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2013 Omnibus SBIR Contract Soliciation of NIH and CDC

Agency: Department of Health and Human Services
Program/Year: SBIR / 2013
Solicitation Number: PHS 201301
Release Date: August 15, 2012
Open Date: August 15, 2012
Close Date: December 3, 2012
001: Visualizing Knowledge about Human Health and the Pathways of Translation
Description: Translational science is very complex and can be characterized in a multitude of ways. Publications, grant applications, progress reports, funding, specific aims, study designs, hypotheses, outcomes, scientific evidence, experts, collaborations, organizations, and networks, as well as many other factors reflect the complex activity of translational and clinical research. These elements are interlinked and often are represented by massive heterogeneous data, e.g. thousands of papers are produced weekly. To make sense of these data and to aid in seeing the big picture, new methods are needed. Data visualization techniques (e.g. maps, networks, clusters, time series) expose patterns, trends and correlations and are proven to be useful for extracting information from abundant data. NCATS invites SBIR proposals that will facilitate the introduction of visualization technology into understanding the big picture of translational science, the evidence behind the knowledge about human health, and interdisciplinary communication of complex scientific information. Main requirements The outcome of this contract is expected to be software that assists in exploring multidimensional data and understanding complex concepts. The software should: • visualize high-dimensional data from potentially diverse data sources • enable data exploration, change of displayed dimensions, and semantic zooming • create personalized views • work with complex data dimensions, utilizing the elements of principal component analysis (PCA) or other appropriate techniques • have transparent, validated, and well-documented protocols for all steps of data processing (cleansing, filtering, analysis, visualization, personalization, etc.) • be accompanied by documentation of data processing algorithms, data accuracy, precision, and other features necessary for the most accurate interpretation of the produced visualization • take advantage of the existing tools and technologies whenever possible • have Application Programming Interface (API) that does not require programming skills Sample areas of interest to NCATS include • Landscape of knowledge about human health with underlying evidence • Knowledge gaps, discrepancies • Comparative evidence • Provenance of information about human health, therapeutics and diagnostics • Translational Pathways: from discovery to clinical practice • The patterns of self-care and health literacy in various cultures and communities • Uncertainty of information about human health coming from clinical practice, research and consumers • Propensity scores in observational studies • Human subject research design • Complex and distributed resources and on-going research activities, e.g. among Clinical and Translational Science Award (CTSA) institutions or NIH Institutes Deliverables The deliverable of Phase I is a visualization of a test dataset(s), which is made meaningful and valuable to NCATS through the process of interactive learning with minimal burden on the NCATS experts. It is envisioned that the offeror’s representative will gather initial information from publically available sources, and then fine-tune it via observing NCATS activities and interactions with NCATS staff to ensure that the presentation of data and analysis is tailored to NCATS interests and facilitates actions, discussions, feedback, and further learning. The Phase II deliverable is web-enabled software that can be used for multidimensional data exploration and analysis, can work with multiple data sources, and can be personalized to the customer needs via generalized interactive learning methodology of Phase I. Data sources The analysis should be done using a number of various data sources, e.g., publications, social media, NIH databases. The identification of appropriate sources is determined by the offeror. The choices must be justified, analyzed, and well documented with advantages and limitations of every source. Other project clarifications The offerors are encouraged to utilize the multiple principal investigator option to bring in experts from academia http://grants.nih.gov/grants/multi_pi/.
Keywords: NCATS
002: Biomarker Study for Creatine Transporter Defect Disorders
Description: Creatine Transporter Deficiency (CTD) is a severe x-linked linked mental retardation disorder. It is caused by mutations in the creatine transporter gene (SLC68A). Mutations in this gene result in an inability to move creatine across the blood brain barrier. This inability to transport creatine across the blood brain barrier results in a severe deficit of creatine in the CNS and this lack impacts energy homeostasis. Currently, diagnostic biomarkers rely on CTD diagnosis. While there are only a few hundred patients who have been accurately diagnosed with this disorder it is estimated that there are upwards of 40,000-50,000 individuals that are now labeled with x-linked mental retardation or autism. Clinical research of potential therapeutics will rely on the availability of a pool of patients, as well as attempts to better understand the extent and progression of the disease through natural history studies. This initiative seeks to develop a biomarker for use in Creatine Transporter Defect disease. This biomarker would correlate to the nature of CTD and allow its use to identify patients suitable for inclusion in clinical trials. There is the potential that this biomarker could find utility as a diagnostic after validation. Main requirements The outcome of this contract is expected to be a biomarker to monitor the effects of creatine depletion in the CNS. This biomarker would be most useful if it could be tracked in blood or urine but cerebral spinal fluid markers would also be acceptable. This biomarker would have a large impact on patients if banked tissue and blood samples could be examined as well. This biomarker must show a difference between normal volunteer, diagnosed CTD patients and the difference from other autistic or cognitively impaired patients whose symptoms are not related to creatine transporter deficiency. This assay should be able to be performed in reasonable throughput. Deliverables Phase 1 A biomarker assay that meets the requirements listed above and also meets the following: • Develop a working assay • Characterize the variability, reproducibility and accuracy of the detection • Demonstrate the utility of the assay by characterizing differences between normal volunteer, diagnosed CTD patients and the difference from other autistic or cognitively impaired patients whose symptoms are not related to creatine transporter deficiency • Deliver the SOP of the working test to NCATS Deliverables Phase 2 • Demonstrate clinical utility by testing a large number of patient samples or banked tissue or plasma samples • Establish a relationship with companies developing therapeutics for the creatine transporter deficiency patients • Deliver final SOP to NCATS for evaluation
Keywords: NCATS
002: Improved Methods for Collection, Preservation, and Transportation of Biological Specimens
Description: Background: CDC has both domestic and international laboratory programs that provide clinical specimen testing for the detection of known and emerging infections, chemical, or radiological agents that pose global health threats. Current methods for collection, storage, and transport of biological specimens are expensive and labor and material intensive. Clinical specimens are often collected by highly trained phlebotomists and other health professionals, transported to laboratories in compliance with shipping regulations for potentially infectious specimens, and shipped cold chain to ensure specimen integrity. There is a need for novel, minimally invasive, low-complexity specimen collection, and preservation technologies. Project Goal: CDC is interested in improving capabilities in low-complexity methods to collect, preserve, and safely transport clinically relevant specimens or samples for endemic/outbreak surveillance and chemical or radionuclide exposure. Additionally, these technologies could translate well to low resource settings or home health care environments. High quality proposals must address the following priority area and preference will be given to proposals that can address any additional areas of interest. Specifically excluded is research that only incrementally advances the current state of the art. Proposals that aim to simply integrate existing methods and technologies will be considered non-responsive. Priority Area of Interest: Technologies/methods that allow for the self-collection of blood specimens in all point of care/contact settings without the necessity for trained personnel, require minimal materials/reagents, yet maintain the integrity of either nucleic acids (DNA and RNA), protein analytes (antigens, enzyme, and antibody), or both, at ambient temperature (0-40oC) for ≥14 days, and allow for inexpensive storage and transportation. Nucleic acids and/or protein analytes must be compatible/interoperable with downstream assays including functional (activity) assays, real-time PCR, real-time RT-PCR, ELISA, sequencing, mass spectroscopy, and serology, as appropriate. Additional Areas of interest: Compatibility of the technologies/methods with additional biological specimens (e.g., serum, sputum, nasopharyngeal swabs/aspirates, whole blood or urine). When warranted, inactivation of infectious agents by methods that do not interfere with detection/measurement of the diagnostic target, to allow laboratory testing under BSL2 conditions. Suitability for testing a broad range of target analytes (including but not limited to, antibodies, antigens, cytokines, enzymes, carbohydrates, small molecules, metals, radionuclides, lipids, and nucleic acids) at clinically relevant concentrations. Potential for FDA clearance or CLIA waiver for use with diagnostics in low resource settings, patient homes, and first responder use, Potential for Point of Care or Point of Need settings or laboratory environments. Impact: Improved capabilities for specimen or sample collection, preservation, inactivation, and transportation will result in faster laboratory testing, reduce public health costs, and improve testing capabilities in low complexity settings. The impact of this initiative is broadly applicable to many CDC’s “Winnable Battles” including HIV, food safety, obesity, achieving and sustaining global immunization goals, and eliminating lymphatic filariasis in the Americas. In addition, this improved capability will support core CDC surveillance programs such as the National Health and Nutrition Examination Survey, National Health Interview Survey, and the National HIV Behavioral Surveillance System. New technologies resulting from this project have commercialization potential within the growing home health testing market, global diagnostics, and traditional laboratory testing venues.
Keywords: CDC OPHPR
003: Automated Instrument to Clean Microtiter Plates
Description: This initiative seeks to develop an automated piece of instrumentation that can be used to clean previously used microtiter plates, making them suitable for reuse. Given the large quantities of microtiter plates required for high throughput screening any such device developed has the potential of a viable commercial market. Currently in high throughput screening the rule of thumb is to treat every Society for Biomolecular Sciences (SBS) standard assay plate that gets run in a screen as a consumable that gets used only once and is then discarded due to the risk of cross contamination. That being the case, the relationship of assay plates to compound plates to be screened is a 1 to 1 association, meaning as your compound library grows, your demand for assay plates increases, driving costs upwards. Due to this 1 to 1 relationship, for many assays the most expensive part of the screen are the assay plates themselves. In addition to the cost of the plates, these plates are typically made of non-biodegradable plastics (polystyrene, polypropylene, etc.) that will eventually end up in a landfill once discarded. A piece of instrumentation that could utilize some technique to clean used assay plates would allow each plate to be treated as a resource instead of as a consumable, which could greatly reduce screening costs in addition to the amount of solid waste generated. Also, as an automated device this instrument could be used as part of the screening process itself, which would reduce the amount of start up time and system real estate required for plate storage for large scale screens. Another benefit of the instrument being automated is it would remove the need for large scale screens to be run in batches, since one set of assay plates could be used for the entire screen allowing for continuous system operation. Given the potential for cost and environmental savings and the high degree of automated instrumentation used in biological laboratory settings any instrument developed that could allow for the reuse of microtiter plates could potentially have a commercial market. Project Goals The preliminary goal of this project is to develop a functional prototype of an instrument capable of removing both biological reagents and compounds from a used SBS standard assay plate, specifically geared towards biochemical assays. The final product will be an instrument, or set of instruments, that could be integrated as a component of a high throughput screening system in an automated fashion, capable of cleaning plates regardless of the number of sample wells. The long term goal of this project is to bring this instrument to market to meet the needs of those researchers using high quantities of assay plates, for both biochemical and ideally cell based assays. Phase I Activities and Expected Deliverables • Develop a prototype instrument or a detailed plan for a device that meets the following specifications: o Can handle 96, 384, or 1536 plate formats; o Has the ability to utilize multiple potential cleaning solutions while minimizing the need for large quantities of reagent; o Has the capacity to completely dry a cleaned plate; o Does not involve any abrasive touching of the interior of each well, the bottom in particular, that could negatively affect the physical integrity of each well; o Has a maximum clean cycle time of 5 minutes total. • Demonstrates a cleaning process for plates to be used within a biochemical assay with the ability to: o Remove over 99% of a biological reagent such as a BSA solution using different assay detection modes, within the dynamic range of the assay in question (absorbance, luminescence, fluorescence, etc. ) to verify wash results (e.g. an absorbance assay utilizing Bradford staining solution); o Remove over 99% of a chemical compound such as Tannic Acid using different assay detection modes, within the dynamic range of the assay in question to verify wash results (e.g. a luminescence based assay utilizing a dose response curve of Tannic Acid as a control to quantify any residual Tannic Acid left in the sample area of the plate); o Does not degrade assay performance with repeated wash cycles, capable of withstanding up to 50 wash cycles total; o Although not a specific requirement towards Phase I completion, there should be some ability or plan to quantify a Sterility Assurance Level (SAL), geared towards later work in Phase II when some focus is given towards the ability to clean cell based assay plates to ensure there is no contamination between uses. • Cost estimates to manufacture a device capable of meeting the specifications listed above. • Provide NCATS with all data resulting from Phase I Activities and Deliverables. Phase II Activities and Expected Deliverables • Build a prototype instrument that meets the Phase I specifications in addition to several others geared towards the device working as part of a larger automated process: o Is accessible enough to have a plate automatically loaded into the device by standard laboratory robotic equipment; o Has a remote programmatic interface allowing the instrument to be controlled by an external software application through standard laboratory communication protocols (RS-232, TCP/IP, etc.); o Can reliably operate for extended periods of time in an automated fashion (overnight usage with a constant plate throughput limited by the duration of the load/unload time of the device and the cleaning process itself). • Develop detailed procedures to be able to quantify the instruments cleaning effectiveness: o Provide detailed protocols to show the effectiveness of the instrument in removing biological reagents from a used assay plate; o Provide detailed protocols to show the effectiveness of the instrument in removing chemical compounds from a used assay plate; o Develop procedures to potentially allow for the cleaning of cell based assay plates, assuming these plates did not require any additional coating to promote cell adhesion. • Demonstrate the ability of the prototype instrument to run the cleaning procedures as described above in an automated fashion: o A set of assay plates should be run for multiple cycles and show no residual biological or chemical contamination from previous uses; o The assay performance should remain close to constant despite using the same plates repeatedly; o The assay performance should be comparable to using new assay plates; o Multiple assay detection modes should be tested as described in Phase I. • Develop a robust manufacturing plan for the instrument, using off the shelf OEM components where possible to minimize expense. • Provide NCATS with all data resulting from Phase II Activities and Deliverables.
Keywords: NCATS
003: Diagnostic Needs for Neglected Tropical Diseases (NTD) Programs
Description: Background: Neglected tropical diseases (NTDs) are bacterial and parasitic infections that disproportionately affect poor and marginalized populations around the world. A subset of NTDs, including lymphatic filariasis, onchocerciasis, schistosomiasis, trachoma and intestinal helminth infections, can be targeted effectively through mass chemotherapy. These NTDs are not considered to cause appreciable mortality; however, they are associated with high levels of morbidity because of the chronic nature of many of the infections. Blindness and disability due to these NTDs increase in prevalence with age, reducing the productivity of adults. Intestinal helminths, among the commonest of infections, have profound effects on the growth and cognitive development of children. The past five years have seen significant increases in the number of countries implementing NTD programs and in the number of persons being treated. These increases are the direct result of generous donations of drugs from pharmaceutical manufacturers and new funding support from the US Agency for International Development (USAID) and the Department for International Development (DFID), among others. Reducing the morbidity caused by NTDs is an objective of the Global Health Initiative (GHI) and the global elimination of lymphatic filariasis and trachoma are specific GHI targets. Available diagnostic tools for lymphatic filariasis (LF), trachoma, schistosomiasis, onchocerciasis and intestinal helminth infections do not at present meet the needs of the control programs. Project Goal: Diagnostic tests are needed to guide programmatic decisions on community treatment for diseases addressed by mass drug administration (MDA). Despite the molecular revolution in biology, little of the new found knowledge of parasite genes and gene products is being translated into tools than can be used in the field to guide program decisions. Tools for mapping and monitoring program impact are still conventional parasitologic methods, based on microscopy. These tests lack sensitivity and are not adequate for NTD programs with elimination endpoints. New antibody tests could provide more sensitive tools to monitor transmission, facilitate decision-making, and conduct surveillance. The potential advantages of antibody-based tests for post-MDA surveillance supports the efforts to develop a standard platform therefore opening opportunities for integrated surveillance for NTDs. Impact: Development of improved diagnostic tools will address one of CDC’s efforts to address lymphatic filariasis (LF in the Americas) and the GHI targets on NTDs. They will also enhance the commitment of donors and policy makers to the control and elimination programs for NTDs by providing higher quality information and increased confidence that public health goals are being met. Significant savings in human and financial resources could be obtained through the development of improved diagnostic tools.
