable for further testing. 2. Preliminary assessment of the prototype’s ability to detect C. auris. This assessment should utilize fresh cultures of C. auris AR 0381, when normalized to concentrations of ~105 CFU/mL in AMIES buffer. This isolate is freely available through the CDC-FDA AR bank. Data from biological replicates, performed on different days, should be provided. Page 126 3. Preliminary assessment of the prototype’s specificity. This assessment should utilize cultures of Saccharomyces cerevisiae AR 0399, when normalized to concentrations of ~105 CFU/mL in AMIES buffer. This isolate is freely available through the CDC-FDA AR bank. Data from biological replicates, performed on different days, should be provided. 4. A report summarizing progress including both raw and summary data. Impact A simple, fast, and highly portable test that can be performed at the point of care, even in resource-limited settings, will improve public health efforts to control C. auris. The requested test will help expand capacity by enabling healthcare facilities to determine their patient’s colonization status upon admission without sending samples to a specialized laboratory. This will help facilities act quickly when positive cases are identified, and therefore provide a greater opportunity to control C. auris before an outbreak occurs. Commercialization Potential If successful through all phases, this technology would result in a diagnostic test that could be commercialized and marketed directly to healthcare facilities. Demand would be driven by increasing awareness and growing financial incentives for facilities to reduce healthcare-associated infections. This test would provide a valuable tool to this end by helping healthcare facilities prevent C. auris-related transmission and infections.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1-2 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Wastewater surveillance provides a powerful independent approach to complement existing surveillance systems. Wastewater surveillance is currently being used to support the COVID-19 response. SARS-CoV-2 RNA is shed in the feces of individuals with both symptomatic and asymptomatic infections and SARS-CoV-2 RNA in wastewater has been demonstrated to be a leading indicator of reported cases and hospitalizations. There is no evidence to date that anyone has become sick with COVID-19 because of exposure to wastewater, but wastewater is a hazardous material and molecular analyses of samples that could potentially contain multiple human pathogens are severely restricted. This results in significant barriers for laboratories onboarding testing and there is a need for a product or procedure to provide molecular preservation (stabilization) and pathogen inactivation from post-sampling of wastewater to help overcome these barriers. Project Goals The goal of the proposed research is to develop a product to inactivate and stabilize wastewater samples for shipping and transport. This product must be amenable to on-site use by stakeholders, such as State Agencies for wastewater monitoring, etc., and could be physical or chemical inactivation. The product can be an all-encompassing portable sampler that inactivates and provides molecular preservation of pathogens in wastewater or be used sequentially with existing samplers without adding additional biosafety risks to the collection procedure. The product will provide a qualitative indicator that the inactivation process has occurred, and the inactivation of the wastewater sample must not interfere with downstream molecular testing. Phase I Activities and Expected Deliverables The expected deliverables are: 1. Develop or adapt a method to inactivate and molecularly preserve SARS-CoV-2, or the proxy virus controls, bovine coronavirus (BCoV), murine coronavirus (MCoV, e.g., murine hepatitis virus), bacteriophage Phi6, or human coronavirus OC43, in wastewater samples; the method must be able to provide an indicator that the inactivation process has occurred. 2. Quantify molecular detection before and after the molecular preservation and inactivation procedure for SARSCoV-2, or the proxy virus controls bovine coronavirus (BCoV), murine coronavirus (MCoV, e.g., murine hepatitis virus), bacteriophage Phi6, or human coronavirus OC43, in wastewater samples. Method development with surrogate viruses will be considered but final evaluation with SARS-CoV-2 must be included. Page 127 3. Conduct matrix evaluation to understand the assay performance using different wastewater types (e.g., raw wastewater, sludge). Impact The product of this proposed research will allow laboratories to test and monitor their wastewater supplies for SARS-CoV-2 and other emerging pathogens without the need for dedicated containment laboratories, which is currently not possible. Once safe processing is available, laboratory capacity can scale up and expand to other pathogens that pose a public health threat and thereby inform control processes and ultimately reduce the burden of infections. Commercialization Potential This research will lead to the development of new products that inactivate infectious material in wastewater samples and provide molecular preservation to benefit stakeholders at every point in the wastewater surveillance process from collection to testing. Potential products include inactivation and stabilization systems, inactivation indicator kits, storage and transport products, and wastewater sampling devices that provide an all-in-one “sample collection-to-inactivated and stabilized infectious material” transport sample container. These products could be used by water managers, universities, businesses, correctional facilities, and healthcare facilities, as well as federal, state, and local public and environmental health agencies. The market for products for wastewater surveillance sample collection and testing has grown exponentially during the COVID-19 pandemic and is likely to continue to grow as public health departments establish longer-term wastewater-based disease surveillance programs for SARSCoV-2 and other disease targets.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Electronic health record (EHR) technologies are increasingly promoted as innovative platforms to streamline preventive health programs and improve compliance with clinical guidelines. EHR alerts have been created to streamline hepatitis C virus (HCV) and HIV screening processes in primary care settings and to develop predictive models that identify patients at a high risk of HIV acquisition who may benefit from pre-exposure prophylaxis (PrEP). To our knowledge, there is a lack of such functionality to identify patients with HIV who are not in care; only at one medical center in New York has such a “homegrown” electronic medical record algorithm been developed to identify persons lost to HIV care. This SBIR project seeks to utilize EHR data that are typically available in EHR systems to develop a “core” algorithm that can be used in multiple healthcare systems to identify patients newly and previously diagnosed with HIV and categorize their linkage to care, antiretroviral (ART) prescriptions, retention in care, and viral suppression status. Interoperability of different EHR systems regarding this functionality will also be explored to improve generalizability and functionality throughout the country. Persons living with HIV may not be engaged in HIV care but may continue to access the health care system in