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

Agency:

Department of Health and Human Services

Branch:

N/A

Program / Phase / Year:

SBIR / Phase I / 2017

Solicitation Number:

PROGRAM SOLICITATION PHS 2018-1

NOTE: The Solicitations and topics listed on this site are copies from the various SBIR agency solicitations and are not necessarily the latest and most up-to-date. For this reason, you should use the agency link listed below which will take you directly to the appropriate agency server where you can read the official version of this solicitation and download the appropriate forms and rules.

The official link for this solicitation is: https://sbir.nih.gov/sites/default/files/PHS2018-1.pdf

Release Date:

July 18, 2017

Open Date:

July 18, 2017

Application Due Date:

October 20, 2017

Close Date:

October 20, 2017

Available Funding Topics

Fast-Track proposals will be accepted. Number of anticipated awards: 2-3 Budget (total costs, per award):
Phase I: up to $300,000 for up to 9 months
Phase II: up to $2,000,000 for up to 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
Cachexia is characterized by a dramatic loss of skeletal muscle and adipose tissue mass, which cannot be reversed by nutritional intervention. More than half of all cancer patients experience cachexia, and it is estimated that nearly one-third of cancer deaths can be attributed to cachexia. Patients suffering from cachexia are often so frail and weak that walking can be extremely difficult. Cachexia occurs in many cancers, usually at the advanced stages of disease. Cancer cachexia is most prevalent in gastric, pancreatic, and esophageal cancer (80%), followed by head and neck cancer (70%), and lung, colorectal, and prostate cancer (60%).
Despite cachexia's impact on mortality and data strongly suggesting that it hinders treatment responses and patients' abilities to tolerate treatment, no effective therapies have been developed to prevent or hamper its progression. Even for patients able to eat—appetite suppression or anorexia is a common cachexia symptom—improved nutrition often offers no respite.
Overall, cachexia is characterized into three prominent stages, namely pre-cachexia, cachexia, and refractory cachexia. Precachexia is characterized by some metabolic and endocrine changes, but weight loss is minimal. In cachexia, the patient undergoes more prominent weight loss, anorexia, muscle mass depletion, and reduced muscle strength. At this point, weight loss can be somewhat countered by health supplements and corticosteroids, but improved muscle function has not been achieved. In refractory cachexia, there is severe body weight, muscle, and fat loss; the reversal of weight loss is negligible even with the dietary supplements.
Over the last few years, researchers have begun to better understand the underlying biology of cancer-and cancer therapy-related cachexia. Findings from several studies point to potential therapeutic approaches, and a number of clinical trials of investigational drugs and drugs approved for other uses have been conducted or are under way.
Project Goals
The goal of this SBIR contract topic is to provide support for the development of targeted agents, including small molecules and biologics, to prevent or treat cachexia related to cancer and/or cancer therapy, including chemotherapy and/or radiotherapy. Proposals submitted in response to this topic must focus on cancer indications with the highest prevalence of cancer-and cancer therapy-related cachexia. Any route of administration is acceptable, but it must be kept in mind that once cachexia has developed, absorption in patients may be impaired.
To apply for this topic, offerors should:
 Identify a therapeutic target and explain in detail the mechanism by which their drug will exhibit efficacy in
preventing or treating cancer-or cancer treatment-related cachexia.
 Provide preliminary data or cite literature to support the role of the target in the development of cancer-or cancer
treatment-related cachexia.
 Demonstrate ownership of, or license for, at least one lead agent (e.g., compound or antibody) with preliminary data
showing that the agent hits the identified target.
 Possess experience with well-validated in vitro assays and in vivo models.
 The scope of work proposed may include structure activity relationships (SAR); medicinal chemistry for small
molecules, antibody, and protein engineering for biologics; formulation; animal efficacy testing; pharmacokinetic,
pharmacodynamic, and toxicological studies; as well as production of GMP bulk drug and clinical product. These data
will establish the rationale for continued development of the experimental agent to the point of filing an investigational
new drug application (IND).
Activities not supported by this topic:
Proposals involving supplements and food products will not be considered.

Phase I Activities and Deliverables
 Demonstrate in vitro efficacy for the agent(s) in appropriate models.
 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.  Perform animal efficacy studies in an appropriate model of cancer-or cancer treatment-related cachexia. Include
controls to preclude drug-drug interations (e.g., the drug for cachexia should not decrease efficacy or increase toxicity for the cancer drug).  Develop a detailed experimental plan necessary for filing an IND or an exploratory IND (for potential SBIR phase II award).
Phase II Activities and Deliverables
 Complete IND-enabling experiments and assessments according to the plan developed in Phase I (e.g., demonstration of desired function and favorable biochemical and biophysical properties, PK/PD studies, safety assessment, preclinical efficacy, GMP manufacturing, and commercial assessment). The plan will be re-evaluated and refined as appropriate.
 Develop and execute an appropriate regulatory strategy. If warranted, provide sufficient data to file an IND or an
exploratory IND for the candidate therapeutic agent.
 Demonstrate the ability to produce a sufficient amount of clinical grade material suitable for an early clinical trial.

Fast-Track proposals will be accepted. Number of anticipated awards: 2-3 Budget (total costs, per award):
Phase I: up to $300,000 for up to 9 months
Phase II: up to $2,000,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
Tumor irradiation promotes recruitment of immune activating cells into the tumor microenvironment, including antigen presenting cells that activate cytotoxic T-cell function. However, tumor irradiation can also recruit immunosuppressive cells into the tumor microenvironment. Local irradiation can also impact tumor growth at a distance from the irradiated tumor site, known as the abscopal effect. This effect is potentially important for tumor control and is mediated through ceramide, cytokines, and the immune system.
Several factors can influence the ability of radiation to enhance immunotherapy, including a) the dose of radiation (IR) per fraction and the number of fractions; b) the total dose of IR; and c) the volume of the irradiated tumor tissue. However, the impact of these variables is not well understood. Inducing anti-tumor, cellular-mediated immune responses has been the subject of some pre-clinical tumor regression studies and is being applied in immune-modulatory clinical trials using antibodies against molecules that suppress immune responses such as PD1, PDL1, and CTLA4 or immune agonists such as OX40, CD27, GITR, 4-1BB, TNFR receptors, ICOS, and VISTA. Overall, discovery of checkpoint protein functional control of T-cells in tumor microenvironment led to the development of checkpoint blockade therapies and many checkpoint inhibitors including Nivolumab, Pembrolizumab, and Atezolizumab, which have been approved by the FDA for several indications. Several clinical trials testing combination of radiation with check point inhibitors are underway and have resulted in mixed results. Furthermore, many of these combination trials lack robust, pre-clinical scientific rationale, raising queries if such checkpoint agents augment the immune modulating effects of radiation. Hence, more agents that can augment immune activation or inhibit immune suppression induced by standard conventional 2 Gy fractions, (3-8 Gy) hypofractionation, and high-dose hypofractionated (>10 Gy) radiotherapy are warranted.

Project Goals
The broad goal of this Topic is to develop agents (cellular therapies, antibodies, small molecules, or miRNA/siRNA/CRISPR-CAS9 based approaches) that can augment (immune stimulation) or negate (immune suppression) one or more of the immune modulation events induced by radiation discussed above. IR can include conventional clinically relevant radiation, hypofractionated radiation, and high-dose hypofractionated radiation. Ionizing radiation (RT) causes changes in the tumor microenvironment that can lead to intra-tumoral as well as distal immune modulation (i.e., so-called abscopal phenomenon). Tumor-associated antigens (TAAs) are released by irradiated dying cancer cells triggering danger signals such as heat-shock protein (Hsp), HMGB1, and calreticulin (i.e., “eat-me” signal for phagocytes). These TAAs and cell debris are eaten by phagocytes such as macrophages, neutrophils, and dendritic cells for antigen processing and presentation. At the same time, RT can induce increased expression of tumor antigens and MHC class I molecules on tumor cells. Consequently, activated antigen presenting cells (APCs) migrate to the draining lymph node, further mature upon encountering T helper cells, and release interferons (IFNs) and IL-12/18 to stimulate Th1 responses that support the differentiation and proliferation of antigen-specific CTLs. Activated antigen-specific CTLs traffic systemically from the draining lymph node to infiltrate and lyse in primary as well as distal tumors. Concomitantly, tumor irradiation can also recruit immunosuppressive cells into the tumor microenvironment. Further, expression of certain negative stimulatory molecules on T-cells and tumor cells (e.g., CTLA-4, PD-1, PDL1) are induced by RT and can curtail the activation of T-cells, leading to an immune suppressive environment. Other immune suppressive function of radiation can occur through induction IL-10 and TGF-β. Augmentation or inhibition of radiation induced immune activation and suppression could enhance anti-tumor effects.
Activities not supported by this topic:
Immune modulating agents that are already being tested in combination with radiation in clinical trials will not be supported. Immune modulating agents that augment or negate immune functions in the absence of radiation will not be supported.
Phase I Activities and Deliverables
 Selection of cancer type(s), organ site(s), immune modulation agent(s), and radiation dose & fractions, with adequate justification.  Proof of concept animal (e.g., mice or rat) studies demonstrating augmentation or inhibition of radiation-induced immune activation or suppression respectively with the combination of radiation and the agent.
o
Demonstrate augmentation of immune activation in irradiated environment with appropriate standard markers showing an increased influx of positive effector immune cells (e.g., T-cells, macrophages, dendritic cells, etc.) in the tumor micro environment.
o
Demonstrate negation of immune suppression in irradiated environment with standard appropriate markers showing reduction in the influx of negative effector immune cells (e.g., neutrophil, T-reg, and MDSCs) in the tumor micro environment.
 Proof of concept animal (e.g., mice or rat) studies demonstrating tumor regression in a syngeneic contra-lateral tumor model whereby regression is observed in both the irradiated primary tumor as well as distal non-irradiated tumor when the agent is combined with radiation.
Phase II Activities and Deliverables
 Perform absorption, distribution, metabolism, and excretion (ADME) of agents with bioavailability and efficacy studies in appropriate animal models with adequate justification. The models chosen may be syngeneic rodent models, humanized rodent models, or canine models and should demonstrate:
o
Improved efficacy, both immune modulation and tumor regression, compared to radiation or agent alone.
o
Radiation sensitizing effects on tumors using standardized in vivo radiation regrowth delayed assays.
o Comparative (i.e., similar or lower) toxicity compared to the agent or radiation alone.
 Perform IND-enabling GLP safety toxicology studies in relevant animal model(s) following FDA guidelines.
 For offerors that have completed advanced pre-clinical work, NCI may support pilot human trials.

Fast-Track proposals will be accepted. Number of anticipated awards: 3-5 Budget (total costs, per award):
Phase I: up to $300,000 for up to 9 months
Phase II: up to $2,000,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
The preclinical development of cancer therapeutics, including the recent trend and focus on cancer immunotherapies, is evolving from the traditional use of mouse models to the use of other animal models including canine, rat, and minipig. Each of these non-mouse models carries its own advantages and abilities to increase the clinical relevance of the model as compared to mouse models. Yet, the wide use of these models for preclinical validation of novel therapeutics is limited by multiple factors including the availability of analytically validated reagents, such as antibodies, and aptamers, for each model system.
While this topic is not limited to the development of canine reagents, canine reagents are of particular interest. Canine models may be particularly useful for the development of novel therapeutics, as canines have intact immune systems that can be used to study the interactions of therapeutics with the immune system. Canine models include companion dogs with spontaneous cancer. It has been shown that canines metabolize drugs similarly to humans (unlike mice), are amenable to serial biologic sample collections, and have comparable tumor biology. Importantly, canines have been shown to respond to human cancer therapeutics. Canine models would be especially valuable for the testing of immunotherapies, as the availability of fully immune competent mouse models is quite limited. While canines are more expensive than mice, canine trials are not nearly as expensive as human trials as the trials can be completed much faster due to shorter progression-free intervals and overall survival times.
A commercial supplier of reagents resulting from this topic is advantageous, as it could provide both the analytical validation for each reagent and a long-term source, as compared to academic labs that may produce reagents for each set of studies. The need for animal model-specific, analytically validated reagents includes a wide range of reagents and antibodies that would enhance the ability to test therapeutics within that animal model. For example, analytically validated canine reagents demonstrated to be both renewable and reproducible would both expand the suite of validated assays amenable to canine studies and provide a long-term commercial source of reagents for follow-up studies. This topic is in line with the Cancer
Moonshot Blue Ribbon Panel’s Recommendation to support a Cancer Immunotherapy Translational Science Network.
Project Goals
The development and ultimate commercialization of analytically validated, non-mouse reagents will facilitate more robust preclinical evaluation of novel therapeutics. Currently, there are several hundred active combination clinical trials involving at least one immunotherapeutic, which is partially a result of the lack of clinically predictive model systems. Reagents developed under this topic are likely to facilitate the use of additional clinically relevant animal models. Thus, a short-term goal of this topic is the creation of a set of reagents that will enable additional preclinical testing of novel therapeutics. In addition, the development of reagents for clinical testing in companion animals (such as canines) will facilitate additional market opportunities and impact of newly developed therapeutics. Thus, the long-term goal of this contract topic is to enable better demonstration of the utility of novel therapeutics for administration in both humans and companion animals. While reagents that enable the use of models for the testing of immunotherapeutics are of particular interest, proposals to develop reagents for the testing of other therapeutic approaches, such as chemotherapy and radiation approaches, will be considered if a strong rationale is provided for the need of such reagents.
Materials developed under this topic may include, but are not limited to, reagents for a wide variety of preclinical assays for target validation, characterization of immune response, mass cytometry, and pharmacodynamic assays. Potential offerors should demonstrate the current need and potential utility of newly developed reagents. The targets and applications of newly developed reagents must be targets and applications that have relevance to the potential clinical efficacy, toxicity, or mechanism of action of newly developed therapeutics. Reagents that will enable immune-relevant assays in non-mouse models, which are not currently possible and/or predictive in mouse models, are of particular interest.

The offerors should provide all relevant controls, reference standards, protocols, and SOPs. In the Phase I, the offerors should develop and validate an appropriate number of reagents and should provide justification for the choice of the number developed (e.g., novelty, utility, and complexity). Analytical validation and characterization of the reagent(s) should include, as appropriate, but not limited to: purity, concentration, storage conditions, reference standards, specificity, linearity, and limits of detection (LOD).
Proposals should demonstrate the broad utility of the developed reagents and assays, as the reagents’ utilities should extend
beyond one specific researcher/research project. Proposals should identify the potential utility of the assay(s) and how it addresses an unmet need. Demonstration of potential utility should include a description of which therapeutics would be the focus of the reagents/assays developed through this topic. Quantitative milestones that can be used to evaluate the utility of the reagents should be clearly defined and justified.
Phase I Activities and Deliverables
 Analytically validate and characterize the reagent(s) for a number of parameters including, as appropriate, but not
limited to: purity, concentration, storage conditions, reference standards, specificity, linearity, limits of detection
(LOD), range, accuracy, and precision.
 Develop pertinent controls and reference standards.
 Conduct tests to characterize the developed reagents to ensure rigor and reproducibility:
o
Reagents designed for in vitro assays: Proposals should demonstrate likelihood of obtaining pertinent non-mouse samples, and projects must include feasibility testing of the characterization test. Veterinary schools are a potential source of canine tumor/matched normal tissue samples.
o
Reagents designed for in vivo assays: Proposals should demonstrate the rationale for feasibility testing in vivo, and projects should include sufficient characterization to suggest proof of concept. In Phase I, it is not required to conduct in vivo studies.
 Provide a proof-of-concept SOP for the reagents and assays. The SOP should include necessary information on the required equipment, operating parameters, sample preparation, standards control solution preparation, procedure, system suitability, calculations, data reporting, and statistics.
 Demonstrate renewability and reproducibility of the developed reagents.
Phase II Activities and Deliverables
 Scale-up production of the reagents to produce sufficient quantities for proof of concept studies.
 Refine the assays to CLIA-grade, as appropriate.
 Establish quality control measures and carryout critical reagent supply chain audits.
 Demonstrate proof-of-concept and compare to currently available assays as a means of validating the proposed
reagents.
 Provide a complete and final SOP based on the studies conducted in Phase II.

Fast-Track proposals will not be accepted.
Number of anticipated awards: 3-5
Budget (total costs, per award):
Phase I: up to $300,000 for up to 9 months
Phase II: up to $1,500,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
Chemical modifications play a crucial role in the regulation of biological processes. Protein function is often modulated by tagging with phosphates, sugars, or lipids, while epigenomic marks on DNA or histones can regulate gene expression up or down. One area that lags behind is the mechanistic understanding of the role of RNA chemical modifications, sometimes
referred to as the ‘epitranscriptome’.

The RNA Modification Database lists more than 60 RNA modifications that occur in eukaryotic cells. Transfer and ribosomal RNA have been shown to be heavily modified, and some of these same modifications also occur in messenger RNA and non-coding RNAs. However, the vast majority of these modifications have not been well-studied in messenger and non-coding RNAs. Even though much about RNA modifications remains to be elucidated, there is emerging evidence that RNA modifications are functionally significant and play important roles in biological processes and diseases in vertebrates.
Several RNA chemical modifications or the enzymes that catalyze the addition of modifications (writers), the removal of modifications (erasers), or translate the effects of modifications (readers) have been associated with a variety of cancers. For example, certain mutations in the N6-methyladenosine (m6A) demethylase (or ‘eraser’) FTO are associated with melanoma and breast cancer risk. Additionally, mutations in the pseudouridine ‘writer’ DKC1 cause dyskeratosis congenita, a disease
associated with premature aging and increased tumor susceptibility. Furthermore, specific DKC1 mutations have been identified in human pituitary adenomas.
These early findings linking the disruption of RNA modifications to cancer initiation and progression highlight the potential importance of the field of epitranscriptomics to understanding cancer biology. However, a lack of experimental tools for monitoring RNA modifications has slowed the potential progress. The purpose of this topic is to incentivize small businesses to generate tools and technologies for monitoring covalently modified eukaryotic RNA. This topic is in line with the Cancer Moonshot Blue Ribbon Panel’s Recommendation to support Development of New Enabling Cancer Technologies.
Project Goals
As discussed at a workshop hosted by the NCI Division of Cancer Biology on ‘RNA Editing, Epitranscriptomics, and Processing in Cancer Progression,’ and at other meetings, the major obstacles hampering efforts to better understand RNA modifications are fundamentally technical in nature. Presently, we lack appropriate tools and technologies for investigating the epitranscriptome broadly and at single nucleotide resolution. Additionally, there is evidence that the availability of tools will drive research in this field. For example, an antibody-based assay for monitoring the m6A modification was developed in 2012, and by 2014 there had been a four-fold increase in the number of m6A publications.
Despite the growing interest in and importance of RNA modifications, the available tools that scientists have to monitor modified RNAs are limited. The purpose of this contract topic is to incentivize small businesses to generate tools, technologies, and products for monitoring covalently modified eukaryotic RNA, including messenger RNA and regulatory RNA. In the long term, these tools and products will allow the investigation of how altered RNA modifications contribute to the initiation and progression of cancer and potentially identify a new class of cancer biomarkers.
Potential tools, technologies, or products may include, but are not limited to:
 Systems or kits that enable high-throughput mapping of specific RNA modifications to residues in individual RNA species using genome-wide sequencing approaches (i.e., approaches analogous to the bisulfite sequencing assays used for detecting methylcytosine or hydroxymethylcytosine in DNA).
 Approaches that enable researchers to sequence RNA without a cDNA intermediate or that otherwise preserve or amplify the RNA modification information. This could include the development or adaptation of nanoscale sequencing devices or other equipment for direct identification and quantitation of sequence-specific RNA modifications.
 Approaches that exploit the ability of certain RNA modifications to disrupt reverse transcription.
 Products that would enable the in vitro or in vivo imaging of modified RNA molecules.
 Assay systems or reagents that facilitate the discovery, detection, or quantitation of modified messenger RNAs and/or
circular RNAs.
 Well-validated antibodies, affinity reagents, or affinity-based assay kits for detection, quantitation, or
immunoprecipitation of modified RNAs. Note, however, that antibodies for N6 Methyladenosine (M6A) would be
considered low priority.
 Products or systems that enable simultaneous detection of many types of RNA modifications at high sensitivity.  Assay systems or reagents that enable researchers to monitor the effect of an RNA modification on the structure or function of an individual RNA.
 The development of analytical software tools to facilitate the identification of modified, circular, or edited RNA from high-throughput sequencing datasets. This could include algorithms that improve our ability to identify which base on a given RNA is modified.

Phase I Activities and Deliverables
The goal of Phase I is to develop proof-of-concept or prototype tools, technologies, or products for monitoring specific RNA modification(s). Activities and deliverables include:
 Identify and justify development of a tool or technology for monitoring a specific RNA modification or set of RNA modifications.  Describe the current state of the art technologies, if any, for monitoring the specific RNA modification(s), and
outline the advantages that the proposed approach will provide.  Develop and characterize the tool or technology for monitoring the specific RNA modification(s).  Specify and justify quantitative milestones that can be used to evaluate the success of the tool or technology being
developed.  Develop an assay or system for testing and benchmarking the specificity and sensitivity of the tool or technology, and compare the tool or technology to existing approaches if applicable.
 Demonstrate the reliability and robustness of the tool, technology, or product. Offerors shall provide a technical evaluation and quality assurance plan with specific detail on shelf life, best practices for use, and equipment required for use.
 Provide justification that the tool, technology, or product can be scaled up at a price point that is compatible with market success and widespread adoption by the basic research community.  Provide proof-of-concept data demonstrating the monitoring of the specific RNA modification(s) in relevant cell or animal models with the potential to benchmark data across a variety of cancer models.
Phase II Activities and Deliverables
The goal of Phase II is development of an optimized commercial resource, product, reagent, kit, or device for monitoring specific RNA modification(s).
Deliverables and activities include:
 Scale up the synthesis and/or manufacture of necessary agents, chemicals, devices, or products.
 Design and implement quality assurance controls and assays to validate production.
 Validate scaled up tool, technology, or product. Specifically, demonstrate the utility, reliability, sensitivity, and
specificity of the tool, technology, or product across relevant in vitro and/or in vivo cancer models (e.g., 2D and 3D tissue culture systems, or in vivo animal models of cancer).  Refine SOPs to allow for user friendly implementation of the tool, technology, or product by the target market.

