NIH and CDC Small Business Innovation Research (SBIR) Contract Solicitation PHS 2019-1

NCATS Topics

This solicitation invites proposals in the following areas:

016 Synthetic Technologies for Advancement of Research and Therapeutics (START)

Fast-Track proposals will not be accepted.

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

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

Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning.

Summary:

Traditional drug development pipelines are largely inefficient, with greater than 80% attrition of new drugs that move into Phase 2 clinical trials. Currently, it takes more than $1 billion and up to 14 years to bring a drug to market. One of the main contributors to this is our inefficiency to access unexplored biologically-relevant chemical space. About 40% of the chemical scaffolds found in natural products are absent in today’s medicinal chemistry repertoire. Natural compounds harbor chemical and structural diversity that can be utilized to develop novel treatments. Most importantly, natural compounds are evolutionarily optimized as drug-like molecules. Challenges of natural products in drug discovery and development include (i) extremely low yields and limited supply, (ii) complex structures that preclude practical synthesis, and (iii) complex structures posing enormous difficulty for structural modifications. Synthetic biology is making promising strides in reshaping and streamlining drug discover thanks to the recent advances in gene editing, gene synthesis, metabolomics and analysis techniques.

Topic Goals:

Current developments in synthetic biology have offered tools to design or modify organisms that can be used for a specific function, allowing for natural biological systems to be tailored as machines that produce desired compounds. Further, synthetic biology has a broad application and can be used to synthesize biologically relevant compounds and therapeutics that are not easily and/or not cost-effectively produced in a traditional laboratory setting. There is also an immense capability to scale-up production of said compounds using bioreactors and other platforms specific for growing microorganisms. Synthetic biology has the potential to accelerate the field of drug development by introducing tools and resources that can readily and efficiently produce desired compounds that are more cost effective.

The primary goal of this topic is to apply synthetic biology to produce and fully characterize both known and novel analogs of naturally occurring compounds to increase the diversity of compounds in drug libraries.

 

We are primarily interested in proposals focused on discovery, isolation and characterization of non-addictive natural compounds to treat pain, opioid abuse disorders and overdose. Other critical areas for therapeutic drug development will be considered pending strong scientific justification.

Phase I Activities and Expected Deliverables:

Phase I proposals must specify clear, appropriate, measurable goals (milestones) to be achieved. Phase I activities and deliverables may include the following:

• Formulate naturally occurring and biologically relevant pathways into a set of design rules that can then be used to engineer new candidate therapeutic molecules:

o Develop novel tools and technologies that would allow engineering of pathways into a host organism

o Develop genetic switches to control of gene expression

o Develop synthetic control systems for the production of bioactive molecules with therapeutic potential

• Expand the current catalog of naturally occurring compounds and their analogs to enhance the diversity of chemical libraries:

o Identify and create biosynthetic gene clusters or pathways for the biosynthesis of natural products

o Apply synthetic biology tools to improve production of natural products from their native sources

o Utilize synthetic biology tools to assemble biosynthetic machinery and optimize yield for natural product production in heterologous hosts

o Synthesize, isolate and fully characterize novel bioactive compounds and demonstrate bioactivity of compounds following isolation

• Provide NCATS with all data and resources (i.e.: molecules created, producer organisms, etc.) resulting from Phase II Activities and Deliverables for independent validation of yield and bioactivity.

 

Phase II Activities and Expected Deliverables:

If Phase I objectives are met, feasibility is demonstrated, and there is sufficient evidence of commercial viability, the offeror can apply for Phase II. Phase II activities and deliverables may include the following:

• Continue the development of tools and technologies and prepare them for dissemination to the scientific community through, for example, licensing or servicing

• Develop a robust manufacturing process to scale-up production of novel compounds o Demonstrate bioactivity of compounds following scaled-up isolation

 

• Develop platforms that would allow large-scale applications of the developed tools and technologies as relevant to synthesis, isolation, characterization and modification of natural compounds

• Provide NCATS with all data and resources (i.e.: molecules created, producer organisms, etc.) resulting from Phase II Activities and Deliverables for independent validation of yield and bioactivity.

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

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

• Present Phase II findings and final deliverables to NCATS Programs Staff via webinar.

017 Universal Medium/Blood Mimetic for Use in Integrated Organs-on-Chips

Fast-Track proposals will not be accepted.

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

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

Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning.

Summary:

The objective of this topic is to develop a universal medium, or blood mimetic, that can be used to perfuse and support multiple tissue constructs or organ types within multiple integrated microphysiological systems (MPS), or organs-on-chips.

Organs-on-chips are bioengineered micro devices that model the function of human organ tissues in vivo. The development of these platforms has provided tools that can be used to investigate the effects of drugs, compounds and therapeutics on human tissues in vitro, providing information on safety and efficacy of promising compounds. They are also used to model a wide variety of disease states and investigate pathophysiology and disease mechanisms in novel ways. However, their full utility can be realized when tissue systems are linked and cellular constructs from multiple organs can interact in a physiologically relevant way, moving towards a "human-on-a-chip". Linking multiple tissue constructs is challenging to achieve as linked organs-on-chips need support in the culture medium for many different tissue construct types, yet the ability to link them is limited because each tissue construct requires specific nutrients and growth factors which may not be optimal for other tissue types. Currently, researchers do not have a fluid that can adequately support multiple human tissues in integrated systems. This means that tissue combinations cannot survive adequately for meaningful studies to be conducted and therefore limits the current utility of integrated organ-on-chip systems.

NCATS has previously issued supplemental funding to investigators funded under the Tissue Chips for Disease Modeling program, and some solutions to the problem have been developed, as in the inclusion of endothelial barriers to create organ-specific niches and the mixing of culture media for linked organ systems by number of systems e.g. 50:50 for two systems; 33:33:33 for three systems. However, these solutions are not tenable for broader adoption of tissue chip technology as they are technically and biologically challenging, cannot fulfil appropriate cellular support, or are not scalable to more than two or three tissue constructs. This SBIR topic will allow experts with experience in extended cell culture to address the issue.

Topic Goals:

This topic aims to address a pressing need in the field of microphysiological systems (MPS), or organs-on-chips, to develop a universal cell culture medium/blood mimetic that can be used to support multi-cellular tissues from multiple organ systems in linked, integrated organ-on-chip platforms. The goal of this project is to create a universal medium/blood mimetic that can be used with multiple tissue types to maintain cells in a healthy and functional state for extended cell culture (>1 month) and can supply the basic universal requirements of cells e.g. appropriate pH, oxygen and carbon dioxide levels, and certain growth factors.

This task will be achieved by addressing the following aspects:

(1) Culture and maintenance of multiple (at least 3) cellularly heterogeneous and discrete induced pluripotent stem cell (iPSC)-derived tissue constructs by perfusion of tissues with a universal medium/blood mimetic on a single or linked cell culture platform(s) e.g. heart, liver and lung through linked microfluidic channels or across permeable membranes;

(2) Creation of a cell medium that will address all basic universal cellular requirements e.g. pH; oxygenation; nutrients and growth factors of multiple interconnected tissue types;

(3) Creation of a cell medium that can retain cells in a viable and/or functional state for at least one month, according to standard metrics of cell health or functionality assays e.g. cell viability and growth; pH buffering; stable gene transcription; and other functional readouts.

Phase I Activities and Expected Deliverables:

• Creation and maintenance of at least three separate mature iPSC-derived cellularly heterogeneous and discrete tissue constructs (e.g. heart, liver and lung) in independent tissue-specific culture media. o Tissues must remain differentiated and in a stable and mature phenotype (as shown by widely accepted cellular and genetic markers) for at least 28 days.

o Tissues must express appropriate functional markers at the end of the >28-day culture period (e.g. albumin production by hepatocytes; calcium transients by neurons; expression of glucose transporter proteins in kidney tubule cells; appropriate RNA expression profiles).

 

• Linkage of at least two separate iPSC-derived tissue constructs perfused by a single culture medium that adequately supports all constructs for at least 7 days. o Tissues must remain differentiated and in a stable and mature phenotype at the end of this >7-day period (as shown by widely accepted cellular and genetic markers).

o Tissues must express appropriate functional markers at the end of this >7-day period.

 

• Monitoring and/or proven absence of cellular distress/death markers or unexpected decreased production of functional markers in tissues in linked systems perfused by single culture medium at the end of the >7-day culture period.

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

 

Phase II Activities and Expected Deliverables:

• Creation of at least three iPSC-derived tissue constructs containing heterogeneous cellular types e.g. hepatocytes, liver-specific endothelial cells, liver-specific immune cells. o Tissues must remain differentiated and in a stable and mature phenotype (as shown by widely accepted cellular and genetic markers) for at least 28 days.

o Tissues must express appropriate functional markers at the end of the >28-day culture period.

 

• Linkage of at least three separate cellularly heterogeneous iPSC-derived tissue constructs perfused by a single culture medium that adequately supports all constructs for at least 28 days. o Tissues must remain differentiated and in a stable and mature phenotype at the end of this >28-day period (as shown by widely accepted cellular and genetic markers).

o Tissues must express appropriate functional markers at the end of this >28-day period.

 

• Proven compatibility with current iterations of microfluidic technology materials and organ-on-chip platforms.

• Development of reliable manufacturing protocols that ensure <5% batch variation of the universal medium.

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

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

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

• Present Phase II findings and demonstrate final deliverables to the NCATS Program staff via webinar.

018 Non-PDMS Biocompatible Alternatives for Organs-on-Chips

Fast-Track proposals will not be accepted.

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

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

Phase II information is provided only for informational purposes to assist Phase I offerors with their long-term strategic planning.

Summary:

The development of organs-on-chips, also known as microphysiological systems (MPS), has provided tools that can be used to investigate the effects of drugs, compounds and therapeutics on human tissues in vitro, providing information on safety and efficacy of promising compounds. They are also used to model a wide variety of disease states and investigate pathophysiology and disease mechanisms in novel ways. Organs-on-chips are often fabricated in part or wholly from polydimethylsiloxane (PDMS), an oxygen-permeable, optically-clear, non-flammable, non-toxic silicon-based organic polymer. However, PDMS absorbs or binds compounds or proteins under certain conditions, leading to loss of drugs or compounds that are introduced into the system. This is undesirable in the context of organs-on-chips as it reduces the ability

to accurately assess protein binding or calculate dosage ranges and responses of small molecules. Additionally, it can lead to cross-contamination of surrounding areas or tissues, reducing the reliability and predictivity of these systems for producing human-relevant drug responses.

Currently, researchers employ a variety of techniques to account for these shortcomings but these are expensive, time-consuming or not feasible to recreate due to the need for specialized equipment. Previously, NCATS has awarded supplemental funding for researchers funded under the Tissue Chips for Drug Screening program to address this issue, leading to development of some surface coating techniques and mathematical modeling to account for various adsorption properties of PDMS. An alternative material is desired for fabrication of organ chips for studies involving small molecule drugs/compounds and therapeutics. Replacement of PDMS will enable a broader range of experiments to be performed on tissue chip platforms and increase the utility of these systems to a wider community.

Topic Goals:

This topic aims to address a pressing need in the field of microphysiological systems (MPS), or organs-on-chips, to develop and produce a biocompatible alternative material that can be used in place of PDMS, which is a silicon-based material currently widely used in the fabrication of organ-on-chip platforms.

This goal will be achieved through the following:

(1) Fabrication of a biocompatible, non-toxic material that could feasibly provide an alternative to PDMS;

(2) Fabrication of a material that mimics the MPS-appropriate properties of PDMS such as gas permeability, optical clarity, non-toxicity, easy fabrication or availability, and predictable molecular binding;

(3) Demonstration of appropriate material properties and a lack of undesirable properties such as drug/compound absorption, channel cross-contamination, or high variability in binding of different compounds.

Phase I Activities and Expected Deliverables:

• Development and production of an alternative material to PDMS that displays at least three of the following nine properties: o Optical clarity – proven ability of material to allow penetration of light at wavelengths of ~400-700nm.

o Gas permeability of oxygen and carbon dioxide.

o Non-toxic and biocompatible to a wide variety of iPSC-derived cells and tissues (5-10 cell/tissue types tested).

o Widely available/accessible, either whole or by material components.

o Proven reliable and reproducible manufacturing properties.

o Easily manipulated without the need for extensive specialist equipment (above what PDMS requires).

o Proven ability for manufacture of microfluidic components e.g. channels, ports, etc.

o Proven lack of microfluidic channel cross-contamination at distances of <20μm for a variety of substances e.g. cell culture media, drugs, compounds, small molecules etc.

o Reliable and predictable (variability <5%) molecular binding properties e.g. Log P, surface binding of plasma proteins etc.

o Non-reactive with other standard materials used in MPS production e.g. glass, PDMS, poly(methyl methacrylate) (PMMA) etc.

 

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

 

Phase II Activities and Expected Deliverables:

• Development of an alternative material to PDMS that displays an additional 4-6 of the following nine properties: o Optical clarity – proven ability of material to allow penetration of light at wavelengths of ~400-700nm.

o Gas permeability of oxygen and carbon dioxide.

o Non-toxic and biocompatible to a wide variety of iPSC-derived cells and tissues (5-10 cell/tissue types tested).

o Widely available/accessible, either whole or by material components.

o Proven reliable and reproducible manufacturing properties.

o Easily manipulated without the need for extensive specialist equipment (above what PDMS requires).

o Proven ability for manufacture of microfluidic components e.g. channels, ports, etc.

 

o Proven lack of microfluidic channel cross-contamination at distances of <20μm for a variety of substances e.g. cell culture media, drugs, compounds, small molecules etc.

o Reliable and predictable (variability <5%) molecular binding properties e.g. Log P, surface binding of plasma proteins etc.

o Non-reactive with other standard materials used in MPS production e.g. glass, PDMS, PMMA etc.

• Proven success in culturing at least 5 types of viable, mature and functional iPSC-derived cell types and/or tissues; o Viability as shown by standard tissue-appropriate markers of cell health and survival e.g. lack of apoptotic markers;

o Maturity as shown by presence of standard tissue-appropriate markers of mature phenotype or lack of dedifferentiation markers;

o Functionality as shown by presence of standard tissue-appropriate markers of cell functionality e.g. albumin secretion in hepatocytes; contractility in cardiomyocytes etc.

 

• Employment of Quality Assurance manufacture standards to ensure the validity of analytical and quantitative measurements.

• Proven success in fabrication and employment of the alternative material in a microfluidic setting.

• Proven success in replacement of PDMS in a microphysiological systems setting e.g. adaptation of existing MPS platforms with PDMS components replaced by the alternative material.

• Provide NCATS Program staff with all data and resources resulting from Phase II Activities and Deliverables.

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

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

• Present Phase II findings and demonstrate final deliverables to the NCATS Program staff via webinar.

 

NATIONAL CANCER INSTITUTE (NCI)

The NCI is the Federal Government’s principal agency established to conduct and support cancer research, training, health information dissemination, and other related programs. As the effector of the National Cancer Program, the NCI supports a comprehensive approach to the problems of cancer through intensive investigation in the cause, diagnosis, prevention, early detection, and treatment of cancer, as well as the rehabilitation and continuing care of cancer patients and families of cancer patients. To speed the translation of research results into widespread application, the National Cancer Act of 1971 authorized a cancer control program to demonstrate and communicate to both the medical community and the general public the latest advances in cancer prevention and management. The NCI SBIR program acts as NCI’s catalyst of innovation for developing and commercializing novel technologies and products to research, prevent, diagnose, and treat cancer.

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

Unless the Fast-Track option is specifically allowed as stated within the topic areas below, applicants are requested to submit only Phase I proposals in response to this solicitation.

NCI Phase IIB Bridge Award

The National Cancer Institute would like to provide notice of a recent funding opportunity entitled the SBIR Phase IIB Bridge Award. This notice is for informational purposes only and is not a call for Phase IIB Bridge Award proposals. This informational notice does not commit the government to making such awards to contract awardees.

Successful transition of SBIR research and technology development into the commercial marketplace is difficult, and SBIR Phase II awardees often encounter significant challenges in navigating the regulatory approval process, raising capital, licensure and production, as they try to advance their projects towards commercialization.

The NCI views the SBIR program as a long-term effort; to help address these difficult issues, the NCI has developed the SBIR Phase IIB Bridge Award under the grants mechanism. The previously-offered Phase IIB Bridge Award was designed to provide additional funding of up to $4M for a period of up to three additional years to facilitate the transition of SBIR Phase II projects to the commercialization stage. The specific requirements for the previously offered Phase IIB Bridge Award can be reviewed in the full RFA announcement: https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-18-011.html.

In FY2011, the NCI expanded the Phase IIB Bridge Award program to allow previous SBIR Phase II contract awardees to compete for SBIR Phase IIB Bridge Award grants. Provided it is available in the future, the Phase IIB Bridge Award program will be open to contractors that are successfully awarded a Phase II contract (or have an exercised Phase II option under a Fast-Track contract). NIH SBIR Phase II contractors who satisfy the above requirements may be able to apply for a Phase IIB Bridge Award under a future Phase IIB Bridge Award grant funding opportunity announcement (FOA), if they meet the eligibility requirements detailed therein. Selection decisions for a Phase IIB Bridge Award will be based both on scientific/technical merit as well as business/commercialization potential.

　

382 Integrated Subcellular Microscopy and ‘Omics in Cancer Cell Biology

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

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

Summary

Advances in microscopy have improved the ability to resolve, describe, and quantify subcellular anatomic structures, organization, and dynamics. Concurrently, single-cell molecular ‘omics technologies have revolutionized our understanding of intracellular processes and intercellular communication. Recent NIH/NCI programs, such as the Physical Sciences-

Oncology Network, the 4-D Nucleome Program, and the Human Tumor Atlas Network, aim to understand cancer from multiple orthogonal perspectives, including employment of technologies such as high-resolution microscopy and multiscale ‘omics. However, experimental or computational methods that facilitate true integration of advanced high-resolution cellular and subcellular microscopy and multi-scale molecular ‘omics technologies are not readily available to the research community. Technologies that offer such integration will facilitate multidimensional spatially preserved mapping of the tumor ecosystem, leading to a broader understanding of tumor heterogeneity, the role of cell-cell and/or cell-matrix interactions in the response to cancer therapy, and will provide data for building predictive computational models of cancer initiation, progression, metastasis, and response to treatment.

Importantly, recommendations of the Cancer Moonshot Blue Ribbon Panel call for technology-based deliverables that combine approaches from disparate fields, such as imaging at the cellular to subcellular scales with single cell "-omics" approaches. It is anticipated that the innovation in the small business sector, can provide instrumentation and enabling technologies to serve the basic cancer biology research needs. NCI currently supports grants within the IMAT portfolio that are poised to respond to such a solicitation. While there are current efforts to promote small business activity within the single-cell analysis community, this proposal offers a complimentary, but distinct, opportunity through its focus on directly linking cellular phenotypes measured through high-resolution cellular and sub-cellular microscopy with multi-scale ‘omics measurements.

These needs include (but are not limited to) technologies that enable:

• multidimensional coupling of subcellular-to-cellular imaging modalities with orthogonal -omics and physicochemical measurement approaches;

• combination of spatial and temporal imaging at the super-resolution scale with phenotypic processes at the cellular scale;

• subcellular mapping and molecular characterization of individual cells in tumor tissue sections that informs on clonal evolution dynamics and heterogeneity;

• determination of subcellular dynamics coupled with computational methods to examine drug response and cancer cell resistance;

• analysis of subcellular processes in cancer that inform on cell phenotypes within the microenvironment or in the context of tissue relevant niches;

Advances in pre-clinical research in these areas have the potential to be translated into new methods to aid the detection and diagnosis of cancer, and to guide clinical decisions. Commercialization of the research tools supported by this contract solicitation will enable a broader community of researchers to engage in these studies, and thus increase the rate of scientific progress in this field.

Project Goals

Projects to be supported under this FOA will support the broader goal of developing an infrastructure to accelerate the microscopy-omics community and enable transformative research in cancer cell biology, diagnostics, or monitoring strategies.

The short-term goal of this FOA will be to stimulate innovation that integrates cellular imaging modalities with technologies that provide single cell -omics level data (e.g. genomic, transcriptomic, proteomic, etc.) that are relevant to cellular processes that are disabled or exploited in cancer. Projects supported by this contract solicitation should enable multidimensional interrogation of cancer cell biology in a manner that combines the spatial-temporal strengths of imaging modalities with complementary orthogonal measurements achieved through -omics and physicochemical approaches.

This solicitation seeks to encourage the development of new imaging platforms, probes, or a unique combination of platforms with image-based approaches that leverage a multidimensional perspective of cancer cell biology. It is anticipated that that projects may include the development of new algorithms or software that facilitates image analysis or multimodal data analysis to render an understanding of cancer cell biology from a multidimensional perspective; however, applications that are solely software based would not be responsive.

Phase I Activities and Deliverables

Phase I activities should generate data to confirm the feasibility and potential of the technology(ies) to combine microscopy at the subcellular scale with orthogonal cell "-omics" and physicochemical measurement approaches.

 

Offerors will need to:

1. Define the cancer biology application the platform(s), device(s) or combined device-computational approaches addresses.

2. Generate proof-of-concept data in a generally accepted cancer cell model system with the means to sense, interrogate, detect or resolve and map spatial cellular anatomy and/or dynamics using microscopy or other imaging modalities with micro- to nano-scale resolution.

3. Demonstrate feasibility of integrating the imaging modality(ies) in Phase I Deliverable #2 with orthogonal assessments at the molecular scale (such as genomic, proteomic, metabolomic, or epigenomic analyses), physicochemical scale (such as redox, pH, force/stiffness), and/or functional scale (such as proliferation, transformation, motility, invasion, resistance, or cell death) to generate multidimensional data.  Offerors should specify quantitative technical and commercially-relevant milestones, that can be used to evaluate the success of the tool or technology being developed. Offerors should also provide appropriate justification relevant to both the development and commercialization of these technologies.

 Quantitative milestones may be relative metrics (e.g. compared to benchmarks, alternative assays) or absolute metrics (e.g. minimum level of detection)

 

Phase II Activities and Deliverables

Phase II activities should support the commercialization of the proposed technology and include the following activities:

1. Demonstrate reliability, robustness and usability in basic and/or clinical cancer research.

2. Demonstrate system performance and functionality against commercially relevant quantitative milestones  Offerors should specify quantitative technical and commercially-relevant milestones, that can be used to evaluate the success of the tool or technology being developed. Offerors should also provide appropriate justification relevant to both the development and commercialization of these technologies

 Quantitative milestones may be relative metrics (e.g. compared to benchmarks, alternative assays) or absolute metrics (e.g. minimum level of detection)

3. Demonstrate utility with benchmark experiments obtained across a range of generally accepted cancer cell model systems.

4. Show feasibility to be scaled up at a price point that is compatible with market success and widespread adoption by the basic research community.

 

383 Smart, Multi-Core Biopsy Needle

Fast track proposals will be accepted.

