DAta | National Center for Advancing Translational Sciences

ID	Title	Body	Facebook Description	Facebook Title	Twitter Description	Twitter Title
4416	About Biomedical Data Translator	As a result of recent scientific advances, there is a tremendous amount of biomedical research data and data available from disease classifications, health records, clinical trials and adverse event reports that could be useful for understanding health and disease and for developing and identifying treatments for diseases. Ideally, these data would be mined collectively to provide insights into the relationship between molecular and cellular processes (the targets of rational drug design) and the signs and symptoms of diseases. Currently, these very rich yet different data sources are housed in various locations, often in forms that are not compatible or interoperable with each other. All of these factors limit the ability to get more treatments to more patients more quickly. To address these problems, NCATS launched the Biomedical Data Translator program, called “Translator” for short. This multiyear, iterative effort will culminate in the development of a comprehensive, relational, N-dimensional Biomedical Data Translator that integrates multiple types of existing data sources, including objective signs and symptoms of disease, drug effects, and intervening types of biological data relevant to understanding pathophysiology. YouTube embed video: https://www.youtube-nocookie.com/embed/AQ6k0N9gK6E&amp;amp;amp;amp;… /&amp;amp;amp;amp;amp;gt; Watch this video to hear NCATS Director Christopher P. Austin, M.D., explain the purpose and goals of the Biomedical Data Translator program. Each data type will be comprehensive (e.g., all diseases, all pathways, all SNPs). It also will be possible for a user to access the Translator for any data type and identify all connections in any other data type. This will enable a shift from the current symptom-based diagnosis of disease to one that is based on a set of molecular and cellular abnormalities and can be targeted by various preventive and therapeutic interventions. NCATS is aware of the many existing efforts to catalogue or connect individual data types. Although these efforts provide proof of principle, the Translator will be broader in scope, with the goal of revealing potential relationships across the spectrum of data types, from signs and symptoms to molecules and drugs. Examples of the types of queries the Translator will enable for the first time could include, but are not limited to, the following: Show every disease that has symptom X and/or affects a particular cell type. Show all molecular pathways that, when perturbed, lead to malfunction of organelle A in organ B in people with X-Y-Z genomic characteristics. Show all the treatments currently being investigated that perturb any pathway that is dysfunctional in diseases characterized by clinical sign X. This effort will require unprecedentedly broad teams of experts to work together in a highly collaborative manner with active program management. Input from clinicians during the design and feasibility assessment will be critical to ensuring appropriate inclusion of clinical data.
4397	Advisory Council Concept Clearances	Concepts describe the basic purpose, scope and objectives of proposed initiatives and represent an early planning stage for potential NCATS activities. Concepts are discussed with the NCATS Advisory Council and Cures Acceleration Network (CAN) Review Board and through other public venues. Council approval of a concept does not guarantee it will become an initiative. That decision is made based on scientific and programmatic priorities and the availability of funds. View approved Advisory Council concept clearances by year: 2023 Concepts 2022 Concepts 2021 Concepts 2020 Concepts 2019 Concepts 2018 Concepts 2017 Concepts 2016 Concepts 2015 Concepts 2014 Concepts 2013 Concepts 2012 Concepts 2023 Preclinical Proof-of-Concept Studies for Rare Diseases Jan. 26 Christine M. Colvis, Ph.D., presented a new concept on preclinical proof-of-concept studies for rare diseases, which are demonstrations of efficacy in a model system prior to conducting regulatory safety studies. A gap exists between early discovery/early preclinical development and investigational new drug (IND)–enabling development due to a lack of funding. The goal of this concept is to bridge the gap between novel compound development and initiation of IND-enabling studies, resulting in identification of meritorious compounds. The aim is to support efficacy testing for repurposing approved therapeutics to treat rare diseases. NCATS proposes to provide funding to test the efficacy of meritorious compounds in an established rare disease preclinical model. This effort will require partnership with a rare diseases steering committee or oversight committee. NCATS anticipates that such a partnership would strengthen potential applications by bringing the patients’ perspective into the translation process earlier than normal; encourage researchers who work adjacent to drug development to think more intentionally about the translational potential of their research; and increase use of existing rare disease models. In terms of appropriateness for NCATS funding, this research puts patients first by requiring partnerships with rare diseases experts, patients, and patient advocates; increasing the use of existing rare disease models, on which meritorious compounds and repurposed therapeutics would be tested; and impelling basic scientists to think more intentionally about designing studies that withstand critical evaluation by industry and having more relevance to the patient population in question. The anticipated outcome will be strong preclinical efficacy data to attract subsequent investment in IND-enabling preclinical development within the rare diseases space. The potential impact is that several of the drug candidates will advance through development within other programs at NCATS or NIH and subsequently be used in clinical trials. Reviewers are being asked to evaluate the number of compounds that transition into full IND-enabling preclinical development and to ensure that major obstacles are addressed (e.g., verifying that drug candidates are evaluated for merit during review, utilizing the best rare diseases models, increasing awareness in the rare diseases community of the partnership opportunities). The concept leverages other NCATS programs and initiatives, including the Division of Rare Diseases Research Innovation (DRDRI) Clinical Trial Readiness for Rare Diseases, Disorders and Syndromes program. In addition, the Division of Preclinical Innovation (DPI) has identified the transition from compound to full IND-enabling development as a “pain point” to be addressed. Strong efficacy data generated in this research would help alleviate this issue. Project/Program Officer: Christine M. Colvis, Ph.D. Director Office of Drug Development Partnership Programs National Center for Advancing Translational Sciences Phone: 301-451-3903 Email: ccolvis@mail.nih.gov 2022 Awards Supporting Cutting-Edge Technology for Translational Science (ASCETTS) Sept. 22 Tyler F. Beck, Ph.D., presented a new concept on establishing ASCETTS, which is filling a gap in research funding opportunities for translational researchers. NCATS proposes this concept to allow early-stage development of new biomedical technologies, which traditionally have been challenging to fund. A distinct lack of funding for investigator-initiated innovation in translational sciences programs for basic science remains a priority. The framework for this concept is the successful Cutting-Edge Basic Research Awards (CEBRA) sponsored by the National Institute on Drug Abuse (NIDA). Though CEBRA has resulted in several exciting projects’ being funded, they are not in the translational sciences. This funding gap in NIH, as well as National Science Foundation, grants has been recognized by other research groups, such as the University of North Carolina (UNC) Office of Technology Commercialization. The objectives of this concept are to create a funding opportunity for innovative technology development and stimulate development of technologies that could be further developed under the Small Business Innovation Research (SBIR)/Small Business Technology Transfer (STTR) program or supported by other investors. Regarding implementation, the aim is to support the development of new technologies leading to translational science advancements, thus bringing more treatments to more people more quickly. The anticipation is that successful ASCETTS should lead to STTR awards or direct engagement with technology and pharmaceutical industry leaders. The long-term outcome would be uptake of new technologies by translational researchers. Examples of potential projects include nanoparticle packaging for alternative drug delivery modalities; dermal implants for monitoring or delivery of drugs; and development of new algorithms to predict threatening drug interactions. Project/Program Officer: Tyler F. Beck, Ph.D. Scientific Program Officer Office of the Director Drug Development Partnership Programs National Center for Advancing Translational Sciences Phone: 301-827-1943 Email: tyler.beck@nih.gov Miniaturization and Automation of Tissue Chip Systems (MATChS) Sept. 22 Dr. Tagle presented a new SBIR grant concept to establish MATChS, which is addressing a translational science gap. Although tissue chips have been successful, have been widely used, and are well-positioned as an alternative method for drug development, widespread adoption of this methodology by industry, regulatory agencies, and biomedical research has been impeded. This can be attributed to the complexity of the supported instrumentation necessary, and the specialized expertise needed to operate those systems. A partnership among NCATS, the National Aeronautics and Space Administration (NASA), and the Center for Advancement of Science in Space, the Tissue Chips in Space program has made key technological innovations toward the automation and miniaturization required for space flight. Since 2018, NCATS scientists have worked with NASA and Space Exploration Technologies Corp. (commonly called SpaceX) payload developers and space implementation partners (e.g., Techshot, Inc., Space Tango) to reduce tissue chip hardware from the size of a typical refrigerator to the size of a shoebox. The objectives are twofold: Translate the lessons learned in re-engineering tissue chip platforms toward a smaller footprint and simplification of systems for ease of use and increase commercialization of the improved tissue chip platforms for widespread use in drug development and in biomedical research. Areas of emphasis include creating bench-top, portable, automated, self-contained systems that maintain 3-D tissue constructs and provide biologically relevant outputs of tissue health and function (e.g., fluid sampling, electrode incorporation, microscopy, biosensors). Emphasis also will be on producing demonstrable pathways to commercialization. NCATS is proposing to use the cooperative agreement small business SBIR/STTR solicitation and will continue to use and implement tissue chips as a promising drug development tool across NIH and other government agencies. NCATS anticipates that more cost savings will be realized in drug development. In its current state, tissue chip technology is estimated to save up to 26 percent of drug development research and development cost in 2024. The success of MATChS will result in the increased availability of automated tissue chip platforms with a smaller and simpler footprint for use beyond drug development and across multiple applications and settings. In the clinical setting, the application will be for personalized patient-specific chips; on the battlefield, for assessment of countermeasures against developing threats; and in drug treatment and spaceflight, in evaluating long-term effects of stressors, including chronic disease. Project/Program Officer: Danilo A. Tagle, Ph.D., M.S. Director Office of Special Initiatives National Center for Advancing Translational Sciences Phone: 301-594-8064 Email: Danilo.Tagle@nih.gov Small Manufacturing Systems to Produce Research-Grade Pharmaceutical Intermediates Sept. 22 Dr. Tagle presented the SBIR contract topic Small Manufacturing Systems to Produce Research-Grade Pharmaceutical Intermediates. The development of preclinical drug candidates is time and cost intensive, averaging 10 to 15 years and costing $2.6 billion. Quality and access to pharmaceutical intermediates (i.e., raw chemical ingredients) by medicinal chemists are among the limiting factors. Most preclinical development involves the chemical synthesis of the candidates. NCATS recognizes that chemists’ on-demand access to pharmaceutical intermediates will speed up the design-synthesize-test cycle. Exploring chemical space in drug development requires two components. The first is access to bulk specialized pharmaceutical intermediates, made in-house or via a contract research organization. The second is focused efforts toward synthesis of drug candidates by medicinal chemists. The hypothesis is that leveraging automation in synthetic chemistry will facilitate access to bulk specialized pharmaceutical intermediates and treatments, with the ability for rapid scale-up. NCATS proposes this concept to develop tools to increase synthetic chemistry throughput to reduce development time for preclinical candidates. The objectives are to (1) develop automated tools for use by synthetic chemists to improve access to pharmaceutical intermediates and (2) increase the rate of exploration of chemical space by accelerating chemical synthesis in drug discovery. The key areas of emphasis for this contract solicitation include utilization of current automation technology in synthetic chemistry adaptable to multiple chemical methodologies and the rapid scale-up of technology that is amenable to real-time data acquisition and monitoring. Current activities related to this concept include the ASPIRE Program and NCATS–DARPA Collaboration for Flexible Manufacturing of Fine Chemical Reagents. This research will provide additional support to develop non–good manufacturing practice reagents for laboratory use. NCATS support will recognize that higher throughput synthetic chemistry will improve the rate of development of preclinical candidates. Improving access to pharmaceutical intermediates will increase the rate of drug candidate development and biological data generation for exploring chemical space. The success of this project will be the creation of an automated synthetic chemistry device to prepare pharmaceutical intermediates quickly on-demand, such that a chemist can focus efforts toward preparing drug candidates for biological testing. For this contract concept, reviewers are being asked to consider the scientific, technical, or programmatic significance of the goals of the proposed research and development activity; availability of the technology and other resources necessary to achieve the required goals; and the extent of identified practical, scientific, or clinical uses for the anticipated results. Comments on each of these features have been provided in the Council materials. Project/Program Officer: Danilo A. Tagle, Ph.D., M.S. Director Office of Special Initiatives National Center for Advancing Translational Sciences Phone: 301-594-8064 Email: Danilo.Tagle@nih.gov Translational Centers for Microphysiological Systems (TraCe MPS) May 20 Dr. Tagle presented a new concept to establish TraCe MPS, which leverages the fact that MPS hold promise as a leading new approaches method (NAM). NCATS continues to play a leadership role domestically and internationally in the development, implementation and adoption of this technology for the drug development process. Despite scientific advancements, the need to translate MPS in the direction of industrial use and regulatory acceptance is great. NCATS proposes this concept to accelerate the translational use of MPS in drug development through regulatory acceptance and adoption for industrial use by drug developers. The aim is to develop tissue chips that are fit-for-purpose for industry needs and have specific context of use (CoU) that will satisfy regulatory approval criteria. The objectives are to establish translational centers focused on regulatory qualification of MPS with active input and engagement from key stakeholders and end users (e.g., FDA and pharmaceutical members of the IQ MPS Affiliate) and engage other NIH ICs in the formation and funding of these translational centers. The expectation is that the translational centers will, through the project period, be able to qualify several MPS models as drug development tools (DDTs). In terms of key areas emphasis, the MPS models will need to meet end-user criteria for biomarkers and assays as defined by industry. The NIH, FDA, and the IQ Consortium will co-develop study designs for each organ system and MPS model that will be suited to have multiple CoUs, each of which could be the basis for qualification by the FDA as a DDT. In addition, discussions are underway to have FDA serve as a center hub. This proposed initiative aligns with the Tissue Chips for Drug Screening program and will be the culmination of NCATS’ investments in developing MPS as in vitro models for safety pharmacology, therapeutic efficacy, and precision medicine. NCATS’ support of this concept is important to continue its leadership in this field and to further spur engagement and investments in using MPS as DDTs. NCATS anticipates that this initiative will pave the way for regulatory and industry use of MPS that will address scientific, legislative, and ethical needs for more predictive NAMs. Project/Program Officer: Danilo A. Tagle, Ph.D., M.S. Director Office of Special Initiatives National Center for Advancing Translational Sciences Phone: 301-594-8064 Email: Danilo.Tagle@nih.gov HEAL LitCoin Pilot Program to Enable Pain and Addiction Research Discoveries May 20 Tyler F. Beck, Ph.D., presented a new contract concept on establishing an NIH HEAL Initiative LitCoin Pilot Program to enable pain and addiction research discoveries. ODDPP envisions LitCoin as a biomedical publication that allows researchers to share results normally not included in high-impact peer-reviewed journals and to do so computationally and without the burden of additional work. In the LitCoin framework, the authors (i.e., researchers) write an abstract-length description of their work and the conclusions and upload the text to the LitCoin server. The NLP algorithms generate knowledge assertions, which are displayed to the researcher for verification. The publisher partner reviews the assertions and approves them for publication. Dr. Beck highlighted that the June 2021 NCATS LitCoin Stakeholder Feedback Workshop and LitCoin Natural Language Processing (NLP) Challenge — organized in collaboration with CrowdPlat, Inc., Bitgrit (Tokyo, Japan), and NTL — informed developing the NCATS LitCoin program. The goals of the broader LitCoin program are threefold: Encourage researchers to share their data their data in a computationally accessible manner; generate highly connected knowledge networks from published works with built-in curation; and encourage the reporting of research findings that may be separate from the researcher’s main hypothesis. In addition to the NLP challenge, NCATS soon will sponsor a conceptual challenge for the design of the LitCoin platform. NCATS is proposing this concept to build a critical component of the LitCoin platform to pilot with pain and addiction research, because it fits with the NIH HEAL Initiative. The proposed platform extends from observation to open data reuse and involves converting human-readable knowledge to machine-readable knowledge. The deliverables of this pilot program and feasibility study are to create a sophisticated web interface that will allow researchers to upload free text describing their findings. A successful system should be able to run NLP algorithms on the text to extract knowledge assertions and display extracted assertions to researchers, allowing confirmations and edits. The system also will need to connect with publisher partners to facilitate easy journal submissions. After confirmation from the publisher of acceptance, the system would deposit the assertions into the LitCoin knowledge graph to allow reuse. Regarding implementation of the project and its expected impact, this research has the potential to fundamentally change the manner in which researchers publish their work by allowing computational-accessible knowledge to be generated as part of the publication process. NCATS, which is well suited to conduct such pilot studies to assess feasibility of transformational concepts, anticipates that this concept will result in findings that may not have been published or accessible to researchers. In addition, publishing failed drug discovery attempts could improve efficiency in drug development. Project/Program Officer: Tyler F. Beck, Ph.D. Scientific Program Officer Office of the Director Drug Development Partnership Programs National Center for Advancing Translational Sciences Phone: 301-827-1943 Email: tyler.beck@nih.gov NIH HEAL Initiative LitCoin Foundational Knowledge Graph May 20 Dr. Beck presented the second ODDPP new contract concept, the NIH HEAL Initiative LitCoin Foundational Knowledge Graph, which also is a critical component of the LitCoin platform to pilot with pain and addiction research. The objectives are to extract free text from existing research publications in the pain and addiction research space and generate knowledge assertions using the NLP systems that emerged from the 2022 LitCoin NLP challenge. The NIH HEAL Initiative investigators will review the NLP-generated assertions extracted from their own publications and verify that they are accurate. Some professional curation to ensure accuracy is expected. The chief deliverable will be a robust knowledge graph with highly accurate knowledge assertions in the pain and addiction research space generated using NLP. This process will involve combining the algorithms received through the 2022 LitCoin NLP challenge into a single system that can generate knowledge assertions and run those assertions on PubMed abstracts in the pain and addition space collected from a portfolio analysis of the NIH HEAL Initiative investigators. The contractor will build a simple web interface to allow researchers to curate their knowledge from prior publications and organize virtual events (e.g., workshops) to engage researchers in the creation of computationally accessible knowledge. This concept is a continuation of the broader NCATS LitCoin initiative and will support the LitCoin Pilot Program. NCATS anticipates that normalizing the pre-curation of extracted knowledge will provide researchers more agency to ensure that their findings are discovered and widely reused. The generated knowledge graph complements other NCATS programs, such as the Biomedical Data Translator. Dr. Beck summarized that NCATS proposes two new concepts to pilot a program that could fundamentally change the way that researchers publish their discoveries by providing a new currency of research consistent with present practices. NCATS anticipates that asking researchers to curate their own generated knowledge will energize them and help them understand how NLP can enhance their own work. If successful, this effort could expand to other fields, leading to a fundamental shift in publication practices, with far-reaching consequences for the generation and reuse of biomedical knowledge. For these contract concepts, the reviewers are being asked to consider the scientific, technical, or programmatic significance of the goals of the proposed R&D activity; availability of the technology and other resources necessary to achieve the required goals; and the extent of identified practical, scientific, or clinical uses for the anticipated results. Comments on each of these features have been provided in the Council materials. Project/Program Officer: Tyler F. Beck, Ph.D. Scientific Program Officer Office of the Director Drug Development Partnership Programs National Center for Advancing Translational Sciences Phone: 301-827-1943 Email: tyler.beck@nih.gov ACTIV-1 Time-Limited Biospecimen Storage and Related Services (COVID19) May 20 Soju Chang, M.D., M.P.H., presented a contract concept for ACTIV-1 time-limited biospecimen storage and related services. Dr. Chang noted that Cynthia Boucher, M.S., project manager for ACTIV-1 and Samuel A. Bozzette, M.D., Ph.D., Chief Medical Officer, OTM, NCATS, would be available for the discussion of this concept. ACTIV-1 is funded through a task order under the Biomedical Advanced Research and Development Authority (BARDA) contract and is managed by NCATS. The period of performance for the BARDA task order is from Aug. 8, 2020, to Sept. 30, 2022. Research samples of whole blood, serum, and plasma were collected from consented participants during the trial and stored in the ACTIV-1 biospecimen storage facility for future use. NCATS proposes this new contract concept to continue the support of existing activities under the BARDA task order and provide additional services after the conclusion of the trial. The objectives are to provide (1) time-limited storage and distribution of deidentified biospecimens, (2) regulatory support and data management of clinical data, and (3) additional statistical analyses. The key areas of emphasis are biospecimen management, clinical data management, and biospecimen analyses. NCATS will manage the biorepository contract funded by OWS. Regarding the expected impact, this resource will permit the medical community to better understand the role of inflammatory markers and cytokines to predict the clinical course of COVID-19 disease and the disease’s response to treatments evaluated in ACTIV-1. The outcome will be publications describing finding related to the results of the biospecimen analyses. For this contract concept, reviewers are being asked to consider the scientific, technical, or programmatic significance of the goals of the proposed R&D activity; availability of the technology and other resources necessary to achieve the required goals; the extent of identified practical, scientific, or clinical uses for the anticipated results; and the adequacy of the inclusion of women, minorities, and individuals across the lifespan in clinical research. Comments on each of these features have been provided in the Council materials. Dr. Chang explained that the ACTIV-1 clinical trial recruited hospitalized adults (age 18 and older) who had COVID-19. Enrollments span across the United States and in Latin America. The trial had no exclusions by gender or race and ethnicity; children, however, were excluded because this was the first trial evaluating two repurposed drugs and one experimental drug to treat COVID-19. NCATS will contribute towards the scientific evidence to better understand the clinical course of COVID-19 and treatment response of immunomodulators tested in ACTIV-1. Project/Program Officer: Soju Chang, M.D., M.P.H., FACPM Medical Officer Division of Clinical Innovation National Center for Advancing Translational Sciences Phone: 301-827-9206 Email: soju.chang@nih.gov Device or Process for the Cleaning of Cell Tissue Culture Flasks May 20 Sam G. Michael presented a new SBIR contract concept for a device or process for cleaning cell-tissue culture flasks, which addresses an unmet need. The use of consumable plastics is prevalent in biomedical research, with well over 90 percent being used once and then disposed. There are many challenges to such a practice. These products are expensive and generate large quantities of laboratory waste. Supply chain shortages have made these products even more expensive or difficult to acquire, impacting the ability of laboratories to perform research. NCATS proposes this SBIR contract topic to identify a small business that can develop a device or a process capable of cleaning, sterilizing and treating tissue culture flasks. Such a process would allow