HHS Annual SBIR Contract Solicitation

038 Improve Contextual Awareness using Social Network Data

Fast-Track proposals will not be accepted.

Direct to Phase II will not be accepted.

Number of anticipated awards: 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

Public health activities within the chronic disease realm have predominantly relied on survey data to gather information on disease prevalence, behavioral models, risk populations, risk probability, and disease progression. Surveys are subject to a number of known limitations, e.g., respondents’ reluctance to participate, social desirability biases, lag time between questionnaire design, data collection and availability, and intermittent coverage of important topics due to associated implementation costs.

Chronic disease control experts and policy makers lack access to real time data and efficient tools to provide contextual awareness to the surveys that are implemented for chronic disease surveillance and program management. The implications of not having a timely and broader understanding of the environment/community affects the representativeness and demographic specificity of the assessment and the data used to drive policy and interventions.

This proposal seeks to develop an analytics platform that can be leveraged by both public health and clinical care to build a cohort around a given chronic indicator (e.g., Tobacco use) by harnessing web and social network data (e.g., Twitter, Facebook, Search data etc.). This national cohort can be utilized to provide specific insights both longitudinally and prospectively to help investigators reveal largely assumption-free insights via systematic generation of hundreds of possible outcomes rather than an arbitrary priority selection of a few outcomes. The approach can also potentially support traditional surveillance by serving as a guiding tool for vetting the inclusion and exclusion of survey questions.

Project Goal

CDC seeks to support the development of an analytics platform that harnesses web and social network data and delivers novel surveillance capabilities for chronic disease indicators. The proposal seeks to build large nationally representative cohorts of social network users for each indicator by key characteristics (e.g., demographics, activity, etc.) that are systematically inferred from user profiles, tweets, posts, and search behaviors. The project will employ

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appropriate informatics tools and techniques to extract and infer traits among the data and allow the creation of cohorts that are reflective of regional U.S. Census estimates. These cohorts can then be analyzed to gain insights and answer a diverse set of questions for national, subnational, and demographic-specific prevalence estimates. Further analysis could help identify co-occurring themes and potentially answer the questions “How many” and “Why?” for any given indicator.

Phase I Activities and Expected Deliverables

• Conduct a review of the data access and use policy of Twitter, Facebook and Search engine data

• Conduct a preliminary study to determine applicable social network data streams and public health indicators

• Identify appropriate informatics solutions (e.g., natural language processing algorithms) to access, monitor, and extract data

• Develop a prototype analytics platform with “Cohort builder“ function and demonstrate the creation of least one nationally representative cohort in the chronic disease domain

Impact

The overall goal is to leverage innovative health technologies to improve health outcomes and subsequently quality of life for individuals living with chronic disease. An analytics platform using social data can more efficiently provide deeper insights into health behaviors as they are occurring and improve policy development as well as delivery of interventions. By harnessing the data produced by social events and interventions, programs can be evaluated as they are implemented, hypothetically generating real-time feedback to maximize effectiveness. Web and social network data can be an important source for identifying new hypotheses and can greatly impact the future direction and investments of the center. The cohort builder and the cohort analysis capabilities will provide benefits to chronic disease surveillance and program management practices. Access to social behavior data in real time will help to drive:

• a contextual awareness to the survey, i.e., know your population

• development/modification of survey questions to improve survey data quality

• ability to monitor changes associated with program interventions between surveys

Commercialization Potential

The analytics platform can immediately operate on a subscription based revenue model from public health and clinical care. Any organization can diversify to support other healthcare initiatives (e.g., Community Health Needs Assessment, etc.) as revenue domains. Information technology companies, government, health systems, health information exchange entities, health care providers, and public health systems are a few of the potential markets.

014 Multiplexed Digital Counting of Single Molecules for Advanced Molecular Diagnosis

Fast-Track proposals will not be accepted.

Direct to Phase II 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

This topic proposal will evaluate the methodological limitations and benefits of direct highly multiplexed digital quantification (HMDQ) of molecules present in samples used in the diagnosis of infectious diseases. Although many multiplexed, quantitative assays have been described for infectious diseases, they suffer from several limitations: 1) Mixed infections are often not detected because only specific agents that are suspected to be present, based on clinical or epidemiological considerations, are tested. 2) Many tests also require multiple controls for quantitation making them difficult to do in a conventional multiplex format. 3) Most platforms are suitable for antigen detection or for nucleic acid detection and use different approaches that are difficult to do simultaneously and do not provide absolute quantitation. 4) Finally, multiplexed assays are often limited in the number that can be performed so that different targets from the same agent or different genotypes cannot be assessed during the initial screen. For example, it is estimated that as many as nine bacterial, viral, and parasitic agents may be present in ticks during feeding and because many of these are pathogenic for humans, domestic animals, or companion animals, it is not uncommon to find co-infections in hosts. The tick vector (Ixodes scapularis) of Lyme disease alone is estimated to cause more than 300,000 cases annually but this vector can also transmit Anaplasma phagocytophilum, Babesia sp., Bartonella, Ehrlichia muris subsp euclairensis and several viruses. The mosquito vector of Zika virus can also transmit several important human viral diseases including dengue and chikungunya virus. Many of the vector-borne diseases present a wide range of symptoms that are often confused with other diseases and co-infections are particularly difficult to recognize. Mixed vector-borne infections present significant diagnostic difficulties for physicians, even when a primary disease agent is recognized, especially as some co-infecting agents require very different therapeutic agents and/or the agents are resistant to those treatments.

Project Goals

The goals of the proposed research are to rapidly, simultaneously, and cost-effectively detect and accurately quantify multiple antigen (protein, carbohydrate) and nucleic acid (DNA, RNA) target molecules used in the primary diagnosis of vector-borne infectious diseases caused by viruses, bacteria, and parasites. The technology should ultimately incorporate innovations which enable large numbers of clinical samples and pools of vectors to be analyzed. The platform must incorporate an open architecture enabling the user to augment or change the specific target molecules as diagnostic and epidemiological interests for emerging vector-borne infectious diseases change (e. g., new agents or genetic types or alternative diagnostic targets are identified). Given the increasing number of studies attempting to relate specific host molecular changes (miRNA, cytokine and other effector molecule gene expression) to specific infectious diseases, the platform must be compatible with performing assays for these biomarkers. The platform and methodology employed must also be compatible with FDA approvals for clinical diagnostic assays for both infectious agents and host biomarkers.

Specific Project Goals:

• Develop assays suitable for use with pools of different vectors and obtain quantitative data from assays.

• Develop assays suitable for use with clinical samples obtained from different vector-borne diseases and obtain quantitative data from assays.

• Expand the range of assays available and move toward commercialization of a subset of those assays.

Phase I Activities and Expected Deliverables:

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• To demonstrate the accurate and simultaneous detection and quantitation of at least 10 (3 viral, 4 bacterial, 3 parasitic) vector-borne disease agents found in pools of ticks and mosquitos (assays and associated data). Commercial reagents or in-house generated reagents may be utilized but the targets must include both antigens and nucleic acids and both types of pools.

• To demonstrate the accurate and simultaneous detection and quantitation of at least 10 (3 viral, 4 bacterial, 3 parasitic) disease agents found in clinical samples originating from 5 different vector-borne diseases transmitted by both ticks and mosquitos (assays and associated data). Commercial reagents or in-house generated reagents may be utilized but the targets must include both antigens and nucleic acids and at least two types of clinical samples (e.g., biopsy tissue, blood, urine). Commercial reagents or in-house generated reagents may be utilized.

Impact

One significant impact of this technology would be to avoid the bias introduced by PCR amplification of nucleic acids from various diagnostic samples where sparse amounts of target DNA limit the laboratorians’ ability to detect it. Bias is introduced by the amplification method, the presence of molecules that interfere with amplification or which provide incorrect products. The ability to directly detect and count DNA, RNA, and protein molecules could greatly increase the speed in which samples are analyzed, the accuracy of the results obtained, and provide the ability to compare relative counts of different types of molecules in the same clinical sample and at different time points during the infection to monitor the patient’s response. A highly multiplexed assay system has the capacity to improve QC in standardizations by increasing the numbers of controls, and can detect multiple mixed co-infections and contaminants simultaneously. This approach can significantly improve the quality of outbreak investigations and is a greatly superior methodology for complex diagnostic samples.

Commercialization Potential

Numerous companies have developed multiplexed platforms for detection of biomolecules. These include microarrays of various types (for both nucleic acid and proteins), flow cytometry, qPCR and ddPC approaches, as well as second (Next Generation) sequencing platforms. Microscopy and direct optical mapping methods can also be highly multiplexed. Some of these approaches have been commercialized in the cancer diagnostic field. These advances are thus heavily covered by commercial and university patents. Companies successful in achieving the goals outlined above should be able to develop strong commercial markets given the number of cases of arbovirus (West Nile, dengue, Zika), rickettsial, parasitic (e. g., malaria, Chagas), and other bacterial etiological agents of interest (e.g., Lyme disease, plague, tularemia).

015 Development of a Drone to be used in Laboratory Automation Projects

Fast-Track proposals will not be accepted.

Phase II information is provided only for informational purposes to assist

Phase I offerors with their long-term strategic planning.

Number of anticipated awards: 1-2

Budget (total costs, per award):

Phase I: $225,000 for 9 months

Phase II: $1,500,000 for 2 years

It is strongly suggested that proposals adhere to the above budget amounts and project periods.

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary:

The objective of this contract is to develop an autonomous drone capable of taking a laboratory consumable (such as a well-plate) from one station to another.

Currently, there are many options for robots in the space of laboratory automation, especially in the area of High Throughput Screening (HTS). Over the years, many pieces of laboratory instrumentation have been designed to allow for the loading of microplates by robotic arms such that they can be used in a continuous fashion as part of an automated system. Although, initially a point of failure, over time the use of industrial quality robotic arms has led to a very high degree of reliability in ensuring a microplate can be delivered from one instrument to another. This has enabled high throughput and more complex experiments to be run on these systems.

These robotic arms bring tremendous benefit to a HTS environment; however, they are not without limitation. Some of the limitations of these robotic systems are the cost, the safety requirements, the work envelope and the expertise required to operate/repair them. Much as robotic arms have gotten steadily more reliable over time within the realm of HTS laboratories, the tremendous interest in commercially available drones has driven the creation of more capable flying vehicles. Some of the functionality has expanded to more accurate flight control even within an indoor environment and the ability to add additional components to the vehicle. The thought behind this contract proposal is that by using low cost commercially available drones and open source software the realm of fully automated laboratory operations could become more accessible to facilities not currently equipped or funded to do so.

NCATS currently has a small internal effort in creating a drone capable of performing these functions. NCATS has developed a high level system design in addition to a functional gripping mechanism and automatic charging station. Although NCATS has interest in this research area, we are not in a position to take this to the level required for a fully functional autonomous drone to be used in a laboratory environment.

Project Goals:

The purpose of this contract proposal is to create an indoor autonomous drone capable of moving commonly used industry standard SLAS footprint Microplates from one location to another. The locations will be commonly used

pieces of instrumentation in a laboratory setting with examples being plate readers, low volume liquid dispensers, multichannel pipette systems and others. Typically, in HTS systems, robotic arms have been used as a microplate transportation system; the goal of this contract is to replace these robotic arms with a drone.

Conceptually, this would involve a general series of events to happen in an automated and programmatic fashion as follows:

• The drone takes off from a base station

• The drone flies to the pick-up location to pick up a microplate

• The drone actuates a gripping mechanism of some sort to pick the microplate up

• The drone flies along a predetermined (or adaptive) flight path to the drop-off location

• The drone drops the microplate off at the drop-off location

• The drone returns to the base station

• This process should be able to repeat without interruption 24 hours per day

For this process to be possible several key components will be required as described in the Phase 1 Activities and Expected Deliverables section.

Phase I Activities and Expected Deliverables:

• A drone with a minimum of the following capabilities:

• Self-contained motor/drive system

• Built in stabilization/control system

• Wireless communication system

• Sensing capabilities to perform onboard in-room navigation

• Lift and payload capability to support a gripper assembly and the weight of a microplate with a lid

• Expansion capability to add additional on-drone computing capabilities as required to enable in-room navigation and control of the gripper assembly

• The capability to recharge at a base station when not in flight such that manual swapping of batteries is not required and the drone can be used in a continuous fashion

• A Gripping Mechanism

• The gripper must be capable of handling SLAS footprint microplates potentially with a lid

• The microplate will adheres to current ANSI/SLAS Microplate Standards

• ANSI/SLAS 1-2004 (R2012) Microplates – Footprint Dimensions (formerly ANSI/SBS 1-2004)

• ANSI/SLAS 2-2004 (R2012) Microplates – Height Dimensions (formerly ANSI/SBS 2-2004)

• ANSI/SLAS 3-2004 (R2012) Microplates – Bottom Outside Flange Dimensions (formerly ANSI/SBS 3-2004)

• ANSI/SLAS 4-2004 (R2012) Microplates – Well Positions (formerly ANSI/SBS 4-2004)

• The gripper should be able to extend or be in a default extended position away from the drone such that the plate can reach beyond the extent of the drone rotors

• This is to ensure that existing plate nests that have already been designed to work with robotic arms that have the capability to extend to a location can continue to be used for a variety of peripheral devices without having to redesign these devices to accommodate a different loading mechanism, such as the payload being held and delivered directly underneath the bottom of the drone

• Ideally, this would be some sort of telescopic-boom mechanism; such that the center of gravity of the drone could remain at the center of the drone while in flight and not extend until it is time to pick-up or drop-off a plate

• The gripper design can be flexible, such as electrical with motors or pneumatic with self-contained rechargeable pneumatic cylinders that could also be recharged at the base station or some other methodology; how the gripper works is not as important as the ability do so

• A Control System with a minimum of the following capabilities:

• Capable of controlling/monitoring the drone with regards to position/flight status

• Capable of defining multiple flight paths and monitoring the drone as it performs the pick-up/drop-off process

• A base station

• The base station is the resting place for the drone where it can recharge batteries and pneumatic components if part of the proposed design

• Provide NCATS with all data resulting from Phase I Activities and Deliverables.

Phase II Activities and Expected Deliverables:

• Build a prototype drone that meets the Phase I specifications.

• Provide a test plan to evaluate every feature of the drone

• Provide NCATS with all data from each executed test to properly evaluate each test condition

• Develop a robust manufacturing plan for the drone, using off the shelf OEM and Open Source components where possible to minimize expense.

Provide NCATS with all data resulting from Phase II Activities and Deliverables.

355 Cell and Animal-Based Models to Advance Cancer Health Disparity Research

Fast-Track proposals will be accepted.

Direct-to-Phase II be will accepted.

Number of anticipated awards: 2-3

Budget (total costs, per award):

Phase I: $300,000 for up to 9 months;

Phase II: $2,000,000 for up to 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Cancer health disparities (CHDs) are defined as differences in the incidence, prevalence, morbidity, and mortality that contribute to an unequal burden of cancer and represent a major public health concern globally. In the United States, several racial/ethnic populations demonstrate increased incidence, mortality and/or more aggressive disease for numerous cancer types. The causes of these CHDs are multifactorial, including differences in access to health care, diet and lifestyle, cultural barriers, environmental exposures, and ancestry-related factors. A growing body of evidence suggests that biological factors may contribute to CHDs. The NCI specifically encourages and funds investigations of biological factors to better understand mechanisms that contribute to CHDs. One limitation in conducting basic, translational, and clinical research investigating the underlying biological causes of CHDs is a substantial lack of relevant in vitro and in vivo-based models. The development and validation of appropriate cell and animal-based models to study underrepresented population groups would greatly advance this field of research.

Project Goals

The primary goal of this topic is to develop new, commercially available models relevant to diverse racial/ethnic populations including American Indians, Alaska Natives, Asians, African Americans, Pacific Islanders, and Hispanic/Latinos. Solicited models include patient-derived cell lines, patient-derived xenograft (PDX) mouse models, and 3D human tissue model culture systems established from racially/ethnically diverse patient populations.

These models may be used to enhance research capabilities of basic scientists and/or provide novel tools to pharmaceutical companies for preclinical oncology studies. Establishing these novel models may influence CHD research in multiple ways including 1) benefiting investigators in this largely underexplored area of research, 2) improving the quality and acceptance of CHD research data, and 3) improving validation and commercialization of cancer therapeutics relevant to diverse patient populations. Lastly, achieving these goals will contribute to the long-term, overarching goal of reducing CHDs.

Cancer cell lines: The use of immortalized cell lines in cancer research has been standard practice for decades. Notably, the scientific integrity of cancer cell lines is critical for maintaining high standards in research. Any cell lines established via this solicitation must be fully confirmed through a rigorous and validated authentication and be contamination-free. Notably, offerors proposing to generate conditionally reprogrammed cells (CRCs) or cell lines matched to PDX animal models will be preferred. CRCs have marked benefits over traditional immortalized cell lines as they are generated using special in vitro conditions that permit cells to pharmacologically bypass replicative senescence without any detectable cell crisis.

PDX Mouse Models: PDX models are commonly used in many clinically relevant research applications including characterization of tumor heterogeneity, in vivo therapeutic target validation studies, therapeutic mechanism of action studies, and therapeutic sensitivity and resistance studies. Furthermore, PDX models are suggested to be a useful tool to mimic human clinical trials using animals.

3D human tissue model culture systems: While immortalized cell lines have been standard practice in cancer research for decades, adequate modeling of the heterogeneity of human cancer is an unmet need. Newly emerging 3D cell culture technologies enable the propagation of normal and malignant epithelial cells, as well as more

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accurately mimicking the in vivo tumor microenvironment (e.g. organoid, spheroid, and organ-on-a-chip models). These 3D model systems need to be previously developed (preferably with validation studies) and either derived from diverse racial/ethnic populations or applicable to the study of CHDs in general.

Phase I Activities and Deliverables

Offerors must clearly demonstrate access to human samples from racial/ethnic minority populations, with appropriate informed consent in place.

Establish an experimental model derived from a racial/ethnic minority population and/or relevant to CHD research. This may include one of the following:

• Human derived cancer cell line

• PDX animal model

• 3D human tissue model culture system

Cancer cell line deliverables: Establish a stable cell line from human tumor cells and passage the cells in culture to determine viability and experimental relevance.

• Detailed documentation must be provided including patient clinical characteristics, passage history, mycoplasma testing results, Identifiler/STR profile of early and late passage showing concordance, and appropriate growth/preparation conditions.

• Develop a standardized, working protocol for establishment of additional cell culture models.

• Demonstrate utility in pre-clinical assays and technical validly for the proposed cell line

o Perform comprehensive and robust studies to confirm model system is phenotypically stable.

o Use a standard chemotherapeutic agent to confirm model system is appropriate to perform drug response assays (e.g. measure cell proliferation, cell death, migration, and/or invasion).

• Applications proposing CRCs or cell lines matched to PDX animal models are preferred due to the increased innovation and potential research applications of the models.

PDX animal model deliverables: Establish a serially transplantable, phenotypically stable, human cancer xenograft model in immunocompromised mice.

• Transplant fresh surgical tissue or biopsy (either subcutaneous or orthotopic) into recipient immunodeficient mice (Passage generation 1).

• Subsequent serial transplantations must be conducted following establishment of initial xenograft outgrowths, typically >10mm in diameter. A minimum of three generations (to passage generation 4) of transplantation is required to establish a stable line.

• Confirm genetic and phenotypic concordance of the tumors in passage generation 4 versus passage generation 1 and patient material (when available).

• Confirm percent human versus mouse DNA in each passage and confirm histopathology of each passage phenotypically matches the patient diagnoses.

• Cryopreserve and bank tumor fragments. Confirm re-growth success rate from a minimum of 5 cryopreserved tumor fragments.

• Develop a standardized, working protocol for establishment of additional models.

• Perform comprehensive molecular characterization of patient samples and earliest PDXs, including whole exome sequencing and mutational status analysis using a CLIA-approved panel.

• Demonstrate utility in pre-clinical assays and technical validly for the proposed model system

o Perform comprehensive and robust studies to confirm model system is phenotypically stable.

o Use a standard chemotherapeutic agent to confirm model system is appropriate to perform drug response assays (e.g. measure tumor growth, angiogenesis, cell proliferation, cell death, migration, and/or invasion).

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3D human tissue model culture system: Establish a 3D culture that mimics the tumor microenvironment. Note that all proposed model systems must be using established technologies with previously demonstrated reproducibility in pre-clinical or chemo-sensitivity assays.

• The model system must address the following requirements:

o Human tumor cells must be derived from a diverse racial/ethnic population

o Heterogeneous population of cell types must be represented

o Structural components that mimic the in vivo tumor microenvironment should be incorporated

• Demonstrate utility in pre-clinical assays and technical validly for the proposed model system

o Perform comprehensive and robust studies to confirm model system is phenotypically stable.

o Use a standard chemotherapeutic agent to confirm model system is appropriate to perform drug response assays (e.g. measure tumor growth, angiogenesis, cell proliferation, cell death, migration, and/or invasion).

All human tissues and cells used to generate the abovementioned models must be well characterized including validation of the genetic ancestry of patients (if applicable) using a panel of ancestry informative makers (AIMs). The AIM panel(s) selected should be relevant to the patient populations being investigated and capable of specifying admixture proportions.

Preferences will be placed on proposals that generate models for indications that have clearly demonstrated cancer health disparities and a paucity of models available to study.

Phase II Activities and Deliverables

Cancer cell lines: It is expected that a panel of cell lines be established from different patient sources. The exact number of cell lines will depend on technique used for establishing the lines (i.e. CRCs or cell lines matched to PDX-models) and the tumor type proposed.

PDX animal models: It is expected that multiple PDX models be established from unique patient sources using established protocols. The exact number of models will depend on the tumor type proposed and any known technical/biological limitations.