Number of anticipated awards: 2-3

Budget (total costs, per award): Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

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

Summary

Tumor recurrence or resistance to treatment often arises due to the underlying genomic or phenotypic heterogeneity of cancer cells and the microenvironment. Tissue cores taken by needle biopsies are used to provide diagnostic and prognostic information about solid tumors. Currently, if multiple cores are needed from a solid tumor, additional needles must be inserted at different locations in the tumor. Problems with this approach include the need for multiple injections, lack of data on positioning and physical parameters (e.g. pH and rigidity) within the tumor, and absence of retaining the layout of the tissue when the tissue is extracted from the needle. The current method lacks capability for measuring physical and biological characteristics like pH, oxygenation, rigidity, and tissue integrity. The goal of this contract solicitation is to support the development and engineering of a smart, multi-core biopsy needle that will allow for simultaneous sampling of a tumor while maintaining and elucidating geographical and physical information, ultimately to gain a better understanding of intra-tumor heterogeneity. The dimensions of the biopsy needles need to be comparable with current methods of aspiration or surgical incision biopsies for specific tumor types, and these new smart devices need to incorporate components to: 1) collect biopsies from multiple tumor cores in a biologically and clinically feasible manner, 2) identify specific locations of the biopsies

relative to the tumor and one another, 3) maintain physical and positioning characteristics of tumor on the extracted tissue, and 4) be adaptable for use under current image-guided biopsy or needle tracking practices.

Project Goals

The development and engineering of a smart, multi-core biopsy needle would allow for simultaneous extraction of tumor core biopsies with 3D positioning [similar to global positioning system technologies (GPS)] and physical parameter data and maintenance of tumor tissue integrity. The biopsy needle must be adaptable for use with image-guidance approaches that are currently used in clinical practice. In the short-term, the project will help provide additional information that can be utilized to elucidate the biological complexity of intra-tumor heterogeneity. In the long-term, it is envisioned that the pH and other physical parameter data (e.g. stiffness) of a tumor across multiple regions could be probed and mapped to the spatial positioning of cancer cells and these data integrated with genotypic and phenotypic data of cancer and stromal cells. Ultimately, the project will have an impact on our understanding of tumor heterogeneity and help guide clinical decisions in designing the course of cancer therapy by obtaining live, intact tumor tissue simultaneously from multiple regions of a solid tumor.

Issues with existing approaches of aspiration and incision biopsies are the need for multiple injections, lack of data on positioning and physical parameters (e.g. pH or rigidity) within the tumor, and absence of retaining the layout of the tissue when the tissue is extracted from the needle. These issues lead to the unmet need addressed with this project, which is the ability to obtain positioning and pH data while maintaining the layout of a tumor from a single biopsy. Activities designed to address this unmet need will be supported, including development of a biopsy needle that has simultaneous multiple core sampling capability. All needles will be required to have positioning and pH sensing capabilities and material coating to allow for maintaining the layout of the tumor once deposited onto a slide or similar platform. The smart, multi-core biopsy needle will also have the capability to be used with current image-guided mechanisms, such as CT, MR, or ultrasound that are often used for obtaining biopsies. The GPS capable smart needle will allow for 3D spatial mapping of the tumor after the tumor is extracted, whereas the image-guided mechanisms are used to guide the needle location during biopsy. This project will be focused on supporting development and engineering of the biopsy needle, and it will not support development of image-guidance technologies alone.

Phase I Activities and Deliverables

• Design and manufacture a smart, multi-core needle device with the following features: o Multiple needles that extract radially from a single, traditional biopsy needle once positioned in a tumor (or other innovative methods to collect multiple cores in a clinically and biologically feasible manner);

o Global positioning system along each of the needles within the tumor to allow for 3D spatial mapping of the tumor;

o Sensors to monitor pH along each of the needles within the tumor (and other physical parameters where possible such as tissue stiffness or rigidity);

o Material coating of the needles (or other innovative methods) to allow for maintaining the layout of the tumor once deposited onto a slide or similar platform;

o Does not significantly damage, change tissue biology, or cause excessive bleeding in regions surrounding the needle placement site;

o Adaptability for use with existing image-guided needle placement methods and needle biopsy procedures.

 

• Identify the tumor type for which the needle will be developed with adequate justification.

• Specify biopsy needle gauges, spacing and other characteristics for the multi-core biopsy needle that will be developed with adequate justification.

• Show preliminary proof-of-concept of the sensor-guided biopsy in a tumor model (engineered phantom or appropriate animal model) to demonstrate the required design and manufacturing features have been achieved.

• Produce written methodology for the sensor manufacturing with quality assurance and control measures using the Standard Operating Procedure (SOP) template.

Phase II Activities and Deliverables

• Optimize the smart, multi-core biopsy needle design and performance for a clinical setting and refine the manufacturing process.

• Show the feasibility of this novel technique to complement current biopsy procedures.

• Demonstrate the performance of the device as designed and intended in fit-for-purpose studies in relevant large animal models.

• Obtain sufficient animal safety data in preparation for 510(K) or IDE application with the FDA.

 

384 Digital Healthcare Platform to Reduce Financial Hardship for Cancer Patients

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

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

Summary

The cost of cancer care has risen exponentially over the last 20 years, with new cancer drugs routinely priced over $120K per year. Concurrently, commercial insurers have been shifting healthcare costs to patients though higher co-pays and deductibles. On average, cancer patients pay about $5K/year in out-of-pocket costs, however, prices higher than $10K a month for individual drugs and biologic agents are common. A growing number of patients experience financial hardship during cancer treatment, which negatively affects their quality of life. When compared to individuals without a cancer history, cancer survivors report higher out-of-pocket costs, lasting years after diagnosis. Further, cancer and its treatment can limit survivors’ ability to work, which further exacerbates the financial burden of cancer. There is growing concern that the exorbitant cost of cancer therapies will limit patients’ access to their potential benefits, leading to poorer treatment response and worse prognosis.

The National Academy of Medicine has cited patient-physician communication as a key strategy for helping patients understand and anticipate the costs of their cancer treatment. However, conversations about cost rarely occur. An important barrier to discussing costs as part of treatment decision making is that oncologists, nurses and other members of the healthcare team seldom know how much patients will have to pay for their care. Estimating a patient’s costs for a course of treatment is time consuming and expensive. It requires someone within the healthcare system to aggregate information about pricing, patient’s insurance coverage, available rebates, and other related information, all of which are stored in different places. Although some systems have dedicated financial counselors or financial navigators who can collate this information and help patients minimize financial burden, even practices willing to devote substantial resources to financial navigation are not equipped to do this for everyone. As a result, many patients begin a course of treatment, only to be blind-sided by expensive medical bills.

Project Goals

The goal of this contract solicitation is to develop an IT-based platform to streamline the calculation of patient’s out-of-pocket costs for cancer treatment. Depending upon clinic workflow, information about costs could be provided by the oncologist or nurse during the clinical encounter or soon after the clinical encounter by a financial navigator. When cost information is readily available, providers can inform patients about the expense of different treatment options; patients can make more informed treatment decisions; and providers, financial navigators or other staff can proactively explore strategies to minimize patients’ financial hardship.

Offerors are required to incorporate a cost calculation function into their proposed platform, which will be used by healthcare providers to estimate a patient’s out-of-pocket costs for cancer therapy. Out-of-pocket cost calculations can be based on the treatment plan for primary and adjuvant therapy, patient’s insurance coverage, or negotiated health system and pharmacy pricing. Additional modules that could also be included as part of the platform are tools to facilitate prescription and other financial assistance and visualization tools to support side-by-side comparisons of alternative treatment options. To be considered responsive, applicants should partner with at least one provider system (hospital, clinic), or insurer. The platforms should be developed for medical oncology providers who treat adult cancer patients. Offerors should design approaches that can be scaled up for the treatment of several cancers, although the platform can initially be developed in the context of a single cancer.

Activities not responsive to this announcement:

Development of applications that are only patient-facing will not be considered responsive.

Phase I Activities and Deliverables:

• Establish a project team with expertise in the areas of software development, computer programming, user-centered design, health communication, oncology, oncology nursing, health services research, and cyber security, as appropriate for the proposed project. Provide a report outlining team member credentials, specific project roles, and timelines for performance.

• Conduct an environmental scan of currently available technological platforms for financial hardship to identify gaps, existing capabilities and resources.

• Identify a partner hospital, clinic or insurer and conduct key informant interviews with anticipated end-users to understand user needs and clinical workflows.

• Provide a report including detailed description and/or technical documentation of the proposed system capabilities and specifications, including: o specific data systems that will support each module of the platform;

o how the platform will interoperate with these systems to extract the necessary data;

o how data will be visualized for the end-users; and

o protections to ensure the confidentiality of patient information.

 

• Develop a prototype that includes: o the database structure for the proposed platform, user-interfaces, and metadata requirements;

o data and security standards for collection, transport, and storage of data inputs that ensure patient privacy following standard NIH policies;

o data visualization, data query functions, feedback and reporting systems for clinical monitoring and research applications; and

o data adaptation for mobile application(s) if applicable.

 

• Conduct a pilot usability testing.

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

Phase II Activities and Deliverables:

Phase II deliverables will focus on specifying technical requirements, testing usability of the prototype and evaluate its implementation in a cancer delivery system.

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

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

• Enhance systems interoperability for deployment in diverse software environments and provider networks. Provide a report detailing communication systems architecture and capability for data reporting to healthcare providers, researchers, electronic health records, and health surveillance systems as appropriate for the proposed project.

• Refine prototype and conduct usability testing

• Test the integration of the technology in the information system of the cancer delivery system. Provide a report documenting the results of system testing and timelines for trouble-shooting.

• Design and conduct a validation study, including: o specify study aims, participant characteristics, recruiting plans, inclusion and exclusion criteria, measures, primary and secondary endpoints, design and comparison conditions (if appropriate), power analyses and sample size, and data analysis plan;

o develop appropriate human subjects protection / IRB submission packages and documentation of approval for the research plan; and

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

 

 

• Prepare a tutorial session for presentation at NCI and/or via webinars describing and illustrating the technology, its intended use and results from the validation study.

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

• Provide the program and contract officers with a letter(s) of commercial commitment.

Fast-Track proposals will be accepted. Number of Anticipated Awards: 2-3 Budget (total costs, per award): Phase I: up to $225,000 for up to 9 months; Phase II: up to $1,500,000 for up to 2 years

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

Summary

One of the consequences of living longer is the symptom burden of cancer survivorship, which is having a substantial impact on quality of life for many survivors. Persistent and late effects of cancer treatment include physical limitations, cognitive sequelae, depression, anxiety, sleep problems, fatigue, sexual dysfunction, and, in some patients, a great deal of pain.

Similarly, when cancer survivors transition from oncology-based to primary care, they still need coordinated monitoring for cancer recurrence, screening, and early detection of second primary cancers, assessment and management of potential physical and psychosocial effects of cancer and its treatment, counseling on health promotion strategies for nutrition, physical activity, tobacco cessation, and alcohol consumption.

Individuals increasingly are using wearable devices and smartphone apps to collect health-related data and help them reach personal health goals. These person-generated health data provide valuable insights into people’s everyday lives and have potential to help individuals more accurately track symptoms and healthcare providers deliver more patient-centered care. Among other things, personal devices can be used to gather patient-reported outcomes (e.g., symptom self-reporting), which can enhance quality of care.

Through this contract topic, NCI is seeking to capitalize on its rich portfolio of research to develop and link data from connected devices and patient reports in meaningful ways to enhance symptom management, timely patient-centered clinical care, and improve health outcomes for cancer survivors --- particularly those who are managing the late and long-term effects of cancer treatment and transitioning to primary and community-based care.

By integrating person-generated health data -- readily collected by connected devices --- with robust symptom lifestyle reporting and management systems, this contract topic encourages novel and essential approaches to improve the quality of life for long-term cancer survivors. This concept helps address the compelling need not just to improve symptom care and ensure adherence to long-term treatment and health promotion strategies, but expand evidence-based self-management strategies, identify recurrence and secondary cancers, and extend survival.

Project Goals

The overall goal is for small businesses to develop "connected health" (software, database systems and/or mobile application) tools which will readily allow for the efficient and comprehensive monitoring, managing, and reporting of patient-reported symptoms by long-term cancer survivors. The result will enhance care quality and effectiveness, provide real-time feedback to cancer survivors, and allow care delivered beyond clinic walls into the home setting, ultimately aiming to improve patient outcomes.

This goal will be accomplished by:

• Building a system/tool/app/device capable of remotely collecting individual health behavior data to support and reinforce efficacious self-management and disease prevention, remote monitoring, behavior modification and personalized intervention patient-reported outcomes.

• A system that follows best behavioral and disease prevention guidelines for adherence to care recommendations while keeping track of psychological needs.

• A system that allows for bi-directionality of symptom data: to bring poorly controlled symptoms to the attention of the cancer care team and use the patient-reported outcome (PRO) data to guide symptom control efforts.

• Prompts to monitor for psychosocial quality of life effects (e.g., sexual dysfunction, marital discord, depression) should be included.

• Integrating accountability tools, checklists, and reminders into the system to ensure safe and timely delivery of services as well as reinforcing positive health behaviors.

Expected Activities and Deliverables

Scope of activities to be supported:

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

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

• The development of a software system with mobile application to connect cancer survivors 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, and individual (survivor)-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 individual cancer survivors to push messages directly through the system.

• The development and testing of a prototype of a platform and applications to be tested with cancer survivors and their healthcare providers, and survivorship researchers.

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

 

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, behavioral science, health services, and computer programming

• Perform an environmental scan of available and relevant software systems designed to support symptom management, health maintenance behaviors and to identify major gaps

• Conduct a small number of key informant interviews with longer-term cancer survivors and primary care providers 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: o Database structure for the proposed modules and user-interfaces (survivors, healthcare provider) and metadata requirements

o Architecture that includes the following components:  a personal health dashboard to track key symptom indicators, and prompt survivor to share critical information with their primary care provider.

 A psycho-social health dashboard to track key factors associated with Quality of Life (QOL) outcomes in cancer survivors

 

o The dashboard would be needed to be able to communicate with the survivor as well as primary care provider and download and upload information

 

•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 tracking and monitoring of care, communications, and survivor support.

•Healthcare provider systems to facilitate 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.

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

•Conduct usability testing mobile applications and user interface features including system management, analyses, and reporting applications.

Phase II Activities and Deliverables:

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

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

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

•Enhance systems interoperability for deployment in diverse software environments and provider networks. Provide a report detailing communication systems architecture and capability for data reporting as appropriate for the proposed project.

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

•Present finding and demonstrate functional product to NCI evaluation panel via webinar.

•Provide the program and contract officers with a letter(s) of commercial commitment.

 

386 Novel Approaches for Local Delivery of Chemopreventive Agents

Fast-Track proposals will 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

The clinical value of an agent is reflected by both its efficacy and its toxicity. In the chemoprevention space, the intention to minimize toxicity is even greater, since agents are administered to a relatively healthy (albeit high-risk) population, and most chemopreventive agents require administration over long periods of time. This limit on toxicity presents a major challenge in the development of chemopreventive agents with acceptable benefit risk ratios.

Our ability to identify populations at higher risk of developing cancer has significantly improved over the past decade. For example, women with Hereditary Breast and Ovarian Cancer syndrome (HBOC) are at increased risk of developing breast and ovarian cancer, and potentially other cancers (e.g., pancreatic); individuals with Lynch syndrome are at increased risk of developing multiple cancer types including colorectal, endometrial, and gastric cancer. We are also able to detect cancer at earlier stages and often as precancerous lesions. Multiple studies have shown that these individuals at high risk for cancer or with precancerous lesions could benefit from chemoprevention approaches. A small number of chemopreventive agents have found some degree of success in the clinic, including tamoxifen and raloxifene for breast cancer prevention, and aspirin and celecoxib for colorectal cancer prevention. However, the systemic toxicities of these agents have limited their widespread use and acceptability.

Local agent delivery is an important strategy to reduce toxicity of chemopreventive agents, while maintaining clinical benefit. Local delivery of an agent can be performed by a physician or self-administered by an individual, which overcomes some of the access barriers that exist in healthcare. A localized chemoprevention approach is ideal in high risk individuals or individuals with premalignant diseases, as the agent can be applied locally to provide high drug concentrations at specific locations from where early disease would originate, while limiting systemic toxicity.

Project Goals

The goal of this concept is to solicit proposals to advance the development and/or application of local delivery devices or formulations for chemoprevention. The technology should be designed for effective delivery of agent to a specific organ while minimizing systemic toxicities. Acceptable toxicities will depend on the agent and target population. Toxicity should not exceed minimal grade 2 local toxicities, while short term local grade 3 toxicity may be acceptable in some populations. The proposed local delivery device/formulation may utilize any technology or agent capable of meeting the goals of this topic. Examples of local administration include topical (for oral, breast, skin or cervical cancers), inhalant or aerosolized (for lung or esophageal cancers), or digestive (for esophageal, stomach, or colorectal cancers). Proposals for development of local delivery devices or formulations via other administration routes or for other cancer types are also encouraged. Potential chemoprevention agents include but are not limited to active metabolites of tamoxifen, aromatase inhibitors, anti-progestin agents, rexinoids, Cox2 inhibitors, PARP inhibitors, Imiquimod, Polyphenon® E, Stat inhibitors, Tyrosine kinase inhibitors, etc.

The activities that fall within the scope of this contract solicitation include development and application of local delivery formulations or devices. Examples of appropriate activities include pre-clinical toxicity and efficacy studies in appropriate animal models, acceptability studies, and initial first-in-human testing. The offerors may develop a local delivery approach for FDA approved chemoprevention agents or for novel chemoprevention agents. For novel chemoprevention agents, the offerors should demonstrate significant reduction in cancer incidence in suitable cancer prevention animal models. Phase II clinical trials and beyond are not appropriate for this mechanism; investigators are encouraged to seek support for these studies from alternative NCI programs.

Notes:

• Novel agents and/or technologies to locally deliver chemoprevention agents to lungs are especially encouraged.

• Local approaches for treatment of invasive cancers will not be accepted.

• Adequate justification for the appropriateness of an agent for chemoprevention is critical.

 

Phase I Activities and Deliverables:

• Select cancer type(s), organ site(s), chemoprevention agent(s), and method(s) of local delivery with adequate justification.

• Demonstrate that the chemoprevention agent is: o Stable in local formulation and/or when incorporated with the local delivery device/technology

o Released at the organ(s) of interest when incorporated into a local delivery device/technology

 

• Perform preliminary proof-of-concept of the local delivery approach in a suitable animal model and demonstrate: o Accumulation/presence of the agent at the organ/tissue of interest at greater concentration than in the circulation (exact metric will depend on the toxicity of the agent under study)

o Reduction in agent concentration in the blood compared to systemic delivery/administration (exact metric will depend on the toxicity of the agent under study)

o Efficacy of the agent with relevant standard tests based on MOA of the agent (e.g., proliferation assay, apoptosis assay)

o Significant reduction in toxicity with the local approach compared to systemic administration; relevant organ observed toxicity could be used with appropriate justification.

 

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Phase II Activities and Deliverables

• For agent(s) (or their metabolites) with known chemoprevention effect when administered systemically (FDA approved): o Demonstrate efficacy in suitable animal model(s)  Perform ADME, bioavailability and efficacy studies of the local delivery approach in suitable animal model(s) and demonstrate: - at least same level of agent concentration at the organ/tissue of interest compared to systemic delivery/administration

- at least 90% higher concentration of the agent in the organ of interest than in the circulation

- at least 90% reduction in agent concentration in the blood compared to systemic delivery/administration

- at least same level of efficacy demonstrated with appropriate standard tests reflecting the MOA of the agent (e.g., proliferation assay, apoptosis assay) compared to systemic delivery/administration

 

 

 

o Perform maximum tolerated dose (MTD) and/or biological active dose study and demonstrate superior therapeutic index using local approach compared to systemic administration with adequate justification.  Toxicity should not exceed minimal grade 2 systemic toxicities while short term local grade 3 toxicity may be acceptable in some populations.

 

o IND Submission  Develop and execute an appropriate regulatory strategy; schedule pre-IND meeting with the FDA.

 Perform IND-enabling GLP safety toxicology studies in relevant animal model(s) following FDA guidelines.

 

•For novel (non-FDA approved) chemoprevention agent(s): o Demonstrate efficacy in suitable animal model(s)  Perform ADME and bioavailability and efficacy studies of the local delivery approach in suitable animal model(s) and demonstrate: - reduction of oncogenic molecular/cellular characteristics reflecting the MOA of the agent (e.g., proliferation assay, apoptosis assay)

- at least 50% reduction in cancer incidence following local administration of the chemoprevention agent in suitable cancer prevention animal model(s)

- Accumulation/presence of the agent at the organ/tissue of interest at greater concentration than in the circulation (exact metric will depend on the toxicity of the agent under study)

- Reduction in agent concentration in the blood compared to systemic delivery/administration (exact metric will depend on the toxicity of the agent under study)

 

 

 

o Perform maximum tolerated dose (MTD) and/or biological active dose study and demonstrate superior therapeutic index using local approach compared to systemic administration with adequate justification  Toxicity should not exceed minimal grade 2 systemic toxicities while short term local grade 3 toxicity may be acceptable in some populations.

 

o Perform IND-enabling safety toxicology studies in relevant animal model(s) to warrant a type B or type C meeting with the FDA.

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

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 3-4

Budget (total costs, per award): Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

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

Summary

Evolution of cancer is complex: from the early lesion to the development of primary tumor to widespread metastasis, numerous and complex interactions occur among normal and malignant cells, as well as their microenvironment. Within the last decade, researchers have found that the tumor environment (TME) is consisted of a multitude of cell types and a host of mediators, whose dynamic interplay contributes to complex tumor behaviors and pose significant therapeutic challenges.

Consisting of non-cancerous cells, TME has an abnormal vasculature, stromal components, immune and non-immune cells embedded in an extracellular matrix (ECM), and plays a critical role in tumor initiation, malignant progression, metastasis and treatment response - barriers to drug delivery and resistance to therapy. There is substantial evidence of a dynamic tripartite interaction between cancer cells, immune cells, and tumor stroma, which contributes to a chronically inflamed TME with pro-tumorigenic immune phenotypes and facilitated tumor metastasis. Both cancer cells and cells in the TME release bioactive molecules (e.g., chemokines, metabolites, and lipid mediators) which can influence cancer progression. Although discovered many years ago via cellular energetics studies (i.e. the Warburg effect) that the metabolic programming and reprogramming of immune cells in TME affects the tumor initiation, the importance of the interconnection of metabolic components and immune signaling pathways for determining the phenotype of tumor-associated macrophage (TAM) was recently noted. In sum, the complex interactions of different cell types (including the immune and non-immune cells), as well as the associated bioactive molecules contribute to the immune-metabolic characteristics of the tumor and its TME.