repeated use of flasks before they are discarded in a burn box for incineration. A key requirement will be that the device or process has the ability to clean flasks while also applying a surface treatment to make them amenable to cell growth. NCATS will help draft evaluation criteria, to be included in the solicitation, for verifying the characteristics of the flask after a cleaning process, including the sterility assurance level and cell viability measurements. Another key area of emphasis will be how to handle the caps, which may prove difficult to clean and may require that each flask have a replacement cap. In terms of implementation, this contract concept aligns with existing Information Technology Resources Branch efforts in laboratory sustainability, particularly in saving plates, tips, and reagents. Regarding the expected impact, NCATS is a proven leader in laboratory sustainability, and its efforts in this space (e.g., IonField Systems SBIR) have saved tons in plastic wastes and hundreds of thousands of dollars. The ability to reuse tissue culture flasks could reduce overall laboratory waste and save laboratories substantial consumable costs, given their general expense. This concept provides an opportunity to a U.S. small business to develop a solution to this problem. The metric of success will be a product or process that can clean flasks for reuse. For this contract concept, reviewers are being asked to consider the scientific, technical, or programmatic significance of the goals of the proposed R&D activity; availability of the technology and other resources necessary to achieve the required goals; and the extent of identified practical, scientific, or clinical uses for the anticipated results. Comments on each of these features have been provided in the Council materials. Project/Program Officer: Samuel G. Michael Chief Information Officer Information Technology Resources Branch Office of Administrative Management National Center for Advancing Translational Sciences Phone: 301-827-7796 Email: michaelsg@mail.nih.gov Botulinum Toxin Potency Assay Using Tissue Chips (BoT PATCh) May 20 Dr. Tagle presented the SBIR grant topic for BoT PATCh. In terms of the gap or need for this research, the mouse lethality bioassay (MLB) or the model dose that kills 50 percent of the population (LD50) assay has been the standard FDA-approved method to determine the safety and potency of each batch of botulinum toxin manufactured for medical and cosmetic uses since 1928. The challenge is that MLB is laborious and expensive and requires a sophisticated animal facility with a skilled and dedicated workforce. Ethical concerns have led to bans on the sale of cosmetic products or their components, which have been tested in animals. These concerns have resulted in rigorous efforts to develop alternative testing methods for the safe use of botulinum toxin in humans. In partnership with the FDA, NCATS has sought to develop such methods. NCATS has matured and validated human neuromuscular junction tissue chips that can provide a useful alternative platform for a NAM for quantitative analysis and titer evaluation of botulinum neurotoxins. NCATS proposes to use the Center’s SBIR program to solicit U mechanism grants to develop and commercialize neuromuscular junction tissue chip platforms that will replace the MLB as a potency assay for botulinum toxin. The two main objectives are to develop and qualify neuromuscular junction tissue chips for BoT PATCh in partnership with the FDA and to establish commercialization avenues through the NCATS SBIR program after the platform has qualified as a DDT. Although several alternative strategies and methodologies have been proposed for botulinum toxin testing, including both ex vivo assays (e.g., mouse phrenic nerve hemidiaphragm tests and non-lethal mouse flaccid paralysis assays) and in vitro assays (e.g., cell-based and nucleic acid tests), all have fallen short of replacing the MLB assay. Qualification as a DDT with the FDA will involve a side-by-side concordance study between the BoT PATCh and the conventional MLB assay. This proposed initiative would leverage the Tissue Chips for Drug Screening program and complement ongoing activities supported by NCATS in developing MPS as in vitro models for safety pharmacology, therapeutic efficacy, and precision medicine. NCATS support of this concept is important to continue its leadership in this field and to spur engagement and investments in developing MPS as DDTs. NCATS anticipates that this initiative will have a great impact on the field by replacing the MLB potency assay or LD50 assay for botulinum toxin. The successful outcome of this activity will lead to a DDT for the assessment of botulinum toxin potency during manufacturing, which will not only affect the cost and ease of use for the assay but also support the reduction, refinement, and replacement (known as the three Rs) of animal testing. For this contract concept, reviewers are being asked to consider the scientific, technical, or programmatic significance of the goals of the proposed R&D activity; availability of the technology and other resources necessary to achieve the required goals; and the extent of identified practical, scientific, or clinical uses for the anticipated results. Comments on each of these features have been provided in the Council materials. Project/Program Officer: Danilo A. Tagle, Ph.D., M.S. Director Office of Special Initiatives National Center for Advancing Translational Sciences Phone: 301-594-8064 Email: Danilo.Tagle@nih.gov Online Education Modules to Advance Understanding of Translational Science Principles Jan. 20 Jessica M. Faupel-Badger, Ph.D., M.P.H., presented a new concept to develop online education modules to advance understanding of translational science principles. An extensive literature review that identified gaps in formal translational science education, experience with NCATS’ internal training program, and feedback received from the community speak to the need for curricula and activities that disseminate effective practices in translational science. The Education Branch recently has developed and implemented two online courses that use examples of successful NCATS-led efforts to demonstrate how specific research advances can be examined to offer insight into the translational process and identify common challenges and solutions applicable to research initiatives across the translational science spectrum. Those efforts have informed principles of effective translational science that have been incorporated into these initial courses. Directly aligning with the NCATS strategic goals, this translational science initiative will increase the capacity of the Education Branch’s teaching experience and educational research and will further develop and formalize core concepts, approaches, and strategies derived from the field’s experience and knowledge. This concept also will increase broad access to translational science and advance innovative evidence-informed approaches to online education. New educational activities will supplement NCATS’ current education and training programs, adding effective practices, and will make progress in establishing translational science as a distinct area of study. Regarding objectives and areas of emphasis, NCATS proposes to develop a portfolio of extramural research education awards that would result in a suite of online education activities, focusing on teaching effective practices and core principles of translational science. Evaluation criteria of the modules include (but are not limited to) data fields on diversity of the participants across all areas (e.g., training and career) and adherence or scale of participation. NCATS anticipates that this concept will broaden and expand foundational translational science knowledge, maximize online learning, and catalyze development of new translational science curricula. Project/Program Officer: Jessica M. Faupel-Badger, Ph.D., M.P.H. Chief Education Branch Office of Policy, Communications and Education National Center for Advancing Translational Sciences Phone: 301-827-4342 Email: badgerje@mail.nih.gov Exosome Therapeutics for Regenerative Medicine (ExTReMe) Jan. 20 Christine M. Happel, Ph.D., presented a new concept focusing on ExTReMe. Despite advances in regenerative medicine, major challenges remain. For example, stem cell transplantation is currently the main method for tissue regeneration, but progress is limited. Hurdles include ensuring a reliable cell source, tumor formation, inappropriate stem cell migration, immune rejection of transplanted stem cells, and complications during surgery and postoperative infection. To address these challenges, NCATS proposes a novel exosome-based therapeutics paradigm to catalyze regenerative medicine. In terms of the therapeutic potential, exosomes are endogenous, small membrane-enclosed carriers of bioactive molecules used for intercellular signaling. Exosome-based intercellular communication can occur bidirectionally during normal cell homeostasis or as a consequence of pathological development. In a diseased cell indicating distress, the stem cell responds by releasing specific repair exosomes. This concept is a paradigm shift in that it will use non-living cellular products, rather than stem cells, to promote tissue regeneration. The exosome-based therapies can promote tissue repair and wound healing that can be better translated into the clinic. ExTReMe would expand knowledge and resources developed by the NIH Common Fund’s ExRNA Communication Program, in which exosomes are being investigated as critical mediators of intercellular communication. In addition, the concept would extend the recently concluded NIH Common Fund Regenerative Medicine Program and leverage the expertise of the NCATS Stem Cell Translation Laboratory (SCTL). The objective of this concept is to transform regenerative medicine through novel exosome-based therapeutics in tissue repair and wound healing, with emphasis on direct exosome therapy (stem cell–isolated, stored as off-the-shelf), as well as designer exosomes (personalized to the individual patient’s needs). This research, when implemented, would focus on investigational new drug (IND)–enabling therapeutics and would involve early engagement with the FDA toward regulatory approval. A milestone-driven approach will be used to ensure that these exosome-based therapeutics for productive regeneration are translated to the clinic. Research activities and results are expected to spur a number of commercial activities beyond the initial NCATS investment. Project/Program Officer: Christine M. Happel, Ph.D. Program Officer Office of Special Initiatives National Center for Advancing Translational Sciences Phone: 301-827-9444 Email: christine.happel@nih.gov Rare Diseases Clinical Research Network (RDCRN) – Rare Disease Clinical Research Consortia Jan. 21 Tiina K. Urv, Ph.D., M.P.H., presented a renewal concept for the RDCRN Rare Disease Clinical Research Consortia (RDCRC). Established by the Rare Disease Act of 2002 to promote highly collaborative, multisite, patient-centric, translational, and clinical research in rare diseases research, the RDCRN, through the RDCRC, has always supported the study of three or more rare diseases at once. This renewal concept addresses several gaps in rare diseases research. The field lacks foundational and translational research that fully describes rare diseases and facilitates the movement of candidate treatments into the clinic. The cost (i.e., time and money) of one‑disease-at-a-time approaches to rare diseases research remains high. Standardized, high-quality data and broad data sharing for rare diseases are needed. NCATS proposes this renewal concept to advance the diagnosis, management, and treatment of rare diseases by focusing on unmet clinical trial readiness essentials that will advance the research by establishing, maintaining, and supporting Rare Disease Centers of Excellence. The objectives are threefold: (1) Lessen the risk of failure in clinical trials by being well prepared prior to starting a trial, (2) develop an effective and efficient research environment for rare diseases research, and (3) facilitate data sharing. The key areas of emphasis are to (1) conduct research studies that promote clinical trial readiness, such as natural history studies, biomarker identification, and outcome measures development; (2) provide a research environment that delivers support and opportunities for students and early-stage investigators and engages patient advocacy groups as full partners with RDCRN; and (3) develop and maintain a cloud-based research environment with shared tools and cross‑network collaborations. In terms of implementation and expected impact, the RDCRN currently supports 20 RDCRCs that study 165 different rare diseases and conducts research at 358 sites (144 co-located at Clinical and Translational Science Awards (CTSA) sites) in 12 countries. Currently, 166 Coalition of Patient Advocacy Groups (CPAGs) partner in the consortia. Within the RDCRN4 cohort, 10 will sunset and 10 will be eligible to recompete. The ORDR facilitates and coordinates rare diseases research at NIH, and the RDCRN plays a significant role. The RDCRN program partners with nine other NIH Institutes/Centers (ICs). The RDCRN is a one-of-a-kind translational research network at NIH, establishing partnerships to address multisystemic disorders, supporting research into very low prevalence rare diseases, and advancing the many-diseases-at-a-time approaches. Success has been, and will continue to be, measured through progress in addressing consortia-specific gaps in clinical trial readiness; publications generated; initiation of longitudinal observational studies and accruals; participation of clinical sites and patient advocacy groups (PAGs) in the research; and the numbers and types of pilot studies and clinical trials conducted. Project/Program Officer: Tiina K. Urv, Ph.D. Program Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-827-2746 Email: Tiina.Urv@nih.gov Rare Disease Clinical Research Network (RDCRN) – Data Management and Coordinating Center Jan. 21 Tiina K. Urv, Ph.D., M.P.H., presented a renewal concept for the RDCRN Data Management and Coordinating Center (DMCC). The objectives are to (1) provide administrative, clinical research, data management, and regulatory support to the individual RDCRCs and the RDCRN; (2) provide a centralized cloud-based research environment with shared resources for the network and participants; and (3) coordinate cross-network activities, such as working group or special interest group meetings. In addition, the DMCC serves as a conduit of information related to the rare diseases research being conducted within the network to both the research community and the general public. The DMCC has three key areas of emphasis: (1) Promote clinical trial readiness and support and facilitate cross-consortia collaboration; (2) establish and promote standards and good data practices, emphasizing scientific rigor, FAIR (Findable, Accessible, Interoperable, and Reusable) data principles, and data sharing; and (3) develop and maintain a cloud-based research environment with shared tools. To date, the DMCC has provided services to more than 2,000 authenticated users across five continents and has developed 12 tools for shared network use (e.g., biospecimen tracking tool, pedigree drawing tool, Ambra Health, RStudio), 55 protocols in REDCap databases, several new and legacy forms, numerous new and legacy variables, and 1.5 terabytes of data in Box. The DMCC collaborated with the NCATS Information Technology Resources Branch to develop a two-pronged cloud-based workspace for RDCRN researchers. The RDCRN is a one-of-a-kind translational research network at NIH. A successful program is one in which the investigators are working in the research environment established by the network and using the tools made available. Success also will be measured by the achievements of the individual RDCRCs and the use and acceptance of DMCC-hosted collaborative tools and activities. Project/Program Officer: Tiina K. Urv, Ph.D. Program Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-827-2746 Email: Tiina.Urv@nih.gov 2021 Ethical Issues in Translational Science Research Sept. 24 Elaine Collier, M.D., presented a renewal concept for support of the Ethical Issues in Translational Science Research program. This program seeks to address bioethical, legal, and social questions affecting ongoing and future research and its translation. The Ethical Issues in Translational Science Research program addresses ethical issues that impede the translation of new discoveries and technologies by developing data and evidence in relevant areas, such as synthetic biology chimeras; gene editing; organoids; data collection, sharing, and privacy; machine learning and artificial intelligence; business models; citizen science; do-it-yourself science; and behavioral science. This program has garnered sustained interest from members of the translational science and ethics communities, and it has engaged stakeholders in ethical issues in translation. Program renewal will continue development of data and evidence to inform ethical issues that affect the translation of new discoveries and technologies and approaches to their application to health. The renewal will expand interest areas to include ethical, legal, and societal challenges related to racial and health disparities in the translation of discoveries at individual, community, institution, and society levels. It also will encourage collaboration among bioethicists, legal scholars, social scientists, and translational scientists. The renewal will extend the Ethical Issues in Translational Science Research program for an additional 5 years. The program will include two submission rounds per year, with only highly meritorious applications in translational science and bioethics research being selected for NCATS’ support. The expected result of this concept renewal is to foster sustained focus for translational science and bioethics research; increase the knowledge base addressing ethical, legal, and societal implications of translation of discoveries’ application to health; and recognize a professional community of experts. Project/Program Officer: Elaine Collier, M.D. Senior Advisor to the Director Office of the Director National Center for Advancing Translational Sciences Phone: 301-814-4286 Email: colliere@mail.nih.gov CTSA Collaborative and Innovative Acceleration (CCIA) Award Sept. 24 The CCIA concept seeks to enhance collaboration with NIH ICs and other stakeholders, emphasize transformative and high-impact projects that address the missions and strategic goals of NCATS and NIH ICs, and support all phases of innovative and high-impact projects. The CCIA program will require the collaboration of at least three CTSA Program Hubs or at least two CTSA Program Hubs plus at least one other eligible organization. The concept will emphasize work in late-stage translational science—such as clinical implementation and public health—and it seeks to change the funding mechanism to a performance-based approach driven by measurable milestones. The current R21 and U01 funding mechanisms will be replaced with UG3 and UH3 funding mechanisms, and awards will transition from UG3 to UH3 based on performance. UG3 awards will be for 2 years and focus on the development, demonstration, and feasibility assessment of innovative solutions that address scientific and operational barriers. UH3 awards will be for up to 3 years and focus on the dissemination, implementation, and evaluation of these innovative solutions. The new CCIA concept will advance translational science through evidence-based approaches, enhance collaboration with NIH ICs and other stakeholders, leverage CTSA Program resources, and enhance the translational process so innovative interventions to improve health can be disseminated more efficiently. This concept is intended to support synergistic activities that improve the translational research process through collaboration and innovation while integrating the CTSA Program with NIH-funded translational research networks and activities that advance translational science. Project/Program Officer: Soju Chang, M.D., M.P.H., FACPM Medical Officer Division of Clinical Innovation National Center for Advancing Translational Sciences Phone: 301-827-9206 Email: soju.chang@nih.gov Machine-Assisted Approaches to Shortening the Diagnostic Odyssey for Rare Diseases Sept. 24 The years-long delay in diagnosis and frequent misdiagnosis of rare diseases (i.e., the diagnostic odyssey) can last decades. NCATS proposes in this concept, via the Small Business Innovation Research (SBIR) program, to accelerate and improve diagnoses for rare diseases using machine learning approaches that are readily usable in front-line clinical settings. One objective of this concept is to develop machine-assisted approaches that accelerate and improve diagnoses for hard-to-diagnose patients and are applicable to a broad array of rare diseases. The strategies that are proposed or developed must be usable or adaptable to more than one health care setting, EHR, or database. The strategies also ideally would be usable and accessible by front-line clinicians and readily integrated into the clinical workflow of multiple care settings. Concept coordinators strive to progress in the following key areas: Permit early identification and escalation of patients at high risk for a rare disease through data mining or via remote assessment in an office or home setting. Permit collection, integration, or assessment of data points from multiple sources. Permit more accurate assessment of the rare disease patient’s overall medical utilization through new measures enabled through machine-assisted approaches. NCATS promotes the idea that small businesses, via the SBIR program, can provide innovative solutions to the identification of patients who are at high risk of having a rare disease or who have been misdiagnosed or are undiagnosed. Success in this area would be achieved via the development of an easy-to-use tool that is valuable to front-line clinicians and integrated into clinical practice, and for which accelerated diagnostic timelines can be shown. Accelerating rare disease diagnosis using available data in EHR or health care system databases could shorten the diagnostic odyssey, save resources through targeted disease-specific care, limit irreversible complications of disease by enabling timely intervention, and change the research environment for rare diseases such that all patients with a rare disease have a chance for disease-modifying therapy. Project/Program Officers: Anne R. Pariser, M.D. Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-402-4338 Email: anne.pariser@nih.gov Lili M. Portilla, M.P.A. Director of Strategic Alliances Office of Strategic Alliances National Center for Advancing Translational Sciences Phone: 301-827-7170 Email: portilll@mail.nih.gov NIH HEAL: Illuminating the Understudied Druggable Proteome Sept. 24 The Illuminating the Understudied Druggable Proteome concept will encourage research on understudied proteins within commonly drugged protein families to identify new targets for human disease. This will lay the groundwork for the exploration of these new targets for drug development by providing support for short-term projects that collect preliminary data on understudied proteins. This is a general concept for both NCATS and the NIH HEAL Initiative, and funding likely would come from both sources. The project will be disease agnostic, potentially covering all human diseases but focusing on NCATS and NIH HEAL Initiative priority areas, such as rare diseases and proteins associated with pain, addiction, and overdose. Successes from the Common Fund IDG program have demonstrated that small research awards around understudied proteins stimulate more research on “new” proteins. The target landscape for drug development would be larger, leading to the development of more treatments for more diseases. Success will be evaluated by monitoring the funding of new grants around targets studied under this initiative and by monitoring publications released around understudied targets. NCATS proposes this concept to expand the target landscape for drug development by providing a needed opportunity for the collection of preliminary data around the role of understudied druggable proteins in human disease and biologic processes. Identifying new targets associated with human disease is a critical first step in the development of novel, more efficacious treatments. Project/Program Officer: Karlie R. Sharma, Ph.D. Program Officer Office of Drug Development Partnership Programs National Center for Advancing Translational Sciences Phone: 301-451-4965 Email: karlie.sharma@nih.gov Helping to End Addiction Long-term (HEAL) New Innovator Awards Sept. 24 HEAL New Innovator Awards will support unusually creative early-career stage investigators from underrepresented backgrounds who propose innovative, high-impact research within the NIH HEAL Initiative domains of pain, addiction, or overdose. The emphasis of these awards is on the idea and the investigator, rather than the specific project. These awards could be applied to basic, translational, or clinical science. The HEAL New Innovator Award already has been established at the NIH, but this application is the first time that it will be focused on the NIH HEAL Initiative and underrepresented groups. Applications for this award will not contain a detailed experimental plan or preliminary data. Instead, they will focus on the potential of both the innovative idea and individual investigator. The major components of the application will be the significance of the project and the problem that it seeks to address, the general approach that will be applied to address the problem in HEAL domains, an explanation of how the project is unusually innovative, and the qualities and experiences of the investigators that qualify them to pursue such research. NCATS proposes this concept to foster original ideas from early-stage investigators in the HEAL fields and increase diversity within biomedical science. Success will be evaluated by monitoring the development of innovative approaches to treat pain, addiction, and overdose, as well as by examining the career trajectories of early-stage investigators from underrepresented groups who receive these awards. Project/Program Officer: Christine M. Colvis, Ph.D. Director Office of Drug Development Partnership Programs National Center for Advancing Translational Sciences Phone: 301-451-3903 Email: ccolvis@mail.nih.gov Trial Innovation Network Infrastructure for the HEAL Pain Management Effectiveness Research Network Sept. 24 One way the NIH HEAL Initiative seeks to stem the opioid crisis is through a focused effort on understanding, managing, and treating pain. Using existing TIN infrastructure, the HEAL Initiative established the ERN to conduct clinical trials addressing pain management questions for multiple pain conditions in one network to confront a need for safe and nonaddictive treatments that alleviate pain. NCATS proposes this concept to continue support of TIN infrastructure through a dedicated FOA for ongoing and future trials in the HEAL ERN. Funding for this concept will be provided by the NIH HEAL Initiative. The HEAL ERN has the following objectives: Compare the effectiveness of existing safe, nonaddictive therapies or ways to deliver current therapies. Strengthen and inform current guidelines for pharmacologic and nonpharmacologic treatments for acute and chronic pain. Provide patients and practitioners with a suite of effective strategies to alleviate pain and reduce reliance on opioids. Manage acute and chronic pain in people from diverse communities. Improve patients’ quality of life. The TIN facilitates the attainment of these objectives by providing infrastructure through three key components: Trial Innovation Centers, Recruitment Innovation Centers, and CTSA Program Hubs. The TIN provides many services to ensure the successful implementation and completion of ERN