3D human tissue model culture system: Further demonstrate pre-clinical utility of the generated 3D model system, with a particular emphasis on the relevancy to CHD research. Furthermore, additional 3D models must be developed derived from diverse racial/ethnic populations and prepared for commercialization.

356 Tools and Technologies for Monitoring RNA

Fast-Track proposals will not be accepted.

Direct-to-Phase II will not be accepted.

Number of anticipated awards: 3-5

Budget (total costs, per award):

Phase I: $250,000 for 9 months;

Phase II: $1,500,000 for 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

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’.

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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.

Project Goals

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 would include, but are not limited to:

• Well-validated antibodies, affinity reagents, or affinity-based assay kits for detection, quantitation, or immunoprecipitation of modified RNAs, or enzymes that write, erase, or bind to these modifications.

• 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.

• Assay systems or reagents that facilitate the discovery, detection or quantitation of modified RNAs.

• 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.

• Products that would enable the in vitro or in vivo imaging of modified RNA molecules.

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• 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 their 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 comparing the tool or technology to existing approaches if applicable.

• Provide a proof-of-concept SOP for the tool or technology.

Phase II Activities and Deliverables

The goal of Phase II is an optimized commercial resource, product, reagent, kit, or device for monitoring specific RNA modification(s).

Decisions for continued product development into Phase II will be based on:

• Demonstration of 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, equipment required for use.

• Demonstration 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.

• Demonstration of preliminary proof-of-concept data demonstrating the monitoring of the specific RNA Modification(s) in cell or animal cancer models with the potential to benchmark data across a variety of cancer models.

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, in vivo animal models of cancer).

• Refine SOPs to allow for user friendly implementation of the tool, technology, or product by the target market.

357 Innovative Tools for Interrogating Tumor Microenvironment Dynamics

Fast-Track proposals will be accepted.

Direct-to-Phase II will be accepted.

Number of anticipated awards: 3-5

Budget (total costs, per award):

Phase I: $300,000 for 9 months;

Phase II: $2,000,000 for 2 years

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PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Tumor microenvironment (TME) is composed of abnormal vasculature, stromal components, immune cells, all embedded in an extracellular matrix (ECM). TME plays a critical role in tumor initiation, malignant progression, metastasis and response and resistance to therapy. Characterized by hypoxia, elevated enzymatic activities, high interstitial fluid pressure and dense stroma structure, TME creates a hostile environment for drug delivery and other forms of cancer treatments. Research efforts and discoveries focusing on TME remediation are critical for improving cancer treatment efficacy. New drugs, molecular targets and agents that can manipulate TME are being discovered from known and novel molecular pathways, high-throughput genomics and proteomics and some of these agents are already in clinical trials. For example antiangiogenic agents, originally designed to starve tumors, were shown to transiently normalize tumor vasculature and improve therapeutic outcome in patients with newly diagnosed and recurrent GBM and several anti-angiogenic agents have been approved for multiple cancer types. Similarly, over the past few years, a few checkpoint inhibitors modulating the immune components of the TME have been approved for multiple cancer types and many more are currently undergoing clinical trials. Recently it was discovered that antifibrosis drugs are capable of normalizing the TME and improve the delivery and efficacy of nano- and molecular medicine. However, there are still very few new agents targeting TME that are reaching the stage of FDA approval. The slow pace in TME-oriented therapeutic discovery can be attributed to lack of techniques capable of rapid and effective in vivo evaluation of TME-manipulating dynamics for the purpose of selecting hit compounds and demonstrating efficacy.

In addition to being good therapeutic targets, TME could also act as biomarkers to:

• diagnose tumors at early stage

• assess tumor prognosis

• predict appropriate therapy to use

• evaluate response to therapy and modulate therapy accordingly

For example, the immune components of the tumor are modulated during tumor initiation and also in response to different therapies, and thus could be used as markers to diagnose tumors early and to determine therapeutic response and modulate therapy accordingly.

Assessment of TME is mostly based on histopathological analysis of tumor biopsies. However, these methods are invasive and non-dynamic (i.e. they lack the ability to evaluate progressive changes in the same tumor over time); thus, the ability to use TME as biomarkers for tumor diagnosis, prognosis and therapy response are rather limited. Imaging methods provide non-invasive and dynamic way to assess TME, even in lesions that are difficult to biopsy, and help determine heterogeneity and obtain serial measurements of the same tissue over time. So, imaging methods could be used to diagnose tumors early and to determine if a tumor is responding to therapies.

Recent advances in sensing and imaging techniques are enabling assessment of 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 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 TME-associated molecular targets has been used in pre-clinical and clinical settings. There are also new developments related to designing bio-responsive sensors to monitor change in pH, oxygen levels, or enzymatic activities in TME directly through nanoparticle-based imaging modalities or indirectly through bio-fluid analyses. Biopsy-implantable chemical sensors allow to collect signals over long period of time (months) to monitor long term changes in TME. All these in vivo methods are valuable tools to dynamically examine the targeting efficiency, associated molecular events and provide insight into normalization of TME and its effect on anticancer drug delivery. ‘Bio-activatable’ delivery vehicles allow for controlled drug delivery, which is activated only with the change of a particular TME parameter. However, most of these studies still remain pre-clinical and the imaging modalities have mostly been limited to pre-clinical studies.

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Identifying and monitoring TME-associated biomarkers in patient populations and effective strategies to manipulate the TME in vivo can enable early tumor detection and prognosis, provide therapy prediction and response information and also enhance effectiveness of anticancer therapies and improve treatment outcomes. To accelerate research and translational efforts focused on sensing, imaging, and manipulation of TME in real time, and TME-inspired drug delivery, the National Cancer Institute (NCI) requests proposals for the development of clinically viable in vivo probing/monitoring techniques of TME-manipulating strategies.

Project Goals

Tumor diagnosis at 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 if a tumor responds to certain therapy is very essential to determining what treatment option would be the best for patients. This will increase overall survival and also prevent use of ineffective treatment options. Once the patient starts treatment, it is essential to monitor the response of tumor to the therapy to determine if it’s working or if modulation in therapy is required.

As precision medicine is becoming an increasingly important area in cancer treatment, the ability to determine changes in TME in general and as related to individual patient, in particular is critical. The development of this knowledge can provide insight into effectiveness of treatment using existing drugs and enabling development of new drugs. TME studies can also further knowledge on local cellular environments and categorizing TME associated cells into small sub-groups defined by their molecular makeup.

Various components of TME can serve as a good biomarker for tumor diagnosis, prognosis, treatment prediction and therapeutic response. 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 current methods to assess immune activation in response to immunotherapy involve biopsy procedures that are invasive and cannot be done on the same tumor over time. Thus it is important to develop methods that are non-invasive and that would enable longitudinal tracking of treatment response.

The goal of this solicitation is to develop non-invasive, in vivo platforms that can: image, assess or interrogate TME dynamics over time for tumor diagnosis and/or treatment prediction/response.

To apply for this topic, the proposed technology should be focused on interrogating one or more of the following TME parameters:

• Tissue oxygenation Level and/or pH

• Vasculature and/or stromal architecture

• Tissue integrity

• Enzymatic activities

• Indication of immunotherapy response

• Response in specific cell type(s) or subtype(s) at the molecular level

The goal of this contract topic is not to solicit any particular technology; so this topic is agnostic to the imaging modality used. 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 and ultrasound. The goal of the topic is to develop imaging tools for TME in the clinic; so the tools developed have 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 considered responsive to this solicitation. Examples of non-responsiveness 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), imaging agents, chemical constructs or linkers that are inherently toxic or immunogenic (i.e. Quantum Dots, Avidin) and probes that targets molecular targets that do not have human equivalent.

Phase I Activities and Deliverables

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Phase I activities should generate scientific data to confirm clinical potential of the proposed agent. Expected activities and deliverables may include:

• Identification and validation of marker(s) for TME

o Preparation of imaging agents based on the validated markers

o Characterize the variation, reproducibility, and accuracy of the tool

o Demonstrate that the agent produces high signal-to-noise ratio

o Demonstrate specific binding/targeting of the agent/probe to the molecular target (TME target)

• Prepare, select and demonstrate TME-targeting probes/sensors based on target specificity and minimal toxicity in vitro

• Optimize detection scheme to demonstrate in vitro signal specificity and correlate signals to molecular target concentrations measured using conventional assays

• Determine optimal dose and detection window through proof-of-concept small animal studies with evidence of systemic stability and minimal toxicity

• 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

• Benchmark experiments against currently state-of-the-art methodologies.

• Present Phase I results and development to NCI staff

For successful completion of benchmarking experiments, demonstrate a minimum of 5x improvement against compatible methodologies.

Phase II Activities and Expected Deliverables

Phase II activities should support commercialization of the proposed agent for clinical use. Expected activities and deliverables may include:

• Demonstrate fast in vivo clearance, rapid tumor accumulation, sufficient in vivo stability, good bioavailability, and low immunogenicity/toxicity of imaging agent or sensors

• Demonstrate high reproducibility and accuracy of the imaging agent in multiple relevant animal models

• Demonstrate superiority over currently available imaging tools

• Perform toxicological studies

• Demonstrate clinical utility

o For diagnosis markers, demonstrate that the agent can detect tumors at early stages and demonstrate superiority to current diagnosis methods

o For predictive/decision markers, 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 markers, 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

• Submit IDE application to obtain necessary regulatory approval for clinical validation.

358 Modulating the Microbiome to Improve Therapeutic Efficacy of Cancer Therapeutics

Fast-Track proposals will not be accepted.

Direct-to-Phase II will not be accepted.

Number of anticipated awards: 2-4

Budget (total costs, per award):

Phase I: $300,000 for 9 months;

Phase II: $2,000,000 for 2 years

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PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Metagenomic studies in humans and animal models have established that there are alterations of the GI microbiota community during development of neoplastic and pre-neoplastic disease, and in tumor-bearing vs. healthy individuals. Understanding the impact of human host/microbiota interactions on the initiation, progression and treatment of cancer, and the molecular mechanisms that govern the outcomes of these interactions, will provide new therapeutic strategies and new targets for the treatment of many human tumors.

One promising approach emerging from recent research is alteration of microbiome function designed to enhance the efficacy of cancer therapies. Recent work demonstrated that individual variability in patient drug response to chemo (and other) therapies can be attributed to actions of the gastrointestinal (GI) microbiota, either through direct metabolic activity on the agent itself, or by effects on host barrier function and immunomodulation that affect drug efficacy. For example, microbial β-glucuronidase activity results in re-activation of toxic metabolites that affect the dose-limiting range of CPT-11, a prodrug form of the topoisomerase inhibitor Irinotecan that is widely used to treat a variety of solid tumors. Antibiotic co-therapy and specific inhibition of bacterial β-glucuronidase activity reduced chemotherapy-induced GI toxicity in several animal models. Other studies have shown that depletion of ROS-regulating Lactobacillus species by antibiotics, results in reduced tumoricidal activity of platinum based drugs. Similarly, the antitumor effects of radiotherapy and several cytotoxic chemotherapeutic drugs such as cyclophosomide (CTX), oxaliplatin, and CpG-ODN, are achieved in part by an immune-mediated bystander effect that requires the recruitment and activation of an intense inflammatory infiltrate to regress tumors.

In addition, the anti-tumor response to immune checkpoint inhibitors of CTLA-1 and PD-L1 were found to be mediated through interactions with of B. fragilis or Bifidobacterium respectively, in tumor xenograft models. When these bacteria were depleted, response to immunotherapy was significantly diminished. As we learn more about how the microbiome affects disease progression and response to treatments, the opportunity to exploit the microbiome for therapeutic benefit is an exciting new approach that should be explored.

Project Goals

The purpose of this SBIR contract solicitation is to develop innovative technologies and methods designed to modulate the GI microbiota in order to enhance the therapeutic efficacy of existing or novel cancer therapies, or ameliorate side effects of these therapies. The goal is to develop effective adjuvant strategies that specifically target critical microbial activities or populations that affect drug efficacy and/or tolerability. Ultimately, this activity will accelerate the development of novel strategies based on the rational targeting and manipulation of human GI microbiome functions for the treatment of human tumors.

To successfully meet this goal, applicants will need to demonstrate that their approach accomplishes the specific perturbation or modulation of microbial function that is desired, and that these approaches have demonstrable benefits in addressing a significant unmet medical need relevant to cancer (e.g. reduction of off-target toxicity). Phase I studies should focus on developing and refining the approach that will be used to modulate GI microbiota or functions performed by the microbiota (such as metabolic or immunomodulatory activity). Applicants should establish appropriate criteria to benchmark or evaluate the success of their approach, and these should be related to the expected level of perturbation or modulation that is required to have therapeutic benefits. Phase II studies should focus on demonstrating that the approaches developed in Phase I studies are effective in an appropriate in vivo model system. Lead candidates should be developed and tested for efficacy in appropriate animal models, and Phase II studies should also measure agent delivery (e.g., probiotics, engineered phage, lipids, nano-particles) and pharmacokinetic targeting (e.g., reduction/increase of specific microbial enzyme activity, signaling ligand, or host interaction) in addition to measured endpoints of tumor regression and/or ablation in vivo.

Applicants are required to identify and justify a cancer type and unmet medical need that can be addressed by their approach. They should also provide a scientifically justified rationale for exploring particular approach(es) for perturbing or modulating the microbiome, and justify the choice of model system to evaluate their approach(es).

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It is anticipated that applicants will test perturbations of the GI microbiome such as, antibiotic treatments, bacteriophage therapies, probiotic supplements, dietary metabolites, drug metabolizing enzymes, modulators of bacterial metabolism, and immunomodulators. However, applicants are free to employ any approach.

The focus of this contract topic is not to search for new mechanisms or effects by which the microbiome affects cancer therapy or progression, but rather to explore microbiome directed intervention strategies that have a rational basis. The contract topic is not intended to develop screening approaches, though applicants may propose to refine or optimize lead compounds or other agents designed to modulate or perturb GI microbiota.

Phase I Activities and Deliverables

• Define and characterize a host/microbe interaction that affects therapeutic efficacy, demonstrated through appropriate in vitro and in vivo experiments.

• Develop targeted microbiota regulated/directed intervention strategies designed to improve, either alone or in combination, patient outcomes for new or current therapeutic agents. Approaches may involve, but are not limited to:

• Narrow spectrum antibiotics

• Bacteriophage therapies

• Probiotics/Prebiotics

• Dietary metabolites

• Expression or delivery of novel drug metabolizing enzymes

• Targeted Inhibitors of bacterial gene expression (miRNAs, small molecules)

• Immunomodulators/vaccines

• Test and refine therapeutic approaches in order to identify lead candidates or agent (e.g. bacteriophage, bacterial strain, enzyme, dietary metabolite, vaccine, etc.) to develop further in Phase II studies

• The lead candidate or agent should be able to successfully accomplish the desired perturbation or modulation of the microbiome to a level that can reasonably be expected to be have an impact on the efficacy of the therapeutic interventions and demonstrate proof of concept for the efficacy of their approach. Offeror should demonstrate proof of concept in an appropriate in vivo model

• Offeror should determine and justify the assays and endpoints that will be used to evaluate the success of their approach (e.g., biomarkers, enzymatic activity, presence or absence of specific microbial populations). If needed, offeror should develop alternative tools/methods to evaluate candidate effects on microbiome function.

• Submit a statement to NCI that specifies the metrics and criteria used to evaluate the success of the approach being developed, and justification for these metrics and criteria from a commercial and scientific perspective.

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 the efficacy of lead candidate(s) or agent(s) from Phase I studies in an appropriately characterized in vivo model

• Identify and measure appropriate pharmacokinetic, pharmacodynamics, and therapeutic endpoints

• Evaluate toxicity and efficacy of therapeutic candidate(s) or agent(s)

• Evaluate immune response to therapeutic approach where appropriate

• Determine the toxicology and safety profile of the lead candidate(s) or agent(s) using appropriate animal models and assays relevant to the specific therapeutic approach being pursued

• Optimize or scale up lead candidate(s) or agent(s) (e.g. bacteriophage, bacterial strain, enzyme, dietary metabolite, vaccine, etc.) from Phase I studies. Activities may include, but are not restricted to:

• Medicinal chemistry to optimize small molecules for in vivo studies

• Scale up production of lead therapeutic candidate(s) or agent(s)

• Optimize delivery method for therapeutic candidate(s) or agent(s)

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• Develop a plan for obtaining regulatory approval to conduct human studies. Offerors should provide plans and a detailed time table for obtaining this regulatory approval

359 Technologies for Differential Isolation of Exosomes and Oncosomes

Fast-Track proposals will not be accepted

Direct to phase II will not be accepted

Number of anticipated awards: 2-3

Budget (total cost per award):

Phase I: $300,000 for 9 months

Phase II: 1,500,000 for 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Both normal and cancer cells shed exosomes and other microvessicles into body fluids. Exosomes collected from the blood and other body fluids of patients diagnosed with various cancers were shown to contain tumor suppressors, phosphoproteins, proteases, growth factors, bioactive lipids, mutant oncoproteins, oncogenic transcripts, microRNA, RNA and genomic DNA (gDNA) fragments. Exosomal trafficking and reciprocal exchange of molecular information among different organs and cell types was reported to contribute to cell-to-cell communication, horizontal cellular transformation, cellular reprogramming, functional alterations, regulation of immune response, and metastasis. Exosomes collected from cancer patients were reported to perform cell-independent miRNA biogenesis, and promote tumorigenesis by mediating an efficient and rapid silencing of miRNAs to reprogram the transcriptome of cells that they physically interact with. In functional studies, exosomes derived from serum collected from cancer patients were reported to activate normal epithelial cells to form tumors, while exosomes from healthy individuals appear to have anti-tumor characteristics. Since exosomes are continuously released by all tissue and carry molecular signatures and effectors of health and disease, they reflect the dynamic changes taking place in tissue microenvironments throughout the different stages of cancer progression. Of clinical significance is the possibility that exosomes in blood and other body fluids may offer a non-invasive or minimally invasive way to assess cancer initiation, progression, risk, survival and treatment outcomes of cancer.

Exosomes are found in several biofluids including amniotic fluid, breast milk, bronchoalveolar fluid, cerebrospinal fluid, malignant ascites, plasma, saliva and urine, and studies reported differential molecular profiles of extracellular vesicles (EVs) in cancer patients’ sera/plasma from breast, prostate, lung, liver, gastric, esophageal, glioblastoma, Kaposi's sarcoma-associated herpesvirus-associated malignancies, and urine from prostate. In addition, it has been reported that the concentration of exosomes is higher in the blood of cancer patients. Unlike cell-free circulating nucleic acids (cfCNA), the exosomal cargo is protected by a phospholipid bilayer membrane. Therefore, the tissue specific biomolecules contained in the exosomes are stable in the body fluids compared to the cfCNAs. This stability and the possibility to collect serial samples of biofluids non-invasively or minimally invasively, over a period of time, offers an unprecedented opportunity to obtain reproducible time-varying tissue specific genotype and phenotype information in body fluids that resemble dynamic changes taking place during cancer initiation, tumor development and metastasis in tissues. Molecular profiles of exosomes in archived samples collected in retrospective and prospective studies may further offer valuable information needed to accelerate cancer research and options for clinical care.

The major bottle neck for using exosomes in cancer research or clinical care is in obtaining enriched preparations of oncosomes from body fluids, where “oncosomes” are defined in this solicitation as exosomes that contain oncogenic cargo and/or unique signatures of the tumor cells from which they emanate. Existing technologies are based on centrifugation, precipitation/centrifugation or affinity purification, which are labor intensiveand time consuming. Currently, we do not have effective technologies that can differentially isolate tissue-specific exosomes and tumor-derived oncosomes from the general population of exosomes in archived body fluids.

The purpose of this contract proposal is 1) to support the development of technologies for differential isolation of tissue-specific exosomes and tumor-derived oncosomes from any body fluid(s), and 2) to obtain enriched, distinct

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preparations useful for downstream comparative molecular profiling or therapeutic use. Applicants must propose to develop an efficient and cost effective platform for complete isolation and separation of exosomes/oncosomes, which are morphologically and functionally intact.

Project Goals

The goal of this contract proposal is to accelerate the use of exosomes from body fluids for cancer research and clinical care. It is also intended for developing technology for differential isolation of tissue-specific exosomes and oncosomes in serial collections of archived body fluids to enable assessment of cancer initiation, progression, risk, aggressiveness, prognosis and/or treatment outcomes. Since exosomes are continuously released from normal, pre-cancerous, tumor, and metastatic tissues, the time-varying genotype and phenotype of exosomes in body fluids may provide a mechanistic understanding of carcinogenesis, tumor initiation, promotion, development, and progression in tissues, and the knowledge gained may lead to better cancer prevention/care/control. Patient-derived exosomes may also serve as targeted drug/antibody delivery systems and immunomodulation agents to yield new precision medicine strategies.

Applicants are required to obtain distinct preparations of exosomes and oncosomes, which originated in a specific tissue/tumor, from routinely collected fresh/archived body fluids. They should demonstrate quality, quantity and reproducibility of isolation and separation using physicochemical and functional studies. The technology platform should be be useful for profiling multiple body fluids from multiple cancer types. The technology should establish automated workflows to reduce human intervention and obtain exosome preparations suitable for research and therapeutic purposes.

To apply for this topic, offerors should:

Have a prototype platform with demonstrated capability for isolating exosomes from complex solutions. Preference will be given for proposals with demonstrated capability for further isolating oncosomes from the general exosome population.

Demonstrate sufficient expertise and necessary resources for robustly characterizing captured exosomes, and verifying persistence of their biological integrity.

Phase I Activities and Deliverables

• Develop a technology for differential isolation of exosomes and oncosomes, which originated in a specific tissue, from body fluid(s) collected from cancer patients (e.g., breast, prostate, colon, lung or brain). The technology must be sufficient for adoption in clinical workflows and therefore demonstrate capability for processing at least 10 mL of clinical fluid specimen in <1 hour.