There are emerging cancer treatment strategies via modulating the immune or metabolic conditions of tumor and its TMEs in recent years with limitations. As an immune-suppressive TME is a barrier to the antitumor function of immune cells, immune priming of TME by radiation has been suggested to promote cancer treatment efficacy. On the other hand, as a sustained inflammation is a common feature of many cancers, novel cancer treatment strategies have been proposed which tackle the inflammation in tumor and TME through the modulation of lipid metabolism and the production of specialized pro-resolving mediators (SPMs). Immunotherapies utilizing checkpoint inhibitors to modulate the immune components of tumor cells and TME have shown efficacy in treating multiple cancer types, and more are currently undergoing clinical trials; however, immunotherapies only work in a restricted group of patient populations. The less than optimal outcome can be attributed to limited knowledge in individual’s immunological profile encompassing inflammatory cells, immuno-suppressor cells and immunomodulatory factors within the tumor and TME. For this reason, tracking the dynamic evolution of heterogeneous cell populations, molecular characteristics, and metabolic signatures to characterize the immunological status within the tumor and its TME would add significant knowledge in cancer progression and could lead to the development of novel therapeutics and more efficacious treatment strategies.

Studies of immune or metabolic signatures of tissues are usually based on histopathological analysis of the tissue biopsies. However, these methods are destructive and lack temporal information; thus, the ability to use tumor and TME-associated molecular, cellular and metabolic signatures for tumor prediction, diagnosis, prognosis, and therapy response are somewhat limited. The use of techniques capable of in vivo molecular characterization and cell mapping of the tumor and its TME, in its physical location and over time, augmented by the assessment of metabolic signatures, can advance research efforts in this increasingly important topic and could accelerate lead compound identification. Clinical applications of responsive technologies could assist in patient stratification, monitor therapeutic response and modulate therapy accordingly.

Recent advances in imaging techniques are enabling assessment of tumor and TME with improved accuracy due to higher monitoring speed, sensitivity, and resolution. For example, magnetic resonance imaging techniques, with both excellent image resolution and depth penetration, are widely used to detect abnormal pre-malignant, tumor and TME structures and conditions: blood oxygenation level dependent (BOLD)-MRI for hypoxic conditions; Chemical Exchange Saturation Transfer (CEST)-MRI for reduced pH; MR angiography for vascular structure and diffusion MRI for structural integrity; and, MR spectroscopy Imaging (MRSI) for interrogating the concentration of various metabolites. Positron Emission Tomography (PET) of radio-nuclei-labeled tumor or TME-associated molecular and immunological targets has been used in pre-clinical and clinical settings. All these in vivo methods are valuable tools to spatiotemporally examine the targeting efficiency, associated molecular events and provide insight into the normalization of tumor and TME, and its effect on anticancer drug delivery. In parallel, although not applicable in vivo, high throughput analytical tools such as liquid chromatography-mass spectroscopy (LC-MS) and other advanced mass spectrometer techniques allow lipidomic and metabolic analyses in TME’s interstitial fluid and provide functional insights into the activities of tumor and its TME.

Longitudinal evaluation of the immunological status, based on multiple immune or metabolic signatures in the tumor and its TME, within the same subject is a comprehensive strategy for early detection of cancer, the prognosis of tumor progression as well as prediction of treatment outcome. To accelerate research and potentially translational efforts focused on dynamic profiling of the immunological status in tumor and TME, the National Cancer Institute (NCI) requests proposals for the development of tools that can dynamically measure multiple immune or metabolic signatures of the tumor and its TME.

Project Goals

Tumor diagnosis at an early stage is critical to improving survival of patients with the tumor. Similarly, being able to predict tumor response to treatment is essential to eliminate the use of ineffective treatment options and allow alternative treatment options. As such, the ability to characterize the dynamic changes in the immune or metabolic signatures of tumor and TME at the molecular, cellular and metabolic levels in an individual patient for early diagnosis and during treatment is critical. The goal of this solicitation is to develop minimally-invasive, imaging and analytical platforms that can repeatedly evaluate immunological status of the tumor and its TME to facilitate pre-clinical research in the immunological space for better cancer diagnosis and treatment prediction. To be considered for this topic, the proposed technology should be focused on interrogating at least two of the following tumor and TME immunological parameters across time via in vivo imaging techniques which can be augmented by additional in vitro analytical measurements. These parameters should allow comprehensive evaluation of an immunology status, based either on signatures from multiple immune pathways, from both etiological and consequential events, or of both immunogenetic and immunosuppressive natures. Proposals to perform in vivo measurements not meeting the above criteria or to solely develop software tools to analyze multiplexed image data are not responsive to this topic.

Potential molecular, cellular, metabolic and physiological parameters to be measured for characterizing immune or metabolic signatures may include but are not limited to the following:

• Gene expression profiles of cells associated with immunological activities;

• Protein expression profiles associated with immunological activities;

• Tissue metabolic profiles associated with immunological activities;

• Tissue integrity and/or pH associated with immunological activities;

• Maps of chemokine receptors associated with immunological activities;

• Maps of enzymatic activities associated with immunological activities;

• Profiles of lipid mediators associated with immunological activities;

• Markers or surrogate markers of inflammation associated with immunological activities;

• Immune and non-immune cell trafficking associated with immunological activities.

Novel or currently existing in vivo imaging agents or probes (targeting specific molecular or cellular signatures) may be developed and optimized to enable molecular, cellular and physiological measurements. In vitro assessment of immunosuppressive and immunomodulatory factors and cells, their individual genomic and proteomic profiles, and complex networks promoting tumor growth can be included as a part of the proposal to enhance the specificity of the in vivo tools. Developing software algorithms or tools specifically for the interpretation of multiplexed measurement from the proposal can be included.

Phase I Activities and Deliverables

Phase I activities should generate scientific data to demonstrate proof of concept that the technology can quantitatively characterize immune and/or metabolic signatures with sufficient signal sensitivity and resolution. Expected activities and deliverables should include but not limited to:

• Optimize detection scheme to demonstrate in vitro signal specificity and correlate signals to cell, molecular target or bioactive mediator concentrations measured using conventional assays;

• Establish calibration curves correlating in vivo signal changes to concentration of cells, molecular targets or bioactive mediators measured via conventional biological assays;

• Demonstrate robust signal changes in response to in vivo perturbation;

• Demonstrate feasibility in generating maps of measurable parameters as a function of time;

• If new molecular targets are proposed, demonstrate specific binding/targeting capabilities of the agent/probe to the molecular target (tumor and/or TME target);

• If new imaging (or detection) agents are proposed, determine optimal dose and detection window through proof-of-concept small animal studies with evidence of systemic stability and minimal toxicity;

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

• Present Phase I results to NCI staff.

For successful completion of benchmarking experiments, demonstrate a minimum of 5x improvement against comparable or gold-standard methodologies.

Phase II Activities and Deliverables

Phase II activities should support commercialization of the proposed technology. Expected activities and deliverables may include:

• Demonstrate in vivo clearance, tumor accumulation, in vivo stability, bioavailability, and the immunogenicity/toxicity of imaging (or detection) agents or probes;

• Demonstrate high reproducibility and accuracy of the imaging agents or probes in multiple relevant animal models;

• Demonstrate superiority over currently available imaging or detection tools in spatial and/or temporal resolution;

• Demonstrate that sensitivity of proposed imaging agents or probes is sufficient to detect in vivo perturbation;

• Demonstrate sensitive maps of measurable parameters as a function of time;

• Perform toxicological studies;

• Demonstrate utility: o for diagnosis, demonstrate that the probes can detect tumors at early stages and demonstrate superiority to current diagnosis methods;

o for predictive/decision, validate the predictive capability of the marker by performing prospective pre-clinical animal trials: stratify the animals into treatment groups and demonstrate that the imaging agent accurately predicts appropriate therapy to use;

o for therapy response, demonstrate that the imaging tool can accurately visualize changes in response to therapy and validate characteristics of response and non-response.

 

388 In vitro Diagnostic for the Liver Flukes Opisthorchis viverrini and Clonorchis sinensis

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 2-3

Budget (total costs, per award): Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

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

Summary

The liver flukes, Opisthorchis viverrini and Clonorchis sinensis, are known to cause cholangiocarcinoma (CCA), a type of liver cancer that develops within the bile duct. These species of flukes are classified as Group I carcinogens by the International Agency for Research on Cancer (IARC). They are primarily transmitted to humans by eating raw or undercooked fish, and it is estimated that approximately 45 million people worldwide are infected. Although CCA is generally considered a rare disease with a worldwide incidence of 2-3 cases per 100,000 people, the incidence in areas where liver fluke infections are prevalent (e.g., Southeast Asia and China) is up to 85 cases per 100,000 people. US veterans who served in Vietnam have shown an increasing incidence of CCA, and a pilot study conducted by the Veterans Administration (VA) suggests that 25% of Vietnam veterans were infected with C. sinensis during their military service. This statistic might not be entirely accurate since the VA test was not designed to detect O. viverrini, the more prevalent fluke in South Vietnam. The VA test, as well as other tests developed in academic laboratories, suffers from low sensitivity and specificity. Detecting fluke infections is the rate-limiting step in intervention as effective treatment is available for fluke infections; therefore, the lack of a reliable test represents an unmet need worldwide and is potentially very important for screening the millions of US veterans who served in southeast Asia. Additionally, the CDC estimates that 10-15% of US immigrants from Asian countries may have been infected. To address this need, this SBIR solicitation will support the development of diagnostic tests or kits to detect chronic and early/mild acute liver fluke infections.

Project Goals

The primary goal of this contract solicitation is to facilitate the commercial development of a diagnostic test(s) to detect chronic and early/mild acute liver fluke infections caused by O. viverrini and C. sinensis and thereby decrease the incidence of CCA and possibly also hepatocellular carcinoma (HCC). For each of the other infectious Group I carcinogens associated with human cancers (i.e., hepatitis B and C, Helicobacter pylori, HPV, EBV), FDA-approved diagnostics are available. Currently, the standard diagnostic tool for liver fluke infection is a fecal smear and either direct examination or variations using concentration to increase the number of eggs within the sample. The sensitivity of these tests is low and requires repeated testing over several days to detect true positives and is not routinely performed in the US. Egg production of the flukes can vary widely (from zero to thousands), depending on adult fluke load as well as the length of the infection. Thus, the limit of detection of these

techniques precludes reliable diagnosis of early, mild, chronic and resolved (please see discussion below) infections. The specificity of these tests is also low since the eggs of many helminths look similar.

The average lifespan of C. sinensis within the human host is reported at 30 years and that of O. viverrini is estimated to be on the same order. Consequently, Vietnam veterans could theoretically fall into one of two categories: (1) those with low level chronic infections, and (2) those with infections that eventually resolved without drug treatment. Diagnostic approaches for Vietnam veterans may be different than for patients with early or mild acute disease.

This solicitation is intended to result in a diagnostic test for O. viverrini and C. sinensis without any preconceived biases regarding the best approach. Therefore, the proposed platform/approach may utilize any technology capable of meeting the stated goals of this contract solicitation. Diagnostic tests that are useful in developed countries where lab equipment is not limited are welcomed, as are simple point-of-care diagnostics that can be utilized in the absence of such equipment.

The short-term goal of this topic is to develop a CLIA diagnostic test or kit to detect chronic and early/mild acute liver fluke infections. The long-term goal is to develop an FDA-approved diagnostic test.

Acceptable technologies/approaches under this contract topic may include, but are not necessarily limited to:

• Antibody based assays

• Point of care diagnostics using synthetic biology

• Biosensors

• Paper or micro-fluidic devices, lab on a chip, dynamic biomaterials

Please note that the following are NOT considered appropriate for development under this contract topic:

• Studies focusing solely on measuring liver fluke infections in animal models

• Development of assays and/or technologies for research use only

• Developing diagnostics to other species of liver flukes, such as Fasciola hepatica

• General studies to identify biomarkers associated with O. viverrini and C. sinensis infection

Phase I Activities and Deliverables

• Develop a working diagnostic assay and/or prototype point-of-care diagnostic device that can identify the target pathogens (O. viverrini and C. sinensis) in low biomass infections.

• Determine the sensitivity, specificity and other performance characteristics (e.g. limit of detection, cross reactivity with other helminth infections, reproducibility, feasibility for newly infected, chronically infected, and resolved infected clinical samples, test stability) of the diagnostic test.

• Conduct initial testing using samples from animal models and/or preferably on patient isolates to demonstrate feasibility.

• Offerors may need to establish a collaboration or partnership with a medical facility or research group in the US or overseas that can provide relevant positive control and patient samples; offerors must provide a letter of support from the partnering organization(s) in the proposal.

Phase II Activities and Deliverables

Activities leading to the ultimate development of an FDA approved diagnostic test, including but not limited to:

• Develop a well-defined test platform under good laboratory practices (GLP) and/or good manufacturing practices (GMP).

• Perform scale-up and production for multi-site evaluations (with at least one independent CLIA-certified laboratory) using clinical isolates.

• Demonstrate suitability of the test for use in the clinic.

• Establish a product development strategy for FDA regulatory approval (as appropriate).

389. Development of Artificial Intelligence (AI) Tools to Understand and Duplicate
     Experts’ Radiation Therapy Planning for Prostate Cancer

Fast-Track proposals will not be accepted.

Number of Anticipated Awards: 2-3

Budget (total costs, per award):  Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

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

Summary

The goal of this topic is to stimulate Artificial Intelligence (AI) technology to improve treatment planning for prostate cancer by training algorithms to “read” standard Computerized Tomography (CT) and/or MRI images and recommend suitable treatment plan approaches. The resulting AI software may be a tool to aid radiation oncologists in reaching consensus treatment planning, reducing professional costs, and improving quality assurance in clinical trials and patient care. Also, by understanding the AI processes used to achieve an optimal solution, the software may have application in training junior radiation oncologists and updating practitioners.

Treatment planning for radiation therapy is becoming increasingly complex with the advent of image-guided radiation therapy (IGRT) and charged particle therapy (CPT). A substantial amount of physician time and effort is allocated to locating and contouring key tumor and normal tissue structures. Prostate cancer is chosen as it is a common disease worldwide, has well-defined risk groups and patient data-bases including outcomes.  The treatment decision process involves assessing the patient’s risk status for disease progression based on tumor size, grade and biomarkers (e.g., prostate specific antigen or other tests); and assigning one of three risk groups: low, intermediate and high. Imaging includes CT and often MRI. Based on the images obtained, the physician and medical physicists plan the target volume to be treated and normal tissue to be avoided. In practice, treatment guidelines are established by consensus papers. However, even between world-renowned experts, treatment plans can exhibit significant differences.

It may be possible to go beyond verbal consensus texts as a basis for defining treatments using an approach similar to AI-based contextual image analysis that does not rely on an understanding of the rationale behind expert “preferences” in treatment plans. Such an AI-based approach would provide an agnostic initial plan, based on computerized image interpretation, upon which the physician and physicist could build a treatment plan.   In addition, by studying the AI processes used to achieve an optimal solution, the processes for clinician decisions could be further optimized. The AI software delivered through this contract solicitation could reduce the time burden of image segmentation 75%, from four hours to one hour or less freeing up time for patient care. (https://www.technologyreview.com/s/602277/deepmind-will-use-ai-to-streamline-targeted-cancer-treatment). It may result in a substantial reduction in time for physicists and physicians and may improve quality control by having AI assist in initial plan.  For smaller facilities with limited funds for staffing, this could improve quality by defining an initial plan developed by AI that could then be reviewed and modified by the physician without starting from unannotated images.

Project Goals

The goal of this contract solicitation is to develop and evaluate AI’s capacity to duplicate expert radiation therapy planning. The purpose is to develop radiation therapy treatment plans through AI interpretation of radiomic data from diagnostic images with the intent of fully or at least largely automating treatment planning to eliminate subjective biases, improve treatment quality and reduce cost. The objective of this FOA is not to achieve a breakthrough in Artificial Intelligence, but rather benefit from the recent advances in the development of treatment planning systems and machine learning to improve radiation therapy by eliminating repetitive, time-consuming and subjective biases in treatment delivery, which can result in sub-optimal plans and inadvertent normal tissue injury.

The initial goal is to improve the outcome for patients with prostate cancer. By developing knowledge-based planning solutions it may be possible to provide a more standardized treatment, which would facilitate quality assurance, possibly extending it to facilities with limited expert personnel, and facilitate the conduct of research by reducing the variability and apparent arbitrariness and/or preference that individuals incorporate in their treatment design. The long-term goal will be to apply this technology to other tumor sites.

Technical scope:

There are many considerations that go into the selection of a target volume for treatment. Nowadays prostate cancer radiation therapy is based on “risk” stratification groups (low, medium and high), which generally determine the tumor dose, volume and other ancillary treatments such as hormonal therapy. Thus, the target volumes include the prostate, varying amounts of the seminal vesicles and the local lymph nodes for the more advanced risk group. The normal tissues are the rectum, particularly the anterior rectal wall, base of the bladder, femoral heads and occasionally additional abdominal content for lymph node fields.

There are emerging algorithms being developed to outline the normal tissues and the prostate. The scope of the activities here would be having three world renowned experts outline the same set of cases of the varying risk group with the process being “watched” by AI. The expert would dictate the thinking of why the chosen treatment volume and dose are being selected and this would be transcribed. Enough training cases would be used (the estimate of training cases needed is part of the proposal) for the AI to then take a second “test” batch of patients being planned and compared how the AI does in comparison to each of the experts. One question would be how many training cases it takes for the AI to reliably anticipate what the expert will do and to understand the discrepancies between the expert and AI.

Next, using the results from the second “test” batch, the plans for the three experts will be compared, as in consensus panels, and the plans by the AI system for each of the experts will be compared to see if the AI “understood” the differences and how AI would reach a consensus.  Should this be effective, one could begin to use the AI to do the initial plan. Some of the cases could be chosen that had grade 2 bowel or bladder side effects to see how the AI and expert plans approach this.

Projects That May Be Supported:

Algorithms for AI are now rapidly emerging. This proposal would allow small businesses and start-ups, often comprising the most creative new people in a field, to test their creativity solving a clinical problem that has some degree routine and repetition.  The support would be used for assembling and anonymizing the treatment planning, supporting some of the time and facilities of the experts and for bringing them together for consensus discussions. The AI group would receive support for time and resources. AI platforms such as Google TensorFlow, IBM Watson or Definiens’ Image Intelligence suites are likely to be used to emulate human cognitive process of treatment planning and then extract information and develop AI algorithms.

Projects That Will NOT Be Supported:

Proposals from the large manufacturers. AI that only outlines tumor and normal tissues but does not select a treatment plan for the three risk groups.

Phase I Activities and Deliverables:

Design and deliver an AI approach to develop radiation therapy planning for prostate cancer.

• • Choose three expert radiation therapy planning teams comprised of a physician and planners (i.e., a person who is knowledgeable in treatment planning with good understanding of the treatment planning system) and evaluate expert cognition process in developing treatment planning for all three strata of patient risk groups (i.e., low, intermediate, and high). 
  • Teams including experts must be identified prior to submission of the proposal.
  • Companies must already have a dataset including patients in the 3 risk groups, including radiation data and outcome (at least one year post treatment to assess toxicity) in hand before Phase I starts. Additional resource datasets that they can use to test the performance of their auto-segmentation tools can be the annotated prostate database from TCIA (The Cancer Imaging Archive) :  https://wiki.cancerimagingarchive.net/display/DOI/NCI-ISBI+2013+Challenge%3A+Automated+Segmentation+of+Prostate+Structures as well as the non-annotated dataset:  https://wiki.cancerimagingarchive.net/display/Public/SPIE-AAPM-NCI+PROSTATEx+Challenges.
  • Identify criteria by which an expert planner develops each treatment plan and plan for each risk group
  • Describe plan on harmonizing imaging for tumor and normal tissue identification
  • Present a justification for the number of training and validation sets that would be needed for each of the risk groups so that the AI results can provide a starting point for the planning team to refine the initial plan and determine the final course of treatment. (If this had been underestimated, it is expected that a suitable number of additional cases will be obtained). 
  • Design and develop computational methods aimed at developing treatment planning for prostate cancer patients.
  • Propose plan to develop, incorporate, compare AI planning system with expert treatment planning system and validate AI based treatment planning system
  • Present AI concept to develop knowledge-based radiotherapy treatment planning to SBIR Development Center and the Radiation Research Program
  • At a minimum, this technology should be applied to standard 3D CT datasets. Use of additional imaging is at the preference of the planning team, which could include MR fusion into the planning CT to define size/shape of the gland rather than using CT alone.
  • Describe and demonstrate cross validation of image delineation, reproducibility of the Planning Target Volume (PTV) and treatment plans.

Activities and deliverables that will be used to evaluate whether the project should continue to be funded for Phase II include:

• Creation of an algorithm.
• Demonstration of the ability for the AI to provide a treatment plan (or 3 options of plans).
• Estimation of the number of cases needed to compare the verbal consensus by the three planning teams and the consensus by the AI from each of the teams.
• Concordance between expert treatment plans and AI plans.
• Use of datasets for training, testing, and validation.
• Execution and validation of computational tool, method, or model.
• Establishment of partnerships for potential empirical validation.

Phase II Activities and Deliverables:

• Refinement of algorithm.
• Demonstration of utility of AI plan as the initial step to then be reviewed and modified by the planning team.
• Apply AI to data sets and determine how many sets are required before physician and AI are largely in agreement.
• Expand types of data sets to include MRI or PET or other sources of information that would improve AI’s performance.
• Establish external partnership(s) for empirical validation of method, as demonstrated with letters of intent from strategic partners.

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

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 3-4

Budget (total costs, per award):  Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

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

Summary

The goal of anti-cancer treatment modalities is to eradicate cancer cells via several killing mechanisms that include metabolic death, apoptotic cell death (apoptosis) and reproductive death (clonogenic death). Apoptosis is programmed cell death leading to nuclear DNA fragmentation, mostly assessed by flow cytometry, enzymatic activity or membrane staining (annexin 5). Loss of key metabolic activity such as loss of NAD(P)H-dependent cellular oxidoreductase enzymatic activity can result in non-viable cells. This is mostly assessed by colorimetric methods. Clonogenic death is defined as the loss of ability of a cancer cell to proliferate indefinitely, which can only be assessed accurately by clonogenic assays and considered the gold standard assay to determine efficacy of a given radiation combined therapeutic modality.  Colorimetric assay for viability and apoptotic assays measure short-term effects, while clonogenic assays measure long-term effects and integrate all forms of cell death, but these assays are costly and labor-intensive.  While high-throughput screening (HTS) systems are available for apoptosis and colorimetric cell viability assessments, there is no HTS technology available for clonogenic assays. Colorimetric / apoptotic assays are more often used in screening than clonogenic assays, but do not directly measure residual cell clonogenic potential. Therefore, there exists an opportunity for using HTS in radiation oncology for screening vast number of drugs or drug combinations to improve the efficacy of radiation treatment, by integrating already developed robotics components, such as automated liquid handlers, centrifuges, incubators, imaging and statistical software as well as an irradiator to assess the effect of radiation in a laboratory. It is well known that cancer recurrence is a common event after treatment and often-attributed to re-population of surviving clones.  Thus, evaluating surviving clones becomes a vital test in-vitro to assess treatment efficacy, making colony-forming assays the gold standard. Further, designing an HTS for clonogenic assays will increase its utility to screen for drugs, radiation sensitizers and protectors in vitro.