Keywords: CDC CGH
003: Development of Nanoparticle Dengue Diagnostic Tests
Description: Background: Dengue is a major public health problem in global tropical and subtropical areas. Primary prevention of this mosquito vector-borne (transmitted) disease is limited because vaccines are only in the late-stage development phase and vector control has been thus far unsuccessful. Dengue presents as an acute febrile illness often without signs or symptoms that differentiate it from other common diseases such as influenza and leptospirosis. Some patients progress to severe dengue near the end of their febrile period, which can result in death. Good clinical management, early in the course of dengue, prevents excess morbidity and mortality. Yet, early clinical management requires accurate laboratory diagnosis to differentiate dengue from other similar presenting diseases (e.g., influenza, leptospirosis). Until recently, dengue diagnostic testing was problematic because most patients present during the first days after onset of fever. Dengue virus (DENV) detection in serum is the only way to make the diagnosis, but anti-DENV IgM levels usually do not reach measurable levels until the critical phase. While molecular testing identifies most persons with dengue, this method is not widely available in developing countries where the disease is endemic. In addition, a soluble non-structural antigen (NS1) can be detected by immunoassay during this period, but is not as sensitive as molecular tests. Nanoparticle-based technology significantly increases the sensitivity of antigen and antibody detection tests and can be used for molecular diagnostics and in multiplex formats. Microresonator constructs and nanowire-based field effect transistors allow this technology to detect biolytes at low femtomolar concentrations. Surface enhanced Raman scattering (SERS) and extrinsic Raman labels (ERLs) have been used with metal nanoparticles (gold, silver) organic reporter molecules to magnify the Raman response by ~106, which surpasses fluorescence. Project Goal: To develop prototype dengue diagnostic tests that identify DENV by either molecular or immuno-detector systems (e.g., DENV specific nucleic acid, NS1 and E antigen) using nanoparticle-based technology that includes but is not limited to SERS and ERLs. The prototype test(s) should be developed as a biochip with a product profile that is amenable to a short-turn-around diagnostic result for use in resource constrained settings. Prototype test(s) would be judged as ‘acceptable’ if they detect a high proportion of dengue cases during the early phase of the febrile illness across all DENV serotypes, in primary and secondary infections and do not cross-react or misdiagnose other flavivirus infections or infections due to other causes of febrile illness that present with signs and symptoms similar to dengue. Impact: The availability of dengue diagnostic tests with high sensitivity and specificity that detect DENV infection soon after the onset of fever would greatly change the public health impact of current secondary prevention activities by improving clinical outcomes, and would provide the basis for evaluation of dengue vaccines following introduction. The market for dengue diagnostic tests has not been estimated, however, it is estimated that 40-60% of the world’s population reside in dengue endemic areas of the world (i.e., 100% cases of dengue are reported annually). Thus, one would expect there would be a many-fold great market for these tests each year.
Keywords: CDC NCEZID
004: Assay Development for High-Throughput Screening of Chemicals of Toxicological Concern
Description: Adverse human health outcomes – a.k.a., “toxicity” – caused by pharmaceutical or environmental compounds are a major cause of drug development failure and public health concern. Methods to evaluate the potential of chemical compounds to induce toxicity are based largely on animal testing, are low-throughput and expensive while giving little insight into mechanisms of toxicity, and have not changed appreciably in the last 50 years despite enormous advances in science. Multiple efforts, including Tox21 in the U.S., REACH in the E.U., and multiple industrial collaborations, are attempting to develop in vitro methods to assess chemical toxicity. These programs must assess toxicity potential in every organ system and identify pathways and/or targets affected. Given the protean nature of these effects, it is likely that hundreds of in vitro assays will need to be developed and tested for their ability to read out chemical effects on particular cell types and pathways. Progress in the field is currently limited by the relatively small number of pathways and cell types that have been developed into high-throughput screening (HTS)-ready assays, and the artificial nature of many of the assays that have been developed (e.g., immortalized/transformed cell lines, heterologous expression with lack of physiologically accurate regulation). The development of HTS-ready assays which can report on particular pathways and cellular phenotypes across the full spectrum of pathway space and toxicological outcomes is needed. Such assays would need to meet strict performance criteria of robustness, reproducibility, and physiological relevance. The assays developed would need to be capable of being run in 384-well or (ideally) 1536-well format and must allow the testing of >100,000 samples per week. Main requirements The outcome of this contract is expected to be one or more novel assays for targets, pathways, and cellular phenotypes related to any type of xenobiotic toxicity. These assays would utilize human cells, including immortalized cell lines, primary cells, and stem cell derived cells, and must be functional in multiwell format with characteristics suitable for automated high-throughput screening. Such assays should be novel, reflecting new pathways or cellular endpoints than are currently available, and be clearly connected to some type of human toxicological response. Such assays could find utility as in chemical assessment and risk management after validation. Deliverables Phase 1 An assay that meets the requirements listed above and also meets the following: • Develop a working assay in 96-well or denser (384, 1536) microwell format • Characterize the sensitivity, specificity, variability, reproducibility, signal: background, dynamic range, and accuracy of the assay, utilizing standard positive and negative controls, Z’ values >0.5 • Demonstrate the utility of the assay by characterizing its ability to detect the effects of compounds known to affect the pathway/cellular phenotype, with a throughput of at least 10,000 samples/day with workstation automation • Are not duplicative of assays already available commercially • Deliver the assay/SOP to NCATS for evaluation Deliverables Phase 2 • Demonstrate miniaturization of assay to work in at least 384-well (preferably 1536-well) format with same technical specifications as listed above • Demonstrate amenability for HTS by successful testing of >100,000 samples/day in fully automated robotic format with maintenance of assay performance • Deliver final assay/SOP to NCATS for evaluation.
Keywords: NCATS
004: Rapid Screening Tests to Prevent Congenital Infections and Ensure Blood Safety
Description: Background: During the past decade, several companies have developed lateral flow immunochromatographic devices to detect antibodies to individual communicable diseases. More recently, these platforms have also been adapted to detect specific antigens associated with these infections. These inexpensive point-of-care (POC) tests offer considerable advantages over conventional laboratory tests, since they can be performed in remote, peripheral settings with little or no instrumentation by primary health care workers. This also allow for counseling (and treatment if appropriate) at the initial consultation. Point-of-care (POC) tests have been used successfully to screen pregnant women for HIV and syphilis to prevent vertical transmission of these infections and therefore prevent congenital disease. In addition, in areas remote from formal, organized blood banks, these and other POC tests have been used to screen potential blood donors to prevent transfusion related infections. Unfortunately, these tests are usually performed as individual tests for antibodies or antigens for single infections. This results in a series of test strips being run in parallel, which may have different flow characteristics, buffers and run times that may lead to confusion and potential inaccuracies. Project Goal: CDC is seeking the development of a highly sensitive, highly specific, rapid and easy to use, disposable multiplex immunochromatographic screening device to detect Hepatitis BsAg and malarial antigen together with antibody to Human Immunodeficiency Virus 1 and 2 (HIV 1/2) and syphilis in a single finger-stick sample of whole blood. The purpose is for screening pregnant women with the intent to prevent vertical transmission of infection. CDC is also interested in a single device to detect Hepatitis BsAg and malarial antigen together with antibody to Hepatitis C Virus (HCV), Human Immunodeficiency Virus 1 and 2 (HIV 1/2) and syphilis in a single finger-stick sample to screen blood donors for transfusion-related infections in settings where conventional laboratory facilities are not available. Optimization of assays to detect both antibodies and specific antigens in the same cassette device on a single specimen is strongly encouraged. Impact: It is anticipated that the development of these two multiplex immunochromatographic test cassettes could result in a significant reduction in rates of congenital HIV and syphilis, together with other infections that can be transmitted from mother to child. In addition, these tests would help make blood transfusions safer in areas where laboratory testing is either not available, or of poor quality.
Keywords: CDC CGH
004: Development of Tests in a Standardized Kit Format for Diagnosis of Arboviral Infections in Resource-Limited, Primary Health Care Setting
Description: Background: Arthropod-borne virus infections may present with clinical symptoms similar to those of other bacterial or viral infections, such as a flu-like illness, encephalitis, or polio-like myelitis. Laboratory diagnosis is essential to determine etiology and calculate disease burden in order to guide treatment and control strategies, particularly if there is an effective vaccine available, such as for yellow fever and Japanese encephalitis. Detection of virus-specific immunoglobulin M (IgM) antibody in an enzyme-linked immunosorbant assay (MAC-ELISA) is the standard serological test for diagnosis of acute arbovirus infections. However, diagnostic tests are not available for many of these “neglected” but medically important arboviral diseases in resource poor laboratories. Samples must be sent to reference laboratories for testing, which delays diagnosis and reduces the number of laboratory-confirmed cases. “In-house” assays developed in reference laboratories are unsuitable for use in laboratories with limited technical capacity, due to the lack of standardized reagents and format. Project Goal: The goal of this project is the development of a laboratory test based on IgM detection to diagnose arboviral infections in a standardized kit format. A prototype yellow fever virus MAC- ELISA should be developed initially showing proof-of-concept. The developed assays should have the characteristics of simplicity and robustness as described by the World Health Organization. The format should be designed so that the assay can easily be modified to test for other arboviruses by switching out a limited number of standardized and validated reagents and controls. The variation, reproducibility, and accuracy of the test should be characterized and benchmarked against current tests. Suitability of the test for use in resource-limited surveillance laboratories should be demonstrated. Impact: The test is meant to be a screening test used at primary health care level. A rapid diagnostic test is essential to support vaccination and surveillance programs by increasing the number of biologically confirmed cases, thus improving the accuracy of disease burden estimates. These data will in turn improve the effectiveness of vaccine programs for vaccine-preventable diseases such as yellow fever. The primary benefit of such diagnostics is intended for resource-poor countries. Such rapid arbovirus diagnostics can be incorporated into resource-poor countries as laboratory capacity-building efforts. Innovative approaches such as “dipstick” technology that can be used in the clinic and the field are already being employed by manufacturers of commercial diagnostic assays for other medically important infectious diseases. Rapid diagnostics is an area that should be of particular interest to small business concerns. Laboratories in developing countries have either no alternative methods or only elaborate and inefficient methods to diagnose arbovirus infections at this time, a gap which a small business has the opportunity to fill.
Keywords: CDC NCEZID
005: Development of Diagnostic Tests for Strongyloidiasis and Schistosomiasis
Description: putting international travelers at risk for infections with these organisms. In a 10-year period from 1997 to 2008, over 400 cases of schistosomiasis were reported in travelers to the international travelers’ health surveillance network (GeoSentinel). In addition, the United States resettles 50,000-80,000 refugees annually from around the world. It is estimated that the prevalence rates of parasites, such as Strongyloides and Schistosoma in many U.S.-bound refugee groups are between 20 and 40%. Diagnosis of these infections in returning travelers and refugees in the United States is difficult because patients often present initially with a constellation of vague symptoms and thus, diagnoses of strongyloidiasis and schistosomiasis typically rely on confirmatory laboratory testing. The availability of parasitic serology testing in the United States is limited to six commercial laboratories and the CDC reference laboratory. Most commercial laboratories use reagents prepared by one or two manufacturers. To further complicate diagnosis, the reliability of these reagents and tests are variable and typically not FDA-cleared. To improve laboratory diagnosis of parasitic diseases, reliable serological tests are needed, especially for schistosomiasis and strongyloidiasis. Project Goal: CDC is particularly interested in the development, validation, and FDA clearance of serological tests for diagnosis of strongyloidiasis and schistosomiasis. Use of recombinant protein targets instead of native parasite materials for detection of parasite specific antibodies will reduce variability and availability and should be considered. All submissions must include validation and FDA clearance as deliverables. Impact: Availability of reliable commercial tests for strongyloidiasis and schistosomiasis will improve clinical management of these diseases.
Keywords: CDC CGH
005: Reducing Antimicrobial Resistance through Improved use of Laboratory Testing Information in Healthcare Facilities
Description: Background: The reduction and eventual elimination of healthcare-associated infections (HAIs) and the combatting of antibiotic resistance in the pathogens causing these infections are national public health priorities as demonstrated in Department of Health and Human Services (HHS) national action plans. Public reporting of HAIs by hospitals using the National Healthcare Safety Network (NHSN) is mandated in over half of all states and the number of states is increasing annually. The public reporting of three HAIs is currently incentivized by the Centers for Medicare and Medicaid Services and this program is slated to expand dramatically in coming years. Meanwhile, as the crisis of antibiotic resistance continues to grow, the need for more detailed surveillance data will increase to preserve remaining drug activity. Electronic data submission provides the best method for meeting increasing informational needs while containing the costs of public reporting. Already several hundred hospitals are submitting electronic data to NHSN to meet present and future mandates for public reporting. Project Goal: To develop a technical prototype for summarizing antimicrobial resistance data (as outlined on the NHSN website) using a laboratory or infection control information system and reporting to NHSN within the CDC clinical document architecture specifications (http://www.cdc.gov/nhsn/CDA_eSurveillance.html). It is expected that a successful project will implement a research plan and evaluate (1) the validity (i.e., accuracy) of the data reported to NHSN and (2) the usability for hospital or regional-based collaborative efforts on reducing antimicrobial resistant infections. Impact: Success of this project would demonstrate the value of electronic submission of antimicrobial resistance data to NHSN, therefore providing risk adjusted resistance patterns to guide infection prevention and antimicrobial stewardship activities at a facility. Infection control information systems and laboratory information systems that enable such electronic reporting will consider this functionality an attractive option to hospitals to comply with state mandates on reporting and adhering to emerging federal policies in this arena. If the experience of reporting HAI data electronically from vendor systems to NHSN is any indication, demonstrating the utility of such reporting for antimicrobial resistance data will be perceived by hospitals engaged in infection prevention activities, either by mandate or quality improvement programs, as an attractive option in making decisions regarding hospital-based health information systems.
Keywords: CDC NCEZID
016: Improving Data, Improving Care, Making it Count
Description: Background: The number of people affected by complex childhood rare conditions (CCRC), such as spina bifida (SB), is estimated to be 1/1500 globally. While the prevalence of these conditions is low, they have high impact in terms of health care costs and impact on the family and the community. Reliable and valid clinical data are scarce and insufficient to identify and evaluate clinical practices that lead to the best outcomes in care for these populations. Diagnosis-specific Electronic Medical Records (EMRs) offer an important opportunity for specific clinical populations and their providers. Currently, most spina bifida clinics are required to enter data in both their institution’s EMR, as well as in the spina bifida electronic medical record (SB-EMR). A software application that will eliminate double data entry and allow each institution to maintain its electronic medical record while also populating a diagnosis-specific record will allow the extraction of data that can be used to measure and evaluate quality of care. This in turn has the potential to significantly impact the health and cost of care of people with spina bifida and other rare disorders. Project Goal: CDC is seeking software that will build on the existing spina bifida electronic medical record (SB-EMR) being used by 19 clinics in the National Spina Bifida Patient Registry (NBSPR). Funding will support the development of intraoperative software to extract relevant data from an institution’s legacy medical record system and input it into the SB-EMR, significantly reducing the resources needed to collect the condition-specific information critical for research. Data can then be used to evaluate the effectiveness of various treatment and prevention approaches for SB patients. Any software product developed as a part of this proposal must follow the Enterprise Performance Life Cycle process for project management, producing each of the required artifacts for a gate review prior to moving to the next stage in the process. Also, it must obtain Authority to Operate (ATO) from the Office of the Chief Information Security Officer (CISO), CDC. Impact: The proposed software tool has applications for other health condition and clinical practices. For example, other registries (e.g., ALS) could use this tool for recording and tracking patient information. In addition, state and local health departments could use a similar tool to avoid double data entry into multiple surveillance systems. Labor and associated resources at the clinic level could be reduced dramatically while improving the quality of data needed to identify health care trends and best practices for care. This project will build on the current expansion of technology and use of EMR as they are rapidly being implemented in health systems across the country. If successful, the technology and tools developed will result in a more efficient and effective data entry operation by which clinical care and prevention can be improved.