Fast-Track proposals will be accepted Number of anticipated awards: 3-5 Budget (total cost per award):
Phase I: up to $300,000 for up to 9 months
Phase II: up to 2,000,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
The clinical value of an agent is reflected by both its efficacy and its toxicity. In the chemoprevention space, where agents are administered to a relatively healthy (albeit high-risk) population, the intention is to minimize toxicity. Most chemopreventive agents require administration over long periods of time. This limit on toxicity presents a major challenge in the development of chemopreventive agents with acceptable benefit risk ratios.
Our ability to identify populations at higher risk of developing cancer has significantly improved over the past decade. For example, women with Hereditary Breast and Ovarian Cancer syndrome (HBOC) are at increased risk of developing breast and ovarian cancer, and potentially other cancers (e.g., pancreatic); individuals with Lynch syndrome are at increased risk of developing multiple cancer types including colorectal, endometrial, ovarian, and gastric cancer. We are also able to detect

cancer at earlier stages and often as precancerous lesions. Multiple studies have shown that these individuals at high risk for cancer or with precancerous lesions could benefit from chemoprevention approaches. A small number of chemopreventive agents have found some degree of success in the clinic, including tamoxifen and raloxifene for breast cancer prevention, and aspirin and celecoxib for colorectal cancer prevention. However, the systemic toxicities of these agents have limited their widespread use and acceptability.
Local agent delivery is an important strategy to reduce toxicity of chemopreventive agents, while maintaining clinical benefit. Local delivery of an agent can be performed by a physician or self-administered by an individual, which overcomes some of the access barriers that exist in healthcare. A localized chemoprevention approach is ideal in high risk individuals or individuals with premalignant diseases, as the agent can be applied locally to provide high drug concentrations at specific locations from where early disease would originate, while limiting systemic toxicity.
Project Goals
The goal of this topic is to advance the development and/or application of local delivery devices or formulations for chemoprevention. The technology should be designed for effective delivery of agent to a specific organ while minimizing systemic toxicities. Acceptable toxicities will depend on the agent and target population. Toxicity should not exceed minimal grade 2 local toxicities, while short term local grade 3 toxicity may be acceptable in some populations. The proposed local delivery device/formulation may utilize any technology or agent capable of meeting the goals of this topic. Examples of local administration include topical (for oral, breast, skin or cervical cancers), inhalant (for lung or esophageal cancers), or digestive (for esophageal, stomach, or colorectal cancers). Proposals for development of local delivery devices or formulations via other administration routes or for other cancer types are also encouraged.
The activities that fall within the scope of this contract solicitation include development and application of local delivery formulations or devices. Examples of appropriate activities include pre-clinical toxicity and efficacy studies in appropriate animal models, acceptability studies, and initial first-in-human testing. A local delivery approach for FDA approved chemoprevention agents or for novel chemoprevention agents may also be developed. For novel chemoprevention agents, significant reduction in cancer incidence in suitable cancer prevention animal models should be demonstrated. Phase II clinical trials and beyond are not appropriate for this mechanism; investigators are encouraged to seek support for these studies from alternative NCI programs.
Phase I Activities and Deliverables
 Select cancer type(s), organ site(s), chemoprevention agent(s), and method(s) of local delivery with adequate justification.
 Demonstrate that the chemoprevention agent is:
o
Stable in local formulation and/or when incorporated with the local delivery device/technology.
o
Released at the organ(s) of interest when incorporated into a local delivery device/technology.
 Perform preliminary proof-of-concept of the local delivery approach in a suitable animal model and demonstrate:
o
Accumulation/presence (>90% higher concentration) of the agent at the organ/tissue of interest than in the circulation.
o
At least 90% reduction in agent concentration in the blood compared to systemic delivery / administration.
o
Efficacy of the agent with relevant standard tests based on MOA of the agent (e.g., proliferation assay, apoptosis assay)
o
Significant reduction in toxicity with the local approach compared to systemic administration; relevant organ observed toxicity could be used with appropriate justification
Phase II Activities and Deliverables
 For agent(s) (or their metabolites) with known chemoprevention effect when administered systemically (FDA
approved):
o Demonstrate efficacy in suitable animal model(s)
• Perform ADME, bioavailability and efficacy studies of the local delivery approach in suitable animal model(s) and demonstrate:

 at least same level of agent concentration at the organ/tissue of interest compared to systemic delivery/administration.
 at least 90% higher concentration of the agent in the organ of interest than in the circulation.
 at least 90% reduction in agent concentration in the blood compared to systemic delivery/administration.
 at least same level of efficacy demonstrated with appropriate standard tests reflecting the MOA of the agent (e.g., proliferation assay, apoptosis assay) compared to systemic delivery/administration.
o
Perform maximum tolerated dose (MTD) and/or biological active dose study and demonstrate superior therapeutic index using local approach compared to systemic administration with adequate justification.
• Toxicity should not exceed minimal grade 2 systemic toxicities while short term local grade 3 toxicity may be acceptable in some populations.
o
IND-enabling studies
•
Develop and execute an appropriate regulatory strategy; schedule pre-IND meeting with the FDA.
•
Perform IND-enabling GLP safety toxicology studies in relevant animal model(s) following FDA guidelines.
 For novel (non-FDA approved) chemoprevention agent(s):
o Demonstrate efficacy in suitable animal model(s)
• Perform ADME and bioavailability and efficacy studies of the local delivery approach in suitable animal model(s) and demonstrate:
 reduction of oncogenic molecular/cellular characteristics reflecting the MOA of the agent (e.g., proliferation assay, apoptosis assay).
 at least 50% reduction in cancer incidence following local administration of the chemoprevention agent in suitable cancer prevention animal model(s).
 at least 90% higher concentration of the agent in the organ of interest than in the circulation.
 at least 90% reduction in agent concentration in the blood compared to systemic delivery/administration.
o
Perform maximum tolerated dose (MTD) and/or biological active dose study and demonstrate superior therapeutic index using local approach compared to systemic administration with adequate justification.
• Toxicity should not exceed minimal grade 2 systemic toxicities while short term local grade 3 toxicity may be acceptable in some populations.
o
Perform IND-enabling safety toxicology studies in relevant animal model(s) to warrant a type B or type C meeting with the FDA.
 For offerors that have completed advanced pre-clinical work, NCI may support pilot human trials.

Fast-Track proposals will be accepted.
Number of anticipated awards: 3-4
Budget (total costs, per award): Phase I: up to $300,000 for up to 9 months Phase II: up to $2,200,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary
Immunotherapies have emerged as one of the promising approaches for cancer treatment by exploiting patients’ own immune
systems to specifically target tumor cells. However, it has been recognized that responses often occur in only a subset of patients in any given immunotherapy. This treatment is also associated with drug toxicity (e.g., cytokine storm) and high cost. As this treatment modality continues to evolve, a significant clinical question that needs to be addressed is to determine which patients would benefit from immunotherapies. In addition, there is increasing need for newer methods to evaluate the efficacy and potential toxicities of the treatment, and monitor cancer patients’ prognosis.
Diagnostic imaging is routinely used to: 1) stratify patients for cancer treatment; and, 2) monitor and provide reliable predictive and/or prognostic information for a specific treatment. With the rapid advancement of imaging technologies, particularly molecular imaging technology development, this technique provides detailed visualizations and measurements of biologic processes taking place inside the body at molecular, cellular, and genetic levels. It offers capability to assess not only
changes in a patient’s tumor size, but also changes in molecular expression and cellular activity. Diagnostic imaging
provides nearly real-time information about tumor target expression levels, potentially allowing physicians to predict which patients may respond to therapies. In addition to patient stratification, diagnostic imaging of therapeutic targets may provide insight into the efficacy and toxicity of the cancer treatment and overall disease progression.
The purpose of this initiative is to provide much needed support for the development of diagnostic imaging technologies to identify patients who are likely to respond to cancer immunotherapies, evaluate the efficacy and potential toxicities of the treatment, and/or monitor cancer patients’ prognosis. The cancer immunotherapies for this topic will include the ones that either have been approved by the FDA, or are still under clinical development. This topic is intended specifically to address cancer immunotherapies that depend upon eliciting an immune response. Projects that do not meet this requirement will not be funded. For example, a monoclonal antibody based therapy that exerts a direct antitumoral effect either by neutralizing the antigen or by activating signaling pathways within the target tumor cells, but does not elicit an immune response for its clinical application, is not considered an immunotherapy and would not be funded. It should be noted that technologies that map the tumor and/or its microenvironment to predict response to immunotherapy should submit the proposal to the topic, “Imaging-Based Tools for Longitudinal and Multi-Dimensional Mapping of the Tumor and its Microenvironment.” The “Diagnostic Imaging for Cancer Immunotherapies” topic is in line with the Cancer Moonshot Blue Ribbon Panel’s Recommendation to support Development of New Enabling Cancer Technologies.
Project Goals
The goals of the project are to develop a diagnostic imaging technology to identify patients who are likely to respond to cancer immunotherapies, evaluate the efficacy and potential toxicities of the treatment, and/or monitor cancer patients’ prognosis. The imaging modality could be one of the following, but is not limited to: optical imaging, PET, SPECT, or MRI. Molecular markers of interest could include but are not limited to: cell surface receptors, immune cells, cellular infiltrates, enzymes, DNAs, or RNAs. The technology development should be platform driven. For example, the procedure for the diagnostic imaging that targets immunotherapy for breast cancer or its subtype should be easily applied for other cancer types/subtypes, such as colon cancer or prostate cancer. To apply for this topic, offerors need to outline and indicate the clinical question and unmet clinical need that their diagnostic imaging will address. Offerors are also required to use validated imaging targets. This solicitation will not support efforts for imaging biomarker discovery.
The long-term goal of this contract topic is to enable small businesses to bring novel modalities of fully developed diagnostic imaging for cancer immunotherapies to the clinic and the market.
Phase I Activities and Deliverables
Phase I activities should generate scientific data confirming the clinical potential of the proposed molecular diagnostic imaging for cancer immunotherapies. The Phase I research plan must contain specific, quantifiable, and testable feasibility milestones.

Expected activities may include:
 Demonstrate proof-of-concept for the development of a diagnostic imaging technology to identify patients who are likely to respond to immunotherapies, and/or evaluate efficacy and toxicities of immunotherapy, and/or monitor tumor prognosis under immunotherapy using the imaging technology.
 Quantify sensitivity and specificity of the imaging technology.
 Conduct preliminary biosafety study for the imaging technology.
 Present Phase I results and future development plan to NCI staff.
Phase II Activities and Deliverables
Phase II should follow the development plan laid out in the Phase I, and should further support commercialization of proposed diagnostic imaging for cancer immunotherapies. The Phase II research plan must contain specific, quantifiable, and testable milestones.
Expected activities may include:
 Complete all pre-clinical and/or clinical experiments according to the development plan.
 Demonstrate capability of diagnostic imaging to: 1) identify whether cancer animal models and/or human patients respond to cancer immunotherapies; and/or, 2) evaluate efficacy and toxicities of cancer immunotherapies in animal models and/or human patients; and/or, 3) monitor tumor prognosis in animal models and/or human patients under cancer immunotherapies.
 Demonstrate high sensitivity and specificity of the imaging technology in animal models and/or human patients.
 Demonstrate high reproducibility and accuracy of the imaging technology in animal models and/or human patients.
 Determine biosafety of the imaging technology with animal or human toxicology studies.
 If warranted, initiate FDA approval process for the candidate imaging technology.

to drug delivery to tumor sites. Over the recent years, immunotherapies utilizing checkpoint inhibitors to modulate the immune components of tumor cells and TME have been approved for multiple cancer types, and more are currently undergoing clinical trials; however, immunotherapies are only effective in a restricted group of patient populations.
The evaluation of tumor and TME at the molecular and cellular level is often based on histopathological analysis of tumor biopsies. However, these methods are invasive and lack spatial and temporal information; thus, the ability to use tumor and TME-associated molecular and cellular signatures for tumor prediction, diagnosis, prognosis, and therapy response are rather limited. Techniques capable of temporal in vivo molecular characterization and cell mapping of the tumor and its TME, in its physical location and over time, can accelerate lead compound identification, assist in patient stratification, monitor therapeutic response and modulate therapy accordingly.
Recent advances in imaging techniques are enabling assessment of tumor and TME with improved accuracy due to higher monitoring speed, sensitivity, and resolution. For example, magnetic resonance imaging techniques, with both excellent image resolution and depth penetration, are widely used to detect abnormal pre-malignant, tumor and TME structures and conditions: blood oxygenation level dependent (BOLD)-MRI for hypoxic conditions, Chemical Exchange Saturation Transfer (CEST)-MRI for reduced pH, MR angiography for vascular structure and diffusion MRI for structural integrity. Positron Emission Tomography (PET) of radio-nuclei-labeled tumor or TME-associated molecular targets has been used in pre-clinical and clinical settings. All these in vivo methods are valuable tools to spatiotemporally examine the targeting efficiency and associated molecular events, and provide insight into the normalization of tumor and TME and its effect on anticancer drug delivery. ‘Bio-activatable’ delivery vehicles allow for controlled drug delivery, which is activated only by the change of tumor and TME parameters. However, most of these studies are pre-clinical, and the imaging modalities have mostly been limited to pre-clinical studies.
Dynamic or longitudinal evaluation of the molecular characteristics and cell populations in tumor and its TME within an individual patient is an effective and personalized strategy for early detection of cancer, the prognosis of tumor progression as well as prediction of treatment outcome. To accelerate research and translational efforts focused on dynamic profiling of tumor and TME in real time, the National Cancer Institute (NCI) requests proposals for the development of clinically viable in vivo technologies that can enable enhanced mapping of human tumors. This topic is in line with the Cancer Moonshot Blue Ribbon Panel’s Recommendation to support Generation of Human Tumor Atlases.
Project Goals
Tumor diagnosis at an early stage, before it has grown too big or spread, is critical to improving survival of patients with the tumor. Similarly, being able to predict tumor response to treatment is essential to prevent the use of ineffective treatment options and allow alternative treatment options. As such, the ability to characterize the dynamic changes in tumor and TME at the molecular and cellular levels in an individual patient for early diagnosis and during treatment is critical. For example, the extent of immune cell infiltration and activation in solid tumors could be used to determine if immunotherapy is working in patients.
The goal of this topic is to develop non-invasive, in vivo imaging-based platforms that can repeatedly generate three-dimensional molecular and cellular maps of the tumor and its TME at different time points for diagnosis and treatment prediction/response. With the emergence of promising immunotherapies, technologies and molecular imaging approaches to track immune response to immunotherapies are of particular interest. The proposed technology should be focused on interrogating one or more of the following tumor and TME parameters across time via in vivo imaging techniques with cellular resolution. The proposed imaging technology should provide three-dimensional information at any given time point. Potential molecular, cellular and physiological parameters to be measured may include but are not limited to the following:
 Gene expression profiles
 Protein expression profiles
 Maps of invading immune cell types in response to immunotherapy
 Maps of various cell types and subtypes in tumor or TME
 Tissue oxygenation profiles
 Vasculature and stromal structures
 Tissue integrity and/or pH
 Maps of enzymatic activities

This contract topic is agnostic to the imaging modality proposed. New imaging modalities could be developed, or agents targeting TME could be developed, using any imaging modality currently available including X-ray, MRI, PET, SPECT, CT, optical, photoacoustic and ultrasound. Novel or currently existing imaging agents or probes (targeting certain molecular or cellular signatures) may be developed and optimized to enable molecular, cellular, and physiological measurements. The goal of the topic is to develop imaging tools for tumor and TME in the clinic; hence, the tools developed need to be clinically feasible and relevant.
Proposals with incremental improvement from the current state of art or having no immediate translational potential will not be funded. Examples of inappropriate proposals may include, but are not limited to: imaging methods that can work only in pre-clinical imaging modalities (i.e. ultrahigh-field MRI or unconventional PET radionuclei labeling), chemical constructs or linkers that are inherently toxic or immunogenic, and agents/probes that focus on molecular targets that do not have human equivalent. Image-based companion diagnostics that do not incorporate mapping of the tumor or TME are not appropriate for this topic and may better address the topic “Diagnostic Imaging for Cancer Immunotherapies.”
Phase I Activities and Deliverables
Phase I activities should generate scientific data to confirm clinical potential of the proposed agent and imaging capability with cellular resolution. Expected activities and deliverables should include but are not limit to:
 Optimize detection scheme to demonstrate in vitro signal specificity and correlate signals to molecular target concentrations measured using conventional assays.
 Establish calibration curves correlating in vivo signal changes to concentration of molecular targets measured via conventional biological assays.
 Demonstrate robust signal changes in response to in vivo perturbation.
 Demonstrate feasibility in generating maps of measurable parameters as a function of time.
 If new molecular targets are proposed, demonstrate specific binding/targeting capabilities of the agent/probe to the molecular target (tumor and/or TME target).
 Determine optimal dose and detection window through proof-of-concept small animal studies with evidence of systemic stability and minimal toxicity.
 Benchmark experiments against current state-of-the-art methodologies. For successful completion of benchmarking experiments, demonstrate a minimum of 5x improvement against comparable methodologies.
Phase II Activities and Deliverables
Phase II activities should support commercialization of the proposed agent for clinical use. Expected activities and deliverables may include:
 Demonstrate in vivo clearance, tumor accumulation, in vivo stability, bioavailability, and the immunogenicity / toxicity of imaging agents or probes.
 Demonstrate high reproducibility and accuracy of the imaging agents or probes in multiple relevant animal models.
 Demonstrate superiority over currently available imaging tools in image resolution.
 Demonstrate that sensitivity of proposed imaging agents or probes is sufficient to detect in vivo perturbation.
 Demonstrate sensitive maps of measurable parameters as a function of time.
 Perform toxicological studies.
 Demonstrate clinical utility.
o
For diagnosis, demonstrate that the probes can detect tumors at early stages and demonstrate superiority to current diagnosis methods.
o
For predictive/decision, validate the predictive capability of the marker by performing prospective pre-clinical animal trials: stratify the animals into treatment groups and demonstrate that the imaging agent accurately predicts appropriate therapy to use.

o
For therapy response, demonstrate that the imaging tool can accurately visualize changes in response to therapy, and validate characteristics of response and non-response.
 Collect sufficient animal and safety data in preparation for an IDE application.

Fast-Track proposals will be accepted. Number of anticipated awards: 1-2 Budget (total costs, per award):
Phase I: up to $225,000 for up to 9 months
Phase II: up to $1,500,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
Uncontrolled symptoms during and following cancer treatment have been associated with emotional distress; diminished functional status and health-related quality of life; treatment delays, discontinuation, and non-adherence; and unplanned hospitalizations and emergency room visits. The evaluation and management of symptoms in cancer care, including multiple co-occurring symptoms (e.g., pain, depression, and insomnia), is complex.
A plethora of evidence-based clinical practice guidelines (CPG) for managing cancer-related symptoms have been developed by national organizations that include the Oncology Nursing Society (ONS), American Society of Clinical Oncology (ASCO), Multinational Association for Supportive Care in Cancer (MASCC), National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), American Cancer Society (ACS), and the National Cancer Institute (NCI). However, implementation of these guidelines in practice has to-date been limited and haphazard, and the available guidelines are not offered to clinicians in a readily actionable format. Sifting through the options contained in multiple guidelines and determining the best approach for a specific patient takes more time than clinicians typically have available. Electronic decision-support would help to bridge this guideline implementation gap, and would allow for rapid dissemination into practice of both new guidelines and guideline updates.
Clinical Decision Support (CDS) is a health information technology designed to directly aid in clinical decision-making. CDS matches the characteristics of individual patients to a computerized knowledge base, and generates patient-specific assessments and recommendations. CDS provides clinicians and other stakeholders with pertinent knowledge and person-specific information, intelligently filtered, and delivered at appropriate times in clinical workflow to enhance health and healthcare delivery (Osheroff et al. JAMIA 2007; 14 (2), 141-145). The overall goal of CDS-Sx is to support health professionals in delivering personalized, evidence-informed, guideline-based clinical decision-making to improve the evaluation and management of cancer-related symptoms.
NCI Blue Ribbon Panel (BRP) Implementation Science Working Group Report urged an immediate strategic investment to provide actionable decision support that accelerates the implementation of evidence-based cancer symptom management guidelines. CDS for symptom management addresses recommendations made by the National Academy of Medicine (NAM), National Quality Forum, and the Coalition to Transform Advanced Care for improvements in symptom management and palliative care across the cancer continuum.
This topic requests proposals to create a system of computable algorithms to improve oncology clinicians’ evaluation and management of common cancer-related symptoms, leveraging nationally endorsed, evidence-based CPGs. The algorithms would be delivered within a CDS that also includes a small set of well-curated resources for patient self-management support, ICD-10 coding, and other features to streamline clinician workflow and support coordinated interdisciplinary symptom management such as templated progress notes and referral pathways. The algorithms will be constructed such that the sequence of evaluation and management activities is triggered by patient-reported outcomes (PRO) data derived from a variety of contemporary PRO measurement systems (e.g., PRO-CTCAE, PROMIS, and NCCN symptom indices) and would offer decision support relevant across the cancer continuum from treatment to survivorship and end-of-life. At commercial scale, the CDS would allow for information to be exported into an electronic health record. This topic is in line with the Cancer Moonshot Blue Ribbon Panel’s Recommendation to support Symptom Management Research.

Project Goals
Despite the plethora of evidence-based cancer CPGs for cancer symptom management, implementation is inconsistent in practice. There are few commercially available decision-support systems that provide guideline-based recommendations in interpretable and actionable ways to healthcare providers at the point-of-care. NCI investment in the development of CDS for symptom management has been sparse.
The overall objective is to develop an electronic, rule-based, clinical decision-support system for symptoms (CDS-Sx) that leverages national CPGs to improve the evaluation and management of symptoms during and following cancer treatment.
This objective will be accomplished by:
 Creating and validating software-ready computable algorithms for evaluation and management of eight common
cancer-related symptoms that have associated national CPGs for cancer symptom management.
o
Computable algorithms will be iteratively developed by panels comprising clinical experts and experts in rule-based CDS system design, leveraging nationally endorsed symptom management guidelines, and aligned to an existing data standard to ensure interoperability with downstream systems.
o
Algorithms will be tailored to different levels of symptom severity and interference, as well as to other clinical and demographic factors such as concurrent symptoms (e.g., depression in the setting of pain and fatigue), disease site, treatment type, age, concurrent medications, comorbid conditions, and allow tailoring to patient goals and preferences.
o
Options for site-specific customization of the algorithms, particularly with respect to resources available at the practice site (e.g., referrals to specialized consult teams) will be included.
o
Included with the algorithm will be resources for patient self-management support; ICD-10 codes to facilitate billing for symptom management services; and features to streamline clinician workflow and support interdisciplinary symptom management, such as templated progress notes and referral pathways.
o
Branching logic within the algorithms should allow for tailoring to different places on the cancer continuum from treatment to survivorship and end-of-life.
 Designing a clinical-decision support software system to deliver the algorithms to clinicians at point-of-care
o
The system will allow for the entry and encoding of the CPGs in a user-friendly manner.
o
The system will present the clinical decision workflow to the clinician using straightforward medical language in an intuitive web-based graphical user interface (GUI) on a tablet, desktop, or laptop computer.
o
The system may be developed using existing software applications that are configured and/or integrated to achieve the desired functionality, or it may be developed as a custom application. However, if the offeror proposes development of a custom application, offeror must provide compelling justification for doing so versus configuration of off-the-shelf solution(s).
o
At commercial scale, the CDS-Sx should have the capacity to interoperate with EHR systems commonly used in oncology settings (e.g. data extractable in HL7CDA or similar format) and be compliant with applicable FDA regulatory guidance for CDS software.
 Conducting iterative cycles of usability testing, CDS-Sx refinement, and user acceptance testing, with a multidisciplinary panel of clinicians, cancer patients and survivors. Clinicians should reflect the breadth of settings where cancer care is delivered, including specialty care, community-based, home-based, and primary care settings.
Activities not supported by this topic:
Applications that do not leverage national practice guidelines, do not incorporate iterative development of the computable algorithms by expert panels, and approaches that do not address the complexities of cancer symptom management (e.g. co-occurring symptoms) will be not be considered for funding.
Activities and Deliverables
Expected CDS-Sx system functionalities include:
 Presentation of the CPG content in an intuitive user interface that fits into the clinician workflow.