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 clinical translation.

Program Goals

The purpose of this contract solicitation 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 an 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 to 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

• Prototype of integrated/customized robotic or automated platform for cell plating, maintaining the temperature and CO₂.
• Develop integrated HTS system that couples plating micro-fluidics, irradiation system, microscopy, imaging software and statistical software for estimating cell survival (inactivation radiobiologic estimates) and dose enhancement and modification factors to demonstrate improved efficacy of radiation treatment.
• Integration of localized radiation exposure with precise real-time dosimetry into HTS platform.

Phase II Activities and Expected Deliverables

• Delivery of a prototype system with validated SOPs that are translatable to other laboratories.
• Imaging of colonies and software to capture and calculate the survival.
• Cross-check validation of HTS data with conventional clonogenic assays.
• 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.
• Software to calculate radiation-inactivation estimates and graphing cell survival curves and calculate dose enhancement factor if done in combination with agents.
• Licensing of individual components for use in the system as needed.

391. Drugs or Devices to Exploit the Immune Response Generated by Radiation Therapy

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 2-3

Budget (total costs, per award):  Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

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

Summary

Tumor irradiation promotes recruitment of immune activating cells into the tumor microenvironment, including antigen presenting cells that activate cytotoxic T-cell function. However, tumor irradiation can also recruit immunosuppressive cells into the tumor microenvironment. Local irradiation can also impact tumor growth at a distance from the irradiated tumor site, known as the abscopal effect. This effect is potentially important for tumor control and is mediated through ceramide, cytokines, and the immune system.

Ionizing radiation can induce the following changes in the tumor micro-environment and such changes can be important targets to develop agents that can augment or negate radiation-induced immune activation or suppression respectively. Tumor-associated antigens (TAAs) are released by irradiated dying cancer cells. TAAs and cell debris are engulfed in the tumor microenvironment by phagocytes such as macrophages, neutrophils, and dendritic cells for antigen processing and presentation.

• RT-induced cell death releases danger signals including heat-shock protein (Hsp), HMGB1, and calreticulin
  (eat-me signal for phagocytes).
• RT induces increased expression of tumor antigens and MHC class I molecules on tumor cells.
• RT-induced T cell activation increases expression of negative stimulatory molecules such as CTLA-4.
• Certain radiation doses may increase tumor production/secretion of immunosuppressive cytokines such as IL-10 and TGFb.
• Activated APCs migrate to the draining lymph node, further mature upon encountering T helper cells, release interferons (IFNs) and IL-12/18 to stimulate Th₁ responses that support the differentiation and proliferation of antigen-specific CTLs. Activated antigen-specific CTLs traffic systematically from the draining lymph node to infiltrate and lyse primary and distal tumors.

Several factors can influence the ability of radiation to enhance immunotherapy, including a) the dose of radiation (IR) per fraction and the number of fractions, b) the total dose of IR, and c) the volume of the irradiated tumor tissue. However, the impact of these variables is not well understood. Inducing anti-tumor cellular-mediated immune responses has been the subject of some pre-clinical tumor regression studies and is being applied in immune-modulatory clinical trials using antibodies against molecules that suppress immune responses such as PD1, PDL1 and CTLA4 or immune agonists such as OX40, CD27, GITR, 4-1BB, TNFR receptors, ICOS, and VISTA. Overall, discovery of checkpoint protein functional control of T-cells in tumor microenvironment led to the development of checkpoint blockade therapy and many checkpoint inhibitors including Nivolumab, Pembrolizumab, and Atezolizumab have been approved by the FDA for several indications. Several clinical trials testing combination of radiation with check point inhibitors are underway and have resulted in mixed results. Further, many of these combination trials lack robust pre-clinical scientific rationale raising queries if such checkpoint agents augment the immune modulating effects of radiation. Hence, more agents and/or devices that can augment immune activation or inhibit immune suppression induced by standard conventional 2 Gy fractions, (3-8 Gy) hypofractionation and high-dose hypofractionated (>10 Gy) radiotherapy are warranted.

Project Goals

Augmentation of radiation induced immune activation and/or inhibition of radiation induced immune suppression could enhance anti-tumor effects. The goal of this solicitation is to develop agents or devices (engineered cellular therapies, antibodies, small molecules, siRNA/CRISPR-CAS9 or in-vivo physical/chemical modulating instrumentation-based approaches) that can augment (immune stimulation) or negate (immune suppression) one or more of the immune modulation events induced by radiation therapy. Radiation therapy can include conventional clinically relevant radiation, hypofractionated radiation, and high-dose hypofractionated radiation.

It is critical that the proposed agent or device must specifically exploit the radiation induced immune response.

Projects That Will NOT Be Supported:

Immune modulating agents that are already being tested in combination with radiation in clinical trials will not be supported.  Testing of immune modulating agents in the absence of radiation will not be supported.

Phase I Activities and Deliverables:

• Selection of cancer type(s), organ site(s), immune modulation agent(s), and radiation dose & fractions, with adequate justification.
• Proof of concept animal (mice or rat) studies demonstrating augmentation or inhibition of radiation-induced immune activation or suppression respectively with the combination of the agent or device.
  • Demonstrate augmentation of immune activation in irradiated environment with appropriate standard markers showing an increased influx of positive effector immune cells (such T-cells, macrophages, dendritic cells etc.) in the tumor micro environment.
  • Demonstrate negation of immune suppression in irradiated environment with standard appropriate markers showing reduction in the influx of negative effector immune cells (such neutrophil, T-reg and MDSCs) in the tumor micro environment.
• Proof of concept animal (mice or rat) studies demonstrating tumor regression in a syngeneic contra-lateral tumor model whereby regression is observed in both the irradiated primary tumor as well as distal non-irradiated tumor when the agent is combined with radiation.

Phase II Activities and Deliverables:

• Perform absorption, distribution, metabolism and excretion (ADME) of agents with bioavailability and efficacy studies in appropriate animal models with adequate justification (the models chosen could be syngeneic rodent models, humanized rodent models or canine models) and demonstrate:
  • Improved efficacy (both immune modulation and tumor regression) compared to radiation or agent alone
  • Radiation sensitizing effects on tumors using standardized in vivo radiation regrowth delayed assays
  • Comparative (similar or lower) toxicity compared to the agent or radiation alone
• Perform IND-enabling GLP safety toxicology studies in relevant animal model(s) following FDA guidelines.
• For offerors that have completed advanced pre-clinical work, NCI will support pilot human trials.

382. Clinical Trials of Systemic Targeted Radionuclide Therapies

Only Fast-Track proposals will 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

This topic calls for “first in human” studies and Phase I/II clinical trials of targeted radionuclide therapy (TRT) for cancer using novel radiopharmaceuticals or TRT treatment strategies as described in the project goals below.

TRT enables personalized cancer treatment by combining the therapeutic effect of radiation therapy with the targeting capability of molecularly targeted agents, such as antibodies used for biologically targeted therapy or immunotherapy. In TRT, a cytotoxic dose of a radioactive isotope is attached to a tumor-targeting agent that binds to malignant tumor cells selectively. For instance, the ability of the antibody to bind only to a tumor-associated antigen 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).

The first clinical application of TRT was the treatment of thyroid cancer with radioactive iodine, and the field of TRT has since expanded with clinically approved indications for non-Hodgkin lymphoma, bone metastases, and neuroendocrine tumors including neuroblastoma. Two radioimmunotherapy agents involving ⁹⁰Y- and ¹³¹I-labeled CD20 (Bexxar and Zevalin) were approved for the treatment of non-Hodgkin lymphoma, but their clinical use has been limited due to lack of coordination between nuclear medicine physicians and oncologists, concerns about radiation safety, and issues surrounding reimbursement. Building on the prior success of ⁸⁹Sr and ¹⁵³Sm, ²²³RaCl₂ (Xofigo) was shown to improve survival for men with bone metastases from castration-resistant prostate cancer and has reinvigorated interest in the development of novel TRT agents. Most recently, ¹⁷⁷Lu-dotatate (Lutathera) has been approved by FDA for treatment of neuroendocrine tumors.

As this class of treatments shows tremendous clinical potential, the NCI SBIR program issued TRT-focused contract solicitation for preclinical research in three consecutive years and awarded 16 contracts in this field. In addition, more than 30 TRT-related grants (14 of them funded by NCI SBIR program) have been awarded by different NCI funding mechanisms. Some of those projects are mature enough to enter the clinical testing phase within the next two years. To facilitate the translation of this investment in pre-clinical studies, there is a need for funding of first-in-human studies (Phase I/II clinical trials) to assess the feasibility, safety, and efficacy of novel TRT compounds (radiopharmaceuticals) or treatment strategies.

Project Goals

This contract solicitation seeks to stimulate research, development, and commercialization of innovative TRT techniques that could potentially improve the treatment efficacy and reduce toxicity to normal tissues. Proposals addressing clinical applications of the following technology areas are encouraged: clinical evaluation of innovative ligands and radiotracers for TRT; novel dosimetry techniques; new patient selection and treatment planning strategies taking into consideration the pharmacokinetics of the radiopharmaceutical and the resulting radiation dose delivered to the tumor and normal tissues in individual patients; and for mature projects, the combination of a TRT with conventional therapies.

To apply for this topic, offerors must have met IND requirements for their product or provide convincing data indicating that an IND will be accepted by the end of the Phase I period of performance.

The short-term goal of the project is to perform clinical studies testing the use of new TRT compounds or strategies for the treatment of cancer as described above.  The long-term goal of the project is to enable a small business to bring a fully developed TRT compound or novel TRT treatment strategy to the clinic and eventually to the market.

Phase I Activities and Deliverables

• For offerors who do not expect to have an IND accepted by September 2019, it is expected that specific plans for a pre-IND meeting with FDA will be described in the SBIR proposal. Pre-IND Phase I work may include:
  • Scale up and manufacturing of the new tested radiopharmaceutical

• • Completion of any activities required for IND submission
  • Finalized Clinical Trial Protocol for submission to FDA
• Examples of other Phase I activities include:
  • Clinical trial initiation activities such as protocol development, site selection and initiation
  • Development of methods and establishment of procedures for radiation dosimetry
  • Completion of regulatory approvals

IND acceptance is critical at the end of Phase I. Offerors that do not have IND acceptance and Phase I deliverables met will not be allowed to move to Phase II.

Phase II Activities and Deliverables

Clinical trials.  Depending on how advanced the development of a new therapeutic strategy is to be tested, the clinical trial might be: (i) feasibility, first-in-human, testing the biodistribution of the radiopharmaceuticals and assessment of therapeutic ratio based on radiation dosimetry; (ii) Phase 1, assessing the safety of the treatment and maximum tolerated dose of the tested compound; or (iii) Phase 2 assessing the optimal treatment strategy and its efficacy, preferably by comparing it in a randomized trial with that of the current standard of care.

• • • Implementation of appropriate dosimetry methods
    • Quantitative assessment of radiation doses delivered to tumor and normal tissues
    • Patient recruitment plan
    • Data safety management plan
    • Registration of clinical trial in ClinicalTrials.gov
    • Data collection
    • Completion of primary endpoint and secondary endpoint data analyses
    • Completion of final report of the primary outcome
    • Reporting of results in ClinicalTrials.gov

382. Sensing Tools to Measure Biological Response to Radiotherapy

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 3-4

Budget (total costs, per award):  Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

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

Summary

Treatment planning for radiation therapy is becoming increasingly complex with the advent of image-guided radiation therapy (IGRT) and charged particle therapy (CPT). Fundamental to treatment planning is dose. The goal of any treatment plan is optimization of dose distribution. In the vast majority of planning this is the physical dose – energy delivery in Joules per kilogram of body mass, or units of Gray (Gy). Simply stated, we engage in creating a complex plan using advanced technology so that we can deliver dose to areas of tumor and avoid dose to areas of normal tissue in order to increase the therapeutic ratio.

To this end, a large portion of the treatment team’s time and effort is allocated to reproducibly positioning, locating and contouring key tumor and normal tissue structures, to optimize physical dose distribution. While defining the geometry remains critical, currently employed dose models consider the patient to be a volume of water and, at most, apply a fixed corrective ratio of the x-ray dose in the context of CPT. Even upon successful efforts to optimize physical dose delivery, tumor control and toxicity vary. Variation in biologic dose (biologic response to a given physical dose) may make even perfect physical dose delivery systems unable to properly deliver dose to tumor in the patient. For example, a physical dose on day one of treatment has a very different biological effect than on the tenth day of treatment across tumor cells and normal tissue. Patients have varying states of baseline health, varying states of genetic capacity to repair radiation related damage, and tumors have varying capacities to survive a given physical dose. To truly optimize dose prescription, what is needed is the ability to specify the temporal, local biologic dose that is delivered via physical dose. The capacity to measure the biologic changes in a host system over time could even lead to rational optimization of physical dose modification of both the forms of radiation being used as well as other agents during the course of therapy. This technology could ultimately allow adaptive combined modality therapy in a spatially individualized fashion. Biologic response and therefore optimal dose prescription may vary in the same patient across time and across location even at the same time. Tools are needed to measure biologic response to delivered physical dose in host systems.

Contemporary engineering and device miniaturization (including nanotechnology offers many compelling properties that could enable a new generation of measurement tools to measure biological response directly and/or indirectly.  Examples include: nanoparticle systems that self-assemble upon interaction with endogenous biomolecules, nanoparticles that target and allow direct imaging assessment of the tumor and its microenvironment, sensor systems that respond to local cues of biological damage and are excreted for ex vivo assessment, among many others. Standard dosimeters, even implantable dosimeters cannot address biology in this context. Even if they could, implantable dosimeters are much larger in scale and can require physical insertion that can have significant morbidity. For this reason, integrated sensor solutions for measurement of biological response will be the focus of this contract solicitation. These systems can be used alone or in combination and can be utilized both in the body to allow volumetric assessment and extracorporeally to allow rapid, lab-test style measurements. Two examples of current physical dose measuring nanoparticle sensor systems include luminescent nanoparticles that provide in vivo bioimaging as a response to soft X-ray use (DOI: 10.1039/c6nr09553d) and a colorimetric plasmonic nanosensor capable of measuring physical dose delivered by ionizing radiotherapy (DOI: 10.1021/acsnano.5b05113). The goal of this solicitation is to expand these sorts of nanoparticles to allow the measurement of biologic changes.

Project Goals

The purpose of this solicitation is to develop in vivo or in vitro sensor tools to measure biologic response to radiation. These will ultimately be used in optimizing the definition and use of radiation dose; specifically, to help to redefine dose from solely the traditional physical dose to include the additional dimension of biological response. The resulting new, multidimensional definition of dose may allow more refined treatment planning and clinical trial development, avoidance of toxicity from overdosing, avoidance of tumor escape from biological under-dosing, and hopefully allow truly personalized medicine to be performed in the combined modality space where chemotherapy, surgery, immunotherapy and radiation are used in combination to treat patients. Ultimately, development of these tools could enable an expanded definition of prescribed dose from the physical to the biologic as well as eliminating subjective biases, improving treatment quality and reducing overall cost.

The overarching goal of this solicitation is to produce a toolbox of sensor tools that will be used to improve the outcome for patients with cancer. By developing biologic response measurement tools, it will ultimately be possible to design and interpret biologically optimized treatment. These “biologic response sensors or dosimeters are to allow study of the biological effects of radiation therapy and potentially that can be correlated with physical dose and other parameters. These biologic dosimeters or sensors should facilitate the development and study of precision radiation oncology. The sensors can be used alone, in combination, in the body, or outside of the body. As an example, a specific nanoparticle would report temporal and spatial information about, for example, one biologic pathway, molecule’s activity, or a complex’s formation/function. Ideally, these biologic response sensors should be able to be imaged via CT or MRI to allow non-invasive dynamic and real-time data collection.  As such, the development and evaluation of systems that can measure in a validated fashion biologic response to physical dose from radiation therapy when used alone and in combination with other agents, will be preferred.

Overall scope:

Such systems are diverse as noted in the above examples (e.g., surface chemistries, material properties, etc.), as such this request does not limit the scope of the technical methodologies allowed. The work requested in this announcement includes any type of systems (including but not limited to nanotechnology) that can convey biological information and that can be correlated with radiation therapy physical dose delivery in treated and untreated human tissue. Thus, sensors should measure biological status in collected liquid or solid samples and/or should evaluate biologic signals in situ that are correlated with tumor control, tumor survival, and toxicity. Mechanisms that involve conjugation and / or chemistry to monitor property changes to nanoparticles (e.g., self-assembly, emission changes, reporter release, etc.) are other examples of methods that fall into the scope of this solicitation.  Furthermore, it is desired that sensors be able to be used serially and in combinations in patients before, during, and after treatment. Such biologic response sensors should function with combination therapy (radiation with chemotherapy or other biologic therapy). Sensors that can be imaged via 4D techniques already utilized in radiation therapy are also of particular interest so that spatial biological data can be collected over time to measure spatial changes correlated to treatment. As noted above, mixtures of these agents that can be differentiated via signal characteristics would be of a high priority as well because it may be true that a combination of markers offers unique biologic insights such as toxicity fingerprints or treatment failure fingerprints. Robust combinatorial analysis capabilities of new agents will be a key goal of this project and should be addressed in applications.

Prior to the start of the project a multidisciplinary team must be constructed. This needs to be outlined in submissions for this award. Creation of a multidisciplinary team to design and evaluate the sensor’s design parameters and goals in terms of biology, chemistry, human toxicity, and reporting capabilities is critical. Examples of desired team members will be radiobiologists, imaging scientists, radiation oncologists, chemists, small animal model specialists, and molecular biologists. Failure to outline such a team in the proposal will be considered non-responsive to the FOA.

Projects That May Be Supported:

Devices/agents that can measure tumor biological change caused by radiation therapy that are injectable or otherwise distributed into in vitro and in vivo models of cancer and normal tissue. Work toward use in humans is of particular interest.  The Phase I application must provide a detailed experimental strategy to develop and deliver the biologic response sensor and identify an appropriate cancer biologic signal for the sensor.

Projects That Will NOT Be Supported:

Systems or tools that measure physical dose delivery only. Devices meant to interact with radiation and either potentiate its effects or mitigate its effects. Software solutions to model these effects without actual particle development would also be considered non-responsive.

Phase I Activities and Deliverables:

• Development of the sensor to measure biologic response to radiation.
• Demonstrate sensor stability in vitro.
• Perform in vitro efficacy studies in the relevant cancer cell line(s) and in normal tissue(s): measurement of the target gene/enzyme/other signal.
• Establish specificity of the construct and conduct validation studies.
• Perform a small in vivo efficacy study in animal model systems to evaluate appropriate correlative endpoints.

Activities and deliverables that will be used to evaluate whether the project should continue to be funded for Phase II include:

• Successful measurement of a biologic signal with the construct designed and produced.
• Concordance between known tissue signaling and sensor response (testing for false positive and false negatives).
• Establishment of partnerships for potential validation.

Phase II Activities and Deliverables

• Refinement process development of construction and purification process to allow GMP production
• Demonstrations of sensor use serially in samples at a minimum that are relevant in a pathology/diagnostic capacity but preferably in vivo (properly powered studies)
• Evaluation of tissue with testing in the context of causing toxicity and evaluation of sensor use to predict and/or measure the degree of this toxicity with a goal to taking these agents to clinical use in humans, in vitro and in vivo
• Consultation with FDA regarding development of an IND.

382. Combinatory Treatment Modalities Utilizing Radiation to Locally Activate or Release
     Systemically Delivered Therapeutics

Fast-Track proposals will 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

This solicitation calls for the development of combinatory treatment modalities utilizing external ionizing radiation to locally activate or release systemically or intratumorally delivered therapeutics. The goal is to leverage an existing radiation therapy infrastructure to provide this radiation.

Systemic administration of therapeutic agents (TA) for cancer treatment is a common practice. However, their presence in normal tissues leads to adverse toxicities limiting the administered dose and the resulting treatment efficacy. The undue toxicity might be avoided if the TA remained encapsulated or inactive until exposed to an extremal radiation within a well-defined volume. In addition, the time of release/activation could be adjusted, so that the concertation of the TA at the target volume reaches levels necessary for an effective treatment. The key criteria towards achieving an effective and safe treatment include safe doses of the external radiation and quantitative control of localized TA release or activation. Remote triggering mechanisms may include X-rays or particle, e.g. proton, beam currently used for radiation therapy (RT) of cancer.

Use of heat or ultrasound to activate or release therapeutic agents has been an active research front in many academic centers with fruitful results. Thermal release of drugs from liposomes has been in clinical practice for years. An example is ThermoDox (Cesion Corporation: http://celsion.com/thermodox/), which uses LTSL (lysolipid thermally sensitive liposome) technology to encapsulate doxorubicin, a proven and commonly used cancer drug. The heat-sensitive liposome rapidly changes structure when heated to 40ºC-45ºC, creating openings in the liposome that release doxorubicin directly into and around the targeted tumor.

This solicitation focuses on systems that might release drugs or induce a toxic effect in response to external ionizing radiation that is currently used for cancer treatment. Such approach promises unique clinical benefits over conventional systems that release their cargo passively or are activated internally. For instance, X-ray might be used to stimulate local release of drugs from nanoparticles, or combination of X-rays with nanoscintilators emitting light that activates photosensitizers in photodynamic therapy (PDT) would allow extension of PDT to deep seated tumors. This approach could be implemented as an addition to the current standard of care involving RT. It will allow to utilize already existing radiation infrastructure. Patients undergoing RT will be given an opportunity to combine it with novel TAs or potent tumoricidal agents that could not be delivered by conventional systemic administration methods. Well defined spatial and temporal control of the TA release or activation will limit the toxicity while maximizing the efficacy of the combinatory treatment leading to an improvement of the quality of life and overall survival of cancer patients. Therefore, there is a need to encourage the development of such technologies.

Project Goals

This contract solicitation seeks to stimulate research, development, and commercialization of innovative techniques that could synergistically improve the effectiveness of RT and TA and reduce toxicity to normal tissues. Proposals addressing the following technology areas are encouraged: new treatment strategies, design, synthesis, and evaluation of innovative TA and formulations.

The short-term goal of the project is to perform feasibility studies for development and use of the combinatory treatment modalities for the treatment of cancer.  The long-term goal of the project is to enable a small business to bring a fully developed combinatory treatment modalities to the clinic and eventually to the market.

To apply for this topic, offerors should:

• Identify or develop an appropriate TA that could be activated by radiation or TA formulations that could be triggered to release the TA by radiation in vivo.
• Define the mechanisms of the proposed TA tumoricidal activity in vivo.
• Identify the set of patients that are likely to be impacted by this technology.