Keywords: CDC NCBDDD
017: Smartphone Application for Global Birth Defects Surveillance
Description: Background: Every year approximately 8 million children are born worldwide with severe birth defects. Currently, data about the magnitude of birth defects prevalence in low and middle income countries are either nonexistent or severely underestimated, creating difficulties for health strategic planners to convince policy makers of the burden and the public health impact of birth defects in their countries. The use of smartphone technology has proven to be a useful tool in the collection of data that is otherwise not available, incomplete or not easy to capture. The use of smartphones is a novel, simple, efficient and instructive approach to the collection of data and offers great potential for encouraging health care personnel to contribute data using their mobile telephones. In particular, this technology would help address a critical need in large continental areas like Africa, South America and East Asia where birth defect registries are limited or do not exist and thus little is known about disease burden and service need. Use of smartphones to establish standard global surveillance data will help to more accurately identify the prevalence of birth defects and expand the reach and impact of clinical and public health services for affected children and their families. Project Goal: CDC is seeking the development of smartphone technology for the implementation of birth defect registries in global settings. Application of smartphone technology has the potential to improve the accuracy of data collection, reduce the time and the cost of data transmission and retrieval, reduce data entry errors and synchronize collected information with a central database. Use of smartphone technology has the potential to address many of the issues involved in global birth defect surveillance such as the standardization of the data collection process. Built-in data quality indicators can assess key elements of data quality such as accuracy of diagnosis (providing clinical decision support to the health provider in the field), completeness of information of a minimal set of required variables, geographic information systems (GIS), timeliness of data transmission, availability of population denominator information, and evaluation of performance. Impact: Many large countries have remote areas where the implementation of appropriate birth defect surveillance is very difficult. A smartphone application will strengthen surveillance by facilitating the standardization of birth defect collection, and storage, transmission and retrieval of data across worldwide communities. Local providers will have access to clinical information and guidelines for initial management of patients with birth defects. In addition, the technology will contribute to the awareness of the public health burden of birth defects, and the need for more targeted prevention strategies leading to a positive global health impact. Once developed, the smartphone application for birth defects registries has the potential to be easily converted into a collection tool for other existing epidemiological data registries with numerous uses and to further applications for insurance companies, government entities and private business.
Keywords: CDC NCBDDD
021: Aerosolized Delivery of Anti-Tubercular Drugs
Description: Background Many currently existing drugs for the treatment of TB, especially MDR TB are moderately potent, show restrictions with absorption or oral bioavailability, and have toxicity profiles that make patient management difficult. Aerosolized delivery offers the potential to bypass these barriers to drug efficacy by achieving high drug concentrations in the infected pulmonary tissue with lower systemic exposure and by bypassing first-pass hepatic metabolism, thus allowing increased immediate potency. Given these potential benefits, an easy to use, aerosolized delivery system would represent a significant advance in the treatment of tuberculosis. Though anti-tubercular drugs have been formulated into aerosolized particles by multiple research groups and numerous papers are available in the literature on formulating inhaled therapies for TB, no formulation has yet to be commercialized. Project Goal The goal of this solicitation is to develop an inexpensive, easy to use, aerosolized delivery system of a combination of anti-tubercular drugs that could be used for the treatment of MDR TB. Phase I activities 1. Development of an aerosolized formulation of a combination of anti-tubercular drugs 2. Development of an inexpensive, easy to use platform for delivery of said formulation 3. Initial testing to quantitatively assess for drug efficacy, toxicity and pharmacokinetics including required in-vitro studies. Phase II activities 1. Preclinical studies including required in-vivo testing in a standardized, reproducible, validated small animal model. 2. Development of a well-defined formulation and delivery platform under good manufacturing practices (GMP); 3. Uniformity from lot to lot and be certified under quality control; 4. Scale-up and production for future Phase I clinical study.
Keywords: NIAID
022: Development of Long-Acting Formulations of HIV Anti-Retrovirals
Description: Background Effective treatment of HIV-infected individuals requires strict adherence to a multi-component regimen of antiretroviral agents that currently must be taken daily on a life-long basis. Non-compliance with recommended dosing regimens is a significant factor contributing to the incomplete suppression of HIV and to the development of drug resistance. The development of long-acting formulations that might significantly simplify the dosing requirements potentially could facilitate improvements in patient adherence. Long-acting formulations also would have utility as components of drug regimens provided to uninfected individuals for pre-exposure prophylaxis (PrEP) purposes. Some orally administered antiretrovirals readily penetrate and accumulate in rectal and female genital tract mucosa and achieve concentrations in those tissues higher than in plasma. Formulations based on antiretrovirals with these properties might have utility both as systemic and PrEP agents and thus are particularly attractive as formulation development candidates. Project Goals The goal of this SBIR contract solicitation is to support small businesses interested in developing novel formulations of antiretroviral drugs that can achieve clinically relevant systemic or tissue concentrations and maintain these levels for an extended period of time. Formulations that need only be administered once per month are of particular interest; however, formulations that extend the dosing interval to once a week or better still might be valuable additions to current or future PrEP and treatment strategies. Antiretroviral agents selected for formulation development should either be FDA-approved or in mid- to late-stage preclinical development (estimated time to clinical evaluation of 1-3 years). Offerors will be responsible for obtaining the parent antiretroviral compounds for their formulation efforts and for resolving any intellectual property issues that might arise regarding use of these compounds. Phase I Activities 1. Develop prototype formulations that address the goals of this solicitation. 2. Develop analytical assays that can be used to assess formulation purity and stability. 3. Assess the pharmacokinetic profile and safety of the formulations in an uninfected animal species. 4. Submit promising formulations to NIAID, if requested, for evaluation in either in vitro HIV-inhibition assays or small animal models of infection. Phase II Activities 1. Scale-up the formulations (activity need not be compliant with cGMP) for further preclinical studies. 2. Conduct additional pharmacology and toxicology evaluations of the formulations in uninfected animals. 3. Conduct bioequivalence studies in uninfected animals.
Keywords: NIAID
023: Improved Formulations for Approved First and Second line anti-Tuberculosis (TB) Drugs
Description: Background There is an urgent need to develop alternative formulations of approved first and second line anti-TB drugs for pediatric use and also to simplify administration. There are few child-friendly formulations of pediatric first and second-line anti-TB medications available to practitioners in the US and globally. It is standard practice to cut or crush un-scored adult tablets and administer them to children in juice or other palatable substances. This has significant potential to deliver incorrect and highly variable doses to children, contributing to ineffective treatment. While consideration of pediatric applications is a recent regulatory requirement for novel drugs in general, this requirement does not apply to approved, TB drugs that are off patent and manufactured as generics. Additionally, treatment of adult and pediatric patients may include the administration of TB drugs that are only available as injectable agents. This often requires that the patient be hospitalized to facilitate administration or visit health centers on a daily basis interfering with employment obligations and compromising adherence. Project Goal The goal of this project is to develop improved formulations for currently approved TB drugs for pediatric use and also to develop alternative formulations for drugs currently administered by injection. The final product should be simple to manufacture, stable under ambient conditions, and ready for testing in Phase I bioequivalence and PK studies. NIAID clinical contract resources could be used to facilitate evaluation of these formulations in target populations at the end of the SBIR contract period. Phase I Activities • Development of prototype formulations that address the goals of this solicitation. • Development of analytical assays to characterize chemical composition, purity and stability of prototype formulations. • Assessment of the pharmacokinetic profile and safety of the formulations in an uninfected animal species. • Development or conduct of drug potency assays for bioequivalence studies. Phase II Activities • Scale-up of the formulations (activity need not be compliant with cGMP) for further preclinical studies. • Conduct of additional pharmacology and toxicology evaluations of the formulations in uninfected animals. • Conduct of bioequivalence studies in uninfected animals or infected animals as appropriate.
Keywords: NIAID
023: Neural Interfaces: Improving Functional Outcomes
Description: Summary The long term goal of neural interfaces for medical rehabilitation purposes is to replace lost functionality for people with physical disabilities. While great strides have been made in the neuroprosthetics field, the state of the art falls far short of complete restoration of function. For example, there is no consensus on the best modality for extracting signals from the central nervous system, peripheral nervous system, or the musculoskeletal system. There is insufficient evidence of reliable, long-term neural interfaces in human subjects. There are no decoding algorithms that allow for quick, natural, and diverse use of multiple degrees of freedom in the end effector. There is insufficient use of sensory input to close the feedback loop. There are no common measures for training and testing of neural interfaces and human subjects. Technical areas of particular interest that address unmet challenges in neuroscience, medicine, materials, and engineering include: (1) Novel, reliable, and scalable biotic-abiotic interfaces for recording neural or muscle signals; innovation in tissue interface systems that demonstrate high-levels of neural-information extraction, low levels of error, and long functional lifetimes are highly encouraged. (2) Reliable, effective, and clinically viable algorithms for decoding limb-control signals; new algorithmic approaches that maximize the amount and rate of limb-control information while reducing the error, degree of pre-processing, and need for recalibration over time are highly encouraged. (3) Novel, reliable, and scalable biotic-abiotic interfaces for providing sensory stimulation. Proposals should address novel methods that go beyond conventional neural stimulation approaches in order to extend the clinical applications of neural stimulation. Approaches may include, but are not limited to electronic, photonic, tactile, ultrasonic, or chemical stimulation platforms. (4) Training and testing methods; identification of common metrics related to function that would allow systematic investigation of signal processing is encouraged. Applications for this RFP should address one or more of these technical areas. Project Goals The purpose of the proposed RFP is to accelerate research in the field of neural or muscle interfaces with the emphasis on a more naturally controlled prosthesis for people with movement impairments by improving the person/device interface. This solicitation seeks novel approaches for the fusion of neural data with the intent of controlling extracorporeal systems. Proposals designed to capture neural-control signals from central nervous system (CNS) and non-CNS sources (e.g., peripheral nervous system, neuro-musculature system, etc.) are encouraged. The long term goal of the project is to create platform software packages with novel algorithms that can be integrated with one or more modular rehabilitation devices. Phase I Activities and Expected Deliverables Phase I research should generate scientific data confirming the clinical potential of the proposed software. Some of the expected activities are: • Design and development of a prototype system(s). • Development of innovative algorithms to improve neural signal processing methods for guided interventions for individuals with movement impairments. • Demonstration of the capabilities of the software. Final Phase I report should include plans for future work and commercialization. Phase II Activities and Expected Deliverables Production of a laboratory or clinic ready hardware and software package with user friendly graphical interface. Draft user manual.
Keywords: NICHD
024: Integrated Multiplex Medical Diagnostics Platforms for Infectious Diseases
Description: Background NIAID supports integrated multiplex medical diagnostics platforms capable of simultaneously identifying multiple pathogens in clinical specimens (swabs, sputum, blood, serum, cerebrospinal fluid, urine, stool, etc.). Platforms that provide diagnostic information on potential early, non-specific symptoms and determine pathogen drug sensitivities are of high priority. Project Goal The final integrated diagnostic product should be capable of aiding healthcare providers in diagnosing individuals exposed to and/or infected with infectious agents. The product should be developed with the ultimate goal of obtaining FDA clearance. Consequently the product should demonstrate sensitivity and specificity equivalent to or exceeding FDA-cleared tests for similar agents. The proposed diagnostic must provide rapid, shortened time from sample to diagnosis (30-40 minutes); offer high sensitivity and specificity; and be easy to use. Importantly, it should not incorporate nucleic acid amplification to detect pathogens, toxins or infectious diseases. The product should function as an integrated, closed sample-to-answer system with automated data analysis and output. It should be capable of integrating new assays and detection of modified or new targets and be cost-effective. Phase I activities should include one or more of the following: • Development and integration of novel methods for sample preparation and concentration into the platform. • Development and integration of novel detection technologies into the platform that do not involve nucleic acid amplification. • Development, optimization, integration, and validation of multiplex assays. • Integration and validation of internal process controls. • Development of software for controlling the platform, displaying the results of the diagnostic tests, and transferring results to laboratory information systems (LIMS). Phase II activities should include one or more of the following: • Continuation of Phase I activities. • Process development for the manufacturing of diagnostic components, including Quality Assurance/Quality Control methods for reagent recovery, characterization, purification, identity, and stability. • Validation of the integrated multiplex medical diagnostic platform. Tests for use on human samples may consider benchmarks required for FDA approval (http://www.fda.gov/cber/devices.htm).
Keywords: NIAID
025: Development of an Inactivated Rotavirus Vaccine for Use in Global Immunization
Description: Background: The currently licensed oral rotavirus vaccines Rotarix™ and Rotateq™ are effective in reducing cases of severe diarrhea among children in high and middle income countries, but are significantly less effective in low income countries. In addition, both vaccines are associated with a low risk of diarrhea and intussusception among infants who receive the first dose of vaccine. To improve the safety and efficacy of oral rotavirus vaccines, CDC scientists have developed a proprietary inactivated rotavirus vaccine (IRV) technology (new human strains and a novel method for rotavirus inactivation) and demonstrated the immunogenicity in mice and protective efficacy in piglets of this IRV by intramuscular (IM) administration. CDC has demonstrated good immunogenicity of the IRV using an innovative microneedle patch technology, achieving comparable antibody titers with a 1/10th of the antigen dose compared to those induced by a full IM dose of vaccine. Microneedles provide a simple and painless method to administer vaccines without using hypodermic needles. They are inexpensive to manufacture and may not need the cold chain, a major advantage for immunization campaigns in the developing world. The findings from this study may allow us to enhance public health through the development of a low cost vaccine with an improved safety and efficacy profile and thus help achieve and sustain global immunization initiatives such as rotavirus vaccines. Project Goal: With the establishment of proof of concept for intramuscular and skin immunization in animals, the CDC has licensed the technology to a number of vaccine manufacturers in the US and emerging developing countries for scale-up and clinical development as a stand-alone IRV first and then a combined pediatric vaccine. However, phase 1 safety data in the country of origin (USA in this case) is a prerequisite for vaccine manufacturers in developing countries to receive approval from their national regulatory agencies for clinical trials of a new vaccine. To meet this requirement, the goal of this project is to propose several specific research areas of interest, (1) production of a Vero cell bank, (2) production of two rotavirus seed banks and, (3) preparation of two pilot vaccine lots under Good Manufacturing Practice (GMP) conditions in partnership with a contract manufacturing organization (CMO). Pilot lots will include the preparation of an injectable IM vaccine first and microneedle patches for skin immunization, if enough funding is available. Impact: Availability of GMP materials and phase I safety data will provide the opportunity to move this project forward, working with partners, to jointly develop this new and innovative IRV for use in children throughout the world. In long term, this IRV can be combined with other pediatric vaccines, such as IPV. Due to the parenteral administration, IRV will be equally effective in all settings, help save more lives, and ultimately increase global health impact through large immunization campaigns.