• Demonstrate that the technology can obtain distinct preparations of exosomes and oncosomes from the routinely collected fresh/archived body fluids, and yields sufficient quantity for downstream analysis. Specifically, demonstrate sufficient yield of nucleic acids for NGS and proteins for LC-MS/MS

• Establish automated workflows sufficient to allow for minimal training for new users.

• Demonstrate that the reproducibility is >90% and yield is >70%

• Demonstrate collection of >75% intact and undamaged exosomes/oncosomes is using physicochemical methods (Transmission electron microscopy, AFM, dynamic light scattering, immunostaining/immunofluorescence).

• Benchmark the developed technology against at least 2 current techniques (e.g. centrifugation, density gradient, immunocapture, size-based filtration, etc.) and demonstrate comparable purity and yield from clinically appropriate sample sizes for the specific bodily fluid.

• Deliver to NCI the SOPs for exosome/oncosome isolation, and the data from physicochemical characterization that demonstrates the quality of the isolated exosomes/oncosomes

Phase II Activities and Deliverables

Adapt the technology to multiple body fluids (i.e., stored or freeze thawed) with varying complexity.

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Demonstrate that the isolated exosomes/oncosomes are morphologically intact by physicochemical methods (Transmission electron microscopy, AFM, dynamic light scattering, immunostaining/immunofluorescence), and functionally active in in vitro systems (transmission of information from exosomes to cells in culture and/or co-culture).

Develop a pre-commercial prototype kit/tool/device for the differential isolation of exosomes/oncosomes.

360 Manufacturing Innovation for the Production of Cell-Based Cancer Immunotherapies

Fast-Track proposals will be accepted.

Direct to Phase II will not be accepted.

Number of anticipated awards: 2 – 4

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

Cancer immunotherapy is a therapeutic approach that directs a patient’s own immune system to eradicate their tumor cells. Past and current NCI investments in adoptive T cells, CAR-T cells, NK cells, and other cell-based cancer immunotherapies have resulted in the translation of many lab-specific approaches into early clinical trials. Importantly, reproducible and robust production methods are critical to ensure that advances in basic research result in successful translation of cell-based therapies. Clinical development of such therapies requires multi-center, randomized clinical trials that must be supported with high quality, consistent and reproducible cell-based products. Patient-specific autologous or allogeneic lots must be adequately characterized to ensure that similar products are given to all patients. For non-patient specific cell-based therapies, large-scale and reproducible manufacturing technologies are needed to produce high-quality products with uniform identity and potency. Current limitations in cell manufacturing can increase both the cost and time required to bring a therapy to market and can result in missed opportunities to evaluate promising new cell-based therapies. Product failures can be attributed to poor product design and characterization, as well as inadequate scale-up and manufacturing processes; therefore, further investments are needed to develop state-of-the art manufacturing technologies and processes to advance cell-based cancer immunotherapies at the commercial-scale. Effective use of science and engineering principles during the early development phase of a cell-based therapy can improve both the efficiency and reliability of the manufacturing process and the quality of the final product. Moreover, it is anticipated that standardized approaches to manufacturing, process analytics, release testing, and product characterization will result in more rapid, cost-effective product development and a higher level of regulatory success. Achieving the desired level of standardization for current and future cell-based cancer immunotherapy products will require both pragmatic research to establish consistent manufacturing processes, as well as the development of new innovations and technologies.

Project Goals

The overall goal of this contract topic is to facilitate the development of innovative methods and technologies capable of improving and modernizing product manufacturing processes for cell-based cancer immunotherapies. This includes the use of autologous, allogeneic, or pluripotent cells. To achieve this goal, offerors submitting proposals under this solicitation are strongly encouraged to establish collaborative relationships with clinical product development companies focused on the development of specific cell-based products. In all cases, it is expected that offerors will demonstrate the utility of their innovation(s) in the context of at least one cell-based product, which is representative of a particular class of cell-based cancer immunotherapies.

Examples of manufacturing innovations/advancements might include, but are not limited to:

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• Automated closed systems for cell separation, genetic modification, differentiation, and/or expansion;

• Low-cost, high-efficiency methods for genetic modification to support cell engineering;

• Standardized assays and/or surrogates to evaluate cell attributes that ensure lot-to-lot consistency in terms of phenotype, functionality, quality and potency;

• Real-time non-destructive test methods with sensors and/or imaging technologies for assessing critical quality attributes (e.g., contamination);

• Process analytics capable of feedback control in response to real-time changes in critical attributes of the cell product.

Under this topic, it is expected that Phase I proposals will focus on novel inventions related to innovations or improvements in cell manufacturing processes, including in-line or on-line (i.e., continuous) process analytics to support product consistency and safety, as well as GMP production of a class of cell therapies. Phase II proposals should focus on demonstrating the scalability and validation of the novel production platform or process improvements developed in Phase I. Engineering and process solutions must be capable of regulatory compliance with FDA Guidelines. The long-term goal of this initiative is to provide the tools necessary for efficient, high-quality manufacturing of novel products in the emerging field of cell-based cancer immunotherapies.

Phase I Activities and Deliverables

• Develop a device/technology/process to support commercially-relevant manufacturing advancements or improvements for the production of a specific class of cell-based cancer immunotherapies (e.g., CAR-T cells, adoptive T-cells, NK cells)

• Establish defined specifications, assays and/or metrics to interpret scientific data supporting the feasibility of the device/technology/process, with respect to reproducible product manufacturing, process analytics, and/or process controls

• Demonstrate the suitability of the device/technology/process to improve relevant manufacturing metrics (e.g., product uniformity, quality, efficiency, cost-effectiveness) for at least one cell-based product, which is representative of a particular class of cell-based cancer immunotherapies

• Provide proof of collaboration or partnership with an entity that is developing a representative cell-based therapeutic agent OR otherwise demonstrate access to a representative cell-based therapeutic agent through other means (e.g., internal drug development program), that can be used for validation of the device/technology/process

• Demonstrate pilot-scale beta-testing of the production process to demonstrate reproducible performance within appropriate specifications for identity, purity, potency, and/or other relevant metric for the chosen cell-based immunotherapy product

Phase II Activities and Deliverables

• Generate scientific data demonstrating the proposed scalability (e.g. scale-up, scale-out, point-of-use) of the production platform, process analytics and/or process controls

• Develop an at-scale prototype of the device/technology/process with detailed specifications for hardware/software that supports the production platform or process analytics/process controls improvements

• Validate the production innovation and/or process improvements, including standards for calibrating any novel process analytics or process controls that monitor production

361 Highly Innovative Tools for Quantifying Redox Effector Dynamics in Cancer

Fast-Track proposals will not be accepted.

Direct to Phase II will not be accepted.

Number of anticipated awards: 2-4

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

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PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

The generation and dynamic interplay of redox effector molecules (e.g., oxygen, free radicals, peroxides, nitrogen oxides, and hydrogen sulfide) are fundamental features underlying the genomic, structural, metabolic and functional alterations observed in cancers. Alterations in redox balance impact all phases of disease including carcinogenesis, disease progression, response to treatment and prevention. For example, the DNA damaging effects of free radicals can mutagenize key oncogenic sites. Redox imbalances occur by abnormalities commonly associated with cancers including mutations in p53, myc and ras pathways. Redox effectors operate to modify protein function at the post-translational level, which plays a significant mechanistic role in the phenotypic plasticity cancer cells demonstrate in the face of oxidative and reductive (hypoxia) stresses. Redox tone is a key regulator of the self-renewal properties of stem-like cancer cells, which has been shown to contribute to tumor resistance to current therapies.

Progress in the cancer biology and pre-clinical space has been limited by the lack of tools that can accurately measure redox parameters in animal models with sufficient spatio-temporal resolution and minimal perturbation of the system. NCI seeks input from the small business community to develop and optimize a new generation of quantitative and specific technologies that will enable and accelerate basic research aimed at understanding basic redox effector mechanisms and the roles they play in the cellular adaptations and complex biology of tumors.

Supporting the development of these technologies will allow researchers to validate and benchmark data obtained across different 3D cell culture platforms and pre-clinical animal model systems with the goal of accurately mimicking tumor environments experienced by patients with cancer. Moreover, an enhanced ability to screen, manipulate, or analyze redox dynamics is an invaluable index in the evaluation of cancer cell-tumor responses to therapeutic interventions in the critical pre-clinical testing phase. These redox data have potential to significantly improve our understanding of tumor biology and ability to better predict treatment responses and long-term efficacy when translated into patients.

Project Goals

There is an unmet need in basic cancer research for probes or technologies that can better measure, characterize, profile, or resolve the spatiotemporal dynamics of redox effectors at the subcellular to cellular levels. Genomic profiles, for instance, cannot capture post-translational redox regulation that occurs with changes in the tumor microenvironment. Redox probes have been traditionally reliant on organic dyes that experience spectral shifts with redox. The current state of the art is genetically encoded redox indicators that couple redox responsive enzyme motifs with indicator proteins. These genetically engineered redox probes have improved response kinetics, but may have limited optical qualities. Given the critical role played by redox effectors, developing a range of new tools will help us better understand how redox effectors regulate cell phenotypes in functional tumor populations.

The goal of this FOA is to develop quantitative tools to measure redox dynamics in biological systems. Ideally, probes or biosensor tools should be minimally invasive as to not significantly perturb the system. The technical approach should: (1) allow for in vivo measurements of redox effector spatiotemporal dynamics; and-or (2) be useable in high throughput systems, for example to allow the screening of cellular response to experimental perturbations, such as exposure to cytotoxic agents. The long term goal is that the technologies developed through this contract can help validate whether data gathered in model experimental systems faithfully represents the redox dynamics of human tumors.

Technologies that have the potential for in vivo use, especially those with potential clinical applications in the long term will be of particular interest, but methods that will be restricted to pre-clinical research applications are also of interest.

To successfully meet this goal, offerors shall develop a technology for the minimally to non-invasive measurement of one or more redox effectors, including but not limited to oxygen, free radicals, reactive oxygen species, peroxides, nitrogen oxides, and hydrogen sulfide. Phase I studies should focus on developing the technology and

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demonstrating proof of concept in an in vitro system. Phase II studies further refine the technology and demonstrate the use of the technology to measure redox effectors. Offerors shall justify their choice of approach with respect to the scientific utility and commercial potential, and specify quantitative milestones that can be used to evaluate the success of the technology being developed.

It is anticipated that offerors shall develop a probe or similar agent that facilitates the measurement of redox effectors by one or more imaging modalities; however, offerors are not restricted to any particular technical approach and label or probe free approaches that can meet the requirements of this contract are welcome.

Offerors are not restricted to any particular technical approach and can propose resource and tool development that incorporates high-risk/high-impact technologies. Examples can include, but are not limited to:

• Redox probes that provide significant advances in sensitivity, selectivity, ratiometric capability, or resolution in reporting the spatial concentration gradients and temporal dynamics of redox effectors at the subcellular, cellular and/or tissue compartment levels.

• Genetically encoded redox biosensors that are expressed in a cell or tissue selective manner in small animal models of cancer for interrogation by non-invasive to minimally invasive imaging modalities.

• Biology-inspired redox sensors (e.g., based on bacterial chemosensors) that through synthetic biology techniques are genetically encoded for expression in a cell or tissue selective manner.

• Nanotechnology scaffolds multiplexed with sensors that permit functional parallel profile analyses of a combination of redox effectors (i.e., oxygen, nitric oxide, hydrogen peroxide, superoxide) and/or related species (e.g., proton, glutathione, ascorbate) across both time and space at the subcellular, cellular and/or tissue compartment levels.

• Instrumentation that enables label-free quantitative measurements of redox-related spatiotemporal dynamics in cancer cells and/or tumors (e.g., Raman spectroscopy-based microscopy, super resolution microscopy).

Technologies that have the potential for in vivo use, especially those with potential clinical applications in the long term will be of particular interest. However, Offerors with technologies that will advance pre-clinical or basic cancer research applications are also of high interest.

Phase I Activities and Deliverables

• Identify and justify development of a sensing tool or probe for specific redox effector species from both a cancer biology and commercial perspective.

• Offerors shall describe the current state of the art technologies for sensing and measuring the redox effector being addressed by their proposal, and outline the advantages that their approach will offer.

• Develop and characterize a redox probe, biosensor or detection platform. Offerors shall specify quantitative milestones that can be used to evaluate the success of the technology being developed, and justify these milestones from the viewpoint of both scientific utility and commercial value.

• Develop an assay or system that demonstrates proof-of-concept testing and benchmarking of specificity and sensitivity parameters of the agent or system for a range of redox effector species (e.g., oxygen, free radicals, hydrogen peroxide, nitric oxide, hydrogen sulfide, NAD/NADH, GSH/GSSG).

• For each redox effector or parameter, a technical description of methodology for each assessment shall be provided that includes how each measurement is calibrated. If measurements are collected serially, the rationale for the order of measurements shall be specified.

• Demonstrate feasibility to sense, interrogate, detect or resolve the spatiotemporal dynamics of redox effector species in live cells or animal model, ideally with a minimally invasive perturbation of the system.

• Provide NCI with proof-of-concept assay SOP.

Phase II Activities and Deliverables

The goal of the Phase II product is an optimized commercial resource, reagent, kit or device that can allow researchers to measure the relevant redox effector molecules in their laboratory. Decisions for continued project development into Phase II will be based on probes, biosensors, assays or systems that:

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• Can demonstrate reliability and robustness. Offerors shall provide a technical evaluation and quality assurance plan with specific detail on shelf life, best practices for use, equipment required for use.

• Can be scaled up at a price point that is compatible with market success and widespread adoption by the basic research community.

• Have potential to benchmark data obtained across different cancer model systems.

Deliverables for the Phase II projects are:

• Scaled up synthesis or manufacture of agents, chemicals, device, or products necessary.

• Design and implement quality assurance controls and assays to validate production.

• Validate scaled up device, chemical or product. Offeror shall demonstrate the utility, reliability and sensitivity of their device, chemical or product across in vitro and/or in vivo models relevant to cancer research.

• Refine SOPs to allow for user friendly implementation of technology by the target market for the agents, chemicals, device, or products.

362 Informatics Tools to Measure Cancer Care Coordination

Fast-Track proposals will be accepted.

Direct to Phase II 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 rapid adoption of Electronic Health Records (EHRs), increased patient engagement, rapid adoption of mobile technology, and shift to value-based care have contributed to an increased use of health information technology (IT) to improve quality and outcomes of patient care.

There is a need for more coordination in cancer care due to the growing complexity of cancer treatment and the increase in cancer survivors that need better coordination within and across clinical teams and care settings. Poorly coordinated care leads to avoidable hospital readmissions, preventable medical errors, harm to patients and higher costs. Care coordination strategies share seven essential tasks: assess patient, develop care plan, identify participants and specify roles, communicate with patients and other participants, execute care plan, monitor and adjust care, and evaluate outcomes. Health IT plays an important role in care coordination in diverse organizations like Kaiser Permanente and the VA.

The measurement process for care coordination is changing from the laborious process of manual chart reviews to EHR-based measurement. New EHR-based care coordination measures are being developed. The National Quality Forum recently endorsed five EHR-based care coordination measures, none in cancer care. At least 12 cancer-specific care coordination measures are available in the National Quality Measures Clearinghouse.

There is a need for informatics tools that automate measurement for existing care coordination measures and have the flexibility to add new measures as they are developed.

The interaction of people, technology, tasks, organization and environment creates a structure – a work system – that shapes workflows, which shape outcomes. Health IT-focused businesses understand (from experience) IT adoption changes workflows and work systems. This understanding coupled with the ability to innovatively use diverse data systems and methods is needed to create scalable informatics tools to measure care coordination to meet the marketplace needs.

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Project Goals

The goal is to create scalable health IT-based informatics tools that measure care coordination in order to assess and improve quality of care and patient outcomes, assist the ongoing healthcare delivery system transformation and improve research efficiency. The tools will help managers and clinical teams realistically assess the effectiveness of existing care coordination and patient engagement processes and help identify areas for improvement, which will help their efforts to transform delivery systems to meet the triple aim objectives of improving patient experience, improving population health and reducing costs. The researchers will gain access to tools that measure the variability in cancer care coordination and patient engagement in diverse settings, which will help identify the characteristics of clinical teams, processes and health systems associated with delivery of high-quality care and to test interventions based on these characteristics.

Activities not responsive to announcement:

Tools that don’t measure care coordination; tools that don’t 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; validation of new measures.

Phase I Activities and Deliverables:

• Project team: Establish a project team, including proven expertise in: software development, user-centered design, care coordination measurement, team communication and clinical workflows, clinical oncology, and the design, deployment and use of health IT in a healthcare delivery organization. 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 required.

• Develop a prototype platform to generate at least 5 cancer-relevant care coordination measures from EHRs and other relevant, IT platforms at one cancer care delivery site and to display them in the right format to the right user at the right time.

• Develop a prototype platform to assess clinical team composition; workflows and team interactions with health IT; flow of relevant data across diverse delivery sites; extent of patient engagement; type of health IT implementation, and organizational structure and policies relevant to the informatics tool development and implementation at one cancer care delivery site.

• Provide a report specifying approach to extend the platform by integrating additional

• care coordination measures and to scale the platform to multiple cancer care delivery sites with diverse IT systems.

• Provide a report detailing plans for implementation of technical assistance and delivery of software, platform, and measures developed, including a review of technical specifications for systems interoperability, within existing EHR and other health IT systems.

• Provide a report on the results of the first round of usability testing and the approach to modify the platform based on this user feedback. .

• Present phase I findings and demonstrate the functional prototype system to an NCI evaluation panel via webinar.

Phase II Activities and Deliverables:

• Enhance, beta test, and finalize system, data standards and protocols for a platform that measures and displays at least 12 existing cancer-related care coordination measures that are integrated within existing clinical workflows in at least three cancer care delivery sites that use at least two different IT systems.

• Enhance, beta test, and finalize system, data standards and protocols for a platform that assesses clinical team composition; workflows and team interactions; flow of relevant data across diverse delivery sites; extent of patient engagement; type of health IT implementation and organizational structure and policies relevant to informatics tool development in at least three cancer care delivery sites and at least two different IT systems.

• Provide a report that synthesizes feedback from all relevant categories of end-users (such as physicians, nurses, care managers and administrators) and summarizes the modifications made to the platform after each round of usability testing.

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• Provide a report specifying lessons learned and recommended next steps to extend the platform by adding a broad set of care coordination measures and to scale the use of the platform to multiple cancer care delivery sites and IT systems.

• Provide a report detailing plans for implementation of technical assistance and delivery of software, platform, and measures developed, including a review of technical specifications for systems interoperability, within existing EHR and other health IT systems.

• Develop systems documentation and user guides to facilitate commercialization, including citation and details of how systems align with current regulations and best practices in user-centered design, interoperability and protection of privacy and confidentiality of information.

• Present phase II findings and demonstrate the system via a webinar at a time convenient to the offeror and NCI program staff.

• In the first year of the contract, provide the program and contract officers with a letter(s) of commercial interest.

• In the second year of the contract, provide the program and contract officers with a letter(s) of commercial commitment.

363 Connecting Cancer Caregivers to Care Teams: Digital Platforms to Support Informal Cancer Caregiving

Fast-Track proposals will be accepted.

Direct-to-Phase II will not be accepted.

Number of anticipated awards: 2-3

Budget (total costs, per award):

Phase I: $225,000 for 9 months;

Phase II: $1,500,000 for 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Informal cancer caregivers are individuals (usually family members or friends) who manage patient care which is typically uncompensated and delivered at home, involves significant amounts of time and energy, and requires the performance of tasks that may be physically, emotionally, socially, or financially demanding. These tasks include monitoring for treatment side effects, helping manage symptom burden, treatment decision-making, administering medication, and performing technical medical tasks (e.g., managing infusion ports, changing dressings). Despite these demands, caregivers are often underprepared to perform the many tasks required of them. Simultaneously, cancer treatment is more frequently provided in outpatient and community-based centers, which increases the day-to-day demands on informal caregivers.

Technology offers the potential of mitigating these demands and alleviating distress and burden for caregivers by offering decision-making tools, strategies for managing and communicating symptoms with providers, assistance with technical medical tasks, and care coordination. Furthermore, a majority of caregivers endorse the idea that technology may aid in preventing burnout and may reduce financial burden on both families and the healthcare system. Despite this, there is a lack of evidence-driven technologies to ease cancer caregiving burden available on the market.

The purpose of the proposed concept is to develop evidence-based technologies to alleviate cancer caregiving burden, assist family/informal caregivers to manage the needs of their care recipients, juggle their own healthcare needs, and enhance caregivers’ connections with their care recipients’ healthcare team. The SBIR mechanism is ideally suited to support this activity because it pairs investigators with software developers to create evidence-based technologies that can be scaled and disseminated with wide reach.

Purpose & Goals

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The overall goal of this project is to develop software, database systems and mobile application tools to support cancer caregivers and connect them with their patients’ care teams. These systems will enhance care quality and effectiveness and will allow care delivered beyond clinic walls into the home setting, ultimately aiming to improve patient outcomes. Systems should be designed to be flexible and customizable, to be modified based on feedback from patients, caregivers, or providers, and to evolve as patient and caregiver needs evolve. Development should utilize an iterative, user-centered design approach informed by actual cancer patients, caregivers, and healthcare providers.

A recent environmental scan of technological resources available to informal cancer caregivers was performed to determine current available software systems and capabilities. The following caregiving support categories were identified based on previous reviews in the topic area: consultation and clinical care delivery, medical skills training, therapy/counseling, financial resources, and peer-to-peer support. Of the ten software systems identified, none provided support in all areas (most provided support in only 1-2 areas). Many of the cancer-focused apps identified targeted patients only; only three targeted caregivers. None of the systems identified directly connected cancer caregivers back to the patients’ healthcare provider team or associated electronic health record (EHR) and patient portals.