other settings, such as other primary care or specialty clinics, emergency rooms, urgent care, and inpatient admissions. Such access can provide opportunities to re-engage them to HIV care. The data derived from the algorithm could be displayed on an EHR dashboard which would be accessible in any clinical setting affiliated with a healthcare system. Healthcare providers could utilize the information displayed to immediately identify a patient as not-in-care, and initiate care coordination and re-engagement efforts. Alternatively, a health care system could query its EHR data at regular intervals, to identify patients who may have fallen out of care. Project Goals This SBIR project seeks to develop a novel EHR-based algorithm to create a dashboard that identifies all patients with HIV and display their current linkage to care, antiretroviral therapy and viral load status. Specific groups highlighted by the algorithm may include patients with a new HIV diagnosis, patients that never linked to HIV care, patients that have disengaged from care (last visit with an HIV provider >6 months prior) and patients with an unsuppressed viral load (VL) on last measurement. Additional Page 129 information, such as age appropriate cancer screening, immunizations (e.g., COVID-19, pneumonia) could also be displayed. Phase I Activities and Expected Deliverables Create an algorithm that uses different data parameters to identify persons with HIV, and their current linkage to care, ART prescription and viral suppression status. Examples of data parameters that can be used include ICD 10 codes, laboratory results, appointment data, pharmacy refill data or similar data sources. Information from the algorithm would be displayed on a new dashboard (utilizing visualization software) within the EHR. The dashboard could use a color system (e.g., red, yellow, green) to easily identify if a patient has diagnosed HIV (new versus known infection), linkage to care status (last visit with HIV clinic provider), on ART (last ART refill date), and/or viral suppression status (last HIV RNA VL result). The goal of Phase I is to determine the feasibility of designing an algorithm based on EHR information that will correctly and accurately identify persons with HIV who may not be engaged in HIV care or have not achieved viral suppression. The expected deliverable will be the algorithm to identify persons with HIV who are not engaged in care or are not virally suppressed using data available in EHR systems and create a dashboard to flag this information. Interoperability of different EHR systems regarding this functionality may also be explored. ImpactPersons with HIV who are retained in care and are virally suppressed are 94% less likely to transmit HIV than persons with undiagnosed HIV. Accordingly, re-engaging people who are not in care confers important individual-level health and population-level prevention benefits, with retention in care and viral suppression as critical components of the HIV care continuum. The national goal of Ending the HIV Epidemic (EHE) is to reduce the number of incident HIV transmissions in the U.S. by at least 90% by 2030. The Treat Pillar of the EHE initiative seeks to treat HIV rapidly and effectively to reach sustained viral suppression. We hypothesize that development of this EHR-based algorithm could be an innovative and effective model to identify out-of-care persons with HIV, including priority groups and hardly reached populations, with the goal of re-engaging them in HIV care. Commercialization Potential There are an estimated 250,000 individuals in the U.S. who are aware of their HIV infection, but not receiving HIV care and treatment. The U.S. government spends $20 billion in annual direct health expenditures for HIV prevention and care. The Ending the HIV Epidemic (EHE) plan will focus on areas where HIV transmission occurs most frequently, providing 57 geographic focus areas (Phase 1 jurisdictions) with an infusion of resources, expertise, and technology. This innovative algorithm should be of interest to EHE Phase 1 jurisdictions, large healthcare systems, hospitals, clinics, and urgent care systems. This algorithm could help identify and re-engage persons with HIV who are not in care, not receiving antiretroviral treatment and/or not virally suppressed. CDC estimates the overall viral suppression rate in the United States is 53 percent. This SBIR project would be a novel and innovative intervention sought after by multiple healthcare systems and models as a necessary component to help jurisdictions achieve the important EHE goals to increase viral suppression to 90 percent nationally by 2030. In addition, technology developed through this project could be applied to other chronic health conditions (such as diabetes, hypertension, or others), for which lifelong or long-term treatment and engagement in care are necessary, potentially leading to a much wider commercialization potential.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Simultaneous detection of serological markers including different antibody classes (IgM and IgG) and antigens in a multiplex fashion, as well as the characterization of molecular fingerprints of infectious agents is important for accurate diagnosis of several diseases. Proper identification of all necessary serological and molecular markers is of particular interest for outbreak investigations Page 130 and molecular surveillance. Thus, the development of platforms capable to simultaneously capture the required molecular and serological information is needed. Advanced characterization of a plethora of infectious agents relies on next generation sequencing (NGS) approaches, primarily using deep amplicon sequencing and Illumina sequencing technology. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) allows next generation RNA sequencing as well as qualitative and quantitative analysis of proteins using capturing antibodies. CITE-Seq can be easily modified from single cell- to a bead-based approach for the specific detection of serological markers while simultaneously performing the conventional NGS protocols for genetic characterization. In combination, such methodologies could significantly improve the diagnosis for several diseases and syndromes including viral hepatitis. Project Goals Develop a multiplex NGS Illumina method for the simultaneous detection of viral hepatitis molecular and serological markers. Phase I Activities and Expected Deliverables 1. Create a standard operating procedure for antibody and antigen labeling. 2. Complete test runs on a MiSeq system to sequence viral hepatitis RNA and detect viral hepatitis serological markers. 3. Create a standard operating procedure for the complete molecular and serological laboratory detection of viral hepatitis. Impact Implementation of a NGS multiplex assay for the simultaneous detection of molecular and serological markers should significantly improve outbreak investigations, molecular surveillance and genetic relatedness studies for viral hepatitis and other infectious diseases. Commercialization Potential State laboratories are likely to benefit from implementing a multiplex approach for outbreak investigation and molecular surveillance of infectious agents able to capture both molecular and serological markers. Commercial labs will also likely benefit from implementing methodologies capable to characterize all serological and molecular markers for given infectious agents in a multiplex fashion.