Keywords: CDC NCIRD
026: Thermostable Dry Measles Vaccine Formulation for Sublingual Administration
Description: Background: Vaccines are one of the most powerful tools available for preventing disease. Measles vaccine has led to the elimination of endemic measles from the Western Hemisphere and a tremendous reduction in global mortality. However, the logistic difficulties inherent in vaccination by injection create barriers to high measles vaccine coverage. Vaccination by injection requires highly skilled vaccinators, maintenance of an expensive cold-chain, vaccine reconstitution with risks of contamination and bio-waste disposal of millions of syringes and needles to prevent reuse or injuries. Needle-free vaccine delivery would lower these barriers and expand the benefits of vaccination to a larger at-risk population. Project Goal: Although sublingual drug delivery has been used for years, only recently has research begun to demonstrate the potential of sublingual vaccine delivery. Proposals are solicited for the development of a thermostable dry measles vaccine formulation to be administered sublingually in a melting tablet, wafer or strip format. The goal of this project is the development of the thermostability of the vaccine formulation in the selected format with < 1 log titer loss after 6 months at 37⁰ C and a clear demonstration of immunogenicity in a small animal model (i.e., cotton rat). Impact: A thermostable sublingual measles vaccine would lower barriers to vaccination, especially in the developing world, by reducing the skill level required to vaccinate, eliminating cold chain requirements and the risks associated with reconstitution and injection. Dry sublingual vaccine would reduce shipping costs, cold chain costs and the direct cost of syringe and needles as well as many hidden costs (e.g., costs of vaccinator training, sharps disposal, disease from needle reuse or injury).
Keywords: CDC NCIRD
033: A Mobile Phone Application (“App”) for Advancing Teen Pregnancy Prevention
Description: Background: The teen birth rate in the US remains high, particularly among racial/ethnic minorities compared with many other industrialized nations. The adverse consequences of teen pregnancy are substantial at individual, family, and community levels. A range of innovative tools and interventions is needed to foster an environment that enables teens to experience better reproductive health. In 2011, more than one-third of US teens ages 13-17 years and over 50% of young adults ages 18-24 years owned a smart phone. Evidence shows that teens access the internet for reproductive health information. Direct access to accurate, evidence-based, comprehensive, and teen-friendly information regarding pregnancy prevention that is also confidential and immediate can be made available with smart phone technology. While evidence related to the public health impact of smart phone apps is limited, similar technology-based tools, including internet-based and text-messaging interventions, have been shown to be effective at increasing health-related knowledge, motivation, and behaviors. Project Goal: CDC is seeking the design and development of complex mobile phone applications for multiple smart phone platforms. The applications should be developed with input from multiple stakeholders, including one or more leading teen pregnancy organizations that already maintain youth-friendly websites with relevant content. The development of the platforms should include a marketing plan for the app that targets teens, caregivers, youth-serving organizations, and health care providers. Teens and provider representatives must be involved in the testing of smartphone platforms, in line with standard practices in product development. The app should be interactive and comprehensive, including information about pregnancy and pregnancy prevention that may include quizzes, games, and other engaging means; a clinic “finder” feature that points users to clinics in their zip code; and a calendar and/or text-messaging feature to support both personal contraceptive use and service utilization. The app should be designed to be acceptable to teens, their caregivers, as well as youth-serving organizations and health care providers, who can promote its utilization in their services. Impact: Mobile phone technology is an important underexplored tool to support the reproductive health of teen girls, with real potential to improve knowledge and attitudes about pregnancy prevention and increase uptake of relevant health services. The product is prime for rapid scalability, as it will be freely available through multiple channels to large numbers of teens with smart phones and can be integrated easily into a wide range of reproductive health programs and services for teen girls. Once launched, the product will be evaluated initially by tracking app downloads, website hits, and related technological means. Once developed, the application could have the potential to be adapted for other audiences.
Keywords: CDC NCCDPHP
034: Development of Biomedical Devices to Elicit Durable Protective Immunity against HIV
Description: Background: Substantial progress has been made recently towards identifying effective HIV prevention strategies. The RV144 trial demonstrated that an HIV vaccine comprised of a recombinant ALVAC prime + gp120 boost regimen was partially efficacious (VE=31.2%), although it’s protective effects waned over the study period and study volunteers faced barriers related to transportation to clinic for the required multiple injections with vaccine. Thus, there is an urgent need to identify innovative approaches to elicit or to boost HIV vaccine-elicited immunity, via simplified immunization regimens. If identified, these approaches have the potential to increase the durability of vaccine-mediated protection against HIV acquisition. Use of platforms to sustainably deliver HIV vaccine antigens, which could also incorporate delivery of antiretroviral drugs, would potentially allow for co-delivery of biomedical preventions for HIV. Project Goal: The goal of this project is to stimulate research and development of biomedical devices that elicit durable protective immunity against HIV. Specific areas of research interest include the development of novel devices to achieve sustained delivery of HIV vaccine antigens to mucosal surfaces for the purpose of priming antiviral immune responses and/or boosting prior vaccine-elicited immune responses with the goal of increasing the duration of protective immunity against HIV as well as reducing the need for multiple visits to a provider. Development of products based upon platforms that have (1) demonstrated high levels of safety, acceptance and adherence in human usage for sustained delivery (e.g. implants, vaginal rings) and (2) intrinsic flexibility for advanced development to incorporate co-delivery of antiretroviral compounds, other HIV microbicides, vaccine adjuvants, or hormonal contraceptives are highly encouraged. The expected end-product is the design and construction of a device that could be used in humans to achieve sustained delivery of HIV vaccine antigens to mucosal surfaces and that is suitable for efficacy assessment in a relevant non-human primate model. It would be expected that there would be documentation providing a detailed description of all testing results, including ex vivo characterization of the device as well as pre-clinical assessment protocols and a preliminary efficacy trial design (including statistical power estimates). Impact: Globally, more than 2.6 million new HIV infections occur each year (>50,000 in the US). As such, the need for efficacious biomedical preventions is needed to complement existing behavioral interventions. Products determined to be efficacious under this proposed evaluation have enormous market potential in HIV prevention.
Keywords: CDC NCHHSTP
035: Development of a Portable Multiplex Assay for Determination of Recent HIV-1 Infection
Description: Background: The estimation of HIV incidence, or the rate of new infections in a population, is an important public health indicator that provides valuable information on the growth of the epidemic and the efficacy of various intervention strategies. Within the past 15 years, a new strategy for estimating HIV incidence has been employed based on the observation that certain biomarkers (mainly HIV-specific antibody levels and avidity) can distinguish recent from long-term infection. Since the immune response to HIV gradually develops post-infection, the immune profile of newly infected individuals will present differently from the immune profile of individuals with chronic infection. Although several laboratory tests have been developed for the purpose of identifying recent infection, most approaches rely on a single assay measure. Relying on a single measure of the immune response is subject to greater misclassification due to inherent immune variation among individuals. Recent studies have shown that a combination of antibody responses or immune measures may reduce misclassification rates and improve incidence estimates. Ideally, multiple immune responses should be measured in a single assay, since it is not always feasible or cost effective to require several different tests for accurate incidence estimates. Project Goal: The goal of the proposed project is to develop a portable and cost-effective assay that is capable of measuring multiple immune responses at the same time (multiplexing). The assay should be able to provide a quantitative or semi-quantitative measure of HIV-specific antibody levels and avidity to multiple antigens using a relatively small volume of plasma (≤ 20μl). The assay should be similar in sensitivity to HIV antibody-based tests that are currently commercially available. While several technologies with multiplexing capability do exist, there are some limitations to the assay formats, as they are typically costly, technically complicated, and not accessible to all testing settings/ laboratories. The technology should be a portable, high-throughput, and a scalable multiplexing platform for determining recent infection. Impact: The availability of a low-cost, portable assay that can measure multiple HIV-specific biomarkers will enhance accessibility to diverse laboratory or field settings, enabling large-scale use of HIV incidence by various public health entities to chart their respective epidemics. The platform may also be suitable for other infectious disease diagnostics.
Keywords: CDC NCHHSTP
036: Testing the Efficacy of Combination HIV Prevention Strategies in Nonhuman Primates
Description: Background: Although substantial progress has been made to identify new biomedical HIV prevention strategies, including topical and oral antiretroviral drug pre-exposure prophylaxis (PrEP) regimens and vaccines, they are not yet approved for general use. However, these preventions (or related derivatives) are likely to be implemented widely in upcoming years. The identification of HIV preventions such as these, despite being only partially efficacious, offer an opportunity for small companies with flexible portfolios to consider the possibility of combining novel or existing biomedical preventions to generate a high probability for complete protection. Because future clinical trials of HIV vaccines will likely incorporate control arms that include PrEP, there is also a need to model whether such combinations may result in additive, synergistic, neutral or even subtractive effects. Non-human primate modeling, to determine the efficacy and interactions of combinations of two partially effective, clinically relevant HIV biomedical prevention approaches, can directly inform clinical trial design and impact the implementation of biomedical preventions against HIV. Project Goal: The long-term goal of this project is to determine, in non-human primates, whether two biomedical HIV preventions, such as vaccines and PrEP, may be combined to achieve additive or synergistic protective efficacy. Proposals are sought where small businesses will combine biomedical preventions, such as vaccines and drugs that are known to have efficacy (complete or partial), to prevent HIV infection in humans or animal models of HIV. In the event that one or both prevention modalities do not have extensive prior assessment in non-human primates or human clinical trials, demonstration of safety and scalability is of primary importance. Safety testing can include use of in vitro or small animal model testing. Proposals should include plans for the design, construction and characterization of prevention modalities suitable for efficacy assessments of the combination of partially effective interventions in a relevant non-human primate model. Proposals should also document a detailed description of the prevention modalities and pre-clinical assessment protocols. Impact: Globally, more than 2.6 million new HIV infections occur each year (>50,000 in the US). As such, the need for efficacious biomedical preventions is urgently needed to complement existing behavioral interventions. This mechanism specifically enables small businesses to rapidly conduct relevant pre-clinical evaluation of combined HIV prevention products in a nonhuman primate model that presages the changing landscape of domestic HIV prevention trials to incorporate PrEP as a standard of care. Combined HIV prevention products in a nonhuman primate model could facilitate the identification of the most promising HIV prevention solutions early in the developmental pipeline, which would accelerate the pace at which they are translated into effective products to prevent HIV infections.
Keywords: CDC NCHHSTP
072: New Methods to Detect and Assess Myocardial Fibrosis
Description: Summary Myocardial fibrosis is a crucial marker of adverse cardiac remodeling. Research suggests a strong correlation between the extent of myocardial fibrosis and adverse myocardial remodeling that occurs after ischemic injury or during the progression of cardiomyopathies and heart failure. Diffuse myocardial fibrosis is thought to provide a high-risk substrate for the development of atrial and ventricular arrhythmias. Therefore, early detection of myocardial fibrosis might be prognostic for the development of heart failure and increased risk of both atrial and ventricular heart rhythm disorders. In addition, a means to easily assess the development of myocardial fibrosis is expected to provide a more effective way to monitor therapeutic efficacy of interventions intended to slow or halt the progression of these cardiac disorders. Although present methods can detect “frank” fibrosis, new methods that target the early stages of fibrogenesis are expected to be extremely useful as they may be more effective in guiding interventions that block further development of fibrosis and prevent the onset of myocardial remodeling associated with heart failure and arrhythmias. Project Goals The goal of this initiative is to significantly advance non-invasive methods to detect, image, and monitor myocardial fibrosis in vivo. Myocardial fibrosis is a hallmark of adverse cardiac remodeling associated with development of heart failure and life-threatening cardiac arrhythmias. Early detection of myocardial fibrosis is essential to development of effective ways to diagnose, treat, and prevent these cardiac disorders. Current methods for detection of myocardial fibrosis, however, are either invasive (e.g., biopsy-based) or unable to detect early fibrogenesis or diffusively distributed fibrosis in the myocardium. This initiative encourages researchers to develop innovative myocardial fibrosis detection methods that overcome current challenges and demonstrate their utility in appropriate experimental models. Phase I Activities and Expected Deliverables Phase I activities are expected to be aimed at demonstration of the method’s feasibility. The studies may be conducted in established animal models or human tissue samples. Examples of Phase I research and expected deliverables may include, but are not limited to: • Design, synthesis and development of fibrosis-targeted imaging agent(s) and demonstration of the ability to detect cardiac fibrosis in well-established animal models • Design and development of MRI-based technology/method to detect diffuse myocardial fibrosis in established experimental models • Identification of serum biomarker(s) of myocardial fibrosis (e.g., extracellular matrix protein fragments, matrix metalloproteinases, microRNAs, post translational modified protein or glycoprotein fragments, etc.) and their limited validation using established animal models or human tissue samples Phase II Activities and Expected Deliverables Phase II research activities are expected to include development, optimization and validation of the product/method, including research work leading to regulatory filing (IND or IDE) and help attract funding from non-federal sources. Examples of expected deliverables may include, but are not limited to: • Development of fibrosis-targeted imaging agent(s) and data demonstrating capability to detect and quantify cardiac fibrosis in established animal models using appropriate clinical imaging platforms • Development of MRI-based methods that enable detection and quantification of diffuse myocardial fibrosis and data demonstrating the method’s utility in established experimental models • Validation of serum biomarker(s) for assessment and monitoring of myocardial fibrosis progression in appropriate human studies
Keywords: NHLBI
073: Evaluating Obstructive Sleep Apnea Dental Device Treatment Compliance
Description: Summary As a therapeutic option, an array of existing oral appliances are approved for the medical treatment of snoring and mild to moderate obstructive sleep apnea but lack specific capabilities necessary to fulfill regulatory requirements and conduct population-based effectiveness research. Integration of oral appliance and electronic monitoring technologies is needed to develop enhanced oral devices capable of addressing regulatory requirements and facilitating population-based research and clinical trials monitoring adherence and effectiveness of sleep apnea treatment. Project Goals Adapt therapeutic oral appliances currently used to maintain an open airway during sleep with electronic and sensor technologies to quantitatively monitor and evaluate patient adherence and the effectiveness of treatment. Validate the implementation of monitoring technologies as needed to fulfill regulatory requirements. Since oral appliances vary in how an open airway is maintained, it is anticipated that 2-3 different oral appliances with integrated monitoring capability. Proposals to develop an oral appliance treatment as opposed to integrate monitoring capabilities into an existing technology will not be considered responsive to this request. Phase I Activities and Expected Deliverables Development of a prototype oral appliance with an integrated capability of monitoring treatment adherence and efficacy up to 24 hours independent of external power sources and connections. The enhanced oral appliance must be should not change acceptance of the device by patients, interfere with therapeutic efficacy of the device, increase patient burden, or introduce potential electrical or biological risks to patient safety over the anticipated life of the instrument. The prototype must demonstrate that the proposed design specifications including sensitivity and longevity of sensor technology have been achieved for successful completion of phase I activities. Phase II Activities and Expected Deliverables A sufficient number of working devices and procedures for deployment and field testing must be developed. These procedures should validate the capabilities of the monitoring technology, demonstrate adherence to therapy, and the efficacy of treatment fulfilling regulatory requirements of the commercial transportation industry. Validation includes field testing in a representative cohort of middle-age men and women diagnosed with sleep apnea and physician-recommended treatment using an oral appliance. The cohort must be designed to allow a stratified analysis of the device capabilities among apnea patients with Epworth Sleepiness Scale scores greater than or equal to 10 compared to apnea patients with scores below 10. The results obtained from device monitoring should be compared with correlative measures such as actigraphy, daytime sleepiness and psychomotor vigilance task to establish that the monitoring capabilities of the integrated device can be used to accurately predict functional outcomes. Proposals to enhance standard medical practice in diagnosis or treatment of sleep apnea will not be considered responsive.