trials. The ERN and TIN networks coalesce into a synergistic structure through which individual NIH HEAL Initiative awards support trial study teams and participant costs. Trials address pain management questions that are of interest to multiple NIH ICs. The NCATS TIN provides clinical support, biostatistical coordination, and recruitment and retention support. Trials are conducted within and outside of CTSA Program Hubs to allow the recruitment of diverse patients with multiple pain conditions. The HEAL ERN currently is conducting five clinical trials: Effectiveness of an mHealth Psychosocial Intervention to Prevent Transitions from Acute to Chronic Postsurgical Pain in Adolescents Integrated Treatment for Veterans with Co-occurring Chronic Pain and Opioid Use Disorder Tailored Non-pharmacotherapy Services for Chronic Pain: Testing Scalable and Pragmatic Approaches A Sequenced Strategy for Improving Outcomes in Patients with Knee Osteoarthritic Pain Optimizing the Use of Ketamine to Reduce Chronic Postsurgical Pain NCATS’ TIN is providing clinical, data, recruitment and retention, and biostatistical support in all clinical trial phases. The trials span multiple demographics, pain conditions, and NIH ICs. Despite COVID-19 delays, all the trials have met their required milestones and have been approved to move forward. Continued support of TIN infrastructure will enable HEAL ERN study teams to complete ongoing studies and facilitate future NIH HEAL Initiative studies by addressing critical roadblocks innovatively, leveraging the expertise and resources of the CTSA Program, and accelerating the translation of interventions into therapies in real-world settings. Trial results will advance NIH HEAL Initiative efforts to stem the opioid crisis by identifying safe, nonaddictive interventions and management strategies for pain; generating an evidence base to inform treatment guidelines for acute and chronic pain; and providing patients and practitioners with a suite of strategies to alleviate pain and reduce reliance on opioids. The goal of this concept is to provide continued support of existing TIN infrastructure that is enabling ongoing and new trials in the HEAL ERN. Funding for this concept will be provided by the NIH HEAL Initiative. Project/Program Officer: Yolanda F. Vallejo, Ph.D. Program Director Division of Clinical Innovation National Center for Advancing Translational Sciences Phone: 301-451-1751 Email: yolanda.vallejo@nih.gov Contract Support for NCATS Intramural R&D Activities June 11 R. Dwayne Lunsford, Ph.D., presented a renewal concept for contract support of the NCATS intramural research and development (R&D) activities. NCATS proposes to renew this concept to complement in-house scientific capabilities of the DPI scientists—who require a variety of support services—and also to maintain access to mission-critical research services. DPI advances translational science by decreasing the risk of investing (i.e., de-risking) in promising new targets and therapies for indications that otherwise lack private-sector funding. Since the original concept was approved in 2015, the DPI has generated data for regulatory filings (pre- IND and IND stage), contributing to 19 INDs. The DPI also developed diverse therapeutic targets and drug candidates (e.g., small molecules, peptides, bio-therapeutics). Regarding implementation and impact, NCATS will issue new requests for proposals (RFPs) addressing the relevant technical service areas. It is expected that contracts will allow seamless continuity of operations supporting ongoing and future collaborations and will include a Determination of Exceptional Circumstances (DEC) clause to protect the IP rights of the collaborators. Project/Program Officer: R. Dwayne Lunsford, Ph.D. Deputy Director Therapeutic Development Branch Division of Preclinical Innovation National Center for Advancing Translational Sciences Phone: 301-402-8462 Email: robert.lunsford@nih.gov LitCoin Prize Competitions June 11 Christine M. Colvis, Ph.D., informed the Council that the LitCoin concept was developed with the desire to help researchers share their data in a model that meets NIH requirements and the needs of investigators. NCATS will pilot test the project with the anticipation that the NIH National Library of Medicine and journal publishers will lead the efforts on a broader scale. Tyler F. Beck, Ph.D., presented the concept for establishing LitCoin prize competitions. This concept addresses three main issues. First, data are not machine-readable. Second, generating computationally accessible data is costly and involves manual curation. Third, few incentives exist to promote data-sharing. In addition, early-career researchers have few mechanisms to share reproducible results outside of their respective disciplines. NCATS proposes to incentivize and enhance the sharing of machine-readable knowledge from biomedical publication free text. Dr. Beck described the LitCoin conceptual framework, which consists of four key roles of engagement: author, NCATS, publisher, and other researchers. The author makes a discovery, writes a short publication, and uploads the text to the LitCoin server. NCATS facilitates a natural language processing (NLP) tool to build assertions and displays them back to the author, who verifies and then submits to the publisher. The publisher reviews the assertions and approves them for publication. The NLP deposits the information to a dedicated database. Other researchers can then cite the published findings and the data remain available and open to the public. NCATS proposes two challenge competitions. Challenge 1, LitCoin NLP Challenge, will be a software contest to generate highly accurate, computationally accessible data from free text. The competition is planned for fall 2021 and winners will be required to grant a broad, permissive license to the NIH to use, alter, and redistribute the software. Challenge 2, LitCoin Concept Challenge, will encompass a competition to generate end-to-end plans to build the LitCoin submission platform, commencing in spring or summer 2022. NCATS anticipates combining ideas from multiple winners to inform and plan the next step, a LitCoin Development concept. To engage stakeholders, NCATS, in collaboration with NLM and four publisher partners, hosted a virtual LitCoin Stakeholder Feedback Workshop June 17–18, 2021. The DDPP sought advice from the Council on key factors to enable success of this program and ideas on enhancing adoption and dissemination of LitCoin. Project/Program Officer: Tyler F. Beck, Ph.D. Scientific Program Officer Office of the Director Drug Development Partnership Programs National Center for Advancing Translational Sciences Phone: 301-827-1943 Email: tyler.beck@nih.gov Clinical and Translational Science Award (UM1) June 11 Erica K. Rosemond, Ph.D., presented the CTSA UM1 award concept. NCATS proposes this concept to support an integrated research and training environment for clinical and translational science. The objectives and areas of emphasis align with the six main objectives of the Program. This concept addresses the RFI responses to decrease applicant administrative burden, increase CTSA Hub flexibility specialization opportunities, and introduce a distinct clinical and translational science research project. NCATS proposes to simplify the application and budget, enhance review quality, and streamline award actions. With the UM1 mechanism, applications will be simpler, less repetitive, more organized, and have a single budget. The Hub career development and optional training components will be separate, allowing for independent scores and reviews. The administrative adjustments will speed processing the awards. In terms of flexibility, this concept will require fewer elements, emphasize unique qualities, and create a Hub-specific research project. The activities of the CTSA will be retained, reorganized and grouped more appropriately, and balanced and focused on the Hub’s activities. These enhancements will allow the Hubs to showcase unique strengths and capabilities. The unique clinical and translational science research project will address existing roadblocks to translational research. This concept builds on the existing CTSA Program and nurtures innovations in clinical and translational science. Project/Program Officer: Erica K. Rosemond, Ph.D. Acting Deputy (Division) Director and Acting (Branch) Chief Division of Clinical Innovation Clinical and Translational Science Awards Program Branch National Center for Advancing Translational Sciences Phone: 301-594-8927 Email: Erica.Rosemond@nih.gov Specialized Innovation Programs (SIPs) (RC2) June 11 Erica K. Rosemond, Ph.D., presented the new SIPs RC2 concept, which aligns with the RFI responses to increase flexibility and diversity across Hubs to leverage strengths and drive innovation, allow awardees to specialize, and balance local efforts with Consortium efforts. The aim of this concept is to provide support to SIPs through an RC2 funding mechanism, with the goal of catalyzing clinical and translational science locally through the support of unique activities, resources and/or expertise at CTSA Hubs. The proposed innovation ecosystem will consist of a CTSA UM1 Hub (local and national collaborations), RC2, Collaborative Innovation Awards (R21/U01), and Consortium-wide centers (U24), all focusing on improving health. The goals of the SIPs are to support highly specialized capabilities or resources—with local impact and considerations for early dissemination—and to create a streamlined program-level tracking of outcomes and impact. SIPs will be peer reviewed separately and only Hub awardees will be eligible to apply. Examples of SIPs include telehealth, regulatory science, clinical informatics, genetics and genomics, pragmatic trials, dissemination and implementation, rural health and health disparities, community outreach and engagement, and other specialized programs. Project/Program Officer: Pablo Cure, M.D., M.P.H. Program Director Division of Clinical Innovation Clinical and Translational Science Awards Program Branch National Center for Advancing Translational Sciences Phone: 301-827-2014 Email: pablo.cure@nih.gov National Research Service Award (NRSA) Institutional Predoctoral and Postdoctoral Research Training Grants (T32) June 11 Mercedes Rubio, Ph.D., presented the NRSA Predoctoral and Postdoctoral Research Training Grant (T32) concept, which aligns with NCATS Strategic Goal 3 to develop and foster innovation in translational training and a highly skilled, creative, and diverse translational science workforce. This NRSA T32, which replaces the CTSA Program TL1, has the objectives to customize research training opportunities, provide high-quality research training, develop characteristics and attributes of successful translational scientists, and promote evidence-informed mentoring practices. In FY 2020, 181 postdoctoral trainees, 305 predoctoral trainees, and 34 short-term/summer training positions were supported. This concept is expected to enhance the career and training education opportunities available to the clinical and translational science workforce and nurture the clinical and translational science field. Project/Program Officer: Mercedes Rubio, Ph.D. Program Director Division of Clinical Innovation National Center for Advancing Translational Sciences Phone: 301-480-8957 Email: rubiome@mail.nih.gov Institutional Career Development Award (K12) June 11 Joan Davis Nagel, M.D., M.P.H., presented the K12 concept. The CTSA Institutional Career Development Program (KL2) offers postdoctoral scholars and junior faculty advanced training in clinical and translational science research and allows 75 percent of protected time for research. The proposed K12 will provide customized career development and education opportunities to align with local institutional strengths and resources; and will promote flexible, innovative learning models to engage scholars in team science, individual development plans, and advanced research training. The concept also will promote evidence-informed mentoring practices and includes a leadership and management component. This concept aligns with NCATS Strategic Goal 3 to develop and foster innovation in translational training and a highly skilled, creative, and diverse translational science workforce. NCATS anticipates that the K12 will nurture the characteristics of a translational scientist, with enhanced tracking of scholar outcomes and measures of impact. The K12 is expected to create a clear and sustainable career pathway for junior faculty, enable scholars to acquire the knowledge and skills needed to cross translational science hurdles, and expand the field of translational science. This concept will support the next generation of diverse clinical and translational scientists who have the knowledge, skill sets, and abilities to advance discoveries across the translational science spectrum to improve health. Project/Program Officer: Joan Davis Nagel, M.D., M.P.H. Medical Officer Division of Clinical Innovation National Center for Advancing Translational Sciences Phone: 301-827-2512 Email: joan.nagel@nih.gov Research Education Grant (R25) June 11 Jamie Mihoko Doyle, Ph.D., presented a concept for the CTSA Research Education Grant (R25). The NIH R25 grant supports activities that complement or enhance workforce training; enhance diversity; help recruit individuals with specific specialty or disciplinary backgrounds; and foster a better understanding of biomedical, behavioral, and clinical research and its implications. Currently, 25 R25 funding opportunities are active across the NIH. Very few training programs have short-term agendas. The current CTSA TL1 programs can include predoctoral, postdoctoral, and short-term positions. This NCATS R25 concept provides an opportunity to expand, enhance, and meet local needs with the objective to support short-term clinical and translational research experiences (10 to 15 weeks) not available through formal NIH training mechanisms. The overarching goal is to build a pathway for a translational science workforce of the future. Project/Program Officer: Jamie Mihoko Doyle, Ph.D. Program Director Division of Clinical Innovation National Center for Advancing Translational Sciences Phone: 301-402-0403 Email: doylejm@mail.nih.gov Helping to End Addiction Long-termSM Initiative or NIH HEAL InitiativeSM Translational Science Training Jan 15 Dr. Colvis presented the NIH HEAL InitiativeSM translational science training concept. The NIH HEAL Initiative, a trans-NIH effort to speed scientific solutions to stem the national opioid public health crisis with a focus on developing novel pharmacotherapies to treat pain, opioid use disorder and overdose. It is well known that therapeutic discovery, development, and deployment is a complex process. Traditional training often occurs within a small segment of this process. In addition, workplace diversity in biomedical research is less than optimal, particularly within therapeutic discovery and development. The objective of this concept is to provide NIH HEAL Initiative funds to support early- and mid-career scientists who are expert in pain or opioid use disorders research to receive in-depth training in therapeutic development in an academic or government translational research center or in an industry setting. The area of emphasis directly addresses the lack of workplace diversity in drug development by specifically providing translational training to individuals from underrepresented groups. The goal is to build a workforce of investigators better equipped to translate scientific discoveries into clinical breakthroughs. The NCATS anticipates that this opportunity will provide the fields of pain, dependency, and overdose with scientists better equipped to design experiments with an emphasis on translating discoveries to affect health. Importantly, incorporating a translational perspective in the early- and mid-career stages will promote the guiding NCATS principle of bringing “more treatments to more patients more quickly.” Project/Program Officers: Christine M. Colvis, Ph.D. Director, Drug Development Partnership Programs Office of the Director National Center for Advancing Translational Sciences Phone: 301-451-3903 Email: ccolvis@mail.nih.gov Steven T. Pittenger, Ph.D. Program Officer Office of the Director Drug Development Partnership Programs National Center for Advancing Translational Sciences Phone: 301-827-5810 Email: steven.pittenger@nih.gov Technological Development and Validation of Remote Measures for Use in Clinical Trials in Individuals with Rare Diseases Jan 15 Tiina K. Urv, Ph.D., and Lili Portilla, M.P.A., presented an SBIR contract concept on technological development and validation of remote measures for use in clinical trials in individuals with rare diseases. Rare disease patients face significant barriers to participation in clinical trials due to travel limitations, health issues, as well as financial difficulties. Although virtual clinical trials (e.g., remote or decentralized trials) leverage technologies to overcome these barriers, validated measures specific for use in remote clinical trials and studies are missing. This concept proposes to use U.S. small businesses to develop and validate sensitive and specific outcome measures that are technologically viable for use in clinical trials in patients with rare diseases. The objectives are two-fold: (1) facilitate virtual studies by developing and validating outcome measures that can be assessed remotely and that are suitable for use in clinical trials and (2) develop robust, user-friendly technologies to collect these assessments. This research will capture accurate and replicable data remotely in the patient’s family environment (e.g., adaptive life skills, strength). It also will collect continuous variables and provide a more accurate assessment of the patient’s real condition through new measurements made possible by technology. Consistent with NCATS mission, this concept supports the three “Ds” to develop, demonstrate and disseminate innovative interventions that benefit public health, enabling a more diverse group of individuals to participate in rare disease clinical trials. Because of the success of NCATS SBIR-funded projects in stimulating technological innovation and meeting research and development needs, commercialization of these technologies is expected to result in significant patient benefit. Project/Program Officers: Tiina K. Urv, Ph.D. Program Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-827-2746 Email: urvtiin@mail.nih.gov Lili M. Portilla, M.P.A. Director, Office of Strategic Alliances National Center for Advancing Translational Sciences Phone: 301-827-7170 Email: lili.portilla@nih.gov CTSA Consortium-Wide Centers: Resources for Rapid Demonstration and Dissemination (C3-R2D2) Jan 15 Audie A. Atienza, Ph.D., presented a concept on establishing the CTSA Consortium-Wide Centers: Resources for Rapid Demonstration and Dissemination (C3-R2D2) initiative, which proposes to leverage capabilities and expertise across the CTSA Program to advance Clinical and Translational Science (CTS). Innovations within CTS require multidisciplinary teams with diverse and unique skill sets. Three centers currently share capabilities and expertise across the consortium: the CTSA Data to Demonstrate Health (CD2H), Centers supported through the Trial Innovation Network (TIN), and the Center for Leading Innovation and Collaboration (CLIC). Over the past few years, CTSAs’ successes have expanded beyond coordinating communications, facilitating data harmonization and data sharing, and using innovative approaches in clinical trial recruitment. NCATS proposes the C3-R2D2 initiative to build on these successes and focus on research demonstration and dissemination at the consortium level. The administrative tasks for the CTSA Program are in the process of being transferred to a support contract mechanism approved by NCATS Council during the January 2020 meeting. The objective of this concept will be to leverage subject matter expertise across the CTSA Program to develop and provide consortium-level resources and capabilities for specific categories of innovative approaches. Potential areas of emphasis may include health information technology (e.g., mobile health/telemedicine, electronic health records interoperability and data exchange), research-impact quantification, trial designs and recruitment approaches, and platforms/processes that facilitate satisfying regulatory requirements. This initiative also will be responsive to emerging high-priority topics. In establishing the C3-R2D2 initiative, NCATS anticipates overcoming clinical and translational science roadblocks; accelerating dissemination methodologies across the CTSA consortium for uptake of knowledge, research tools, methods, and data; and identifying, implementing, and disseminating consortium-wide resources for faster adoption to positively affect patients and public health. The overarching goal is to rapidly accelerate CTSA consortium-wide collaborations toward innovative, game-changing, high-impact clinical and translational science advances. Project/Program Officer: Audie A. Atienza, Ph.D. Program Director Division of Clinical Innovation National Center for Advancing Translational Sciences Phone: 301-435-0198 Email: audie.atienza@nih.gov Clinical Trial Readiness (CTR) for Rare Diseases Jan 15 Alice Chen Grady, M.D., presented a renewal concept for the CTR for Rare Diseases, Disorders and Syndromes grants program, aiming to support studies that are addressing critical gaps in rare diseases clinical trials, including lack of (1) validated biomarkers and clinical outcome assessments necessary for selecting appropriate endpoints in rare diseases and (2) a trial readiness priority area needed by regulatory agencies. NCATS proposes this renewal concept to support projects focused on efficiently and effectively advancing candidate rare diseases therapeutics (or diagnostics) into clinical trials and to increase their likelihood of success in upcoming clinical trials. The program focuses on rare diseases that currently (or soon will have) candidate therapeutics or diagnostics ready for testing in clinical trials and projects that leverage partnerships and existing NCATS resources (e.g., RDCRN). The first CTR grants were awarded in summer of FY 2019. To date, NCATS and the NICHD have collaborated to fund two Small Research Grant (R03) awards and 16 Exploratory/Developmental Research Grant (R21) awards, through three funding cycles. Regarding accomplishments, nine publications citing this relatively young CTR program have been reported in the NIH Research Portfolio Online Reporting Tools, and several projects show promising data. For example, Children’s Hospital of Philadelphia investigators are working to validate an objective outcome measure of therapeutic response in a pediatric rare disease population. NCATS and the NICHD recognize an ongoing need to provide FOAs for studies that address specific gaps in understanding the natural history of disease, suitable biomarkers, and appropriate clinical outcome measures. Project/Program Officer: Alice Chen Grady, M.D. Program Officer Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-827-2015 Email: alice.chen2@nih.gov 2020 Small Research Grants for NCATS Clinical and Translational Science Award (CTSA) Program Sept. 17 Erica K. Rosemond, Ph.D., presented a concept to establish small research grants within the CTSA Program. These grants will address the challenge of speeding up the clinical and translational science research process that typically takes multiple steps and time to deliver a solution to any single operational problem. To speed up this research process, NCATS is proposing small clinical and translational science research projects, which can be leveraged to advance science more quickly and identify “fast-fail” decision points in the project. The objectives and emphasis will be that these small, self-contained research projects can (1) address general roadblocks in science or operations that limits the efficiency and effectiveness of translation, and (2) develop, demonstrate or disseminate innovative solutions or new or improved treatments that will have an impact on improving the health of patients. In addition, the small research grants will provide an opportunity to support the transition of clinical and translational scientists to achieve independent investigator status. In implementation, these grants will help research support projects get over a roadblock, catalyze a tangible scientific outcome and allow projects to fail fast resulting in a change in approach. The overall impact will be assisting young (i.e., early-career) investigators in building their independent research portfolios and transitioning to careers as independent academic translational scientists. Project/Program Officer: Erica K. Rosemond, Ph.D. Deputy Director, CTSA Program Hubs Division of Clinical Innovation National Center for Advancing Translational Sciences Phone: 301-594-8927 Email: rosemonde@mail.nih.gov Translational Ethics Collaboratories Sept. 17 Elaine Collier, M.D., presented a concept of a translational ethics collaboratories program, a next phase in the NCATS ethics research program. Although novel discoveries and emerging technologies offer potential to improve health, the possibility for harm to health or to the norms of individuals, families and communities—as well as of society—remain. The goals of the concept are threefold: (1) support institution-independent collaborative transdisciplinary teams to conduct research on ethical, legal and societal issues related to the application of a novel discovery or emerging technology to improve health, (2) provide research ethics consultation outreach to the research community in a selected area of emphasis, and (3) collect data on this consultation model. The collaboratory area of emphasis (e.g., synthetic biology, gene modification or data aggregation) must present an ethical issue involved in translation and requires a research consultation project. NCATS is the only NIH Institute or Center that targets systemic issues agnostic of disease, specialty or age across the entire research spectrum, from basic and clinical research to research focused on health care and public health. The translational ethics collaboratories will fill a gap in the knowledge and practice necessary to advance novel discoveries to improve human health in emerging areas. NCATS anticipates that the collaboration of translational scientists, ethicists, legal scholars and social scientists becomes comfortable and routine and facilitates interdisciplinary translational ethics research and consultation. The outcome will provide evidence on the usefulness of research ethics consultation and the effectiveness of models. Project/Program Officer: Elaine Collier, M.D. Senior Advisor to the Director Office of the Director National Center for Advancing Translational Sciences Phone: 301-814-4286 Email: colliere@mail.nih.gov Genetic and Rare Diseases (GARD) Information Center Sept. 17 Eric Wk Sid, M.D., M.H.A., presented a renewal concept for the GARD Information Center. GARD was launched in response to the Rare Diseases Act of 2002 and congressional mandate to provide consumer health information on rare diseases. Over the past 5 years, the demand for information— with contact center inquiry volume doubling and research evidence exponentially increasing — has outpaced GARD staff’s capabilities to manually maintain and expand content. The GARD Information Center currently is the most visited NCATS webpage, and the traffic (2 million users per month) has at times paralleled that of the NIH home page. The goal of this concept renewal is to modernize the GARD program and enhance NCATS’ public health role in delivering reliable information about rare diseases to patients and caregivers. The objectives will be to sustainably audit research on the more than 7,000 current and newly identified rare diseases and enhance the ability of GARD to be of maximum use to patients and caregivers. The key areas of emphasis include developing both a research dashboard to