 Graphical user interface with branching logic that allows for the clinician to quickly select responses and arrive at
clear and specific clinical guidance for patient evaluation and management.
 Ability to make both minor and major revisions to the CDS-Sx system, such as adding new symptom management guidelines, or updating content when guidelines are revised, through the user interface and without changes to software code.
 Ability for clinician to print patient self-management materials or send them via email or text message.
Phase I Activities and Deliverables:
 Establish a project team with expertise in the areas of clinical decision-support, cancer symptom management, cancer care delivery, knowledge translation and implementation science, human factors engineering, and software design.
 Develop a replicable consensus-based methodology to synthesize and transform evidence-based guideline recommendations from their narrative prose formulation into algorithms for symptom assessment and treatment, converting the content into computable language, decision-points, and logic flows. Algorithms should reflect health IT standards, including Health Level 7 (HL7) and the Clinical Quality Framework (CQF) Initiative (http://cqframework.info).
 Develop algorithms for evidence-based evaluation and management of two symptoms (specifically, constipation and fatigue) that reflect the anticipated spectrum of algorithm complexity with respect to the number of decision nodes and separate pathways, based on prior research Algorithms for evaluation and management should be evidence-based, and should leverage symptom management guidelines and patient self-management support materials that are offered and updated regularly by organizations such as ONS, ASCO, NCCN, AHRQ, ACS, ESMO, and NCI-PDQ. Algorithms should reflect recommendations for specific pharmacological and behavioral interventions, including recommendations to initiate medications or explicit adjustments for medication doses, laboratory tests, supportive care referrals, and behavioral self-care suggestions. The curation of guideline materials into the algorithms should include an approach to annotate the material to convey the source(s) of the evidence, and to address any intellectual property issues. Algorithms must clearly address the complexities of cancer symptom management (e.g., algorithms must integrate with one another to address multiple co-occurring symptoms, and must consider the multiple factors that may aggravate and/or alleviate symptoms).
 Identify the approach and specific standards (e.g., CDISC, SDTM, and ICD) for standardization and encoding of data points in the algorithms to provide for computability and interoperability with downstream systems. At commercial scale, the CDS-Sx would allow for information to be exported into the electronic health record in a standard format to strengthen documentation, support metrics of care quality and value, and document re-evaluation of symptoms and intensification of management as warranted.
 Formalize CDS-Sx design considerations, including proposing novel features for CDS that enhance usability in busy practice settings.
 Curate patient self-management support material for inclusion.
 Demonstrate the algorithm development and curation methodology using two common symptoms (constipation and fatigue).
 Pilot test the CDS-Sx algorithms with a multidisciplinary panel of clinicians (including physicians, nurse practitioners, physician assistants, registered nurses, social workers, psychologists, and physical therapists). While the pilot test group need not be large, it should reflect the breadth of settings where cancer care is delivered including specialty care settings, comprehensive cancer centers, community-based cancer settings, and primary care. Refine the prototype algorithms in an iterative manner based on results of pilot testing.
 For the CDS-SX:
o
Specify the user requirements for the system.
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Provide an analysis of available open source, off-the-shelf (OTS) software systems, including options developed in the academic setting such as SEBASTIAN (Lobach et al 2016; JMIR Med Inform; 4 (4), e36) in terms of their suitability for use, and customization and integration requirements.
o
Recommend a design approach (i.e., custom development, integration of OTS software, or a combination).
o
Phase II Activities and Deliverables:
 Using the methodology developed in Phase I, create the assessment and management algorithms for six (6) additional symptoms (specifically pain, insomnia, nausea/vomiting, diarrhea, dermatologic toxicities, and psychological distress [anxiety and depression]).
 Specify detailed functional and non-functional requirements for the system.
 Specify technical requirements (add more detail to specification created in Phase I).
 Maintain a traceability matrix that details the relationship between user, functional, and technical requirements.
 Using the wireframe developed in Phase I build a production system CDS-Sx using an agile methodology.
 Develop test scripts for functional and user testing.
 Prior to usability testing, validate the accuracy of the CDS-Sx recommendations against the algorithms; identify and correct any logical inconsistencies or non-agreement in the symptom evaluation and management recommendations generated using the CDS-Sx employing test cases that include simulated patient data targeting boundary conditions for
each decision node and multiple branches in the algorithm’s decision logic. Documentation of successful tests must be
provided.
 Conduct preliminary usability testing with a small, diverse group of early adopter clinicians to test CDS-Sx in their clinic settings and to provide feedback to be used to iteratively improve the design, UI, and workflow.
 Conduct usability testing with a multidisciplinary panel of clinicians (i.e., including physicians, nurse practitioners, physician assistants, registered nurses, social workers, psychologists, and physical therapists), cancer patients, and survivors. The clinician testing group should reflect the breadth of settings where cancer care is delivered including specialty care settings, comprehensive cancer centers, community-based cancer settings, and primary care settings.
 Conduct final user acceptance testing with a diverse group of end-user clinicians. The sample for end-user testing should also be diverse with respect to practice site and patient population served (e.g., diverse tumor sites, radiation, medical and surgical oncology, and active treatment and survivorship), and should include clinicians in comprehensive cancer centers, community-based settings, home-based care, and primary care settings.
 Create standardized data extract (e.g., HL7 C-CDA or CDA/Progress Note) that can be imported/integrated into
existing EHR solutions (e.g., Epic).
 Present Phase II findings and demonstrate the technology to an NCI evaluation panel via webinar.
 In the first year of the Phase II contract, provide the program and contract officers with letters of commercial interest.
 In the second year of the Phase II contract, provide the program and contract officials with a letter(s) of commercial commitment.
 Create a dissemination/publication plan that outlines potential presentations at national meetings and publications
resulting from this scientific development work.

Fast-Track proposals will be accepted. Number of anticipated awards: 3-4 Budget (total costs, per award):
Phase I: up to $225,000 for up to 9 months
Phase II: up to $1,500,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
The goal of this topic is to develop mobile applications for reporting toxicities after radiation therapy, either alone or in combination with other modalities in accordance with Patient Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE). Cancer survivorship is expected to improve over the next decade. Radiotherapy plays a major role in improving survival. However, cancer registries do not collect information on treatment-related toxicities; treatment-related adverse effects after radiation therapy are not being reported accurately. Therefore, mobile apps in accordance with PRO-CTCAE provided to patients for reporting of treatment-related toxicities with an interface to hospital-managed patient databases are needed. Such mobile apps would allow early reporting of toxicities by patients to their physicians, by which clinicians could intervene to provide appropriate treatment and better designs in future patient-centric clinical trials. These mobile apps will be made available for patients’ use at radiation oncology academic research centers and radiation oncology clinics around the world. This need, when filled, will ultimately help improve treatment outcomes.
Project Goals
Improvements and access to treatments around the world will result in improved survival of cancer patients. Radiotherapy, alone or in combination, plays a major role in the treatment of cancer. Currently, treatment decisions in radiotherapy/radiochemotherapy are primarily defined by disease stage, tumor location, volume, and patient co-morbidities, together with normal tissue tolerance for surrounding organs. As there are variations in sensitivities of individual patients and tumors to radiation, a substantial number of patients suffer from severe to life-threatening adverse effects, as well as debilitating late reactions. Acute side effects (e.g., skin reactions, mucositis, etc.) are often dose-limiting, but may be reversible in contrast to the late effects such as fibrosis in the lungs and cognitive decline, which are irreversible and progressive.
Consider: 1) Treatment-related toxicities are not being reported accurately and/or adequately by patients; 2) existing cancer registries often do not capture such information; 3) clinicians often underestimate the toxicity burden among patients; and 4) there is a post-treatment health-related quality-of-life (HRQOL) discordance among patients and clinicians. In this context, PRO-CTCAE, which is a patient-centric approach necessary for reporting adverse effects, is gaining importance.
Smartphone apps have become valuable tools in health care management for many diseases, but none addresses improving
patients’ HRQOL after radiotherapy/radiochemotherapy. A mobile app that interfaces with hospital managed patient
databases, and collects and archives toxicity data will allow clinicians to interact with their patients early to provide personalized care. Further, increasingly granular data driven by patient reports will also help clinicians to design better future clinical trials with active patient participation (patient-centric) in radiation oncology. The goal is to develop a mobile app for reporting toxicities for use with iOS and Android platforms.
In Phase I the contractor will define project needs and develop requirements by “mind-mapping” (i.e., collecting information to develop ideas and concepts via creative, logical, and hierarchical means towards the specific goal of developing mobile apps for surveillance of post-treatment toxicities) expert opinions on radiation therapy-induced normal tissue toxicities in accordance with PRO-CTCAE. Treatment-related toxicities will depend on patient profile, organ/site, disease stage, tumor type, treatment, volume, location, and patient co-morbidities. Contractors may address toxicities related to the treatment of a specific organ/site or inclusive of all organ/sites. Project documentation, proposed functionalities, specifications, and technical documents are essential. Activities will also include designing the application, coding, framing, developing screens, and delivering a prototype app on iOS and/or Android platforms, and then conducting a small-scale usability test with at least 25 cancer patients.
Phase II activities will include further development, refinement, and validation of the app. Specifically, these activities are refinement of coding, based on Phase I usability testing, interfacing with databases, and integration of analytics (e.g., tracking

download numbers; identifying, reporting, and eliminating bugs; requesting features; etc), as well as introducing additional features. Such additional features may include developing a module for social networking among patients and their families to develop a support structure and assist clinicians in designing patient-centric clinical trials. Contractors must validate the product with an expanded “large-scale test” with the appropriate radiation therapy patient groups of interests and identify potential customers for marketing. The number of patients required for validation should be determined in consultation with a biostatistician and proposed to NCI by the offeror.
Activities not supported by this topic:
Any proposal that does not address specific goals of addressing normal tissue toxicity induced by radiation therapy alone or in combination with other treatment modalities will not be considered for funding.
Phase I Activities and Deliverables:
Develop application requirements and proto-type in iOS and/or Android platforms.
 Establish a project team, including expertise in: mobile app development, radiation oncology specific to the treatment of at least one anatomical tumor location/site, and relevant adverse effects related to a specific tumor site or all sites. Demonstrate verifiable knowledge and design of systems architecture, health IT interoperability, data security and HIPAA and other laws and regulations to protect privacy and confidentiality of patient information will be essential.
 Conduct a focused workshop with appropriate key opinion leaders (consisting of no more than 12 experts) to deliver a definitive list of reportable normal tissue toxicities in accordance with PRO-CTCAE. The list should attribute toxicities based on pre-defined patient profiles, a specific disease site or multiple sites, disease stage, tumor and treatment type, treatment volume, patient co-morbidities, etc.
 In consultation with NCI, develop requirements for mobile application(s).
o The app must be able to assist clinicians to better design patient centric future clinical trials.
 Deliver project documentation – functionalities, specifications, and technical documents.
 Create application design, framing, screens, and coding.
 Deliver product requirement documentation to NCI.
 Develop a prototype mobile application on the iOS and/or Android platforms.
 Design app to address potential users including radiation oncology/cancer clinics, academic/research/clinical centers,
individuals within healthcare systems, health insurance companies and health IT departments.
 Perform small scale usability testing with at least 25 cancer patients.
[Note: The offeror may be required to be meet compliance with HIPPAA privacy act policies.]
Phase II Activities and Deliverables
Develop and refine applications for use in iOS and/or Android platforms.  Refine coding, interface with databases, and introduce features and functionalities.  Refine the prototype based on Phase I usability and internal testing results.  Integrate analytics (to track downloads, identify bugs, opportunities to improvise, etc.).  Introduce and refine features, and eliminate bugs.  Validate the product with an expanded testing with a larger cohort for adverse effects related to the treatment of a
specific tumor site or all tumor sites.
 Product features could also allow social networking to develop support structure among patients and their families
based on patient-reported symptoms.
 Provide letters of interest from potential customers.
 Provide letters of commitment to purchase the product from customers.

 Provide letter of acceptance of the product by the iOS and/or Android platforms.
 The offeror will be required to be meet compliance with HIPPAA privacy act, IT security, and compliance policies.

Fast-Track proposals will be accepted. Number of anticipated awards: 2-3 Budget (total costs, per award):
Phase I: up to $225,000 for up to 9 months
Phase II: up to $1,500,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
The rapid adoption of wearable and external sensing platforms since 2015, by the consumer health market, has paved the way for similar platforms to act as objective measures for continuous, out of clinic, cancer research and patient assessment. The passive, continuously measured data streams generated by current or future physical and chemical/biological sensors will allow direct/indirect measures of cancer progression and its symptoms. Increased out-of-clinic patient and clinician engagement via these tools will allow more precise delivery of cancer care during treatment, as well as during cancer remission. Ultimately, these passive sensing platforms of digital biomarkers will afford clinicians: 1) more objective metrics of response to therapeutics; 2) control and auto-reporting of symptoms and their fluctuations; 3) monitoring of side-effects of experimental or standard of care therapies; and, 4) more ecologically valid clinical endpoints, all decreasing assessment burden via increased continuity of physiological measurement sampling and patient context, outside of the standard clinical visit.
Near real-time analytical capabilities, such as these devices offer, represent an opportunity to measure population based statistics from large cohorts of cancer patients from a myriad of devices currently available or being developed. From vital signs, activity, or non-invasive patch based measures of biochemistry from bodily fluids to external monitoring of environment, these tools will offer a more complete picture of patient performance status, fatigue, other symptoms, cachexia, and patient monitoring (e.g., drug metabolism, toxicity, adherence, or side effects) during clinical trials, in convenient small form factors with the ability to auto-report these data for research purposes or informed clinical assessment of patients outside of the clinic.
In order to ascertain the potential of these tools for more precise delivery of cancer care and patient monitoring, much clinical cancer research must be performed to understand sensor measurement versus cancer progression and patient context outside of the clinic. As much of the power of these technologies lies in their ability to offer a granularity not seen before in patient specific data, the research to advance this to the clinical setting will rely on either existing commercial tools already or research grade platforms not yet translated. Moreover, as any one wearable sensor-specific parameter will unlikely allow for both patient physiology and context in which the measurement was taken, multiple devices and subsequent parameters will be necessary to enable commercialization of more targeted and specific devices for clinical cancer care or assessment.
There is a considerable need for scalable informatics tools that allow automated data aggregation, integration, and machine learning algorithms that can pull from disparate data sets across device vendors and have the flexibility to add new measures as they are developed. Furthermore, a central software platform that could obtain wearable, implantable, or external device data and uniformly compare/contrast/couple data streams to understand physiology versus patient context with respect to time will advance this unique approach to aid cancer patients, clinician assessment, and clinical trial design. This topic is in line with the Cancer Moonshot Blue Ribbon Panel’s Recommendation to support Symptom Management Research.
Project Goals
The goal of this solicitation is to advance the development, and subsequent commercialization, of scalable informatics tools and resources for their broad adoption across the burgeoning clinical cancer research applications that continuous, passive monitoring of multiple biological parameters via wearable platform technologies are beginning to be used. A limitation to their current use in cancer research is that device manufacturers and platform technology developers do not utilize identical data sets/standards, and no resources are available to easily assess large multiparameter data sets via traditional

bioinformatics methods. As such, the primary focus of this contract topic is on data agnostic informatics tools and resources that can be adopted easily in the cancer research communities for cohort studies involving their monitoring platform(s) of choice to understand their specific research problem/patient cohort of choice. Informatics tools include mobile apps for sensor data retrieval; computer software tools and platforms to aggregate, integrate and organize data streams from multiple devices; and machine learning-based informatics platforms for subsequent interpretation of integrated data streams derived from a myriad of continuous passive monitoring devices that could be used by cancer researchers. The informatics resources include sensor and patient data repositories and platforms that provide data, workflow, and a workspace for online research collaboration, evaluation as well as dissemination of informatics tools and resources, and support for population-based research.
The overall scope of the topic includes the entire spectrum of passive continuous monitoring devices being commercialized or developed, extending from wearable sensor platforms and implantable devices to external monitoring devices for all phases of cancer clinical research. Offerors will be expected to propose well-designed project plans with clearly defined milestones that will eventually lead to commercially viable solutions for: 1) sustained development and evolution of passive continuous monitoring platform informatics tools and resources; and, 2) their broad adoption in clinical cancer research.
Activities not supported by this topic:
 Tools that do not allow the integration and subsequent interpretation of a myriad of current wearable sensor platforms,
simultaneously, or that rely solely on inertial sensing type wearables.
 Tools that are not scalable to future wearable, implantable or external out of clinic monitoring tools.
 Tools that do not incorporate safeguards to protect privacy and confidentiality of information.
 Design approaches that don’t account for scalability, interoperability or user-centered design.
 Approaches that don’t plan for using tools in diverse sites and IT systems.
Phase I Activities and Deliverables
 Establish a project team including proven expertise in: sensor technology for physiological monitoring, wireless sensor integration with mobile devices, secure wireless transport of health data using standards based protocols, secure cloud computing models, bioanalytical technologies, epidemiology, biostatistics / bioinformatics, and systems architecture.
 Provide a report including a detailed description and/or technical documentation of proposed:
o
Development of bioinformatic methods or algorithms (e.g., machine learning, etc.) for wearable sensor data integration across data inputs from diverse wearable bio-/sensor platforms, including harmonization of data of the same biometric from different vendor device platforms;
o
Evaluation of wide range of wearable, implantable, and external sensors platforms that would be of legitimate use for out of clinic patient monitoring and/or understanding disease/symptom progression (e.g., therapy-induced fatigue, patient performance status, cachexia, experimental therapeutic side effects or toxicity, etc.) vs. the myriad of potential physical and / or physiological factors;
o
Database structure for the proposed system's chem-/bio-/physical sensor based data inputs and metadata requirements;
o
Database formats that support the import and export of individual datasets and coalesced datasets, store structured data from different sources of wearable sensor data, and are readily used for data integration and QC protocols;
o
Specific approach to QC;
o
Technology compatibility matrix for Phase I and Phase II wearable sensor data sources by platform, sensor type, sensor technology, and differing device data streams as well as and back-end server systems to be developed;
o
Data visualization, feedback, and reporting systems for population or clinical monitoring and research applications;
o
Data integration approaches to leverage multiple data input streams;
o
Data types for exchange of physiological-metrics between mobile platforms and secure servers;
o
Data standards for transfer and importation of individual wearable sensor data and storage of individual and coalesced wearable sensor data;
o
Transparent, documented, and non-proprietary bio-/informatic methods; and

o
Description of additional software and hardware required for use of the tool.
 Provide wireframes and user workflows for proposed Graphical User Interface (GUI) and software functions that;
o
Support the import and export of individual datasets and coalesced datasets;
o
Implement, script, or automate all features and functions of the data integration tool(s); and
o
Conduct QC of coalesced datasets.
 Develop a functional prototype system from planned Phase I compatibility matrix that includes:
o
Front-end mobile applications to facilitate and control the collection and transport of multiple wearable chem/bio-/physical sensor data inputs and any associated metadata used within the system;
o
Integration with several wearable chem-/bio-/physical sensor;
o
Automated data screening algorithms and importation protocols for data transferred from the mobile application to the back-end server systems;
o
Software systems GUI (web-or computer-based);
o
Software tools as mobile and web applications;
o
Back-end user-interface controls for custom data integration and visualization for individual or group-level data; and
o
Finalize database formats and structure, data collection, transport, and importation methods for targeted data inputs.
 Present Phase I findings in a detailed report and demonstrate the final prototype to an NCI evaluation panel.
Phase II Activities and Deliverables
 Expand the informatic methods to include other research grade sensor data points or streams, in addition to already identified commercialized wearable sensor data, and demonstrate data integration across inputs from diverse sensor platforms.
 Demonstrate database integration capability to collect data from four different parameters and collected from three distinct wearable device platforms, as well as to be adaptable to at least 20 more current, or future, platforms designed for physiological or objective measurements of patients outside of the clinic.
 Participate in validation and scale-up between the offeror, NCI, and/or NCI-identified third party sources to access relevant input data types for the proposed project. Validation within established cohort studies with wearable sensor data (e.g., pre-identified analytes of use to monitoring of syndrome-specific therapeutics, patient fatigue, or similar cancer cachexia-specific physiological metric, etc.) will serve: 1) to train and validate the expanded bioinformatic methods; and, 2) to demonstrate the application of these methods through scalable software to automate complex data integration tasks for wearable sensor data sources.
 Beta-test and finalize front-end mobile applications developed in Phase I.
 Beta-test and finalize automated file transfer, screening, and database importation protocols and systems.
 Perform regression testing for both front-end and back-end system functions.
 Demonstrate usability of scalable software through the following:
o
Beta-test and finalize automated file transfer, database importation protocols, wearable biosensor data integration applications and reporting tools developed in Phase I;
o
Develop beta-test, finalize, and demonstrate the GUI; and
o
Demonstrate the software systems ability to integrate data from planned Phase II technology compatibility matrix data sources using automated algorithms and analytic methods.
 Conduct usability testing of the GUI elements of the sensor-specific data integration tool(s).
 Conduct usability testing of consumer/patient-facing mobile applications and any associated web portals and care team/researcher-facing user interface features including system management, analyses, and reporting applications.
 Develop systems documentation to support the software and informatic methods.

 In the first year of the Phase II contract, provide the program and contract officers with a letter(s) of commercial interest.  In the second year of the Phase II contract, provide the program and contract officers with a letter(s) of commercial commitment.