Phase I SBIR proposals will be accepted. Fast-Track proposals will not be accepted. Phase I clinical trials will not be accepted. Number of anticipated awards: 1 Budget (total costs): Phase I: up to $243,500 for up to 6 months; Phase II of up to $1,000,000 and a Phase II duration of up to 2 years PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED. Background Influenza is the cause of considerable morbidity and mortality globally resulting in an estimated 290,000-650,000 fatalities annually and is a pathogen of significant public health importance. Vaccination remains the most effective measure against influenza infection. In addition to annual epidemics, pandemics are also a major concern as demonstrated by three major influenza pandemics in the 20th century in 1918, 1957 and 1968, and the first influenza pandemic of the 21st century in 2009 that spread worldwide in a short period, causing significant morbidity and mortality. In addition, circulation and infection of humans with novel avian influenza viruses from subtypes H5N1, H7N7, H7N1, H7N3, H7N9, and H9N2 has occurred. Vaccination remains the most effective measure against influenza infection. However, currently available vaccines include egg- or cell-derived inactivated split or live attenuated vaccines or insect cell-derived recombinant hemagglutinin (HA) protein. Apart from antibody responses to the globular head region of HA, antibody responses to the HA stalk, neuraminidase (NA), M2e and cell-mediated immune (CMI) responses to conserved internal proteins such as nucleoprotein (NP) have been shown to play a major role in viral clearance. Currently available vaccines are standardized based on HA content, although inactivated detergent-split vaccines do contain variable amounts of other viral proteins and the antibody responses to them varies. Furthermore, inactivated vaccines are not efficient in inducing/recalling CMI responses. Hence, a vaccine that induces antibody responses to all known antibody targets of influenza virus and, when delivered as nanoparticles, induces CMI responses to major conserved internal proteins, is needed to provide both the depth and breadth required. Project Goals The primary objective is to develop a recombinant protein and/or peptide-based influenza vaccine that can induce both humoral and cell-mediated immune responses, with sufficient breadth and depth to major antibody and CMI target proteins, when delivered with appropriate nanoparticles. The nanoparticle technology and recombinant protein/peptide synthesis process should be scalable with batch-to-batch consistency. Phase I Activities and Expected Deliverables 1. Develop a recombinant protein and/or peptide-based vaccine that contains HA, NA, M1, stalks of HA and the conserved protein, NP, from H1N1, H3N2 and B (Yamagata and Victoria lineages) viruses. 2. Demonstrate induction of antibody responses to HA, NA, M2e, stalks of HA and CMI responses to NP induced by the candidate vaccine as compared to those induced by a licensed, inactivated vaccine in appropriate animal models, mice and/or ferrets. 3. Compare immune responses induced by candidate vaccine by intranasal vs intramuscular routes in animal models, mice and/or ferrets. Page 132 Impact Currently available influenza vaccines induce strain-specific antibody responses against the vaccine strains included in the vaccine. Furthermore, they are poor inducers of CMI responses. If there is a mismatch between the circulating strain/s and vaccine strains, the vaccine efficacy will be suboptimum. Hence, a vaccine that induces a broader antibody and CMI responses to confer protection against disease, reduces morbidity, viral loads and symptoms will have a major impact on public health. Commercialization Potential Currently, there are no licensed recombinant protein/peptide influenza vaccines that contain, apart from HA, defined amounts of NA, M1 and NP to induce both humoral and cell-mediated immune responses. Hence, a vaccine that induces antibody responses to HA, NA, M2e, and stalk, and CMI responses to conserved internal protein NP, would increase the needed breadth and depth of vaccination and would have tremendous commercialization potential as this will provide broader protection from disease, even when the circulating strains of viruses are different from those contained in the vaccine.