quantify and visualize the research evidence in the rare disease portfolio and a translational science framework to educate consumers on rare disease evidence interpretation. A total of 34 public datasets comprising 3.8 million data points are now integrated into GARD’s database from existing NCATS programs and other rare diseases resources. In this next phase, efforts will focus on investigating translational science approaches to leverage these data. NCATS anticipates that this GARD modernization will clear the contact center’s inquiry backlog by automating processes to stay abreast of new research findings and improve the ability of rare disease patients and caregivers to make decisions using these data, with the outcome of shortening the diagnostic journey for patients with rare diseases. Project/Program Officer: Eric Wk Sid, M.D., M.H.A. Program Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-827-3073 Email: eric.sid@nih.gov Scanning for Conditions with Electronic Nose Technology (SCENT) Sept. 17 Danilo Tagle, Ph.D., M.S., presented the SCENT concept. The goal is to develop a noninvasive and portable diagnostic device that provides rapid and accurate diagnosis of a variety of medical conditions, facilitating treatment of patients. The most pervasive method of sensing in nature, detection of scents and odors, has scarcely been used in the diagnosis of disease. This concept aims to reverse engineer a bio-mimic of the sense of smell found in canines for disease diagnostics, involving several steps — from the detection of the smell/odor, to data acquisition and processing, to comparisons of known patterns, and the readout via a mobile device or portable system. Leah Tolosa Croucher, Ph.D., explained that the objectives of the concept are to use volatile organic compounds (VOCs) that are released through the skin and/or breath as the key substrate, integrate the components of the various SCENT instrumentation and software, and establish VOC signatures unique for each disease. The SCENT devices will adhere to the Affordable, Sensitive, Specific, User-friendly, Rapid and robust, Equipment-free and Deliverable to end users (ASSURED) criteria outlined by the World Health Organization (WHO). Machine learning and artificial intelligence will be incorporated to rapidly analyze the VOC signatures unique for each disease and condition, and to ensure that the WHO ASSURED criteria are met. The anticipated result would be a market-ready handheld/wearable, noninvasive diagnostic device that is expected to decentralize diagnostic testing, bringing it closer to patients and resulting in improved care and patient outcomes. Project/Program Officers: Danilo A. Tagle, Ph.D., M.S. Associate Director for Special Initiatives Office of the Director Office of Special Initiatives National Center for Advancing Translational Sciences Phone: 301-594-8064 Email: Danilo.Tagle@nih.gov Leah Tolosa Croucher, Ph.D. Program Officer Office of the Director Office of Special Initiatives National Center for Advancing Translational Sciences Phone: 240-701-2580 Email: Leah.Croucher@nih.gov Novel Explorations in Rare Diseases (NERD) Sept. 17 Dr. Pariser presented the novel explorations in rare diseases concept and noted the rationale for such a program. Extracting rare disease patient information from existing health care system databases is exceedingly challenging and often unreliable. The available tools are not readily usable for rare diseases, especially multi-disease explorations/analyses. Data extraction is unique to individual data environments (e.g., electronic health record (EHR) system, region/location). NCATS is proposing this concept to quantify the impact, including cost and health care utilization, of rare diseases on patients and health care systems. The objectives are threefold: (1) develop methodology to accurately and broadly estimate the prevalence of rare diseases and associated health care utilization, (2) develop patient journey maps across different diseases to objectively describe and quantify the diagnostic odyssey and (3) adapt machine learning software and tools to derive this information directly from primary source data. Key focus areas include identifying, with reproducibility, patients with rare diseases within different health care databases, quantifying the overall impact, and working with partners and/or vendors to develop the necessary methodology and tools. Regarding implementation, a NERD 14-disease pilot is being conducted intramurally, and some efforts are in progress externally with academic and industry partners in the United States and Western Australia. NCATS envisions this concept as having the transformative potential to improve understanding of the magnitude of rare diseases and their impacts on the health care and research systems and on the well-being of patients and their survival. Project/Program Officer: Anne R. Pariser, M.D. Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-402-4338 Email: anne.pariser@nih.gov Rare Diseases Informatics Platform (RDIP) Sept. 17 Dr. Pariser presented a concept to establish a rare diseases informatics platform, which builds on the NCATS GARD and NERD proposals. This concept will address several needs. First, most rare disease information routinely used are estimates and are not easily traceable back to the primary data sources. Second, current data analysis efforts are discrete, siloed and do not comprehensively meet the perquisite for timely rare diseases information. Third, the ability to collect and integrate rare disease information from multiple sources (e.g., insurance, EHR or research) is lacking. To address these needs, NCATS proposes this concept to support the collection, integration and analysis of rare diseases data from diverse sources. This information will inform NCATS’ rare diseases research initiatives and priorities. The objectives are to create and staff an RDIP or knowledge center; collect, integrate and analyze rare diseases data from diverse sources to provide objective information for multiple purposes; and incorporate ongoing ORDR data initiatives within one central location. NERD is being designed as a model for building the RDIP, which will harmonize approaches or data models to integrate with or leverage other ongoing NCATS informatics programs, such as GARD, DCI-data initiatives and the Biomedical Data Translator. Project/Program Officer: Anne R. Pariser, M.D. Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-402-4338 Email: anne.pariser@nih.gov Bespoke Gene Therapy Consortium (BGTC) Coordinating Center Sept. 17 P.J. Brooks, Ph.D., presented a concept on the BGTC Coordinating Center. Many monogenic rare diseases could benefit from gene therapy using adeno-associated virus (AAV) vectors. For diseases of no commercial interest, navigating the multiple steps (e.g., vector production and toxicity testing) necessary to get to a clinical trial, as well as the clinical trial itself, is a major challenge. To address this challenge, NCATS, the FDA Center for Biologics Evaluation and Research, and the Foundation for the NIH (FNIH) are establishing the BGTC, a major component of the FNIH Gene Therapy Accelerated Medicines Partnership (AMP). NCATS proposes a BGTC Coordinating Center to support these multiple steps using contract mechanisms, all under the direction of the Coordinating Center. The objectives are to coordinate contract activities for the BGTC and evaluate novel collaborative approaches to support gene therapy clinical trials for rare diseases. In addition to accelerating rare diseases clinical trials, other areas of emphasis for this concept include collaboration with multiple stakeholders (e.g., FDA, private industry, nonprofits and rare diseases PAGs) and commitment to ensuring that the diseases chosen for study will include those affecting racial and ethnic minority populations. The BGTC Coordination Center and its activities are expected to be synergistic with other NCATS programs and initiatives, such as the Platform Vector Gene Therapy (PaVe-GT) project. In the long-term, knowledge gained and best practices will be parlayed into the AAV-based gene therapy clinical trials for rare diseases handbook and broadly disseminated. Project/Program Officer: Philip John (P.J.) Brooks, Ph.D. Program Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-443-0513 Email: pj.brooks@nih.gov A Specialized Platform for Innovative Research Exploration—ASPIRE-ing Beyond HEAL May 14 Danilo A. Tagle, Ph.D., M.S., presented a new concept to expand the ASPIRE Program. He reminded the Council that the ASPIRE initiative originally was proposed in September 2017 to address key translational challenges: (1) the uninterrogated vast chemical space (1063) of potential pharmacologically active molecules, (2) the undrugged biological space (5 × 105), and (3) an outdated reaction toolkit for accessing the relevant chemical space. To address these issues, NCATS convened the “Workshop on Automated Chemical Synthesis” on Oct. 19–20, 2017, to identify the associated research opportunities, challenges and roadblocks. Subsequently, NCATS officially launched ASPIRE in 2018, as a pilot program funded by the Helping to End Addiction Long-termSM Initiative, or NIH HEAL InitiativeSM with an extramural component through prize competitions and challenges, and an intramural component to build an automated chemistry infrastructure. For this new concept that goes beyond the initial HEAL investment, Dr. Tagle noted the goals will be to establish a collaborative structure involving multidisciplinary expert teams from NCATS intramural and extramural scientists that takes advantage of the validated open-source infrastructure as well as tools and technologies within NCATS Division of Preclinical Innovation toward general translational challenges in synthetic chemistry. Samuel Michael described the intramural components of the ASPIRE modular platform, which includes automation, informatics, consumables, chemistry, analytical, and biology modules, as well as technology development. The initial platform will be a 16-module design with integrated automation and technology components. Dr. Tagle highlighted that the outcome will be a disseminatable platform for automated chemical synthesis, biological testing, and machine learning–driven optimization. NCATS anticipates that this platform will broadly enable the identification and synthesis of novel biologically active chemical structures with drug-like characteristics. The potential exists for a much-needed expansion of the chemical space toward new and improved therapeutics, which would catalyze an innovative and collaborative ecosystem. Project/Program Officers: Danilo A. Tagle, Ph.D., M.S. Associate Director for Special Initiatives Office of the Director Office of Special Initiatives National Center for Advancing Translational Sciences Phone: 301-594-8064 Email: Danilo.Tagle@nih.gov Samuel G. Michael Chief Information Officer Information Technology Resources Branch Office of Administrative Management National Center for Advancing Translational Sciences Phone: 301-827-7796 Email: michaelsg@mail.nih.gov Extended-Longevity Tissue Chips for Modeling Chronic Exposures May 14 Lucie A. Low, Ph.D., presented a concept on extended-longevity tissue chips for modeling chronic exposures. Dr. Low noted that NCATS has been the leader in developing and advancing the tissue chip/MPS technology and remains key leaders in the field to guide and facilitate ongoing efforts across the NIH, FDA, industry and other government agencies. As tissue chip technology is becoming more mainstream and industrialized, other funding agencies now are supporting their own tissue chip programs. This initiative would be a joint initiative between two divisions within the National Aeronautics and Space Administration (NASA), the Biomedical Advanced Research and Development Authority and the Translational Research Institute for Space Health. In addition, six NIH Institutes and Centers have expressed interest in joining. The partner agencies are in the process of obligating funds for this initiative. NCATS and NASA recently signed a memorandum of understanding to express interest in this joint initiative. Tissue chips generally are designed to last up to 28 days of culture per FDA requirements for drug testing. However, participants attending two NCATS and NASA co-sponsored workshops on the “State of the Science” for tissue chips identified the need to extend the tissue chip lifespan beyond 6 months (i.e., extended longevity tissue chips). This enables broader use of tissue chip technology for a number of applications. Therefore, the goals of this concept are to extend the lifespan of tissue chips beyond 6 months and to model their exposure to perturbations (e.g., drugs or compounds, radiation and environmental hazards) during the 6-month period. The outcome will be reproducible and viable platform operation for long-term tissue chip function with proficiency for continuous monitoring, probing and sampling of the biological tissues. The research will enable in vitro assessment of long-term safety and toxicity studies and provide platforms that can be used for testing drug candidates, drug combinations and drug-drug interactions over extended time periods (e.g., platforms that can give accurate readouts at 18 or 180 days). NCATS hopes the initiative will spur development of robust automated platforms that are amenable to remote operation and sensing of tissue function. A key aim of Cures Acceleration Network (CAN) programs is the “handoff” of mature technologies to new users. In line with this aim, and unique to this tissue chip initiative, is that external partners will provide 75% of funding, and NCATS investments will be minimal. Project/Program Officer: Lucie A. Low, Ph.D. Scientific Program Manager Office of the Director Office of Special Initiatives National Center for Advancing Translational Sciences Phone: 301-594-7609 Email: a href="mailto:lucie.low@nih.gov">lucie.low@nih.gov Drug Screening with Biofabricated 3-D Disease Tissue Models May 14 Dobrila D. Rudnicki, Ph.D., presented a concept on drug screening with biofabricated 3-D disease tissue models. This concept expands existing NCATS initiatives, including the Pilot Program for Collaborative Drug Discovery Research using Bioprinted Skin Tissue and the Drug Screening with Biofabricated 3-D Skin Disease Tissue Models. The goals and primary objectives are threefold: (1) to synergize extramural and NCATS intramural expertise and resources, (2) to develop physiologically relevant and validated 3-D models that can be incorporated into novel drug screening platforms, and (3) to advance discovery and development of more effective and safe treatments for a number of diseases. Dr. Rudnicki explained that the program will support intramural-extramural collaborations for the development of these models and will provide important resources and protocols enabling the extramural community to continue development in this area. The program will help shift the paradigm from 2-D to 3-D models for drug screening and enhance the strength and value of intramural-extramural collaborations to advance translation. Project/Program Officer: Dobrila D. Rudnicki, Ph.D. Program Director Office of the Director Office of Special Initiatives National Center for Advancing Translational Sciences Phone: 301-594-2080 Email: drobrila.rudnicki@nih.gov Artificial Intelligence in Health Care May 14 Karlie R. Sharma, Ph.D., presented a concept on advancing artificial intelligence (AI) in health care. The concept was developed in collaboration with Christine M. Cutillo, M.M.C.i. and will leverage NCATS’ existing AI and informatics efforts. The importance of using AI in health care is well emphasized in the clinical community, but translating such innovative tools for clinical applications remains a challenge. In recent weeks, many laboratories and companies have attempted to use AI for COVID‑19 treatments. These, in addition to other recent examples, illustrate the urgent need for new paradigms for the development and application of these innovative AI-based tools before and as they are deployed into clinical care settings, because misdiagnoses from AI systems can result in fatal consequences. Dr. Sharma highlighted several unique challenges that have impeded the progress of AI in health care; these challenges include barriers to data sharing, ineffective implementation into clinical care workflows, and transparency in ethical issues. To address these issues, NCATS sponsored a workshop focusing on machine intelligence in health care in July 2019. Three key topics emerged from the discussion that rose to the top as timely and aligning with the NCATS purview: testing algorithms in the real world prior to their implementation, prioritizing reproducibility and robustness of AI systems, and improving communication across groups developing these systems and the community that will use them. This concept aims to (1) develop a pipeline for testing algorithms prior to implementation in the clinic, and (2) in the long-term, improve trust in and uptake of AI systems in the health care setting. In a proof-of-concept approach, NCATS will develop and test the pipeline with use case algorithms and demonstration projects (Stage 1), then use the tested pipeline to assess newly developed algorithms focused on urgent clinical needs in a variety of disease areas (Stage 2). The outcomes of the research will be (1) a fully formed and vetted pipeline equipped with standard operating procedures, creating a framework for comprehensive algorithm assessment in real-world environments; (2) distributable algorithms that can be implemented across health systems worldwide; and (3) dissemination of results and resources to the broader research community to facilitate the creation of other AI pipelines by the community modeled after the initiative-developed pipeline. NCATS anticipates that the incorporation of these algorithms into clinical practice will create new sources of reliable information for clinicians to better diagnose and treat patients. Project/Program Officers: Karlie R. Sharma, Ph.D. Program Officer Office of the Director Drug Development Partnership Programs National Center for Advancing Translational Sciences Phone: 301-451-4965 Email: karlie.sharma@nih.gov Christine M. Cutillo, M.M.C.i. Data Science Lead Office of the Director National Center for Advancing Translational Sciences Phone: 301-402-4006 Email: cutilloc@mail.nih.gov Multisensory Virtual/Augmented Reality (VR/AR) Systems and Rehabilitation for Rare Disease Patients May 14 Mr. Michael presented the SBIR contract concept on the topic multisensory VR/AR and rehabilitation for patients with rare diseases. The senses (e.g., audio, visual and hand haptics) are limited in current VR/AR systems but could benefit from taking advantage of other senses that include full-body haptics (e.g., TESLASUIT), smell and taste. Research has shown that VR/AR immersive experience can reduce pain and discomfort in rehabilitation and, potentially, in clinical settings. In addition, the AI and machine learning algorithms can generate individualized immersive experiences, which must be verified for efficacy, user needs, and preferences. The challenge is that individuals respond differently to these environments and systems must be tailored. This contract concept will support the development of multisensory VR/AR systems that adapt intelligently to each individual for the assessment and rehabilitation of patients with rare diseases. The aim is to assess the efficacy of the systems in clinical and rehabilitation settings for these patients through biofeedback readings and user self-reports. Developing such systems could benefit the ORDR by enabling technology-based applications for the rare diseases community. Applications include pain management and rehabilitation, remote monitoring and data capture for clinical trials, and diagnostic assistance for rare diseases with motor components. NCATS will solicit SBIR applications to develop a virtual environment proof-of-concept system that incorporates dynamic audio, visual, full-body haptic and olfactory stimuli. The system should incorporate runtime logfile capabilities for remote patient monitoring and performance analytics and a human-in-the-loop system model that addresses patient personalization and biofeedback. The outcome will be a system that provides users a VR/AR pipeline to influence the accessibility, affordability and accuracy of therapeutic treatment and clinical use; design guidelines and efficacy considerations for existing VR/AR platforms; a multisensory tool or suite of tools for remote patient monitoring; and an AI-driven user behavioral model for adapting rehabilitation stimuli. The intent is that these remote-based systems would assist with clinical monitoring and rehabilitation efforts for patients with rare diseases, especially in cases where travel is impossible or difficult. The systems are intended to benefit the entire research community. Project/Program Officer: Samuel G. Michael Chief Information Officer Information Technology Resources Branch Office of Administrative Management National Center for Advancing Translational Sciences Phone: 301-827-7796 Email: michaelsg@mail.nih.gov Platform for Rapidly Deployable Autonomous Laboratory May 14 Mr. Michael presented the SBIR contract concept on the topic of a platform for a rapidly deployable autonomous laboratory, which aligns with the NCATS ASPIRE initiative. The COVID-19 pandemic—and subsequent physical distancing and closing of research laboratories—has led to the postponement of critical experiments necessary for developing novel diagnostics and potential therapeutic interventions. The purpose of this SBIR contract concept is to develop next-generation distributed, AI-enabled, fully automated laboratories that are linked to a cloud-based virtual research organization (VRO) to acquire, harmonize, store, analyze and share data generated during experimentation. The goals are to create a platform consisting of modular automated devices capable of performing laboratory tasks for both diagnostic and therapeutic discovery purposes. NCATS will solicit SBIR applications to develop the following: (1) a distributed, modular, autonomous lab instrumentation platform that focuses on such areas as HTS for drug discovery, next-generation sequencing, high content imaging, and polymerase chain reaction diagnostics and (2) a cloud-based VRO that connects each automated laboratory and AI methods that integrate the lab data into the VRO, allowing real-time data collection and analysis. NCATS will leverage its collaboration with Kebotix, Inc., on AI/machine learning models and HTS. Carleen Klumpp-Thomas, M.S. described an example of use of the proposed platform. In collaboration with the National Institute of Biomedical Imaging and Bioengineering (NIBIB), one of its a small laboratory without automated equipment was upgraded. The automation increased the laboratory’s analysis capacity from 500 to 10,000 samples, and copious data were collected in real time and exported into a VRO. Mr. Michael noted that the outcomes of the SBIR contract concept will be a system that provide users (1) a platform that enables the on-demand initiation of physical experiments across laboratories, (2) a cloud‑based VRO that houses data suited for analysis, and (3) a modular platform that can quickly add or scale up additional resources necessary for responding to public health emergencies. NCATS anticipates that using SBIR contract mechanisms will create opportunities for small businesses to facilitate an emergency commercialization for rapidly scalable instrumentation. Project/Program Officers: Samuel G. Michael Chief Information Officer Information Technology Resources Branch Office of Administrative Management National Center for Advancing Translational Sciences Phone: 301-827-7796 Email: michaelsg@mail.nih.gov Carleen A. Klumpp-Thomas Research Services Core Lead Division of Preclinical Innovation National Center for Advancing Translational Sciences Phone: 301-827-1789 Email: klumppc@mail.nih.gov Clinical and Translational Science Awards Program Operations Support Jan. 16 Clare K. Schmitt, Ph.D., presented a contract concept for operations support for the CTSA Program–related grantee and NCATS staff activities. The aims of the CTSA Program are to accelerate translation of research discoveries into improved care for patients by addressing systemwide clinical and translational research problems collaboratively; disseminate the expertise, tools, training and clinical research innovations for effective treatments; and support a diverse translational science workforce. The goal of this operations support contract concept is to provide effective and efficient management of this large, complex national CTSA Program, including the ongoing administrative tasks (e.g., supporting the consortium-wide agendas and large-scale Program deliverables). Specific operations support tasks will include transfer of the NCATS Specific, Measurable, Achievable, Realistic and Timetable (SMART) institutional review board (IRB) platform from the current grantee for long-term management and receipt and distribution of funds from other NIH Institutes and Centers and sister agencies for emergent clinical trial needs. In addition, the operations support contract will provide meeting and conference support and manage data safety monitoring-related activities in clinical trials. The expected outcomes will be the consolidation of multiple activities under one contract and addition of needed tasks, allowing grantees to focus their intellect and efforts on addressing the CTSA Program goals and, therefore, NCATS goals. Regarding plans to promote and ensure sustainability, the activities and platforms will be hosted on the NCATS cloud platform, so a transition plan is required. Project/Program Officer: Clare K. Schmitt, Ph.D. Deputy Director Division of Clinical Innovation National Center for Advancing Translational Sciences Phone: 301-827-3787 Email: clare.schmitt@nih.gov Supporting Clinical Trials of a Prime Genome Editor in Multiple Genetic Diseases Jan. 16 P.J. Brooks, Ph.D., presented the concept of supporting clinical trials of a prime editor (e.g., CRISPR) for the treatment of multiple genetic diseases. The current approach to gene-editing clinical trials is focusing on one disease at a time. This approach is based on commercial considerations, which is not optimal for addressing the thousands of rare monogenic diseases that exist. In 2019, researchers discovered a modified CRISPR Cas9 (CRISPR-associated protein 9) technology that has the potential to correct 90 percent of human disease–causing mutations without introducing double-strand DNA breaks or increasing the risk of cancer. The DCI and ORDR are interested in expanding these findings to NCATS programs and clinical trials. The concept goals are to assess the feasibility of clinical trials of a prime editor in multiple rare monogenic diseases and identify and overcome any feasibility challenges for such trials. Dr. Brooks emphasized that the concept would leverage ongoing efforts, such as the NCATS CTSA Program and the NIH Common Fund Somatic Cell Genome Editing program. This initiative will use the general framework of the CCIA program and will support clinical trials that focus on defects in a somatic cell type to which a single prime editor can be delivered (e.g., liver hepatocytes). Depending on the technology delivery method, potential regulatory issues involving the FDA Center for Biologics Evaluation and Research may need to be addressed. Several outcomes are expected, including identifying and overcoming challenges in conducting these types of clinical trials, increasing the number of rare disease patients in trials, and maximizing the clinical impact of somatic genome editing. If successful, this project will fundamentally change the way genome editing in rare diseases clinical trials are conducted. Results will be disseminated to both the gene editing and rare disease research communities via the CTSA Program and publications. Ultimately, the goal is to identify a regulatory pathway for clinical trials