The following are specific modules that the caregiving platform should consider:

(1) Direct communication with the patients’ healthcare provider teams;

(2) Care plan dissemination/updates pushed directly from healthcare provider teams to caregivers;

(3) Tracking/monitoring of patients’ care delivery, patient reported outcomes, side effects, etc. using structured data entry forms, standard measures (e.g., PROMIS®) or ecological momentary assessment;

(4) Guidance for assisting with daily medical tasks;

(5) Assistance with patient’s activities of daily living;

(6) Opportunities for peer-to-peer connection; including informal caregivers (e.g., family members) as well as informal caregiving communities for social support;

(7) Guidance for caregiver self-care (including physical and emotional well-being);

(8) Local information/service referrals when available and appropriate

The platform should allow end-users (i.e., patients and caregivers) the ability to opt in or opt out of studies.

Scope of activities to be supported:

• A review of currently available technological platforms for cancer caregivers to identify gaps, existing capabilities and resources.

• Interviews/focus groups with cancer caregivers, patients, healthcare providers, and caregiving researchers to further identify areas of unmet caregiving needs.

• The development of a software system with mobile application to connect cancer patients and their caregivers with healthcare provider teams to extend clinical interactions and provide further information resources and service referral. Key task domains should include organization-level (hospital or clinic), provider-level, caregiver-level, and patient-level dashboards that allow for assessment of adherence to treatment and post-treatment clinical practice guidelines, capability to identify high-risk patients, ability to identify care gaps and enable clinical data query functions.

• The development of secure bi-directional communication system to allow healthcare providers and authorized caregivers to push messages, including adjustments to the care plan, directly through the system.

• The development and testing of a prototype of a platform and caregiver-facing applications to be tested with cancer caregivers, patients and caregiving researchers.

• Further enhancement and refinement of the software system and mobile application.

Activities not responsive to announcement:

Tools that don’t target cancer caregivers; tools that don’t incorporate safeguards to protect privacy and confidentiality of information; design approaches that don’t account for scalability, interoperability or user-centered design.

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Phase I Activities and Deliverables:

• Establish a project team with expertise in the areas of software development, patient-centered design, health communication, oncology, oncology nursing, palliative care, family medicine behavioral science, health services, and computer programming. Note that team members may have dual expertise (eg. e.g., oncology nurse with palliative care expertise; behavioral scientist with communications background).

• Perform an environmental scan of available and relevant software systems designed to support cancer patients and caregivers to identify major gaps

• Conduct a small number of key informant interviews with cancer patients and caregivers to further refine and prioritize areas of unmet needs

• Provide a report including detailed description and/or technical documentation of the proposed system capabilities and specifications, including:

• structure for the proposed caregiving support modules and user-interfaces (caregiver, patient, Database healthcare provider) and metadata requirements

• Architecture that includes the following components:

• A provider/ clinic health system dashboard to be able to communicate with the caregiver and download and upload information and integrate that information with electronic health records where possible and appropriate

• A caregiver application and dashboard to be able to communicate with provider and download and upload information

• A function within the application that allows the caregiver to communicate with other caregivers within the network of caregivers on the application "community"

• A dashboard/database that would communicate to caregivers, patients, and providers about community resources

• Data and security standards for collection, transport, and storage of data inputs that ensure patient and caregiver privacy following standard NIH policies.

• Data visualization, feedback and reporting systems for clinical monitoring and research applications

• Data adaptation for mobile application(s)

• Develop a functional prototype of the software system that includes:

• Front-end mobile application(s) to facilitate care plan dissemination, tracking and monitoring or care, communications and caregiver support.

• Healthcare provider systems to facilitate care plan prescription, remote patient care monitoring, communications and resource provisions (e.g. content management for tailored caregiver support).

• Required server systems architecture to facilitate interaction with necessary provider Health IT systems or patient facing portals and personal health records.

• Present Phase I findings and demonstrate functional prototype to an NCI evaluation Panel

Phase II Activities and Deliverables

• Establish a project team for Phase II activities and outcomes. This team should include personnel with training and research experience in chronic disease patient clinical trial or intervention design, implementation, and statistical methods for validation/evaluation as appropriate for the proposed project. Provide a report outlining team member credentials, specific project roles, and timelines for performance.

• Evaluate specific IT customization requirements to support hardware, software, or communications system integration of the technology into the target clinical, health system or service, or other relevant software environment in preparation for validation. Provide a report documenting the specific IT customization requirements and timelines for implementation.

• Evaluate, enhance as necessary and provide documentation that the technology and communications systems maintain compliance with HIPAA, data security, privacy, and consent management protocols as required for the proposed project.

• Develop a prototype into a pilot system for usability testing.

• Enhance systems interoperability for deployment in diverse software environments and provider networks. Provide a report detailing communication systems architecture and capability for data reporting to patients,

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caregivers, healthcare providers, researchers, electronic health records, and health surveillance systems as appropriate for the proposed project.

• Conduct beta-testing of the software system and corresponding portals and mobile applications

• Conduct usability testing of caregiver/patient/care team/researcher facing mobile applications and care team/researcher facing user interface features including system management, analyses, and reporting applications.

• Test the integration of the technology into the target clinical, health system or service, or other relevant software environment in preparation for validation. Provide a report documenting the results of system testing and timelines for trouble-shooting.

• Develop user support documentation to support all applicable potential users of the technology, including but not limited to patients/consumers, family/caregivers, and providers. Provide a report documenting user support resources, including but not limited to, links to online resources and copies of electronic or paper user support resources as appropriate.

• Develop appropriate human subjects protection / IRB submission packages and documentation of approval for your research plan.

• Develop final study design including aims, participant characteristics, recruiting plans, inclusion and exclusion criteria, measures, primary and secondary endpoints, design and comparison conditions (if appropriate), power analyses and sample size, and data analysis plan.

• Create a publication plan outlining potential research and other publications resulting from the research

• Provide study progress reports quarterly, documenting recruitment and enrollment, retention, data quality assurance and control measures, and relevant study specific milestones.

• Prepare a tutorial session for presentation at NCI and/or via webinars describing and illustrating the technology and intended use.

• Include funds in budget to present Phase II findings and demonstrate the technology to an NCI evaluation panel.

• In the first year of the contract, provide the program and contract officers with a letter(s) of commercial interest.

• In the second year of the contract, provide the program and contract officers with a letter(s) of commercial commitment.

364 Methods and Software for Integration of Cancer Metabolomic Data with Other –Omic and Imaging Data

Fast-Track proposals will be accepted.

Direct-to-Phase II will not be accepted.

Number of anticipated awards: 2-3

Budget (total costs, per award): Phase I: $225,000 for 9 months; Phase II: $1,500,000 for 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Metabolomics is the study of small molecules participating in cellular metabolism. Advances in metabolic profiling technologies have made it possible to simultaneously assay hundreds of metabolites, providing insight into an organism’s metabolic status. Several studies suggest that metabolomics may identify novel biomarkers for a diverse range of disease, including cancer. Furthermore, metabolites may play important regulatory roles in disease pathways and even serve as effectors of disease processes.

The metabolome is particularly responsive to both environmental and biological regulatory mechanisms, such as epigenetic and post-translational modification and transcription. Additionally, metabolites are the closest link to the phenotype and therefore offer a unique opportunity for phenotype characterization. However, metabolomics alone is unlikely sufficient to achieve this. Therefore, developing bioinformatic methods for integration of metabolite data with other -omic (proteomics, transcriptomics, genomics, epigenomics) and/or cancer imaging data would allow for

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significant advances in deciphering the biological relationships resulting in an observed phenotype. Importantly, this will also help leverage existing human data to combine metabolite and other –omics and/or cancer imaging data to detect subtler and more complex associations among variables, thereby promoting greater efficiency and return on investment. In turn, it will enhance opportunities to identify novel cancer biomarkers of risk, aggressiveness, therapeutic effectiveness, and prognosis, develop and/or enhance predictive models of cancer, and evaluate the tumor microenvironment. Ultimately, developing these bioinformatics methods will support precision medicine-focused clinical research.

Project Goals

The goal of this project is to develop new and innovative bioinformatic methods to integrate metabolite data with and other –omics and/or cancer imaging data and ultimately design scalable software tool(s) that apply these methods to automate the integration of the data. In Phase I, offerors should provide evidence that bioinformatic methods integrating identified metabolite data with other –omics and/or imaging data have been effectively developed, can be implemented across data inputs from at least one analytical technology used in metabolomics and at least one analytical technology used in genomics, proteomics, epigenomics, transcriptomics, or cancer imaging; and demonstrate readiness to proceed to Phase II. Additionally, phase I should be used to demonstrate the framework for scalable software tool(s) that apply the bioinformatic methods to automate the integration of metabolite and other –omics and/or cancer imaging data. In Phase II, offerors should expand the bioinformatic methods to include unidentified metabolite peaks, in addition to identified metabolite data, and demonstrate metabolite data integration other –omics and/or cancer imaging data.

To apply for this topic, offerors will need to demonstrate usability of scalable software through the following: 1) beta-test and finalize automated file transfer, data importation protocols, metabolite and genomic data integration applications and reporting tools developed in Phase I; 2) demonstrate that the software system adheres to established community data formats (e.g. standards of the Genomic Data Commons) and uses open application programming interfaces (APIs); 3) develop, beta-test, finalize and demonstrate the graphical user interface (GUI); and 4) demonstrate the software system’s ability to integrate data from planned Phase II technology compatibility matrix data sources using automated algorithms and bioinformatic methods.

Phase I Activities and Deliverables

• Establish a project team including proven expertise in metabolomics analytical technologies, genomics, proteomics, epigenomics, transcriptomics and/or cancer imaging analytical technologies (as appropriate), cancer biology, epidemiology, biostatistics/bioinformatics, statistical genetics (if genomic data is being integrated), computer technology, and software implementation (including requirements analyst, software engineer, user interface design, quality assurance, and technical documentation).

• Develop bioinformatic methods for identified metabolite data integration with other –omics and/or cancer imaging data for at least one analytical technology used in metabolomics (preferably liquid-chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), and/or NMR) and at least one analytical technology used in in genomics, proteomics, epigenomics, transcriptomics, or cancer imaging. Datasets with cancer outcomes must be used.

• Develop data formats that support the import and export of individual datasets and “combined” datasets, store structured data from different sources of metabolite and other –omics and/or cancer imaging data, and are readily used for data integration and QC protocols.

• Finalize data formats and structure, data collection, transport and importation methods for targeted Phase I data inputs.

• Provide wireframes and user workflows for the proposed graphical user interface (GUI) and software functions that:

• Support the import and export of individual datasets and “combined” datasets;

• Implement, script or automate all features and functions of the data integration tool(s); and

• Conduct QC of “combined” datasets.

• Provide a report including a detailed description and/or technical documentation of the proposed:

• Specific approach to metabolite and other –omic and/or cancer imaging data integration;

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• Specific approach to QC;

• Data standards for transfer and importation of individual metabolite other –omic and/or cancer imaging data and storage of individual and “combined” metabolite and other –omic and/or cancer imaging data;

• Data visualization, feedback, and reporting systems for individual and “combined” metabolite and other –omic and/or cancer imaging data;

• Technology compatibility matrix for Phase I and Phase II metabolomics and other –omic and/or cancer imaging data sources, including identified metabolites (Phase I) / unidentified metabolite peaks (Phase II).

• Software tool(s);

• Transparent, documented, and non-proprietary bioinformatic methods; and

• Description of additional software and/or hardware required for use of the tool.

• Finalized data formats and structure, data collection, transport, and importation methods for targeted data inputs; and

• Includes funds in budget to present Phase I findings and demonstrate the wireframes and user workflows for the GUI and software functions to an NCI evaluation panel.

• Develop functional prototype software that integrates data from planned Phase I technology compatibility matrix data sources using automated algorithms and methods.

• Include funds in the Phase I budget to present project deliverable and the prototype software tools to an NCI panel for evaluation.

Phase II Activities and Deliverables

• Expand the bioinformatic methods to include unidentified metabolite peaks, in addition to identified metabolite data, and demonstrate metabolite data integration with other –omics and/or cancer imaging data, using at least one analytical technologies used in metabolomics (preferably liquid-chromatography-mass spectrometry (LC-MS), gas chromatography-mass spectrometry (GC-MS), and/or NMR) and at least one analytical technology used in in genomics, proteomics, epigenomics, transcriptomics, or cancer imaging. Datasets with cancer outcomes must be used.

• Demonstrate usability of scalable software through the following:

• Beta-test and finalize automated file transfer, data importation protocols, metabolite and genomic data integration applications and reporting tools developed in Phase I.

• Demonstrate that the software system adheres to established community data formats (e.g. standards of the Genomic Data Commons) and uses open APIs;

• Develop, beta-test, finalize and demonstrate the GUI.

• Demonstrate the software systems ability to integrate data from planned Phase II technology compatibility matrix data sources using automated algorithms and bioinformatic methods.

• Conducts usability testing of the GUI elements of the metabolomics and other –omic and/or cancer imaging data integration tool(s).

• Develop systems documentation where applicable to support the software and bioinformatic methods.

• In the first year of the contract, provide the program and contract officers with a letter(s) of commercial interest.

• In the second year of the contract, provide the program and contract officers with a letter(s) of commercial commitment.

365 Imaging Informatics Tools and Resources for Clinical Cancer Research

Fast-Track proposals will be accepted.

Direct-to-Phase II will not be accepted.

Number of anticipated awards: 2-3

Budget (total costs, per award):

Phase I: $225,000 for 9 months;

Phase II: $1,500,000 for 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

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Summary

The goal of this contract topic is to support the sustainment and evolution of advanced cancer imaging informatics tools and resources and their broad adoption for clinical research applications through innovative translation and commercialization. The primary focus of this contract topic is on cancer imaging informatics tools and resources that have garnered significant adoption in the cancer imaging research communities. Imaging informatics tools include computer software tools and platforms to deploy and organize the processing, analysis, and interpretation of medical images to extract and help interpret clinical information, for supporting diagnosis, informing treatment, and providing therapy monitoring and evaluation (using, for example, quantitative imaging tools). Imaging informatics resources include image 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 SBIR contract award will support enhancement and ongoing support of advanced cancer imaging informatics tools and resources to address Big Data opportunities and challenges and target critical unmet needs for validated clinical decision support tools and resources towards meeting precision medicine goals in cancer clinical research.

Project Goals

The primary goal of the proposed SBIR contracts is to develop and implement solutions for sustained support for the advanced development, evolution, and broad adoption of cancer imaging informatics tools and resources. Successful solutions should address the following challenges: 1) Imaging informatics tools and resources developed in the academic research environment are typically not fully developed in terms of usability and documentation, or their interoperability with other tools and data types. 2) Due in part to the continuous development nature of the funded research projects, few imaging informatics tools and resources are comprehensively evaluated for specific clinical applications and translated to suitable commercial products for broader adoption. 3) The overall lack of solutions for sustaining support and evolution for these tools and resources has limited the development teams’ ability to evolve these tools and resources to continuingly meet user needs.

The overall scope of proposed funding approach includes the entire spectrum of cancer imaging, extending from microscopic, pathological imaging to in vivo clinical imaging for all phases of cancer clinical research. Offerors will be expected to formulate and execute well designed project plans with clearly defined milestones that will eventually lead to commercially viable solutions for 1) sustained development and evolution of cancer imaging informatics tools and resources and 2) their broad adoption in clinical cancer research.

Awardees will deliver enhanced services such as training, documentation, and help desk support that improve the overall usability, user adoption, and evaluation of the tools and resources for commercial translation. They are expected to develop and implement necessary technical solutions and business processes for hosting the selected cancer imaging informatics tools and resources and providing other necessary user support services for engaging user communities to promote broad adoption. They will enhance the tools and resources to meet evolving user needs. Early phase R&D such as the development of novel imaging acquisition schemes, new image analyses algorithms or software is not responsive to the solicitation.

Phase I Activities and Deliverables

The Phase I proposal is expected to identify roadblocks and provide innovative yet feasible solutions necessary for commercial translation of the targeted cancer imaging informatics tools and resources. The offerors are required to demonstrate prior experience with the cancer imaging informatics tools and resources addressed in the proposal. Example of such proposals include improvements to the informatics tools and resources necessary for meeting key usability and interoperability metrics to enable phase II implementation on commercially viable platforms. Phase I work is expected to develop use indications for the underlying cancer imaging informatics tools and resources, performance requirements necessary for supporting clinical research and applications goals, as well as critical hardware and software system specifications of informatics platforms for Phase II deployment of the underlying informatics tools and resources.

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Key deliverables will be:

• Design specifications for enhancing image informatics tools and resources to support required usability, data and tools interoperability, patient data protection, as well as other features required for supporting phase II commercialization,

• Clear documentation of the tools and resources, and

• An early phase product prototype and detailed project plan for phase II implementation, as well as a demonstration of the prototype to NCI (using funds set aside for this purpose).

An example might include a phase I proposal to improve existing open imaging informatics tools and resources for use in drug trials or co-clinical trials that support the requirements of traceability and reproducibility for FDA filing.

Phase II Activities and Deliverables

• Phase II projects will be expected to implement requirements identified in Phase I, and launch a commercially-viable prototype cancer imaging informatics product targeted to the usage defined in Phase I. The system design process should encourage user-user and user-developer interactions for evaluation and further evolution of the informatics tools and resources and associated documentation.

• The offerors are expected to develop and implement a business process that will promote broad adoption of the tools and resources by actively engaging the user communities; seek support and undertake efforts to achieve recognition, certification, and adoption by clinical trials groups and professional societies; and eventually engage with regulatory agencies such as the FDA for adoption in drug trials and co-clinical trials. The business process should also address plans for long term sustainability, such as sustained hosting of tools, data, training, and associated resources, as appropriate.

• The proposed product implementation should also address the unique requirements for clinical application of imaging informatics tools and resources, including legal, financial, and marketing complexities associated with the development and release of the targeted commercial product(s).

Key deliverables for phase II projects will be enhanced image informatics tools and resources that are evaluated by key user groups and are appropriately validated for use in a clinical cancer research setting.

366 Clonogenic High-Throughput Assay for Screening Anti-Cancer Agents and Radiation Modulators

Fast-Track proposals will not be accepted.

Direct to Phase II 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 $2,000,000 for up to 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

The ultimate goal of any cancer treatment modality is to specifically eradicate cancer cells by inducing cell death by mechanisms that include metabolic death, cell apoptosis, and/or reproductive death (clonogenic death). Clonogenic death is defined as the indefinite loss of the proliferative ability of a cancer cell and is best assessed by colony-forming assays. Colorimetric and metabolic assays for determining cell viability and apoptosis measure short-term endpoints, but are subject to artifacts since they do not measure the clongenic potential of cancer cells. Clonogenic assays are longer-term and are more labor-intensive, but are less susceptible to these artifacts.

Over the past several decades in vitro high-throughput screening (HTS) systems have evolved and are routinely used to screen agents for cytotoxicity. However, current HTS methodologies do not directly measure clonogenic potential

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and are thus not able to accurately predict the efficacy of an agent either in subsequent preclinical animal model testing or in clinical trials. Further, it is well known that cancer recurrence is a common problem after treatment. This results from the re-population and redistribution of surviving tumor cell clonogens. Direct measurement of a tumor’s clonogenic potential provides an integrated output of all cell death mechanisms and measures any capacity of residual cells to regrow; the definition of treatment failure. HTS systems to screen agents based on their ability to inhibit clonogenic potential of cells have been developed mostly in the academic setting. Advances in automated microscopy and robotics are facilitating these efforts. Further development, integration of robotics and softwares and commercialization of HTS clonogenic assay for screening anti-cancer agents and radiation modulators could greatly enhance the predictive power of HTS results and be applied to chemotherapeutic, radiologic or combined modality treatment testing.

Chemotherapy is used for both solid and hematologic malignancies. In addition, more than half of US cancer patients undergo radiotherapy alone or in combination with drugs; percentage of which is expected to only increase. Screening that allows for more accurate testing of chemotherapeutic and combinatorial treatments will better focus development to more promising agents and accelerate development of drug and drug-radiotherapy combinations. With expanded global access to radiotherapy and increased utilization rate, pharma and academics will be further incentivized to discover agents with anti-cancer and radiation sensitizing properties. Assays that are adaptable to the incorporation of molecular targeting, imaging, and evaluation of genetically defined cell panels for drug screening and discovery will be required with ongoing precision medicine initiatives. Companies can utilize clonogenic HTS assays to screen for new agents and to test newly identified agents in combination for radiation. Results from this type of screen should improve success in subsequent in-vivo model testing and will accelerate translation.

Program Goals

The purpose of this contract topic is to: (i) promote stronger academic industry partnerships in radiobiology to develop clonogenic survival-based HTS systems (ii) to exploit recent advances in the technical maturity of HTS technologies and combine them with advances in clonogenic assays, (iii) encourage small businesses to specifically develop HTS systems for screening potential anti-cancer agents based on a clonogenic endpoint, and (iv) integrate relevant technologies. Colony-forming assay survival experiments currently involve the use of several drug and/or drug + radiation doses as well as several plated cell numbers for each cell line and hence the assays are labor and material intensive. Further, developing a HTS system with a clonogenic endpoint will enhance screening/cross validating chemotherapeutic agents as well as radiation effect modulators and combinatorial treatments, while reducing labor and costs.

To apply for this topic, offerors need may design integration of robotic instrumentation, micro-fluidics, thermal and gas control, colony counting microscopic imaging and image analysis. An integrated system may also require the development of “bridging” components and graphic user interfaces. Offerors are required to develop standard operating procedures matched to validated cell lines for use with the integrated system. Offerors must include an integration of microfluidics/culture system with radiation exposure under conditions allowing precise dosimetry, which is critical. Offerors are also required to integrate and adopt software to capture and calculate survival. This solicitation is not intended for development of systems with non-clonogenic endpoints.