Approaches using systemic administration of agents that act as radiation sensitizers are not appropriate for this solicitation. This solicitation is not intended for the development of the instrumentation for triggering the release of the TA. While modification of the device for eventual use with the TA in the clinic is acceptable, it must not be the focus of the proposal.

Phase I Activities and Deliverables

• Demonstrate that the expected release/activation action with a proper amplitude can be induced in vitro and in vivo by safe doses of radiation.
• Demonstrate (if appropriate) tumor-specific targeting and localization of the TA and activation of the TA only after exposure to radiation.
• Carry out a pilot animal pharmacokinetic/pharmacodynamic studies utilizing an appropriate animal model.
• Significantly characterize the chemistry and purity of the TA and chemistry of the reaction.

Phase II Activities and Deliverables

• Demonstrate an improved therapeutic efficacy and improved therapeutic index, assessment of toxicity to normal tissues in vivo.
• Development of the manufacturing and scale-up scheme.
• IND-enabling studies carried out in a suitable pre-clinical environment for PK/PD, preclinical efficacy, and safety assessment.
• When appropriate, demonstration of similar or higher efficacy of the proposed strategy when compared to current therapies.

382. Targeted Therapy for Cancer- and Cancer Therapy-Related Cachexia

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 2-3

Budget (total costs, per award):  Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

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

Summary

Cachexia is characterized by a dramatic loss of skeletal muscle and adipose tissue mass, which cannot be reversed by nutritional intervention. More than half of all cancer patients experience cachexia, and it is estimated that nearly one-third of cancer deaths can be attributed to cachexia. Patients suffering from cachexia are often so frail and weak that walking can be extremely difficult. Cachexia occurs in many cancers, usually at the advanced stages of disease. Cancer cachexia is most prevalent in gastric, pancreatic, and esophageal cancer (80%), followed by head and neck cancer (70%), and lung, colorectal, and prostate cancer (60%). Despite cachexia's impact on mortality and data strongly suggesting that it hinders treatment responses and patients' abilities to tolerate treatment, no effective therapies have been developed to prevent or hamper its progression. Even for patients able to eat—appetite suppression or anorexia is a common cachexia symptom—improved nutrition often offers no respite. Overall, cachexia is characterized into three prominent stages, namely pre-cachexia, cachexia, and refractory cachexia. Pre-cachexia is characterized by some metabolic and endocrine changes, but weight loss is minimal. In cachexia, the patient undergoes more prominent weight loss, anorexia, muscle mass depletion, and reduced muscle strength. At this point, weight loss can be somewhat countered by health supplements and corticosteroids, but improved muscle function has not been achieved. In refractory cachexia, there is severe body weight, muscle, and fat loss; the reversal of weight loss is negligible even with the dietary supplements.

Over the last few years, researchers have begun to better understand the underlying biology of cancer- and cancer therapy-related cachexia. Findings from several studies point to potential therapeutic approaches, and a number of clinical trials of investigational drugs and drugs approved for other uses have been conducted or are under way. For recent research on the biological pathways involved in cachexia, please refer to Abstracts from the 3^rd Cancer Cachexia Conference published J Cachexia Sarcopenia Muscle. 2017 Feb; 8(1): 145–160. Published online 2017 Feb 27. doi:  10.1002/jcsm.12186.

Project Goals

The goal of this SBIR contract solicitation is to provide support for the development of targeted agents, including small molecules and biologics, to prevent or treat cachexia related to cancer and/or cancer therapy, including chemotherapy and/or radiotherapy. Proposals submitted in response to this topic must focus on cancer indications with the highest prevalence of cancer- and cancer therapy-related cachexia. Any route of administration is acceptable, but it must be kept in mind that once cachexia has developed, absorption in patients may be impaired.

To apply for this Topic, offerors should:

• Identify a therapeutic target and explain in detail the mechanism by which their drug will exhibit efficacy in preventing or treating cancer- or cancer therapy-related cachexia.
• Provide preliminary data or cite literature to support the role of the target in the development of cancer- or cancer treatment-related cachexia.
• Demonstrate ownership of, or license for, at least one lead agent (e.g., compound or antibody) with preliminary data showing that the agent hits the identified target.
• Possess experience with well-validated in vitro assays and in vivo models. Preliminary animal studies establishing proof-of-concept efficacy must be completed in Phase I. Common animal models used in cachexia research include: Lewis Lung Carcinoma (LLC), C-26 colon adenocarcinoma and Apc^Min/+ mice. More recently, orthotopic patient-derived pancreatic xenograft models have been employed to more closely recapitulate the muscle wasting seen in human disease.
• The scope of work proposed may include structure activity relationships (SAR); medicinal chemistry for small molecules, antibody, and protein engineering for biologics; formulation; animal efficacy testing; pharmacokinetic, pharmacodynamic, and toxicological studies; as well as production of GMP bulk drug and clinical product. These data will establish the rationale for continued development of the experimental agent to the point of filing an investigational new drug application (IND).
• Offerors must also have the appropriate team members including expertise in: cachexia, drug development, and regulatory strategy.

Activities not supported by this Topic: 

Proposals involving supplements and food products will not be considered.

Projects proposing to develop anti-tumor agents will not be considered.

Phase I Activities and Deliverables

• Demonstrate in vitro efficacy for the agent(s) in appropriate models.
• Conduct structure-activity relationship (SAR) studies, medicinal chemistry, and/or lead biologic optimization (as appropriate).
• Perform animal toxicology and pharmacology studies as appropriate for the agent(s) selected for development.
• Perform animal efficacy studies in an appropriate model of cancer- or cancer treatment-related cachexia (see examples above). Include controls to preclude drug-drug interactions (e.g., the drug for cachexia should not decrease efficacy or increase toxicity for standard-of-care cancer drug).
• Develop a detailed experimental plan necessary for filing an IND or an exploratory IND (for potential SBIR phase II award).
   

Phase II Activities and Deliverables

• Complete IND-enabling experiments and assessments according to the plan developed in Phase I (e.g., demonstration of desired function and favorable biochemical and biophysical properties, PK/PD studies, safety assessment, additional preclinical efficacy as warranted, GMP manufacturing, and commercial assessment). The plan will be re-evaluated and refined as appropriate.
• Develop and execute an appropriate regulatory strategy. If warranted, provide sufficient data to file an IND or an exploratory IND for the candidate therapeutic agent.
• Demonstrate the ability to produce a sufficient amount of clinical grade material suitable for an early clinical trial.

382. Imaging for Cancer Immunotherapies

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 3-4

Budget (total costs, per award): Phase I: up to $300,000 for up to 9 months; Phase II: up to $2,000,000 for up to 2 years

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

Summary

Immunotherapies have emerged as one of the promising approaches for cancer treatment by exploiting patients’ own immune systems to specifically target tumor cells. However, it has been recognized that responses often occur in only a subset of patients in any given immunotherapy. This treatment is also associated with drug toxicity (e.g., cytokine storm), potential development of autoimmune diseases, in addition to the high cost. As this treatment modality continues to evolve, a significant clinical question that needs to be addressed is to determine which patients would benefit from immunotherapies. In addition, there is increasing need for newer methods to evaluate the efficacy and potential toxicities of the treatment, monitor cancer patients’ prognosis, and implement early interventional steps to minimize adverse effects upon completion of immunotherapies.

Cancer imaging is routinely used to: 1) stratify patients for cancer treatment; and, 2) monitor and provide reliable predictive and/or prognostic information for a specific treatment. With the rapid advancement of imaging technologies, particularly molecular imaging technology, this technique provides detailed visualizations and measurements of biologic processes taking place inside the body at molecular, cellular, anatomical, and functional levels. As such, imaging capability offers capability to assess early changes in molecular expression, cellular activity, and functional perturbation in response to therapies. Furthermore, cancer imaging provides nearly real-time information about tumor target expression levels, potentially allowing physicians to predict which patients may respond to therapies. In addition to patient stratification, cancer imaging of therapeutic targets may provide insight into predicting efficacy and reducing toxicity of the cancer treatment and overall disease progression.

The purpose of this initiative is to provide much needed support for the development of cancer imaging technologies or approaches to identify patients who are likely to respond to cancer immunotherapies, evaluate the efficacy and potential toxicities of the treatment, and/or monitor cancer patients’ treatment prognosis.  This solicitation is intended specifically to address cancer immunotherapies that depend upon eliciting an immune response. Projects that do not meet this requirement will not be funded. For example, a monoclonal antibody-based therapy that exerts a direct antitumoral effect either by neutralizing the antigen or by activating signaling pathways within the target tumor cells but does not elicit an immune response for its clinical application, is not considered an immunotherapy and would not be funded.

 

Project Goals

The goals of the solicitation are to develop a cancer imaging technology to identify patients who are likely to respond to cancer immunotherapies, evaluate the efficacy and potential toxicities of the treatment, and/or monitor cancer patients’ prognosis. The imaging modality could be one of the following, but is not limited to: ultrasound imaging, optical imaging, photoacoustic imaging, PET, SPECT, MRI or combination of multiple modalities. Molecular markers of interest could include but are not limited to: cell surface receptors, immune or associated non-immune cells, cellular infiltrates, enzymes, metabolites or metabolic states, DNAs, RNAs, or epigenetic modifications. The technology development should be platform driven. For example, the procedure for the cancer imaging that targets immunotherapy for breast cancer or its subtype should be easily applied for other cancer types/subtypes, such as colon cancer or prostate cancer. To apply for this topic, offerors need to outline and indicate the clinical question and unmet clinical need that their cancer imaging will address. Offerors are also required to use novel or validated imaging targets. This solicitation will not support efforts for imaging biomarker discovery

The long-term goal of this solicitation is to enable small businesses to bring novel or improved imaging modalities of fully developed imaging technologies for cancer immunotherapies to the clinic and the market.

Phase I Activities and Deliverables:

Phase I activities should generate scientific data confirming the clinical potential of the proposed imaging for cancer immunotherapies. The Phase I research plan must contain specific, quantifiable, and testable feasibility milestones.

Expected activities may include:

• Demonstrate proof-of-concept for the development of a novel, modification of an existing imaging technology or approach to identify patients who are likely to respond to immunotherapies, and/or evaluate efficacy and toxicities of immunotherapy, and/or monitor tumor prognosis under immunotherapy using the imaging technology.
• Quantify sensitivity and specificity of such imaging technology or approach.
• Conduct preliminary biosafety study for the imaging technology or approach.
• Benchmark experiments against current state-of-the-art methodologies.
• Present Phase I results and future development plan to NCI staff.
   

Phase II Activities and Deliverables:

Phase II should follow the development plan laid out in the Phase I and should further support commercialization of proposed imaging technology for cancer immunotherapies. The Phase II research plan must contain specific, quantifiable, and testable milestones.

Expected activities may include:

• Complete all experiments according to the development plan.
• Demonstrate capability of imaging technology to: 1) identify whether cancer animal models and/or human patients respond to cancer immunotherapies; and/or, 2) evaluate efficacy and toxicities of cancer immunotherapies in animal models and/or human patients; and/or, 3) monitor tumor prognosis in animal models and/or human patients under cancer immunotherapies.
• Demonstrate high sensitivity and specificity of the imaging technology in animal models and/or human patients.
• Demonstrate high reproducibility and accuracy of the imaging technology in animal models and/or human patients.
• Determine biosafety of the imaging technology with animal or human toxicology studies.
• If warranted, initiate FDA approval process for the candidate imaging technology.

 

 

 

National Heart, Lung, and Blood Institute (NHLBI)

The NHLBI plans, conducts and supports research, clinical trials and demonstration and education projects related to the causes, prevention, diagnosis, and treatment of heart, lung, and blood (including blood vessel), and sleep disorders. It also supports research on the clinical use of blood and all aspects of the management and safety of blood resources. The NHLBI SBIR/STTR program fosters basic, applied, and clinical research on all product and service development related to the mission of the NHLBI.

For more information on the NHLBI SBIR/STTR programs, visit our website at: https://sbir.nih.gov/nhlbi

Limited Amount of Award

For budgetary, administrative, or programmatic reasons, the NHLBI may not fund a proposal and does not intend to fund proposals for more than the budget listed for each topic.

NHLBI Topics

This solicitation invites proposals in the following areas:

106. Active MRI Needle

Fast-Track proposals will be accepted.

Number of anticipated awards: 2 Phase I, 2 Phase II

Budget (total costs, per contract): Phase I: up to $300,000 for up to 12 months; Phase II: up to $2,500,000 for up to 2 years

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

Summary

Needle access to deep organs is common to numerous catheter, radiological, and surgical procedures, both diagnostic and therapeutic, including access to blood vessels, pericardial and cardiac chambers, viscera, etc.  MRI operation affords exquisite imaging and delineation of soft tissue beyond what is afforded by X-ray fluoroscopy, CT, and ultrasound guidance.  “Passive” needles visualized solely by their materials properties, afford inadequate tracking and visualization into and around precise or precious structures.  “Active” MRI catheter devices contain electronic elements to accomplish MRI visibility.  This solicitation aims to support the development of an active MRI needle tools for commercial clinical availability.

Project Goals

The goals of this project are to develop and obtain market clearance for an active MRI needle to be used in patients.

Phase I Activities and Expected Deliverables

The deliverable is a market-cleared system including active MRI needle and all necessary accessories for MRI-guided active needle access in patients. “Active” refers to visualization by virtue of serving as one or more resonant antennae connected or coupled to the MRI hardware system. 

The deliverable must have the following characteristics

1. Available in a range of sizes as small as 21G and as large as 18G
2. Available in a range of lengths as short as 5cm and as long as 20cm
3. Accommodates guidewires from 0.014” to 0.035” outer diameter for the 21G to 18G embodiments, respectively
4. Luer-type hub connection for syringes
5. Conical hub inside Luer to simplify guidewire insertion
6. Electrical isolation type “CF” for patient safety
7. Free from clinically-important heating during continuous MRI at base magnetic fields up to 1.5T.  
8. Visualized using continuous (“active profiled”) or interrupted (“active marker”) antenna or resonator designs
1. Provides confident certain visualization of the needle tip under the full range of operating conditions.
10. Ergonomic signal transmission system that does not impede mechanical operation of needle (such as a heavy connector cable to the scanner).
11. Accessory capabilities, such as connectors, transmission lines, and/or coil configuration files, as required for operation with MRI systems, at least including the MRI system manufacturer allowing testing by NHLBI DIR (Siemens). This requires evidence of a collaboration agreement with a system manufacturer.
50. Proposals that include novel strategies to mitigate heating of the needle or of transmission lines (connectors to MRI scanner hardware) are encouraged
1000. Proposals for novel visualization strategies are welcomed

A Phase I award would develop and test an actively visualized needle system in vivo.   The contractor should provide a detailed report of pre-IDE interactions with the Food and Drug Administration to identify requirements for premarket notification [510(K)] under Phase II, including the summary of mutual understanding.

The contracting DIR lab is willing to provide feedback about design at all stages of development.  The contracting DIR lab will test the final deliverable device for success in vivo in swine.   This requires specific hardware compatibility with the NIH Siemens Aera 1.5T MRI system.

Phase II Activities and Expected Deliverables

A phase II award would allow testing and regulatory development for the device (described under phase I) suitable for marketing in the United States, whether under premarket notification [510(k)] marketing clearance.  510(k) clearance would constitute the deliverable. 

107. Transcatheter Potts Shunt

Fast-Track proposals will be accepted.

Number of anticipated awards: 2 Phase I, 1 Phase II

Budget (total costs, per award):  Phase I: up to $400,000 for up to 12 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

Pulmonary hypertension of diverse etiologies causes severe symptoms and high mortality rate. Symptoms include inability to exercise, shortness of breath, right-sided congestive heart failure, and sudden death.  New pharmacologic options have significantly prolonged survival in adults with severe pulmonary hypertension.  These therapeutic options have led to nationwide centers of excellence for the care of pulmonary hypertension.  Despite successful pharmacotherapy, the disease progresses in the majority causing progressive right ventricular failure and declining functional status.  Heart-lung transplantation may not be an option.

Potts Shunt (between the left pulmonary artery and the descending thoracic aorta) is a surgical procedure that can divert blood flow to relieve right heart failure in patients with end-stage pulmonary hypertension {J Blanc, N Engl J Med, 2004;350:6, PMID 14762197 }.  It can be offered as a bridge to transplantation or as a destination therapy.  Surgical Potts shunt is morbid and complex.  A catheter-based Potts shunt has been described using commercial off-the-shelf devices, but shortcomings of these devices have caused fatal complications and limited adoption of the technique.

A simplified catheter system for Potts shunt would enable a new therapeutic option for severe or otherwise end-stage patients with severe pulmonary artery hypertension who are refractory to pharmacologic therapy. 

The commercial market is small enough to discourage the early development costs of a transcatheter Potts shunt.  There is a considerable unmet need for a purpose-built non-surgical aorto-pulmonary anastomosis system.

Project Goals

The goals of this project are to develop and test a transcatheter Potts Shunt prototype system in vivo in Phase I, and in Phase II to develop a clinical device and obtain an FDA Investigational Device Exemption for first human testing in the United States.

Phase I Activities and Expected Deliverables

The deliverable is a catheter system to establish a non-surgical Potts shunt (transcatheter pulmonary-to-aortic anastomosis) to treat refractory pulmonary artery hypertension.  

The system includes:

1. Catheter system to allow traversal from donor to recipient blood vessel (typically left pulmonary artery and descending aorta).
2. Catheter traversal system between donor and recipient blood vessel (most likely using transcatheter electrosurgery techniques)
3. A system to establish donor and recipient side-to-side anastomoses, secure from extravasation, in a range of expected anatomies in adults requiring Potts shunt for severe pulmonary artery hypertension.  Proposed solutions should accommodate both adjacent and non-adjacent donor/recipient pairs.
4. Delivery systems are ideally 12 French or smaller
5. Solutions should be sufficiently resistive to allow patient-tailored shunt that balance decompressive flow against excessive shunt causing lower extremity hypoxemia
6. Solutions should not cause hemodynamically significant obstruction in either donor or recipient vessel
7. Solutions must resist inadvertent operator “pull-through” from both donor and recipient vessel
8. Considerable detail should be supplied about the intended mechanical and biological performance of the anastomoses, including resistance to inadvertent separation and pull-through, hemorrhage, thrombosis, neointimal overgrowth, angulation, distortion or failure by patient and cardiovascular motion, and anticipated flow characteristics
1. The implant and the delivery system should be conspicuous under the intended image-guidance modality; MRI compatibility is considered important
10. Solutions must address mural recoil, kinking, and motion throughout the cardiac and respiratory cycles.
11. Preferred solutions could also accommodate growing children by allowing late post-dilatation to adult vessel dimensions (ultimately dilatable to adult size vessels).

Phase I should focus on mechanical and biological performance of the proposed endograft, taking into account mechanical strength required for the application; geometry of the access vessels and geometry and morphology of target vessels; features to accommodate late post-dilatation achieve larger size in growing children, implantation, and visualization strategies.

At the conclusion of phase I, a candidate device design should be selected for clinical development based on in vivo performance of a mature prototype resembling a final design.  The contractor should provide a detailed report of pre-IDE interactions with the Food and Drug Administration to identify requirements for IDE development under Phase II, including the summary of mutual understanding.

The sponsoring NHLBI laboratory may offer to perform a limited number in vivo proof-of-principal experiments in swine (by mutual agreement) to confirm mechanical performance.

Phase II Activities and Expected Deliverables

The specific Phase II deliverables are as described under Phase I.  At the conclusion of phase II, the offeror should submit an investigational device exemption (IDE) for a USA first-in-human research protocol, involving at least 15 subjects.   If the exemption is not granted during Phase II, the offeror must provide an FDA response that indicates the specific deficiencies are limited to Current Good Manufacturing Design Verification and Validation, and that offeror proposed plan would be considered acceptable.  Furthermore, such a deficient application must be accompanied by a plan for Phase IIb funding and matching funding.

The sponsoring NHLBI laboratory may perform a limited number of in vivo proof-of-principal experiments in swine (by mutual agreement). 

NHLBI offers but does not require to perform the clinical trial at no expense to the offeror, to participate in the development of the clinical protocol, and to provide clinical research services.   The vendor is expected to perform or obtain safety-related in vivo experiments and data to support the IDE. 

382. Device System for Transcatheter Repair of Postinfarction Ventricular Septal Defect

Fast-Track proposals will be accepted.

Number of anticipated awards: 1 Phase I, 1 Phase II

Budget (total costs, per award):  Phase I: up to $400,000 for 12-18 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

Postinfarction ventricular septal defect (VSD) is an uncommon but devastating mechanical complication of acute myocardial infarction with extremely high mortality.  Patients already suffering myocardial dysfunction usually die from acute volume overload superimposed on cardiogenic shock.  Surgical repair confers an unacceptably high mortality, and the sole nitinol occluder device currently available under Humanitarian Device Exemption (St Jude Amplatzer Muscular VSD occluder) is highly unsatisfactory (too small, too rigid, too permeable, wrong geometry) and usually unsuccessful.

There is a clear need for a purpose-built device to achieve early occlusion of postinfarction VSD, which could be lifesaving in approximately 2-4000 patients annually.   This market size is too small for the large medical device manufacturers to address, but fortunately is suitable for Humanitarian Device Exemption regulatory pathway.

Project Goals

The goal of the project is to develop a device for percutaneous closure of postinfarction VSD in adults. First a prototype would be developed and tested in animals, and ultimately a clinical-grade device would undergo regulatory development for clinical testing, which NIH DIR offers to assist in performing.

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.

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

Phase I Activities and Expected Deliverables

A phase I award would develop and test a postinfarction VSD occluder prototype.  The NHLBI Division of Intramural Research laboratory may be willing to test the 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:

1. Delivery profile of 12-14 Fr or smaller
2. Suitable for antegrade (transvenous) or retrograde (transarterial) transcatheter delivery
3. Designs must address a range of defect diameters from 20-40mm.  Because these defects are variable and non-uniform, designs are invited that specifically address this heterogeneity, including with non-circular profiles.
4. Designs are invited that are able to accommodate a range of ventricular septal wall  thicknesses
5. Designs are invited to accommodate specific anatomic variations, including postinfarction VSDs at or near the ventricular apex and bordering on the anterior or posterior free wall
6. Designs are invited that are self-centering so that the central portion of the device fills the entire space created by the VSD
7. Devices must be completely repositionable and recapturable without exacerbating myocardial injury
8. Devices must contain a central guidewire port to allow position to be maintained despite retrieval or repositioning
1. Designs are invited that have small, little or no right ventricular disc to avoid interference from right ventricular trabeculation
10. Designs that balance the forces required to assure permanent fixation without tearing necrotic margins, even if retrieved or repositioned
11. Devices must achieve nearly complete hemostasis (obliteration of shunt flow) within two hours or fewer, although immediate hemostasis is preferred.  Most designs will require low-profile hemostatic material within the “left ventricular” and “septal neck” elements of the device.  Because of the risk of hemolysis the designs that impose a “barrier” are preferred over permeable “meshes.”
50. Implants must be MRI compatible so that cardiac function and flow can be measured unimpeded after implantation using MRI, and MRI conspicuity is desirable
1000. Designs having absorbable components are welcomed
14. The implant should have mechanisms or a range of morphologies to avoid heart valve entrapment or distortion
15. Proposals should include specific plans, and device features, to allow operator recovery of the device if it embolizes after release
16. 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 must be kink-resistant under the intended use conditions.
17. The device should accomplish acute or subacute occlusion without early or late thromboembolism, and proposals should specifically address these considerations
18. The system should be accompanied by a proposed robust methodology or device to select the appropriate device size
19. The results of a pre-IDE meeting with FDA CDRH, which indicates a sufficiently mature device and which will guide Phase II.