of a prime editor that includes rare disease patients. Project/Program Officer: Philip John (P.J.) Brooks, Ph.D. Program Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-443-0513 Email: pj.brooks@nih.gov SaME Therapeutics—Clinical Trials of Drugs Targeting Shared Molecular Etiologies in Rare Diseases Jan. 16 Dr. Brooks presented the concept of supporting rare diseases clinical trials of drugs targeting SaME therapeutics. Although thousands of rare diseases exist, the number of underlying causes (i.e., etiologies) is small. The SaME approach is the focus of ongoing drug development. In addition, drugs targeting SaME in different cancers are considered state-of-the-art in oncology, and the approach has established a regulatory pathway for these types of FDA drug approvals. Although discussion and interest in SaME for rare diseases have increased in the Collaborative Forum on Rare Diseases and the International Rare Disease Research Consortium, no clinical trials are ongoing. The goals of the concept are to adapt the oncology SaME approach to rare diseases and identify and overcome any challenges. It is anticipated that recruiting for clinical trials based on SaME will dramatically increase the number of rare disease patients in trials, translating to more treatments delivered to more patients more rapidly. The concept will leverage the RDCRN, and the results will be disseminated to the community via this Network and publications. The expected outcome will be the ability to stratify patients according to underlying etiology rather than traditional clinical characteristics, thus transforming rare disease clinical trials. Project/Program Officer: Philip John (P.J.) Brooks, Ph.D. Program Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-443-0513 Email: pj.brooks@nih.gov 2019 Rare Diseases Are Not Rare! Challenge 2.0 Sept. 19 Alice Chen Grady, M.D., explained that the first NCATS rare diseases prize competition, Challenge 1.0, sought creative ways to raise awareness about rare diseases and the need for expanded research, new treatments and patient support. The competition opened in 2018, and nearly 50 submissions were received. Participation was widespread and generated innovative works of art that educated the public about rare diseases. For details on the three winning submissions and honorable mentions, visit the NCATS Rare Diseases Are Not Rare! Challenge Winners and Honorable Mentions page of this site. The overarching goals of Challenge 2.0 are to change the public perception of “rare” and foster collaborations across the rare disease community. Metrics for success will be defined in advance and could possibly inform ORDR public-facing programs. Children can directly submit entries with the appropriate consent. In addition to increasing public awareness about rare diseases, the many people affected, and common challenges encountered, NCATS could use the Challenge 2.0 submissions to strongly convey the message about the ongoing need for rare diseases research and new treatments. This concept builds on the success of the NCATS 2018 prize competition and aligns with some ongoing rare diseases activities, such as the patient organization-sponsored competitions and the emphasis of the NCATS RDCRN to study multiple diseases at a time and include patient groups as partners in research. Project/Program Officer: Alice Chen, M.D. Medical Officer Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-827-2015 Email: alice.chen2@nih.gov Ethical, Legal and Societal Implications in Translational Research May 16 Emerging discoveries and technologies raise potential ethical and legal issues that also may have societal implications. Evidence suggests that the familiarity and collaboration of translational researchers and bioethics and legal scholars can be beneficial. To advance discoveries to impact health responsibly, engagement and collaboration of researchers, scholars, communities and the public are needed. Major obstacles that need to be addressed regarding ongoing research and activities in this area include the establishment of the Neuroethics Working Group within NIH’s Brain Research through the Advancing Innovative Neurotechnologies (BRAIN) Initiative and the National Human Genome Research Institute’s Ethical, Legal and Social Implications Research Program. The objectives of this initiative are to increase recognition of and research on these issues, encourage research on these challenging questions to collect data, foster collaboration between the two communities, and provide empirical data and frameworks for addressing these issues. The outcomes will be increases in projects, scholarship, research collaborations and stakeholder engagement in these areas. Project/Program Officer: Elaine Collier, M.D. Senior Advisor to the Director Office of the Director National Center for Advancing Translational Sciences Phone: 301-814-4286 Email: colliere@mail.nih.gov Non-Viral Delivery Technologies for Somatic Genome Editing Therapeutics May 16 Somatic genome editing has the potential to treat a large number of rare genetic disorders and has therapeutic implications for common diseases. Therapeutic benefit is maximized if the genome editing machinery has broad coverage in many somatic cell types. For many diseases, the ability to deliver genome editors to relevant cell types is the limiting factor. Non-viral delivery methods allow transient expression of genome editors, which is expected to reduce toxicity. The objective of this initiative is to support the development of non-viral technologies to deliver genome editing machinery to a wide variety of cells and tissues, especially in cell types with no effective delivery technology currently available. Project/Program Officer: Philip John (P.J.) Brooks, Ph.D. Program Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-443-0513 Email: pj.brooks@nih.gov Alternatives to Commercially Available Cell Culture Insert Membranes and Manufacturing Techniques May 16 Despite the increased focus on the use of more complex cellular and tissue models (e.g., 3-D tissue printing) to provide physiologically relevant platforms for enhancing the development of therapeutics for patients, challenges exist. Biodegradable cell culture-insert membranes that also provide structural support are needed, as existing commercially available alternatives are insufficient. The objective of this initiative is to a support a small business, via an SBIR contract mechanism, that can provide a commercial solution to manufacture cell culture insert membranes in an automated and reproducible manner. Project/Program Officer: Samuel G. Michael Chief Information Officer Information Technology Resources Branch Office of Administrative Management National Center for Advancing Translational Sciences Phone: 301-827-7796 Email: michaelsg@mail.nih.gov Multidisciplinary Approaches to Shortening the Diagnostic Odyssey for Rare Diseases May 16 Many patients with a rare disease experience years-long delays in receiving a correct diagnosis (i.e., the “diagnostic odyssey”), lending to considerable anxiety and despair for patients and families as well as potential delays in treatment. Current approaches to the rare disease diagnostic odyssey typically occur through idiosyncratic referrals to a small number of disease experts at tertiary care centers. The objective of this concept is to improve diagnostic accuracy and accelerate diagnosis for these patients through a multidisciplinary process that can be performed at the primary or secondary care levels by front-line providers. Novel approaches need to be developed that should focus on an integrated combination of clinical, computer-assisted and genomics assessments to speed diagnosis and improve accuracy. Some current activity exists in each of these areas, but no comprehensive methods have been developed that are using multiple approaches simultaneously that have been adopted by front-line clinicians. The outcome will be the development of a broadly adaptable, facile process with the potential impact of advancing the International Rare Diseases Research Consortium’s 2027 goals of achieving an accurate diagnosis within one year of a rare disease patient presenting for medical evaluation. Project/Program Officer: Anne R. Pariser, M.D. Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-402-4338 Email: anne.pariser@nih.gov 2018 Drug Development Collaboratory Sept. 27 The proposed Drug Development Collaboratory would include the intramural Therapeutic Development Branch – within the NCATS Division of Preclinical Innovation – to conduct Investigational New Drug (IND)-enabling studies, develop regulatory strategy and allow changes in drug delivery and formulation. The goals of the Collaboratory are to develop a strategic process for applicants to collaborate across multiple NCATS programs; optimize drug delivery method, formulation and regulatory strategy; develop milestones; assist with clinical trial study design; and provide continuity of support across existing programs. NCATS Therapeutic Development Branch will provide IND-enabling data and expertise. Applicant institutions will provide access to disease-specific knowledge, expertise, access to models/assays and access to patient populations that are available at applicant institutions. NCATS Drug Development Partnership programs will support preclinical through early-stage clinical trials that are conducted at applicant institutions. HEAL Pain Effectiveness Research Network (HEAL Pain-ERN) Sept. 27 The evidence for optimal pain management, such as long-term opioid use for management of chronic pain, is often insufficient. The NIH Help End Addiction Long-term (HEAL) Pain-ERN would conduct clinical trials and studies to establish interventions or programs to manage, reduce or prevent acute and chronic pain in ways that reduce risk for addiction and provide evidence to inform practice-based guidelines. The HEAL Pain-ERN will leverage the existing Clinical and Translational Science Award Trial Innovation Network (TIN) to implement studies of interest to multiple NIH Institutes and Centers (ICs). The proposed infrastructure would include TIN Clinical and Data Coordinating Centers and a Pain Leadership Group that would report to entities within NIH, including the Pain IC Councils and the NIH Pain IC Directors. The National Institute of Neurological Disorders and Stroke will provide the repositories for clinical data and biosamples. A trans-NIH group will write the FOAs. The trials and studies will use standard outcome measures whenever possible, and all data will be stored centrally to ensure data sharing. The initiative will help coordinate pain research across different disciplines, help resolve the problem of having limited outcome measures for pain and provide more functional pain measures. CTSA Program: Competitive Supplement Applications to Develop, Demonstrate and Disseminate Translational Science Advances Sept. 27 This program will provide supplements to translational science projects that address the goals of the Clinical and Translational Science Awards (CTSA) Program. These are peer-reviewed competitive supplements that could extend beyond the scope of the parent grant. The supplements will allow projects to respond to emerging scientific opportunities, stimulate high-priority translational science areas and provide the opportunity to extend new projects, activities and collaborations across the CTSA Program consortium. The supplements will allow the development of new approaches, the demonstration of their efficacy and the dissemination of the findings. Success will be measured in terms of the ability of the proposed activities to advance translational science and increase and broaden the overall impact of the CTSA Program. CTSA Program Collaborative Projects Program May 10 The objective of the Clinical and Translational Science Awards (CTSA) Program Collaborative Projects Program is to support innovative and sustainable approaches to overcome roadblocks in translation by building upon strengths at individual CTSA Program hubs. The program will support dissemination of successful methods and processes developed at individual hubs, thereby strengthening and enhancing the impact of the CTSA Program. The program is expected to have a sustainable and transformative impact on multiple domains of translational science. Examples of challenges to be addressed include the lack of underrepresented minorities participating in clinical trials, the lack of natural language processing capacity in translational research, and variations in training opportunities across the CTSA Program. For more information, please see the CTSA Program Collaborative Innovation Awards. Non-Polydimethylsiloxane Biocompatible Alternatives for Organs-on-Chips May 10 Polydimethylsiloxane (PDMS) is widely used in the construction of tissue chips. However, PDMS sometimes displays undesirable properties, such as drug absorption, which can lead to drug/compound loss and/or cross-contamination of surrounding areas or tissues. What is needed is an alternative material, in whole or in part, for fabricating tissue chips. The objective of the Non-Polydimethylsiloxane Biocompatible Alternatives for Organs-on-Chips initiative is to find such alternative materials that would improve the in vivo predictive capabilities and reliability of various microfluidics platforms. Limited supplemental funding has previously been provided to tissue chip project researchers to develop PDMS alternatives; however, this initiative would expand the opportunity to a broader community. Synthetic Technologies for Advancement of Research and Therapeutics May 10 The cost of developing a new drug now exceeds $1 billion. One factor exacerbating the situation is that libraries of compounds have exhausted the limits of structural diversity; it is increasingly difficult to find new compounds with chemical activity. Use of natural products for therapies has been limited due to low yields in their host organism, limited supply of some host organisms, the complexity of natural compounds’ structures and the difficulty of modifying them. Synthetic biology can generate novel, biologically active compounds through advances in scientific disciplines (e.g., gene editing, gene synthesis, automation, metabolomics) to enhance the diversity of drug libraries. The Synthetic Technologies for Advancement of Research and Therapeutics (START) program would formulate natural, biologically relevant pathways to engineer new and safer therapies; expand the current catalog of naturally occurring compounds and their analogues; identify, characterize and synthesize novel bioactive compounds; and enhance productivity and yield of biological systems that produce natural compounds. The START program has the potential to catalyze the field of synthetic biology for drug development. Universal Medium/Blood Mimetic for Use in Integrated Organs-on-Chips May 10 For the Tissue Chip for Drug Screening program to continue to be successful, organ chips need to be integrated to form multi-tissue platforms. This was a goal from the outset of the program. Integrating systems is challenging, however, due to the tissue chips’ 3-D structure, heterogeneity of cell types and fluid flow. The objective of the Universal Medium/Blood Mimetic for Use in Integrated Organs-on-Chips initiative is for small businesses, using the NCATS Small Business Innovation Research (SBIR) contract mechanism, to develop a universal medium/blood mimetic that could be used in integrated systems and maintain cell viability and function for at least one month. Having a universal medium will enable researchers to link many new tissue types, increasing the utility of the chips and expanding access to the technology to a wider community for commercialization and dissemination. Also, such a medium could be used in other systems across laboratories and could have utility in other tissue-engineered systems, such as 3-D bioprinting. Clinical Trial Readiness for Rare Diseases Jan. 11 The objective of the Clinical Trial Readiness for Rare Diseases initiative is to support clinical studies that address obstacles to the design of trials needed for rare diseases. Such trials are critical in the development and evaluation of new treatments for rare diseases. This initiative aims to support studies that address these bottlenecks by focusing on specific gaps in natural history data and biological and clinical outcome measures. Addressing bottlenecks in rare diseases clinical development will accelerate progress from discovery to patient benefit and thus is directly aligned with the mission of NCATS and NIH. Read the full Concept Clearance (PDF - 282KB). 2017 Rare Diseases Clinical Research Network Program Sept. 7 The Rare Diseases Clinical Research Network (RDCRN) program was established in late 2003, with expansion and renewal occurring in 2009 and 2014. Through this reissuance, this cooperative agreement research program will continue to facilitate identification of biomarkers for disease risk and disease severity/activity and measures of clinical outcome applicable to clinical trials. It also will encourage development of new approaches to diagnosis, prevention and treatment of rare diseases. The RDCRN will consist of all funded Rare Disease Clinical Research Consortia (RDCRC) and a single Data Management and Coordinating Center. It will support the continuation of a collaborative and coordinated network of RDCRCs composed of investigators at multiple institutions/sites and patient advocacy groups committed to investigation of rare diseases working in partnership to enhance clinical research focusing on natural history studies, providing training to young investigators, and sharing of resources in a multidisciplinary approach. Read the full Concept Clearance (PDF - 63KB). 2016 CTSA Program Data to Health Initiative Sept. 15 The objective of NCATS’ CTSA Program Data to Health initiative is to demonstrate and disseminate through its Clinical and Translational Science Awards (CTSA) Program the advances in informatics that can help catalyze the translation of discoveries into health benefits. To maximize its potential impact on human health, NCATS, through the CTSA Program, should promote the collaborative collection, management and analysis of biomedical research data from diverse sources, including CTSA Program-affiliated researchers, health care organizations, mobile devices, patients and/or caregivers. Read the full Concept Clearance (PDF - 95KB). NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules Sept. 15 NCATS launched the Discovering New Therapeutic Uses for Existing Molecules program in May 2012. The objective of a re-issued initiative is to support the exploration of new therapeutic uses for investigational drugs or biologics (assets) from across a broad range of human diseases. Assets have undergone significant preclinical and safety testing in humans and are ready for additional testing in patient populations. Bringing together the best assets from pharmaceutical companies with the best new ideas from academic researchers could produce new treatments much more quickly than starting from scratch. The overarching goal is to enable an efficient drug repurposing partnership model that is adopted broadly by the biomedical research community. Read the full Concept Clearance (PDF - 71KB). Development of Drone Labware June 13 The objective of this contract is to develop an autonomous drone capable of taking a laboratory consumable (such as a well plate) from one station to another. NCATS has had success in using the Small Business Innovation Research contract mechanism to address needs for improvement in the high-throughput screening (HTS) realm. NCATS believes that there would be a potential market opportunity for a small business to develop lab drone technology for HTS applications because: Drones have a much greater range of motion than stationary robotic arms and are cheaper to maintain. In an HTS setting, it is difficult to have robotic arms in shared workspaces, due to synchronization concerns and the possibility of collision. Lab drones can occupy the same airspace, allowing for the coordination of multiple drones in the same work area. The open-source community is constantly developing new tools to make drones more efficient and cheaper. While there is a great deal of drone technology in the marketplace, its use in the lab is limited and not available to the research community, specifically in the HTS field. Read the full Concept Clearance (PDF - 60KB). The NIH/NCATS Registry Program June 13 The objective of this initiative is to provide a coordinated and comprehensive approach for NCATS to promote standardized patient registries that are feasible and sustainable and that result in high-quality data to advance clinical research and therapy development. The awardee(s) will provide centralized operational, informatics, and data and project management support to ensure a sound and efficient approach to supporting high-quality and high-impact patient registries for NCATS. Patient registries, collections of standardized information, are an indispensable resource in rare diseases research, since they contribute to multiple phases of the research lifecycle, including participant recruitment for research studies (contact registries); development of datasets to better understand disease progression, biomarkers and clinical outcomes (natural history registries); and collection of safety and efficacy data after regulatory approval (post-marketing registry). Read the full Concept Clearance (PDF - 22KB). Clinical and Translational Science Data Metrics Coordinating Center Jan. 14 The Clinical and Translational Science Awards (CTSA) Program supports a national network of medical research institutions — called hubs ― that work together to improve the translational research process to get more treatments to more patients more quickly. Ensuring that this investment transforms the entire spectrum of clinical and translational science, including multi-site clinical trials, requires CTSA Program hubs to catalyze innovation in training, research tools and processes. Achieving this goal requires significant coordination and collaboration across the CTSA Program hubs. The functions of the proposed center are integral to the success of the entire CTSA Program. Read the full Concept Clearance (PDF - 87KB). Collaborative Innovation Pilot Projects for the CTSA Program Jan. 14 The purpose of this initiative is to allow teams of investigators from different Clinical and Translational Science Awards (CTSA) Program hubs to carry out collaborative, innovative projects to evaluate novel approaches to important translational science questions. This exploratory grant program will allow some novel approaches to be quickly evaluated for feasibility and will provide a potential source of funding for collaborative innovative approaches that are not well suited to the Collaborative Innovation Awards (PAR-15-172 and PAR-15-173). Read the full Concept Clearance (PDF - 66KB). 2015 Drug Repurposing/Repositioning Sept. 3 The purpose of this concept is to develop a set of funding opportunity announcements (FOAs) to support robust, preclinical studies (to establish rationale for a clinical trial), clinical trial planning and clinical trial implementation. The preclinical studies will serve as “use cases” to demonstrate the usefulness of the drug-indication pairing method. Appropriate FOAs will be issued to complement the ongoing NCATS New Therapeutic Uses initiatives. While the goal of an individual project will be to explore the potential new use of existing investigational and Food and Drug Administration-approved drugs, NCATS seeks to identify strategies that may improve the efficiency of drug repurposing studies. Funding will be used to repurpose drugs where the hypothesis originates from the use of a publicly available method for identifying new indications for existing drugs such as independent crowdsourcing strategies for investigational drugs or computational algorithms. Read the full Concept Clearance (PDF - 34KB). Ethical, Legal and Social Implications of Biomedical and Translational Research Sept. 3 As technology and science advance, members of the research community confront evolving and recurring questions about the ethical, legal and social implications (ELSI) of their research and its translation to improve human health. ELSI arise across the entire spectrum of biomedical and translational research, including basic, preclinical, clinical, behavioral, implementation and dissemination science as well as population health. This collaborative initiative with multiple NIH Institutes and Centers (ICs) would seek research projects that address the ELSI of biomedical and translational research of high importance to the participating NIH ICs. Applications to conduct empiric research as well as those that propose to develop new conceptual frameworks would be allowed. Interdisciplinary and collaborative projects using multiple approaches would be strongly encouraged. ELSI research is critical in the biomedical and translational science domain. The results of projects under this initiative are expected to contribute knowledge that will enhance the ethical conduct and social value of biomedical and translational research in support of the NIH mission. Read the full Concept Clearance (PDF - 18KB). Translational Research Informatics and Operations Support Sept. 3 The purpose of this contract requirement is to provide coordinated and comprehensive scientific and technical support for NCATS translational and clinical research operations and management in order to harmonize and centralize activities across NCATS. Activities are wide-ranging and will include translational and clinical research operations support, information management, safety oversight and administrative support. This contract will provide clinical, operational and administrative support for the Clinical and Translational Science Awards Program to achieve its goals to catalyze clinical and translational science. The contractor will assist NCATS staff in managing the clinical and operational activities and provide information management of NCATS’ clinical activities. A centralized information system will allow NCATS to quantify and describe characteristics of individual clinical studies to analyze the overall clinical program. Additionally, the awardee will provide support for ensuring human subject safety and quality monitoring of NCATS clinical studies. Read the full Concept Clearance (PDF - 26KB). Collaborative Innovation Supplements for CTSA Program June 18 This supplement program will allow NCATS to provide administrative supplement funds to investigators from different Clinical and Translational Science Awards (CTSA) hubs to carry out collaborative, innovative demonstration projects and move towards dissemination. The focus is aligned with that of the Collaborative Innovation Awards but intended to be smaller in scale and shorter in duration. This supplement program will allow novel approaches to be quickly evaluated for feasibility and provide a potential source of funding for collaborative innovative approaches that are not well suited to the Collaborative Innovation Awards program (PAR-15-172 and PAR-15-173). The purpose of the administrative supplement is to allow teams of investigators from different CTSA hubs to carry out collaborative, innovative projects to evaluate novel approaches to important translational science questions. Read the full Concept Clearance (PDF - 22KB). Development of SmartPlate Technology June 18 The term “smartplate” was adopted to imply flexibility to the technology and multiple applications of the smartphone. Once a platform was built to create a phone that could perform a variety of functions, as opposed to simply one, a huge amount of innovative ideas sprang forth. The key goal of this Small Business Innovation Research solicitation is to fundamentally transform the idea of a microtiter plate from a single-use laboratory ware for an experiment to nearly becoming an instrument that could provide more data about the tested samples by in-line monitoring and sensing technologies. Instead of