Phase I Activities and Expected Deliverables

• Delivery of a prototype system with validated SOPs that are translatable to other laboratories.

• Defined cell line panels that have been shown to be appropriate for use with the system and the clonogenic endpoint. Validation of representative “hits” using conventional clonogenic assay.

• Licensing of individual components for use in the system as needed.

Phase II Activities and Expected Deliverables

• Demonstration of system validation with manually assessed comparator(s) using drugs, radiation and combinations of known activity (e.g. Cis-platinum, radiation and combined treatment)

• Demonstration of software integration for analysis and output of clonogenic survival data in an easily interpretable format.

367 Predictive Biomarkers to Improve Radiation Treatment

Fast-Track proposals will be accepted.

Direct-to-Phase II will not be accepted.

Number of anticipated awards: 2-3

Budget (total costs, per award):

Phase I: $300,000 for 9 months;

Phase II: $2,000,000 for 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Radiotherapy is an important definitive and palliative treatment modality for millions of patients with cancer and is used alone or in combination with drug therapy. However, a variety of patient, tumor, and treatment-related factors will influence its outcome. Significant advances in delivery and distribution of dose for radiotherapy have been made over the years. Currently, treatment decisions in radiotherapy/radiochemotherapy are primarily defined by disease stage, tumor location, treatment volume, and patient co-morbidities, together with general guidelines concerning normal tissue tolerance for surrounding organs. However, treatment planning does not take into account individual patient’s, or a cohort of patients’ sensitivities or radiation sensitivity of tumors. This is an important limitation in personalized care, as there are known variations in individual patient normal tissue sensitivities to radiation, but treatments are based on population normal tissue as well as sensitivities of tumors to radiation. As molecularly targeted therapy is being integrated into radiotherapy and chemotherapy, selecting the “right type of treatment” is critical to improve outcomes.

A substantial number of patients treated with radiotherapy suffer from severe to life-threatening adverse acute 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 lung, telangiectasia, and atrophy, which are irreversible and progressive. A biomarker-based test that can predict the risk of developing severe radiotherapy-related complications or predict the sensitivity/response of a tumor may allow customization of treatment or delivery of suitable alternative treatment. However, discovery, development, and validation of predictive biomarkers of individual and tumor radiation hypersensitivity are challenging. The challenges include low incidence of normal tissue complications in the clinic, the need for long-term studies for predicting late effects and the combination of chemotherapy with radiation as standard of care for most tumors. Differences in radiation sensitivity of tumors may allow modification of dose to the tumor to minimize normal tissue damage, or maximize tumor cell killing, or may also allow the use of radiation effect modulators to achieve better therapeutic outcome. However, spatial and temporal heterogeneity in tumor characteristics is an important paradigm in the development of tumor radiation sensitivity predictive tests.

Project Goals

The goal of this contract topic is to develop a simple cost effective test that can be used by clinicians to personalize radiation/chemoradiotherapy treatment regimens. This contract solicitation seeks to identify, develop, and validate a simple, cost-effective test to rapidly assess inter-individual differences in radiation sensitivity of an individual patient’s tumor to radiation therapy and/or predict early and late complications among cancer patients prior to starting radiation therapy. The test developed in response to this solicitation may evaluate normal tissue to predict radiation-therapy related toxicities in specific patient populations, or be developed to predict heightened responsiveness to radiation-therapy.

Treatment decisions for personalized approach to radiotherapy should take into account the likelihood of a severe adverse event due to damage of normal tissue as well as a predicted sensitivity of the patient’s individual tumor. A predictive biomarker of individual radiation sensitivity can measure any biological changes in response to absorbed ionizing radiation, which is able to predict imminent normal tissue injury prior to radiotherapy and help determine radiotherapy suitability. Similarly, a predictive biomarker of tumor radiation sensitivity allows, in advance of treatment, an indication of sensitivity or resistance to radiation treatment by a specific tumor type and subtype.

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Radiation biomarkers are an emerging and rapidly developing area of research, with potential applications in predicting individual radiosensitivity, predicting severity of normal tissue injury among patients, assessing and monitoring of tumor response to radiation therapy as well as in estimating dose to accidentally radiation-exposed individuals. The purpose of this contract topic is to develop a radiation biomarker test that may allow personalization of radiation therapy with curative intent.

A variety of radiation biomarkers have already been explored or are currently under development at different technology readiness levels (TRLs) at different government agencies and programs. This contract topic intends to leverage on these advances. These assays include but are not limited to (i) fibroblast clonogenic assay, (ii) measurement of DNA damage foci, (iii) damaged base metabolites, (iv) various types of chromosome aberrations studied in different phases of cell cycles, serum biomarkers, gene expression changes, (v) protein and microRNA expression changes, (vi) and genetic tests.

To be of practical value in the clinic, where radiation exposures are well-defined in terms of dose, distribution and timing, and thus quite different from radiation accidents, a predictive radiation biomarker should be (i) able to predict heterogeneity of radiation responses among a specific group of patients or tumors in clinic, (ii) specific to radiation, (iii) sensitive, (iv) able to show signal persistence as applicable to radiation therapy or have known time-course kinetics of signal, (v) amenable for non-invasive or minimally-invasive sampling, (vi) amenable to automation to improve quality control and assurance, (vii) have a quick turn-around time between sampling and results (though speed is not as critical as in the countermeasures scenarios), (viii) and be cost effective. All applications must include a biological hypothesis and rationale for the selected patient population and indication (e.g. developing biomarkers to indicate mucositis in a patient population with a biological signature that may predispose them to mucositis).

This contract topic aims to encourage the development and validation of predictive radiation biomarkers for clinical applications as described above. Both the FDA and the Centers for Medicare and Medicaid Services (CMS) through Clinical Laboratory Improvement Amendment (CLIA) regulate diagnostic tests. A reasonable predictive radiation biomarker development process for identifying likely “over-responders” to radiation treatment may involve biomarker discovery, assay design and validation, determination of assay feasibility, assay optimization and harmonization, assessing the assay performance characteristics (reproducibility, sensitivity, specificity etc.), determining the effect of confounders, if any, determination of suitable assay platforms and platform migration as may often be needed, and clinical validation with a locked-down assay before regulatory submission and commercialization. Early pre-IDE interaction with FDA is therefore critical. NCI’s Program Directors may be invited by the awardees to participate in the pre-IDE discussions with FDA. The following activities and deliverables are applicable to both biomarkers for acute early effects and surrogate endpoints for late effects.

Phase I Activities and Deliverables

Phase I contract proposals must describe (i) a quantitative estimate of the patient population that will benefit from the availability of such predictive radiation biomarkers for the applicable cancer type/organ site, (ii) a plan for generating evidence that the proposed biomarker or biomarkers are relevant in the prediction of radiation hyper-sensitivity among patients with cancer and logical approach in the developmental pathway to clinic from discovery, (iii) a description of assay characteristics including sensitivity and specificity and the effects of known confounders, if any, (iv) level of technological maturity, describing critical technology elements allowing technology readiness assessment by the reviewers, (v) and a description of the proposed regulatory pathway for approval and pre-IDE consultation with FDA.

Activities and deliverables include the following:

• Discovery and early development

• Demonstrate biomarker prevalence and utility

• Develop a working qualitative test correlating the presence or absence of the biomarker(s) with potential outcome or a quantitative assay to assess radiation sensitivity

• Demonstrate feasibility

• Preclinical development and technical validity

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• Provide assay characteristics, including but not limited to performance, reproducibility, specificity, and sensitivity data using frozen (or other) samples from past clinical trials, or retrospective clinical studies providing adequate power calculations

• Illustrate the performance of the biomarker(s) with receiver operating characteristic (ROC) data

• Demonstrate suitability of the test for use in the clinic, including kinetics of biomarker, if transient.

• Determine the effect of confounders, such as any induction or concurrent chemotherapy regimens.

• Provide defined metrics for measurements of success

• Deliver the SOP of the working test or assay to NCI.

• Benchmark the technology against quantitative milestones proposed by offers to measure success

• Provide description of proposed regulatory pathway for approval and pre-IDE consultation with FDA

Phase II Activities and Deliverables

Phase II contract proposals must describe (i) the setting and intended use of the predictive biomarker(s) in retrospective or prospective studies using human tissue samples (frozen or fresh), (ii) a logical approach to regulatory approval, (iii) a description of assay platform and platform migration, if necessary, (iv) a demonstration of clinical utility and clinical validation, (v) a proposed schedule for meeting with FDA regulators regarding approval.

Activities and deliverables include the following:

• Provide a schedule of proposed meetings with FDA regarding approval

• Early-trial development

• Retrospective tests using archived, frozen samples from past clinical trials, or prospective trials using fresh human samples.

• Full development

• Demonstrate clinical utility

• Demonstrate clinical validity in a large prospective randomized clinical trial

368 Molecularly Targeted Radiation Therapy for Cancer Treatment

Fast-Track proposals will be accepted.

Direct-to-Phase II will not be accepted.

Number of anticipated awards: 2-3

Budget (total costs, per award):

Phase I: $300,000 for 9 months;

Phase II: $2,000,000 for 2 years

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Targeted radionuclide therapy (TRT) enables personalized cancer treatment by combining the therapeutic effect of radiation therapy with the targeting capability of molecular therapies. In TRT, a cytotoxic dose of a radioactive isotope is attached to monoclonal antibodies, receptor ligands, or synthetic molecules that target malignant tumor cells selectively. The ability of these molecules to bind specifically to a tumor-associated structure ensures that the tumor gets a lethal dose of radiation, while normal tissue gets only a minimal dose. This minimizes toxicity to normal tissues and can increase therapeutic efficacy (therapeutic index) leading to a reduction of overall treatment costs.

Currently available TRT compounds such as Zevalin and Bexxar have been developed and approved in the United States for use in the treatment of non Hodgkins Lymphoma (NHL). Although these drugs have shown a response rate of approximately 80%, they have failed to show a survival advantage in patients. Large multicenter trials to

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study long- term survival are currently underway. Because these drugs have had modest commercial success to date, private investment in molecularly-targeted radiation pharmaceuticals remains at low levels. As this class of treatments shows tremendous clinical potential, there is a need to encourage the development of next-generation technologies (see below) for cancers other than NHL, including solid tumors, where the clinical need is most acute.

Project Goals

This contract solicitation seeks to stimulate research, development, and commercialization of innovative TRT techniques that could potentially shorten treatment cycles and reduce toxicity to normal tissues. Proposals addressing the following technology areas are encouraged: new treatment strategies; design, synthesis and evaluation of innovative ligands and radiotracers for TRT; novel radioisotope generators and radioisotope production techniques; dosimetry techniques; new treatment planning strategies facilitating combination of TRT with conventional therapies; and new conjugation chemistries that can link the radioisotopes to targeting agents other than antibodies (e.g. existing small molecule chemotherapeutic drugs) are also encouraged.

The short-term goal of the project is to perform feasibility studies for development and use of possible radiotherapeutics for the treatment of cancer. The long-term goal of the project is to enable a small business to bring a fully developed TRT compound or TRT-supporting technology to the clinic and eventually to the market.

Phase I Activities and Deliverables

Phase I activities should support the technical feasibility of the innovative approach. Specific activities and deliverables during Phase I should include:

• Proof-of-concept of the conjugation or attachment of the radioisotope to the antibody or other targeting moiety.

• Radiation dosimetry studies in an appropriate small animal model

• Proof-of-concept small animal studies demonstrating an improved therapeutic efficacy and improved therapeutic index, assessment of toxicity to normal tissues, and pharmacokinetic/pharmacodynamic studies utilizing an appropriate animal model.

Phase II Activities and Deliverables

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.

• Specific activities and deliverables during Phase II should include:

• Demonstration of the TRT manufacturing and scale-up scheme

• IND-enabling studies, preferably in consultation with FDA, carried out in a suitable pre-clinical environment.

• When appropriate, demonstration of similar or higher specificity and sensitivity of the technology when compared to other technologies.

• Offerors are encouraged to demonstrate knowledge of appropriate FDA regulations and strategies for securing insurance reimbursement.

369 Development of Pediatric Cancer Drug Delivery Devices

Fast-Track proposals will be accepted.

Direct-to-Phase II will not be accepted.

Number of anticipated awards: 2-4

Budget (total costs, per award):

Phase I: $300,000 for 9 months;

Phase II: $2,000,000 for 2 years

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PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Drug delivery systems are continually advancing and greatly assist the capabilities of cancer therapies and cancer survival. Yet, the pediatric population has not benefited, to the same extent as adult populations, from these advances in cancer therapy delivery device design and technology. A tailored dosage system for delivering cancer therapeutics to pediatrics is required. In addition to biological response differences, pediatrics vary anatomical with age and therefore require cancer therapy delivery devices and ports to be tailored for compatibility with anatomical dimensions of the patient. This topic is focused on drug delivery devices as opposed to drug delivery materials and vehicles. For example, in the case of central nervous system tumors—implantable drug delivery ports, pumps and ommaya reservoirs required for drug delivery to the cerebrospinal fluid often pose many issues for pediatric patients. Issues of device displacement, catheter migration and catheter fracture have all been reported and are primarily due to anatomical miss-compliance. Additionally, complications such as infection and insufficient wound healing are common because of devices with large profiles designed for use in adults. Furthermore, developmental and behavioral characteristics of young children should also be considered when designing a tailored device for pediatric patients – this includes changes in anatomy size for long-term implantable devices and mobility needs of children at different stages of development.

There is a need for versatile, efficient cancer therapy delivery devices that meet the needs of pediatric populations. This solicitation aims to aid the development of appropriate cancer therapy delivery devices that reflect pediatric patient specific designs and dosage parameters for pediatrics.

Project Goals

The purpose of this announcement is to assist the development of cancer drug delivery systems compatible to the needs of pediatric patients. This topic includes pediatric focused therapeutic targets within acceptable dosages suitable for pediatric patients and/or drug delivery systems designed to suit the needs of pediatric anatomical dimensions. Successful applicants will develop technologies to aid the administration of cancer therapies to pediatric patients, taking into account pediatric specific issues which include but are not limited to: dosage limitations, size restraints, comfort level and mobility. Adaption of currently available delivery devices for the pediatric population is also encouraged. One example is in the treatment of pediatric retinoblastoma where there have been some recent advances in the development of an episcleral device for delivering localized therapy to the retina and choroid, which has been tested in rabbits and is now proposed for testing in pediatric patients. This solicitation is not limited to cancer type or site, yet, justification of the need for pediatric-specific design parameters is encouraged. The offeror is required to outline and indicate the clinical question and unmet clinical need that the pediatric drug delivery device will address. This solicitation is not intended for drug formulation or nano-delivery systems; instead it is focused on delivery mechanisms and devices. In Phase I, offerors should demonstrate the proof of concept for the device proposed. Phase II projects will validate the device in the clinical setting.

Expected Activities and Deliverables

Phase I Activities and Expected Deliverables

• Select cancer type(s), site(s) and cancer drugs for the development of delivery device with adequate justification

• Design and develop a prototype of a drug delivery device that is

• Suitable for the anatomical restrictions of pediatric patients.

• Suitable for the dosage limitations of pediatric patients.

• Demonstrate preliminary proof-of-concept of the device in a suitable animal model.

• Develop the required specifications necessary to make the device clinic ready.

• Demonstrate understanding of the requirements to file a regulatory application for the device

Phase II Activities and Expected Deliverables

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• Build a device according to the specifications developed in Phase I.

• Optimize the device design and performance for a clinical setting, and

• Show the feasibility of this novel approach/technique that will fit in with current clinical workflow.

• Demonstrate the safety and efficacy of the device in relevant animal models as required by FDA.

• Develop and execute an appropriate regulatory strategy. If warranted, provide sufficient data to submit a regulatory application to obtain approval for clinical application.

• For offerors that have completed advanced pre-clinical work, NCI will support pilot human trials.

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NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES (NCATS)

The mission of the National Center for Advancing Translational Sciences is to catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions. For additional information, please visit our home page at http://www.ncats.nih.gov.

It is strongly suggested that potential offerors not exceed the total costs (direct costs, facilities and administrative (F&A)/indirect costs, and fee) listed under each topic area.

098 Testing and Validation of Technologies for Inclusion in the CART Demonstration Project for Collaborative Aging Research

Phase I only proposals will not be accepted.

Fast-Track proposals will be accepted.

Direct-to-Phase II proposals will be accepted.

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Number of anticipated awards: 3

Budget (total costs):

Phase I: up to $150,000 for up to 6 months

Phase II: up to $1,000,000 for up to 24 months

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

New strategies are needed to develop an evidence-based healthcare system for the aging population, including those with chronic disabilities. Technologies that combine data from multiple sources, create meaningful presentations and visualizations and integrate information into a patient’s electronically accessible health record are needed. These technologies also need to be combined with systems that can interact with the health care team and respond with timely interventions. To date, evidence is lacking demonstrating that home-based healthcare technologies improve or stabilize health so that the aging population can remain at home longer and avoid unnecessary hospitalizations or admissions to a nursing home. This SBIR contract aims to develop research evidence to support the use of technologies in the home that address heart, lung, blood, or sleep diseases using the Collaborative Aging (in Place) Research Using Technology (CART) research infrastructure and provide evidence for scaling up after the demonstration project.

The purpose of the trans-NIH, inter-agency Collaborative Aging (in Place) Research Using Technology (CART) grant funding opportunity (RFA-AG-16-021) is to develop the infrastructure to improve the capacity of the research community to rapidly and effectively conduct research utilizing technology to facilitate aging in place, with a special emphasis on people from underrepresented groups. The underrepresented groups include those living in rural areas, section 202 housing, PACE Program and others. The CART grant funding opportunity focuses on the following: 1) Algorithmic and other data aspects of in-home technologies; 2) Validation of devices and sensed data; 3) Protecting privacy and security for in-home technologies; 4) Making sensed data actionable for home healthcare; and 5) Methods for successful engagement by patients, physicians, caregivers, and payers. This initiative grew out of a visioning workshop held by the National Heart Lung and Blood Institute, National Science Foundation, and the Computing Community Consortium on the technology needed to enable successful aging in place (http://www.cra.org/ccc/visioning/visioning-activities/aging-in-place). The workshop discussion centered on four main topics: designing for the population, sensing innovations required to enhance health, using technology to identify and support transitions in health and utilizing new non-health technologies to support health in smart homes. Workshop panelists highlighted the challenges of talking across disciplines and the need to develop standard metrics that allow better collaborations among diverse disciplines. More information is available in the White Paper. This announcement solicits proposals relevant to heart, lung, blood or sleep disorders. Technologies for cardiovascular diseases are of interest, for example, because cardiovascular diseases account for over 17% of total health care dollars spent nationwide. This work is needed before the potential benefits of these devices can be fully leveraged in a health care system.

Project Goals

This contract solicitation will support the testing and validation of existing technologies within the context of the CART Demonstration Project being developed under a separate grant award (RFA-AG-16-021). The trans-agency CART Demonstration Project seeks to develop and test the feasibility of a research infrastructure supporting in-home care utilizing innovative technology targeted to reduce hospitalizations, emergency room visits or admissions to a nursing home for older populations. After iterative testing of in-home cardiovascular, respiratory, hematological, or sleep technologies, the results will be compiled and study outcomes assessed with the potential for adoption in future phases of the CART Programs.

Phase I Activities and Expected Deliverables

All proposals submitted under this topic must provide evidence that significant development milestones (detailed below) for a specific remote/mobile/wireless or other technology or system have already been achieved to demonstrate readiness for Phase II SBIR contract. In addition, the proposed technologies must be compatible with

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the CART platform requirements. These milestones will be evaluated in addition to standard review criteria for all submissions. The following milestones are expected to be completed during Phase I prior to the start of a Phase II award, or should be demonstrated prior to submission of a Direct to Phase II proposal.

• Provide evidence that a working prototype, including all major functional components of the technology, is ready for formal validation in a Phase II SBIR project with minimal further development other than that required to perform the validation or outcomes research.

• Provide the process for installing and monitoring the technology installed for CART homes (approximately 5-10 homes and possibly more).

• Provide documentation that the product to be evaluated has been developed based on theory and/or empirical evidence.

• Present evidence that appropriate focus groups, interviews, cognitive or user testing with potential end-users of the device/software tool, etc. have been conducted to demonstrate that the feasibility, acceptability, and usability of the product have been established.

Phase II Activities and Expected Deliverables

• Evaluate specific IT customization requirements specified by the CART grant funding opportunity (RFA-AG-16-021) to support hardware, software, or communications system integration of the technology into the target clinical setting, health system or service, or other relevant software environment in preparation for validation. Provide a report documenting the specific IT customization requirements and timelines for implementation. This will be done according to the CART specifications. The CART specifications will be developed within a year of the CART grant award and will require collaboration with the small business partner awarded a contract.

• Test the integration of the technology into the target clinical setting, health system or service, or other relevant software environment in preparation for validation. This may occur as an iterative process.

• Provide a report documenting the results of system testing, validation, and timelines for problem mitigation.

• Develop user support documentation to support all applicable potential users of the technology, including but not limited to patients/consumers, family/caregivers, and providers. Provide a report documenting user support resources including, but not limited to, links to online resources and copies of electronic or paper user support resources as appropriate.

Provide a report including the following at a minimum:

• Appropriate human subjects protection / IRB submission packages and documentation of approval for your research plan;

• Study design including aims, participant characteristics, recruiting plans, inclusion and exclusion criteria, measures, primary and secondary endpoints, design and comparison conditions (if appropriate), power analyses and sample size, and data analysis plan. Publication plan in collaboration with the CART collaborators outlining potential research and whitepaper publications resulting from the research, including anticipated lead and co-author lists.