Fast-Track proposals will be accepted. Number of anticipated awards: 2-3 Budget (total costs, per award):
Phase I: up to $225,000 for up to 9 months Phase II: up to $1,500,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
Radiotherapy, both with or without systemic therapy, is administered to over half a million patients annually in the United States alone. The decision regarding what kind of radiotherapy to employ (e.g., Intensity Modulated Radiation Therapy, Proton therapy, Stereotactic Body Radiation Therapy, etc.) and which, if any, drugs to add to radiotherapy for a patient are usually based upon rather crude criteria (e.g., age, TNM stage, histological grade, etc.) that frequently fail to accurately predict the outcome of the treatment administered. Better tools are needed to improve decision-making and thereby decreasing both over and under-treatment.
For more than two decades, almost every patient treated by radiotherapy in the United States has undergone a “treatment planning” CT scan; some patients also undergo MRI or PET scans in addition to CT scans. Recent advances in image analysis, pattern recognition, and data characterization enable high throughput extraction of quantitative imaging features from these images. This emerging field of imaging studies (“Radiomics”) allows us to quantify various tumor phenotypes that can be visualized non-invasively by analyzing numerous imaging features such as tumor shape, boundary features, tumor size, texture, uptake or density distributions, etc. These data can be combined with other patient data and be mined with sophisticated bioinformatics tools to develop models that may improve diagnostic, prognostic, and predictive accuracy.
Radiomic tools thus could be used with treatment planning CT and other scans to extract a treasure trove of information that by using the right tools/algorithms could help greatly improve decision making in radiotherapy. This topic is in line with the
Cancer Moonshot Blue Ribbon Panel’s Recommendation to support Development of New Enabling Cancer Technologies.
Project Goals
Radiomic studies for lung cancer using CT and FDG PET images have shown that tumor image features and parameters can describe the nature of disease and predict patient outcomes. Other localized diseases such as brain, breast, kidney lung, liver, and esophageal cancers have also been analyzed with different imaging modalities such as FDG PET, CT, MRI, and ultrasound. Studies have shown that Radiomics has the potential to impact clinical care by contributing to cancer diagnosis, assessing tumor prognosis, assisting in biopsy decision and helping to select the right chemotherapeutic regimen. Computer aided diagnostic tools are being developed for diagnostic radiology but so far the tools for radiotherapy decision making remain sparse. Radiotherapy treatment prescription involves:
1) selecting the type of radiation (e.g., 3-dimensional conformal RT, Intensity modulated RT, Stereotactic body RT, Stereotactic radiosurgery, Proton RT, Carbon ion RT, Low dose rate brachytherapy, High dose rate brachytherapy, etc.); 2) selecting drugs that can enhance the effects of radiation on tumors (e.g., cisplatin, temozolomide, cetuximab, mitomycin, gemcitabine, etc.); 3) selecting drugs that can decrease the effects of radiation on organs-at-risk (e.g., amifostine, memantine, etc.); and, 4) selecting the total dose of radiation, the dose per fraction, the number of fractions of radiation, the sequencing of those fractions with the drugs, etc.
At present the radiotherapy prescription is too often "one size fits all" and based upon relatively rudimentary criteria such as age, TNM stage, and histological grade. Studies that explore the utility of radiomics have indicated that the use of image analysis tools will help refine and personalize cancer decision-making, thereby increasing tumor control and decreasing adverse effects. Furthermore, their use may facilitate more robust "mid-course corrections" (i.e., adaptive therapy), since CT

scanning for readjustment of radiotherapy treatment plans is often repeated during a course of radiotherapy on account of weight loss or tumor shrinkage.
The short-term goal of this contract topic is to develop new approaches and refine existing “radiomics” tools for radiotherapy treatment planning images to enable more accurate decision making support for radiation therapy treatment planning. These can include (but are not limited to) the following:
 Selection, extraction and qualification of imaging features.
 Integration with clinical, molecular and other “omics” data.
 Novel data mining and analysis methodologies to handle the enormous amount of data.
 Testing and validation of those tools in datasets from single-institutions, multi-institutional clinical trials and/or
clinical practices).
 Testing differences in treatment plans and their outcomes using radiomics tools vs standard of care plans. It is expected that the proposed innovation will be driven by clinical practice. Therefore, in addition to standard proposal components; the contract proposal must contain specific discussion of the target patient population and evidence of an existing clinical problem which is addressed by the proposed method. The proposal must also contain an analysis of competitive methods to address the same problem and an explanation of competitive technical advantages of the proposed algorithm. All Phase II or Fast-Track proposals MUST contain a section entitled “Regulatory Plan” that 1) demonstrates an understanding of the regulatory requirements for clearing the software device through the FDA, if appropriate; 2) details the
company’s plan to meet the requirements, and 3) explains how the proposed work helps to meet these requirements. If
regulatory approval is not expected to be required, the offeror must provide an extensive justification for this. The long-term goal of this program is to eventually commercialize an image analysis software toolkit for decision support in radiation oncology.
Activities not supported by this topic:
Development of algorithms for image acquisition and/or routine image processing tools is not appropriate for this topic and will not be considered for funding. Development of computer aided diagnosis/detection systems not intended for radiation oncology are also not appropriate and will not be considered for funding.
Phase I Activities and Deliverables
 Select radiomic features that are suitable for the proposed organ site and imaging modality (such as treatment planning CT) for improving treatment plans and/or their modification during therapy.
 Develop appropriate tools and algorithms to extract the features from the images, characterize the data and assess the stability of the features. These may be developed de-novo or adapted from sources such as Pyradiomics and other QIN developed tools, but with a focus on developing tools that would be more specific to radiation oncology. Combinations with other validated outcome measures (such as genomic and specific cancer type phenotype profiles) to make treatment planning more comprehensive are encouraged.
 Use the obtained radiomics data from treatment planning CTs (and other scans) to develop models for treatment plans and predict outcomes in radiation oncology.
 Test the models for differences in treatment plans and/or their outcomes using appropriate training data sets.
 The company must obtain feedback from radiation oncologists at a minimum of 3 different institutions regarding user specifications and clinical need. This input must be included as part of the technical specifications of the product.
 Testing and validation of the software tool on a small subset of clinical images to demonstrate feasibility.
Phase II Activities and Deliverables
 Validate the software using a validation data set.
 Perform the required clinical studies as required by FDA for approval as a stand-alone decision support tool or as a package.
 Present Phase II findings and demonstrate the final prototype to an NCI evaluation panel via webinar.

Fast-Track proposals will not be accepted.
Number of anticipated awards: 2-3
Budget (total costs, per award):
Phase I: up to $225,000 for up to 9 months
Phase II: up to $1,500,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
The goal of this topic is to see if Artificial Intelligence (AI) technology can be used to improve treatment planning for prostate cancer by developing algorithms to “read” standard Computerized Tomography (CT) images in context with clinical information and recommend suitable treatment plan approaches. The resulting tool may aid radiation oncologists in reaching unbiased consensus treatment planning, help train junior radiation oncologists, update practitioners, reduce professional costs, and improve quality assurance in clinical trials and patient care. Treatment planning for radiation therapy has become increasingly complex with the advent of image-guided radiation therapy and charged particle therapy. A substantial amount of physician time and effort are required to contour key tumor and normal tissue structures. The process involves assessing the patient’s risk for disease progression based on tumor volume; histological grade and biomarkers (e.g., prostate specific antigen or other tests); and assigning one of three risk groups as defined in the National Comprehensive Cancer Network (NCCN) guidelines: low, intermediate, or high. See NCCN guidelines here: https://www.trikobe.org/nccn/guideline/urological/english/prostate.pdf. Radiation treatment will use external beam radiation with or without androgen deprivation. Imaging uses CT and often magnetic resonance imaging. Based on these, the physician and medical physicists plan the target volume to be treated, radiation dose, and normal tissue to be spared. In practice, treatment guidelines are established by consensus papers. However, proposed plans among even world renowned experts often differ.
Thus, it may be possible to go beyond verbal consensus text and understand the rationale among expert “preferences” in
treatment plans by using AI-based contextual image analysis that uses feature extracting algorithms and/or interactive machine learning to formulate treatment plan. Such an approach would provide an initial plan to the physician upon which to facilitate treatment planning, build consensus, and help understand expert thinking.
Project Goals
The goal of this contract topic is to develop and evaluate the concept that AI can be used to understand and duplicate experts’ radiation therapy planning. The purpose is to understand how human cognition performs in work, focused in the context of developing radiation therapy treatment plans, and then incorporate such an understanding into machine learning with the intent to automate treatment planning to reduce subjective biases, improve treatment quality, and reduce cost. This contract topic does not intend to achieve a breakthrough in AI technology. The objective is to integrate recent advances in treatment planning systems and machine learning to improve radiation therapy by eliminating repetitive, time-consuming, and subjective biases in treatment delivery. Subjective biases could result in normal tissue injury and compromise therapeutic
benefit. Machine learning approaches may involve extraction of relevant features from “consensus image datasets” of expert
medical teams and then applying them to train machines with an initial focus on prostate cancer. The broad and highly impactful goal is to improve the outcome for patients with prostate cancer. By developing knowledge-based planning solutions, it may be possible to provide a more standardized treatment at a significantly lower cost. This may facilitate quality assurance, possibly extending it to facilities with limited expert personnel and enabling the conduct of research by reducing the variability and potential arbitrariness and/or preference that individuals incorporate in their treatment design. The goal of this project is to encourage creative small businesses to design, develop, and build approaches to AI-based treatment planning systems to improve radiation therapy. Progress here could be applied to other disease sites.
Activities supported by this topic:
Proposals that develop AI software that only outlines tumor and normal tissues but does not select a treatment plan for the three risk groups will not be considered for funding.

Phase I Activities and Deliverables
 Establish a project team to develop an AI tool to understand and improve treatment planning for prostate cancer, comprising of cross disciplinary expertise. This cross disciplinary expertise will require proven expertise in AI, application development, radiation treatment planning for prostate cancer, IT experience in a healthcare setting, data security, HIPAA, and other laws and regulations to protect privacy and confidentiality of patient information.
o
Choose one expert radiation therapy planning team comprising of a physician and planners (i.e., a person who is knowledgeable in treatment planning with good understanding of the treatment planning system) and evaluate expert cognition process in developing treatment planning strategies for all three strata of patient risk groups (i.e., low, intermediate, and high based on NCCN guidelines).
o
Note: For Phase II, three independent teams will be required so that there can be comparison between expert teams using the same set of cases.
 Identify criteria used by an expert planner to develop each treatment plan for each risk group (i.e., low, intermediate, and high NCCN).
o Based on the expert planning methods, develop an AI based planning process including feature extraction. Existing algorithms could be used for feature selection. Expected innovation is in using AI for treatment planning. Plan will use external beam radiation, fields to be determined by expert team, with or without androgen deprivation therapy per expert’s discretion. Other forms of treatment will not be considered for this project.
 Design and develop computational algorithms/methods aimed at improving treatment planning for prostate cancer
patients.
 Propose plan to develop, incorporate, and compare the AI methods with expert treatment planning methods and
validate AI based treatment planning system.
o There should be a minimum of 10 patients per risk group or a suitable number that the research team feels is sufficient for the AI algorithm to begin the initial planning. Provide justification for the selected number of patients. Retrospective de-identified data could be used for this purpose.
 Present AI concept to develop knowledge based radiotherapy treatment planning to NCI’s SBIR Development Center
and the Radiation Research Program.
 Design and deliver an AI approach to improve radiation therapy planning for prostate cancer to be tested in Phase II.
 Present an estimate of the number of training and validation sets that would be needed for each of the risk groups so that the AI results can provide a starting point for the planning team to refine the initial plan and determine the final course of treatment.
o Establish a set of patient records for the three risk groups to be used in Phase II among the 3 expert teams.
 At a minimum, apply this technology to standard 3D CT datasets. Use of additional imaging is at the preference of the planning team.
Phase II Activities and Deliverables
 Refinement of algorithm based on the results of Phase I.
 Demonstration of utility of AI plan as the initial step to be reviewed and then modified by the planning team.
 Establish sufficient cases in each of the three treatment categories for the comparison among expert groups, based on Phase I deliverables.
 Expand to a minimum of three independent expert treatment planning teams and have each expert team plan the 3 risk
groups. There will be 3 consensus reviews: a) comparing the plans among the 3 expert panels done by the “standard”
hands-on approach; b) comparison of the 3 AI produced plans; and, c) an analysis of how the hands-on and AI based
plans differ.
 Compare the consensus approach of the expert hands-on plans to the consensus among the AI plans to see where there was agreement or disagreement and see if this difference can be understood and rectified. This would enable the AI to refine its algorithm.

 Evaluate developed AI software to see if it can match the performance of the expert teams (each team would have 3 categories of patients). Examine differences and present plans to refine the performance of the AI.
 Expand types of data sets to include MRI or PET or other sources of data that would improve AI’s performance. Establish external partnership(s) for future validation of method, as demonstrated with letters of intent from strategic partners.

Fast-Track proposals will be accepted.
Number of anticipated awards: [1-2 Phase I, 1 Phase II]
Budget (total costs):
Phase I: $400,000 for 12-18 months
Phase II: $3,000,000 for 24-36 months
It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.
Summary
This solicitation will develop an ensemble of devices to enable a broad array of novel catheter treatments for structural heart disease in adults and children. These devices will deliver and secure sutures inside the beating heart without surgery and promise a dramatic impact on cardiovascular therapeutics.
Project Goals
The goals are to develop and test a collection of independent catheter devices for transcatheter electrosurgery procedures to treat adult and pediatric structural and congenital heart diseases without surgery. NHLBI has demonstrated the preclinical feasibility of such procedures including pledgeted suture annuloplasty, but commercially available tools are poorly suited for these applications in humans because of features including inadequate length, flexibility, radiopacity, and caliber. The devices are all variants of standard surgical tools specially adapted for application through flexible catheters under conventional imaging guidance including conspicuous sutures and pledgets, deflectable catheters for directing guidewires, knot pushers and lock devices to deliver and secure stitches under tension. Together this group of regulatory Class I or Class II tools would enable a wide range of novel but attainable non-surgical interventional cardiovascular procedures such as intracameral suture annuloplasty, valvular leaflet repair, and extraanatomic bypass.
Phase I Activities and Expected Deliverables
A phase I award would develop and test working prototypes in swine. The contracting intramural laboratory wishes to test the final prototypes in vivo, and offers one no-cost testing round to the contractor if desired.
Below is a list of individual devices which are part of the suite, along with specific requirements. The devices must be able to function alone or together as components of the multifunctional suite.
1. Radiopaque sutures
a.
Must be visible in vivo under fluoroscopy and echocardiography
b.
MRI compatible although a small susceptibility artefact may be desirable to impart visibility.

c.
Exhibits mechanical and biological properties (tensile strength, strength retention, tissue reaction/thrombogenicity) similar to a commercial comparator known to perform satisfactorily (size O Ethibond EXCEL suture). Smaller caliber alternatives may be considered with appropriate justification.
d.
Preferred embodiments have different colors to each half, to simplify tying
e.
Minimal length 240cm
f.
Non-absorbable
g.
Hemocompatible
2. Guidewire to suture ‘connector’
a.
A low-profile device the can securely connect a 0.014” coronary guidewire to the radiopaque suture (item #1) with smooth transition, to allow the operator to pull one end of the guidewire in order to exchange for the suture through and across tissues through catheter devices. The connector “transition” must allow safe and reliable traversal of fibrotic annular structures.
b.
Must resist unlocking at high (>20N) forces
c.
Novel docking or crimping or connecting solutions are welcome
d.
May be integrated directly onto the suture.
e.
A preferred solution can pass through a 0.038”-compatible catheter lumen
f.
Hemocompatible
3. Catheter knot pusher
a.
A low-profile catheter device that can deliver a half-hitch or superior non-sliding suture along a transcatheter intracameral trajectory
b.
Length at least 110cm
c.
Must be able to pass through a fully deflected Abbott St Jude Agilis SML curl deflectable sheath 8.5Fr, and preferably would also pass curved coronary guiding catheters 8Fr to deliver a knot along two radiopaque sutures (item #1 above) and alongside one or more 0.014” guiding catheters
d.
Must be designed to allow tension to be maintained on the rail suture during delivery of each hitch
e.
A preferred embodiment would have a safety feature to enable the operator to loosen the knot.
4. Radiopaque felt or fabric pledgets
a.
Intended to allow sutures to apply focal tension to cardiovascular tissue without pull-through, including myocardium, annular tissue, and valvular leaflets
b.
Must be visible in vivo under fluoroscopy and echocardiography. The visibility maybe imparted focally using metal markers, or diffusely.
c.
MRI compatible although a small susceptibility artefact may be desirable to impart visibility.
d.
Must exhibit equivalent mechanical and biological properties to Ethicon Teflon Pledgets, ref PCP-20
e.
Hemocompatible
5. Deflectable steering catheter
a.
Intended to guide at least one 0.014” guidewires traversing myocardial, annular, and leaflet tissue.
b.
A preferred embodiment has a mechanism to deliver precisely a second traversing guidewire a known distance (4-10mm, preferably adjustable) defined proximity to the first traversing guidewire.
c.
Preferred embodiments are deliverable through a 2.8mm inner diameter curved guiding sheath
d.
Preformed with at least two embodiments: one fixed curved such as a multipurpose-curve catheter, another curved with a 180-to-235-degree retroflex curve catheter, to allow apposition to both sides of valve annulus from transvenous, transarterial, transseptal, and transapical access routes. Preferred embodiments are deflectable up to 235-degrees/
e.
Must be conspicuous under fluoroscopy and under ultrasonography.
f.
Mechanical properties: resembling coronary guiding catheters or deflectable guiding sheaths to allow delivery of two commercial rigid 0.014” effector guidewires (with mechanical characteristics resembling Asahi Astato XS-20 guidewires).
g.
Hemocompatible
6. Adjustable transcatheter suture lock
a.
Allows secure and permanent locking of the pledgeted suture under tension
b.
Allows adjustment of tension, reversal or tension, and full retrieval after application
c.
The design prevents loss of suture tension during application
d.
Visible under X-ray and echocardiography
e.
MRI compatible although a small susceptibility artefact may be desirable to impart visibility.
f.
The lock delivery system need not be MRI compatible.
g.
Biocompatible and hemocompatible

h.
Must fit through 8.5Fr Agilis sml curl deflectable sheath during full deflection and alongside one or more O sutures and one or more 0.014” guidewires
7. Transcatheter Suture cutter
a.
Must cut suture through an 8.5Fr Agilis sml curl fully deflected, alongside one or more 0.014” guidewires
b.
Must have effector visible under X-ray and preferably also under ultrasound
c.
Must effectively cut the accompanying sutures in this suite
Phase II Activities and Expected Deliverables
In addition to meeting all requirements for Phase I, a phase II award would allow commercial introduction of the suite of tools together or independently as 510(k) devices substantially equivalent to marketed predicate devices. If this is not feasible, the phase II deliverable would be all testing and regulatory development for the device to be used in human investigation in the United States, under Investigational Device Exemption, along with devices sufficient to test in 30 human subjects.
The contracting DIR lab offers to perform an IDE clinical trial at no cost to the awardee. Complete IDE documentation and license and a suitable supply of clinical materials would constitute the deliverable.

Fast-Track proposals will be accepted.
Number of anticipated awards: [1 Phase I, 1 Phase II]
Budget (total costs):
Phase I: $200,000 for 12 months
Phase II: $2,000,000 for 24 months
It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.
Summary
The solicitation will support the small business development of specific guidewire devices to ease and simplify transcaval access to the aorta, to make the procedure available to a wider range of patients and operators.
Project Goals
The goals are to develop and commercialize specific tools to simplify transcaval access to the aorta. The tools are a tapered guidewire and a connector-switch to a common electrosurgery generator. These will greatly simplify transcaval access procedures, reducing the required operator skill, making the procedure more accessible to a wider array of patients and operators, and reduce the cost of the procedure.
Phase I Activities and Expected Deliverables
A phase I award would develop and test a suite of working prototypes in swine. The contracting intramural laboratory wishes to test the final prototype in vivo, and offers an earlier stage test to the contractor at no cost.
Below is a list of individual devices which are part of the suite, along with specific requirements. The devices must be able to function alone or together as components of the multifunctional suite.
8. Tapered transcameral guidewire
a.
Intended to cross a vascular or chamber wall with a 0.014” tip and then seamlessly transition to a rigid 0.35” shaft
b.
Preferred embodiments have a long continuously tapered core, a lubricious and electrically insulating coating except at the tip.
c.
Tip mechanical properties must resemble Asahi Astato XS 20 guidewire
d.
Shaft mechanical properties must resemble Cook Lunderquist guidewire

e.
Approximately distal 10cm is 0.014”, approximately next 20-30cm is tapered, remainder of wire has 0.035” outer diameter. Total length is 2.6-3m
9. Electrosurgical connector
a.
Serves to replace a Bovie electrosurgery pencil connector to a guidewire, otherwise accomplished using a forceps
b.
Connects to the back end of a 0.014” and 0.035” guidewire, such as using a screw-type friction clamp
c.
Connects to a conventional electrosurgery generator such as Medtronic Valleylab FX
d.
Allows controlled actuation only of the “cutting” switch
e.
A preferred embodiment allows a preset time-limit to individual actuations for each button press, such as 1second timeout, before the button is again depressed.
f.
A preferred embodiment also has a switch lockout to assure no inadvertent actuation
Phase II Activities and Expected Deliverables
In addition to meeting all requirements for Phase I, a phase II award would allow commercial introduction of the suite of tools together or independently as 510(k) devices substantially equivalent to marketed predicate devices. If this is not feasible, the phase II deliverable would be all testing and regulatory development for the device to be used in human investigation in the United States, under Investigational Device Exemption, along with devices sufficient to test in 30 human subjects.
The contracting DIR lab offers to perform an IDE clinical trial at no cost to the awardee. Complete IDE documentation and license and a suitable supply of clinical materials would constitute the deliverable.

Background
Despite the widespread use of GMP-established pharma cell substrates (e.g., CHOs, 293 etc.) in development of recombinant HIV Env protein antigens, critical bottlenecks still exist in their use for large-scale, high-yield GMP manufacturing; yields often are on the order of mg/L compared to mAbs at gm/L. Some of the limitations relate to their intrinsic incapacities to metabolically produce high levels of stable properly folded, properly glycosylated recombinant HIV Env protein, often times requiring extensive clonal screening to identify the rare high-level producer clone. These constraints have a cascading effect in increasing the overall cost and time for production of HIV vaccine antigens from millions of dollars and years of upstream and downstream process development. As such, there is an urgency to evaluate alternative strategies/technologies capable for developing highly productive cellular substrates suitable for high yield GMP manufacturing of HIV antigens and reduced product development lead times. Traditional downstream purification processes for HIV Env purification are equally plagued with similar inefficiencies either requiring expensive lectins or multi-step purification cycles resulting in low yields. Alternative approaches to HIV Env purification are needed to improve yields and expedite the overall purification process and costs.
Project Goals
The objective is to evaluate and modulate the molecular pathways involved in regulating and enhancing HIV envelope/antigen expression in mammalian cell lines and to accelerate development of purification platforms in a CGMP manufacturing setting. Key areas of support will include, but are not limited to, the following:
Phase I activities may include the following non-CGMP activities:
 Exploration of methodologies to improve HIV Envelope protein expression in mammalian cell substrates. The following approaches may include: alteration of codon usage, improvements in expression cassettes including the use of novel selection markers or other selection approaches, evaluation of Env mRNA sequence
 Exploration of methodologies to improve of existing cell substrates by removal of deleterious proteases, targeting of genes involved in glycosylation, improved secretion or other post-translational modifications that enhance yield and/or stability, or removal of endogenous retroviruses.
 Methodologies to improve HIV Env expression or cell substrates can include traditional gene modification approaches as well as novel technologies such as siRNA and/or CRISPR/Cas9 gene targeting.  Development of strategies to accelerate phase appropriate manufacturing including transient transfection or stable cell pool approaches for HIV Env GMP manufacture  Improvement of HIV envelope downstream protein purification methodologies including affinity purification approaches or other strategies.
Phase II activities may include the following CGMP activities:

 CGMP development of the improved Cell Substrates explored in Phase I, including additional IND-enabling
characterization studies, development of technical reports, generation of MCB, etc  CGMP Process Development of the improved Downstream purification methodologies developed in Phase 1, including
technical reports, development of scale-up approaches, etc.