limiting these plates to a variety of plastics with a lifespan of one use, if different materials and manufacturing techniques were utilized, it could greatly affect the purpose(s) for which a plate could be used. Imagine the plate as a multilayer circuit, for example; it could be possible for a variety of monitor and control applications be built directly into the plate, such as temperature, relative humidity, and CO2 and O2 levels, instead of relying on external pieces of instrumentation to perform these measurements. A key goal tied to this technology is to greatly improve the utility of a microtiter plate being completely disposable and instead treat each plate as a fully integrated device that can be used many times. Read the full Concept Clearance (PDF - 39KB). Development of Stem Cell- or iPS Cell-Based Assays for Compound Toxicity Evaluation June 18 There is a growing interest in testing environmental chemicals by using human stem cell or cells derived from induced pluripotent stem (iPS) cells, because transformed and immortal cell lines lack xenobiotic metabolic capability and fail to represent normal physiology and pathophysiology. For the phase I contract, the goal is to develop toxicologically related assays in a homogenous format that can be used in human stem cell or iPS-derived cells with short-time compound treatment. For phase II contracts, the goal is to miniaturize the assays into 384-well and 1,536-well plate formats. Assays with various endpoints using iPS-derived cells in a 1,536-well plate format will greatly speed up the capacity of screening thousands of environmental chemicals. Also, using human stem cells and/or iPS-derived stem cells will make this screening approach even more relevant and the data more valuable in establishing predictive models of how these chemicals compounds affect human tissues and pathways, ultimately making this technology the basis for future screening for the Toxicology in the 21st Century program and other quantitative high-throughput screening initiatives. The purpose of the Small Business Innovation Research (SBIR) contract solicitation is to use assays developed from the SBIR contract proposals to test toxicologically related targets in a large compound collection of environmental chemicals and pharmaceutical compounds. Read the full Concept Clearance (PDF - 104KB). NCATS Exploratory Clinical Trials for Small Business June 18 This proposed funding opportunity announcement (FOA) will use small businesses under the Small Business Innovation Research/Small Business Technology Transfer grant program to support early and exploratory clinical trials. Examples of appropriate clinical studies under this FOA include those whose primary aim is to evaluate and optimize the dose, formulation, safety, tolerability or pharmacokinetics of an intervention or diagnostic in healthy volunteers or the target population; conduct prospective clinical validation of a therapeutic intervention; and evaluate whether an intervention produces sufficient evidence of short-term activity (e.g., biomarker activity, dose-response trends, pharmacodynamic response) in a human proof-of-concept trial. The purpose of the FOA is to support applications from small businesses for clinical trials (i.e., phase I and II clinical studies) of drugs, biologics, devices or diagnostics — as well as surgical, behavioral or rehabilitation therapies — that contribute to the justification for and provide the data required to design a future trial to confirm efficacy (i.e., a phase III clinical trial). Read the full Concept Clearance (PDF - 46KB). R&D Contract Support for NCATS Translational Sciences June 18 NCATS is interested in advancing collaborative research projects across the phases of the translational science spectrum. These research projects are designed to overcome key obstacles and inefficiencies in the translational process. While the mechanisms for overcoming obstacles differ, multiple NCATS programs require access to contract resources to achieve their missions. For example, the Therapeutics for Rare and Neglected Diseases (TRND) and Bridging Interventional Development Gaps (BrIDGs) programs heavily rely on contract research organizations (CROs) to provide manufacturing, pharmacology, toxicology, regulatory and clinical operations services to achieve milestones of their projects. All projects within TRND and BrIDGs programs require services compliant with Good Manufacturing Practice and Good Laboratory Practice, which cannot be performed within NCATS’ own laboratories. Other NCATS programs, such as Chemistry Technology and Matrix Combination Screening, regularly use CROs to profile molecules that are being investigated internally. Under this proposed initiative, NCATS will request proposals from vendors to provide long-term contract services for NCATS programs in various preclinical and clinical therapeutic development areas. The purpose of the request for proposals is to obtain long-term contract laboratory services in support of the mission of the NCATS Division of Preclinical Innovation. Read the full Concept Clearance (PDF - 87KB). Small Business Translational Science Innovation Award Program June 18 This proposed Small Business Innovation Research/Small Business Technology Transfer program announcement (PA) will focus on innovative translational science. Translating biomedical discoveries into clinical applications is essential to improving human health. It is also a complex process with high costs and substantial failure rates that can result in delays of years or decades before improved patient outcomes result from discoveries in biomedical research. The scientific and operational issues that underlie most translational inefficiency are not specific to a particular disease, discipline, institution or geographic locale. Rather, they are systematic issues, which require systematic and generalizable solutions. Further, every stage of the translational process currently is fraught with ineffectiveness and in need of bold, innovative new solutions. Through this PA, we aim to enlist the small business community in this effort. We anticipate that the efforts supported through this PA will proceed in parallel with and synergize with ongoing activities in the Clinical and Translational Science Awards (CTSA) consortium under PAR-15-172 and PAR-15-173. The goal of the proposed PA is to incentivize small businesses to develop products to address bold and innovative new solutions to problems in translational sciences, as outlined in PAR-15-172 and PAR-15-173. Another goal is to stimulate partnerships between small businesses and the CTSA network. Read the full Concept Clearance (PDF - 47KB). 2014 Innovative Collaborations for the CTSA Consortium Sept. 19 Turning discoveries into clinical advances is a long and inefficient process. The proposed initiative aims to accelerate translational research in specific areas of research and at the same time to more broadly advance our understanding of translational science, the field focused on best scientific and operational methods. The focus of the innovative collaborations initiative is less on the development of technologies de novo, but more on the demonstration that innovative approaches can be applied to translational research problems, or can help address roadblocks. The projects should define the positive outcome, describe how it is measured, and include plans for next steps under different outcome scenarios. At project completion, the data generated should allow for a decision as to whether the approach should be abandoned in favor of alternatives, or whether it should be optimized and disseminated more widely in support of translational research. Therefore, data quality is critical, and robust experimental approaches are encouraged. When feasible, approaches might for example include the randomization or cluster randomization to different interventions that would allow for comparisons between contemporary arms or between pre- and post-intervention scenarios. Projects under this initiative are demonstration projects, and will be considered successful if they provide high-quality data on an innovative and generalizable approach so that the field moves forward. The projects are thus expected to have an impact almost regardless of their outcome by accelerating the uptake of an effective innovation, or by alternatively making it clear which approaches should be discontinued in favor of alternative investments. As appropriate, projects will include pre-defined milestones to monitor progress. The goal of this initiative is to stimulate collaborative research in the CTSA consortium. Building on the existing strengths at the CTSA hubs, and utilizing resources already funded by NCATS under the CTSA program, the collaborative projects under the proposed initiative will address important gaps in clinical and translational research, and will advance innovative solutions with the goal to get more treatments to more patients more quickly. Read the full Concept Clearance (PDF - 122KB). Proposed CTSA Initiatives May 16 The Clinical and Translational Science Awards (CTSA) program has evolved continually since its inception in 2006. In 2011, the CTSA program was positioned under the leadership of NCATS to build upon its existing strengths and to ensure its further development in alignment with the NCATS mission to enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions. An Institute of Medicine (IOM) study of the CTSA program, released in June 2013, recommended that NCATS take a more active role in the program’s governance and direction, formalize the evaluation processes of the program, advance innovation in education and training programs, and ensure community engagement in all phases of research, among other recommendations. In December 2013, NCATS tasked a Working Group of its Advisory Council with developing measurable goals for the CTSA program. The Working Group reported to the NCATS Advisory Council in May 2014. NCATS is proposing to develop a number of new initiatives starting in Fiscal Year 2015 that are aimed at further strengthening the CTSA program, taking into account the IOM and Council Working Group reports. The proposed set of initiatives will emphasize measurable progress in overcoming barriers to translational efficiency across the translational science spectrum and will include, but not be limited to, preclinical research, clinical research and training. Platform Delivery Technologies for Nucleic Acid Therapeutics Jan. 16 Nucleic acids have shown proof of concept as therapeutics in preclinical models of numerous genetic diseases. The major hurdle is finding effective methods to deliver nucleic acids to specific cell types, particularly to the nervous system. Platform-type nucleic acid delivery technologies that are safe and effective could, in principle, enable therapies for multiple genetic diseases for which there are no treatments, but also increase therapeutic options for more common conditions, such as viral infection. The goal of the proposed funding opportunity will be to encourage SBIR /STTR applications for platform technologies to deliver nucleic acid therapeutics (siRNAs, miRNAs, antisense oligonucleotides, splice-switching oligonucleotides, plasmid/chromosomal DNAs, or messenger RNA) to specific cell types in humans. To be responsive to this solicitation, technologies must be, in principle, applicable to the treatment of multiple diseases. 2013 Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Opportunities May 17 NCATS is interested in the development of innovative tools, technologies and intervention (drug, device, diagnostic) platforms that would support the creation of novel therapeutics and/or diagnostics, especially for rare and neglected diseases. The NCATS SBIR/STTR program proposes to initiate new funding opportunity announcements (FOAs) for small businesses on topics relevant to the Center’s mission. NCATS SBIR/STTR set-aside funds will support opportunities for the following topics using SBIR Phase I and Phase II award mechanisms: Development of neurocognitive pediatric tools for measuring and analyzing clinical study endpoints in rare neurocognitive disorders Development of biomarkers for rare diseases as endpoints for clinical trial measurements As part of the U.S. Public Health Service’s 2014-1 SBIR Contract Solicitation call for topics, NCATS will develop solicitations for the topics listed below. All research topics for this contract solicitation must have received concept review. Topics selected for Phase I project awards must have the potential to continue to Phase II. Portable parathyroid hormone pump and calcium monitoring device Development of improved genome-editing technologies Development of droplet detection system for high-throughput screening Platforms for the rapid development of cell-based assays for rare diseases Ethical Challenges in Translational Research: Evidence-Based Research Jan. 23 Researchers face many ethical challenges in the translation of basic findings into clinical testing and, ultimately, implementation in the clinic. Evidence-based research is needed to provide data to inform solutions. This concept proposes to help the Clinical and Translational Science Awards community and NIH-funded networks by integrating evidence-based ethics research into current research activities. The concept will be supported with bioethics funding from the NIH Office of the Director. Increasing National Capacity for Clinical and Translational Research Jan. 23 Industry, academia and regulatory bodies exhibit willingness to change currently inefficient practices in translational research. However, all in the biomedical research community need a national environment that supports innovation. This concept will provide opportunities to pilot expansion of innovative and effective practices, methodologies and technologies across multiple sites in real time to support a sustainable national capacity for translation research. 2012 Strengthening Community-Engaged Research in the Clinical and Translational Science Awards Program Sept. 14 The development of innovative approaches to engage communities in research efforts and to improve the dissemination and implementation to the community of insights from NIH research are important for developing and implementing new preventives, diagnostics and therapeutics. This concept will identify major challenges to effective community-engaged clinical research, especially those encountered by institutes and centers at the National Institutes of Health, and will solicit focused, highly innovative demonstration projects to test strategies to overcome these barriers.
4384	CTSA Program-Supported Researcher Is Translating Laboratory Discoveries into Better Hearing for Cochlear Implant Patients	As a young trainee at a hospital in India, Suhrud Rajguru, Ph.D., was captivated by the biomedical technologies that physicians were using to care for patients: dialysis devices, heart-lung machines and imaging equipment, to name a few. “I was introduced to the emerging field of biomedical engineering at a young age, and I was fascinated by the idea of merging biology, medicine and engineering to develop tools to improve human health,” said Rajguru. Inspired by the possibilities, Rajguru pursued an undergraduate degree in biomedical engineering at the University of Mumbai in India and a doctoral degree in bioengineering at the University of Utah, where he began studying balance disorders afflicting the inner ear. In his subsequent postdoctoral work at Northwestern University, he researched technology to improve cochlear implants, which are electronic devices surgically implanted in the inner ear to replace lost function. Suhrud Rajguru, Ph.D., participated in a CTSA-supported program that allowed him to refine and test his hypothermia device in a rat model of cochlear implantation. (Angie Del-Llano/University of Miami) In 2011, Rajguru accepted a position as an assistant professor in the University of Miami Departments of Biomedical Engineering and Otolaryngology and continued his work on cochlear implants. Efforts in his laboratory involved addressing a problem with current cochlear implant surgeries: Inserting the device can damage inner ear cells and impair patients’ residual hearing. Preserving residual hearing is critical, as it enables patients to benefit from supplemental hearing aids and other therapies. Rajguru knew that exposing nerve cells to low temperatures — termed “mild therapeutic hypothermia” — after trauma and injury could protect them from damage. Initial studies in his laboratory suggested that using this approach with inner ear cells during cochlear implant surgery might have a similar effect, possibly preventing residual hearing loss. Through a collaboration with Lucent Medical Systems in Seattle, Washington, and researchers at the University of Miami, Rajguru developed a device to deliver hypothermia during surgery. However, he needed additional funding to continue testing this innovative technology. While attending a research “boot camp” offered through the University of Miami’s Clinical and Translational Science Institute (CTSI), funded through NCATS’ Clinical and Translational Science Awards (CTSA) Program, Rajguru learned about the range of CTSI research resources available to scientists. NCATS’ CTSA Program supports a national network of medical research institutions — called hubs ― through which researchers work together to improve the translational research process to get more treatments to more patients more quickly. Through its CTSI pilot research awards program, the University of Miami provides funds for new investigators with promising translational research projects to generate preliminary data for further research. Rajguru successfully applied for the CTSI pilot funding and used it to further refine and test his hypothermia device in a rat model of cochlear implantation. Rajguru and his team found that rats receiving therapeutic hypothermia with the device had less implantation-related inner ear damage and significantly better-preserved residual hearing compared to those not given the treatment. While the device showed promise in rats, the path to treating human patients was less clear. “While developing the technology, I realized how little I knew about the therapeutic development process and the commercial considerations involved in translating science into the clinic,” said Rajguru. Rajguru soon had an opportunity to learn more. In February 2015, he presented this work at the University of Miami’s CaneSearch Research Symposium, a CTSA Program-supported translational research poster competition. Rajguru’s poster was among the winners, and, as part of his award, he participated in the Translational Medicine Certificate Program at the Eureka Institute for Translational Medicine in Siracusa, Italy. The course is designed to help scientists move research innovations into commercial space. “It was my first introduction to the facets of translational medicine beyond the preclinical stage, such as starting clinical trials, navigating regulatory issues and considering the business aspects of moving innovations into the commercial space,” Rajguru said. Upon his return to Miami, Rajguru worked to disseminate his knowledge gained at Eureka to other translational scientists. He and his CTSI colleagues successfully applied for a supplemental award from NCATS’ “train-the-trainer” program to develop Innovation Corps (I-Corps) at the university. The NIH I-Corps program is a collaborative effort with the National Science Foundation, which established I-Corps team training to help accelerate the commercialization of early-stage biomedical technologies. The “train-the-trainer” program’s aim is to foster I-Corps leaders who, in turn, provide entrepreneurship training for other translational scientists. These individuals also will help disseminate the best evidence-based practices in a systematic way to benefit a broad range of researchers and others. As project director of the program, at the time this article was written, Rajguru was attending a spring 2016 training and planned to develop an I-Corps short course program at the university. In the interim, Rajguru is continuing his work to advance his hypothermia approach to the clinic. He has developed two successful NIH grant proposals for awards from the National Institute on Deafness and Other Communication Disorders (NIDCD). The NIDCD funds are supporting work to develop a hypothermia device for humans and to determine the mechanisms by which hypothermia therapy protects inner ear cells. Rajguru credits senior mentors leading the CTSI’s grant writing workshop and biostatistics core for this success. “Dr. Rajguru’s work embodies an important goal of the CTSA Program: to equip the next generation of researchers with the skills needed in translational science,” said Petra Kaufmann, M.D., M.Sc., director of the Office of Rare Diseases Research and Division of Clinical Innovation at NCATS. “By developing innovative scientific approaches, demonstrating their utility and disseminating their results and knowledge to the scientific community, he sets a prime example of how our CTSA Program is making a crucial difference.” Rajguru and his colleagues also have engaged with a potential industry partner to bring the hypothermia device to practice and plan clinical trials. Experts from the CTSI’s Novel Clinical and Translational Methods, Technologies and Resources program helped Rajguru with disclosures, patent filings and contract negotiations with the industry partners. “The support NCATS provided through the CTSA Program has played a tremendous role in helping advance my research from the laboratory to the clinic, where I hope it can improve cochlear implant surgery and lead to better outcomes and quality of life for patients,” said Rajguru. Posted April 2016
4368	NCATS and FDA Host Assay Guidance Workshop	More than 100 participants attended the “Assay Guidance Workshop for High-Throughput Screening and Lead Discovery” on April 5–6, 2016, in College Park, Maryland. Hosted by NCATS and the Food and Drug Administration (FDA), the workshop was designed to provide participants with a broad and practical perspective on how to develop and implement robust assays for early-stage drug discovery projects. Participants included researchers from NIH, FDA, National Institute of Standards and Technology, industry and academia. Workshop leaders with more than 20 years of drug discovery experience covered a broad range of critical concepts underlying robust assay development and screening strategies, including the following: Practical approaches for developing robust biochemical and cell-based assays in vitro assays for testing compound toxicity Strategies to identify and mitigate common assay artifacts The use of important statistical and data analysis concepts for improved data collection and go/no-go decision points Assessment of absorption, distribution, metabolism and excretion (ADME) properties of lead molecules There was also open discussion for participants to share experiences and seek practical advice about individual research interests. The workshop was initiated as an extension of NCATS’ Assay Guidance Manual (AGM). Originally developed by Eli Lilly and Company, the AGM is a freely available best practices resource that provides step-by-step guidance on planning and developing projects from high-throughput screening to lead optimization and early phases of regulated drug development. With contributions from more than 100 scientists worldwide, the AGM is managed by an editorial staff of 26 experts from industry, academia, and government who update the manual on a quarterly basis. The next workshop is scheduled for October 2016. Contact Nathan Coussens for details.
4335	CAN Review Board Concept Clearances	Concepts describe the basic purpose, scope and objectives of proposed initiatives and represent an early planning stage for potential NCATS activities. Concepts are discussed with the NCATS Advisory Council and Cures Acceleration Network (CAN) Review Board and through other public venues. Council approval of a concept does not guarantee it will become an initiative. That decision is made based on scientific and programmatic priorities and the availability of funds. View approved CAN Review Board concept clearances by year: 2020 Concepts 2019 Concepts 2018 Concepts 2017 Concepts 2016 Concepts 2015 Concepts 2014 Concepts 2020 Biomedical Translator—User Interface (UI) Development Jan. 16 Christine M. Colvis, Ph.D., presented a contract concept for developing a UI for the NCATS Biomedical Translator (Translator). Approved in December 2015, the Translator program aims to enable exploring computationally assisted knowledge graphs and constructing new research hypotheses. NCATS has completed the feasibility phase of Translator and moved to the development phase. Dr. Colvis explained that NCATS has invested in user-centered design work for the UI, but not its development. The goals of this concept are to develop an agile UI for Translator that will allow the broader research community to use Translator and provide researchers the ability to query the data system for key information for addressing research questions. NCATS recognizes that proper execution of user-interface design will require collaboration involving a team with expertise in user-centered design and biomedical science. In 2019, NCATS engaged the 18F (an abbreviation for 1800 F Street) Office, Technical Transformation Services, General Services Administration, to conduct user-centered design research and identify core use cases. The 18F report recommended engaging interface developers through a contract mechanism. Aside from delivery of a Translator UI that is intuitive for researchers, other expected outcomes will be an unprecedented view of biomedical information and data presentations that enhance human reasoning and understanding of specific aspects of medicine, both biologic and physiologic. No broadly used system like Translator currently exists elsewhere. All results and software developed will be publicly available through GitHub. For the long term, Translator aims to foster community-driven adoption of data-sharing standards and practices. Project/Program Officer: Christine M. Colvis, Ph.D. Director, Drug Development Partnership Programs Office of the Director National Center for Advancing Translational Sciences Phone: 301-451-3903 Email: ccolvis@mail.nih.gov 2019 Microphysiological Systems Scientific Conference: International Standardization and Harmonization of Microphysiological Systems Dec. 13 Dr. Tagle presented a concept for sponsoring an MPS scientific conference to promote international standardization and harmonization of MPS. Several recent activities warrant development of an international standard. In fact, the MPS technology has expanded internationally, and progress has been significant in developing MPS for a number of human organs and organ systems. Tissue chips and other 3-D models are converging in application. The goals are to lay the groundwork for an orderly transition of MPS strategic, organizational and funding aspects to other stakeholders; convene annual scientific conferences; use these forums as the main conduit of information, technology and data sharing; and establish a training environment for the next generation of MPS scientists. NCATS anticipates that the outcome—an international scientific conference devoted to MPS—will be self-sustaining through registration fees and sponsorship after a brief period of CAN support. One major effect will be an increased awareness in the research community about the potential use of tissue chips in drug development as an approach that more accurately reflects the human response when compared to existing in vitro and in vivo animal models. Project/Program Officer: Danilo A. Tagle, Ph.D., M.S. Associate Director for Special Initiatives Office of the Director National Center for Advancing Translational Sciences Phone: 301-594-8064 Email: tagled@mail.nih.gov Microphysiological Systems (MPS) Database Center Sept. 19 Danilo A. Tagle, Ph.D., presented the concept re-issue to continue the