Provide study progress reports quarterly, documenting recruitment and enrollment, retention, data QA/QC measure, and relevant study-specific milestones for the technology used in the CART home.

This small-scale, path-building work requires significant economies of effort and the basic organizational operations and execution responsibilities for the entire project will need to be shared between the CART and small business collaborators. The small business contractor will contribute and participate in the CART committees and provide feedback to the committees based on the technologies proposed. In addition, the small business contractor will fully comply or negotiate the CART requirements for testing and validation of the technologies proposed.

099 Inhalational 5A Apolipoprotein A-I Mimetic Peptide for the Treatment of Asthma (SBIR-TT)

Fast-Track proposals will be accepted.

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Direct-to-Phase II proposals will not be accepted.

Number of anticipated awards: 2

Budget (total costs):

Phase I: up to $225,000 for up to 12 months

Phase II: up to $1,500,000 for up to 24 months

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

New treatments are needed for severe asthmatics who do not respond to standard therapy with inhaled steroids, especially those with a “type 2 low” phenotype, such as individuals with neutrophil-predominant inflammation. This solicitation is for the development and early commercialization of an inhalational formulation of the 5A apolipoprotein A-I (apoA-I) mimetic peptide that can be administered to asthmatic subjects in Phase I clinical trials and subsequently developed into a new treatment for severe asthma.

ApoA-I is the major protein component of high-density lipoproteins, which mediates reverse cholesterol transport out of cells by interacting with the ATP-binding cassette subfamily member 1 (ABCA1). ApoA-I also has anti-inflammatory, anti-oxidant, and immunomodulatory properties. NHLBI investigators have shown that systemic administration of the 5A apoA-I mimetic peptide, which is a bi-helical peptide that recapitulates the α-helical structure of apoA-I and mediates reverse cholesterol transport out of cells by interacting with ABCA1, attenuates the induction of airway inflammation, mucous cell metaplasia, and airway hyperresponsiveness in house dust mite (HDM)-challenged mice. In addition, they have shown that apoA-I has a protective effect in allergic asthma. Apoa1-knockout mice, which were sensitized and challenged with ovalbumin (OVA), have increased neutrophilic airway inflammation that was primarily mediated by increased G-CSF expression, with associated increases in type 1 (IFN-γ, TNF-α) and Th17 (IL-17A) cytokines. The increased neutrophilic airway inflammation in the OVA-challenged Apoa1-knockout mice was inhibited by intranasal administration of the 5A apoA-I mimetic peptide. Lastly, serum apoA-I levels are positively correlated with FEV1 in atopic asthmatic subjects, which suggests that circulating apoA-I may improve airflow obstruction. These murine and human translational studies serve as the conceptual basis for developing the 5A apoA-I mimetic peptide into a novel inhalational treatment for severe asthma.

Project Goals

The overall goal of this project is to prepare, in both manufacturing processes and preclinical evaluation, an inhalational 5A apoA-I mimetic peptide that will be the subject of a future Investigational New Drug (IND) application to the US Food and Drug Administration (FDA) focused on the treatment of type 2 low phenotype asthma patients, such as those with neutrophil-predominant inflammation. Successful submission and allowance to proceed of the IND will enable the company to collaborate on the conduct of a clinical trial with intramural clinicians at the NIH Clinical Center, at the company’s discretion. During review, preference will be given to companies or teams with a demonstrated prior ability to successfully bring either a peptide therapeutic or an inhalational therapeutic to, at a minimum, Phase 1 clinical studies in the US.

Additional Project Information

This is an SBIR Technology Transfer (TT) contract topic from the NHLBI. This is a program whereby inventions from the NHLBI Division of Intramural Research (DIR) are licensed on an exclusive or non-exclusive basis to qualified small businesses with the intent that those businesses develop these inventions into commercial products that benefit the public. The contractor funded under this NHLBI SBIR TT contract topic shall work closely with the NHLBI inventor(s) of this technology, who will assist in pre-clinical experiments and will perform a clinical trial using the offeror’s product. The NHLBI inventor(s) will provide assistance in a collaborative manner with provision of 5A apoA-I mimetic peptide for SBIR Phase I comparability studies, experimental designs and techniques, clinical considerations, and discussions during the entire award period.

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An SBIR TT contractor will automatically be granted a royalty-free, non-exclusive license to make and use, but not to sell or offer to sell, for background inventions covered by the NIH-owned patent rights only within the scope and term of the award. However, an SBIR offeror or SBIR contractor can apply for an exclusive or non-exclusive commercialization license to make, use, and sell products or services incorporating the NIH background invention(s). Offerors submitting an SBIR contract proposal in response to this solicitation are strongly encouraged to concurrently submit an application for a commercialization license to such background invention(s). Under the NHLBI SBIR TT program, the SBIR contract award process will be conducted in parallel with, but separate from, the review of any applications for a commercialization license. The criteria to determine eligibility of an offeror to receive a commercialization license will depend on their technical eligibility to receive the SBIR award but will be assessed independently of the SBIR process.

To apply for a license to commercialize this NIH invention, an SBIR offeror or contractor must submit a license application to the NHLBI Licensing and Patenting Manager: Cristina Thalhammer-Reyero; thalhamc@nih.gov; (301) 435-4507. A license application and model license agreements are available at http://www.ott.nih.gov/sites/default/files/documents/pdfs/licapp.pdf and http://www.ott.nih.gov/forms-model-agreements#MLA

This license application provides NIH with information about the potential licensee, some of the terms desired, and the potential licensee's plans for development and/or commercialization of the invention. License applications will be treated in accordance with Federal patent licensing regulations as provided in 37 CFR Part 404. A further description of the NIH licensing process is available at http://www.ott.nih.gov/licensing-process. NIH will notify an SBIR offeror who has submitted an application for an exclusive commercialization license if another application for an exclusive license to the background invention is received at any time before such a license is granted.

NHLBI will share any unpublished patent applications with offerors subject to their agreement to the terms and execution of a confidential disclosure agreement.

Any invention developed by the contractor during the course of the NIH TT contract period of performance will be owned by the contractor subject to the terms of Section 5.5 Technical Data Rights in this Request For Proposals.

Relevant NIH Publications and Patent Applications

Sethi AA, Stonik JA, Thomas F, Demosky SJ, Amar M, Neufeld E, Brewer HB, Davidson WS, D'Souza W, Sviridov D, Remaley AT. Asymmetry in the lipid affinity of bihelical amphipathic peptides. A structural determinant for the specificity of ABCA1-dependent cholesterol efflux by peptides. J Biol Chem 2008;283:32273-32282. http://www.jbc.org/content/283/47/32273.long

Amar MJ, D’Souza W, Turner S, Demosky S, Sviridov D, Stonik J, Luchoomun J, Voogt J, Hellerstein M, Remaley AT. 5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice. J Pharmacol Exp Ther 2010;334:634-641. http://jpet.aspetjournals.org/content/334/2/634.long

Tabet F, Remaley AT, Segaliny AI, Millet J, Yan L, Nakhla S, Barter PJ, Rye KA, Lambert G. The 5A apolipoprotein A-I mimetic peptide displays anti-inflammatory and anti-oxidant properties in vivo and in vitro. Arterioscler Thromb Vasc Biol 2010;30:246-252. http://atvb.ahajournals.org/content/30/2/246.long

Yao X, Dai C, Fredriksson K, Dagur PK, McCoy JP, Qu X, Yu ZX, Keeran KJ, Zywicke GJ, Amar MJ, Remaley AT, Levine SJ. 5A, an apolipoprotein A-I mimetic peptide, attenuates the induction of house dust mite-induced asthma. J Immunol 2011;186:576-583. http://www.jimmunol.org/content/186/1/576.long

Dai C, Yao X, Keeran KJ, Zywicke GJ, Qu X, Yu ZX, Dagur PK, McCoy JP, Remaley AT, Levine SJ. Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism. Am J Respir Cell Mol Biol 2012;47:186-195. http://www.atsjournals.org/doi/abs/10.1165/rcmb.2011-0322OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed#.Vusaa-nVtNE

Barochia AV, Kaler M, Cuento RA, Gordon EM, Weir NA, Sampson M, Fontana JR, MacDonald S, Moss J,

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Manganiello V, Remaley AT, Levine SJ. Serum apolipoprotein A-I and large high-density lipoprotein particles are positively correlated with FEV1 in atopic asthma. Am J Respir Crit Care Med 2015;191:990-1000. http://www.atsjournals.org/doi/abs/10.1164/rccm.201411-1990OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed#.VusakunVtNE

Issued Patents, expiring 10/14/2025: NIH Reference Number E-114-2004/0 (https://www.ott.nih.gov/technology/e-114-2004)

• US 7,572,771, issued August 11, 2009;

• US 8,071,746, issued December 6, 2011;

• US 8,148,323, issued April 3, 2012;

• EP 05815961.7, issued May 26, 2010;

• JP 2007-536912, issued September 21, 2012

Phase I Activities and Expected Deliverables

A Phase I award should be used to demonstrate that a comparable 5A apoA-I mimetic peptide can be synthesized and attenuate allergen-induced airway inflammation when administered by a pulmonary route in a pre-clinical asthma model.

The specific deliverables would be:

• Synthesis of a non-GMP grade 5A apoA-I mimetic peptide for comparability studies with the 5A peptide that was previously utilized by NHLBI investigators. NHLBI investigators can provide reference test material for comparability studies.

• Dose ranging animal studies will be performed to reproduce experiments showing that the 5A apoA-I mimetic peptide significantly suppresses house dust mite (HDM)-induced airway inflammation. Three doses of the 5A apoA-I mimetic peptide or control peptide, 0.1, 1, and 10 mg/kg, in 10 μl of saline, will be administered by pulmonary delivery, 5 days per week for 4 weeks and compared to an untreated group that receives pulmonary delivery of the vehicle alone (e.g., saline). Inhibition of airway inflammation in HDM-challenged mice by pulmonary delivery of the 5A apoA-I mimetic peptide will be assessed by quantifying the number of eosinophils in bronchoalveolar lavage fluid. A greater than 25% reduction will be considered significant. NHLBI investigators had previously sensitized and challenged A/J mice by intranasal instillation of 25 μg of HDM in 10 μl of saline, 5 days per week, for 4 weeks and concurrently administered either the 5A apoA-I mimetic peptide (1 mg/kg/day) or a control peptide (that represented the scrambled sequence of an apolipoprotein E mimetic peptide). The 5A apoA-I mimetic peptide should be delivered via a pulmonary route in the morning and the HDM should be administered in the afternoon. NHLBI investigators performed three independent experiments with 10 mice per group (J Immunology, 2011, 186: 576).

Phase II Activities and Expected Deliverables

A Phase II award should be used to develop an inhaled formulation of the 5A apoA-I mimetic peptide for future use in human clinical trials. In addition, the deliverables will include stability testing of the inhaled formulation of the 5A apoA-I mimetic peptide and early pre-clinical animal studies. These deliverables will initiate safety testing and regulatory development of an inhaled formulation of the 5A apoA-I mimetic peptide.

The specific deliverables would be:

• Generation and synthesis of an inhaled GMP formulation of both the 5A apoA-I mimetic peptide and control peptide.

• Development and validation of GLP-bioanalytical test methods for the inhaled formulation of the GMP-grade 5A apoA-I mimetic peptide.

• GLP stability testing of the inhaled formulation of the GMP-grade 5A apoA-I mimetic peptide. The awardee should have expertise in peptide chemistry and analysis and devise a plan that adequately assesses

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stability of the α-helical structure of the 5A apoA-I mimetic peptide, demonstrates that no chemical changes have occurred (e.g., hydrolysis, deamidation, oxidation, etc.), as well as performs cGMP release and serum stability assays.

• GLP toxicity studies to establish the NOAL (no observed adverse effect level) and MTD (maximum tolerated dose) of the inhaled 5A apoA-I mimetic peptide in the rat using GMP-grade 5A apoA-I mimetic peptide and appropriate controls (e.g., vehicle, control peptide).

• Acute GLP respiratory and systemic PK/TK studies in rats (males and females) using the GMP-grade 5A apoA-I mimetic peptide and appropriate controls (e.g., vehicle, control peptide).

• Daily repeat GLP dosing respiratory and systemic PK/TK studies in rats (male and female) using the GMP-grade 5A apoA-I mimetic peptide for a minimum of 14 days and appropriate controls (e.g., vehicle, control peptide).

• Generation of a development plan to support a successful IND application to the FDA for an inhaled formulation of the 5A apoA-I mimetic peptide. The development plan will address: (i) CMC manufacturing of the inhaled formulation of the 5A apoA-I mimetic peptide, (ii) pre-clinical studies, and (iii) Phase 1 clinical trials. The development plan will be discussed at a pre-IND meeting with the FDA and modified as necessary.

Offerors are encouraged to consider the NHLBI Phase IIB Bridge (http://1.usa.gov/1q9yTyP) and Phase IIB Small Market Award (http://1.usa.gov/1v0Wxn1) programs to support additional development beyond Phase II.

100 MRI Myocardial Needle Chemoablation Catheter

Fast-Track proposals will be accepted.

Direct-to-Phase II proposals will be accepted.

Number of anticipated awards: 1

Budget (total costs):

Phase I: up to $300,000 for up to 18 months

Phase II: up to $2,000,000 for up to 24 months

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Myocardial catheter ablation is commonly performed for the treatment of rhythm disorders, using radiofrequency energy, typically guided using X-ray and/or electromagnetic positioning. Available non-surgical technologies do not allow clear depiction of myocardium being ablated. MRI-guided needle catheter chemo-ablation, for example using focal injection of caustic agents such as acetic acid doped with MRI contrast agents, may allow targeted disruption of small segments of myocardium in the treatment of rhythm disorders such as ventricular tachycardia and in the treatment of structural heart disease such as hypertrophic cardiomyopathy. Preclinical feasibility of at least two different MRI injection needle catheter systems has been demonstrated and published for the application of direct endomyocardial cell injection, including by our labs. No commercial options are available.

An MRI myocardial needle injection catheter system may enable a new family of non-surgical cardiovascular treatments for rhythm and structural heart disease.

Project Goals

The goal of the project is to develop an endomyocardial injection needle chemoablation catheter that is safe for operation during MRI, to allow targeted myocardial delivery of caustic agents. First a prototype would be developed and tested in animals, and ultimately a clinical-grade device would undergo regulatory development for clinical testing. NIH offers to perform clinical testing at no charge to the contractor.

Offerors are encouraged to include concrete milestones in their proposals, along with detailed research and development plans, risk analysis, and contingency plans, both for Phase I and Phase II.

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Proposals must include a detailed description of the regulatory strategy, including plans for a pre-submission meeting with the US Food and Drug Administration (FDA) in Phase I. Offerors must include key personnel on the project with appropriate and relevant regulatory experience.

Offerors are advised to plan travel to NHLBI in Bethesda, Maryland, and are expected to plan meetings at project initiation, mid-project to determine what iteration is necessary, and at project completion.

Phase I Activities and Expected Deliverables

A Phase I award would support the development and testing of a myocardial injection needle prototype. The contracting DIR lab is willing to provide feedback about design at all stages of development. The contracting DIR lab will test the final deliverable device for success in vivo in swine.

Specific Phase I deliverables include:

• 9Fr or smaller.

• Suitable for use via femoral artery retrograde across aortic valve and via jugular and femoral venous access to the right sided cardiac chambers.

• A needle that can be delivered to multiple endomyocardial targets, achieve stable positioning, and that can penetrate the myocardium without causing significant harm while delivering injectate. Solutions should allow a user-selected injection depth and may be spring-loaded or offer alternative penetration capabilities.

• Sufficient radius of curvature to access all parts of left ventricle endocardial surface including left ventricle outflow tract, and all parts of right ventricle including septum and outflow tract. Suitable solutions incorporate deflectable catheters with extensible needle elements; alternative embodiments may use multiple coaxial curved catheters that can be torqued, or other approaches.

• Visibility during MRI: (1) “Active” design incorporating MRI receiver coils for mandatory shaft and tip and needle visibility during MRI; (2) Receiver coils should be conspicuous under MRI using “profiling” or “tracking” techniques as described in publications from the contracting NHLBI DIR laboratory (See Saikus CE and Lederman RJ, JACC Cardiovascular Imaging, 2009, http://www.pubmed.gov/19909937); (3) The “active” receiver coils must operate for testing on a Siemens Aera 1.5T MRI scanner installed at contracting NHLBI DIR laboratory.

• There should be a distinct imaging signature to confirm needle deployment. One suitable option is a separate receiver channel for the needle.

• Simultaneous ability to record intracardiac electrograms from the needle site, either bipolar or unipolar, including safe electrode transmission lines.

• Free from clinically-important heating (2oC at 1W/kg SAR) during continuous MRI at 1.5T.

• Proposals for alternative visualization and heat-mitigation strategies, such as “active” or “inductively-coupled” receiver coils, are encouraged, but must operate for testing on a Siemens Aera 1.5T MRI scanner installed at the contracting NHLBI DIR laboratory.

• A comprehensive report of test results, including in vivo test results if not performed at NHLBI.

• Sufficient devices to test the final device in vivo at the contracting NHLBI DIR laboratory.

• A detailed report of pre-submission interactions with the FDA Center for Devices and Radiological Health (CDRH) identifying requirements for Investigational Device Exemption (IDE) development under Phase II, including meeting minutes, if available.

Consideration for transition to Phase II funding will include regulatory progress toward US market access. Consideration may include the status of the contractor’s interactions with the FDA. NHLBI encourages contractors to consider requesting designation to the FDA’s Expedited Access for PMA Devices (EAP) program (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM393978.pdf) during the Phase I award period.

Phase II Activities and Expected Deliverables

A Phase II award would allow mechanical and safety testing and regulatory development for the device to be used in human investigation, whether under Investigational Device Exemption (IDE) or under 510(k) marketing clearance.

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Activities in Phase II should align with the required testing and development milestones agreed upon with the FDA in Phase I. The contracting DIR lab offers to perform an IDE clinical trial at no cost to the awardee.

IDE license or 510(k) clearance, along with twenty clinical investigational prototypes, would constitute the deliverable.

The offeror should provide clear project milestones that trigger review and payment, along with detailed research and development plans, risk analysis, and contingency plans.

Representative project milestones include, not necessarily sequentially:

• a device build and short-term survival study to identify additional failure modes.

• elements of a quality system including product specification, design and failure mode analysis, design verification and test plan, biocompatibility and sterility assessment and plan, design review, design freeze.

• manufacturing plan.

• iterative ex vivo testing such as animal explants.

• iteration for unexpected design or device failure.

• pre-submission meetings with FDA.

• chronic or acute GLP animal studies as required.

• design of clinical protocol including informed consent, risk analysis for early feasibility, and case report form, whether or not conducted in collaboration with NHLBI Division of Intramural Research laboratory.

• preparation of IDE.

• submission and resubmission of IDE.

• manufacturing of test articles.

Specific Phase II deliverables include:

• All characteristics of Phase I deliverable, and in addition:

• Catheter outer diameter reduced to 8Fr or smaller for phase II.

• A complete report of prior investigation along with all other elements of the IDE application and accompanying regulatory correspondence.

• Suitability of the injection system for delivery of viable cells, while outside the scope of this contract, is encouraged.

101 Membranous Ventricular Septal Defect (pmVSD) Transcatheter Occluder System

Fast-Track proposals will be accepted.

Direct-to-Phase II proposals will be accepted.

Number of anticipated awards: 1

Budget (total costs):

Phase I: up to $400,000 for up to 21 months

Phase II: up to $3,000,000 for up to 36 months

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Ventricular septal defect is the most common congenital heart defect. Membranous-type ventricular septal defect (pmVSD) accounts for over two thirds of ventricular septal defects, and approximately half require repair. Surgical repair is morbid, and may require two staged surgical procedures. No suitable device is marketed for transcatheter repair of pmVSD. Commercial development of catheter-based devices to treat structural heart disease in children is limited by the relatively small market size and the relatively large upfront costs.

The purpose of this solicitation is to support early-stage pre-clinical and clinical development of a transcatheter device system to treat pmVSD without surgery.

Project Goals

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The goal of the project is to develop a device for percutaneous closure of membranous VSD in infants and children, with an acceptable low rate of complete heart block compared with surgical closure. First a prototype would be developed and tested in animals, and ultimately a clinical-grade device would undergo regulatory development for clinical testing at NIH.

Offerors are encouraged to include concrete milestones in their proposals, along with detailed research and development plans, risk analysis, and contingency plans, both for Phase I and Phase II.

Proposals must include a detailed description of the regulatory strategy, including plans for a pre-submission meeting with the US Food and Drug Administration (FDA) in Phase I. Offerors must include key personnel on the project with appropriate and relevant regulatory experience.

Offerors are advised to plan travel to NHLBI in Bethesda, Maryland, and are expected to plan meetings at project initiation, mid-project to determine what iteration is necessary, and at project completion.

Phase I Activities and Expected Deliverables

A Phase I award would support the development and testing of a pmVSD occluder prototype suitable for children and newborn infants. The NHLBI Division of Intramural Research laboratory offers to test a final prototype in vivo, at no expense to the offeror. The offeror is expected independently to perform animal testing as needed to meet Phase I requirements.

Device requirements include:

• A design specifically to achieve occlusion of membranous-type ventricular septal defects in children and newborn infants.

• The implant should accommodate a range of defects average diameters sized 2mm to 18mm, using multiple device sizes if necessary.

• The implant should be designed specifically to minimize or avoid conduction system injury that would risk immediate or late complete heart block.

• The implant should have mechanisms or a range of morphologies to avoid entrapment or distortion of the aortic valve or to avoid late injury to the aortic valve root or leaflets.

• The implant should be available with transmyocardial or interventricular “neck” length and width dimension.

• The implant should conform to ventricular cavities without causing geometric distortion or obstruction of ventricular outflow tracts.