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

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.  Complete Investigational Device Exemption 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 or an expedited Premarket Approval 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:

1. a device build and short-term survival study to identify additional failure modes
2. 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
3. manufacturing plan
4. iterative ex vivo testing such as animal explants
5. iteration for unexpected design or device failure
6. FDA pre-IDE meeting #1 and #2
7. modeling and fatigue study for chronic implant
8. chronic GLP animal studies
1. 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
10. preparation of IDE
11. submission and resubmission of IDE
50. 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.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) conducts and supports research to expand and disseminate fundamental knowledge about the effects of alcohol on health and well-being, and apply that knowledge to improve diagnosis, prevention, and treatment of alcohol-related problems, including alcohol use disorder, across the lifespan. To learn more about the NIAAA, please visit our web page at https://www.niaaa.nih.gov.

16. A Wearable Alcohol Biosensor that Quantifies Blood Alcohol Concentration in Real Time

Only Fast-Track proposals will be accepted.

Number of anticipated awards: 1-3

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

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

Background

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) seeks a wearable or otherwise discreet device capable of measuring, recording and storing blood alcohol levels in real time. Alcohol biosensors that can be worn discreetly and used by individuals during their daily lives will advance the mission of NIAAA in the arenas of research, treatment, rehabilitation, and recovery.

For example, research that seeks to understand the progression of medical conditions exacerbated by alcohol to discover treatments depends on the ability to accurately measure and record alcohol consumption over time Wearable alcohol biosensors will simplify the process of determining real time (and thus retrospective) alcohol consumption for both the scientists and the participants by providing an objective, biomedical measure of alcohol consumption; allowing participants to avoid the inconvenience and discomfort of having blood drawn at regular intervals.  Likewise, during treatment of individuals with alcohol use disorder (AUD), and especially in clinical trials designed to identify the most effective treatments for AUD, it is essential to know accurately how much alcohol trial participants have consumed to determine the effectiveness of the intervention being studied. The current method of determining alcohol consumption (Time-Line Followback (TLFB)) is cumbersome, time-consuming, relies on retrospective recall and can be highly variable from one interviewer to another. Wearable alcohol biosensors will decrease the assessment variability experienced with the TLFB and increase the rigor and reproducibility of measuring alcohol consumption in clinical trials.  Current technological developments in electronics, miniaturization, wireless technology, and biophysical techniques of alcohol detection in humans increase the likelihood of successful development of a useful alcohol biosensor in the short term.

Objectives

NIAAA seeks the design and production of a wearable device to measure, record, and store blood alcohol levels in real time. The device should be inconspicuous, low profile, and appealing to the wearer. The design can take the form of jewelry, clothing, or any other format located in contact with the human body. A non-invasive technology is preferred.   The detection of alcohol should be passive, real time, and accurate.

Alcohol biosensors that detect consumed alcohol in sweat or sweat vapor have been used in criminal justice settings for a decade or more.  More recently, advances in more discreet wearable alcohol sensing devices has been made; however, these still depend on detection of alcohol in the sweat, rather than in blood. It is important to note that there is a forty-minute to two-hour lag in detection of alcohol in sweat relative to actual blood alcohol levels. Under certain circumstances, this can have significant consequences.  For this reason, this solicitation seeks the development of techniques to quantitate alcohol in blood or interstitial fluid and their incorporation into a wearable device.  Only advances in alcohol detection that depart from measuring alcohol in sweat or sweat vapor will be responsive to this solicitation.   Offerors are encouraged to pursue any technology - including but not limited to- biophysical, optical, wave, or other novel approaches- that works in a non-invasive way and can be incorporated into a wearable. NIAAA recognizes that there are other technologies that also offer promise; so innovative, original approaches to alcohol quantification as well as the adaptation and miniaturization of existing technologies are welcome.

The device should be able to quantitate blood alcohol level, interpret, and store the data or transmit it to a smartphone or other device by wireless transmission.  The device should have the ability to verify standardization at regular intervals and to indicate loss of functionality.  The power source should be dependable and rechargeable.  Data storage and transmission must be completely secure for the protection of the privacy of the individual.  A form of subject identification would be an added benefit.  The device can be removable with the ability record the exact time the device is removed.  Ideally, the device will be stable, with expectation of long term function. The design must be acceptable to the wearer from comfort, privacy, financial, and convenience standpoints. 

It is envisioned that wearable alcohol monitors will serve useful purposes in research, clinical, and treatment settings, may play a role in public safety, and will be of interest in the consumer market to individuals interested in tracking personal health parameters.   Designs may emphasize any of these potential market subsets or may seek to be broadly marketable.   

While achievable lower limits of detection remain to be demonstrated, devices capable of detecting 0.02% BAC would be of value to NIAAA.

To apply for this topic, offerors should:

Include a description of the technology by which the device will quantitate blood alcohol level. Provide preliminary data or cite literature to support the rationale for the underlying approach.  If modifying an existing technology to wearable scale, describe the potential for success of the miniaturization process.   Explanations of data handling should discuss how the device will collect, interpret, store and protect the data or transmit it to a smartphone or other device by wireless transmission and address data security measures. The approach should address the ability to verify standardization at regular intervals and to alert a loss of functionality.  The power source, charging duration, and battery life (if applicable) should be addressed.  

Since wearable alcohol biosensors may be of great benefit to treatment professionals, clinicians, researchers, and individuals, designs may emphasize any of these potential market subsets or may seek to be broadly marketable.  Proposals should identify the intended target audience(s) and provide the rationale for their design decisions regarding both technology and form factor.

This SBIR will not support:

Development or improvement of biosensors that detect alcohol exuded through the skin in sweat or vapor.

Phase I activities and expected deliverables  

• Demonstration of the ability of the technology to detect alcohol.
• Demonstration that the detection signal is proportional to amount or concentration of alcohol.
• Demonstration of the specificity of alcohol detection in blood or a solution approximating the physiological mixture.
• Demonstration of the limit of detection (sensitivity).

While not required, if validation of new or existing technology in human subjects is proposed in the Phase II portion, evidence of the availability of existing clinical infrastructure and knowledge and familiarity with NIH and FDA regulations on human protections must be provided before progression to the Phase II.

As the development of a wearable alcohol biosensor is a priority for NIAAA ((https://www.niaaa.nih.gov/sites/default/files/StrategicPlan_NIAAA_optimized_2017-2020.pdf) and NIH (https://www.nih.gov/sites/default/files/about-nih/strategic-plan-fy2016-2020-508.pdf), NIAAA envisions that the Phase I milestones will be quickly met, leading to rapid advancement to the Phase II period.

Phase II activities and expected deliverables

• Incorporation the alcohol sensor into a discreet, attractive, wearable device in a form factor in contact with the human body.
• Refinements of functionality, accuracy, security, and integration of data collection, data transmission and data storage.
• Further refinement of accuracy of quantitation of blood alcohol concentration.  Development of an algorithm that accurately converts the detection signal to blood alcohol concentration.
• Demonstration that the detection of alcohol is passive, not requiring action on the part of the wearer.
• Demonstration of frequency of measurement.
• Demonstration that the device shows the time of detection and that the BAC value corresponds to the time of measurement.
• Summary of human testing completed.
• Plans for process of manufacture.
• A functional, marketable, wearable alcohol biosensor is the specific deliverable of the Phase II portion of the contract.

17. Data Science Tools for Alcohol Research

Fast-Track proposals will not be accepted.
Number of anticipated awards: 1-2
Budget (total costs, per award): Phase I: up to $225,000 for 6-12 months.

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

Summary

NIAAA supported studies in genomics, imaging, electrophysiology and optogenetics, electronic health records, and personal wearable devices presents new challenges in analyses and interpretations and opportunities for discovery. Data science includes and extends beyond bioinformatics and computational neuroscience to discover new relationships and pathways for complex systems of normal human function and during adaptations due to disorders or disease. The volumes of data produced by NIAAA-supported research, along with publicly available databases and future results, can be analyzed using data science approaches. However, many of the tools needed to answer questions in alcohol research require specific applications, algorithms or toolkits that are not currently available.

 

Project Goal

The goal is to develop data science analysis algorithms, mathematical models, and software tools in alcohol research, integrating data across disciplines and clinical and basic sciences realms.

Phase I Activities and Deliverables

Specific deliverables are:

• New algorithms for integrative analysis of current NIAAA and public ‘big data’ sets, including machine learning, deep learning, artificial intelligence, data mining and other model based and model-free approaches.
• Software applications for data interfaces for aggregation, imputation, harmonization, or visualization of data from multiple sources, including current and future NIH data systems (i.e. NCBI (National Center for Biotechnology Information), dbGaP (database of Genotypes and Phenotypes), National Institute of Mental Health Data Archive), or other studies of alcohol research.
• Algorithms and/or software tools for improving data collection, i.e. smart phone apps, extraction of specific alcohol research parameters from existing large databases and established public health studies, biological sensors or wearable devices.
• Generation and validation of computational and/or systems biology models of alcohol exposure and use on cellular, organ, network, or organism scales.  Multiscale models are appropriate, along with models that include data from clinical and basic science research.

Activities and deliverables are expected to use currently available data sets and databases. The generation of new primary data is not supported by this topic.

 

 

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 https://www.niaid.nih.gov/research/role.

Fast Track proposals will be accepted
Number of anticipated awards: 1-2
Budget (total costs, per award):  Phase I: up to $300,000 for up to one year; Phase II: up to $2,000,000 for up to 3 years

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

Background

Antiretroviral drugs are effective in controlling an HIV infected person’s viral load by inhibiting the fusion of the virus to a CD4 T-cell or inhibiting HIV enzymes such as reverse transcriptase, integrase and protease.  The success of these drugs is dependent on their ability to bind to a reactive site on their target. Attempts to generate small molecule inhibitors to other HIV proteins have been difficult since they lack a reactive site that can bind a small molecule.  This leaves multiple HIV expressed proteins in an infected cell as “undruggable”.  Targeting therapeutics to one or more HIV proteins may be an effective way of shutting down viral replication, preventing cellular transmission and ultimately lead to a sustained viral remission.

Newly developed methods have demonstrated the ability of specially prepared reagents to harness the ubiquitin proteasome system for the degradation of targeted proteins.  Reagents can be prepared to bind specifically to proteins without the need of a reactive site.  This technology can be expanded to HIV expressed proteins in an infected cell and ultimately target them for degradation in the proteasome.  Current strategies which target HIV proteins with a small molecule are limited to the inhibition of a single function.  However, the total elimination of an HIV protein from an infected cell would remove all of its biological functions and provide a more thorough consideration of its importance in HIV infectivity. 

Project Goals

The goal of this contract solicitation is to support the development of reagents that specifically bind to HIV expressed proteins in an infected cell and deliver them to the proteasome for degradation.

Phase I activities may include:

• Designing, optimizing and testing strategies for both targeting HIV proteins and degrading HIV proteins through the ubiquitin proteasome system
• Performing proof-of-concept of HIV protein degradation in cell lines
• Evaluating off-target effects
• Performing proof-of-concept studies in an HIV animal model

Phase II activities may include:

• Optimizing delivery to target HIV infected cells with minimal off target effects
• Evaluating in nonhuman primates’ organ toxicity, immune responses/adverse events and pharmacokinetic/pharmacodynamic parameters
• Performing IND-enabling studies in consultation with the FDA

 

Particle-Based Delivery of HIV Env Immunogens

Fast Track proposals will be accepted Number of anticipated awards: 3-4 Budget (total costs, per award): Phase I: up to $300,000/year for up to 2 years; Phase II: up to $1,000,000 per year up to 3 years

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

Background

A major focus of HIV vaccine research has been the development of immunogens that elicit broadly neutralizing antibody responses targeting the envelope protein (Env). While the field has predominantly focused on immunogen design and soluble antigens, the targeted and controlled delivery of antigens has not received much attention and is a gap in the HIV field that needs to be addressed. Lipid- and polymer-based nanoparticle platforms have been shown to induce HIV-specific antibody and cellular immune responses in animal studies. HIV immunogens delivered via particle-based modalities may elicit better humoral and cellular immune responses. Specifically, multivalent/repetitive antigenic display on particle-based carriers may allow for higher avidity interactions and stimulate a diverse set of B cells. Consequently, such multivalent antigen display may mediate efficient engagement and activation of B cells, promoting stimulation of lower avidity cells from the germline antibody repertoire thereby enhancing affinity maturation resulting in superior antibody responses characterized by improved breadth, potency, and durability. Additionally, the ability of nanoparticles to target specific cells and release antigens in a controlled and sustained manner without the complications of viral vector toxicity and anti-vector immune responses makes nanoparticles a promising alternative to viral vectors. Altogether, for elicitation of potent, protective and durable immune responses, HIV immunogen design and particulate delivery of antigens should remain mutually inclusive and should converge for the development of HIV vaccine candidates capable of effectively inducing B/T-cell activation.

Project Goals

Tailored immunogens (such as Envs, monomers, native and/or native-like trimers, nucleic acids/RNA) combined with effective multivalent antigenic display on nanoparticles for delivery may provide a strategy to promote strong and long-lived neutralizing antibody responses against HIV and direct affinity maturation toward HIV neutralizing antibodies.

Phase I activities may include:

• Engineering, fabricating nanoparticle platforms/systems and approaches (such as synthetic and/or self-assembling and/or covalent chemical attachment of an antigen to a nanoparticle) for delivering existing and/or novel HIV immunogens (such as Envs, monomers, native and/or native-like trimers, nucleic acids/RNA) that can augment HIV vaccine development by way of enhanced presentation, trafficking and targeting the antigen presentation pathway(s) for the induction of broad humoral and cellular immune responses

• Evaluating particulate systems (such as synthetic and/or self-assembling and/or covalent chemical attachment of an antigen to a nanoparticle) that can facilitate co-delivery and/or co-formulation of HIV antigens (such as Envs, monomers, native and/or native-like trimers, nucleic acids/RNA) with licensed or novel adjuvants/TLR agonists

• Developing optimal parameters/conditions for incorporation of HIV antigen(s) in nanoparticulate formulation

• Assessing the effects of modulating particle size, shape, surface properties, composition and modulus/elastic properties of particulate delivery system components on immune responses

• Conducting pre-formulation/formulation studies on particulate antigen combinations to understand the interactions and compatibility of components (excipients, buffers, pH) and effect on antigen epitope integrity and its performance

• Developing assays and test methods to analyze and characterize the particulate-antigen formulations through in vitro (biophysical, physicochemical, binding assays) and/or in vivo testing (small animal studies)

• Developing assays to quantify encapsulation efficiency, immunogen release and expression

• Studying conditions for controlling particle size and size distribution, charge, composition, and aggregation

• Conducting short term stability studies (generate baseline data) on particulated HIV antigen formulations

• Evaluating particulated formulation technologies for fabrication and development of HIV vaccine development;

• Testing for batch-to-batch reproducibility and consistency of particulate formulations for manufacturing, impact of changes in scale, size of the batches

• Conducting studies to evaluate the sterile filterability of particulated formulations and assess the composition of components post sterilization

• Developing an efficient process for early stage/pre-clinical studies, which could be adapted to scale-up studies which can subsequently lead to the production of clinical grade material in conformance with current good manufacturing practices (cGMP)

• Evaluating the immunogenicity and effectiveness of particle-based HIV protein and nucleic acid/RNA vaccine candidates using different co-delivery strategies such as, but not limited to, co-administration, colocalization, encapsulation, surface adsorption of antigens (vs. soluble antigen) in animal models

• Investigating the influence of heterologous prime-boost vaccination strategies on targeting germline B cell activation and maturation

• Investigating the effects of route of immunization, dose, dosage form and dose-sparing capacity of particulate formulations on the particle distribution and kinetics of immunogen immune response

Phase II activities may include:

• Developing lead nanoparticle antigen formulation into an efficient, stable and reproducible process

• Generating a pilot lot and/or scale-up studies based on optimized conditions that can subsequently lead to the production of clinical grade material in conformance with current Good Manufacturing Practices (cGMP)

• Developing cGMP manufacturing processes for developing nanoparticle formulations

• Translating into in vitro studies to proof of concept studies in NHPs, as warranted

• Developing methods to evaluate compositional quality on critical components in nanoparticles. For example, but not limited to, quality, manufacturability and stability/degradation of lipids and related components

• Evaluating the performance, effectiveness, and toxicity of particulated HIV vaccine candidates vs. soluble antigen in small animal models

• Establishing quality assurance and quality control, methodology and development protocols for generation of HIV antigen-adjuvanted formulations for codelivery

 

Co-Delivery and Formulation of Adjuvants for HIV Vaccines

Fast Track proposals will be accepted Number of anticipated awards: 3-4 Budget (total costs, per award): Phase I: up to $300,000/year for up to 2 years; Phase II: up to $1,000,000 per year up to 3 years

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

Background

The RV144 Phase III Thai trial, which tested the heterologous prime-boost combination of two vaccines: ALVAC^{® HIV vaccine (prime) and AIDSVAX® B/E vaccine adjuvanted with Alum (boost), showed limited 31% protective efficacy and revealed the need for novel and more potent vaccine formulations. Co-delivery of adjuvant/immunomodulators with HIV antigens have the potential to modulate the type, quality and durability of antigen-specific immune responses through a variety of mechanisms that include the induction of regulatory T cells or by altering the profile of the pathogenic lymphocyte response (e.g., Th1 to Th2 or vice versa). Significantly, induction of protective and long lasting durable immune responses, activation of germline B cells along with enhanced magnitude and breadth of antibodies that can be harnessed by optimal HIV antigen-adjuvant/immunomodulators/Toll-like receptor agonists (TLR) formulations would aid in the rational design of a safe and effective preventive HIV vaccine. More recent efforts have focused on testing adjuvant formulations that can boost the immune response and generate broadly neutralizing antibodies to HIV-1 Env. Despite these efforts, significant challenges remain towards achieving optimal and effective immunogen/adjuvant formulations for an efficacious HIV vaccine.}

While ongoing new strategies and efforts for developing effective HIV vaccine have predominantly focused on design of new HIV immunogens and targets, an understudied area of investigation is with studies involving co-delivery and formulation of HIV immunogens with adjuvants. As such, several challenges remain, including poorly understood and variable humoral and cellular immune responses in preclinical and clinical setting, lack of consistent tier 2 broadly neutralizing antibodies (nAbs); maintenance of Env immunogenicity; selection of optimal inoculation sites and trafficking to lymphatics; stability of the incorporated and/or co-delivered antigens and Env neutralizing epitopes in select adjuvant formulations; induction of mucosal immunity and long-term maintenance/durability of the immune response. Moreover, access to promising new/proprietary adjuvant systems developed by commercial organizations, development of effective combination of adjuvant formulations and public-private partnership is highly desirable and warranted for HIV vaccine development. While alum-based adjuvants and variations of oil-in-water approaches have been tested with other non-HIV recombinant protein immunogens, the results obtained from other immunogens, which are generally more stable and less glycosylated than Env protein, have been difficult to extrapolate to HIV vaccines. Finally, the empirical basis of studies and the large inter-laboratory variations in antigen/adjuvant mixture formulations and protein stability assays used to characterize these mixtures further limits the usefulness of these data for HIV vaccine research.

Project goals

Co-delivery of adjuvants with antigens coupled with immunogen design are not mutually exclusive and should converge to accelerate the development of safe and effective adjuvanted HIV vaccine candidates that are capable of effective B/T-cell activation, enhanced antibody avidity or broadening of effector immune responses while minimizing reactogenicity and preserving the protective immune responses against HIV. The primary goal of this contract solicitation is to support, accelerate and advance early stage and/or pre-clinical development and optimization of a promising HIV antigen-adjuvant formulation or select combination-adjuvant(s) for co-delivery/co-administration for a preventative HIV vaccine.

Phase I activities may include:

• Developing optimal parameters/conditions for HIV protein antigen(s) and adjuvant co-formulations

• Evaluating formulations with immunomodulatory agents such as mineral salts, microbial products, emulsions, cytokines, chemokines, polymers, liposomes, saponins, carbohydrate adjuvants, TLR agonists etc.

• Developing, harmonizing all relevant analytical assays and testing methods for physicochemical, biophysical and functional/potency characterization of antigen-adjuvant formulations and its individual components, as applicable

• Evaluating and screening compatibility of excipients, buffers, pH on adjuvanted antigen formulations and its performance

• Measuring the effects of these interactions using critical in vitro performance metrics and quality attributes related to vaccine adsorption, desorption, potency, antigen integrity and stability

• Developing and optimizing novel adjuvant combinations by admixing previously known individual adjuvants, including characterization of adjuvant combinations previously shown to enhance immune responses synergistically and/or additively

• Evaluating conditions for vaccine presentation as a two-vial system with bedside mixing and/or one vial co-formulation of adjuvanted antigen

• As appropriate, evaluating and comparing different adjuvanted formulations in small animal models, assess the influence of route of administration, delivery and dose-sparing capacity of HIV antigen-adjuvanted vaccines on the kinetics of immune response

• Conducting short term stability studies to generate baseline data on antigen-adjuvant formulations

• Testing for batch-to-batch reproducibility and consistency of adjuvanted formulations for manufacturing

Phase II activities may include:

• Developing lead antigen-adjuvant formulation into an efficient, stable and reproducible formulation process

• Generating a pilot lot and/or scale-up studies based on optimized conditions that can subsequently lead to the production of clinical grade material in conformance with current Good Manufacturing Practices (cGMP)

• cGMP manufacturing processes for developing adjuvanted formulation

• Evaluating the performance, effectiveness, and toxicity of adjuvanted HIV vaccine candidates vs. soluble antigen in small animal models

• Evaluation of adjuvants in NHP studies

• Establishing quality assurance and quality control, methodology and development protocols for generation of HIV antigen-adjuvanted formulations for co-delivery

• As appropriate, collaborate and/or partner with different labs to harmonize inter-laboratory variations in antigen/adjuvant mixture formulations and for characterization and protein stability assays

 

Effective Targeted Delivery of RNA-based Vaccines and Therapeutics

Fast Track proposals will be accepted Number of anticipated awards: 1-2 Budget (total costs, per award): Phase I: up to $300,000 for up to 1 year; Phase II: up to $2,000,000 for up to 3 years

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

Background

RNA-based vaccines and therapeutics have emerged as great promise for HIV prevention and treatment, respectively. However, many obstacles still need to be overcome, in particular RNA instability, manufacturing problems, and clinically relevant delivery mechanisms of RNA into target cells. RNA vaccine approaches have some advantages in relation to other vaccine technologies; they can be delivered directly into the cytoplasm and do not require nuclear localization to generate expression. Improvements of methods for mRNA synthesis and stabilization and development of improved self-amplifying RNAs have recently yielded promising results. RNA approaches also stimulate the host’s innate defense system, in part through activation of the TLR pathways that recognize single and double stranded RNAs. Furthermore, RNA-based therapeutics have shown the potential to silence HIV effectively upon direct transfection in vitro, but delivery into cells in vivo is still unsatisfactory. Vector-based (lentivirus, adeno-associated virus) delivery to quiescent cells has proven inefficient, and the vectors themselves pose a risk to the host. To enhance stability and to confer vehicle-free delivery, RNA-based drugs have been chemically modified to improve their properties. Progress was also made in chemical-based delivery strategies, e.g., liposomes, molecular-sized chemical conjugates, and supramolecular nanocarriers. An additional advantage is that RNA can be produced in vitro in a cell-free manner, avoiding safety and manufacturing issues associated with cell culture. Despite these advances, nucleic acids per se are relatively large, negatively charged polymers, and significant clinical challenges from the standpoint of delivery to cells still persist.