Microphysiological Systems (MPS) Database Center (DC) currently hosted and managed by the University of Pittsburgh Drug Discovery Institute. Dr. Tagle noted that establishing the MPS Database Center was first approved on Sept. 7, 2017, by the Council and Board as database support for the Tissue Chip Program. The MPS Database—which is the central archive for aggregate preclinical, clinical and experimental MPS data generated in the Tissue Chips Testing Centers (TCTCs)—also is being used by developers and other stakeholders, including the pharmaceutical industry. To date, the database contains 58 MPS (i.e., tissue chips) experimental models covering 11 organ systems, which were developed at 14 TCTCs. Data from 171 studies are being housed, including images and videos deposited by eight data developers. Dr. Tagle emphasized that all data submitted to the MPS DC will be made publicly available to the research community. Since November 2018, the MPS database usage has steadily increased: 109 users are currently registered and, on average, 86 new users view or download data each month. The MPS database has the potential to transition to a self-sustaining business model after the 2-year funding cycle. Dr. Tagle summarized the ongoing research activities in this area and noted that the MPS Database Center is a collaborative partnership between NCATS, the FDA and the MPS affiliate of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). Project/Program Officer: Danilo A. Tagle, Ph.D., M.S. Associate Director for Special Initiatives Office of the Director National Center for Advancing Translational Sciences Phone: 301-594-8064 Email: tagled@mail.nih.gov Order of Magnitude Increases in the Efficiency of Adeno-Associated Virus (AAV) Vector Production for Human Gene Therapy May 16 Multiple clinical successes in clinical trials using Adeno-Associated Virus (AAV) vectors have been witnessed in recent years. At present, the major limiting factor to extending this approach to other rare diseases is the ability to manufacture clinical-grade AAV vectors. The objective of this initiative is to develop at least one independently validated technology that increases efficiency of AAV vector production for human gene therapy by a factor of tenfold or more. If successful, this initiative would substantially increase the number of rare disease gene therapy clinical trials. In addition, the developed technology could be used for research projects conducted by NCATS’ Division of Preclinical Innovation. Project/Program Officer: Philip John (P.J.) Brooks, Ph.D. Program Director Office of Rare Diseases Research National Center for Advancing Translational Sciences Phone: 301-443-0513 Email: pj.brooks@nih.gov Synthetic Technologies for Advancement of Research and Therapeutics (START) – Engineering Novel Therapeutics Jan. 10 The objective of this initiative is to employ synthetic biology (SB) – along with newly available tools in genetic engineering, gene synthesis and metabolomics – to construct and incorporate new biosynthetic or artificial metabolic pathways to accelerate and enable the design and construction of engineered cell therapies for the production of compounds with a strong therapeutic and disease relevance. SB can be applied in a variety of ways for therapeutic development for a number of diseases, such as for metabolic diseases through the construction and clinical implementation of mammalian synthetic gene networks that can accurately detect dysregulated metabolic signals and initiate the production and delivery of appropriate dosage of therapeutic molecules/compounds. The program will focus on developing desired synthetic therapeutic products in a scalable, cGMP compliant manner; generating a catalog of biologically relevant pathways that can be used in a “plug-and-play” scenario to generate biologics; engineering novel protein motifs that increase bioavailability in currently difficult to target tissue types; and expanding the available catalog of biologics used to treat diseases, such as rare metabolic disorders. Project/Program Officer: Danilo A. Tagle, Ph.D., M.S. Associate Director for Special Initiatives Office of the Director National Center for Advancing Translational Sciences Phone: 301-594-8064 Email: tagled@mail.nih.gov 2018 Drug Screening of Biofabricated 3-D Disease Tissue Models Sept. 27 Less than 12 percent of the drugs that enter drug trials receive approval. This is often a consequence of using overly simplistic two-dimensional (2-D) testing models that are not good predictors of a drug’s performance in later stages of drug development. Three-dimensional (3-D) biofabrication enables the manufacture of more complex and more physiologically relevant testing models. This program will utilize 3-D biofabrication to develop better models that will be incorporated in novel drug screening platforms. NCATS already has established a 3-D Bioprinting Laboratory, and its current projects include biofabrication of skin, retina, blood-brain barrier and cancer models. To enhance collaboration between the laboratory and scientist in academia, a pilot program for Collaborative Drug Discovery Research Using Bioprinted Skin Tissue was developed. Skin tissue was selected because it has a relatively simple layered structure. The work with skin can be used to inform development of other tissue with layered structures such as liver and kidney tissue and other disease models. NCATS is working to develop 3-D biofabricated models of psoriasis with Columbia University and squamous cell carcinoma with The Rockefeller University. The next step is to incorporate the models in high-throughput drug screening platforms and extend the program to incorporate 3-D biofabrication of other tissue types. The ultimate goal of this initiative is to provide strong evidence of success for utilization of 3-D tissue models for drug screening. The program will inform development of 3-D platforms across multiple diseases. Biofabricated 3-D Tissue Models of Nociception, Addiction and Overdose for Drug Screening Sept. 27 NIH has recently launched the HEAL (Helping to End Addiction Long-term) Initiative, a multidisciplinary, trans-agency effort aimed to rapidly advance the development of scientific solutions towards the national opioid public health crisis. This program will be one component of the NCATS-lead and HEAL-supported “Trans-NIH collaborative to develop human-based platforms and novel drugs to treat pain, addiction and overdose.” The initiative aims to apply 3-D biofabrication technologies to develop novel multicellular tissue constructs for drug screening by using human induced pluripotent stem cell (iPSC)-derived cells representing sensory/pain neurons, brain regions and other tissues involved in pain, addiction and/or overdose, including tissue models of the blood-brain barrier. The proposed initiative will foster strong collaborations among the NCATS intramural 3-D Bioprinting Laboratory and external research community. The goal of the initiative is to establish physiologically and pharmacologically relevant biofabricated 3-D tissue models of pain, addiction and/or overdose in multiwall plate format for drug screening. The ultimate goal of the initiative is to disseminate the acquired knowledge, tools and technologies to scientific community; facilitate application of more physiologically relevant and validated 3-D models for drug screening; and help advance identification of novel, safe and effective treatments for pain, addiction and/or overdose. Tissue Chips to Model Nociception, Addiction and Overdose: “Tissue Chips to HEAL” Sept. 27 NCATS is leading a trans-NIH collaborative to develop human-based screening platforms and novel drugs to treat pain and opioid use disorders as part of the NIH Help End Addiction Long-term (HEAL) initiative, and tissue chips plays a big part in this effort. This initiative will address the lack of valid models in this field by developing and testing tissue chips that can model the mechanisms and/or effects of nociceptive (pain) signaling, addiction or overdose, using human tissues in physiologically relevant in vitro platforms. The initiative could help to reveal the mechanisms underlying an individual’s pain response to tissue damage or disease, any related opioid use, and potential overdose. It also could provide insights into the impact of physiological comorbidities, therapeutic responses and addiction treatment outcomes. Areas of interest include the appropriate modeling of a pain/addiction/overdose-relevant organ system, a chip that provides a more useful readout than assays that are already available, and end points that can be demonstrated to correlate with clinical measures of pain, addiction and overdose. The program will include developing quantitative end points that correlate with clinical measures of pain, addiction and overdose and the use mature human-derived tissues for central and peripheral nervous system tissues and non-nervous system tissues. To accomplish this tissue developers will need to partner with pain experts as collaborators. “Clinical Trials on a Chip”: Tissue Chips to Inform Clinical Trials for Rare Diseases Sept. 27 There is a significant gap in developing therapeutics for diseases/disorders that are life-threatening and/or chronically debilitating including for neurological disorders, cancer and rare diseases, especially in pediatric populations. Drug development for these diseases/disorders is challenging, time-consuming and fraught with risk and thus expensive. In particular, failure rates in late-stage clinical trials are disproportionately high for these diseases/disorders, due to complexity, the difficulty of examining the pathophysiology directly in vivo and, in part, inadequately designed clinical trials. This new initiative seeks to build upon previous successes in the use of tissue chips to support the use of this technology to inform clinical trial design and elucidate pathophysiology of the diseases; assist with the selection of best drug candidates for clinical trials; and improve the selection of patient populations and identification of reliable clinical trial endpoints. Tissue chips can help streamline clinical trials by helping to select and stratify subgroups in preclinical and early clinical trial stages and by providing safety and efficacy data. This can be accomplished by populating chips with induced pluripotent stem cell-derived and commercially available cell sources that represent genotypic and phenotypic spectrum of the patient population for various group of diseases and disorders. Among the goals under this new initiative is the use of data from tissue chips in the clinical trials decision-making process. It also will include production of tissue chips that allow physicians and patients to make informed decisions about appropriate treatment regimens. The project will have broad and significant impact by validating the usefulness of tissue chip platforms in a clinical setting and will be disease-relevant, particularly for rare diseases and other human disorders for which there are no adequate models. 2017 Biomedical Data Translator Dec. 15 The objective of the Biomedical Data Translator (Translator) program is to support research to develop a computational platform that enables connections among conventionally siloed data types. Translator is intended to integrate multiple types of existing data sources, including objective signs and symptoms of disease, drug effects and intervening types of biological data relevant to understanding pathophysiology, in an ecosystem that will reveal complex relationships that help scientists better understand disease and generate hypotheses and treatment options. Current awardees are assessing the feasibility of establishing a computational platform for meeting the goals of the Translator program. In addition to assessing the feasibility of a platform, the awardees are identifying data integration and inclusion barriers, as well as a plan for data quality control and updates. Read the full Concept Clearance (PDF - 99KB). NCATS Collaborative Rare Disease Platform Vector Gene Therapy Trial Dec. 15 NCATS proposes a novel public-private partnership model for explicitly platform-based gene therapy clinical trials. The approach involves using well-characterized viral vectors as gene delivery vehicles for the treatment of at least three rare genetic diseases that share the same therapeutic target tissue or cell type. The diseases chosen for this gene therapy platform trial should be those currently under study within the Rare Diseases Clinical Research Network, to maximize the benefit of natural history data and disease-specific expertise within the program. The NCATS Office of Strategic Alliances will play a key role in creating agreements and managing interactions and partnership between NCATS, academia and industry partners. Read the full Concept Clearance (PDF - 100KB). Automated Synthesis Platform for Innovative Research and Execution Sept. 7 The Automated Synthesis Platform for Innovative Research and Execution (ASPIRE) will serve as an unprecedented portal for automated rapid testing of hypotheses regarding novel biologically relevant chemical entities designed through computational approaches to interact with specific therapeutic targets. The envisioned platform will have the capacity for remote worldwide access and the ability to support real-time collaborative research that will integrate efforts from diverse investigators all over the world from academia, government and industry to solve complex biomedical challenges. ASPIRE will be coupled with next-generation computational systems that generate chemical predictions and will, in turn, provide automated small-scale synthesis of said compounds for immediate/in-line biological testing using existing or adopted robotic high-throughput screening and analytic systems. Read the full Concept Clearance (PDF - 56KB). NIH-CASIS Coordinated Program in Tissue Chip Systems for Translational Research in Space Sept. 7 The objective of this initiative is to exploit space-specific phenomena to conduct inflight studies, using tissue chips. Conducting biomedical research at the International Space Station – National Laboratory (ISS-NL), using tissue chip technology, provides unprecedented opportunities to study the effects of microgravity and extreme radiation exposure at the ISS-NL and its effects on many of the human body's systems. The reissuance of this FOA by NIH and CASIS will further expand the number of projects that delve into the molecular basis, including epigenome changes, for these human conditions and provide information for novel targets for drug development and innovative treatment modalities. Translation of this research to the ISS-NL promises to accelerate the discovery of molecular mechanisms that underlie a range of common human disorders and advance understanding of therapeutic targets and treatments in a reduced fluid-shear, microgravity environment that recapitulates cellular and tissue matrices of Earth. NextGen Tissue Chip Testing Centers Sept. 7 The objective of this reissuance is to continue the support of Tissue Chips Testing Centers (TCTCs) beyond the two-year pilot funding and leverage previous NCATS investment in infrastructure to provide independent validation of tissue chip platforms for various organ systems. The proposed initiative will involve a co-resourcing partnership with pharma to expand the testing of compounds on Microphysiological Systems (MPS) disease models for safety and efficacy using predefined assays according to U.S. Food and Drug Administration and pharmaceutical industry standards, and to fully utilize tissue chip technology in drug discovery and development through an integrative strategy using MPS to be directed at a critical unmet medical need for which historical approaches have been unproductive (e.g., heart failure therapy). 2016 NIH-CASIS Coordinated Program in Tissue Chip Systems for Translational Research in Space June 13 This proposed initiative seeks to leverage recent advances in tissue engineering and microfabrication to create microphysiological systems and organ-on-chip technology platforms that recapitulate human physiology, to better determine the molecular basis of human disease and/or the effectiveness of diagnostic markers and therapeutic intervention for disease treatment. The initiative will focus on the deployment and further development of tissue chip technology to facilitate space-related research at the International Space Station and integrate results from that research into an improved understanding of human physiology. This initiative will advance biomedical research approaches and clinical technologies for use on Earth and in space and for research in Earth- and space-based facilities that could improve human health. It is now widely known that accelerated aging occurs in space, due to muscle wasting, osteoporosis, reduced cardiopulmonary function, immune response, and other factors, but that these conditions are reversible when astronauts return to Earth. It is anticipated that this initiative by NCATS and the Center for the Advancement of Science in Space will delve into the molecular basis, including epigenome changes, for these human conditions and provide information for novel targets for drug development. Read the full Concept Clearance (PDF - 20KB). 2015 3-D Bioprinting of Human Live Tissues for Drug Screening Dec. 11 Bioprinting of architecturally defined and physiologically relevant human live tissues is emerging as a key enabling technology for drug discovery. 3-D bioprinting of human live tissues has the potential to accelerate the drug discovery process, enabling treatments to be developed faster and at a lower cost by bridging the predictability gap between in vitro and in vivo assays and positive clinical outcomes. The major reason for the low success rate in drug development is the lack of efficacy in clinical trials. This failure in the late stages of clinical development is in large part due to the use of simplistic in vitro cell assays and non-predictive in vivo animal models during the drug discovery and development process. 3-D bioprinting of human live tissues derived from human stem cells is expected to provide data that are more relevant to the whole body response than traditional studies with two-dimensional cell cultures. The purpose of this initiative is to generate architecturally defined human tissues that closely resemble in vivo human tissues for drug screening by integrating groundbreaking tissue bioengineering, 3-D printing, cell development, stem cell and disease biology, and noninvasive detection technologies. This program will create the infrastructure necessary to enable 3-D bioprinting for the fabrication of tissues at NCATS and to establish collaborations with the research community to advance and disseminate its use for drug discovery. Read the full Concept Clearance (PDF - 25KB). Increasing Access to Compounds and Tox Data Dec. 11 The underlying mechanism of toxicity discovered in or after Phase I trials often is not investigated. NCATS would work with multiple pharmaceutical companies, the Food and Drug Administration and companies that develop predictive toxicology tools. This initiative would broker relationships between pharmaceutical companies and academic researchers who could conduct research to better understand and perhaps help to overcome toxicities detected in drugs that gave a safety signal in Phase I trials that were not predicted based on preclinical studies. The research would help answer the question of why preclinical tools sometimes fail to predict toxicity by providing researchers with access to the compounds, as well as associated preclinical and clinical data. The goal of this initiative is to increase access to compounds that did not have a safety signal in preclinical studies but were later shown to have toxicity in humans. The program would investigate underlying mechanisms for the human toxicity and explore potential reasons why preclinical tools failed. The information would be incorporated into predictive modeling to benefit drug development. Read the full Concept Clearance (PDF - 33KB). Proof of Principle (POP) Awards Dec. 11 The proposed program is aimed at preclinical research projects that develop, demonstrate or deploy interventions to improve human health. Often, prospective grantees have applied for NIH support but did not receive funding because they lack a specific piece of translational data. The program would fund generation of the needed data to make the project more competitive for subsequent funding or otherwise move the project forward. The program would strengthen applications for programs across NIH, and perhaps at a future stage, across the entire translational research enterprise. Applications to be considered for potential funding will be those that have a broad and significant impact, and each project will be completed in a relatively short time. Read the full Concept Clearance (PDF - 44KB). Proteome Profiling in the Clinic Dec. 11 The Human Genome Project cannot be used fully for precision medicine without profiling the proteome and its dynamically regulated post-translational modifications (e.g., phosphorylation, ubiquitination). Genomic tools do not allow the analysis of post-translational modifications at all. Indeed, the lack of well-established protein markers might explain some of the failures in clinical trials that are solely based on genetic data. New sensitive clinical tests, reliable panels of protein biomarkers and quantifiable assays are urgently needed in the clinic. The initiative will establish new clinical tests and protein biomarkers based on quantitative proteomics, phosphoproteomics and validated antibodies; optimize technical and analytical tools and easy-to-use resources and databases for physicians and clinical staff; and perform combined analysis of genetic and proteomic data for decision making in personalized health care. Quantitative read-outs will promote better understanding and longitudinal monitoring of pathophysiology and drug effects. Read the full Concept Clearance (PDF - 31KB). SaME Therapeutics: Targeting Shared Molecular Etiologies Underlying Multiple Diseases to Accelerate Translation Dec. 11 While the number of disorders with a known molecular basis continues to increase rapidly, the number with an effective treatment continues to lag far behind. What is needed to overcome this translational roadblock is a fundamental change in the current symptom-based, one-disease-at-a-time approach to drug development and clinical trials. An explicit focus on identifying SMEs for translation represents such a fundamental change, which ultimately will bring more rationally designed treatments to more patients more quickly. In contrast to the current approach to disease based on clinical presentation, the concept of SaME therapeutics is to focus on shared molecular etiologies underlying multiple diseases using systems biology as a framework for drug development and clinical trials. An important part of this initiative will be to develop a matrix of diseases and molecular etiologies to identify shared molecular etiologies (SMEs) underlying multiple diseases, and to stimulate novel clinical trials of SME-targeted drugs based on grouping patients by SME rather than clinical phenotype. Read the full Concept Clearance (PDF - 41KB). Sensors and Devices to Detect Clinical Outcomes Dec. 11 Many sensors and devices are available; however, the clinical utility of these is limited. This proposal will focus on solving technical, computational, engineering, social and cultural barriers to collecting, integrating and analyzing data from multiple devices and sensors and patients’ health care data in the context of addressing a pilot study of a compelling clinical question that could not be answered without such data integration. A diverse collaborative team (technology leaders, patients, data scientists, etc.) is required to uniformly collect and analyze sensor and device data for assessing clinical outcomes that could not be answered without data integration. Read the full Concept Clearance (PDF - 31KB). Tissues-on-Chips: Part II Dec. 11 The goal of Part I of the Tissue Chip for Drug Screening program was to develop bioengineered micro-devices that represent functional units of the 10 major human organ systems: circulatory, respiratory, integumentary, reproductive, endocrine, gastrointestinal, nervous, urinary, musculoskeletal and immune. In the first part of this program, several unique and novel in vitro platforms have demonstrated human organotypic physiological functions and responses to drug exposure, ensuring that safe and effective therapeutics are identified sooner and ineffective or toxic ones are rejected early in the drug development process. These micro-fabricated devices also have proven to be useful for modeling human diseases, and they may prove to be sufficient alternatives to animal testing. Despite these successes, there is a clear need to advance the technology to fully exploit the use of the tissues-on-chips not only at the preclinical stage but also as a clinical tool. The purpose of the proposed request for applications is to foster a multitude of new research applications including, but not limited to, studies in personalized medicine, environment exposures, reproduction and development, autoimmune disorders, infectious diseases, cancer, countermeasures for chemical warfare, immune responses and neuro-inflammation. Read the full Concept Clearance (PDF - 123KB). 2014 Micro-Awards for Researchers Who Need to Get Past a Small Hurdle Sept. 19 The concept is based on experience with the several NCATS programs, which revealed that some applicants lacked specific critical pieces of data to present competitive proposals. Gap analysis showed that a few programs at NIH exist to meet this need, but they do not focus on the translational space, nor are they aimed at projects that have already undergone the NIH review process. This concept would provide proof-of-principle (PoP) micro‑awards to investigators who had undergone NIH review to fund the generation of predominantly preclinical data needed to make a project more competitive or otherwise move the project forward. Measures of success could include receipt of funding, or achievement of relevant milestones such as the creation of intellectual property or the preparation of an Investigational New Drug package. If PoP awards are successful, the approach could be expanded across the entire translational research spectrum or beyond NIH. Devices and Sensors to Detect Clinical Outcomes Sept. 19 An array of devices and sensors are available to collect physiological, environmental or patient‑reported information in real time, but their use is limited by a lack of information about how to collect, manage, analyze and interpret the data. There also is a need for best practices and standards for the integration of sensor and device data with medical record and other data to describe clinically relevant outcomes. This concept would focus on integrating real-time data from multiple sources in order to characterize patients or disease status in a clinically meaningful way. The emphasis would be on devices that are already available and the data would be made publicly available at the end of the program. Access to Compounds, Toxicology/PK Data, Patient Populations Sept. 19 The underlying mechanism of toxicity discovered in phase 1 trials often goes without further investigation. This concept would focus on uncovering such toxicity mechanisms, helping answer the question of why preclinical tools sometimes fail to predict toxicity. Researchers would be provided with the compounds as well as associated preclinical and clinical data. Once the mechanisms are identified, it could be possible to build complementary models, assays, or tools to increase prediction success rates and improve safety. The concept entails collaboration with pharmaceutical firms, the FDA, and companies that develop predictive toxicology tools. Measurable outcomes could include the number of compounds brought into the program and the number of toxicity mechanisms elucidated.