• The delivery system catheter outer diameter must be 9Fr or smaller and should be suitable for fully transcatheter repair without requiring surgical cardiac exposure.

• The implant and delivery system should avoid entrapment or early/late injury to tricuspid valve with attention to aneurysmal septal segments.

• The proposed solution should have a mechanism to assure proper orientation if that is important to the functionality of specific design.

• Designs amenable to both antegrade and retrograde delivery are desirable.

• The delivery system should secure against unplanned release.

• Proposals should include specific plans for operator recovery of the device if it embolizes after release.

• Implants must be MRI compatible so that cardiac function and flow can be measured unimpeded after implantation using MRI, and MRI conspicuity is desirable.

• The delivery system and implant must be conspicuous under the proposed image-guidance modality whether ultrasound or X-ray, and must be conspicuous under X-ray after release.

• The delivery system should be designed to mitigate hemodynamic embarrassment caused by interruption of tricuspid valve function during implant procedures.

• The device should accomplish acute or subacute occlusion without early or late thromboembolism, and proposals should specifically address these considerations.

• The system should be accompanied by a proposed robust methodology or device to select the appropriate device size.

• Build of a phantom for bench testing of the device design(s), retrieval tool, and size selection tool/methodology.

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• The offeror must independently demonstrate satisfactory device performance in VSD, preferably pmVSD, in vivo.

• A comprehensive report of test results, including in vivo test results if not performed at NHLBI.

• A detailed report of pre-submission interactions with the FDA Center for Devices and Radiological Health (CDRH), indicating a sufficiently mature device and identifying requirements for Investigational Device Exemption (IDE) development under Phase II, including meeting minutes, if available.

Final payment is contingent on meeting all of the above requirements.

Consideration for transition to Phase II funding will include regulatory progress toward US market access. Consideration may include the status of the contractor’s interactions with the FDA. NHLBI encourages contractors to consider requesting designation to the FDA’s Expedited Access for PMA Devices (EAP) program (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM393978) during the Phase I award period.

Phase II Activities and Expected Deliverables

In addition to meeting all requirements specified for Phase I, the Phase II award would allow mechanical and safety testing and regulatory development for the device to be used in human investigation. The NHLBI Division of Intramural Research laboratory offers but does not require to perform an IDE clinical trial at no cost to the awardee. Activities in Phase II should align with the required testing and development milestones agreed upon with the FDA in Phase I.

Complete IDE documentation and license and a suitable supply of clinical materials would constitute the final deliverable. The offeror will provide a complete report of prior investigation along with all other elements of the IDE application and accompanying regulatory correspondence. For all purposes, a humanitarian device exemption (HDE) or an expedited Premarket Approval (PMA) would be considered responsive in place of IDE.

The offeror should provide clear project milestones that trigger review and payment, along with detailed research and development plans, risk analysis, and contingency plans. Representative project milestones include, not necessarily sequentially:

• a device build and short-term survival study to identify additional failure modes.

• elements of a quality system including product specification, design and failure mode analysis, design verification and validation and test plan, biocompatibility and sterility assessment and plan, design review, design freeze, design transfer to manufacturing.

• manufacturing plan.

• iterative ex vivo testing such as animal explants.

• iteration for unexpected design or device failure.

• pre-submission meetings with FDA.

• modeling and fatigue study for chronic implant.

• chronic GLP animal studies.

• design of clinical protocol including informed consent, risk analysis for early feasibility, and case report form, whether or not conducted in collaboration with NHLBI Division of Intramural Research laboratory.

• preparation of IDE.

• submission and resubmission of IDE.

• manufacturing of test articles.

The offeror is expected to conduct animal experiments and provide care as required to obtain the IDE. The offeror is advised to propose how to proceed in case of hold from FDA.

Offerors are encouraged to consider the NHLBI Phase IIB Small Market Award (http://1.usa.gov/1v0Wxn1) program to support additional development beyond Phase II. The NHLBI Phase IIB Small Market Award provides up to an additional $3M over 3 years, with an expectation that applicants secure independent third-party investor funds.

102 Transcatheter Occluder Device for Paravalvular Leaks

Fast-Track proposals will be accepted.

Direct-to-Phase II proposals will be accepted.

Number of anticipated awards: 1

Budget (total costs):

Phase I: up to $400,000 for up to 21 months;

Phase II: up to $3,000,000 for up to 36 months

PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.

Summary

Over fifty thousand prosthetic heart valves are implanted in the United States annually. A discrete fraction develop significant regurgitation around the implant site, related to technical dehiscence or poor seating related to calcification, friability, or infection. The problem affects both mitral and aortic valves, whether implanted surgically or via a transcatheter route. The problem persists especially after surgically implanted valves despite technical refinement of transcatheter devices. Paravalvular regurgitation manifests as congestive heart failure from volume overload, or hemolytic anemia from mechanical cell injury. Surgical revision confers high morbidity and mortality. A variety of nitinol cardiac occluder devices have been employed off-label, but most are poorly suited for the application and none achieve simple and reliable occlusion.

The purpose of this solicitation is to support early-stage pre-clinical and clinical development of a purpose-built transcatheter occluder device for paravalvular leaks, to address this important unmet need.

Project Goals

The goal of the project is to develop a device for percutaneous closure of paravalvular leak. First a prototype would be developed and tested in vitro. Ultimately a clinical-grade device would undergo regulatory development for clinical testing in the USA.

Offerors are encouraged to include concrete milestones in their proposals, along with detailed research and development plans, risk analysis, and contingency plans, both for Phase I and Phase II.

Proposals must include a detailed description of the regulatory strategy, including a plan for a pre-submission meeting with the US Food and Drug Administration (FDA) in Phase I prior to the start of major engineering work or bench research. Offerors must include key personnel on the project with appropriate regulatory experience. Team members should have demonstrated experience with cardiovascular device product development, including permanent implants.

Offerors are advised to plan travel to NHLBI in Bethesda, Maryland, and are expected to plan for meetings at project initiation, mid-project to determine what iteration is necessary, and at project completion.

Phase I Activities and Expected Deliverables

A Phase I award would support the development and testing of a catheter system for implantation of a paravalvular leak occluder. The offeror is expected independently to perform animal testing as needed to meet Phase I requirements.

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Device requirements include:

• Up to 8Fr delivery system.

• Suitable to occlude regurgitation around surgically implanted aortic and mitral valve prostheses. Applicability to transcatheter valves is welcome.

• Ability to traverse complex geometry characteristic of paravalvular leaks.

• Ability to conform to complex and poorly visualized and highly variable regurgitant orifices.

• Demonstrating early hemostasis.

• Designs are encouraged that conform through bladder inflation or through expansion of superelastic materials or other novel approaches.

• Must be retrievable and removable before final implantation.

• Designs should avoid interference with function of the target prosthetic mechanical heart valves.

• Ability to reposition before final implantation is desirable.

• Low risk of embolization after implantation.

• Delivery designs are encouraged that retain delivery catheter position at the target (such as with a buddy guidewire) until conclusion of the procedure.

• Devices should be conspicuous during positioning and after final implantation, with attention to challenges imposed by metallic surgical valves.

• The devices should not impose an undue risk of thromboembolism and stroke after implantation.

• Implants should be MRI compatible so that cardiac function and flow can be measured unimpeded after implantation using MRI. MRI conspicuity is desirable.

• The delivery system and implant must be conspicuous under the proposed image-guidance modality whether ultrasound or X-ray, and must be conspicuous under X-ray after release.

• The system should be accompanied by a proposed robust methodology or device to select the appropriate device size.

Expected deliverables include:

• A detailed report of pre-submission interactions with the FDA Center for Devices and Radiological Health (CDRH), indicating a sufficiently mature device and identifying requirements for Investigational Device Exemption (IDE) development under Phase II, including meeting minutes, if available.

• A final prototype with phantom testing.

Final payment is contingent on meeting all of the above requirements.

Consideration for transition to Phase II funding will include progress toward regulatory progress toward US market access. Consideration may include the status of the contractor’s interactions with the FDA. NHLBI encourages contractors to consider requesting designation to the FDA’s Expedited Access for PMA Devices (EAP) program (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM393978) during the Phase I award period.

Phase II Activities and Expected Deliverables

In addition to meeting all requirements specified for Phase I, the Phase II award would allow mechanical and safety testing and regulatory development for the device to be used in human investigation. The NHLBI Division of Intramural Research laboratory offers but does not require to perform an IDE clinical trial at no cost to the awardee. Activities in Phase II should align with the required testing and development milestones agreed upon with the FDA in Phase I.

Complete IDE documentation and license and a suitable supply of clinical materials would constitute the final deliverable. The offeror will provide a complete report of prior investigation along with all other elements of the IDE application and accompanying regulatory correspondence. For all purposes, a humanitarian device exemption (HDE) or an expedited Premarket Approval (PMA) would be considered responsive in place of IDE.

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The offeror should provide clear project milestones that trigger review and payment, along with detailed research and development plans, risk analysis, and contingency plans. Representative project milestones include, not necessarily sequentially:

• a device build and, if required, a short-term survival study to identify additional failure modes.

• elements of a quality system including product specification, design and failure mode analysis, design verification and validation and test plan, biocompatibility and sterility assessment and plan, design review, design freeze, design transfer to manufacturing.

• manufacturing plan.

• iterative ex vivo testing such as animal explants.

• iteration for unexpected design or device failure.

• pre-submission meetings with FDA.

• modeling and fatigue study for chronic implant if required.

• chronic or acute GLP animal studies as required.

• design of clinical protocol including informed consent, risk analysis for early feasibility, and case report form, whether or not conducted in collaboration with NHLBI Division of Intramural Research laboratory.

• preparation of IDE.

• submission and resubmission of IDE.

• manufacturing of test articles.

The offeror is expected to conduct animal experiments and provide care as required to obtain the IDE. The offeror is advised to propose how to proceed in case of hold from FDA.

Offerors are encouraged to consider the NHLBI Phase IIB Bridge (http://1.usa.gov/1q9yTyP) and Phase IIB Small Market Award (http://1.usa.gov/1v0Wxn1) programs to support additional development beyond Phase II. The NHLBI Phase IIB programs provide up to an additional $3M over 3 years, with an expectation that applicants secure independent third-party investor funds.

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NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID)

The National Institute of Allergy and Infectious Diseases (NIAID) conducts and supports basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases. For more than 60 years, NIAID research has led to new therapies, vaccines, diagnostic tests, and other technologies that have improved the health of millions of people in the United States and around the world. To learn more about the NIAID, please visit our web page at http://www.niaid.nih.gov/about/whoWeAre/Pages/moreWhoWeAre.aspx.

040 Effective Targeted Delivery of RNA-based Vaccines and Therapeutics

Direct to Phase II will be accepted

Fast Track will not be accepted

Number of anticipated awards: 1-2

Budget (total costs):

Phase I: $300,000 for up to one year

Phase II: $2,000,000 for up to 3 years

Background:

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:

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• 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.

041 Simplified Sequencing for TB Drug Resistance Testing

Direct to Phase II will be accepted

Fast Track will be accepted

Number of anticipated awards: 1-2

Budget (total costs):

Phase I: up to $600,000 per year for up to two years;

Phase II: up to $3,000,000 for up to 3 years

Background:

People living with HIV/AIDS have increased mortality when infected with MDR and XDR TB, worsened by delays starting an appropriate treatment regimen due to poor access to drug sensitivity testing (DST). While the WHO recommends routine DST at each new presentation of TB, only 12% of newly infected individuals globally had access to a resistance test in 2014. Poor laboratory infrastructure and high cost have been cited as primary factors blocking access to TB resistance testing. Current WHO-approved testing approaches, such as GeneXpert and line probe assays at present detect only a limited set of resistance mutations relevant for up to two TB drugs. Additionally, current molecular tests have been shown to have lower sensitivity in populations with a high HIV burden, due to the lower bacillary load among HIV/TB co-infected patients and higher prevalence of smear negative disease.

Sequencing-based diagnostics hold great promise for the establishment of low-cost, simplified TB drug resistance testing, capable of determining resistance to a broad range of drugs and in diverse TB strains. Crucially, the data generated from sequencing-based diagnostics can concurrently be used for individualizing therapy as well as allow surveillance of the prevalence and emergence of resistance, and accurately determining TB transmission patterns in a population.

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In order to improve the quality of patient care through accurate testing, while concurrently enabling global surveillance of resistance patterns, a simplified sequencing device integrated with an accurate sequencing analysis software platform, is needed.

Project goal:

The goal of this project is to develop a low-cost, easy-to-use platform for TB drug resistance testing and surveillance for settings with high HIV prevalence and limited information technology and laboratory resources. The resulting platform must rapidly and accurately generate sequence data from smear negative sputum to enable the prediction of resistance to all first and second line anti-TB drugs while performing highly accurate analysis of the sequence data to produce clinically actionable resistance reports.

Phase I activities:

• Develop a technique allowing simultaneous sequencing from a single sputum sample (patient sample or spiked) of at least 40 key genes and genetic regions associated with resistance to at least the following tuberculosis drugs: isoniazid, rifampin, ethambutol, pyrazinamide, kanamycin, amikacin, capreomycin, streptomycin, moxifloxacin, ofloxacin, para-amino salicylic acid, cycloserine ethionamide/protionamide, terizidone.

• Refine technique to generate accurate sequencing data on first and second line drugs from single smear negative culture positive sputum sample.

Phase II activities:

• Develop a self-contained device for settings with limited laboratory resources incorporating the following :

• Simple operation requiring few steps, and minimal operator training

• No need for external electricity (battery power can be proposed)

• Short per-sample running time with high sample throughput

• Sufficient accuracy to allow clinically relevant results

• Operate with no significant biosafety concerns,

• Software to interpret data to provide immediate clear results for susceptibility to TB drugs listed above with no need for clinician interpretation, aligning with global efforts to standardize reporting language,

• Ability to upload sequencing data to central data repository

042 Qualitative HIV RNA Home Test

Direct to Phase II proposals will be accepted

Fast-Track proposals will not be accepted

Number of anticipated awards: 1-2

Budget (total costs):

Phase I: up to $300,000 for up to 1 year

Phase II: up to $3,000,000 for up to 3 years

Background:

Approximately 37 million people are living with HIV, with 15 million accessing antiretroviral therapy (ART). Recently revised WHO guidelines recommend that all people diagnosed with HIV be offered ART at any CD4 count, which will result in many more people on ART. Current ART regimens are very potent and reduce HIV viral load in blood to undetectable levels in most patients, which in turn significantly reduces mortality and morbidity and reduces transmission of HIV. However, viral rebound can occur through non-adherence or resistance. In either case, it is critical to identify viral rebound as early as possible in order to avoid drug resistance and clinical progression. The ability to easily monitor HIV plasma RNA in blood at home would help identify viral rebound early and allow intervention. Ideally, HIV RNA testing at home should be as easy as glucose monitoring for diabetics. If priced appropriately, this technology may be useful for home monitoring in resource limited settings where patients live far from the clinical care site. Such a technology could also be used for home monitoring of individuals enrolled in clinical trials involving a treatment interruption who need to have their viral load monitored

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very frequently, in-home monitoring for individuals using pre-exposure prophylaxis (PrEP), where HIV infection must be detected very early to avoid resistance to the drugs in the PrEP regimen, and in-home monitoring for high risk individuals to allow early detection and early treatment, which may lead to smaller HIV reservoirs and reduced transmission.

Project goal:

The goal of this solicitation is to develop a method for HIV RNA home testing. The method need not be quantitative, but should detect HIV RNA with a sensitivity of at least 98% and specificity of at least 98% if the viral load is 1000 HIV RNA copies per ml of blood or higher. The proposed method must include a procedure for obtaining finger stick blood such that the blood can be easily manipulated and transferred to the test medium. Proposals can include the use of a small handheld unit to be used with individual test strips or cartridges, but device free, disposable units are preferred. Test units may require refrigeration, but stability at room temperature is preferable. All necessary materials should be supplied with the test and no additional materials should be required. The amount of handling required by the operator should be suitable for home testing by untrained individuals.

Phase I activities may include:

• Development of simple methods for: a) obtaining finger stick blood and easily transferring blood or plasma to the test medium, b) detecting HIV plasma RNA, but not cell associated HIV DNA and RNA, with a cutoff of 1000 RNA copies per ml of blood, c) providing an easily readable output. (see additional specifications above)

• Combining the methods into an inexpensive, easy to use, integrated assay platform (up to $100 for handheld unit, up to $10 per test unit/cartridge)

• Initial testing on laboratory isolates, including several HIV subtypes

Phase II activities may include:

• Validation testing to include sensitivity, specificity and lower limit of detection, with comparison to FDA-approved HIV viral load test methods

• Development of a well-defined test platform under good manufacturing practices (GMP)

• Development of a quality control program to ensure lot-to-lot consistency

• Scale-up and production for multi-site evaluations using clinical isolates

043 Adjuvant Development

Fast-Track proposals will not be accepted.

Direct-to-phase II proposals will be accepted

Number of anticipated awards: 1-3

Budget (total costs):

Phase I: $225,000 for up to 1 year

Phase II: $1,500,000 for up to 3 years

Background:

Adjuvants stimulate innate and/or adaptive immune responses. For the purpose of this SBIR, 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.” Currently, only three adjuvants have been licensed 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.

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Project Goal:

The goal of this 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 non-HIV infectious pathogens. For this solicitation, a combination-adjuvant is defined as a complex exhibiting synergy between individual adjuvants, such as: overall enhancement of the immune response; potential for adjuvant-dose sparing to reduce reactogenicity while preserving immunogenicity; or broadening of effector responses, such as through target-epitope spreading or enhanced antibody avidity. The adjuvant products supported by this program must be studied and further developed toward human licensure with currently licensed or new investigational vaccines, and may not be developed as stand-alone agents.

Phase I Activities

Depending on the developmental stage at which an adjuvant is entered into the

Program, the offeror may choose to perform one or more of the following:

• Optimization of one candidate compound for enhanced safety and efficacy. Studies may include:

• 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 immune responses synergistically.

• 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.

• Preliminary studies in a suitable animal model to evaluate the protective efficacy of a lead adjuvant:vaccine or adjuvant/immunotherapeutic combination.

• Analysis of vaccine efficacy through the use of a combination adjuvant and studies to evaluate the safety profile of the combination adjuvant:vaccine or adjuvant/immunotherapeutic formulation.

Phase II Activities

Extended pre-clinical studies that may include IND-enabling studies such as:

• Additional animal testing of the lead adjuvant:vaccine or adjuvant/immunotherapeutic combination to evaluate immunogenicity, protective efficacy and immune mechanisms of protection.

• Pilot lot or cGMP manufacturing of adjuvant or adjuvant:vaccine or adjuvant/immunotherapeutic compound.

• 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 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).

• 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 activity themselves.

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• The development and/or optimization of a pathogen-specific vaccine component.

044 Vaccine Adjuvant Screening and Discovery

Fast-Track proposals will not be accepted.

Direct-to-phase II proposals will be accepted

Number of anticipated awards: 1-3

Budget (total costs):

Phase I: $225,000 for up to 1 year

Phase II: $1,500,000 with appropriate justification by the applicant for up to 3 years

Background:

Vaccine adjuvants stimulate innate and/or adaptive immune responses. For the purpose of this SBIR, 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.” Currently, only three adjuvants have been licensed 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. The gaps that need to be addressed by new adjuvants include improvements to existing, insufficiently efficacious vaccines (e.g., the acellular pertussis vaccine), and development of vaccines: for emerging threats (e.g., Ebola outbreaks); for special populations that poorly respond to existing vaccines (i.e., elderly, newborns/infants, immunosuppressed patients); or to treat/prevent immune-mediated diseases (e.g., allergen immunotherapy, autoimmunity, transplant rejection). Recent advances in innate immunity have provided a significant number of new putative targets for vaccine adjuvants. Simultaneously, progress is slowly being made in the identification of in vitro correlates of adjuvanticity which allows the design of in vitro screening assays to discover novel adjuvant candidates in a systematic manner.

Project Goal:

The objective of this program is to support the screening for new adjuvant candidates, 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 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 leads 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

045 Database Resources Integration

Fast-Track proposals will not be accepted

Direct-to-phase II proposals will be accepted

Number of anticipated awards: 1-2

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Budget (total costs):

Phase I: $225,000 for up to 1 year

Phase II: $1,500,000 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 immunology research community for data sharing, knowledge dissemination, standard development and integrative analyses:

• ImmPort (https://immport.niaid.nih.gov/): a unique resource primarily for public data sharing of immunological studies funded by DAIT

• 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 ITN’s clinical studies and specimen, as well as data and analysis code underlying the consortium’s publications

• IEDB (http://www.iedb.org/): a bioinformatics resource that offers easy searching of experimental data characterizing antibody and T cell epitopes, including epitopes involved in infectious disease, allergy, autoimmunity, and transplant, 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 have been serving the research community well, there is a growing need for a search and retrieval system (e.g., NCBI Entrez, Google-like interface) that enables integrated access to these resources. The development of such system, supplemented with a set of data integration standards and tools, will position the research community to better utilize existing databases for immunology research.

Project Goal

The goal of this project is to support the development of a data retrieval and discovery system for integrated access to DAIT funded bioinformatics resource for data query, knowledge dissemination and integrative analyses.

Phase I Activities

Phase I activities should focus on providing evidence that bioinformatics methods have been developed effectively and can be applied to the data, information, knowledge and tools across the identified DAIT database resources. The offeror may choose to perform the following:

1. Prototyping an integrated retrieval system that has a user interface to enable searching of the identified databases. The system should support text searching using simple Boolean queries, downloading of data in various formats and linking of data, information and tools between these databases based on inferred relationships.

2. Implementation of data and metadata standards to facilitate the transformation and integration of data from the identified databases into analyzable datasets for immune modeling and biomarker prediction.