Fast Track proposals will be accepted Number of anticipated awards: 2-3 Budget (total costs):
Phase I: $300,000/year for up to2 years
Phase II: $1,000,000/year for up to 3 years
Background
Development of improved drug regimens to shorten treatment for MDR and DS TB and improve tolerance and safety is an extremely high research priority. Clofazimine is a drug approved decades ago for treatment of leprosy. Animal studies of the drug for TB treatment indicate that it may significantly reduce treatment duration, particularly in combinations including
PZA. The effectiveness of the “Bangladesh” regimen provides support that inclusion of CFZ in MDR regimens may shorten
treatment from 18 to 9-10 months, at least in populations with a low rate of resistance to other MDR drugs.
However, tolerance to orally administered clofazimine is often limited by skin discoloration and GI adverse events. In addition, CFZ substantially increased the QT interval. Inhaled delivery offers the potential to bypass these barriers while still maintaining effectiveness in the lungs by achieving high drug concentrations in the infected pulmonary tissue with lower systemic exposure, thus allowing increased immediate potency. A published study of inhaled delivery of a microparticle formulation of CFZ in a mouse TB model demonstrated that inhaled CFZ reduced lung CFUs much more substantially at 4 weeks than similar doses given by gavage. Given these potential benefits, an easy-to-use inhalation delivery system for CFZ would represent a significant advance in the treatment of tuberculosis. Though anti-tubercular drugs have been formulated into aerosolized particles by multiple research groups and numerous papers are available in the literature on formulating inhaled therapies for TB, no formulation has yet to be commercialized.
Project Goal
The goal of this solicitation is to develop an inexpensive, easy-to-use, inhaled delivery system for clofazimine to be used with combinations of systemic anti-tubercular drugs to improve the treatment of MDR and DS TB.
Phase I activities
1.
Development of an inhaled formulation of clofazimine.
2.
Development of an inexpensive, hand-held, self-contained platform for delivery of this formulation.
3.
Initial testing to quantitatively assess for drug efficacy, toxicity, and pharmacokinetics including required in-vitro studies.
Phase II activities
1.
Preclinical studies including required in-vivo testing in a standardized, reproducible, validated small animal model.
2.
Development of a well-defined formulation and delivery platform under good manufacturing practices (GMP).
3.
Quality control for ensuring and certifying uniformity from lot to lot.
4.
Scale-up and production for future Phase I clinical study.

Fast-Track proposals will be accepted Number of anticipated awards: 1-2 Budget (total costs):

Phase I: $300,000 for up to 1 year
Phase II: $2,000,000 for up to 3 years
Background
One of the most significant hurdles to overcome in evaluating strategies to cure HIV infection is the lack of a simple method for quantifying changes in the size of the latent reservoir of replication-competent HIV in resting CD4+ memory T cells in individuals on highly effective antiretroviral therapy. Most of the HIV DNA in these cells represents defective virus; less than 0.01% of highly purified resting CD4 cells harbor replication-competent provirus. As a result, PCR-based methods tend to over-estimate the size of the reservoir and do not correlate with the number of cells producing functional virus in a viral outgrowth assay. However, viral outgrowth assays are labor-intensive and require large volumes of blood.
Project Goal
The goal of this project is to design a high-throughput assay platform that can be used to reproducibly quantify changes in the size of the replication-competent latent HIV reservoir in resting CD4+ memory T cells isolated from individuals on highly effective antiretroviral therapy. Applicants must provide a plan for validating the assay by demonstrating correlation with quantitative viral outgrowth assays (QVOA) and/or functional non-induced HIV proviruses using cells isolated from virally suppressed HIV+ individuals on optimized antiretroviral therapy.
Phase I activities
 Development of technologies for detecting replication-competent latent proviruses
 Validation of detection methods using standardized controls
 Optimization of sensitivity to detect low-frequency latently infected cells
 Demonstration of correlation with replication-competent provirus vs. defective provirus
Phase II activities
 Further optimization of the assay platform technology and validation of assay reproducibility
 Increased throughput
 Comparison of assay to other methods published in the literature
 Testing of clinical samples from diverse cohorts of HIV+ individuals with varying levels of residual viral reservoirs
 Comparison of blood vs. tissue samples from virally suppressed individuals
 Modification of assay to detect latent HIV in humanized mouse models and latent SIV in nonhuman primate models
in the context of optimized antiretroviral therapy
 Use of assay to demonstrate changes in the size of the latent HIV/SIV reservoir in response to an intervention

Fast-Track proposals will be accepted. Number of anticipated awards: 1-2 Budget (total costs):
Phase I: $300,000 for up to 1 year
Phase II: $2,000,000 for up to 3 years
Background
RNA-based vaccines and therapeutics have emerged as great promise for HIV prevention and treatment, respectively. However, many obstacles still need to be overcome, in particular RNA instability, manufacturing problems, and clinically relevant delivery mechanisms of RNA into target cells.
RNA vaccine approaches have some advantages in relation to other vaccine technologies; they can be delivered directly into the cytoplasm and do not require nuclear localization to generate expression. Improvements of methods for mRNA synthesis and stabilization and development of improved self-amplifying RNAs have recently yielded promising results. RNA

approaches also stimulate the host’s innate defense system, in part through activation of the TLR pathways that recognize single and double stranded RNAs.
Furthermore, RNA-based therapeutics have shown the potential to silence HIV effectively upon direct transfection in vitro, but delivery into cells in vivo is still unsatisfactory. Vector-based (lentivirus, adeno-associated virus) delivery to quiescent cells has proven inefficient, and the vectors themselves pose a risk to the host. To enhance stability and to confer vehicle-free delivery, RNA-based drugs have been chemically modified to improve their properties. Progress was also made in chemical-based delivery strategies, e.g., liposomes, molecular-sized chemical conjugates, and supramolecular nanocarriers. An additional advantage is that RNA can be produced in vitro in a cell-free manner, avoiding safety and manufacturing issues associated with cell culture. Despite these advances, nucleic acids per se are relatively large, negatively charged polymers, and significant clinical challenges from the standpoint of delivery to cells still persist.
Project Goals
The primary goal of this contract solicitation is to encourage small businesses to develop improved platform technologies for the delivery of RNA into specific cells and tissues to improve the efficacy of HIV vaccines or therapeutics. Examples of HIV RNA vaccines include, but are not limited to mRNA and self-amplifying RNAs. Examples of RNA therapeutics include small interfering RNA (siRNA), microRNA (miRNA), microRNA antagonists, aptamers, messenger RNA (mRNA), splice-switching oligonucleotides, antisense oligonucleotides, and plasmid or other circular DNAs encoding messenger RNAs and transcription regulatory sequences. To enhance the efficacy of traditional HIV vaccines and therapeutics, combinations of cytokines, adjuvants, broadly neutralizing monoclonal antibodies, immune checkpoint inhibitors, etc. can also be co-delivered in mRNA form.
The short-term goal of this project is to perform feasibility studies for the development and use of delivery mechanisms for RNA-based HIV vaccines and therapies. The long-term goal of this project is to enable a small business to bring fully developed delivery systems for RNA-based HIV vaccines and therapies to the clinic and eventually to the market.
Phase I activities may include:
 Design and test in vitro small-scale delivery strategies for RNA-based HIV vaccines or therapeutics, including
exosomes, nanoparticles, liposomes, viral vectors, condensates, carriers, or delivery devices.  Assess potency and stability of RNA-based HIV vaccines or therapeutics.  Improve RNA stability through chemical modifications.  Perform proof-of-concept HIV animal model studies for assessment of organ toxicity, HIV immune responses, innate
immune responses (e.g., Toll-like receptor activation), and pharmacokinetic/pharmacodynamic studies, if applicable.  For RNA-based therapeutics:
 Evaluate off-target effects in cell lines and primary PBMC.
 Develop strategies for eliminating off-target effects, including software tools for re-designing RNAs.
Phase II activities may include:
 Scale-up manufacturing of RNA-based vaccines or therapeutics  IND-enabling studies, preferably in consultation with the FDA  For RNA-based vaccines:
 Test improved delivery mechanism for efficacy and mechanism of action in animal models of HIV.  For RNA-based therapeutics:
 Demonstrate that the RNA delivery approach is effective and non-toxic in animal models for HIV.  When appropriate, demonstration of superiority of developed technology compared to other delivery mechanisms.
Where cooperation of other vendors or collaborators is critical for implementation of proposed technology, the offeror should provide evidence of such cooperation (through written partnering agreements, or letters of intent to enter into such agreements) as part of the Phase II proposal.

Fast-Track 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 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 toleragenic adjuvants for autoimmune or allergic diseases. Traditionally, adjuvants are defined as compounds that stimulate innate and/or adaptive immune responses. The goal of this program is to support the discovery of novel vaccine adjuvants as well as adjuvants with tolerogenic properties. 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 three adjuvants have been approved for clinical use as components of vaccines in the United States aluminum hydroxide/aluminum phosphate (alum); ASO4, a combination of 4’-monophosphoryl lipid A (MPL) adsorbed to alum as an adjuvant for an HPV vaccine; and the oil-in-water emulsion MF59 as part of the FLUAD influenza vaccine for people age 65 years and older. The gaps that need to be addressed by new adjuvants include improvements to existing efficacious vaccines (e.g., the acellular pertussis vaccine), and development of vaccines: for emerging threats (e.g., Ebola outbreaks); for special populations that respond poorly to existing vaccines (i.e., elderly, newborns/infants, immunosuppressed patients); or to treat/prevent immune-mediated diseases (e.g., allergic rhinitis, asthma, food allergy, autoimmunity, transplant rejection). Recent advances in understanding innate immunity have led to new putative targets for vaccine adjuvants and for allergen immunotherapy. Simultaneously, progress is slowly 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 field of tolerogenic adjuvants is still in its infancy. No compounds have been licensed yet in the US and immune-mediated diseases continue to be treated mostly with broadly immunosuppressive drugs or long-term single or multi-allergen immunotherapy. In contrast to drugs, tolerogenic (or immunomodulatory) adjuvants would interfere with immune responses to specific antigens through a variety of mechanisms which include the induction of regulatory T cells, or by changing the profile of the pathogenic lymphocyte response (e.g., Th1/Th2/Th17, etc). The combination of tolerogenic adjuvants with allergen immunotherapy should aim at accelerating tolerance induction, increasing the magnitude of tolerance and decreasing the duration of treatment.
Project 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; their characterization; and early-stage optimization.
Phase I Activities include, but are not limited to:
 Optimize and scale-up screening assays to identify new potential vaccine-or tolerogenic adjuvant candidates
 Create targeted libraries of putative ligands of innate immune receptors
 Pilot screening assays to validate HTS approaches for identifying adjuvant candidates
 Develop in silico screening approaches to pre-select adjuvant candidates
Phase II Activities include, but are not limited to:
 High-throughput screening 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 and/or
formulation

 Screening of adjuvant candidates for their usefulness in special populations, such as the use of cells from cord blood or infants and/or elderly/frail humans or animal models representing human special populations

Fast-Track 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 for up to 3 years
Background
Adjuvants stimulate innate and/or adaptive immune responses. 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 three adjuvants have been approved for clinical use as components of vaccines in the United States -aluminum hydroxide/aluminum phosphate (alum), 4’-monophosphoryl lipid A (MPL), adsorbed to alum as an adjuvant for an HPV vaccine, and the oil-in-water emulsion MF59 as part of the FLUAD influenza vaccine for people age 65 years and older. Additional efforts are needed to more fully develop the potential capabilities of promising adjuvants, particularly for special populations such as the young, elderly and immune-compromised. In addition, adjuvants may facilitate the development of immunotherapeutics for immune-mediated diseases, such as allergen immunotherapy to treat/prevent 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 US and immune-mediated diseases continue to be treated mostly with broadly immunosuppressive drugs or long-term single or multi-allergen immunotherapy. In contrast to drugs, tolerogenic or immunomodulatory adjuvants would interfere with immune responses to specific antigens through a variety of mechanisms which include the induction of regulatory T cells, or by changing the profile of the pathogenic lymphocyte response (e.g., Th1 to Th2 or vice versa). The combination of tolerogenic adjuvants with allergen immunotherapy should aim at accelerating tolerance induction, increasing the magnitude of tolerance, and decreasing the duration of treatment.
Project Goal
The goal of each project is to accelerate pre-clinical development and optimization of a single lead adjuvant candidate or a select combination-adjuvant for prevention of human disease caused by infectious pathogens, or for autoimmune or allergic diseases. 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; 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. The adjuvant products supported by this program may be studied and further developed toward human licensure with currently licensed or new investigational vaccines, and/or may be developed as stand-alone immuno-stimulatory or immuno-regulatory agents.
Phase I Activities
Depending on the developmental stage at which an adjuvant is entered into the Program, the offeror may choose to perform one or more of the following:
 Optimization of one candidate compound for enhanced safety and efficacy. Studies may include:
 Structural alterations of the adjuvant or modifications to formulation; or
 Optimization of heterologous prime-boost-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 and/or additively
 Establishment of an immunological profile of activity and immunotoxicity that can be used to evaluate the capability of the adjuvant to advance to human testing

DB pathway in
 Preliminary studies in a suitable animal model to evaluate the protective or tolerizing efficacy of a lead adjuvant:vaccine  Analysis of vaccine efficacy through the use of a combination adjuvant and studies to evaluate the safety profile of the combination adjuvant:vaccine-formulation
Phase II Activities
Extended pre-clinical studies that may include IND-enabling studies such as:
 Additional animal testing of the lead adjuvant:vaccine combination to evaluate immunogenicity or tolerance
induction, protective efficacy and immune mechanisms of protection
 Pilot lot or cGMP manufacturing of adjuvant or adjuvant:vaccine
 Advanced formulation and stability studies
 Toxicology testing
 Establishment of quality assurance and quality control protocols
 Pharmacokinetics/absorption, distribution, metabolism and excretion studies
This SBIR will not support:
 The further development of an adjuvant that has been previously licensed for use with any vaccine
 The conduct of clinical trials (see
http://osp.od.nih.gov/sites/default/files/NIH%20Definition%20of%20Clinical%20Trial%2010-23-2014UPDATED_
0.pdf for the NIH definition of a clinical trial)
 The discovery and initial characterization of adjuvant candidates
 The development of adjuvants or vaccines to prevent or treat cancer
 Development of platforms, such as vehicles, or delivery systems that have no immunostimulatory or tolerogenic
activity themselves
 The discovery, development and/or optimization of an immunogen component of a vaccine

Fast-Track 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 for up to 3 years
Background
This Funding Opportunity Announcement (FOA) is intended to address the limited availability of reagents (e.g., antibodies, proteins, ligands) for the identification and discrimination of immune cells of non-mammalian models (e.g., arthropods, amphibians, fish, nematodes, marine echinoids). Non-mammalian models are easily tractable model systems to study basic, conserved immune defense pathways and mechanisms. For example, characterization of the Drosophilia Toll signaling pathway facilitated the discovery of mammalian Toll-Like Receptors (TLR), which helped to launch 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 Nfmosquitoes, the intermediate hosts for Plasmodia parasites. Results from such studies can guide research in mammalian systems and provide insights into immune responses against pathogens transmitted to humans. Work leading towards a better understanding of immune regulation within non-mammalian models has been constrained by the limited availability of antibodies and other immune-based reagents for the use in scientific studies.
Project Goal

Development and validation of reliable antibodies against non-mammalian immune cell markers or other reagents that allow for the identification and tracking of primary immune cells.
Phase I Activities include, but are not limited to:
 Identification of protein targets (immune cell markers, receptors with immune function)  Development of antibodies/reagents that allow for the identification and/or discrimination between primary immune cells from non-mammalian species
Phase II Activities include, but are not limited to:
 Validation of antibodies/reagents  Screening for cross-reactivity with related molecules on other non-mammalian species and/or mammalian immune cells  Scale-up production
This SBIR will not support:
 Development of antibodies/reagents against immune markers on mammalian cells
 Development of antibodies/reagents against markers on cells not involved in immune responses

Fast-Track proposals will be accepted. Number of anticipated awards: 1-3 Budget (direct costs):
Phase I: $300,000/year for up to 2 years
Phase II: $1,000,000/year for up to 3 years
Background
The NIAID’s Division of Allergy, Immunology and Transplantation (DAIT) supports a wide range of research programs
spanning basic immunology, translational and clinical research on protective immunity and immune-mediated diseases, including autoimmune and primary immunodeficiency diseases, allergic diseases, graft-versus host disease (GVHD) and allograft rejection in organ, tissue and cell transplantation. Major constraints encountered in designing mechanism of action studies are related to limited quantity of biological specimens available for study and the paucity of robust, validated, miniaturized assays that can reliably and reproducibly assess immune function, disease state or effects of therapy. The restricted amounts of tissue, cells and fluids that can be collected from adult, pediatric or immunocompromised patients are often inadequate for the application of conventional assays that interrogate immune function. Novel, multi-parameter, sample sparing assays are needed to obtain maximal biologic information from limited amounts of biological materials.
Project Goal
The goal of this proposal is to accelerate commercial development of novel, standardized sample sparing assays that improve monitoring of the immune system using limited amounts of biological sample. Sample sparing immune assays of interest may include, but are not limited to monitoring or assessments of the following:
 Antigen-specific immune responses
 Distinct immune cell populations
 T-cell and B-cell regulatory networks
 Innate immune responses
 Markers of T-cell turnover and homing to lymphoid tissue
 Cytokine and signaling networks
 Gene and protein expression and regulation
 Mucosal inflammatory and innate immune response

Technologies that address novel sample preparation or cell isolation processes are also included in the areas of interest for this announcement.
The sample sparing assays developed through this funding opportunity must address challenges, gaps or unmet needs in the study of human immune responses and provide clear advantages over existing assays.
Phase I Activities
Depending on the developmental stage of the sample sparing assay the offeror may choose to perform one or more of the following:
 Preliminary studies performed in a suitable animal model or in human samples to evaluate the assay feasibility (scientific and technical)
 Establish assay’s quality of performance, assay reproducibility and validation
 Define process controls
 Establish potential for commercialization
Phase II Activities
 Further technology developments and assay improvements  Development and validation of prototype platforms  Development of quality control program to enable longitudinal measurements in compliance with Good Clinical
Laboratory Practice
This SBIR will not support:
 Any phase clinical trial  Identification of new biomarkers  Validation of biomarker candidates  Proposals focused exclusively on animal studies and animal disease models. Animals may be used in assay
development phase but all assays must be validated using primary human samples
 Development of assays using established cell lines without validation in primary human samples
 Virus-induced cancers
 Studies that do not fall within NIAID mission

Fast-Track proposals will be accepted. Number of anticipated awards: 1-2 Budget (total costs):
Phase I: $300,000/year for up to 2 years
Phase II: $1,000,000/year for up to 3 years
Background
The NIAID Division of Allergy, Immunology, and Transplantation (DAIT) has funded the following bioinformatics resources to meet the needs of the immunology research community for data sharing, knowledge dissemination, standard development and integrative analyses:
 ImmPort (https://immport.niaid.nih.gov/): a unique resource for public data sharing of clinical immunology and research studies
 ImmuneSpace (https://www.immunespace.org/): a data management and analysis platform where datasets from the Human Immunology Project Consortium (HIPC) program can be easily explored and analyzed using state-of-the-art computational tools
 ITN TrialShare (https://www.itntrialshare.org/): a web portal of the Immune Tolerance Network (ITN) that shares information about the ITN’s clinical studies and specimen bio-repository

 IEDB (http://www.iedb.org/): a bioinformatics resource that offers easy searching of experimental data
characterizing antibody and T cell epitopes studied in humans, non-human primates, and other animal species. It
also hosts tools for epitope analyses
 ImmGen (https://www.immgen.org/): a public resource that provides a complete microarray analysis of gene
expression and regulation in the immune system of the mouse
While the data, knowledge and tools provided by these resources are freely available, their usage becomes limited to specific domains because the data representations (the internal method used to represent the type of data) stored in the repository for search, retrieval and presentation tools are specific to the individual repository. There is a growing need for informatics tools and approaches that make it easy for researchers to make data Findable, Accessible, Interoperable and Reusable (FAIR). Tools that facilitate this integration can contribute to transparency and reproducibility and ultimately accelerate research.
Project Goal
The goal of this project is to support the development of new and/or improved methods that make data FAIR in order for popular search engines to index and provide relevant search results for research data sets that are available for public use. These tools will complement the capabilities of more specialized search interfaces or services such as those provided by DAIT-funded data repositories.
Phase I Activities
Phase I activities must include performing a gap analysis of the above-mentioned databases according to the FAIR principles and developing informatics tools to address the identified gaps. The offeror may choose to develop tools with one or more of the following functionalities:
1.
Novel approaches to make data more findable by utilizing information that includes but is not limited to data, metadata, associated literature, and text.
2.
Approaches that extract information about features of the data and make it FAIR so a search engine can find it.
3.
Approaches that perform quality control by verifying ontology mapping, conformance to data description standards or other pre-processing steps involved in making data FAIR.
Phase II Activities
1.
Improve stability, scalability, and usability of the informatics tools prototyped during Phase I.
2.
Add functionalities and capacities to these systems based on research community’s needs.

Fast-Track proposals will be accepted. Number of anticipated awards: 1-2 Budget (total costs):
Phase I: $225,000 for up to 1 year
Phase II: $1,500,000 for up to 3 years
Background
Malaria and Neglected Tropical Diseases (NTDs) disproportionately affect the poorest people in developing countries. The World Health Organization disease burden reduction targets for 2030 include global elimination of leprosy, lymphatic filariasis, trachoma, onchocerciasis, and human African trypanosomiasis (HAT), and a reduction in the malaria mortality rate by 90%. Impressive progress is being made towards these goals. For example, malaria incidence rates fell 37% globally between 2000 and 2015; an 80% reduction in new HAT cases was seen between 2000 and 2014, and 18 countries have been able to stop preventive chemotherapy for lymphatic filariasis, as have eight countries for trachoma. However, we currently lack diagnostic tools with optimal sensitivity and specificity for use in the elimination and post-elimination phases. For example, microscopy and available rapid diagnostic tests (RDTs) have been largely adequate for malaria control but lack the sensitivity to detect asymptomatic infections. In the case of HAT, current diagnostic methods are limited by sensitivity and

reproducibility, and the lumbar puncture method is invasive and less than ideal. For these diseases slated for elimination, there is a pressing need for new diagnostic tools that can detect subclinical infections that serve as a disease reservoir and contribute to onward transmission. Such diagnostics would be intended for use in active-infection-detection interventions such as mass-screen-and-treat, targeted mass-drug-administration, post-elimination surveillance and for detecting cases in low-prevalence areas.
Project Goal
The goal of this project is to develop a low-cost, diagnostic platform with appropriate sensitivity and specificity for the detection of subclinical malaria or select NTD infections (leprosy, lymphatic filariasis, trachoma, onchocerciasis, HAT) for use in disease elimination campaigns in resource-limited settings. The final product should demonstrate the necessary sensitivity and specificity to reliably detect asymptomatic infections that are outside the limits of detection of currently available diagnostics.
Phase I Activities can include but are not limited to:
 Development of a prototype point-of-care diagnostic device that can identify one or more target pathogens in low biomass infections.  Determination of the sensitivity, specificity and other performance characteristics (e.g. time to result, limit of detection, test stability) of the diagnostic.  Initial testing on laboratory isolates.
Phase II Activities can include but are not limited to:
 Development of well-defined test platform under good manufacturing practices (GMP).
 Scale up and production for multi-site evaluations using clinical isolates.
 Product development strategy for regulatory approval and demonstration of clinical application.
This SBIR will not support:
 The design and conduct of clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial for the NIH definition of a clinical trial). For clinical trial support, please refer to the NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement program announcement or the NIAID Investigator-Initiated Clinical Trial Resources webpage.