4333	Global Substance Registration System (GSRS)	The GSRS resource is a registration system for the ingredients in medicinal products. This project, developed by NCATS scientists, makes it easier for regulators and other stakeholders to exchange information about substances in medicines, supporting scientific research on the use and safety of these products. The GSRS effort is similar to the periodic table of elements, which is a basic system of classifying chemical elements based on specific scientific criteria. These classifications are accepted worldwide, but that was not always the case. Scientists and alchemists of the past used to describe simple substances using arbitrary names, symbols and categorization. It was difficult for early scientists to agree about what was a real element and even more difficult to be sure, systematically, that the scientists were describing the same substance with their specific names and symbols. The GSRS resource will catalog the ingredients in medicinal products. (Stock Photo) The development of the periodic table of elements revolutionized the way scientists talked about substances, enabling the use of a common terminology for known and unknown elements. However, no such system currently exists for identifying the complex substances that are ingredients in today’s medicinal products. The main goal of GSRS is the production of software, called GSRS, to assist agencies in registering and documenting information about substances found in medicines. Instead of relying on drug or chemical names, which vary across countries and regions, GSRS will enable substances to be defined by standardized, scientific descriptions. First, the substance is classified into one of a few categories (e.g., chemical, protein, plant substance). Then researchers use certain criteria (e.g., chemical structure, DNA sequence) to distinguish substances in each category from one another. When enough information is available, a substance is assigned a unique identification code, which can be used as a quick way to refer to that substance in the future. Staff from the U.S. Food and Drug Administration (FDA) and regulatory authorities from several other countries work together with NCATS on GSRS software development. FDA deployed GSRS software in 2017 as a replacement for the agency’s previous registration system. In addition, the European Medical Agency has committed to using the GSRS software. Scientific Synopsis The GSRS effort provides a common identifier for ingredients in medicinal products by using a consistent definition of substances, including active substances under clinical investigation, based on the ISO 11238 standard. Working closely with that standard’s authors and regulatory authorities from various countries, NCATS is developing an information system to register and store substance-related information and provide identifiers. This effort will ensure that a robust substance registration software (GSRS) supports the additional needs of national and regional authorities and is consistent with the ISO 11238 standard. The system will support all substance types described in the standard and provide multiple language capability for the naming of substances and controlled terminology used within the system. Public Health Impact Globalization presents tremendous challenges and opportunities for national regulatory agencies, the pharmaceutical industry and global health. Emerging diseases and the health effects of catastrophic events respect no national boundaries, nor does the increasing volume of substandard, contaminated and counterfeit products that overburdens national regulators. Ingredients for pharmaceutical products are typically sourced on a global basis, and it is rare that all ingredients for a single product are produced within one jurisdiction. To regulate the global supply chain efficiently and better respond to and prepare for catastrophic events, it is essential to have a global information system for pharmaceutical ingredients.	The GSRS resource is a registration system for the ingredients in medicinal products.	Global Substance Registration System (GSRS)	The GSRS resource is a registration system for the ingredients in medicinal products.	Global Substance Registration System (GSRS)
4103	Breathing Easier: First Treatment for Rare Lung Disease Approved	In 1994, Sue Byrnes brought her daughter, newly diagnosed with a rare lung disease called lymphangioleiomyomatosis (LAM), to Francis McCormack, M.D., a pulmonary physician-scientist at the University of Cincinnati. Byrnes wanted to know what, if anything, McCormack could do, but with scarce research on the condition and no existing treatments, he could offer little encouragement. LAM is a progressive lung disease that mostly affects women of child-bearing years. In LAM patients, smooth muscle cells invade the lungs and grow uncontrollably. Over years, this abnormal tissue builds up and blocks airflow, making it increasingly harder for patients to breathe and carry out everyday activities. Typically, patients survive about 20 to 30 years after diagnosis. LAM is very rare, affecting only about 30,000 to 50,000 people worldwide, or three to five people per million. This number is likely higher, however, because the disease is greatly underdiagnosed. Byrnes, frustrated by the lack of research and treatments to help her daughter, established The LAM Foundation with McCormack’s help. To date, its advocates have raised more than $20 million, collaborated with academic and government scientists, and stimulated much of the existing research on the disease. In 2015, that investment paid off: In the most monumental victory to date for LAM patients, research coordinated by the Foundation and carried out with its scientific partners in NCATS’ Rare Diseases Clinical Research Network (RDCRN) culminated in the first Food and Drug Administration (FDA)–approved treatment for LAM. It Takes a Village The road to this long-awaited success involved the Multicenter International LAM Efficacy of Sirolimus (MILES) Trial, based at the University of Cincinnati and Cincinnati Children’s Hospital Medical Center and led by McCormack. The investigator-initiated, international clinical trial was unprecedented in size and scope for such a rare disease and was enabled by a seamless collaboration among RDCRN-supported scientists and LAM Foundation advocates. A lymphangioleiomyomatosis (LAM) patient (right) with her daughter (left). The daughter is preparing to enter college and, someday, contribute to understanding this disease for which treatment included her mother undergoing two double-lung transplants. (Frank McCormack, M.D./University of Cincinnati) “The process had a huge learning curve at every level,” remarked Bruce Trapnell, M.D., a pulmonologist and professor of medicine and pediatrics who is the principal investigator of the RDCRN’s Rare Lung Diseases Consortium (RLDC), through which the trial was conducted. “We had never established this kind of network before by ourselves, and the teamwork among The LAM Foundation, the administrative team and our researchers was absolutely indispensable and a pivotal part of the infrastructure that made this possible.” Because the limited number of rare disease patients can make gathering information and designing clinical studies difficult, collaborations among government, academia, industry and patient advocacy groups are essential to advancing knowledge and treatments for rare diseases. NCATS, with its mission to make the translational process of science more efficient to bring more treatments to more patients more quickly, underscores the power of collaboration through programs such as the RDCRN. This network is designed to advance medical research on rare diseases by providing support for clinical studies and facilitating collaboration, study enrollment and data sharing. The RDCRN consists of 22 distinct clinical research consortia and a Data Management and Coordinating Center (DMCC). Through the RDCRN, which requires consortia to pair with patient advocacy groups as research partners, scientists from multiple disciplines at hundreds of clinical sites around the world work together to study more than 200 rare diseases. It was this team approach that enabled the multi-site LAM trial. An International Undertaking Earlier NIH- and LAM Foundation–funded studies using LAM cell cultures and animal models suggested that a signaling protein called mTOR becomes overactive in patients with the condition. Experts knew that the drug sirolimus — already approved to prevent organ rejection in patients receiving transplants — lowers mTOR activity, so they suspected sirolimus could be a potential therapeutic candidate for LAM. With help from The LAM Foundation and the RDCRN, the RLDC researchers designed the MILES Trial to test sirolimus in LAM patients. Pfizer, which owns sirolimus, donated the drug for the trial. Because McCormack and LAM Foundation advocates had spent decades building a worldwide patient network, they knew to establish MILES study sites in geographic regions close to where LAM patients lived. With 13 sites across the United States, Canada and Japan, the widespread nature of the trial meant that teamwork among RLDC researchers, RDCRN personnel, study monitors and The LAM Foundation was crucial to success. Foundation members reached out to their worldwide network of patients to inform them of the study and recruit participants. This outreach resulted in the participation of 89 LAM patients, an impressive sample size given the incredibly rare nature of the disease. At the time, experts estimated that only about 800 people in the United States had been diagnosed with LAM, although that number now is 1,400. RDCRN and DMCC experts provided a wide range of support, including helping with trial design; collecting, managing and analyzing the data; providing international and U.S. regulatory expertise; and training study personnel. A trial of this magnitude would not have been possible without the infrastructure provided by the RDCRN. We simply would not have had the audacity to attempt it. The DMCC provided real-time troubleshooting and guidance throughout the process, said McCormack. The Office for Clinical and Translational Research (OCTR) at Cincinnati Children’s Hospital Medical Center also helped manage the complex regulatory and logistical aspects of conducting an international, multisite trial. These duties included institutional review board negotiations and submissions, regulatory compliance, site monitoring, data and budget management and participant recruitment and management. The Road to Approval The trial results showed that sirolimus, taken over 12 months, stabilized patients’ lung function, reduced symptoms and improved quality of life. The research was published in the April 18, 2011, issue of the New England Journal of Medicine. The team used the results of the rigorously designed trial to submit an application to the FDA for approval of sirolimus as a LAM treatment. In May 2015, the FDA announced its approval, making sirolimus the first-ever approved treatment for LAM. On the left is a normal lung and on the right is a lung affected by lymphangioleiomyomatosis. (Frank McCormack, M.D./University of Cincinnati) “The approval of sirolimus as a therapy for LAM is a major milestone for LAM patients as well as for the broader rare diseases research community,” said Petra Kaufmann, M.D., M.Sc., director of the Office of Rare Diseases Research and the Division of Clinical Innovation. “This success shows that the RDCRN model is well-suited to overcome the unique challenges of rare diseases research and fulfill NCATS’ mission to help translate discoveries into better health.” This approval means that more insurance companies now may cover sirolimus for LAM, making it easier and less financially burdensome for patients to access the drug. It also means that physicians will feel more comfortable prescribing the drug. Finally, FDA approval can facilitate government approval in other countries, in some cases making the drug accessible for the first time. “Being diagnosed with a rare disease is difficult because for most rare diseases, there is so little research and no treatment, leaving relatively little hope,” said Andrea Slattery, board chair of The LAM Foundation and a LAM patient herself. “To have an FDA-approved drug after just 20 years of advocacy and research is hugely gratifying. It shows that our model of collaboration is working and allows us to serve as a beacon of hope for the thousands of other rare diseases that don’t yet have treatments, much less a cure.” The RLDC team currently is designing a second clinical trial of sirolimus in LAM patients with milder disease. The hope is that giving a lower dose of therapy for a longer period of time during earlier stages of LAM, while lung function is still fairly normal, will halt progression to more advanced stages of the condition. Although sirolimus stabilizes lung function for LAM patients, it is not a cure. The LAM Foundation and the RLDC will continue to work together to find one. According to Slattery, “Our motto at the Foundation is that collaboration is the key to the cure.” McCormack certainly agrees: “The remarkable outcome of our collective efforts with LAM illustrates the great strides that can be made in rare diseases research when industry, clinical investigators, patient advocates and the government work together toward a common goal to improve the lives of patients.” Posted March 2016 The MILES Trial was supported by grants from the NCATS Office of Rare Diseases Research; the FDA; the Canadian Institutes of Health Research; Pfizer; the Japanese Ministry of Health, Labor, and Welfare; The LAM Foundation; the Tuberous Sclerosis Alliance; Cincinnati Children’s Hospital Medical Center; Vi and John Adler; the Adler Foundation; and the National Heart, Lung, and Blood Institute. Pfizer provided the study drug and funding for some study visit costs.
4081	January 2016 Council/CAN Review Board Meeting	The Jan. 14, 2016, joint meeting of the NCATS Advisory Council and the Cures Acceleration Network Review Board featured the following meeting materials. Presentations NCATS Director’s Report (PDF - 2MB) - Christopher P. Austin, M.D., director, NCATS CAN Review Board Update (PDF - 169KB) - Freda C. Lewis-Hall, M.D., chief medical officer, Pfizer NCATS Strategic Planning Update (PDF - 347KB) - Dorit Zuk, Ph.D., director, Office of Policy, Communications and Strategic Alliances, NCATS Concept Clearance: Clinical and Translational Science Data Metrics Coordinating Center (PDF - 133KB) - Petra Kaufmann, M.D., M.Sc., director, Office of Rare Diseases Research and the Division of Clinical Innovation, NCATS Concept Clearance: Collaborative Innovation Pilot Projects for the CTSA Program (PDF - 161KB) - Petra Kaufmann, M.D., M.Sc., director, Office of Rare Diseases Research and the Division of Clinical Innovation, NCATS NCATS Partnerships with NIH Common Fund: Overview and Extracellular RNA (ExRNA) Communication Program (PDF - 1MB) - Danilo A. Tagle, Ph.D., associate director for special initiatives, NCATS Undiagnosed Diseases Network (UDN) Program (PDF - 2MB) - Carson R. Loomis, Ph.D., senior advisor to the director, NCATS; and David J. Eckstein, Ph.D., senior health scientist administrator, Office of Rare Diseases Research, NCATS Update from the CTSA and ORDR Programs (PDF - 2MB) - Petra Kaufmann, M.D., M.Sc., director, Office of Rare Diseases Research and the Division of Clinical Innovation, NCATS Additional Meeting Information Agenda (PDF - 80KB) Videocast Minutes (PDF - 220KB) Federal Register Notice Concept Clearances
3989	NCATS’ Small Business Funding Helps Launch New Platform for Rare Diseases Drug Discovery	February 2019 UpdateFebruary 2022 UpdateIn early 2013, Christopher Gibson, an M.D./Ph.D. student at the University of Utah, was exploring potential treatments for cerebral cavernous malformation (CCM), a rare disorder in which misshapen, weakened vessels leak blood into the brain and cause strokes. He had hoped his Ph.D. research would complement his planned future work as a cardiothoracic surgeon treating patients with related conditions. Science intervened: While developing an approach to screen existing drugs for their potential to treat CCM, Gibson saw a way to expand that method into an enterprise to discover hundreds of treatments for thousands of diseases. Deferring his goal of becoming a physician, and with support from NCATS’ Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs, Gibson founded a rapidly growing drug discovery company that has, in its first year, attracted more than $3.5 million in private investments.The SBIR and STTR programs are among the tools in NCATS’ arsenal to catalyze innovation in translational science. Often, academic scientists like Gibson make important discoveries in the laboratory but lack the resources and know-how to carry those ideas into the realm of commercialization, where new interventions can be developed and delivered to patients. The NCATS SBIR and STTR programs bridge this translational gap by providing grants, contracts and technical assistance to small businesses and research organizations focused on advancing translational research and technologies that will improve disease prevention, detection and treatment.An Idea Is BornGibson’s idea was born the day a computer beat biologists at their own game. He and his colleagues were screening for potential CCM drugs using human endothelial cells, which make up the inner walls of blood vessels. The researchers genetically engineered the cells to display CCM-like defects, which included abnormal levels of proteins that normally keep vessels intact. After screening more than 2,000 drugs, the team had a pair of highly trained cell biologists compete against an automated computer program — developed by scientists at the Broad Institute — to select the drugs that most effectively reversed the CCM cells’ defects.Recursion Pharmaceuticals co-founder and CEO Chris Gibson, Ph.D. (back row, second from right), and his team have developed more than 200 rare disease models on which to test potential drug therapies. (Recursion Pharmaceuticals Photo).Using microscopic imaging to visualize changes in these cells, the biologists and the computer each selected 39 drugs that appeared to normalize the cells. Remarkably, there was no overlap between the biologists’ and computer’s sets of chosen compounds. To confirm the findings, the researchers screened both sets in another batch of CCM cells, this time measuring the agents’ abilities to normalize dysfunctional cell behavior. One compound from the biologists’ set reversed the defect; to the scientists’ surprise, seven of the computer’s compounds did so.“That moment convinced me that the computer was seeing what humans can’t. I realized that our high-throughput screening approach, coupled with automated computer analysis, could enable us to much more quickly and efficiently discover potential treatments, not just for CCM but for any number of other rare genetic diseases,” Gibson said. “And screening with existing drugs — repurposing — means that potential therapies can reach patients much sooner than starting from scratch.”Seeing an opportunity to expand and commercialize this platform, in summer 2013, Gibson enrolled in Stanford Ignite, an entrepreneurship training program through the Stanford University Graduate School of Business. He worked with classmates to further develop his idea, ultimately pitching it to a panel of investors and industry experts.During the program, Gibson realized that he could take his platform much further than he had first envisioned. “Our initial idea was to start a company and repeat our CCM approach for several other diseases,” Gibson explained. “But the brainstorming at the Stanford Ignite program made us think bigger. We realized, ‘Why focus on one disease at a time? Why not use automation and robotics to carry out high-throughput drug repurposing screens for lots of rare diseases in parallel?’”From the Ground UpIn November 2013, Gibson and his partners founded Recursion Pharmaceuticals. Gibson received his Ph.D. the following month, and in spring 2014, he applied for NCATS SBIR Phase 2 funding, a $1 million award granted to applicants who already have established the technical merit and feasibility of a project.Although he wouldn’t find out until many months later that he had received the award, Gibson did know early on that his application had received a very high score. That score — and, later, the SBIR award — helped Recursion attract an additional $3.5 million in private investments.“The investors specifically said that our SBIR score was instrumental in validating the scientific feasibility of our endeavor,” Gibson said. The SBIR award also garnered attention from major pharmaceutical companies, and negotiations are underway with several large firms. “The SBIR award helped legitimize our project in the eyes of both investors and the pharmaceutical industry and thus was instrumental in getting the company off the ground.”The SBIR award and private investments quickly enabled Recursion to establish a core group of employees and a few initial rare disease models. The company has continued to grow rapidly.“Recursion represents a truly pioneering approach, and I’m excited to watch how the company’s stellar team fosters its innovative platform to advance medical science and, hopefully, promising therapies for patients,” said Craig Wegner, Ph.D., head of the Boston Emerging Innovations Unit, Scientific Partnering & Alliances, within AstraZeneca’s Innovative Medicines and Early Development Biotech Unit.Looking into the FutureToday Recursion has 10 full-time employees and is actively recruiting for at least six more full-time positions. In addition to CCM, the team has developed more than 200 rare disease models on which to test potential therapies and is currently working to validate 12 promising repurposed drug candidates for several rare diseases.“The large number of currently untreatable rare diseases and the fact that each one can affect multiple organs make the traditional ‘one disease at a time/one organ at a time’ translational model untenable,” said NCATS Director Christopher P. Austin, M.D. “Recursion’s approach to transforming drug discovery for rare diseases is a great potential way to tackle this problem.”But Gibson and Recursion are just getting started. “Our goal over the next 10 years is to help bring 100 or more new treatments to patients by generating lead therapeutic candidates through the Recursion platform,” Gibson said.Although the team began with rare diseases, the platform can be adapted to study any number of common diseases and conditions. Already, the Recursion scientists have begun pilot studies to use their system to screen for potential therapies for viral infections, aging, inflammation and cancer.“The platform can be used to test the effects of thousands of drugs on any biological process of interest,” Gibson said. “It not only can help us discover new therapies but also learn more about basic biology as a whole. Any scientist with a good idea should consider the SBIR/STTR program. It has been transformational for us.”Posted March 2016February 2019 Update: A Promising Therapy Enters Clinical TrialsRecursion has now entered its first clinical trial, with a potential treatment for familial CCM. Through this Phase I study, researchers will evaluate the safety of REC-994, one of the first drugs identified through the machine learning approach that led to Recursion’s current drug discovery platform.Pam Jacobson, director of Recursion’s High-Throughput Screening Cell Culture Core, examines cells being prepared for the drug discovery platform. (Recursion Pharmaceuticals Photo)Using artificial intelligence to learn and improve over time, Recursion’s platform also has identified a potential drug to treat neurofibromatosis type 2, a rare tumor disorder. Recursion recently licensed the rights to develop the drug, which the Recursion team hopes to move quickly toward clinical trials, based on some initial clinical data already available.Since the NCATS SBIR Phase 2 award in 2014, which enabled Recursion to hire a core group of employees and attract its first private investments, the company has expanded to more than 120 employees and raised more than $80 million. In addition, from the first few rare disease models made possible by the NCATS funding and other investments, the company has expanded its capabilities to discover therapeutic candidates for several hundred rare and common indications. Recursion is using these models in its own drug discovery programs and in several partnerships with large pharmaceutical companies, including a partnership with Takeda to identify potential new drugs for rare diseases. In less than 18 months, Takeda has exercised an option to continue development of potential drugs for two different rare diseases.The Recursion team at the opening of the company’s downtown Salt Lake City headquarters in fall 2018. (Recursion Pharmaceuticals Photo)“We are very pleased with the momentum of our progress since receiving our SBIR grants from NCATS,” said Ron Alfa, M.D., Ph.D., senior vice president at Recursion. “Our ultimate goal is to reimagine the drug discovery process to find new medicines in a fraction of the time and cost of pharmaceutical development today.”Posted February 2019February 2022 Update: IPO Signals Continued Success for Drug DevelopmentIn April 2021, Recursion reached another major milestone by raising $436 million after its initial public offering (IPO) on the Nasdaq Stock Market. Since receiving an NCATS SBIR Direct to Phase 2 award in 2014, the biotechnology company has doubled the size of its venture rounds — from $60 million in Series B funding in 2017 to $121 million in financing in 2019 to a $239 million round in 2020.The company is using these investments to advance its drug development pipeline. Recursion’s pipeline includes four drugs currently going through the U.S. Food and Drug Administration approval process to treat several rare diseases, as well as additional treatments in earlier stages of development. Recursion was able to leverage its early SBIR funding from NCATS to secure investments — including a strategic collaboration with Bayer — and to reach important clinical and corporate milestones. In all, Recursion has 37 programs under its roof that focus on areas of significant unmet need. NCATS, through its SBIR program, recognizes the importance of early seed grant funding to help support initial stages of research that can accelerate new approaches for addressing rare and common diseases.“We’ve always made bold bets in pursuit of our mission: Decode biology to radically improve lives. Today is no different,” said Chris Gibson, co-founder and CEO of Recursion.Posted February 2022
3983	Prior NIH Approval of Human Subjects Research Frequently Asked Questions	Why do grantees need prior approval for pilot studies involving human subjects? What is the goal of this policy? Which human subjects projects require prior approval? How do potential grantees obtain prior approval? What information and documents are required in a prior approval request? Who should submit prior approval request documents and to whom? How long does it take to receive approval? How will grantees be notified of decisions regarding prior approval requests? What happens if NCATS denies the request for prior approval? If a grantee has not received a response to a prior approval request, may the grantee proceed with the pilot study or K-scholar project? Is prior approval required for studies that have been determined by the local IRB to fall under Human Subjects Research Exemption 4 (45 CFR 46.101[4])? Why do grantees need prior approval for pilot studies involving human subjects? Consistent with NIH policy on Human Subjects Protections, NCATS grantees should seek approval from NCATS to conduct research involving human subjects that could not be described in the original peer-reviewed grant application. Recipients who are part of large clinical research networks or consortia that plan to add new protocols (e.g., small future research projects, pilot projects) after the award has been made must follow the awarding Institute or Center’s procedures for approval of new protocols. For more information, please refer to Prior NIH Approval of Human Subjects Research in Active Awards Initially Submitted without Definitive Plans for Human Subjects Involvement (Delayed Onset Awards): Updated Notice (NOT-OD-18-590). NCATS grantees and their authorized organization representative (AOR) should contact their NCATS program officer and grants management official before submitting the request to obtain prior approval for pilot projects. What is the goal of this policy? The goal of this policy is to allow grantees to conduct human subjects research through the pilot award program or K-scholar projects that were not a part of the peer-reviewed application and to ensure the protection of human subjects involved in research. Which human subjects projects require prior approval? Prior approval is required for human subjects research with all pilot projects funded by NCATS, in full or partially, and for any pilot projects using institutional commitment specifically mentioned in the grant application. Also, prior approval for human subjects research is required for all K-scholar projects. For K-scholar projects, if the time devoted to the research project is supported by the grant and it involves human subjects, it is subject to the prior approval process and must be submitted to NCATS. How do potential grantees obtain prior approval? NCATS has provided information regarding the prior approval process to its grantees. Those who have additional questions should contact their grants management specialists and program officers. What information and documents are required in a prior approval request? NCATS will provide a document transmittal letter with file naming conventions to facilitate this process. Required information and documents include: If applicable to the CTSA Program, the CTSA Program Hub Investigator last name/first initial Protocol title NIH biosketch of pilot project investigator or KL2 scholar performing clinical study Complete clinical research protocol Informed consent document Assent document (if applicable) Identification of specific amendment/portion of protocol supported by NCATS funding (if entire parent protocol is included in submission) Explanation of exactly what is being supported by NCATS pilot or KL2 scholar funding Product information: clinical investigator brochure, package insert or description of device Documentation that Investigational New Drug (IND) or Investigational Device Exemption (IDE) has been obtained or letter from the Food and Drug Administration that the study is IND-exempt or the IDE has a waiver New or revised human subjects section that clearly describes the risk, protections, benefits and importance of the knowledge to be gained by the revised or new activities (as described in Part II of NIH competing application instructions) Inclusion plans for women, minorities and children (if applicable) Targeted Enrollment Table or Inclusion Data Record (optional) Data and Safety Monitoring Plan or Board, if applicable Certification that the pilot project awardee or KL2 scholar and any key personnel directly involved in the study have taken appropriate education in protection of human subjects, if not provided previously Although not required, NCATS strongly recommends submitting the institutional review board (IRB) approval letter (including IRB approvals from each participating site if proposing multi-site trial). If IRB approval is pending, in some cases, NCATS may make a prior approval decision pending final IRB approval. Who should submit prior approval request documents and to whom? The AOR submits a prior approval packet via e-mail to the grants management specialist assigned to the grant. The packet will go from the business office to the grants management specialist, with a copy to the program officer. How long does it take to receive approval? NCATS has up to 30 days, after receipt of a complete packet, to respond to a prior approval request. It is our goal to expedite the prior approval review process, so it is important for grantees to submit all necessary documents and to promptly follow up on messages asking clarifying questions or requesting additional information. Please note that grantees are not required to include an IRB approval as part of the submitted packet, to allow for parallel processes. However, when possible, we encourage grantees to submit prior approval requests to NCATS after receiving IRB approval. If a grantee submits an application packet to NCATS prior to obtaining IRB approval, then NCATS approval is given pending the IRB approval. How will grantees be notified of decisions regarding prior approval requests? NCATS will email the AORs and copy the principal investigators notifying grantees of prior approval request decisions. What happens if NCATS denies the request for prior approval? There are two options: Work with the NCATS program officer to determine whether barriers to prior approval could be eliminated by revising the proposed pilot project. Conduct the project without use of any NCATS funds or NCATS-supported infrastructure. This prohibition includes use of NCATS funding for personnel costs associated with the research. If a grantee has not received a response to a prior approval request, may the grantee proceed with the pilot study or K-scholar project? No. The grantee must wait for NCATS to provide a decision in writing to the grantee’s AOR. Is prior approval required for studies that have been determined by the local IRB to fall under Human Subjects Research Exemption 4 (45 CFR 46.101[4])? No. Studies that fall under Exemption 4 of 45 CFR part 46.101(b) are still human subjects research; however, if the local IRB Office notifies the grantee that the IRB determined the project is exempt from formal IRB Committee review under 45 CFR part 46.101(b) (4) (Exemption 4), then NCATS’ prior approval is not required for that research project. While NCATS’ prior approval is not necessary for studies that an IRB determines fall under Exemption 4, the grantee does need to (1) notify NCATS of the study and (2) submit to NCATS the IRB confirmation/approval letter with the Exemption 4 determination for inclusion in the official grant file.

Download XML

Subscribe to NCATS News