Project Goals

The primary goal of this contract solicitation is to encourage small businesses to develop improved platform technologies for the delivery of RNA into specific cells and tissues to improve the efficacy of HIV vaccines or therapeutics. Examples of HIV RNA vaccines include, but are not limited to mRNA and self-amplifying RNAs. Examples of RNA therapeutics include small interfering RNA (siRNA), microRNA (miRNA), microRNA antagonists, aptamers, messenger RNA (mRNA), splice-switching oligonucleotides, antisense oligonucleotides, and plasmid or other circular DNAs encoding messenger RNAs and transcription regulatory sequences. To enhance the efficacy of traditional HIV vaccines and therapeutics, combinations of cytokines, adjuvants, broadly neutralizing monoclonal antibodies, immune checkpoint inhibitors, etc. can also be co-delivered in mRNA form. The short-term goal of this project is to perform feasibility studies for the development and use of delivery mechanisms for RNA-based HIV vaccines and therapies. The long-term goal of this project is to enable a small business to bring fully developed delivery systems for RNA-based HIV vaccines and therapies to the clinic and eventually to the market.

Phase I activities may include:

• Design and test in vitro small-scale delivery strategies for RNA-based HIV vaccines or therapeutics, including exosomes, nanoparticles, liposomes, viral vectors, condensates, carriers, or delivery devices

• Assess potency and stability of RNA-based HIV vaccines or therapeutics.

• Improve RNA stability through chemical modifications

• Perform proof-of-concept HIV animal model studies for assessment of organ toxicity, HIV immune responses, innate immune responses (e.g., Toll-like receptor activation), and pharmacokinetic/pharmacodynamic studies, if applicable

• For RNA-based therapeutics: o Evaluate off-target effects in cell lines and primary PBMC.

o 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: o Test improved delivery mechanism for efficacy and mechanism of action in animal models of HIV

• For RNA-based therapeutics: o 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.

 

Methods Improving HIV Protein Expression: Cell Substrate and Protein Purification

Fast Track proposals will be accepted Number of anticipated awards: 3-4 Budget (total costs, per award): Phase I: up to $300,000 for up to 2 years; Phase II: up to $1,000,000 per year up to 3 years

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

Background

There is an urgent need to have multiple HIV envelope immunogen components for use in HIV vaccine clinical studies. Results of the RV144 vaccine clinical trial indicated that antibody responses to the gp120 Env proteins were the major components of the vaccine that contributed to the efficacy signal. In addition, the discovery of both broad and potent neutralizing antibodies against the HIV envelope in HIV infected individuals, provides additional evidence that the human immune system can respond effectively to the HIV envelope and so envelope could be the major component of an effective HIV vaccine.

Results of contract manufacturing organizations (CMOs) efforts to produce envelope proteins using pre-existing platforms developed for Chinese hamster ovary (CHO)-based monoclonal antibody production have been disappointing. Despite the widespread use of GMP-established pharma cell substrates (e.g., CHOs, 293 etc.) in development of monoclonal antibodies and recombinant protein antigens, critical bottlenecks still exist in their use for large-scale, high-yield GMP manufacturing of HIV protein antigens. For example, the use of CHO-based protein expressions systems previously used for the generation of monoclonal antibodies (mAbs) have resulted in significantly lower yields of HIV envelope proteins (100-1000x fold lower) compared to mAb expression (mgs/l of envelope product compared to the typical g/l yield of mAb). Additional limitations relate to their intrinsic incapacities to metabolically express high levels of stable, properly folded and glycosylated recombinant HIV Env protein; often times requiring extensive clonal screening to identify the rare high-level producer clone.

Beyond issues of primary yield of the expression system, traditional downstream purification processes for HIV Env purification are equally plagued with inefficiencies due to multi-step purification cycles resulting in low yields. As a result, subsequent purification schemes for mAbs are not readily transferrable to HIV envelope purification and often result in 80-90% losses of envelope material. Moreover, purification schemes developed for one HIV envelope are not necessarily suitable for another HIV envelope due to the potentially large differences in post-translational modifications. While, monoclonal antibodies may be able to withstand harsh viral clearance procedures, whereas HIV envelopes which are more sensitive glycoproteins may not be able to sustain the harsh viral clearance procedures.

These constraints have a cascading effect in increasing the overall cost and time for production of HIV vaccine antigens from millions of dollars and years of upstream and downstream process development. These problems demonstrate the need for new approaches to enhance and expedite the screening, production and purification of HIV envelope protein candidates. As such, there is an urgency to evaluate alternative strategies and technologies capable for developing highly productive cellular substrates suitable for high yield GMP manufacturing of HIV antigens and reduced product development lead times.

Project Goals

The goal of this contract solicitation is to support research to improve the expression yield in a specific cell culture system (i.e. CHO), and the purification yield using specific purification regimens designed for HIV envelope protein suitable for use as clinical immunogens. Projects may focus on any step of envelope expression and yield, improvement of substrates (i.e. CRISPR/Cas9 editing, siRNA delivery and gene silencing) by evaluating and modulating the molecular pathways involved in regulating and enhancing HIV envelope/antigen expression in mammalian cell lines. The projects may also focus on development of purification platforms.

Phase 1 activities may include:

• Improving HIV Env protein expression in existing cell substrates or development of novel cell substrates should be explored through the following approaches: improving existing cell substrates o altering codon usage

o targeting host cells genes that increase expression

o improved expression cassettes for the recombinant protein and novel selection marker genes

o identifying auxiliary proteins essential for protein production, modifying components of secretory and processing pathways, enhancement of cellular processes (e.g. chaperonins)

o functional phenotypic screening

o enhancement of transcription or of evaluating mRNA sequence and structure

o alteration of epigenetic targets

o methodologies to alter post-translational modifications including glycosylation or disulfide composition, and secreted protein

o the production of intracellular, membrane-associated, or secreted protein.

 

• Improving existing cell substrates o by removal of deleterious proteases,

o addition of enzymes involved in glycosylation

o removal of deleterious proteases

o alteration in epigenetic targets

 

• Using of functional genomics to identify gene function and editing. Focusing on siRNA technologies and delivery methods into cell substrates coupled with high throughput screening and analytics, modulation of gene function, expression, regulation and mutation of target cell. Evaluating newer technologies such as CRISPR/Cas9 targeted gene editing stimulating genetic modifications to prepare productive stable cell lines will also be evaluated.

• Evaluating transient transfection/gene expression technologies to support and accelerate phase appropriate manufacturing

• Developing and improving HIV envelope protein purification methodologies including (but not limited to), affinity purification approaches and/or other highly novel strategies;

• Developing analytical assays and testing methods for characterization, identification, quantitation of expressed product during cell line development

• Establishing conditions for removal of host cell protein clearance, endogenous retroviruses (viral inactivation and clearance).

• Developing research cell bank

• Testing and characterizing cell lines and evaluating quality attributes/metrics prior to advancing the cell substrate and processes to GMP scale

• Establishing conditions for removal of host cell protein clearance, viral inactivation and clearance.

Phase 2 activities may include:

• GMP development and manufacturing lead cell substrates (e.g., Master Cell bank generation)

• Translating and scaling-up of process development activities including downstream purification unit operations to GMP setting

 

Reagents for Immunologic Analysis of Non-mammalian and Underrepresented Mammalian Models

Fast-Track proposals will be accepted Number of anticipated awards: 3-5 Budget (total costs, per award): Phase I: up to $300,000/year for up to 2 years; Phase II: up to $1,000,000/year with appropriate justification by the applicant for up to 3 years

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

Background:

This goal of this program is to address the limited availability of reagents (e.g., antibodies, proteins, ligands) for the identification and discrimination of immune cells and the characterization of immune responses in non-mammalian models (e.g., arthropods, amphibians, fish, nematodes, marine echinoids) and mammalian models for which immunologic reagents are limited (e.g. guinea pig, ferret, cotton rat).

Non-mammalian models are easily tractable model systems to study basic, conserved immune defense pathways and mechanisms. For example, characterization of the Drosophilia Toll signaling pathway facilitated the discovery of mammalian Toll-Like Receptors (TLR), which helped to launch the field of innate immunity. Non-mammalian models can be much more easily adapted to high-throughput screening formats than mammalian organisms. Caenorhabditis elegans has been used for whole organism high-throughput screening assays to identify developmental and immune response genes, as well as for drug screening. Many non-mammalian species are natural hosts for human pathogens and share many conserved innate immune pathways with humans, such as the Nf-B pathway in mosquitoes, the intermediate hosts for Plasmodia parasites. However, studies to better understand immune regulation within non-mammalian models have been constrained by the limited availability of antibodies and other immune-based reagents for use in scientific studies.

There are certain mammalian models that display many features of human immunity but are similarly underutilized due to the limitations noted above. For example, the progression of disease that follows infection of guinea pigs with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), displays many features of human TB. While this model has been used for more than 100 years as a research tool to understand and describe disease mechanisms, immunologic analyses are constrained by the limited availability of immunological reagents specific for the guinea pig. Another example is the ferret model, one of the best animal models of human influenza infection, where immunologic studies also have been limited by the lack of immunological reagents.

Project Goal:

Development and validation of reliable antibodies and reagents for the identification and tracking of primary immune cells and/or the analysis of immune function/responses (e.g. cytokines, chemokines, intracellular signaling) in non-mammalian models and underrepresented mammalian models.

Phase I Activities must include at least the following 2 activities:

•Identification of immune cell markers, receptors with immune function, and other molecules important for immune function; and

•Development of antibodies and/or other reagents against these targets.

Phase II Activities include, but are not limited to:

•Validation of antibodies/reagents.

•Screening for cross-reactivity with related molecules on other non-mammalian species and/or mammalian immune cells.

•Scale-up production.

This SBIR Topic will not support:

•Identification of immune target molecules and development of antibodies/reagents against immune markers or molecules specifically for mice, rats, dogs, non-human primates or humans.

•Development of antibodies/reagents not involved in immune responses.

•Development of novel or refined animal models

 

B Cell Receptor and T Cell Receptor Repertoire Computational Tools

Fast-Track proposals will not be accepted Number of anticipated awards: 1-3 Budget (total costs, per award): Phase I: up to $450,000 for up to 2 years;

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

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

Background:

Antigen specificity is a fundamental feature of adaptive immunity, underlying immune homeostasis and control of infection by pathogens in higher vertebrates. B cells and T cells form the two arms of the adaptive immune system, each expressing antigen-specific receptors, B cell receptors (BCR) and T cell receptors (TCR), respectively. Previously, the characterization of receptor sequence repertoires relied on low-resolution approaches, but with the advent of high-throughput sequencing, it has become possible to characterize the receptor repertoires at unprecedented depth. Subsequently, receptor repertoire sequences profiling has become an important part of basic and clinical immunology research, including vaccine design and monitoring responses to therapy.

Project Goal:

The goal of this program is to support the development of computational tools to accelerate the analysis of B cell receptor and T cell receptor repertoire sequence data. These tools should improve the ability to collect, compile and compare receptor sequence data for analysis and comparison across cell-types and infectious and immune-mediated diseases. A secondary goal is to facilitate the connection between receptor repertoire patterns and antigen or epitope prediction. Tools generated should have demonstrated utility to compile and interrogate data available to the public, such as NCBI’s Single Read Archive, but may also demonstrate use for other publicly available sources of data.

Phase I Activities include, but are not limited to:

• Development of computational tools to organize and interrogate receptor sequence data available in existing public databases.

• Development of computational tools to correlate receptor sequence to antigen identity.

Phase II Activities include, but are not limited to:

• Validation of computational tools to correlate receptor sequence to antigen identity.

• Validation of computational tools to interrogate receptor sequence data in public databases.

This SBIR will not support:

• Any phase clinical trial.

• Proposals focused exclusively on animal studies and animal disease models.

• Studies that do not fall within NIAID mission.

 

Development of Sample Sparing Assays

Fast-Track proposals will not be accepted

Number of anticipated awards: 1-3 Budget (total costs, per award): Phase I: up to $150,000 for up to 6 months; Phase II: up to $1,000,000 for up to 2 years

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

Background

The NIAID’s Division of Allergy, Immunology and Transplantation (DAIT) supports a wide range of research programs spanning basic immunology, translational and clinical research on protective immunity and immune-mediated diseases, including autoimmune and primary immunodeficiency diseases, allergic diseases, graft-versus host disease (GVHD) and allograft rejection in organ, tissue and cell transplantation. Major constraints encountered in designing mechanism of action studies are related to limited quantity of biological specimens available for study and the paucity of robust, validated, miniaturized assays that can reliably and reproducibly assess immune function, disease state or effects of therapy. The restricted amounts of tissue, cells and fluids that can be collected from adult, pediatric or immunocompromised patients are often inadequate for the application of conventional assays that interrogate immune function. Novel, multi-parameter, sample sparing assays are needed to obtain maximal biologic information from limited amounts of biological materials.

Project Goal

The goal of this proposal is to accelerate commercial development of novel, standardized sample sparing assays that improve monitoring of the immune system using limited amounts of biological sample. Sample sparing immune assays of interest may include, but are not limited to monitoring or assessments of the following:

• Antigen-specific immune responses

• Distinct immune cell populations

• T-cell and B-cell regulatory networks

• Innate immune responses

• Markers of T-cell turnover and homing to lymphoid tissue

• Cytokine and signaling networks

• Gene and protein expression and regulation

• Mucosal inflammatory and innate immune response

Technologies that address novel sample preparation or cell isolation processes are also included in the areas of interest for this announcement.

The sample sparing assays developed through this funding opportunity must address challenges, gaps or unmet needs in the study of human immune responses and provide clear advantages over existing assays.

Phase I Activities

Depending on the developmental stage of the sample sparing assay the offeror may choose to perform one or more of the following:

• Preliminary studies performed in a suitable animal model or in human samples to evaluate the assay feasibility (scientific and technical)

• Establish assay’s quality of performance, assay reproducibility and validation

• Define process controls

• Establish potential for commercialization

Phase II Activities

• Further technology developments and assay improvements

• Development and validation of prototype platforms

• Development of quality control program to enable longitudinal measurements in compliance with Good Clinical Laboratory Practice

 

This SBIR Topic will not support:

• Any phase clinical trial

• Identification of new biomarkers

• Validation of biomarker candidates

• Proposals focused exclusively on animal studies and animal disease models. Animals may be used in assay development phase but all assays must be validated using primary human samples

• Development of assays using established cell lines without validation in primary human samples

• Virus-induced cancers

• Studies that do not fall within NIAID mission

 

Adjuvant Discovery for Vaccines and for Autoimmune and Allergic Diseases

Fast-Track proposals will be accepted Number of anticipated awards: 1-3 Budget (total costs, per award): Phase I: up to $300,000/year for up to 2 years; Phase II: up to $1,000,000/year for up to 3 years

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

Background:

The goal of this program is to support the screening for new vaccine adjuvant candidates against infectious diseases or for tolerogenic adjuvants for autoimmune or allergic diseases. Traditionally, adjuvants are defined as compounds that stimulate innate and/or adaptive immune responses. The goal of this program is to support the discovery of novel vaccine adjuvants as well as adjuvants with tolerogenic properties. For the purpose of this SBIR, vaccine adjuvants are defined according to the U.S. Food and Drug Administration (FDA) as "agents added to, or used in conjunction with, vaccine antigens to augment or potentiate (and possibly target) the specific immune response to the antigen." Tolerogenic adjuvants are defined as compounds that promote immunoregulatory or immunosuppressive signals to induce non-responsiveness to self-antigens in autoimmune diseases, or environmental antigens in allergic diseases.

Currently, only four 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; MPL and QS-21 combined in a liposomal formulation for a varicella vaccine; and the oil-in-water emulsion MF59 as part of the FLUAD influenza vaccine for people age 65 years and older. The gaps that need to be addressed by new adjuvants include improvements to existing efficacious vaccines (e.g., the acellular pertussis vaccine), and development of vaccines: for emerging threats (e.g., Ebola outbreaks); for special populations that respond poorly to existing vaccines (i.e., elderly, newborns/infants, immunosuppressed patients); or to treat/prevent immune-mediated diseases (e.g., allergic rhinitis, asthma, food allergy, autoimmunity, transplant rejection). Recent advances in understanding innate immunity have led to new putative targets for vaccine adjuvants and for allergen immunotherapy. Simultaneously, progress is slowly being made in the identification of in vitro correlates of clinical adjuvanticity which allows the design of in vitro screening assays to discover novel adjuvant candidates in a systematic manner.

The field of tolerogenic adjuvants is still in its infancy. No compounds have been licensed yet in the US and immune-mediated diseases continue to be treated mostly with broadly immunosuppressive drugs or long-term single or multi-allergen immunotherapy. In contrast to drugs, tolerogenic (or immunomodulatory) adjuvants would interfere with immune responses to specific antigens through a variety of mechanisms which include the induction of regulatory T cells, or by changing the profile of the pathogenic lymphocyte response (e.g., Th1/Th2/Th17, etc). The combination of tolerogenic adjuvants with allergen immunotherapy should aim at accelerating tolerance induction, increasing the magnitude of tolerance and decreasing the duration of treatment.

Project Goal:

The objective of this program is to support the screening for new adjuvant candidates for vaccines against infectious diseases or for autoimmune and allergic diseases; their characterization; and early-stage optimization.

Phase I Activities include, but are not limited to:

• Optimize and scale-up screening assays to identify new potential vaccine- or tolerogenic adjuvant candidates

• Create targeted libraries of putative ligands of innate immune receptors

• Pilot screening assays to validate HTS approaches for identifying adjuvant candidates

• Develop in silico screening approaches to pre-select adjuvant candidates

Phase II Activities include, but are not limited to:

• High-throughput screening of compound libraries and confirmation of adjuvant activity of lead compounds

• Confirmatory in vitro screening of hits identified by HTS or in silico prediction algorithms

• Optimization of lead candidates identified through screening campaigns through medicinal chemistry and/or formulation

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

 

Adjuvant Development for Vaccines and for Autoimmune and Allergic Diseases

Fast-Track proposals will be accepted Number of anticipated awards: 1-3 Budget (total costs, per award): Phase I: up to $300,000/year for up to 2 years; Phase II: up to $1,000,000/year for up to 3 years

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

Background:

Adjuvants stimulate innate and/or adaptive immune responses. For the purpose of this SBIR, vaccine adjuvants are defined according to the U.S. Food and Drug Administration (FDA) as "agents added to, or used in conjunction with, vaccine antigens to augment or potentiate (and possibly target) the specific immune response to the antigen". Tolerogenic adjuvants are defined as compounds that promote immunoregulatory or immunosuppressive signals to induce non-responsiveness to self-antigens in autoimmune diseases, or environmental antigens in allergic diseases. Currently, only four 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; MPL and QS-21 combined in a liposomal formulation for a varicella vaccine; and the oil-in-water emulsion MF59 as part of the FLUAD influenza vaccine for people age 65 years and older. Additional efforts are needed to more fully develop the potential capabilities of promising adjuvants, particularly for special populations such as the young, elderly and immune-compromised. In addition, adjuvants may facilitate the development of immunotherapeutics for immune-mediated diseases, such as allergen immunotherapy to treat/prevent immune-mediated diseases (e.g., allergic rhinitis, asthma, food allergy, autoimmunity, transplant rejection). The field of tolerogenic adjuvants is still in its infancy. No compounds have been licensed yet in the US and immune-mediated diseases continue to be treated mostly with broadly immunosuppressive drugs or long-term single or multi-allergen immunotherapy. In contrast to drugs, tolerogenic or immunomodulatory adjuvants would interfere with immune responses to specific antigens through a variety of mechanisms which include the induction of regulatory T cells, or by changing the profile of the pathogenic lymphocyte response (e.g., Th1 to Th2 or vice versa). The combination of tolerogenic adjuvants with allergen immunotherapy should aim at accelerating tolerance induction, increasing the magnitude of tolerance, and decreasing the duration of treatment.

Project Goal:

The goal of each project is to accelerate pre-clinical development and optimization of a single lead adjuvant candidate or a select combination-adjuvant for prevention of human disease caused by non-HIV infectious pathogens, or for autoimmune or allergic diseases. For this solicitation, a combination-adjuvant is defined as a complex exhibiting synergy between individual adjuvants, such as: overall enhancement or tolerization of the immune response depending on the focus and nature of the vaccine antigen; potential for adjuvant-dose sparing to reduce reactogenicity while preserving immunogenicity or tolerizing effects; or broadening of effector responses, such as through target-epitope spreading or enhanced antibody avidity. The adjuvant products supported by this program must be studied and further developed toward human licensure with currently licensed or new investigational vaccines, and may not be developed as stand-alone agents.

 

Phase I Activities:

Depending on the developmental stage at which an adjuvant is entered into the Program, the offeror may choose to perform one or more of the following:

• Optimization of one candidate compound for enhanced safety and efficacy. Studies may include: o Structural alterations of the adjuvant or modifications to formulation; or

o Optimization of heterologous prime-boost-regimens.

• Development of novel combinations of previously described individual adjuvants, including the further characterization of an adjuvant combination previously shown to enhance or tolerize immune responses synergistically.

• 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 or tolerizing efficacy of a lead adjuvant:vaccine.

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

Phase II Activities

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

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

• Pilot lot or cGMP manufacturing of adjuvant or adjuvant:vaccine.

• Advanced formulation and stability studies.

• Toxicology testing.

• Establishment of quality assurance and quality control protocols.

• Pharmacokinetics/absorption, distribution, metabolism and excretion studies.

This SBIR Topic will not support:

• The further development of an adjuvant that has been previously licensed for use with any vaccine.

• The conduct of clinical trials (see Appendix H.1 for the NIH definition of a clinical trial).