Fast-Track proposals will be accepted. Number of anticipated awards: 3-4 Budget (total costs):
Phase I: $225,000 for up to 1 year
Phase II: $1,500,000 for up to 3 years
Background
There is a critical need to develop new and improved vaccines and therapeutics for high priority pathogens such as influenza, Mycobacterium tuberculosis (Mtb), and HIV. Research investments in sequencing these pathogens have resulted in an explosion of publicly available genomic data, creating a need for intuitive and efficient software tools to analyze massive amounts of data and enable prediction and/or identification of new targets and control strategies for treatment and prevention. This solicitation will support software development in two specific and separate areas (one area per proposal):
1.
Non-Coding RNA: Although non-coding RNAs (ncRNAs) have been identified as promising biomarkers and therapeutic targets for a number of human diseases, translational efforts in the infectious disease field are largely lacking. A critical barrier to translation is our lack of understanding of the functional roles of ncRNAs in infectious disease. The development of software packages to analyze existing ncRNA data sets will assist researchers in

identifying the most promising ncRNAs for future mechanistic studies, helping to overcome this barrier and move the field forward from discovery to translation.
2.
Influenza vaccines: Public databases now contain genomic sequences for tens of thousands of influenza viruses as well as associated in vitro, in vivo, and in some cases clinical data. Engaging the software industry in the development of predictive software linking genetic sequencing information with other types of data such as antigenicity, protein structure, viral fitness and/or vaccine efficacy, is anticipated to bring a new dimension to the annual influenza vaccine strain selection process and vaccine development, decreasing the likelihood of vaccine strain mismatch and leading to more effective influenza vaccines.
Project Goal
The goal of this project is the development of computational software that provides sensitive tools to enable translational research on high priority infectious disease pathogens by analyzing massive amounts of existing data. Use of novel cognitive computational strategies that combine large complex data sets and machine learning algorithms is encouraged to translate information into knowledge that can help drive more informed decision-making. The scope of software development is limited to two priority areas:
 Analyzing large-scale ncRNA data to identify expression patterns associated with influenza, Mtb, or HIV infection and/or disease progression to guide future mechanistic and translational studies (e.g., algorithms/analytics that enable target prediction/identification, structure analysis, functionality determination, quantification of ncRNA expression levels, etc.).
 Predicting influenza virus evolution to improve vaccine strain selection and vaccine efficacy.
Phase I activities can include but are not limited to:
 Develop a functional software prototype.
 Demonstrate capability of the software to: (1) analyze large-scale ncRNA data to identify expression patterns associated with influenza, Mtb, or HIV infection and/or disease progression (Area 1); or (2) link influenza genetic sequencing information with other types of data such as antigenicity, protein structure, viral fitness and/or vaccine efficacy to predict influenza virus evolution and improve vaccine strain selection and vaccine efficacy (Area 2).
Phase II activities can include but are not limited to:
 Evaluate, revise, and enhance the software prototype.
 Perform beta testing of the software with relevant end users.
 Incorporate user feedback from beta tests.
 Develop user support and instructional guides to facilitate commercialization.
This SBIR will not support:
 The design and conduct of clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial for the NIH definition of a clinical trial). For clinical trial support, please refer to the NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement program announcement or the NIAID Investigator-Initiated Clinical Trial Resources webpage.
 Use of novel or non-publicly available datasets to develop and demonstrate the utility of the computational software and tools.

Fast-Track proposals will be accepted Number of anticipated awards: 2-3 Budget (total costs):
Phase I: $225,000 for up to 1 year
Phase II: $1,500,000 for up to 3 years

Background
For a wide range of pathogens, the first contact between the pathogen and the human host occurs at a mucosal surface, such as the gastrointestinal tract. Ideally, vaccines against enteric infections would elicit protective immunity at both systemic and mucosal compartments. Non-living, subunit, or conjugate vaccines given parenterally may induce systemic responses, but generally elicit less-than-optimal responses, if any, in mucosal tissues. Oral administration of such vaccines is not practical because the acidic stomach environment may degrade the antigen, which then requires increased amounts of vaccine to reach the target, inductive site. One strategy to overcome this limitation is to include components that elicit mucosal immunity when formulating parenteral vaccines. Mucosal adjuvants, such as bacterial toxins or toxin derivatives, induce homing receptor expression on T cells and B cells that leads to their migration to intestinal mucosal compartments and, thus, ultimately elicits protective immunity. Examples of enteric infections for which vaccine candidates are under development include Enterotoxigenic E. coli, Shigella spp., Salmonella spp., Campylobacter jejuni, Clostridium difficile, C. botulinum, and enteric viruses (e.g., norovirus or rotavirus), and the addition of mucosal adjuvants to their formulation may enhance vaccine immunogenicity and efficacy. Thus, the overall goal of this topic is to formulate parenterally delivered enteric vaccines that will elicit mucosal immune responses in addition to systemic immune responses.
Project Goals
 To determine the best vaccine:adjuvant formulation(s) of current enteric vaccine candidate(s) that induce immune
responses at both mucosal and systemic compartments;  To characterize systemic and mucosal immune responses to parenterally-delivered enteric vaccine candidates;  To encourage collaboration between academic institutions and small business entities to determine the optimal
formulation for such vaccines.
Phase I activities may include but are not limited to:
 Identification of enteric vaccine candidate(s) and relevant adjuvant(s) that may be delivered parenterally to mice and that induce systemic and intestinal immune responses;  Performance of preliminary studies in mouse model with various vaccine:adjuvant combinations to determine immunogenicity and optimal dose;  Development of in vitro assays to evaluate immune responses, including functional assays using mucosal and systemic samples;  Selection of at least two vaccine:adjuvant combinations for further studies; each vaccine must target a different enteric disease.
Phase II activities may include but are not limited to:
 Confirmation of preliminary results obtained during Phase I with the selected vaccine:adjuvant combinations;  Additional testing of lead vaccine candidate(s) for progress towards IND-enabling studies, including but not limited
to testing to improve safety, efficacy, and QA/QC;  Pilot lot cGMP manufacturing of the vaccine candidate(s);  Formulation, stability, and toxicology studies, as appropriate, for later stages in the vaccine product development
pathway.
This SBIR will not support:
 The design and conduct of clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial) for the NIH definition of a clinical trial). For SBIR phase II clinical trial support, see the NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement program announcement.
 Platform development such as vehicle or delivery systems.

Fast-Track proposals will be accepted. Number of anticipated awards: 2-3

Budget (total costs): Phase I: $450,000 for up to 2 years Phase II: $3,000,000 for up to 3 years
Background
There is an unmet need to improve vaccine performance to combat malaria and pertussis, which are considered significant public health threats. Recent advances in the field of malaria vaccine development have led to the achievement of significant milestones. Several malaria vaccines are now in late stage development or are being considered for widespread deployment. However, these vaccine candidates have only been shown to provide short-term protection, suggesting a need for further improvement. Similarly, widely accepted acellular vaccines for pertussis are showing waning protection, resulting in outbreaks of pertussis, a disease that was previously thought to have been controlled. Knowledge about immunological memory and correlates of vaccine protection is constantly evolving; newly available vaccine delivery tools, strategies, and formulations are currently being optimized with prototype antigens to develop vaccines with enhanced protective immunity. This contract topic aims to leverage the new knowledge and tools, and calls for the development of novel vaccine technologies and strategies that promote sustained vaccine efficacy against malaria or pertussis.
Project Goals
 To identify or develop novel vaccine technologies, such as delivery platforms or formulations, that induce long-term protection against malaria or pertussis;  To develop new vaccines or vaccine strategies using technologies that induce long-term immunity and sustainable efficacy against malaria or pertussis.
Phase I activities can include but are not limited to:
 Identification and evaluation of novel formulations (e.g., adjuvants, adjuvant systems), delivery platforms (e.g., viral vectors), or vaccine strategies (e.g., novel prime-boost regimens) to induce long-term immunity or surrogate markers for long-term protection;
 Development of in vitro surrogate assays to evaluate induction of long-term immunity or protection using
phenotypic markers;
 In vivo proof-of-concept studies to demonstrate sustainable protection in appropriate animal models.
Phase II activities can include but are not limited to:
 Additional testing and process development of the lead technologies and/or vaccine candidate(s) in the product development pathway leading to IND-enabling studies, including but not limited to testing to improve safety, efficacy, and QA/QC;
 Further definitive preclinical testing in non-human primate models;
 Pilot lot cGMP manufacturing, as appropriate, for further refinement of the vaccine candidate(s);
 Stability and toxicology studies, as appropriate, for later stages of the vaccine product development pathway.
This SBIR will not support:
 The design and conduct of clinical trials (see http://www.niaid.nih.gov/researchfunding/glossary/pages/c.aspx#clintrial) for the NIH definition of a clinical trial). For SBIR phase II clinical trial support, see the NIAID SBIR Phase II Clinical Trial Implementation Cooperative Agreement program announcement.
 Technology development using prototype antigens other than known or newly identified protective antigens for malaria and pertussis.

Number of Anticipated Awards: 3-4.
Phase I and Fast-Track proposals will be accepted. Fast-Track proposals include Phase I and Phase II activities.
Budget (total costs):
Phase I: $225,000 for 6 months
Phase II: $1,500,000 for 2 years
Fast-Track budget may not exceed $1,725,000 and Fast-Track duration may not exceed 2 years 6 months.
It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.
Objective
This RFP solicits the research and development of digital markers for detection of acute marijuana intoxication. In the content of this solicitation the digital markers are described as smart phone-based diagnostic test data or real time, data-driven signals. The proposed digital markers must be created on Apple Inc.’s ResearchKit or/and Android ResearchStack frameworks. Both frameworks are open-source software platform which make it easy for researchers and developers to create mobile applications (apps) for specific biomedical research questions by circumventing the development of custom code. Mobile app development on custom platforms will not be funded. Then, the offerors are expected to test the apps clinically and validate the embedded digital markers. It is envisioned that the developed and validated digital markers will be consolidated into novel digital health tools for use in clinical research and law enforcement procedures.
Background
As marijuana is being medically and recreationally legalized in many states, there is a growing concern over marijuana intoxication. A major public health concern is the increased risk of marijuana-impaired driving, because the number of individuals testing positive for marijuana constituents and the proportion who was involved in traffic fatalities doubled in the three years. According to the 2017 report issued by the Governors Highway Safety Association (GHSA) and the Foundation for Advancing Alcohol Responsibility, drugs are now involved in more fatal U.S. crashes than alcohol alone, and marijuana-impaired driving significantly contributes to this trend. However, currently there is no quantitative biologic test that can accurately determine whether an individual is acutely impaired following marijuana consumption.
When marijuana is absorbed, the concentration of tetrahydrocannabinol (THC), one of the psychoactive marijuana constituents, decreases rapidly in the blood stream due to the distribution through the hepatic metabolism and absorption into fat cells. Over time, THC is slowly released back into the bloodstream and subsequently excreted in the urine. The rapid and variable absorption and release of THC into the blood stream makes it difficult to correlate the level of THC with impairment in chronic marijuana users. In addition, due to the multiple marijuana species, there are over 100 marijuana metabolites. These metabolites can be detected in the blood, however, they have been not associated with the psychoactive effects of marijuana use. This translates into unreliable blood tests for marijuana detection which have high rate of false positive results. One alternative is a saliva-based screening tool. The oral fluid is easy to collect, non-invasive, and is associated with recent cannabis intake. Unfortunately, recent studies have shown that the saliva-based tests have a two-to five-fold greater

variability than the blood tests, and the level of marijuana detection is also not precise. In the absence of a quantitative, biospecimen-based test for marijuana intoxication and psychomotor impairment, the Diagnostic and Statistical Manual IV (DSM
V) test remains the only diagnostic gold standard used by drug recognition experts and mental health professionals.
Using digital parameters of person's psychomotor impartment in the response to the marijuana consumption may represent more reliable and correlative approach for diagnostics. To test this hypothesis, the National Institute on Drug Abuse (NIDA) plans to support the identification, development, testing and validation of digital markers for detection of psychomotor impairment due to marijuana intoxication. To increase the project efficiency and to increase interoperability and sustainability of the research tools produced as the result of this solicitation, NIDA requests that the proposed markers be developed and clinically validated using mobile applications created on Apple Inc.’s ResearchKit or Android ResearchStack frameworks. Both frameworks are open-source and allow researchers and developers to easily create biomedical apps by circumventing the development of custom code. Due to the availability of these pre-coded platforms, NIDA will limit the costs directly associated with the app design to no more than $50,000 per project (with the maximum of $30,000 for the Phase I and $20,000 for the Phase II). Mobile app development on custom platforms will not be funded. The majority of proposed work should be focused on testing objective digital variables in response to marijuana intoxication-associated impairment and correlate those digital variables with one of more existing or (novel) biomarkers, imaging technologies and DSM V test results. Offerors are expected to have in-house capabilities or the established practice or experience to detect THC in biological specimens and quantify the level of the cognitive/psychomotor impairments in human subjects.
The app features may leverage and integrate with the internal sensors, compatible add-apters and external hardware to monitor the measurable markers of marijuana intoxication. Examples of the app features may include, but not limited to, accelerometer, microphone, gyroscope, facial or eye pupil’s changes recognition software, glucometers, inhalers, skin voltage sensor, heart rate sensor, other existing and newly developed sensors.
In the future, the clinical studies using the validated apps may be more cost-efficient than the analogous ones using physiological biomarkers. The Fast Track projects may include consolidation of the validated markers into novel digital health technologies/tools to be used in the future outside of the research purposes. It is envisioned that the final app/tool will meet the FDA device class II designation.
The developed products could have enormous impact meeting a critical, unmet need for clinical research and law enforcement procedures.
Phase I Activities and Expected Deliverables
Develop a mobile application prototype and test its feasibility to measure psychomotor impairment following marijuana consumption. Conduct research on selection of the digital markers of marijuana intoxication.
Technical Requirements
1.
Identify and describe selected digital markers. Customize the variables to be highly specific to the detection of marijuana-dependent dysfunction. Present the conceptual framework of the selected digital markers.
2.
Develop a prototype of mobile application software using ResearchKit or/and Android ResearchStack frameworks with integration of digital markers. Create a video of the app prototype to clearly demonstrate the app functionality. Develop the white paper describing the app built upon the proposed markers and the design of the “proof-ofconcept” study.
3.
Conduct the “proof-of-concept” study testing feasibility and usability of digital biomarkers to detect marijuana intoxication
a.
Obtain IRB approval for clinical studies.
b.
Enroll healthy volunteers for the pilot clinical study and screen them for eligibility.
c.
Demonstrate the capability of the app in the pilot clinical study. NIDA requests that the offerors should use NIDA Drug Supply Program to obtain marijuana or TCH for this clinical research.
https://www.drugabuse.gov/researchers/research-resources/nida-drug-supply-program
d.
Determine the feasibility by achieving reproducible, highly sensitive measurements of the cognitive/psychomotor impairment.
e.
Compare the digital data with clinical standards (biological specimens or imaging technologies) and DSM V tests.

Phase II Activities and Expected Deliverables
Test and validate the mobile application to measure cognitive and psychomotor impairment at marijuana intoxication.
Technical Requirements
1.
Revise and improve software in response to the needs identified in the Phase I. Optimize the digital variables as needed. Complete the enhanced software design based on the final system requirement document.
2.
Determine efficiency and sensitivity of the digital markers to quantitatively measure the cognitive/psychomotor impairment at a known doses of THC.
3.
Determine the app performance by demonstrating of the linear range, detection limits, and specificity.
4.
Validate the digital biomarkers with a large cohort of marijuana users using clinical standards (biological specimens or imaging technologies) and DSM V test. Determine the residual effects of recent marijuana intake vs cumulative effects of chronic use vs poly-substance abuse (including alcohol and stimulants). Expand the statistical data and determine sensor accuracy and precision levels. Verify the diagnostic specificity, sensitivity and reproducibility.
5.
Test the digital biomarkers for confounding effects of a) pre-existing cognitive and educational deficits; b) co-mobility with other psychiatric disorders, and c) medications for drug abuse or other neurologic disorders. Validate objectivity and reliability.
6.
Conduct the efficiency survey with professionals representing the target end-users. Collect survey’s feedback and analyze the data.
7.
Prepare the plan to address FDA-regulations if a Health IT Tool is to be used in the future outside of the research purposes.
8.
Prepare strategy for implementation and dissemination.

Number of anticipated awards: 4
Budget (total costs, per award including F&A and fee):
Phase I: $225,000 for 8 months
Phase II: $1,500,000 for 1 year
Fast-Track proposals will not be accepted.
NIDA strongly suggests that proposals adhere to the above project period. NIDA may not fund proposals with budgets exceeding the above amounts and project periods.
Summary
The National Institute on Drug Abuse (NIDA) has an interest in assisting people to overcome substance use disorders (SUDs) and to achieve and maintain sustained recovery. There are effective pharmacological and behavioral treatments for some substance use disorders, however not all individuals respond to treatment and long-term success rates tend to be low. Following the approval of neuromodulatory devices for the treatment of mental health disorders such as depression, obsessive compulsive disorder and neurological disorders such as Parkinson’s disease, there is a growing interest to apply neuromodulatory technologies to SUDs. Studies that examine the effects of neuromodulation on nicotine, alcohol and cocaine use have suggested that this technology may have a significant potential for therapeutic use in SUDs. However, further work is needed to build upon these preliminary research studies that use prototypic neuromodulatory technologies. Limited data are available that describe the relationship between changes in brain circuitry and behavioral responses, the types of SUD behavioral activities responsive to neuromodulation, the number of treatments needed to establish and maintain behavioral responses, or the duration and persistence of such responses. For example, the current data suggest that for the therapeutic effects of rTMS and tDCS to have any lasting effect, repeated treatments and thus repeated clinic visits are needed. Current constraints to the therapeutic use of neuromodulatory devices lies in the size, cost, and complexity of current generation tools. The lack of portability of neuromodulatory devices and need for repeated daily clinical treatment increases patient costs and hinders the studies required to improve the development and ultimate acceptance of these modalities. In order to accelerate the portability of neuromodulatory device research, NIDA is seeking SBIR proposals to develop portable neuromodulation devices that by their flexibility of use will be able to extend the current research and provide novel tools to evaluate the use of neuromodulation for SUD treatment.

Project Goals
To build on established well-controlled, published empirical studies by developing commercially viable portable neuromodulatory devices for the treatment of SUDs. Successful awardees will develop new or convert existing neuromodulatory technologies used for other indications to treat SUDs, in a manner that will facilitate wide application and enhance market penetration. The technologies should translate peer-reviewed academic research studies using prototypic neuromodulatory technologies into FDA-approvable commercial products.
 The portable neuromodulatory devices produced should demonstrate similar efficacy to modulate brain circuitry, as
validated by neuroimaging to that of prototypic devices as reported in the literature
 The portable neuromodulatory device should be oriented towards specific SUD-related indications
 In addition to being efficacious, devices should be safe and practical given cost/benefit considerations
o Examples include transcranial magnetic stimulation, direct current stimulation, and vagal stimulation, while development of new invasive technologies (e.g., deep-brain stimulation), might be more difficult to justify in terms of risk/reward ratio and likely patient acceptability.
The Phase I contract proposal must include:
 Go/no-go decision tree with quantitative, not subjective milestones  Objective measures that examine both the delivered dosage/treatment duration and the proposed mechanisms of action of the portable neuromodulatory device. Studies should include validated empirically established
comparators.  Studies designed to address all project-specific questions of feasibility.  Detailed discussion of potential pitfalls, side effects and safety issues associated with the technology and how these
concerns are to be mitigated.  Device development plan with the appropriate regulatory authorities at the FDA and provide a regulatory pathway in the contract application.
Phase I Activities and Expected Deliverables
This phase focuses on characterizing the neuromodulatory device and parameters of the device, including:  Building a prototypic and appropriately-sized functional device; demonstrate feasibility  Ensuring the portable neuromodulatory device includes a refractory period or other suitable mechanism to safeguard
from overuse of the device.  Showing bio-equivalency based on protypic measure and demonstrate device capability, for example, by comparing
the effects using imaging or other techniques (fMRI, EEG, etc).  Complete initial safety studies  Complete a proof-of-concept clinical trial  The Contractor will design a clinical study to assess the feasibility and acceptability of the device. The study should
have a minimum of 15 enrolled participants. If desired, NIDA may provide assistance with the study design and finding clinical partners.  A milestone on the acceptability of integrating portable devices with pharmacotherapies or behavioral therapies to maximize treatment efficacy, functional and/or clinical outcomes will be required
 Following determination of milestone acceptability by NIDA, a 1-week outpatient study will be conducted. This study is to evaluate 1) measures of acceptability including retention of the portable device, 2) measures of discomfort, 3) portability, and 4) durability. This study should have a minimum of 24 enrolled participants
Phase II Activities and Expected Deliverables
Phase II involves clinical studies on the effects of the portable neuromodulatory device to the user and device usability.
NIDA is required to review the clinical protocols prior to study initiation.  Lab test of device followed by improvement finalization  A test on SUD with a minimum of 15 enrolled participants. If desired, NIDA may provide assistance with the study
design and finding clinical partners.  File an IDE, Complete IDE-enabling studies, and retesting of device in a Phase I condition  Detailed commercialization plan, including cost analysis, market strategy to extend treatment effects and reduce
relapse, device sales and reimbursement possibilities

Planned Timing of Awards
 The Phase I report will be due exactly 11 months after the date of issuance of the Phase I contract.  No extensions will be granted for Phase I.
Page

Fast-Track proposals will not be accepted. Number of anticipated awards: 1 -2 Budget (total costs):
Phase I: up to $150,000 for up to 6 months
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Background
A protective space with negative pressure and air flow is necessary for safe manipulation of human specimens that may contain of communicable pathogens. Use of biosafety cabinets (BSCs) with HEPA filtration is the best method to protect both laboratory workers from exposure and potential infection and the surrounding environment from contamination. Biosafety cabinets are readily accessible in the global north, but are expensive, and require continuous maintenance to ensure their effective removal of pathogens from lab spaces. In many countries where dangerous pathogens are endemic, there is limited infrastructure and resources to purchase such equipment. Further, laboratories in resource-poor countries have limited space and may lack technical expertise to maintain BSCs. Annual inspection of filters as well as airflow speed and pressure is required for certification and safe use of BSCs.

Project Goals
To offer sustainable biocontainment to global laboratories by developing an inexpensive cabinet with modular components that are easy to assemble, dissemble and transport.
Phase I Activities and Expected Deliverables
To engineer the BSC cabinet modules so that all motor parts and filters are easily accessible and can be replaced or repaired by laymen as needed. Modular BSC cabinets will be designed with robust, multi-membrane filter components that are durable and easy to maintain.
For Successful Phase I Awardees ONLY (Expected Phase II Deliverables)
During Phase II of this project, the modular BSCs will be piloted in three or more laboratories of varying infrastructure, funding and capabilities (local/rural, state/exurban, national/urban) as well as in a field situation.
Ease of assembly and use: Instructional materials and necessary tools will be provided to pilot labs; hands-on training will be provided if needed. BSCs will be used once assembled, then dismantled, moved and reassembled. Ideally, assembly training required will be nominal, and assembly/disassembly time will be less than one hour.
Quality testing (Field): Test materials (small particulates, glow dust) will be used to ensure quality of filtration in polluted and unhygienic locations. Air flow pressure will be measured and compared before and after contamination with particulates.
Repair and maintenance: Instructions and tools required for repair (motor, filter change, etc.) will be provided to lab designees. Adjustments to protocols and modules will evolve as needed to simplify field maintenance.
Impact
The availability of a portable BSC that can be maintained with minimal experience and expense will enable more rapid detection of infections at their source, thereby preventing larger clusters of disease and epidemics. The modular BSC will be cost-saving in that specimens can be tested at source laboratories without the need for transport to city reference labs. Further, the modular BSC will reduce time to diagnosis, as specimens can be tested closer to the point of care, thereby reducing morbidity and mortality. Finally, the modular BSC will protect laboratory staff and environments, reducing unnecessary illness and increasing biosafety and biosecurity practices.
Commercialization Potential
There is a need for this product, since 1) International labs with some infrastructure and funding require a product like this in order to meet minimal safety and quality standards, and 2) International labs with little infrastructure and funding cannot safely handle human specimens from potentially infected persons without this product.