Keywords: NHLBI
074: Improving Safety and Efficacy of Red Blood Cells for Transfusion
Description: Summary Red blood cell (RBC) products for transfusion undergo metabolic and physical changes in both the cellular and plasma fractions during storage (RBCs can be stored up to 42 days currently) which may be associated with non-infectious risks and reduced tissue oxygenation capacity. The changes that occur during storage have been referred to in the literature as the RBCs “storage lesion”. Many of these changes have been characterized and include increasing levels of microparticles and potassium; free hemoglobin release; decrease in pH, adenosine triphosphate, and 2,3-diphosphoglycerate; loss of RBC membrane flexibility; and changes in enzymatic functionality resulting in a loss of nitric oxide (NO) signaling. Current research suggests that the storage lesion may result in extravascular hemolysis and inflammation, vasoconstriction, and potentially suboptimal tissue oxygenation. Many retrospective and prospective studies, including a recent meta-analysis of 21 studies, have demonstrated that the transfusion of RBC units which have been stored for longer periods (up to 42 days) appears to be associated with increased recipient morbidity and mortality; but these associations may be confounded by severity of illness. Two large blinded, multi-center randomized trials are currently underway in the United States and in Canada to determine if “younger” vs. “older” or “standard age” blood is equally safe and effective in complex cardiovascular surgery and ICU patients, respectively, but the results of these studies will not be known for several years. While it is unclear at this stage whether the RBC storage lesion results in serious adverse clinical outcomes in transfusion recipients, it would seem biologically plausible that a reduction in the number of potentially toxic elements in RBC supernatants, as well as an increase in the concentration of well-preserved RBCs, would be beneficial in many ways. These potential benefits could include 1) improved effectiveness of RBC products; 2) markedly reduced adverse events; and 3) optimal tissue oxygenation by fully functioning RBCs. Developing improved blood bank storage and transfusion processes and practices to mitigate the RBCs “storage lesion”, improve the effectiveness of transfusion, and safely maintain the shelf-life of RBC components at or near the current FDA mandated maximal storage limit of 42 days, will be important to assuring blood availability for future public health needs. There is scientific evidence that some of the RBC storage lesion changes might be reduced, restored or mitigated by changes in blood storage conditions and/or through manipulation prior to transfusion with processes such as washing, filtration and/or renitrosylation. Multiple strategies may be needed because targeting any single parameter may be insufficient to markedly improve RBC product quality. The National Blood Collection and Utilization Survey Report estimates that a total of 17.3 million blood units were collected and 14.6 million RBCs units were transfused in the United States in 2008. Except for pediatric transfusions, blood banks always deliver the oldest available RBC units when a RBC transfusion is requested to optimize their inventory management. It is anticipated that a product and/or process developed for this contract Depending on the product, the market may be any or all of the following: blood centers, blood banks, and hospitals as these are the facilities that collect, produce and/or transfuse RBC component units. Applicants are encouraged to explore utilization of the NHLBI SMARTT program (https://www.nhlbismartt.org/ ) to assist with the preclinical and early clinical study planning and regulatory support for IND/IDE applications associated with this contract topic. Project Goals The purpose of this SBIR contract solicitation is to develop new additive solutions, storage bags and/or new processes to enhance RBCs function and survival after storage and transfusion and/or reduce non-infectious complications associated with allogeneic RBC component transfusions. Accepted products, devices or technologies for the contract topic include, but are not limited to: • New additive solutions for RBC component storage, • Novel RBC component storage bags or modification of current storage bags, • Small footprint cell washer and associated disposables for use in hospital blood banks and transfusion services, • Pre- or post-storage processes and systems that will deliver a more therapeutic, less toxic transfused RBC component, • Development of kits, including combinatorial approaches such as devices and technologies, to achieve the project goals. Development of products and/or procedures for the sole purpose of leukoreduction will not be considered responsive to this solicitation. Phase I Activities and Expected Deliverables In Phase I, the investigator(s) are expected to complete proof-of-concept, become knowledgeable of regulatory requirements for required IND/IDE approval, and present the Phase I results and the development plan to NHLBI staff. The Phase I research plan must contain specific, quantifiable, and testable feasibility milestones along with alternate approaches if unexpected data are generated. The new technology needs to result in a demonstrable reduction in the development of the RBC storage lesion such as a decrease in the number of red blood cell microparticles and/or better preserved RBC rheology. Phase II Activities and Expected Deliverables Phase II should follow the development plan laid out in the Phase I if the FDA has approved the approach and feasibility has been demonstrated. Phase II studies should focus on developing the required technologies and working towards the initiation of clinical testing. Deliverables include the provision of evidence of having initiated the process leading to IND/IDE submission (and hopefully approval), and the documentation that the plan is feasible and that there are alternate approaches if any contradictory data are generated. When appropriate, it must be documented that production of sufficient amount of clinical grade material suitable for an early clinical trial can occur. The Phase II research plan must contain specific, quantifiable, and testable feasibility milestones.
Keywords: NHLBI
075: Dedicated Pediatric Cardiac MRI Receive Coils
Description: Summary Clinical MRI systems use local surface receive devices (coils) to provide optimized signal to noise and enable fast imaging using parallel imaging techniques. These surface coils are designed for adult patients and function poorly for pediatric patients. Pediatric coils are targeted at a certain age group and due to the wide range of pediatric patient sizes (from neonates to preadolescents) it is not possible to design one set of surface coils that fit all pediatric patients. In this solicitation we seek a set of dedicated cardiac MRI coils that will cover the entire range of pediatric patients. Project Goals The aim is to create a set of four (4) different pediatric cardiac MRI receive coil arrays to cover the size ranges of the pediatric population: 1) Neonate/Premie, 2) 3 months – 2 years, 3) 4-8 years, 4) 10-12 years. The coils could consist of a semi-rigid shell in the shape of the pediatric torso and multiple receiver coil elements will be placed on the shell. Optimal design in terms of coil element sizes and placement needs to be determined (through simulation and prototyping) during the project. The goal is to have coils with a large number of coil elements (16-64) optimized for parallel imaging (rate 4 for 2D imaging and rates 4-8 for 3D imaging). We envision an iterative development process where prototype coils are refined and optimized based on actual experiments in pediatric patients at the NHLBI operated MRI system at Children’s National Medical Center (Phase I). Commercial products will be developed based on the prototypes (Phase II). Phase I Activities and Expected Deliverables Phase I will be focused on developing and fine-tuning prototypes. The end goal of the project (after phase II) is to have a commercial set of 4 coils, but for phase I, two (2) coils will be expected (e.g. sizes 1 and 4 above). Phase I will be initiated with discussions between the vendor and NHLBI about coil sizes, element counts, and parallel imaging performance expectations. The deliverables for Phase I are: • Initial survey of reasonable coil geometries for the 4 body sizes mentioned above. • Simulations of optimal element size and count for all 4 coil sizes. • Two prototype coils (sizes 1 and 4). Compatible with a Siemens 64-channel, 1.5T Aera MRI system (Dual Density Signal Transfer system). • Coil test data needed for a) Siemens safety compliance, b) NHLBI NMR Safety Committee approval for human use. Phase II Activities and Expected Deliverables Phase II represents the final commercialization of the set of four (4) coils. Expected deliverables: • One set of (4) coils approved for human use.
Keywords: NHLBI
076: MRI Myocardial Biopsy Forceps
Description: Summary Endomyocardial biopsies are performed approximately 10,000 times each year worldwide. The procedure suffers large anatomic sampling error because of no current appropriate image guidance. Endomyocardial biopsy is currently performed without targeting, whether under X-ray or ultrasound guidance. This may account for the known low diagnostic yield and high sampling error. Image-guided myocardial biopsy using MRI might enhance the diagnostic utility and safety of myocardial biopsy in inflammatory or infiltrative cardiomyopathies. This solution would be especially attractive in pediatrics, where the risk of and need for biopsy is higher than in adults, yet the need more frequent. Project Goals The goal of the project is to develop a myocardial biopsy catheter of materials safe for MRI operation yet sufficiently sharp to extract myocardial tissue effectively. First a prototype would be developed and tested in animals, and ultimately a clinical-grade device would undergo regulatory development for clinical testing at NIH. The deliverable would likely have fixed development costs and low marginal production costs, and therefore is suitable for commercialization after initial SBIR investment. Phase I Activities and Expected Deliverables A phase I award would develop and test a bioptome prototype. The awardee deliverable would be tested in vivo in the contracting Division of Intramural Research (DIR) lab (cardiovascular intervention program). The specific deliverable would be: • Biopsy forceps catheter with an outer diameter 6-7 French • Bioptome sharpness equivalent or superior to commercially available stainless steel myocardial biopsy forceps catheters • Able successfully to cut endomyocardial biopsy specimens 1-2mm x 2-3mm each • Deflectable curve or shapeable to impart a curve analogous to Stanford-style endomyocardial bioptome • Suitable for transjugular or transfemoral biopsy of the right ventricle or transfemoral retrograde aortic biopsy of the left ventricle • Free from clinically-important heating (2oC at 1W/kg SAR) during MRI at 1.5-3.0T • Visibility during MRI. If visible using magnetic susceptibility phenomena, the tip should be distinctly visible, and at least the distal 40cm of the shaft should also be visible. In general, susceptibility markers should be > 3mm in diameter using commonly used steady state free precession or fast gradient echo MRI techniques. • There should be a characteristic imaging signature that distinguishes the “open” from the “closed” position of the biopsy forceps, using MRI • Proposals for alternative visualization strategies, such as “active” or “inductively-coupled” receiver coils, are welcomed. Phase II Activities and Expected Deliverables A phase II award would allow mechanical and safety testing and regulatory development for the device to be used in human investigation, whether under Investigational Device Exemption or under 510(k) marketing clearance. The contracting DIR lab would perform an IDE clinical trial at no cost to the awardee. IDE license or 510(k) clearance would constitute the deliverable. The specific deliverable would be: • Biopsy forceps catheter with an outer diameter 6-7 French • Bioptome sharpness equivalent or superior to commercially available stainless steel myocardial biopsy forceps catheters • Able successfully to cut endomyocardial biopsy specimens 1-2mm x 2-3mm each • Deflectable curve or shapeable to impart a curve analogous to Stanford-style endomyocardial bioptome • Suitable for transjugular or transfemoral biopsy of the right ventricle or transfemoral retrograde aortic biopsy of the left ventricle • Free from clinically-important heating (2oC at 1W/kg SAR) during MRI at 1.5-3.0T • Visibility during MRI. If visible using magnetic susceptibility phenomena, the tip should be distinctly visible, and at least the distal 40cm of the shaft should also be visible. In general, susceptibility markers should be > 3mm in diameter using commonly used steady state free precession or fast gradient echo MRI techniques. • There should be a characteristic imaging signature that distinguishes the “open” from the “closed” position of the biopsy forceps, using MRI • Proposals for alternative visualization strategies, such as “active” or “inductively-coupled” receiver coils, are welcomed.
Keywords: NHLBI
077: Passive MRI Guidewire
Description: Summary MRI-guided catheter procedures can avoid radiation and may allow surgery to be avoided in a range of applications. A safe clinical guidewire is not commercially available. A complex “active” electronic MRI guidewire is being developed by DIR. However, a more simple and versatile “passive” MRI guidewire also is valuable to be used as part of multi-step procedures (such as catheter exchange), but is neither commercially available nor attractive to manufacture in DIR. Several prototypes have been reported in the literature but none have been commercialized. Such a device would have utility in cardiovascular and in non-cardiovascular applications. This contract solicitation is to obtain an exchange-length guidewire that is safe for operation during MRI. Project Goals The goal of the project is to develop an exchange-length guidewire that is safe for operation during MRI. First a prototype would be developed and tested in animals, and ultimately a clinical-grade device would undergo regulatory development for clinical testing at NIH. The deliverable would likely have fixed development costs and low marginal production costs, and therefore is suitable for commercialization after initial SBIR investment. Phase I Activities and Expected Deliverables A phase I award would develop and test a guidewire prototype. The awardee deliverable would be tested in vivo in the contracting DIR lab (cardiovascular intervention program). The specific deliverable would be: • 0.035” outer diameter x 2.6-3.0 meters length allowing unencumbered catheter exchange • Mechanical properties matching up to two commercially available X-ray guidewires, in descending priority order: (1) Wholey {steerable and torquable angled guidewire}, (2) Supra-Core {steerable and torquable shapeable soft-tip and stiff-shaft} • Shapeable tip is strongly preferred over a J tip • Free from clinically-important heating (2oC at 1W/kg SAR) during MRI at 1.5-3.0T • Visibility during MRI. If using individual susceptibility markers, they should be positioned at the tip and along the shaft in a pattern that allows the operator to delineate/differentiate them. Susceptibility markers should be > 3mm in diameter using commonly used steady state free precession or fast gradient echo MRI techniques • Proposals for alternative visualization strategies, such as “active” or “inductively-coupled” receiver coils, are welcomed. Phase II Activities and Expected Deliverables A phase II award would allow mechanical and electrical testing and regulatory development for the device to be used in human investigation, whether under Investigational Device Exemption or under 510(k) marketing clearance. The contracting DIR lab would perform an IDE clinical trial at no cost to the awardee. The specific deliverable would be: • 0.035” outer diameter x 2.6-3.0 meters length allowing unencumbered catheter exchange • Mechanical properties matching up to two commercially available X-ray guidewires, in descending priority order: (1) Wholey {steerable and torquable angled guidewire}, (2) Supra-Core {steerable and torquable shapeable soft-tip and stiff-shaft} • Shapeable tip is strongly preferred over a J tip • Free from clinically-important heating (2oC at 1W/kg SAR) during MRI at 1.5-3.0T • Visibility during MRI. If using individual susceptibility markers, they should be positioned at the tip and along the shaft in a pattern that allows the operator to delineate/differentiate them. Susceptibility markers should be > 3mm in diameter using commonly used steady state free precession or fast gradient echo MRI techniques • Proposals for alternative visualization strategies, such as “active” or “inductively-coupled” receiver coils, are welcomed.