• The discovery and initial characterization of adjuvant candidates.

• The development of adjuvants or vaccines to prevent or treat cancer.

• Development of platforms, such as vehicles, or delivery systems that have no immunostimulatory or tolerogenic activity themselves.

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

Fast-Track proposals will be accepted Number of anticipated awards: 1-2 Budget (total costs): Phase I: up to $300,000 for up to 1 year; Phase II: up to $1,500,000 for up to 3 years

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

Background:

The capabilities inherent in smartphones represent a largely untapped opportunity to improve point-of-care (POC) diagnostics for infectious diseases in low resource settings (LRS), where laboratory equipment is scarce and infrastructure is often unreliable. Smartphone features that could be adapted to enhance POC diagnostics include fast computing power, internet connectivity, geo-positioning, a high-quality camera, and long-lasting power/batteries. Smartphones have the potential to increase POC diagnostic sensitivity and specificity through machine-interpreted results; reduce operator error by ensuring accurate collection of data and relevant metadata; and improve analysis and stewardship of results through remote analysis and data storage. Further development of novel technologies, computational tools, and algorithms is needed to transform smartphones into platforms capable of improving POC diagnostic performance, interpretation of results, and data transmission.

Project Goals:

The goal of this solicitation is to develop both i) a low cost, rapid, easy-to-use, smartphone-compatible, infectious disease POC diagnostic for use in LRS; and ii) computational tools and algorithms necessary to effectively link the diagnostic test to the smartphone and achieve enhanced performance. The final products should be independent of smartphone manufacturer and operating system, and a physical connection between the test and the smartphone is not required. Algorithms should at a minimum capture all information needed to use, read, and interpret the test (for example in a 2D barcode), as well as provide verification that the test was run correctly. Ideally, the diagnostic test time from sample to answer should be one hour or less including sample processing. Stability of assay reagents at room temperature is preferred.

The development of a smartphone-compatible POC diagnostic and all associated technologies, computational tools and algorithms that address the following research areas are of particular interest:

• Improved sensitivity and reduced time to diagnosis for tuberculosis

• Improved sensitivity for malaria diagnosis

• Ability to accurately distinguish between influenza and other respiratory pathogens

• Ability to accurately distinguish between bacterial and viral pneumonia

• Detection of onchocerciasis (river blindness) adult worms

Phase I activities may include:

• Development of a smartphone-compatible, low cost, field-portable, rapid POC diagnostic

• Development of a functional software prototype to enhance the performance of the POC diagnostic

• Integration of the diagnostic assay and the smartphone without requiring high cost adapters, and independent of the smartphone manufacturer

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

• Confirmation that accuracy is sufficient to allow clinically relevant results

• Demonstration of software capabilities to ensure accurate data collection, identify failure modes, interpret and share results in a secure environment

• Performance of initial testing on laboratory isolates

Phase II activities may include:

• Further optimization of the smartphone-linked assay platform technology and validation of assay reproducibility

• Testing of de-identified clinical samples from diverse cohorts with varying levels of infection

• Evaluation, revision, and enhancement of the software prototype

• Performance of software beta testing with relevant end users

This SBIR Topic will not support:

• The development of a prototype POC diagnostic alone without the associated technologies, computational tools and algorithms required to integrate with a smartphone

• The design and conduct of clinical trials (see Appendix H.1 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.

 

Development of POC Assays to Quantify anti-Tuberculosis Antibiotics in Blood

Fast-Track proposals will be accepted Number of anticipated awards: 1-2 Budget (total costs, per award): Phase I: up to $300,000/year for up to 1 year; Phase II: up to $1,500,000/year for up to 3 years

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

Background:

Tuberculosis (TB) is currently the leading infectious cause of death worldwide. TB treatment includes multiple different combinations of antibiotics, doses, and long time periods depending on whether TB is classified as drug-sensitive or drug-resistant. Moreover, therapy is often modified due to factors such as identification of antibiotic resistance, drug-induced toxicity, treatment failure, antibiotic availability, etc. Rapid determination of blood antibiotic concentrations in the clinical laboratory using technologies that do not require sophisticated equipment would allow clinicians to monitor antibiotic concentrations during treatment and allow for dose adjustments to increase efficacy. This would prevent or reduce the development of resistance, treatment failure, and antibiotic induced toxicity and could improve patient survival. Currently, TB antibiotic concentrations are measured only in highly specialized laboratories using expensive instruments, making regular monitoring of antibiotic blood concentrations essentially impractical in the global clinical field.

Project goal:

The goal of this project is to develop a rapid POC test to quantify TB antibiotic blood concentrations. Desired outcomes include a portable device (e.g. sensors, readers, etc.) requiring a small blood sample (e.g. strips, capillary tubes, etc.) that will provide consistent rapid readouts during the patient’s visit (less than 1 hour).

Phase I activities may include:

• Development of a prototype POC test to quantify TB antibiotic concentrations.

• Optimization of the POC test to quantify concentrations for multiple antibiotics in one sample simultaneously.

• Evaluation of the POC test to reliably quantify antibiotic concentrations directly from total blood and/or plasma.

 

Phase II activities may include:

• Determination of validity, sensitivity, and specificity of the POC test.

• Optimization of POC test characteristics, such as portability and development of operator manual.

• Evaluation and determination of the stability of the POC test kit (e.g. shelf life, storage conditions, etc.)

• Scale-up manufacturing of POC test kits.

This SBIR will not support:

• The design and conduct of clinical trials (see Appendix H.1 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.

 

POC Diagnostic for Gonorrhea and Determination of Antimicrobial Susceptibility

Fast-Track proposals will be accepted Number of anticipated awards: 1-2 Budget (total costs, per award): Phase I: up to $300,000 for up to 1 year; Phase II: up to $1,500,000 for up to 3 years

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

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Background:

There are over 450,000 cases of gonorrhea reported in the U.S. annually. Of particular concern is that the causative agent, Neisseria gonorrhoeae, is naturally competent and easily acquires resistance to antimicrobials. The U.S. Centers for Disease Control and Prevention changes the recommendation for the treatment of gonorrhea when surveillance data indicate ≥5% resistance to the class of antimicrobial being used at the time. Over the last several decades this change has been implemented numerous times, such that the cephalosporins are the last class of antimicrobials left to treat gonorrhea. Cephalosporin resistance is increasing worldwide, and the loss of this antibiotic as a treatment option would make gonorrhea clinically untreatable. However, since treatment recommendations are based on ≥5% resistance, it is clear that the vast majority of circulating isolates are still sensitive to previously-recommended classes of antimicrobials. Re-introduction of these classes of antimicrobials into clinical use would allow for the continued successful treatment of gonorrhea even if cephalosporin resistance becomes widespread. In order to best select the appropriate and most effective therapy, clinicians need real-time antimicrobial sensitivity tests to characterize phenotypes of infecting N. gonorrhoeae strains.

Project goal:

The goal of this project is to develop a rapid (≤ one hour) point-of-care diagnostic capable of: i) identifying N. gonorrhoeae; and ii) determining the infecting strain’s susceptibility to at least three classes of antibiotics (e.g. quinolones, macrolides, etc.) directly from the patient sample (e.g. urine, urethral/vaginal/cervical swab).

Phase I activities may include:

• Development of a prototype product that demonstrates the rapid determination of the antimicrobial susceptibility profile of one or more N. gonorrhoeae isolates

• Integration of platform to rapidly identify N. gonorrhoeae and antimicrobial susceptibility

• Development of sample preparation methods consistent with the product platform

Phase II activities may include:

• Integration of platform to rapidly identify N. gonorrhoeae and antimicrobial susceptibility

• Development of sample preparation methods consistent with the product platform

• Further development of the prototype product to determine performance characteristics

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

This SBIR Topic will not support:

• The design and conduct of clinical trials (see Appendix H.1 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.

NATIONAL INSTITUTE ON DRUG ABUSE (NIDA)

NIDA’s mission is to advance science on the causes and consequences of drug use and addiction and to apply that knowledge to improve individual and public health.

This involves:

• Strategically supporting and conducting basic and clinical research on drug use (including nicotine), its consequences, and the underlying neurobiological, behavioral, and social mechanisms involved.

• Ensuring the effective translation, implementation, and dissemination of scientific research findings to improve the prevention and treatment of substance use disorders and enhance public awareness of addiction as a brain disorder.

 

DEA-Compliant Drug Detection and Deactivation Technology to Deter Opioid Theft in Hospitals for Next Generation Controlled Substance Diversion Prevention Program (CSDPP)

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 3-4

Budget (total costs, per award): Phase I: up to $225,000 for up to 6 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.

In addition, NIDA strongly encourages the offerors submitting a proposal to this Topic to include potential participation in the I-Corps™ at NIH program within its Phase I proposal. For details about the I-Corps™ at NIH program see Section 2.5.

Background:

With an increasing number of opioid prescriptions and related opioid misuse and abuse, health care facilities have become sites for diversion of controlled substances. Unfortunately, the diversion of opioids in hospitals is common and can lead to serious patient safety issues, harm to the diverter, and significant liability risk to the organization. The lack of efficient security regarding opioid access has led to its increased diversion and/or abuse. It is estimated that 10-15% of healthcare workers (HCWs) have experience addiction at some point in their careers. The likelihood of deliberate misuse of prescription drugs in hospitals, when compared to street drugs, may rise because prescription drugs are often available and can be readily accessed. There also seems to be a misconception that misuse of drugs for stress alleviation by HCWs may be manageable because of their familiarity with the drugs that may help them to "control" its use. However, the diversion of controlled opioid substances and the associated addiction puts both HCWs and patients at high risk of harm. Issues range from inadequate pain relief to longer-term pain sequelae, and also include inaccurate documentation of patient care in the medical record, exposure to infectious diseases from contaminated needles and drugs, and impaired HCW performance.

When offerors develop their proposals, they should use the existing guidelines, for example current guidelines from American Society of Health-System Pharmacists (ASHP), that support a safe patient-care environment, protect co-workers, and discourage controlled the diversion of substances. These guidelines provide a detailed and comprehensive framework to support health care organizations in developing their controlled substances diversion programs (CSDPPs) and to protect patients, employees, the organization, and the community at-large. Ultimately, each health care organization is responsible for developing a CSDPP that complies with applicable federal and state laws and regulations and also incorporates technology and diligent surveillance to review process compliance and effectiveness, strengthen controls, and proactively prevent diversion.

The current guidelines highlight that substances returns and waste streams remain among the key sources of opioid diversion in the hospitals. Thus, there is an urgent need to develop improved technologies / surveillance systems. An improved surveillance system technology are expected to reduce waste-handling practices and to maintain chain of custody to minimize the risk of diversion. Opioid waste may include expired-date medications, medication products appropriately prepared but not administrated to the patient, and the product remaining after a partly used medication is removed from its prepared or originally packaged unit. All items should be time stamped as close to the time of preparation and administration as feasible.

Currently, there is little continuity or generally adhere to standard practices for opioid waste disposal across various health facility systems. DEA compliance is partly addressed by having two healthcare providers licensed to dispense drugs and to timely documenting the disposal of the controlled substances. The recommended procedure includes definitions of key issues, including verification of the drug label, and volume or quantity being wasted. This documentation process is time

 

consuming and not proactive. The limited tools and strategies for effective opioid waste deactivation or disposal is a key issue that may benefit from the development of more efficient and pro-active disposal systems.

There is a need for modern technologies with the integrated systems to monitor medication dispensing and disposal, provide effective diversion prevention efforts, proactively prevent diversion, and effectively confirm compliance regarding opioid waste control.

Project Goals:

The primary goal of this funding opportunity is to incentivize small businesses to develop a new commercially viable devices, tools, technologies or integrated systems for drug detection and deactivation to deter opioid theft in hospitals. NIDA envisions that a new technologically advanced system shall combine a device with analytical approaches that 1) accurately measure waste volume and/or quantities, 2) efficiently synchronize waste information with pre-existing data records, 3) deactivate the opioid waste, and 3) continuously monitor disposal of controlled substances, while securing unused portions and simplifying the process. The purpose of deactivation is to render the controlled substances to a non-retrievable state and to prevent diversion of any portion of such substance to illicit purposes.

A new technology could provide a quantitative assurance against opioid waste theft, as well as saving valuable time for auditing substance disposal data. Implementation can reduce liability risks for the hospitals, improve patient safety, and improve HCW performance. Achieving these goals are expected to contribute to the overarching goal of reducing opioid theft by bringing medical facilities into compliance and establishing next generation CSDPPs.

It is highly encouraged that offerors refer to the current guidelines, for example AHSP guidelines, for discouraging controlled substances diversion and to work with potential purchasers in order to establish a clear regulatory and acquisition/commercialization strategies.

The potential features of new device or system may include, but are not limited to:

• Hospital’s level of compliance with the current guidelines, for example AHSP guidelines;

• Compliance with DEA regulations and definition of non-retrievable;

• Identification of staff disposing the opioid waste and time of disposing;

• Detection and identification of substance waste;

• Deactivation of substances with lock & key to deter diversion;

• Integration into a hospital’s data continuum (electronic medical record, internal inventory system and purchasing systems).

Phase I Activities and Deliverables

The goal of Phase I is to develop a proof-of-concept or prototype technology for opioid detection, deactivation and disposal. Offerors must clearly demonstrate the understanding of the key elements of effective CSDPP and needs for the new generation of drug detection and deactivation technologies. It is expected that the technology developed does not interfere in any way with healthcare provision. Activities and deliverables should include:

• Identify and justify the development of a technology for opioids detection, deactivation and disposal in hospitals.

• Identify the key features of a technology to be compatible with existing hospital systems. Design the core structure and process architecture that further optimize the detection and minimize the occurrence of controlled substance diversion.

• Describe the current state of the art technologies and approaches controlled substance detection, deactivation and disposal and outline the advantages that new approaches will provide for CSDPP.

• Describe how a technology is compliant with DEA, EPA, and ASHP regulations and guidelines.

• Specify and justify quantitative milestones that can be used to evaluate the success of a technology being developed.

• Develop an assay or system for testing and benchmarking the specificity and sensitivity of a technology. Develop milestones to compare it to existing approaches.

• Demonstrate utility and technical validly of a technology in a laboratory study.

• Develop a device or system prototype and describe the architecture of its integration to the modeled CSDPP. Provide an example of a proof-of-concept standard operation procedure (SOP) for incorporation of the innovative approach to CSDPP.

Phase II Activities and Deliverables

The goal of Phase II is to develop and test the technology to deter opioid theft in clinical setting and optimize for CSDPPs in hospitals. These activities should support commercialization of the product with varying complexity.

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

• Successful proof-of-concept data demonstrating adaptively of the product to the key elements of the best practice of CSDPPs.

• Evidence that the technology can be scaled up and compatible with the general hospital’s procedures and DEA/ EPA/ ASHP regulations.

• Evidence for commercialization feasibility by providing feedback from potential purchasers and end-users.

Activities and deliverables in Phase II include:

• Demonstrate high accuracy and reliability of the device or technology.

• Demonstrate superiority over currently available tools and procedures.

• Enhance and validate the technology in the pilot study. Demonstrate utility and capability of the technology in clinical setting.

• Provide a report that synthesizes feedback from all relevant categories of end-users (such as physicians, nurses, pharmacists, administration of pharmacy service and hospital) and summarizes the modifications made the technology after usability testing.

• Further enhance and refine the systems for deployment in diverse software environments and provider network. Provide a report detailing the communication systems architecture and capability for data reporting to hospital’s administration.

• Refine SOPs to allow friendly implementation of the tool by the target market.

• Provide a report detailing plans for obtaining DEA regulatory approval and implementation to the market.

References:

ASHP Guidelines on Preventing Diversion of Controlled Substances:

http://www.ajhp.org/content/ajhp/early/2016/12/22/ajhp160919.full.pdf?sso-checked=true

Drug Enforcement Administration, 21 CFR Parts 1300, 13001, 1304, 1307, and 1317. Disposal of Controlled Substances. Federal Register, v.79, No174 /Tuesday, September 9, 2014/Rules and Regulations

 

Fast-Track proposals will be accepted.

Number of Anticipated Awards: 4-6

Budget (total costs, per award): Phase I: up to $225,000 for up to 6 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.

In addition, NIDA strongly encourages the offerors submitting a proposal to this topic to include potential participation in the I-Corps™ at NIH program within its Phase I proposal. For details about the I-Corps™ at NIH program see Section 2.5.

Background:

The United States is in the midst of an opioid crisis. Over-prescription of opioid analgesic pain relievers contributed to a rapid escalation of use and misuse of these substances across the country. In 2016, more than 2.6 million Americans were diagnosed with opioid use disorder (OUD) and more than 42,000 have died of overdose involving opioids. This death rate is

more than any year on record and has quadrupled since 1999 (1,2). Leveraging the potential of available data bases and health IT technologies may help to combat opioid crisis by targeting various aspects of the problem ranging from the prevention of opioid misuse to OUD treatment.

Project Goals:

The purpose of this RFP is to solicit data-driven solutions and services that focus on issues related to opioid use prevention, opioid use, opioid overdose prevention or OUD treatment. Small businesses – offerors are encouraged to use already existing databases and adapt pre-coded Health IT solutions for use in the OUD marketplace. For the proposed purposes the offerors may assume free of charge or minimum cost access to the federal data resources. However, it is encouraged that offerors contact NIDA to ensure resource availability, levels of restrictions, and data release process prior submission of their proposals. It is also highly encouraged that offerors work with potential purchasers in order to establish a clear acquisition/commercialization strategy.

Usage. In order to develop a clearer understating of the opioid crisis, public health data and misuse reporting is expected to be important. Among the expectations are an achievement of learning who is at risk of opioid misuse or abuse and why. Accessible information about at-risk populations seems likely to better inform policymakers, public health officials, first responders, and other stakeholders who are tasked with prevention or intervention efforts by better identifying issues related to more effective prevention and treatment strategies.

Overdose Prevention. A crucial step in combating the opioid epidemic is to intervene prior to an opioid overdose related event. In order to do so, federal, state and local stakeholders need tools to predict and analyze the supply and movement of legal and illicit opioids. This includes both physician prescription patterns and the illegal market for opioids that includes prescription opioids, heroin, fentanyl and other synthetic opioids. By analysis of existing databases, information and correlations are likely to be identified that will allow stakeholders to respond prior to major risks in their communities. This includes being able to predict when and where a population is at risk for opioid availability, misuse and overdose so that first responders are better prepared for emergency situations and opioid overdose treatment, for instance by having drugs such as naloxone readily available in trained first responders and clinicians.

Treatment. Understanding of the patters of OUD treatment process and the available resources is an essential part of successful OUD treatment and reduction of the relapse rate. Unfortunately, most patients with OUD report no use or do not complete the OUD treatment. One likely reason for this shortcoming is that access to treatment and recovery services is not always available. Despite various efforts across the country, states, counties and cities to increase treatment access and to promote evidence-based approaches, opioid overdose and overdose-related mortality continue to increase. Accessible technologies for data analysis can help those involved in providing treatment services, better understand treatment options, address gaps in access to treatment, and improve the range of options available in communities.

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

• Analytical tools that can be used to appropriately monitor and control the movement of prescription opioids at pharmacies where unused or unneeded opioids can be returned, and sources of out of circulation opioids can be identified.

• Analytical tools to detect sources and movement of illicit opioid sales online.

• Technologies to improve access to available treatment and recovery services.

• Informational technologies to promote evidence-based approaches to reduce opioid use, opioid overdoses, overdose-related mortality, and the prevalence of opioid use disorder.

• Products that use innovative technologies to strengthen understanding of the opioid epidemic through better public health data gathering, analysis and reporting.

• Advanced real-time technologies to track fentanyl overdoses and to enable area hospitals, local health departments and first-responders to allocate resources where they are most needed.

• Analytical approaches to identify vulnerable and high-risk populations for opioid abuse, addiction, or overdose.

• Products to better understand opioid use patterns and how the frequency and quantity of use can be monitored.

• Sophisticated approaches to better identify behavioral indicators, patient characteristics, and environmental conditions for at-risk populations.

• Tools to ensure clinicians have a full, accurate picture of a patient’s medical history when prescribing or dispensing opioids.

• Studies to define new opioid prescribing patterns through predictive models of prescription opioid usage.

• Facilitating tools that transmit information security and capture the opioid prescription data in real-time from across state lines.

Examples of federal data sources available to the offerors may include, but are not limited to

Data Sets from Federal Government (excluding HHS):

- O*Net Database (Department of Education)

- National Center for Education Statistics 2016 Outcome Measures (Department of Education)

- Bureau of Economic Analysis Input-Output Accounts (Department of Commerce)

- Current Population Survey (CPS) (Department of Labor)

- Local Unemployment Statistics- Labor force data by county annual averages (Department of Labor)

- National EMS Information System (NEMSIS) (Department of Transportation)

- Mortgage Loan Data (Federal Housing Finance Authority)

Data Sets from HHS:

- Medical Expenditure Panel Survey (MEPS) (Agency for Healthcare Research and Quality)

- Healthcare Cost and Utilization Project (HCUP) (Agency for Health Care Quality and Research)

- CDC WONDER -- Multiple Causes of Death (Centers for Disease Control and Prevention)

- Medicare Part D Opioid Prescribing Data (Centers for Medicare & Medicaid Services)

- Medicare Part D Prescribing Data (Centers for Medicare and Medicaid Services)

- Uniform Data Service (Health Resources and Service Administration)

- Area Health Resource File (Health Resources and Services Administration)

- Buprenorphine Treatment Practitioner Locator (Substance Abuse and Mental Health Services Administration)

- National Survey on Drug Use and Health (NSDUH) (Substance Abuse and Mental Health Services Administration)

- Treatment Episode Data Set (TEDS) (Substance Abuse and Mental Health Services Administration)

Phase 1 Activities and Deliverables:

The goal of Phase I is to develop a proof-of-concept or prototype of data-driven technology for opioid use prevention, opioid use, opioid overdose prevention or OUD treatment. Activities and deliverables include:

• Identify and justify the development of a health-IT tool or technology;

• Describe the current state of the art technologies, if any, and needs for new solutions;

• Specify and justify quantitative milestones that can be used to evaluate the success of a technology being developed;

• Identify the key features of a health IT tool or technology to be commercially feasible and useful.

• Design a prototype of software structure and process architecture;

• Describe how a health-IT tool or technology is compliant with health IT regulations and guidelines for data security.

Phase II Activities and Deliverables:

The goal of Phase II is to develop and betta-test the technology for opioid use prevention, opioid use, opioid overdose prevention or OUD treatment. Offerors should develop an at-scale prototype of the technology with detailed specifications that supports future commercialization of the product with varying complexity. Decisions for continued product development into Phase II will be based on:

• Successful proof-of-concept data demonstrating adaptively of the product to the market needs;

• Description of the value of the product and expected impact to the society;

• Description of the market and/or market segments;

• Evidence for commercialization feasibility by providing feedback from potential purchasers and end-users.