Fast-Track proposals will not be accepted.
Number of anticipated awards: 1
Budget (total costs):
Phase I: up to $150,000 for up to 12 months
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Background
Cysticercosis is a neglected parasitic infection targeted for priority public health action. Cysticercosis is caused by larval cysts of the tapeworm Taenia solium (T. solium) acquired by eating pork tapeworm egg-contaminated food or through accidental self-infection due to poor personal hygiene of subjects with taeniasis (the harboring of adult worm stage in the gastro-intestinal tract). When these cysts infect the brain (neurocysticercosis), they can result in seizures. Neurocysticercosis (NCC) is the leading cause of adult onset epilepsy in the developing world, accounting for about 29% of epilepsy cases in endemic areas (Nash 2014). In areas with large U.S. immigrant populations, up to 10% of emergency room seizure patients had NCC (Ong et al., 2012). NCC is reportable in 6 U.S. southwest border states. NCC related hospital costs in California exceeded $17 million (Croker et al., 2012). Globally, human cysticercosis poses the highest burden for disability-adjusted life years (DALYs) associated with food-borne infection (Torgerson et al., 2015). A fecal–oral-transmitted disease, cysticercosis can be spread by people directly or indirectly through food contamination. Infected persons often are unaware of their infection or of the potential risks regarding transmission (Sorvillo et al., 2011).
As humans are the only reservoir of T. solium, finding subjects with taeniasis is critical to control and eliminate T. solium related diseases. Current laboratory tools to detect infected cases are inadequate. Developing a valid point-of-care (bedside medical diagnostic) test for taeniasis coproantigen can support efforts to control and eliminate T. solium. This test could be used to screen subjects at high risk for taeniasis, potentially preventing spread of infection by food handlers, within households, and among other community members, thereby reducing epilepsy burden.
Currently, finding taeniasis carriers relies on either microscopy, by polymerase chain reaction (PCR), and/or detection of taeniasis coproantigen in the stool in the enzyme-linked immunosorbent assay (ELISA) platform. Microscopy is not sensitive and cannot differentiate between T. saginata and T. solium. PCR for detection of T. solium performs well but cannot be used in the field or for monitoring effects of treatment of subjects with taeniasis. The Taeniasis coproantigen ELISA-based platform detects current, active case of taeniasis and could quantify the amount of antigens in the stool.
Unfortunately, the current ELISA-based platform also cannot be used in the field and more importantly, uses polyclonal antibodies against T. saginata which makes it not species-specific and increases batch-to-batch variation. Public health officials need a better test reagent that is species-specific and avoids batch-to-batch variation.
By developing a taeniasis coproantigen assay, we could screen subjects at high risk for taeniasis, especially food handlers, to improve US food safety and to prevent neurocysticercosis in the US population. Globally, the availability of a point-of-care test for taeniasis coproantigen would support the effort to control and eliminate
T. solium.

Project Goals
To develop a human taeniasis coproantigen detection assay using capture reagents that are species-specific and heat-stable and have minimal batch-to-batch variation.
Phase I Activities and Expected Deliverables
1.
Find monoclonal antibodies/aptamers that will bind to T. solium adult worm extracts but not to Phosphate buffered saline or normal stool samples
2.
Submit to CDC 5 monoclonal antibody clones or 5 aptamers (sequences and aptamer products) that bind with high affinity to T. solium adult worm extracts but NOT to normal stool samples
3.
Submit to CDC a detailed report of the strategy and the analysis of the monoclonal antibodies or aptamers which include the sequences of the 5 aptamers selected
For Successful Phase I Awardees ONLY (Expected Phase II Deliverables)
1.
Develop an ELISA using those monoclonal antibodies or aptamers with the expected deliverable: an ELISA kit with monoclonal antibodies or aptamers that could differentiate human taeniasis positive stool samples from negative samples with a sensitivity of 95% and a specificity of 95%.
2.
Develop a dipstick test to determine if a stool sample is positive or not with the expected deliverable: A dipstick assay with a quantitative results based on fluorescence that could be read by a mobile phone reader.
3.
Conduct heat stability study for the all developed assays with the expected deliverable: a test with self-life of1 year at 4 C.
Impact
Availability of a species-specific taeniasis coproantigen ELISA assay will improve the service of the CDC Reference Diagnostic Laboratory in helping states and clinicians to detect, treat, and monitor the effects of treatment for a patient with taeniasis. The point-of-care test will benefit US public health by finding patients with taeniasis, the source of transmission. Globally, availability of the taeniasis coproantigen rapid test will allow program managers to find and treat patients with taeniasis and eventually, eliminate taeniasis and reduce global epilepsy burden.
Commercialization Potential
The ELISA kit could be sold to state public health laboratories, and the point-of-care test could be sold to all interested parties.

Fast-Track proposals will not be accepted.
Number of anticipated awards: 1
Budget (total costs):
Phase I: up to $150,000 for up to 12 months
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Background
Nutrition, Physical Activity, and Obesity are key objectives for Healthy People 2020. A 2015 executive order directed federal agencies to apply behavioral insights to improve the effectiveness and efficiency of government programs and the CDC’s 2017 Food Service Guidelines for Federal Facilities encourage the use of behavioral design strategies to make healthier foods and beverages easier for consumers to choose. However, little guidance exists to help public health professionals (such as public health departments) and private and public sector building operations (such as food service and vending operators) apply behavioral design strategies in order to enable healthier dietary or physical activity behaviors. Tools such as the Sustainable Facilities Tool (sftool.gov) and USDA’s Smarter Lunchroom tool provides

initial guidance but lack the necessary breadth and detail in operationalizing behavioral design approaches toward dietary or physical activity practices. Building and design firms recognize that nearly all aspects of their work will influence the occupant’s or user’s experience and behavior, however, they neither have the expertise nor inclination to consider health as a primary outcome. These firms do recognize the value of health and potential return on investment (ROI) to their clients and thus, are willing and interested to incorporate health-enabling design. This can be assisted by the translation of evidence from numerous fields, such as psychology, community design, and public health, into guidance on how our experience and behaviors are affected by our environment. Although this remains an unmet ideal, the field can be moved forward via tools that translate and operationalize evidence-basedstrategies that alter the human experience with the built environment for the advancement of public health.
This SBIR contract seeks to build a web-based platform that assists the architecture and design community to incorporate behavioral design strategies in the built environment to enable healthy behaviors. The proposed tool will also allow users to provide direct feedback into the platform, in order to add to the evidence-base on behavioral design’s practical applications, and to create best practices through platform modification.
Ultimately, the goal is for health to be a normative consideration and outcome in the design and construction of the places we live, work, and play. This platform will:
1.
Assist and enhance changes within the food environment, making healthier choices easier or more likely for consumers
2.
Support environmental changes that enable and encourage safe and convenient opportunities for physical activity at the building, neighborhood and community level
Project Goals
1.
Translate concepts and aspects introduced in the Health, Behavioral Design, and Built Environment White Paper, published in March 2017 by the National Collaborative on Childhood Obesity Research (NCCOR) (http://www.nccor.org/wp-content/uploads/2017/03/nccor-behavioral-design-whitepaper-final.pdf) to operationalize behavioral design strategies to enable healthy behaviors. Translation of concepts and aspects will initially take the form of checklists and toolkits for each setting (i.e., worksites, assisted-living facilities) and venue (i.e., vending machines, cafeterias).
2.
Design and build a web-based tool that demonstrates how each concept/aspect of the environment and resulting human experience can be modified to enable healthier behaviors (i.e., dietary choices, physical activity, and social interaction/cohesiveness).
Phase I Activities and Expected Deliverables
Phase 1 (0-12 mos)
1.
Collaborate with an innovative design/architectural firm that can use architectural modelling, design thinking, and industry insights to layout a basic web-platform assisting those in the building and design community to understand the potential health impacts of their work. The contract partner will need expertise in behavioral science and how space, time, material, and information can influence behavior.
2.
Develop checklists and guide (i.e., toolkits) for application for each setting and venue, with subject matter expert input (i.e., nutrition and PA scientists).
3.
Create a framework to guide design choices by how they influence behaviors or actions with health outcomes.
For Successful Phase I Awardees ONLY (Expected Phase II Deliverables)
1.
Design a user-interface that allows architects, designers, and public health professionals to construct, understand, and interact with the specified environment (e.g., setting and venue).
2.
Apply and operationalize behavioral design aspects/concepts, as described for example in the White Paper Figure 4, to the platform.
3.
Test and make modifications to the web-based tool as necessary.
4.
Allow users to share success stories and practice-based evidence, in order to advance and improve the evolving application. This can be accomplished via web based collaborative methods (sharing).

Impact
Improvement of food and physical activity environments can lead to many positive long-term health, social, and economic outcomes, including:
 reductions in chronic disease and early death
 increased productivity
 decreased absenteeism
 reduced healthcare costs
 improvements in mental health and cognition
 prevention of falls
 reduction of health inequities
 reduced stress
 improved sleep
 increased life satisfaction
Commercialization Potential
There are numerous methods to commercialize these concepts, particularly the web-based tool emerging from Phase a successful Phase I & II. For example, fee-based access by design and architecture firms can be part of the pay-to-play version of this interface and can enable advanced features such as saving projects, networking within business or between businesses and clientele, or interfacing with other design software. However, the most simple income generating method for this project is to connect the various aspects of this work with the materials providers that enable it to work and allow them to advertise. For example, building and design materials and machinery of all kinds and the companies that specialize in their installation [e.g., paint, glass, flooring, lighting systems, HVAC systems, etc] can use this tool to target products to specific projects and needs. Design, building, and planning firms will all be interested in advertising their services on such a website.

Fast-Track proposals will not be accepted.
Number of anticipated awards: 1
Budget (total costs):
Phase I: up to $150,000 for up to 12 months
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Background
Endophthalmitis is a rare, but severe infectious complication of corneal transplant surgery (keratoplasty) that requires prolonged treatment with intraocular antimicrobial drugs and results in vision loss for over half of patients. Post-keratoplasty endophthalmitis incidence has more than doubled from 2007 to 2014 according to adverse event surveillance conducted by the Eye Bank Association of America, and fungi (primarily Candida yeast) caused the majority of cases. Moreover, the proportion of post-keratoplasty fungal endophthalmitis is increasing and CDC has received several recent reports of fungal endophthalmitis clusters associated with corneal tissue banks and corneal surgery centers. The predominant Candida yeast etiology among post-keratoplasty fungal endophthalmitis cases suggests that donor skin and gastrointestinal flora are a possible source of contamination, and that corneal tissue handling and storage after donor extraction might allow transmission of fungal contaminants to recipients. Currently, the main corneal tissue storage and transport solution used in the United States does not contain an antifungal drug, and may provide a permissive environment for donor contaminant fungi to grow.
Project Goals
The specific research aim is to develop a liquid solution for corneal tissue storage and transport that contains an antifungal drug that inhibits growth of contaminant fungi for at least 14 days following donor tissue extraction. The solution must be usable in compliance with current corneal tissue storage, evaluation and transport procedure guidance and regulations.
Phase I Activities and Expected Deliverables
The primary activity is formulation of a liquid solution that serves the purpose of currently available products, and that contains an effective antifungal that is safe for use and non-damaging to corneal tissue.
Monthly Deliverables:
 Assemble list of viable antifungals (e.g., Amphotericin B) and design in vitro and in vivo studies to
demonstrate effectiveness against Candida and other fungi, optimize antifungal concentration, and
demonstrate that the product does not adversely affect corneal tissue quality and health.
 Present preliminary data on efficacy and safety, showing effective antifungal properties without compromise
of corneal tissue health and quality.
 Present data supporting optimized antifungal and ingredient concentrations, and advanced evidence of
product suitability for further development and ultimate regulatory evaluation.

Impact
A corneal storage and transport solution containing safe and effective antifungals could reduce morbidity, vision loss and healthcare expenditures due to post-keratoplasty fungal endophthalmitis, and could reduce the recent increase in fungal endophthalmitis incidence. Previously, a product currently on the market was reformulated to include antibiotics effective against bacteria, and surveillance data indicated a subsequent decrease in bacterial endophthalmitis although causality was not established. We speculate that adding an antifungal may result in similar effects for fungal endophthalmitis, preventing these devastating and sight-threatening eye infections. We expect many stakeholders will benefit from this product going to market. Eye banks, which harvest donor corneas where contamination might occur, will have an added layer of security by storing tissue in antifungal-containing media immediately after harvest, which will prevent pathogenic fungi from growing. In addition, the Eye Bank Association of America, which collects and reports on adverse events linked to corneal transplants, has been advocating for a product like this for several years in an effort to reduce the increasing trend in fungal endophthalmitis. Finally, this product would be a straightforward win for a small business; corneal storage solution is universally used and required by those who work with and transplant corneal tissue and the urgent need for reduced risk of fungal contamination during the corneal harvest-storage-transplant process is currently unmet by any other product on the market.
Commercialization Potential
Successfully developed and marketed to surgeons, this product will have significant commercial potential as there is currently no similar competing product available to corneal surgeons in the United States. The primary target market for this product will be corneal surgeons who perform corneal transplants (keratoplasties), as well as eye banks who procure corneal storage media and must respond to the demands of their clients (corneal surgeons).

surveillance. For example, PulseNet, a national subtyping network of over 80 labs nationally and over 80 international laboratories, tracks foodborne outbreaks and currently relies on isolates for generating molecular fingerprints for foodborne bacterial surveillance for over 90,000 isolates.
In response to these new challenges, this proposal aims to develop new molecular fingerprinting techniques that can be used with specimens such as stool. The assay approach will rely on PCR amplification of informative regions and sequencing of amplicons using short read technology such as the Illumina platforms. An algorithm for the identification of heterogeneous regions for isolate subtyping and design of conserved flanking primers is necessary for the development of these assays, but are currently not available commercially or in the open source community. Providing an algorithm for development of these primers, or the primers generated from the algorithm, would be of great use to the public health community and could be used in both public health laboratories nationally and internationally as well as infection control groups in a health care setting.
Project Goals
The offeror will provide an innovative bioinformatics algorithm in their software platform that allows the user to design amplicons that can be sequenced to determine the subtype of a pathogen. Specifically, the software must identify

heterogeneous regions which are useful for strain typing and also flanked by conserved sites suitable for primers. The resolution of strain subtyping must be equivalent to current WGS-based subtyping techniques for isolates and can distinguish isolates associated with an outbreak from background cases. The algorithm must include an option to measure and adjust the amount of heterogeneity so that the user may decide how much is needed for subtyping. The software must identify these regions either automatically (defining subgroups naturally) or allow the user to pre-define the groups or subtypes for which the primers will be designed and include the ability to consider Illumina or other sequencing adapters and multiplex barcodes when testing for primer-to-primer interactions. Ideally, the software must be packaged so that it could work directly with existing infrastructure such as high-performance computing (HPC) resources.
Phase I Activities and Expected Deliverables
The contractor will design the algorithm to meet the above specifications and perform in silico validation of amplicons. The contractor will use epidemiologically relevant sequence data from the relevant pathogen groups for testing their algorithm and will be expected to provide preliminary results upon completion of phase I. The results must include primers, fasta files for amplicons, in silico PCR results, annotated bedgraphs and coverage histograms.
For Successful Phase I Awardees ONLY (Expected Phase II Deliverables)
In Phase II, the contractor will further refine the algorithm and primers based on laboratory results. The contractor will also evaluate the usefulness of the software for developing assays for generating molecular fingerprints of pathogens. At the completion of Phase II, the contractor will provide a stand-alone license for a single copy of the software which is a compiled, command-line binary that runs on the high performance computing clusters and standalone Linux workstations installed with Ubuntu; sample configuration files and documentation must be included in the binary install. With this software, the developers must create training documentation that instructs the user in how to operate the software to generate primers in conserved regions that flank heterogeneous regions and generate the output outlined in the Activities and Expected Deliverables section above.
Impact
This novel bioinformatics approach would enable public health professionals to identify phylogenetically informative regions and design rapid PCR subtyping approaches that detect and subtype pathogens directly from disease state stool and other specimen types. In addition, this approach will significantly improve assay development strategies by incorporating multiple steps to assay design into a single, streamlined platform. Furthermore, the assays that are developed will be deployed in public health labs worldwide, allowing for continued surveillance of these pathogens and the identification of outbreaks in the absence of cultures.
Commercialization Potential
Currently there are no software programs on the market that design primers around heterogeneous regions in bacterial genomes for a sequencing-based subtyping workflow. The addition of this product to the subtyping market is necessary now that CIDT tests are being more widely used not just for identifying pathogens associated with foodborne infections but also febrile illnesses, respiratory illnesses, and other disease types. Due to the rapid adoption of CIDTs in the health sector, the design of novel and innovative approaches for subtyping directly from specimens is needed within the public health surveillance community. With the product the awardee designs, subtyping can begin with the same specimen on which a CIDT test is performed, rather than the isolate which can take several days to weeks to culture. By being able to more rapidly subtype pathogens, outbreaks are detected sooner which means the public can be alerted to health threats sooner and more lives saved. This software product or the primers designed using this product would be of interest to public health professionals and those in the health care sector that need to identify related illnesses through subtyping to detect and stop outbreaks.

Fast-Track proposals will not be accepted.
Number of anticipated awards: 1
Budget (total costs):
Phase I: up to $150,000 for up to 12 months

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Background
Several species of the genus Brucella, Gram-negative, facultative intracellular coccobacilli, cause brucellosis in animals and humans. Whereas the zoonotic potential of Brucella melitensis, B. abortus, and B. suis is well known, and manifests itself in a disease burden of more than 500,000 annual human cases worldwide, the extent to which B. canis is transmitted from infected dogs to humans is unclear. Human brucellosis infections are difficult to diagnose and difficult to treat. There is no human vaccine available in the United States. B. melitensis, B. abortus, and B. suis are Select Agents, with a low infectious dose, which makes brucellosis one of the most frequent laboratory-acquired infections. Serological assays are a critical tool for diagnosis of brucellosis and for monitoring exposed personnel for evidence of infection. However, there are currently no
B. canis serological tests available to detect and measure the humoral immune response in humans.
Brucella strains such as B. melitensis, B. abortus, and B. suis have an O-specific polysaccharide as part of the outer membrane lipopolysaccharide and are designated as “smooth” strains. In contrast, other strains such as B. canis, B. ovis, and the live attenuated bovine vaccine strain B. abortus RB51, are missing the O-specific polysaccharide from the outer
membrane lipopolysaccharide and are designated as “rough” strains. The lack of this specific lipopolysaccharide means that standard Brucella serological assays do not work for “rough” strains. The identification of specific antigens of rough Brucella strains is a prerequisite for the development of serological assays.
Project Goals
The goal of this project is to develop assays for detection of antibodies against rough Brucella strains such as B. canis and bovine vaccine strain B. abortus RB51, which are known human pathogens. Presently, we are not able to offer serological diagnosis to infected patients, or monitoring to exposed individuals.
Phase I Activities and Expected Deliverables
Phase I: Screen entire proteome of Brucella species using sera from canine and human infections to identify specific B. canis and B. abortus RB51 antigens that are recognized by antibodies. If successful, antigens (e.g., proteins) identified in Phase I will be used in Phase II to develop a diagnostic serologic assay.
For Successful Phase I Awardees ONLY (Expected Phase II Deliverables)
Develop optimized serodiagnostic assays with high specificity and sensitivity based on the Phase I analysis of the humoral immune response to B. canis. Current Brucella serology assays lack specificity and sensitivity and are not able to detect infection by rough strains such as B. canis. Depending on data from Phase I, combinations of antigens could be used to detect infection by both smooth and rough strains.
Impact
At present, we are unable to gauge the burden of B. canis human infections or risk associated with exposure to B. canis infected animals because we have no diagnostic tools for serological surveillance. We are also not able to measure the antibody response in potentially exposed occupational risk groups such as veterinarians, physicians, clinical microbiologists, dog breeders, dog kennel and animal shelter workers, and in pet owners whose dogs develop B. canis infection. Comprehensive screening of the B. canis proteome for specific antigenic targets would allow for development of serological methods to detect and respond to human exposure cases and strengthen public health in the US and globally by gaining insight into B. canis dog-to-human transmission patterns and risk factors.
Commercialization Potential
The worldwide burden of brucellosis has been estimated at 500,000 cases/year; however, this is likely underestimated due to the lack of optimal diagnostics. All presently available assays to detect host antibody responses to exposure and infection by smooth Brucella strains are lacking specificity and sensitivity. Inactivated whole cell preparations or LPS extracts serve as crude capture antigens with high levels of cross-reactivity. There are no serology assays available for detection of human antibody responses against rough Brucella strains. There is a critical need to find specific, immunogenic markers whose epitopes can be analyzed, synthesized and developed into optimized serological diagnostic assays. Development and use of

such assays would be of interest to public health laboratories, private diagnostic laboratories, and academic brucellosis researchers.