Keywords: NHLBI
078: Transthoracic Cardiac Access Ports and Closure Devices
Description: Summary Implanting large appliances, such as mitral valve replacement, currently requires cardiac surgery and cardiopulmonary bypass. Minithoracotomy access remains high risk. NHLBI has shown early feasibility of direct transthoracic large-port access to the beating heart, and effective closure using nitinol appliances in animal models. The objective of this contract solicitation is to support the commercial development of purpose-built access ports and closure devices for direct transthoracic cardiac access to the left and right ventricles. Project Goals Safe non-surgical access to the beating heart would be attractive to implant large appliances (such as mitral valve replacement), to repair complex congenital or structural heart defects, or to deliver smaller appliances such as transcatheter aortic valve replacement in the large minority of patients ineligible for transvascular delivery. NHLBI DIR has demonstrated early feasibility of this approach using MRI guidance and off-the-shelf nitinol closure devices. A purpose-built device would be necessary for safe and robust transthoracic access port and closure. Phase I Activities and Expected Deliverables A phase I award would develop and test a port and closure device system prototype. The awardee deliverable would be tested in vivo in the contracting DIR lab (cardiovascular intervention program). Applicants are directed to several publications from NHLBI regarding this topic in calendar year 2011 (Pubmed ID: 21234923, 22192372, and 2192373), accessible from www.ncbi.nlm.nih.gov/pubmed?term=21234923,22192372,2192373. The specific deliverables include: • Access Port o Access port in at least two sizes, one being 32Fr and another 24Fr, to accommodate implantation of large prostheses o The port (“introducer sheath”) should incorporate features to assure retention inside the endocavitary space once delivered, to avoid inadvertent exit from the targeted ventricular cavity. o The port should have a mechanism to protect against damage to endoventricular contents (papillary muscles, chordae tendinae, valve leaflets) during delivery. o The system should have a hemostatic valve or equivalent mechanism to allow large appliances to be introduced into the heart from a transthoracic access port without significant blood loss and without entry of air. o The system should feature sufficient taper, rigidity, and curvature to be introduced into the left or right ventricle via intercostal and subxiphoid trajectories, and characteristics to accomplish non-surgical intercostal separation if necessary. o The system should allow delivery into the heart through the chest initially over a 0.035” guidewire o The port should have length sufficient to reach the mid-left atrium or proximal ascending aorta from a transthoracic (subxiphoid and intercostal) access route in most patients. o The system should be conspicuous under multiple imaging modalities, including ultrasound and MRI. o The entire system should be MRI compatible (free from magnetic displacement and from significant magnetic susceptibility artifact) based on materials compatibility. o The system should be curved to allow operation within a large-bore (70cm diameter) MRI system. • Myocardial Closure System o The myocardial port must be closed with high reliability, immediate hemostasis, and with a reliable bail-out mechanism in case of failure. Targeted clinical reliability will be successful deployment and immediate hemostasis in 99.9% of attempts. o Anticipated closure mechanisms include permanent implants with suitable fixation mechanisms or suture-delivery. Any closure mechanism must assure high reliability of deployment, high reliability of success, robust immediate hemostasis, extremely low risk of late erosion or pseudoaneurysm, and trivial or no degradation of myocardial function. o One minimal mechanism of bailout is a parallel guidewire that allows a bailout/temporizing hemostatic mechanism to be inserted quickly and reliably should hemostasis fail, to allow controlled surgical rescue. Other options are invited. o The design should be safe from early and late myocardial erosion. o The proposal should include a risk/failure analysis o Operational considerations should be described, including whether the closure system is deployed at the beginning of the transcardiac procedure (“pre-close”) or at the conclusion. • Strategies should be defined for use and withdrawal of secondary drainage catheters after the access port is closed. Phase II Activities and Expected Deliverables A phase II award would allow mechanical, fatigue, and biocompatibility testing and regulatory development for the device to be used in human investigation, under Investigational Device Exemption. We expect the device will require a PMA for marketing, which is expensive. The contracting DIR lab would perform an IDE clinical trial at no cost to the awardee. The specific Phase II deliverables are as described under Phase I. • The phase II award would consist of the contractor obtaining an IDE based on the design finalized in phase I.
Keywords: NHLBI
079: Bioabsorbable Stents for Pediatric Pulmonary Artery Stenosis and Aortic Coarctation
Description: Summary Mechanical stents to relieve obstructive cardiovascular lesions could have great utility in pediatric cardiology, but are unsuitable for small children. Commercially available stents limit vessel growth and require future surgical removal. Absorbable stents might revolutionize the treatment of congenital heart disease in children. Small children require small delivery systems for devices that are larger than adult coronary arteries. Specific target diseases include aortic coarctation and pulmonic stenosis, which currently require open surgical repair or multiple X-ray-guided catheter procedures in early childhood. Project Goals These are transcatheter stents to be delivered using conventional interventional cardiovascular techniques including guiding catheters or sheaths, translesional guidewires, and balloon-expandable or self-expanding delivery systems. Conventional and novel approaches are welcomed. Specific requirements of the stents include small delivery systems (5-6 French or smaller); sufficient radial force to resist elastic recoil for the two applications; sustained radial strength suited to the application for at least 6 months; controlled degradation within 6-12 months; inflammatory response that does not cause significant stenosis, restenosis, or aneurysm; resistance to downstream embolization or toxicity; and nominal calibers suitable for the most common lesions (pulmonary artery stenosis and aortic coarctation, see below) . Proposed stent nominal geometry should be diameter (6-10mm), length (range 10-25mm), delivery system (5-6 French or smaller). The radial hoop strength of the deployed device should approach that of commercial balloon-expandable stent such as the Cordis Palmaz Genesis. Percutaneous vascular access routes for the pulmonary artery application include femoral and jugular venous. Percutaneous vascular access routes for aortic coarctation application include transvenous-transeptal antegrade and retrograde transfemoral artery. The implant or the delivery system should be conspicuous under the intended image-guidance modality. Offerings should specifically provide the high radial force required to overcome immediate recoil of the intended applications, and should allow “direct stent” treatment technique for native and iatrogenic lesions. Phase I Activities and Expected Deliverables Phase I should focus on mechanical and biological performance of the proposed biodegradable stents in the intended use for pulmonary artery stenosis and aortic coarctation, taking into account mechanical strength required for the application; geometry of the access vessels and geometry and morphology of target vessels including tapering and branching; strategies to avoid inflammatory restenosis or constriction; and delivery, implantation, and visualization strategies. At the conclusion of phase I, a candidate device design should be selected for clinical development based on in vivo performance of a mature prototype resembling a final design. The sponsoring NHLBI laboratory is willing to perform a limited number in vivo proof-of-principal experiments in swine (by mutual agreement) to confirm mechanical performance. Phase II Activities and Expected Deliverables At the conclusion of phase II, the offeror should obtain an investigational device exemption (IDE), and a supply of devices provided, for a first-in-human research protocol, involving at least 10 subjects, to be performed by the sponsoring NHLBI laboratory. The sponsoring NHLBI laboratory is willing to perform a limited number of in vivo proof-of-principal experiments in swine (by mutual agreement). NHLBI offers to perform the clinical trial at no expense to the offeror, to participate in the development of the clinical protocol, and to provide clinical research services. The vendor is expected to perform or obtain safety-related in vivo experiments and data to support the IDE. The specific Phase II deliverables are as described under Phase I. • The phase II award would consist of the contractor obtaining an IDE based on the design finalized in phase I.
Keywords: NHLBI
080: Fluorescent Nanodiamonds for In Vitro and In Vivo Biological Imaging
Description: Summary There is a need to develop a biocompatible fluorescent label that never photobleaches or blinks, and that is brighter than commonly used dyes. Fluorescent nanodiamonds (FNDs) are 10 to 100 nm sized biocompatible particles with indefinite photo-stability that make them superior imaging probes for a wide range of applications. Whereas organic dyes and quantum dots are neither biocompatible nor photo-stable as they photobleach and blink, and gold nanoparticles exhibit weak, size and shape dependent fluorescence, FNDs do not photo-bleach or blink and can provide bright fluorescence. In particular, their near-infrared fluorescence and biocompatibility make them ideally suited for in vivo diagnostic applications. The commercial potential for fluorescent nanodiamonds is enormous. Because of their superior fluorescence characteristics and inherent biocompatibility, FNDs could replace the most commonly used optical probes; quantum dots (QDs) and organic fluorophores. The nanodiamond fluorescence comes from nitrogen-vacancy (N-V) centers, point defects in the diamond structure. By adjusting the number of N-V centers created in a particle, its brightness can be tuned for a desired application. FND near-infrared emissions are not only optimal for in vivo imaging but also can be used as an optical readout of magnetic resonance. Furthermore, the relatively long fluorescence lifetime (~17 ns) of FNDs compared to ~1-2 ns lifetime of in vivo autofluorescence makes FNDs ideal background-free agents for time-gated imaging of, for instance various, cardiac myopathies or blood malignancies where typically blood hemoglobin interference in fluorescence spectrum has limited the uses of optical imaging for these pathologies. At the single-molecule level, they can be used to track labeled biomolecules over extended periods of time, and due to their wide excitation spectra, can be used as stable multispectral fiducial markers for ultra high resolution microscopy across multiple wavelengths to study sub cellular structures with nm precision. While these are just a few of the biomedical applications of FNDs, the energy level structure and electron spin coherence of N-V centers have potential novel applications in ultra-low magnetic field detection, ultra-sensitive NMR, ultra-low power consuming spin-based spintronics, and quantum computing. The commercial routes to develop this product for are numerous and highly profitable. Project Goals Currently there is no commercial source of fluorescent nanodiamonds appropriate for biomedical imaging applications. This is a rapidly emerging field that would be well served by a source of well characterized FNDs that could be further processed by the end user for a wide range of applications in biomedical imaging and nanotechnology. Phase I Activities and Expected Deliverables In Phase I, we expect 100 grams of fluorescent nanodiamonds. The mean diameter of the nanodiamonds should be in the range of 10 to 80 nm, with a coefficient of variation not to exceed 60%. The peak fluorescence emission of the nanodiamonds will be in the range of 650-750 nm and they will be photostable, i.e., not photobleach, under continuous laser excitation of 20 mW or less in the range of 500-600 nm. A minimum of 50% of the fluorescent nanodiamonds will be at least 10 times brighter (i.e., 10-fold higher fluorescence emission at the peak emission wavelength with an optical bandwidth of 30 nm) than Alexa680, which is a commonly used near infrared dye. These specifications can be confirmed with total internal reflection fluorescence microscopy (TIRFM) measurements in which the brightness of fluorescent nanodiamonds and Alexa680 can be compared side-by-side under identical conditions. We are prepared to assist with these measurements if requested. We have successfully made fluorescent nanodiamonds (~30 nm diameter), but their brightness must be improved with optimization of the N-V center creation and annealing process. The contracting company will be expected to optimize the process, deliver well-characterized fluorescent nanodiamonds, and provide a description of the irradiation, annealing, and any additional processing such that an expert in the field could reproduce the process. We can assist the company with the characterization of the nanodiamonds. Phase II Activities and Expected Deliverables In Phase II, the deliverables will be a range of FNDs with different levels of brightness and different sizes. Furthermore, the more challenging deliverable in Phase II will be a high-yield product with narrow size and brightness distributions. These well-defined distributions can either be achieved by determining a method that generates the desired distributions directly, or by separating the fluorescent nanodiamonds based on size and brightness after the fact, a technique that would solve a problem that the fields of nanotechnology and molecular imaging have been struggling with.
Keywords: NHLBI
147: A Mobile Application to Help Patients Take their Pill Medications as Prescribed: Improving Medication Adherence
Description: It is strongly suggested that proposals adhere to the above budget amounts and project periods. Proposals with budgets exceeding the above amounts and project periods may not be funded. Drugs don’t work in patients who don’t take them. — C. Everett Koop, M.D, former U.S. Surgeon General Medication adherence is described as the extent to which patients take medications as prescribed by their health care providers. A World Health Organization (WHO) report confirms that almost half of patients with chronic illnesses do not take medications as prescribed. Low medication adherence greatly lowers efficacy; and it leads to preventable prolongation of illnesses, re-hospitalizations and sometimes death. Approximately 125,000 Americans die annually (342 people every day) due to poor medication adherence. Every day, prescription non-adherence costs more than $270 million in additional hospitalization and other medical costs. Nine out of every 10 outpatients are taking prescribed medicines improperly, contributing to prolonged or additional illness. Cost of non-adherence to medications is estimated approximately $100 billion a year in the U.S. In addition, other forms of medication non-adherence such as misuse, underuse or overuse (abuse) also have negative consequences in individuals. Medication non-adherence is especially burdensome to patients with substance use disorders who are prescribed medications for psychiatric and medical conditions. In addition, approximately 50% of patients prescribed Buprenorphine for opioid dependence and NRT/other medications for smoking cessation report taking medications as prescribed. NIDA seeks to develop and test prototype mobile/tablet technology-based application to provide a low-cost, highly personalized, interactive patient-centric medication adherence tool that improves upon currently available mobile technology-based medication adherence applications. Background Information The WHO, Institute of Medicine (IOM), National Institute of Health (NIH), American Heart Association (AHA) and advocacy organizations have all acknowledged that this is both a complex and a difficult issue to solve but the time for action is now. Barriers to medication adherence are complex, variable and reside at multiple levels: the patient, the provider, the healthcare system and their interactions. Systematic reviews have found that existing medication adherence interventions yield only modest benefits and while simple reminder systems do work, most of the systems were complex, cost-prohibitive and labor-intensive greatly limiting generalizability. Adherence is an active process but existing low-cost solutions are passive. Examples of commercially available apps for Android and Apple devices: Pillbox Alert, Med Minder, Med Helper - Prescription App, MyMedSchedule, Dosecast, RxmindMe, Intelecare. They are typically simple to use and employ visual aids but are limited by patient input of their medications; sole reliance on reminders; predominant focus on the use of English language; and not always Health Insurance Privacy and Portability Act of 1996 (HIPPA) and Health Information Technology for Economic and Clinical Health (HITECH) Act compliant. Other solutions use electronic pillboxes which record pill use by the patient and in some cases, provide reminders: MEMS cap, Wisepill device, Med-eMonitor, etc. These products have limited main stream application due to high costs of these stand-alone devices that typically record one medication per container; with limited links to real-time and interactive feedback or education; and most have limited programming capacity. The newer FDA approved medical devices such as the SIMpill® Medication Adherence System and the PillStation® medication adherence system are more complex and offer adherence reminders and organization solutions but do not provide tailored interventions based on the patient’s baseline, nor do they address adverse effects, other barriers to medication adherence. Phase I Activities and Expected Deliverables Develop and test the acceptability and feasibility of a mobile/tablet-based technology application prototype that improves medication adherence by successfully addressing the barriers to medication adherence and contain the following features: • Allow multiple user input and interaction (i.e. between physician, pharmacy, patient, caregiver/parent) and superiority to existing mobile applications and electronic pillbox/medication monitoring tools; • The core medication adherence enhancement solution is to be a mobile application. However, hybrid solutions that link to external systems will be preferred, e.g. demonstrate capacity to link to external electronic databases, such as pharmacy, laboratory and/or medication information systems; other existing stand alone medication monitoring tools such as electronic pillboxes, etc.; • Account for low health literacy and visual impairment needs of patient; • Demonstrate capabilities for GIS, GPS, SMS, phone, Bluetooth, online, video and other platforms of real-time communication; • Eliminate patient need to enter medication information (i.e. names and doses of medications) through the use of barcodes, photo/camera capabilities and similar technologies; • Demonstrate capabilities to link to patient’s record in EMR, EHR, pharmacy database and other healthcare systems (e.g. appointment scheduling systems, provider locations, etc.); • Use computational modeling, branching logic and/or query functions to develop sophisticated adherence solution algorithms for the software; • Provide a baseline ecological momentary assessment of patient’s status (such psychiatric and/or physical symptoms, mood states, drug cravings/drug use) and its impact on medication adherence, so that customized interventions can be delivered to the patient, based on their ability; • Offer a menu of customizable adherence strategies, based on each individual’s baseline rate of medication adherence, ranging from simple to complex (and provide some rating mechanism for the strategies offered); • Offer tailored medication education content suited for adult learning and links to reliable information databases; • Link to social media sites, email and other communication resources to enable caregiver, parent, significant other person support/monitoring; • Build in incentives (financial and other positive reinforcements) for meeting medication adherence goals; • Demonstrate scalability and cost-effectiveness; • Must be HIPPA and HITECH Act compliant; • Demonstrate feasibility, acceptability and preliminary efficacy in improving medication adherence: test the application on 9 patients receiving a FDA approved medication to gather preliminary data on the reliability of the system and its ease of use by patients, providers and caregivers; • Demonstrate that the proposed research activity will likely lead to a marketable product or process, including consideration of the potential barriers to entry and the competitive market landscape. This may include a letter of commitment for additional investment or support from a private sector party or other non-SBIR funding sources. Phase II Activities and Expected Deliverables Develop and validate a production model prototype by using the system in substance abusing patients undergoing treatment with an FDA approved medication either for treating addiction such as buprenorphine or a psychiatric disorder such as Major Depressive Disorder. Provide evidence for commercialization potential, i.e., record of successfully commercializing prior SBIR/STTR or other research projects, commitments of additional investment from private sector or other non-SBIR funding sources, and any other indicators of commercial potential for the proposed research.