3. Implementation of bioinformatics pipelines to enable interoperation of data and tools of these databases.

Phase II Activities

Extend Phase I to include the following:

1. Production implementation of the bioinformatics systems prototyped during Phase I.

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2. Add functionalities and capacities of these systems based on research community’s needs.

3. Integration of more public databases relevant to immunology research.

4. Adoption of new integrative tools to support discovery and validation of biomarkers across multiple types of molecular data, clinical phenotypes, animal and cell line models.

This SBIR will not support:

The design and implementation of a data warehouse.

046 Rapid Point-of-Care Diagnostics to Detect Serologic Status of Individuals for Select Viral Infections

Fast-Track proposals will be accepted.

Direct-to-Phase II proposals will be accepted.

Number of anticipated awards: 1-2

Budget (total costs):

Phase I: $225,000 for up to one year

Phase II: $1,500,000 for up to 3 years.

Background:

Congenital infection with cytomegalovirus (CMV) is one of the leading non-genetic causes of birth defects, affecting approximately one in every 150 children born in the U.S., and is a leading cause worldwide of sensoneural hearing loss in babies with or without other symptoms of congenital infection. Neonates infected with herpes simplex virus (HSV) manifest with one of three disease classifications (disseminated disease; central nervous system disease; or skin, eye, and mouth disease) with varying degrees of morbidity and mortality, depending on standards of medical practice across the world. The development of vaccines for CMV and HSV pose significant challenges for vaccine manufacturers. One of these challenges is how to efficiently identify and enroll eligible study subjects in large Phase III efficacy trials. Phase III studies would need to enroll thousands of seronegative subjects, and because the seroprevalence rates for CMV and HSV are high in the target population for vaccination (women of childbearing potential), this will require the screening of tens to hundreds of thousands of potential volunteers. The availability of rapid, accurate and cost-effective POC serodiagnostics would de-risk the development of CMV and HSV vaccines by vastly improving the logistics of enrollment for these large Phase III studies. Specifically, a rapid POC test that could be utilized during initial study screening visits would permit the efficient identification and enrollment of potential vaccinees. In addition, should a vaccine be licensed for seronegative women only, the POC test would permit the efficient implementation of a vaccination strategy in resource-limited countries. For small businesses interested in this topic, reagents such as recombinant CMV and HSV antigens are readily available from the research community to support the development of such a rapid POC serodiagnostic.

Project Goal:

The goal of this project is to develop rapid POC diagnostic tests that can determine whether a person has pre-existing antibody to HSV or CMV as an indicator of prior virus infection. The final product should be self-contained, require only a small blood sample (e.g., from a finger stick), provide an immediate (less than 30 minute) readout, and demonstrate the necessary sensitivity and specificity to allow screening of clinical trial subjects/patients for prior virus infection.

Phase I activities can include but are not limited to:

• Development of the prototype POC diagnostic product for detection of HSV or CMV antibodies.

• Determination of the sensitivity, specificity and other performance characteristics (e.g. time to result, limit of detection, test stability) of the product.

Phase II activities can include but are not limited to:

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• Further development of the prototype POC diagnostic product for detection of HSV or CMV antibodies.

• Further determination of the sensitivity, specificity and other performance characteristics (e.g. time to result, limit of detection, test stability) of the product.

• Final validation testing and scale-up manufacturing of test kits.

This SBIR will not support:

• Nucleic acid-based diagnostics.

• Serodiagnostics that require extensive equipment or time (> 30 minutes) to conduct the assays.

• 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.

047 Development of Microbiome-based Products for Infectious Diseases

Fast-Track proposals will be accepted.

Direct to Phase II proposals will be accepted.

Number of anticipated awards: 1-2

Budget (total costs):

Phase I: $225,000 for up to one year

Phase II: $1,500,000 for up to 3 years

Background:

The majority of microbiome research to date has been largely descriptive and has focused on the characterization of the microbiome composition. However, there has been a recent shift in the microbiome field to focus on the functional capacity of the microbes present. This shift in microbiome research has led to the development of potential microbiome-based products for use as therapeutic interventions, thus presenting a need for innovation in the characterization and preclinical development of this novel product class. Currently, several microbiome-based products consisting of live bacteria are being developed as therapeutic interventions for vaginal and enteric infectious diseases. These products can be very complex, oftentimes originating from human stool or other diverse microbial communities. As such, there are many challenges associated with the preclinical development of these complex microbiome-based products. New and innovative ways to conduct IND-enabling studies (e.g. characterization assays to support lot release) are now needed to further advance these products for future human clinical trials.

Project Goal:

The goal of this project is to enable small businesses that have an existing microbiome-based product (consisting of live microorganisms, such as bacteria) intended for the treatment or prevention of infectious diseases to further their product development by focusing on preclinical studies. In particular, small businesses are encouraged to focus on IND-enabling studies to support the characterization, manufacture and release using product-specific assays. Focus should be on characterizing the product in terms of identity, genetic stability, purity, potency, transference of genetic material, and mechanism(s) of action. New methods to set appropriate specifications are also needed. In addition, novel methods to manufacture complex microbial ecosystems and raw materials are encouraged. Finally, novel formulations such as spray drying, lyophilization, and packaging of microbiome-based products for long-term stability are encouraged. The following FDA document, entitled “Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information”, should serve as guidance to small businesses seeking to submit proposals on this topic.

Phase I activities can include but are not limited to:

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• Development of novel analytical methods to fully characterize individual and combinations of components (e.g. live microorganisms, such as bacteria) of microbiome-based products.

• Development or conduct of assays to support lot release testing, such as identity or potency testing.

• Development or conduct of assays to demonstrate product stability.

• Development of methods and analytical technologies to support chemistry, manufacturing and control information, such as formulation, encapsulation, and lyophilization.

Phase II activities can include but are not limited to:

• Development of methods and analytical technologies to support chemistry, manufacturing and control information, such as formulation encapsulation and lyophilization.

• Scale-up formulation activities that may help support future clinical trials.

• Conduct of appropriate safety (e.g. toxicology) studies of formulations intended for clinical evaluation in the appropriate systems.

• Conduct of long-term stability studies to ensure product shelf life.

• Validation of assays to support lot release testing.

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.

Studies focused on discovering new microbiome-based products.

A new indication for an existing microbiome-based product (e.g. probiotics).

048 Non-Invasive Rapid Diagnostics for Respiratory Diseases in Children

Fast-Track proposals will be accepted.

Direct to Phase II proposals will be accepted.

Number of anticipated awards: 2-3

Budget (total costs):

Phase I: $225,000 for up to one year

Phase II: $1,500,000 for up to 3 years

Background:

Lower respiratory tract infections and pneumonias cause a significant burden of disease and mortality, particularly in children under the age of five. There is a need for simple tools to diagnose lung infections in children. Current clinical diagnostic methods for respiratory diseases typically take days-to-weeks, and may require multiple samples obtained by invasive methods. Sputum or bronchoalveolar lavage are the most common clinical specimens obtained for current diagnostic tests; however, most children and many adults are unable to produce sputum. Sputum induction and lavage sampling are highly invasive processes, causing discomfort to the patient and often resulting in unreliable sampling of potential pathogens. As a result, information from current diagnostics and specimens could be complicated by the presence of colonizing bacteria that are non-pathogenic and may not adequately define the underlying disease state. Non-invasive rapid diagnostic approaches are needed to enable a more timely and meaningful diagnosis and allow the patient to receive appropriate treatment before disease becomes severe. Potential benefits of non-invasive rapid diagnostics for lower respiratory tract infections include, but are not limited to:

• Improved patient compliance and willingness to seek early medical treatment

• Reduced risk of exacerbating disease due to diagnostic procedures

• Ability to monitor the patient’s infectious status over time, and to monitor success of treatment

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Project Goal:

The goal of this project is to develop rapid, sensitive diagnostics for lower respiratory tract infections (of bacterial, viral, and/or fungal origin) that would be suitable for children and utilize non-invasive specimen collection methods. Examples of non-invasive specimen types may include, but are not limited to analytes in exhaled breath, saliva, oral swabs, and bodily secretions (urine, tears, and sweat). The proposed diagnostic device (and associated components) should be simple to use, compatible with point-of-care use by healthcare personnel, employ reagents that can be stored under ambient conditions, and be compatible with U.S. regulatory guidelines for testing and validation. Utilization of appropriately consented, de-identified human-derived material in preclinical studies in support of compliance with regulatory requirements is permitted and encouraged. Additional human-derived sample collection is allowed under this solicitation.

Phase I activities can include but are not limited to:

• Development of an approach for the identification and examination of analytes associated with lower respiratory tract infections caused by a specific pathogen(s).

• Development of a prototype device to demonstrate its feasibility for pathogen detection.

• Determination of the sensitivity, specificity and other performance characteristics (e.g. time to result, limit of detection, test stability) of the product.

Phase II activities can include but are not limited to:

• Evaluation of the ability of diagnostic device to distinguish different types of respiratory infections (e.g. of bacterial, viral, and/or fungal origin).

• Assessment of the utility of the device to distinguish between bacterial colonization and active infection.

• In preclinical disease models, evaluation of changes in analyte pattern after antibiotic administration.

• Conduct of additional validation studies with de-identified human specimens to identify factors that may influence or confound the diagnostic result.

• Product development strategy for regulatory approval and demonstration of clinical utility.

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.

• Validation testing that would be reported back to the patient or the treating physician.

• The development of technologies that rely solely on nucleic acid amplification followed by a hybridization detection step for detection of a pathogen-specific antigen or a host-response antibody.

• The development of diagnostics requiring culture-bottle and/or streak plate incubations.

• Proposals that do not have the ultimate goal of detection and identification of pathogens in human clinical samples.

• The development of environmental or workplace pathogen/toxin detection technologies.

• The development of diagnostics for HIV.

049 Phage-based Diagnostic Platforms for Rapid Detection of Bacterial Pathogens

Fast-Track proposals will be accepted.

Direct to Phase II proposals will be accepted.

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Number of anticipated awards: 2-3

Budget (total costs):

Phase I: $225,000 for up to one year

Phase II: $1,500,000 for up to 3 years

Background:

Resistance of bacterial pathogens to antibiotics is rapidly increasing, both in hospital environments and community settings, and it has become a national priority to find product-based solutions to this serious medical problem. Consequently, there is an urgent need for rapid, highly sensitive, easy-to-use, cost-effective clinical diagnostics that can identify bacterial pathogens and determine antibiotic susceptibility. Such diagnostic platforms have the potential to impact antibacterial resistance by helping physicians to determine the most effective treatments for infected individuals and thereby reduce the use of broad-spectrum antibiotics. In addition, these platforms may also support more efficient stratification of patients for clinical trials. Bacteriophages in particular offer many desirable characteristics which make them well-suited as a platform for rapid bacterial diagnostics tests. They are easily produced, remarkably diverse and target bacteria with exquisite specificity. The use of bacteriophage may also allow for detection of bacterial pathogens directly from clinical samples and potentially eliminate the need for primary culture methods. Assays utilizing phage detection in combination with drug testing offer the potential not only for pathogen identification but also for rapid determination of antibiotic susceptibility profiles critical for appropriate treatment decisions in the clinic.

Project goal:

The goal of this project is to leverage bacteriophages or their relevant biochemical components as tools for the development of rapid diagnostic platforms to detect bacterial pathogens that cause serious infections in humans. Responsive proposals must address bacteria recently classified by the Centers for Disease Control and Prevention (CDC) as antibiotic resistance threats. Because drug resistance is key to the threat posed by these pathogens, bacteriophage-based diagnostic platforms that can both identify the pathogens, as well as provide an assessment of antibiotic susceptibility, are preferred.

Phase I activities can include but are not limited to:

• Detailed characterization of specific bacteriophages, or relevant biochemical components, that demonstrate utility for detecting clinically-relevant bacterial pathogens.

• Determination of diagnostic sensitivity and selectivity sufficient to meet the needs of the intended clinical application.

• Development of a prototype device that can identify one or more target pathogens and their antibiotic susceptibility in a spiked specimen matrix that represents the intended clinical application.

Phase II activities can include but are not limited to:

• Demonstration that prototype device detects, with sufficient sensitivity and selectivity, a representative sampling of bacterial pathogens found in the clinic.

• Demonstration of feasibility for determining antibiotic susceptibility using well-characterized clinical isolates of target pathogen(s).

• Development of standardized plan for manufacturing of components.

• Validation of diagnostic device prototype with blinded clinical samples.

• Development of a product development plan for achieving regulatory approval and demonstrating clinical utility for bacteriophage-based detection system.

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

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Cooperative Agreement program announcement or the NIAID Investigator-Initiated Clinical Trial Resources webpage.

161 Virtual Reality Tools to Enhance Evidence Based Treatment of Substance Use Disorders

Fast Track is not allowed.

Direct to Phase II is not allowed.

Information about Phase II is provided for planning purposes only.

Number of Anticipated Awards: 2-3

Budget (total cost):

Phase I: $150,000 for 6 months.

Phase II: For planning purposes, this may be sought with an estimated award of $1,000,000 for two years to test clinical outcome of IT approaches to augment standard treatment in a patient population in comparison with stand treatment alone. Further, Phase II will include a description of the path toward clinical adoption of this VR based IT approach.

Background:

There are numerous existing evidence-based behavioral treatment approaches for substance use disorders. A significant proportion of patients who receive treatment using evidence-based behavioral therapies relapse, suggesting that additional adaptations are needed to enhance the effectiveness of these therapies. Technology driven approaches (e.g., cell phone based applications, text messaging interventions, ecological momentary assessment (EMAs)) to improving evidence-based treatments have shown some success.

Virtual reality is unique among other technological enhancements in that it can recreate some elements of the social situations and physical environments that typically trigger relapse, allowing patients to practice skills they will need when they encounter such situations in real life. The potential for VR to enhance treatment effects has been demonstrated in domains outside of substance use (e.g., Manzoni et al., 2015 1). In addition to the potential to increase the potency of interventions by allowing patients to practice skills in realistic virtual settings, VR also has the potential to extend access to treatment outside of clinical settings, this could increase the frequency of treatment for patients and could be particularly beneficial for patients who live in rural areas or who have other health or financial barriers that make it difficult for them to get to appointments on a regular basis.

The ultimate goal is to have VR-enhanced treatments facilitate improved treatment outcomes as well as make treatment more accessible.

Numerous evidence-based substance abuse treatments may lend themselves to virtual reality adaptation. Examples may include:

• Cognitive Behavioral Therapy variations

• Contingency Management

• Motivational Interviewing/Motivational Enhancement Therapy variations

• Multisystemic Therapy

• Multidimensional Family Therapy

• The Matrix Model

• 12-Step Facilitation Therapy

• Behavioral Therapy

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Project Goals:

Develop Virtual Reality (VR) IT approach to be used to improve behavioral treatment approaches for substance abuse disorders with the following elements:

• Complete initial development and proof-of-concept for VR-enhanced evidence-based substance abuse treatment that takes advantage of the unique abilities to VR. This may include, but is not limited to, presenting a variety of virtual stimuli and environments that might illicit or inhibit drug seeking behavior or relapse using widely available commercial VR platforms (e.g., Oculus Rift, PlayStation Morpheus, HTC Vive, Samsung Gear VR).

• Complete initial efficacy/effectiveness testing of the VR-enhanced treatment to demonstrate impact on meaningful clinical outcomes.

• Obtain and document feedback that may include surveys, focus groups, user testing from relevant stakeholders who would be involved in implementing VR-enhanced treatments into substance abuse clinical treatment. This includes, but is not limited to, patients who would use the VR-enhanced treatment, clinicians who might use VR-enhanced therapy as part of their practice in private practice and larger clinical settings, and payers. This feedback should identify any challenges or barriers to implementing VR-enhanced therapy in both clinical settings as well as its potential to extend treatment outside of clinical settings (e.g., HIPPA privacy requirements, obstacles to reimbursement, patient safety concerns, etc.).

Make modifications that incorporate input received from the above surveys, focus groups and user testing.

Phase I Activities and Expected Deliverables:

Technical Requirements

• Seek feedback from a panel of health care professionals who are potential end users (e.g. therapists who are using the EBT in clinical practice) on what features and functions these professionals would most like to see and most likely convince them to employ this VR-enhanced approach.

• Assemble a team of professionals to develop a proof-of-concept VR-enhanced evidence-based substance use treatment for patients with substance use disorders. The adapted intervention must be capable of implementation on an existing commercially available consumer VR system (e.g., Oculus Rift, PlayStation Morpheus, HTC Vive, Samsung Gear VR) that use head mounted displays. At a minimum, it is expected that this proof-of-concept system would yield at least 1-2 hours of interactive content. The final amount of content should be determined by the EBP that is being adapted. Furthermore, documentation accompanying the proof-of-concept should indicate how the VR-enhanced intervention would be used to modify the existing EBP across the full treatment course indicated by the existing EBP (i.e., number of sessions, length of sessions, sequence of content, etc.).

• Conduct exploratory research with relevant stakeholders to understand the implications of HIPPA standards, data security and other considerations that would be required for clinical use (e.g., insurance reimbursement, etc.).

• Ensure that the VR system balances the need for high quality graphics to enhance user engagement, while also ensuring that the intervention could be implemented via widely available commercial technologies. Widely available technologies include consumer-grade laptop or desktop computers, tablet-based computers and/or smartphones.

• Collect quantitative and qualitative data on patient reactions to VR-enhanced treatment, including, but not limited to, ratings of graphics quality, immersive qualities, engagement, functionality, usability, acceptability, physical reactions (e.g., dizziness), interactivity, etc. Diverse patient perspectives should be solicited, and specific attention paid to features that could be easily modified to enhance the tailoring of the intervention and to enhance cultural relevance of the intervention.

• Examine clinician reactions to VR-enhanced proof concept including, but not limited to potential for inclusion in existing clinical workflow, expected patient engagement, expected clinical value, etc.

• In this phase of the research, testing for complete therapeutic outcomes is premature. However, for a treatment to work, it must produce change. Therefore, potential positive impact on the patient, which can include

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biological, psychological, and/or therapeutic outcomes, should be measured. These data will be critical in determining if this project will move forward.

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1 Manzoni et al., VR-enhanced CBT for obesity treatment: A randomized Control Study with Year Follow-up: http://www.ncbi.nlm.nih.gov/pubmed/26430819

162 Analytical Tools and Approaches for (Multidimensional) Scholarly Research Assessment and Decision Support in the Biomedical Enterprise.

Number of Anticipated Awards: 2-3.

Fast-Track proposals and Direct to Phase II proposals will be accepted.

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 3 years.

It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded.

Contemporary science evaluates and is also a subject to evaluation. Research assessment is increasingly becoming an integral part of any scientific activity. Among the reasons for such attention is the increasing demand by the public and government to demonstrate cost-benefit measures of the research programs within the institutions, especially those that are publically funded. Policy makers now explicitly expect science to demonstrate its value to society. Another reason is the current economical atmosphere where budgets are strained and funding is difficult to secure, making the ongoing, diverse and thorough assessment of an immense importance for the progression of scientific and research programs. The current consummate availability of and ability to collect and analyze large scale datasets also contributes to the increased interest in research assessment. While a decade ago, scientific evaluation relied mainly on citations and publications counts, most of which were done manually, today this data is not only available digitally but can also be triangulated with other data types. For example, publications and citations counts can be triangulated with collaborative indicators, text analysis and econometric measures producing multi-level view of an institution, program or an individual. Research funders begin to expect not only publications but also other indicators to be given as the proposed outputs and outcomes of research in proposals, signaling that other forms of scholarly products and novel metrics may play an important part in research evaluation. Appropriately, in the 2016-2020 Strategic plan, NIH announced the intent to take greater leadership in developing and validating the methodologies that are needed to evaluate scientific investments and to use transparent, scientific approaches in decision making.

The RFP solicits the research and development of advanced and sophisticated analytical models, tools and metrics to enhance the professional evaluation and decision making in life sciences management and administration. Those metrics must be developed to be embraced broadly by the life science community, be readily understandable by non-scientists and grounded in outcomes that are highly valued by the general public, funders and the policy makers. It is envisioned that, if proven, those metrics will be used by the NGOs/disease foundations, advocacy groups, research funders, policy makers and by the academic institutional bodies (e.g. promotion committees).

Examples of the projects may include, but not limited to:

• Studies to define and validate the metrics specifically measuring how virtuous the research is (quality, transparency, reproducibility, integrity and potential for translation/application).

• Studies to compare/investigate the relationship between traditional metrics, like text citations and expert evaluations, and webometrics/altmetrics, like social media usage analysis.

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• Tools and approaches to quantify relationships between publications and registered products (drugs, devices, diagnostics, etc.), to help increase public appreciation of the societal value of life science discoveries, to provide instructive insights for policy makers, to guide funding decision making and path selection that would accelerate progress towards cures.

• Application of advanced empirical methods to altmetrics: large-scale studies assessing the reliability, validity and context of the metrics.

• Analytical approaches answering the question of how can research -productive scientists be identified, clustered, and configured for optimal research synergies.

• Sophisticated technologies to accurately analyze the demographics of research users, e.g. scholars or non-scholars, career stage, what was the actual research product they used and why, etc.

• Sophisticated approaches and tools that, based on bibliometrics or otherwise, would enable the meaningful nomination of research studies for replication.

• Sophisticated approaches and tools for the standardized evaluation of evidence in large numbers of biomedical research documents (project progress reports, research manuscripts, etc.)

• For student education, building the models of good and bad scientific behavior with demonstration of the possible consequences of both.

• Products that track a variety of scholarly activities such as teaching and service activities correlating them with the lecture attendance and popularity status of the reading lists

• Approaches to directly compare or intelligently combine the metrics (biblio- or alt-) and peer review

• Studies to investigate the new forms of impact measurements that are broader, speedier and more diversified than traditional metrics