Fast-Track proposals will not be accepted.
Number of anticipated awards: 1
Budget (total costs):
Phase I: up to $150,000 for up to 12 months
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Background
Rabies, caused by Rabies virus (RABV) and related lyssaviruses, is one of the most deadly zoonotic diseases responsible for up to 70,000 estimated human deaths worldwide each year. Rapid and accurate laboratory diagnosis of rabies is essential for timely administration of post-exposure prophylaxis in humans and control of the disease in animals. Currently, only the direct fluorescent antibody (DFA) test is recommended for routine rabies diagnostics. DFA is a rapid and sensitive method, but its accuracy depends on the quality of brain tissue, availability of high-quality anti-rabies diagnostic conjugates, accessibility to a fluorescence microscope and, most importantly, an experienced diagnostician. Reverse Transcription-Polymerase Chain Reaction (RT-PCR)-based diagnostic methods have been widely adapted for the diagnosis of other viral pathogens, but there is currently no widely accepted rapid real-time RT-PCR assay for the detection of all lyssaviruses. The CDC rabies molecular diagnostic team has developed and validated a new multiplex real-time RT-PCR assay named LN34, which uses a combination of degenerate primers and probes along with probe modifications to achieve superior phylogenetic breadth, while maintaining sensitivity and specificity. The primers and probes of the LN34 assay target the highly conserved non-coding leader region and part of the nucleoprotein (N) coding sequence of the lyssavirus genome to maintain assay robustness. The probes were further modified by locked nucleotides to increase their melting temperature to meet the requirements for an optimal real-time RT-PCR assay. The LN34 assay was able to detect all rabies-causing variants in a validation panel that included representative RABV isolates from most regions of the world and 13 additional lyssavirus species. The LN34 assay was successfully used for both ante-mortem and post-mortem diagnosis using over 200 clinical samples as well as field derived surveillance samples. An algorithm of using the LN34 assay for rabies diagnostics has been developed based on the international validation data. The algorithm also comprised of a beta-actin real-time RT-PCR assay to measure the quality of the sample tested. This combined assay represents a major improvement over previously published rabies-specific PCR or RT-PCR assays because of its ability to universally detect RABV and other lyssaviruses, its high throughput capability and its simplicity of use, which can be quickly adapted in a laboratory to enhance the capacity of rabies molecular diagnostics. The LN34 assay provides an alternative approach for rabies diagnostics, especially in rural areas and rabies endemic regions that lack the conditions and broad experience to run the standard DFA assay. Nevertheless, the cost of the assay will be an important factor for its adaptation both in US (rabies surveillances test more 100,000 samples each year) and developing countries. We are looking for a products to further combined the LN34/beta-actin real-time RT-PCR assays and reduce the reaction volume to simplify the assay cost and set-up.
Project Goals
1.
Develop a reaction kit combining the LN34/beta-actin real-time RT-PCR assays into a single reaction.
2.
Select enzymes and reaction volumes to further reduce the cost for the assay.
3.
Develop a dry-bead format and optimize the reaction conditions for diagnostic laboratories.
Phase I Activities and Expected Deliverables
1.
Utilize artificial positive control RNA and rabies-negative brain samples to optimize the multiple assay combining LN34/beta-actin real-time RT-PCR assays (end of the 4th month).
2.
Test low cost enzymes to further reduce the cost of the reaction kit, develop a dry-bead format for the reaction kits to improve the stabilities of the reaction kits (end of the 6th month).
3.
Optimize the reaction in a low volume format to further reduce the cost of the reaction (end of the 6th month)
For Successful Phase I Awardees ONLY (Expected Phase II Deliverables)

-
1.
Large-scale production of the optimized real-time RT-PCR reaction kits and the start of large scale validation of these kits in multiple laboratories where both CLIA samples and field collected samples will be tested. The validation data must lead to the development of a standardized algorithm of using this assay for rabies diagnostics.
2.
Based on the validation data through multiple laboratories, a standardized commercial kit will be optimized and finalized at the end of 24 months. A widely available and utilized new PCR-based rabies diagnostic assay will enhance rabies diagnostics and surveillances, and make a key contribution to the goal of canine rabies eradication by 2030.
Impact
A PCR-based rabies diagnostic is expected to be recommended later this year as multiple research and validation data for using PCR-based rabies diagnostics are highly supportive. Laboratories in the US and in most developing countries have real-time PCR capability and have the expertise required for conducting real-time PCR assays for the diagnosis of viral infections and, therefore, for rabies molecular diagnostics.
Successful commercialization of a real-time PCR-based rabies diagnostic will further improve the rabies diagnostic capacities in many laboratories domestically and internationally. An assay that can detect highly variable rabies viruses and other lyssaviruses can be used in areas endemic to both rabies viruses and other lyssaviruses and will enhance clinical rabies diagnostics and surveillance.
Commercialization Potential
This new multiplex assay should be able to detect all the available rabies virus variants and other lyssaviruses. It can be used for rabies diagnostics domestically and around the world, especially in regions with both canine rabies and lyssaviruses. Development of this assay could represent a significant advancement compared to previously published PCR-based rabies diagnostics assays, which only detected a limited number of rabies variants or limited other lyssaviruses.

Fast-Track proposals will not be accepted.
Number of anticipated awards: 1
Budget (total costs):
Phase I: up to $150,000 for up to 12 months
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Background
Next generation sequencing (NGS) is used to determine the genetic sequence of pathogens. For public health laboratory surveillance activities, a high quality genome sequence is required to serve as a comparator or “reference sequence.” To generate the highest quality reference genome sequence requires the use of optical mapping (OM) to resolve sequence inversions and identify the ends of chromosomes. An optical map is like a restriction enzyme map for the entire genome. Currently, OM data and NGS data are assembled using separate software systems. However, no tool exists that can fully integrate all types of NGS data and OM data for graphical display. The few tools that do exist are limited in their functionality and visualization capabilities. This is especially problematic when working with large genomes with tens of thousands of data points that can take multiple days to analyze.
Project Goals
Although OM is currently used as a quality control tool for NGS assemblies, if an efficient tool were available to combine both datasets, optical mapping data could be used to accelerate or automate genome assemblies. Development of a tool would allow users to integrate optical mapping and sequencing data from any platform, thereby reduce investigation response time and increase sequence data quality.
Phase I Activities and Expected Deliverables

The project goal is to create a user-friendly graphical interface that can assemble, combine, and compare OM and NGS data generated from any platform. This tool will automatically scale optical maps based on NGS assemblies and should scale well with larger multi-chromosome genomes. Algorithms will be developed to match NGS assemblies to optical maps, scaffold sequencing reads using optical maps, and perform quality filtering for both sequencing reads and optical mapping reads. The tool will also have standard report generation and data export capabilities. All methods should be callable via a RESTful API. The tool will have access/group control, and users in the same group will be able to share data.
Month Deliverable 1 Import OM and NGS data from any platform 2.5 Develop algorithms to scaffold sequence data using optical mapping data 4 Develop algorithms to compare optical maps with NGS assemblies 6 Develop graphical interface and reporting
For Successful Phase I Awardees ONLY (Expected Phase II Deliverables)
Updates and added features to the tool and algorithms will be driven by advancements in OM and NGS technologies. Possible updates to the tool in Phase II include integration of long read NGS data to be used for scaffolding, automated misassembly prediction algorithms, collaboration capabilities, and improved graphics and usability.
Month Deliverable 9 Integrate long read NGS data for scaffolding 12 Develop misassembly prediction algorithms 15 Increase collaboration capabilities 18-24 Optimize commercialization potential
Impact
By developing a software tool that can visualize all types of optical mapping and NGS data, bioinformaticians can more effectively analyze sequencing data for various customers. Algorithms developed for this project could also be applied to future analytical tools. Further, this tool could be distributed to customer laboratories so that researchers can fully interrogate or reanalyze their own sequence assemblies, which is technically difficult at this time.
Commercialization Potential
The genome sequencing market is expected to grow to $20 billion by 2020. As this market grows and the complexity sequencing analysis increases, there will be broad demand for data analysis and visualization tools. The product market will only be as large as the overlap of both the sequencing and optical mapping markets (maximum $1B), but the technology developed for analyzing and visualizing sequencing data can be applied to new analytical tools for the larger market. In the future, we envision suites of tools for performing multivariable analysis of genomic sequencing data.

Fast-Track proposals will not be accepted.
Number of anticipated awards: 1
Budget (total costs):
Phase I: up to $150,000 for up to 6 months
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Background
Molecular identification of infectious agents most commonly requires nucleic acid extraction, PCR amplification, and sequencing. Despite the availability of automated platforms, most standard laboratory protocols rely on manual procedures. Importantly, exposure to infectious materials during manual processing is a major safety concern, particularly when processing highly infectious agents. Moreover, manual processing affects reproducibility of testing, reduces throughput and increases sample processing time; as a consequence, time to accurate identification is delayed. Manual processing also introduces an increased risk of contamination which may confound results by the amplification of contaminating nucleic acids many fold during PCR processing. Thus, the implementation of a fully automated, closed platform is highly desirable for the efficient molecular identification of infectious agents, including hepatotropic viruses and other enteric, airborne and blood-borne pathogens. The CDC Division of Viral Hepatitis has designed and built an automated platform for the construction of DNA libraries from clinical samples in a compound fashion suitable for amplicon deep sequencing using the popular MiSeq instrument. Whereas capable of high throughput sample processing, this workstation is expensive and has a relatively large footprint. These characteristics impose limitations for the commercialization of a workstation suitable for smaller laboratories and clinical facilities. Thus, there is an important, and increasingly growing need for significantly smaller, ideally benchtop, comprehensive workstations capable of performing the same compound processes at a considerably reduced cost, yet exhibiting comparable biosafety standards and quality results. Whereas a number of units are commercially available for each of the individual steps of the compound process, there are no existing platforms capable of performing the entire process from A to Z in an automated, compound manner.
Project Goals
The aim of this proposal is to develop and evaluate a new, small footprint, benchtop automated nucleic acid extraction, amplification and sequencing system that fundamentally improves laboratory safety and quality control (QC). This platform consolidates all manual laboratory operations related to next-Generation Sequencing into a single compound process performed automatically by a single workstation in a small footprint, ideally at a reduced cost. The workstation should be

capable of being used in support of clinical testing, surveillance programs and outbreak investigations conducted by clinical and public health laboratories using NGS, which recently became a mainstay technology for the detection of pathogen drug resistance and transmission networks enabling public health interventions and management of patients in clinical settings. The workstation should be capable of performing RNA/DNA extraction from clinical samples, RT-PCR, nested PCR/tagging, amplicon clean up, quantification and pooling, resulting in DNA libraries ready for amplicon deep sequencing using the MiSeq platform. Whereas assembling workstations by integrating existing liquid handling robotic stations with stand-alone thermal cyclers, spectrophotometers and cappers/decappers (for specimen aliquoting) is possible, the resulting process is prone to all of the negative characteristics of manual processing outlined above. The goal of this project is to devise a new, affordable instrument that can perform all necessary functions starting from receipt of biological samples (such as whole blood, plasma, serum, stool, sputum and other) to construction of DNA libraries. This novel platform would be expected to significantly reduce constraints for established complex molecular next-generation sequencing-based methods. It should also contribute to strengthening quality control and biosafety in clinical and public health laboratories. This workstation will be capable of preparing DNA libraries for different pathogens and will require no manual steps except for the initial setup of the instrument for loading reagents/kits and clinical specimens. The unit is expected to be sufficiently flexible to accommodate different laboratory protocols. It should be readily adaptable to: (1) generate DNA libraries for the MiSeq illumina; (2) handle biological specimens such as whole blood, plasma and serum; (3) handle variable numbers of specimens from low to medium throughput; (4) use specific/customized reagents and kits for different pathogens. Availability of various preloaded programs for specific processing of specimens from different pathogens is also desirable. In such cases, user input should allow the incorporation of specific conditions (pathogen, number of samples, etc.) into the workstation controller to allow specific conditions from run to run. Substantial modifications and new programs must be registered in the workstation for quality control management in clinical and public health laboratories. Handling of laboratory protocols by the workstation should be highly reproducible and accurate to comply with clinical test requirements and automatic reporting on conducted tests should be outputted and available to managers and accounts with elevated privileges.
Phase I Activities and Expected Deliverables
During Phase I, the unit design and industrial diagrams with the final layout will be generated. Computer modeling of the final design is required for testing virtual laboratory protocols and fine tuning of individual processes and steps. The workstation is expected to perform the entire laboratory protocol starting from clinical samples to the NGS library within a few hours (between 8-12 hours) without any user intervention. It will be easily programmable, accommodate different specimen types (whole blood, plasma, and serum), variable numbers of specimens and sample volumes. It will be controlled by computer programs, which may be initiated manually or automatically using barcoded reagent kits. For enhanced QC, workstation data will be used to automatically detect instrument errors and control instrument maintenance.
For Successful Phase I Awardees ONLY (Expected Phase II deliverables)
For Phase II, full development and assembly of the pilot workstation is expected. It is important that the company awarded the contract demonstrate feasibility of performing all of the required steps to convert the prototype into a full-fledged platform. As aforementioned, the workstation is expected to be suitable for processing clinical samples for identification of pathogens. The platform will be extensively tested for its performance using serum panels specifically developed from specimens collected from individuals infected with hepatitis C viruses. Once developed, the workstation is expected to be thoroughly evaluated for use with other pathogens as well. Robustness of the automated workstation will be evaluated in comparison with currently established laboratory gold standards. Each step of the process will be assessed for reproducibility, accuracy, sensitivity, specificity, potential for cross-contamination, yield, time-to-run, safety, and throughput. Another criterion is the long-term stability of performance during continuous use. A full biosafety evaluation of the unit will have to be performed. Assessment of aerosols and user exposure will be conducted. Safety guidelines and recommendations will be put forward. This unit is expected to have a large market for state health laboratories and clinical laboratories, as well as reference laboratories worldwide.
Impact
Implementation of the workstation allows for continuous monitoring and evaluation of data, minimizing human errors and significantly improving accuracy of clinical testing and surveillance. It will significantly reduce hands-on time and exposure to infectious materials, thus fundamentally improving safety of laboratory work. The instrument is expected to have a broad use in public health and clinical laboratories. It is expected that the workstation will significantly improve quality of testing and accelerate sample processing for the identification of infectious agents and for outbreak investigations and molecular surveillance of different infectious agents. Both clinical and public health laboratories are expected to benefit from a commercially available fully automated, inexpensive, benchtop workstation for performing NGS. It will significantly reduce

complexity of the laboratory process for technical personnel in clinical and public health laboratories, while cardinally improving throughput and reproducibility of testing, reducing contamination, and keeping the cost per tested specimen low. Availability of the workstation makes massive and complex genetic testing as defined by Advanced Molecular Detection affordable and attainable for many laboratories in the United States and worldwide, fundamentally improving outbreak investigations, public health surveillance, and the identification and treatment of infectious diseases.
Commercialization Potential
The laboratory workstation is expected to have a very large market owing to a significant and rapidly growing need for complex genetic identification and testing of infectious agents for patient management in clinical settings (drug and antibiotic resistance) and for devising public health interventions to control viral and bacterial diseases. Each clinical and public health laboratory that is expected to conduct genetic testing and identification but lacks equipment and personnel capable of handling the demands of NGS is a potential customer. Integration of liquid handling platforms with many instruments is currently used to manage such tasks. However, a prohibitive cost, large footprint and complexity of the integrated assemblies reduce their application. A single, affordable, standalone instrument with a small footprint, specifically designed for performing all laboratory procedures required for NGS of different pathogens in a completely automated, closed mode will be useful to many laboratories in the United States and worldwide.

Fast-Track proposals will not be accepted.
Number of anticipated awards: 1
Budget (total costs):
Phase I: up to $150,000 for up to 6 months
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Background
Persons who inject drugs (PWID) are at increased risk of acquiring HIV, hepatitis C virus (HCV), hepatitis B virus (HBV), and bacterial infections. Persons who inject drugs can substantially reduce their risk of getting and transmitting HIV, viral hepatitis and other blood borne infections by using a sterile needle and syringe for every injection. In many jurisdictions, persons who inject drugs can access sterile needles and syringes through syringe services programs (SSPs) and through pharmacies without a prescription (http://lawatlas.org/ ). The science shows that access to sterile syringes can reduce needle sharing and does not result in increased injection frequency, injection drug use, or unsafe disposal of syringes.
The National Alliance of State and Territorial AIDS Directors (NASTAD) and the Urban Coalition for HIV/AIDS Prevention Services (UCHAPS) published “Syringe Service Program Development and Implementation Guidelines for State and Local Health Departments” in 2012 (http://www.uchaps.org/assets/NASTAD-UCHAPS-SSPGuidelines-8-2012.pdf ). These guidelines state that pharmacies and pharmacy organizations are a resource and strong ally for SSPs and describe a
“Pharmacy Distribution Model” and “Pharmacy Voucher Program” as service delivery models for SSPs. Pharmacists are
equipped to apply risk reduction strategies among PWID by selling non-prescription syringes, promoting safe injection practices, discussing safe syringe disposal, performing HIV and HCV testing, administering recommended immunizations (e.g., Tdap, hepatitis A, hepatitis B), providing counseling and education (e.g., sexually transmitted infections, HIV, HCV, HBV, substance abuse), assessing medications and adherence, and linking patients to appropriate healthcare. In addition, pharmacists counsel patients and family members on naloxone administration in order to address injection related opioid overdose concerns. A training program for implementation of a pharmacy-based statewide naloxone distribution program demonstrated that promotion and distribution of materials along with training resulted in increased dispensing of naloxone (Morton KJ, J Am Pharm Assoc 2017 https://doi.org/10.1016/j.japh.2017.01.017 )
Pharmacists are legally allowed to sell sterile needles and syringes in most areas of the United States; in fact, other than through SSPs, pharmacies are essentially the only option for a person to access a sterile syringe legally. As an example of the magnitude of the syringe sales in pharmacies, a 2015 survey of nearly 80% of the more than 1,000 community pharmacies in Massachusetts, where there is no limit on the number of syringes that can be sold, found that 97% of community pharmacies reported selling nonprescription syringes. They also reported median sales per store of 75 per week which translates into nearly 100,000 nonprescription syringes sold statewide per week (Stopka TJ, J Am Pharm Assoc 2017 https://doi.org/10.1016/j.japh.2016.12.077 ).

Syringe access programs provide a framework, typically developed by a state or local health department, within which nonprescription syringe sales (NPSS)-specific guidance for HIV prevention counselling, pharmacist and pharmacy staff education, syringe disposal or referrals are provided. To date, three states, Minnesota, New York and California have established pharmacy-based syringe access programs. These programs can serve as a model for the establishment of similar services in areas with injection drug use and low SSP coverage. However, in most pharmacies, NPSS is left to the discretion of the pharmacist. Education and tools are needed to support pharmacists in the delivery of risk reduction services to lower risk behaviors, facilitate safe disposal of syringes, and provide referrals for substance abuse treatment.
Project Goals
The primary goal of this project is to develop a toolkit for pharmacies to implement risk reduction services targeting PWID who access syringes through pharmacies. Pharmacists should be provided training and tools to implement pharmacy-based syringe programs and risk reduction services in order to improve the health of their local communities through the prevention of blood-borne pathogens, safe syringe disposal, testing for HIV and HCV with rapid point-of-care tests, linking to clinical care providers, mental health care providers, SUBSTANCE ABUSE PROVIDERS and other services. The training curriculum can be developed for on-line use or for in-person use (e.g. to be delivered at pharmacy conferences or meetings) and should be designed such that Continuing Pharmacy Education (CPE) accreditation can be attained by pharmacists and pharmacy technicians. The final development of the on-line or in-person training and accreditation can be secured during Phase II.
Phase I Activities and Expected Deliverables
Develop a prototype for a pharmacy-based syringe program and toolkit to implement risk reduction services for pharmacy-based risk reduction services associated with NPSS. Tools can include products that provide safer methods for injection and for safe syringe disposal. For example, risk reduction materials may include commercially available products provided to PWID such as alcohol swabs, sterile filters for needles, sterile ‘works,’ and a portable sharps container. The toolkit should include pamphlets that describe safe injection and safe syringe disposal and a list of referrals tailored to the local area developed in conjunction with the local health department. The toolkit should be packaged in a manner that facilitates distribution from the pharmacy either from a counter or a private consultation room. The toolkit should be designed so it will be affordable to potential customers which may include pharmacies, health departments, or commercial companies that sell sterile needles, sharps containers, or other products used for safe injections. The design may be tiered such that different customers may purchase individual components that meet their needs. The offeror may propose development of new materials to support safe injection, risk reduction, and safe syringe disposal (e.g., a new sterile filter to attach to commercially available syringes that will be easy to use and acceptable to PWID). The offeror should develop a training curriculum to implement a prototype for a platform for pharmacists and pharmacy staff to implement the toolkit for pharmacy-based risk reduction services associated with NPSS to PWID within the usual customary practice of their business process. The offeror should propose a pilot of the training curriculum and prototype in several pharmacies in one jurisdiction that would benefit from enhanced NPSS for PWID. The training and prototype should accommodate the laws and regulations for pharmacy syringe sales in that jurisdiction. The pilot should quantify the number of PWID clients served with the toolkit, numbers of syringes dispensed, and a variety of other metrics for monitoring and evaluation as outlined from the publication from the National Alliance of State and Territorial AIDS Directors (NASTAD) and the Urban Coalition for HIV/AIDS Prevention Services (UCHAPS) guidelines on “Syringe Service Program Development and Implementation Guidelines for State and Local Health Departments” http://www.uchaps.org/assets/NASTAD-UCHAPS-SSPGuidelines-8-2012.pdf ). Other metrics may be proposed as well.
Impact
If pharmacies are provided with toolkits, they can collaborate with state and local health departments, insurers, syringe-service programs, and other healthcare facilities to provide linkage and continuity of care, testing for blood-borne pathogens, and other risk reduction services for PWID in order to address public health concerns. Pharmacists can be a vital resource for prevention of transmission of blood-borne pathogens among PWID if they are given the appropriate tools.
Commercialization Potential
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Pharmacists and pharmacy technicians can obtain proprietary continuing education and/or certificate programs that may be paid for by the individual pharmacist or technician or paid for by a pharmacy company.

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Pharmacies, health departments, insurers or other organizations can purchase materials for a pharmacy-based syringe services program that may include web-based materials, printed materials, and a package of materials to be distributed along with syringes at the time of sale to support risk reduction (e.g., disposal container, alcohol swabs, materials needed for clean injections, sterile filters for needles).
•
Pharmacies, health departments, insurers or other organizations can purchase newly developed products to support safe injection (e.g., a new filter to attach to syringes).

Fast-Track proposals will not be accepted.
Number of anticipated awards: 1
Budget (total costs):
Phase I: up to $150,000 for up to 6 months
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Background
Current inactivated polio vaccine (IPV) products are sensitive to both freezing and elevated temperatures and therefore must be shipped and stored between 2°C and 8°C, a requirement that imposes financial and logistical challenges in their global distribution. This results in significant wastage of vaccine in the current formulations since multi-use vials must be discarded at the end of an immunization session and cannot be returned to the refrigerator for later use. Because IPV cannot be lyophilized in its current formulation, the vaccine cannot be dry-preserved.
Inactivated polio vaccine products based on the attenuated Sabin poliovirus strains have been developed as an alternative to the inactivated virulent strains used in conventional IPV, and such products have been licensed for use in several countries. Whereas stabilization of vaccines can be achieved in a partially dried state for a limited amount of time (several days) when stored at room or higher temperatures (i.e., 37°C), long-term stabilization of the vaccine requires arresting molecular mobility to stop the degradation processes during storage. Drying polio vaccines can be very damaging if performed in the absence of protective fillers such as simple sugars like sucrose.
Alternative preservation methods that increase vaccine stability at high temperatures could reduce shipping costs, improve cold chain logistics, and reduce vaccine wastage in the field.
Project Goals
Proposals are solicited for the development of a heat-stable, Sabin-based inactivated polio vaccine administered by needle and syringe. Heat stability is defined as no loss in antigenicity (as measured by standard vaccine potency tests) and no reduction in immunogenicity (as measured in accepted animal models for IPV potency) following heat challenge.
Phase I Activities and Expected Deliverables
1.
Develop a formulation and process for dry-preserving polio vaccines.
2.
Generate a Sabin-IPV by inactivating dry-preserved oral polio vaccine (OPV).
3.
Assess heat stability by in vitro potency tests, at the following storage conditions:
a. 1 hour at 70°C
b. 1 month at 37°C
c. 1 month at 25°C
d. 3 months at 37°C
e. 3 months at 25°C
4.
Prepare vaccine formulations for in vivo IPV potency assay using Wistar rat model.
For Successful Phase I Awardees ONLY (Expected Phase II Deliverables)

1.
Optimize formulation and processing parameters for heat stable Sabin-IPV.
2.
Production scale up for heat stable Sabin-IPV and generation of GMP lots.
Impact
A heat stable Sabin-IPV could increase vaccine availability by reducing storage and transport costs, as well as reducing vaccine wastage. This would potentially allow vaccines to be transported to areas of the United States and in the developing world where using icepacks or coolers to transport vaccines is challenging. A heat stable vaccine technology could significantly impact the progress of polio eradication as well as immunization programs for other vaccine preventable diseases.
Commercialization Potential
A heat-stable Sabin-IPV would most likely be licensed to vaccine manufacturers. Polio vaccine manufacturers produce and distribute vaccines to prevent polio in the US and globally to support the Global Polio Eradication Initiative.

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

Available Funding Topics