Keywords: NIDA
148: Products for at-home Deactivation of Psychoactive Prescription Medicines
Description: Objective: This topic addresses the need to fund research and development activities to promote the commercial development and testing of an inexpensive prescription medicine disposal system that would provide a simple means for patients (prescription drug “end-users” defined by the Drug Enforcement Administration) or members of their household to safely render prescription drugs unusable and effectively contained in order to minimize the potential for diversion or accidental exposure to children or pets. Methods proposed may include approaches or agents that mechanically destroy or chemically neutralize prescription drugs for either safe home disposal or safe transit for disposal by another facility. For example, such a product or agent could be distributed by practitioners and pharmacies along with scheduled medications. As an ancillary benefit, such a product holds the potential to minimize drugs entering the watershed and other adverse environmental effects. Background Last year in America, 210 million prescriptions for opioids were written- enough medication for every American to have a 30-day supply. Nearly every American household will at some time be in possession of controlled substances. A large percentage of prescription medicines are never used or are used in much smaller quantities than prescribed. For example, a recent study showed that among upper extremity surgery patients, who were prescribed an average dose of 30 narcotic pills, approximately half only used 2 days worth of pills or fewer Rodgers et al 2012). This illustrates how leftover medicine is a large problem. Death of an elderly family member or medication changes can also result in surplus controlled substances in the home. Results from the most recent (2010) National Survey on Drug Use and Health (NSDUH) show prescription drug misuse is generally initiated via “diversion”- when people are given psychoactive pills (or steal) from friends or relatives. Accordingly, safe drug disposal is a pillar of the President’s Prescription Drug Strategy http://www.whitehouse.gov/sites/default/files/ondcp/issues-content/presc... (page 7) and Drug Enforcement Administration (DEA) is in the process of rulemaking on the Secure and Responsible Drug Disposal Act of 2010. This rulemaking likely will involve a combination of take-back and other means to return medication to facilities with incinerators. Aside from cost, one problem with all such programs is the drug remains available to use/misuse/abuse until incineration or other final disposal. Currently, DEA provides labor-intensive prescription drug disposal “takeback” programs that visit sites to collect unused medications from households (e.g. http://www.deadiversion.usdoj.gov/drug_disposal/non_registrant/transcrip...). Federal sponsorship of this program underscores the high interest in this problem. Although there are products like drug shredding machines that are deployed in nursing homes and other care-giving venues www.ultimateproducts.us/DrugShredder.htm#features, there are few alternatives for safe medication removal by patients in the home. For most scheduled medicines, the Food and Drug Administration (FDA) recommends mixing the medicines with coffee grounds or kitty litter and then throwing these medicines in the trash. This process presumes availability of such material in the household. Notably, in addition to risk of diversion, household disposal of some medications in solid waste (especially in transdermal patches) http://www.fda.gov/Drugs/DrugSafety/ucm300747.htm can create hazards to children and pets. FDA has recommended that only a subset of medications be flushed - http://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesa.... Flushing some types of unused medications into the water supply can create environmental hazards and is only recommended for medications that pose the most imminent risk if accidentally ingested. An in-home prescription medicine deactivation or disposal system would meet the goal of having an immediate method to render unused medicine harmless. Recent advances in technology offer the opportunity for companies to add technology-based features such as mobile phone applications that could include medication expiration dates and disposal reminders. Families with small children and pets are likely audiences for this product in terms of prevention of poisoning. As such, sales of this product may benefit from positioning by child-proofing and pet-proofing products. Parents of teenagers (particularly teens who are known to have experimented with alcohol or marijuana) are likely consumers of this product as well. At home drug test kits are routinely sold in pharmacies, and positioning this product near opioid test-kits is a natural marketing strategy. Finally, “green” consumers, interested in reducing their environmental impact may consider such a product for its environmental benefits. Phase I Activities and Expected Deliverables This SBIR topic will help address the need for safe, at-home deactivation of divertible medications for home disposal in solid or liquid waste or before transit for third-party disposal. It is expected that potential offerors can demonstrate with preliminary data that agents or devices in their proposals (such as chemical-based drug-deactivating agents, nanomaterials or mechanical processes) will inactivate the proposed chemical class of psychoactive medication and its medium of delivery (e.g. tablet, capsule, or patch) in direct application (not embedded in a device or product). It is not expected that a single agent or device would be suitable or capable of deactivating all classes of medication or deactivating across all forms of medication delivery. Specifically, the contractor will be provided with funding to develop this agent or device into a consumer-friendly, low-cost, and simple-to-use product for home use that contains the drug-deactivating device or agent, into which medication may be dropped, inserted, mixed or adhered for inactivation and disposal. Phase I testing should include testing the product for ease of portability, storage, and use. The device or product should be able to be handled and transported by an elderly or physically-challenged consumer. Because repeat use of this type of product hinges on the user experience being at minimum not unpleasant, focus groups may address ease of use and aesthetic factors for the “disposal system”. Phase I may also include development and testing of materials such as instruction sets, educational materials, calendars, and mobile applications to facilitate use the product. Deliverables will include: 1. Product usability testing to establish that the product can be easily used by the targeted users, including elderly patients and their caregivers, families with young and teenage children (particularly women). For example, testing should assess the degree to which having to open the medication container for inactivation of its contents paradoxically introduces exposure and toxicity risk. Additionally, tests should ensure the product provides an optimized aesthetic experience (i.e., does not emit unpleasant or noticeable odors) and is amenable to cleaning, if the product is a reusable device. 2. Market research to determine how the proposed product could either compete with, compliment, or assist existing drug-disposal schemes, like in-person drop-off boxes at participating pharmacies or programs that provide mailers to consumers to mail unused medications to an incineration service. This research should be geared toward determining whether the product would have a market for direct sales to families, or would be best distributed by pharmacies as part of the costs of scheduled drug dispensing. Notably, the product should have a unit cost low enough to be either sold readily directly to consumers or distributed routinely with medications and prescriptions along with patient information sheets. 3. Risk-assessment and solutions for product liability issues with regard to incompletely-deactivated medications, such as from misuse of the product. 4. Toxicology assessment to demonstrate that the agent or product itself (or as an amalgam with a medication), is non-toxic and either directly disposable or eligible for transport by the postal service or other commercial carriers. Phase II Activities and Expected Deliverables Projects that demonstrate feasibility, safety, and marketability of the product/device in Phase I may be extended into Phase II. In Phase II, the offeror will be expected to have packaged the deactivating agent or device in a deployable form for mass-distribution. In addition, in Phase II the offeror will be expected to conduct assays, tests or surveys to assess: 1. Degree of adherence by prescribers, pharmacies, and/or home users 2. Whether use under normal household conditions improves outcomes (e.g., reduces calls to poison centers, changes total medication reported used or total medication reported destroyed). Such a test should include random or quasi-random assignment of patients and families typically prescribed narcotics and likely to have leftover medicine (e.g., acute injury patients or patients undergoing orthopedic surgery.) Because certain individuals are at high risk for substance misuse it is recommended investigators stratify assignment based on whether people have a history of a substance use disorder, chronic pain, or mental illness. 3. The classes of chemical compositions or delivery systems of medicines (transdermal patch, tablets, capsules) for which the device or agent is most effective or exclusively effective. This might be specific individual medicines. 4. Adverse events from use of the product 5. The durability or shelf-life of the product, so as to establish and provide expiration dates of products that use chemical or nano-particle based inactivating agents. 6. Development of ancillary materials to ensure adoption and consistent use- such as educational and public-awareness materials, a programmable adherence application for a mobile phone, or paper reminder calendars.
Keywords: NIDA
149: Development of Predictive in vivo Screening Systems for Phenotypic Drug Discovery for Smoking Cessation
Description: Summary Phenotypic drug discovery is a complement to target-based drug discovery and provides an alternative approach that begins by querying more complex cellular of physiological systems instead of specific targets. The possible advantage resides in the fact that a relevant biological context is interrogated without predisposed bias toward mechanism(s). Thus, an opportunity is created to identify compounds that may interact with one or more targets or pathways not anticipated by a single mechanism-driven hypothesis. In essence, phenotypic approaches screen multiple mechanisms and targets simultaneously. This solicitation for Small Business Innovation Research (SBIR) contract proposals invites contract proposals from small business concerns (SBCs) for a multi-pronged research program to develop and evaluate a weighted battery of animal behavioral tests that can be used for the phenotypic drug discovery and development of smoking cessation medications. The battery should be, preferably, high- or medium- throughput and designed to improve the predictive validity of in vivo screening of drug candidates. Since people continue to smoke for many different reasons - withdrawal relief, pleasure, taste, improvement in concentration, weight control, stress control, arousal, etc. – the battery should be capable of assessing the multiple components (reinforcement, affective, cognitive, etc.) that underlie smoking. The offeror is expected to identify and propose the behavioral domains of particular importance to human tobacco dependence, and to develop the necessary animal behavioral protocols to test multiple processes believed to be contributing to smoking in humans. It is not necessary that the behavioral measures model the aspects of smoking in precise fashion. That is, this contract solicitation focuses on the predictive (and construct) validity of the behavioral battery, not on its face validity. The SBC must screen in uniform fashion and, then, build a large database of pharmacological signatures of currently available medications (with known anti-smoking efficacy in humans) comprised of measures reflecting the reinforcement, affective, cognitive, etc. functions. The critical part of this solicitation is the focus on biostatistical/computational solutions and modeling. Bioinformatics algorithms are to be developed which will complement and enhance the statistical power to recognize phenotypic profiles of drugs. Proposals are expected to include animal behavior tests only. Background Information Despite major developments in computational, in vitro and ex vivo model systems, in vivo animal testing remains a necessary part of drug development. This solicitation invites offers from SBCs interested in developing a weighted battery of animal behavioral tests/assays (rat or mouse) to function as a screening system for preclinical development of smoking cessation medications. In this solicitation, behavioral assay is defined as a means of qualifying a dependent biological variable. In this solicitation, animal model is defined as a theoretical description of the way a system (or disease) works. The animal model induces under- or over-expression of a biological variable which assay quantifies. This solicitation seeks to establish a battery of carefully selected behavioral tests/assays that will provide a comprehensive behavioral assessment of domains of particular importance in tobacco smoking and quitting. A battery must be comprised of currently used and available tests whose appropriateness and validation could be assessed through literature search. Applications proposing new animal models or assays are not allowed. This assay battery will be used to obtain standardized data on the responses to existing first-line pharmacotherapies that have been approved by FDA as aids for smoking cessation (i.e. varenicline, bupropion ), and second-line pharmacotherapies (i.e. clonidine, nortriptyline). Measuring several domains and several medications will result in obtaining a rich dataset, which is to be systematically analyzed for identification of critical parameters or axes, selecting the most useful features and identifying underlying variables. The critical parameters in each domain are to be selected to be combined into final, “lean”, standardized and validated battery of assays, with the goal to provide superior reliability, greater statistical power and higher throughput than standard methods. This validated battery of assays will be used for in vivo screening of anti-smoking drug candidates to advance future research and discovery in this area. Because of the importance of tobacco-dependence treatment to national tobacco control efforts, the National Cancer Institute and the National Institute on Drug Abuse (NIDA) convened a meeting, entitled “Translational Medication Development for Nicotine Dependence Workshop.” Participants from industry, academia and government agencies provided their views on the greatest opportunities for accelerating the translational efforts in the area of nicotine dependence. One of the challenges in medications development for addictive disorders is to determine the predictive validity of preclinical and clinical pharmacology models of various aspects of drug dependence. Several pharmacotherapies are, in fact, available to support treatment of nicotine (tobacco) dependence, including ones with an overt nicotinic mechanism of action, such as nicotine replacement therapies and varenicline (Chantix®, Champix®), others, in which nicotinic mechanisms may be a component, such as bupropion (Zyban®), and still others, for which there is no obvious nicotinic component to their action (e.g., the second-line medication clonidine, an α2 adrenergic agonist). Each of these drugs significantly improves the quit-rate compared to placebo. With these currently available medications, however, only about 20% of smokers are able to maintain long-term abstinence, and more efficacious pharmacotherapies need to be developed promptly. Scientific knowledge to be achieved through research supported by this contract Basic research into the mechanisms of nicotine addiction has the benefit of the availability of a wide array of preclinical animal behavioral models and assays. A number of these tests have seen extensive use as research tools, and, as a result, they are known to have utility in studying the mechanisms and processes related to addiction and drug abuse relapse. In addition, some of these models, such as drug-self administration and drug discrimination, have demonstrated translational utility in providing preclinical data in support of the development of varenicline. However, given that varenicline is the only smoking cessation pharmacotherapy to have been developed through the typical pharmaceutical industry drug discovery approach, there is little evidence for the predictive validity of any of these animal behavioral models for medication development for drug addiction. Indeed, since inadequate efficacy remains a significant cause of failure in the drug development process, improvements in the ability to predict efficacy at various stages across the drug development process are warranted. The intent of this contract solicitation is to fund small business concerns (SBCs) capable to undertake screening of anti-smoking medications (with various mechanisms of action and known to demonstrate some efficacy in humans) in multiple animal behavior paradigms. Although addiction is frequently and preferentially conceptualized in terms of reward and reinforcement, this contract solicitation seeks to collect data simultaneously in other domains that may be relevant to drug addiction and drug abuse relapse, namely cognition and affect. For each of these domains, there exist well-established assays and models that have validity within the domain (e.g., for reward and reinforcement – drug self-administration, intra-cranial self-stimulation; for cognition - pre-pulse inhibition, 5 choice serial reaction time; affect - open-field test, elevated plus-maze). It is important to note that these examples are not intended to be exclusive or prescriptive; other models may be worthy of validation in this effort. The purpose of this initiative is to support research to estimate if individually and/or collectively these tests are predictive of medication efficacy in clinical trials. A critical part of this solicitation focuses on improving the reproducibility of preclinical data which will be obtained. Given the high cost of clinical drug development, factors such as low reproducibility and translatability, or heterogeneity in study design that hinder the comparison of preclinical data are major disincentives for investment in development of novel treatments. Diseases of addiction are not among the priorities for pharmaceutical companies. In addition, a major concern highlighted in other CNS- and non-neurologic disease areas is the poor reproducibility of preclinical data for compounds progressing from academic laboratories to industrial development programs and, ultimately, to clinical trials. The reasons for these obstacles are multiple and varied, but methodological issues related to the design, execution, and reporting of preclinical studies are important components. Thus, offerors are expected to meticulously address methodological issues in their applications and, if successfully selected, in execution of this contract. Fig 1 illustrates the basics of the concept. Please note that the examples of behavioral paradigms are not intended to be exclusive or prescriptive. The offeror is expected to identify and propose the behavioral domains of particular importance, and to develop the necessary animal behavioral protocols to test multiple processes believed to be contributing to smoking in humans. In general, the tests chosen should be ones that have been used pre-clinically, so that reliability of the data generated has been established and that there exists some conceptual understanding of what the test measures. In addition, while considering models for the reward and positive reinforcement domain, investigators must be aware that certain animal behavioral tests appear not to generate reliable data with nicotine, and these should not be proposed (e.g., conditioned place preference, nicotine-primed reinstatement). Equally, it is important to highlight the fact that this contract solicitation is not intended as a mechanism to support the development of new behavioral models, assays or tests, or to uncover novel behavioral processes or neurobiological mechanisms. Nor is it intended to be directed only to investigators with addiction research expertise. NIDA welcomes the interest of small businesses who have expertise with animal models that have not seen wide use in addiction research (e.g., potentiated startle, elevated plus maze), but that might be useful as part of a screening battery. Offerors must provide the rationale for: • Selecting the model system. A detailed description of the animal model characteristics such as a definition of study population using a common strain and individual commercial stock designations of each animal provider, diet, housing conditions, microbial status and handling should be described. Before using compounds in the rat or mouse, detailed information about the cross-reactivity of the compounds with the target in the rat or mouse is necessary. For example, lower binding affinity in mice would require higher dosing which, in turn, might compromise target specificity and affect the results of testing. In addition, other interspecies differences should be taken into consideration. Bupropion is metabolized differently in the rat compared to human and mouse. Therefore, offerors need to specify how they will address this and similar species differences (e.g., comparison of dosing with bupropion compared to its metabolite over a sufficient dose/time range). • Selecting the assays/models for the behavioral domains to be studied. Provide the rationale for the selected domains, assays, models and end points. The proposed tests must be validated for their specificity and selectivity to measure clinically relevant symptom(s) or physiological parameters. It is expected that, regardless of the model or assay chosen for testing, investigators will propose an approach that is sensitive to the need for relatively high throughput assessment. Approaches that require lengthy training or assessment periods will be deemed not feasible. For behavioral domains different from Reward, testing in nondependent animals is expected. Testing in animal models of nicotine dependence is not required, although may be proposed if justified and deemed consistent with high- and medium-throughput. There are a variety of behavioral tests in the behavioral neuroscience field that could be adapted to this purpose of phenotypic drug screening. For the selection and validation of the tests, it is important to recognize that some drugs that provide similar phenotypic effects have differential effectiveness in aiding smoking cessation. For example, nicotine improves attentional function and does help with smoking cessation, whereas amphetamine also improves attentional function but there is no evidence for it aiding smoking cessation. Buproprion is an antidepressant and aids smoking cessation but sertraline which also is an antidepressant has not been found to help smoking cessation. It is thus important to integrate the phenotypic information with the neuropharmacological information to help develop a more integrated neurobehavioral approach. Importantly, the selected behavioral tests/models must provide internal behavioral validation such as learning rate or habituation which offers assurance that the conditions of the tests are appropriate. • Adequacy of controls. Verification that interventional drugs reached and engaged the target. A potential concern about the specificity of drug effects in this screen – establishing a balance between sensitivity and specificity- should be addressed through selection of appropriate drug controls. The evaluation of both of these components, sensitivity and specificity, of predictive validity is vital in work of this type to avoid costly clinical studies of false-positive drugs that affect behaviors in preclinical screens but are ineffective in humans that are addicted to tobacco. • Selecting the dose, timing and route of administration for the medications being tested. A drug administration and dose regimen that is adapted to the pharmacokinetic properties of the drug, and to the duration of the study requires careful consideration. The rationale for dosing the animal must be evident from appropriate pharmacodynamic and pharmacokinetic assays, published in the literature or obtained in applicants’ laboratories. The route of administration is important not only because of animal welfare, but also out of consideration that the oral route is the desired route of administration in humans. Hence, oral dosing is preferable whenever possible. Frequent subcutaneous, intraperitoneal or intravenous injections lead to considerable stress in the animals and could influence test outcome. Assistant application devices, such as minipumps, should be avoided wherever possible, as they require surgery, additional control groups and can cause technical complications. For testing, a minimum of 3 doses of first and second line medications should be proposed. All of the medications are to be screened in each model proposed for evaluation. • Selecting the experimental design. o Must describe methods of blinding, strategies for randomization and /or stratification. To improve the reliability of the proposed studies, the offeror must use randomization to eliminate systematic differences between treatment groups; induce the condition under investigation without knowledge of whether or not the animal will get the drug of interest; and assess the outcome in a blinded fashion. o Demonstrate the reconciliation between statistical needs for the detection of biological effects and constraints of animal welfare, cost and time. To guard against 'underpowered' studies, researchers must calculate the number of animals required to have a reasonable chance of detecting the anticipated effect given the expected variance of the data. A detailed discussion about the use of appropriate statistics must be provided, including the evidence that applicants consulted a statistician to obtain information about the sufficient group size, and the appropriate statistical method to be applied for data analysis for each behavioral test and adapting the statistical approach for combining data across behavioral tests in developing an optimized predictive ‘screening system.’ o Detailed description of statistical methods used in analysis and interpretation of results • Guidelines on nicotine dose selection for in vivo research. If the models, in which in vivo nicotine dosage is warranted, are selected for this project, an evidence for species-specific nicotine dosage ranges must be presented. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. Guidelines on nicotine dose selection for in vivo research must be consulted (Psychopharmacology (2007) 190:269–319). Phase I Activities and Expected Deliverables • Select the behavioral assays and models representing the behavioral domains of particular importance believed to be contributing to smoking and quitting in humans. • Develop the necessary animal behavioral protocols to test multiple processes in those identified domains. Must finalize the selection of model systems, controls, experimental design, the dose, timing and route of administration, and provide verification that interventional drugs reached and engaged the target. • Demonstrate that the selected behavioral tests are capable of high or medium throughput. • Must agree and comply with good reporting practices, such as ARRIVE Guidelines. The ARRIVE guidelines consist of a checklist of 20 items describing the minimum information that all scientific publications reporting research using animals should include, such as the number and specific characteristics of animals used (including species, strain, sex, and genetic background); details of housing and husbandry; and the experimental, statistical, and analytical methods (including details of methods used to reduce bias such as randomization and blinding). All the items in the checklist have been included to promote high-quality, comprehensive reporting to allow an accurate critical review of what was done and what was found (see: Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research, PloS Biology, 2010, Volume 8, issue 6, 1-5.) • To eliminate bias, all results, negative and positive, must be reported. • Must provide data interpretation, including alternative interpretations. Must include the review of relevant literature in support or in disagreement with results. Phase II Activities and Expected Deliverables • Establish the battery of carefully selected behavioral tests. • Demonstrate that the battery of carefully selected behavioral tests is capable of high or medium throughput. Demonstrate that this battery can make data collection and analysis more efficient without compromising the quality of the phenotypic assessment. • Demonstrate that the battery of carefully selected behavioral tests is sufficiently sensitive to produce a comprehensive behavioral assessment in functional domains of cardinal importance for tobacco dependence. • In selected model systems, using appropriate controls, experimental design, the dose, timing and route of administration, obtain standardized data on the responses to existing first-line pharmacotherapies that have been approved by FDA as aids for smoking cessation (i.e. varenicline, bupropion ), and second-line pharmacotherapies (i.e. clonidine, nortriptyline). • Establish, test and validate the bioinformatics algorithms/processes which are able to quickly and reliably recognize phenotypic profiles produced by varenicline, bupropion, clonidine and nortriptyline. The proposed bioinformatic approach must aid the predictions of the therapeutic effect of candidate compounds for smoking cessation to be developed in the future. • Confirm that multivariate and/or bioinformatics algorithms are able to discriminate between varenicline-, bupropion-, clonidine- and nortriptyline-treated animals and at least two positive and two negative controls. • Demonstrate the compliance with good reporting practices, such as ARRIVE Guidelines. The ARRIVE guidelines consist of a checklist of 20 items describing the minimum information that all scientific publications reporting research using animals should include, such as the number and specific characteristics of animals used (including species, strain, sex, and genetic background); details of housing and husbandry; and the experimental, statistical, and analytical methods (including details of methods used to reduce bias such as randomization and blinding). All the items in the checklist have been included to promote high-quality, comprehensive reporting to allow an accurate critical review of what was done and what was found (see: Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research, PloS Biology, 2010, Volume 8, issue 6, 1-5.) • Collect and report all results, negative and positive. • Must provide data interpretation, including alternative interpretations. Must include the review of relevant literature in support or in disagreement with results. • Creating the all-inclusive platform which is comprised of hardware that evaluates the behaviors of domains of importance, and software that recognizes and analyzes behavior is encouraged.
Keywords: NIDA
150: Video Game Targeting Relapse Prevention in Youth with Substance Use Disorders
Description: Objective This topic addresses the need for improved relapse rates among adolescent substance abusers. A video game should be designed for substance using adolescents in a commercializable and compelling package, for the purpose of reinforcing and maintaining behavior changes (e.g., skills development) accomplished through a theory-driven and evidence-based therapy. The video game may be compatible with an off the shelf commercially available gaming system. The project may, depending on the console selected, also involve development of peripherals for use with the system. The technology used must be familiar and accessible to youth, and developmentally appropriate. Background Despite advances in the development of treatments for adolescents with substance use disorders, relapse remains a significant concern. Although approaches to adolescent substance abuse almost exclusively focus on abstinence, relapse is likely to occur for one third to one half of youth, within 12 months of treatment completion (Grella, Joshi & Hser, 2004; Winters, Botzet, & Fahnhorst, 2011). Some studies report that less than half of adolescents are abstinent 3 months after discharge from outpatient treatment programs (Brown et al., 2001, Dennis et al., 2004, Kaminer et al., 2002, Winters, 2003). In the study of adolescent relapse risk, continuing care and aftercare have repeatedly been shown to reduce the likelihood of relapse and enhance the maintenance of treatment gains (Burleson, Kaminer, & Burke, 2012; Winters et al., 2011). Digital media and communication technology is pervasive in youth culture. Developing a video game for the purpose of maintaining treatment gains, using technology that is appealing, accessible and familiar to youth, and developmentally-appropriate, has the potential to greatly improve relapse rates in this population. This technology could improve engagement and reach, as well as reduce the cost and time burden of implementation on community treatment providers. Recent research by Girard et al (2009) has shown that participating in video game sessions that included behaviors that were incompatible with smoking cigarettes (crushing virtual cigarettes), within a virtual environment was more efficacious for smoking cessation than a similar game in which patients found and crushed virtual balls. The mechanism of this treatment is not well understood and it may be a form of extinction, counter conditioning, exposure with response prevention, or re-evaluative conditioning. Nonetheless, such practice in a “game” environment may be uniquely helpful because it can deliver a large “dose” of alternative practice in a manner that people not just tolerate but also enjoy. The fact Girard et al’s short duration gaming experience could improve outcomes in comparison with a “placebo” control suggests that video games may hold great promise for treating addiction. Phase I Activities and Expected Deliverables • Modification of an existing game or development of a new therapeutic game for use by one or several players (e.g., internet based, social networking opportunity) • Development of peripherals to interact with the game as needed • The game should provide opportunities for participants to practice skills learned in treatment or other opportunities that reinforce behavior changes/gains made through treatment • The game should allow for personalization when appropriate (e.g., selection of drug of choice, or multiple drugs) • The game should include a variety of difficulty levels of increasing intensity, with opportunities for participants to refine skills • The game should be able to recognize and keep track of the participant’s performance over time so the participant can experience improvement in game play • The game should record, store, and provide for downloading into a database, information regarding system use by each player such as time played, used to determine the extent of adherence and the “dose” required • The game may allow for cooperation and interaction with other participants when the game is played as a group exercise • A pilot study with a small group of adolescent substance abuse treatment completers (N=9) o The study will expose participants to the game weekly for 30 minutes a session, for 4 weeks o Measures collected at baseline will include drugs of choice, and timeline follow-back o Measures collected following each game exposure session will include acceptability, suggestions for improvement, AES/SAES, craving ratings, urine drug screening and cotinine screening (for smokers) and treatment engagement data o Measures collected 1 month after treatment entry will include timeline follow-back o The pilot testing may be done in an iterative fashion so that multiple small focus groups are exposed to the program and it is modified in response to their comments Phase II Activities and Expected Deliverables Modification of program developed in Phase I, in response to customer feedback followed by an RCT Pilot clinical study evaluating the effectiveness of the newly developed video game (TAU + 1 month of access to the video game vs. TAU alone). Outcomes collected will include AEs, SAEs, system use information (durations, preferred contexts/levels, times accessed), initial abstinence/use via urine screening, follow up abstinence/use via time-line follow back.
Keywords: NIDA
313: RNAi Cancer Therapeutics using Nanotechnology
Description: In 2011, the SBIR Development Center hosted an industry roundtable to solicit inputs from life science industry professionals on emerging areas that are ripe for technology development by the small business community. Participants at this meeting expressed strong interest in using the SBIR mechanism to foster and encourage the development of novel RNA interference (RNAi) delivery platforms, particularly as a strategy for addressing therapeutic targets previously deemed “undruggable” by small molecules. Such therapeutics are gaining prominence due to their versatility and efficiency in treating cancer, as well as a variety of other genetic diseases; however, treating patients with RNAi has proven challenging, as it is difficult to achieve intracellular delivery to specific tissues and organs expressing the target gene. In particular, cellular uptake of naked RNAi is extremely inefficient owing to its polyanionic nature. The majority of intravenously administered RNAi is removed from circulation by hepatic and renal clearance, and the remaining RNAi is subject to degradation by nonspecific nucleases in the blood. Moreover, injecting large quantities of RNAi may elicit an immune response, and other “off-target” effects may result in toxicity. While RNAi delivery to tumor cells poses these and other challenges, the ability to overcome these challenges is expected to facilitate the development of new and highly efficacious anti-cancer agents. Nanoparticle-based delivery systems are especially attractive as such strategies afford the opportunity to target specific cell, tissue, and organ types, while also increasing circulation half-life and shielding RNAi from degradation. Importantly, ongoing clinical trials are successfully utilizing nanoparticle-based delivery systems for cancer-related RNAi therapeutics, indicating that nanotechnology-based approaches hold great promise. To accelerate such efforts, the National Cancer Institute (NCI) requests proposals for the development of novel, commercially viable nanotechnology-based platforms for the delivery of RNAi cancer therapeutics. Project Goals Proposals submitted under this contract topic should involve the design, fabrication, characterization, and preclinical evaluation of novel nanoparticle-based drug formulations capable of delivering candidate RNAi therapeutics for the treatment of cancer. Of particular interest are delivery systems that can achieve targeted delivery of RNAi to tumor cells, favorable pharmacokinetics and circulation times, and efficient uptake of RNAi by tumor cells. Nanotechnologies which minimize immune responses and/or off-target effects of RNAi are also desirable. Nanotechnology-based RNAi therapeutic agents acceptable under this contract topic include siRNA, shRNA, miRNA, other ncRNA(s) and combinations thereof. Antisense oligonucleotides are also acceptable. This contract topic is not intended to fund basic research to identify molecular targets for RNAi therapy, conduct exhaustive comparative studies of multiple nanoparticle delivery systems, or establish new animal models. Concepts delivering DNA, messenger RNA, and/or proteins are also not acceptable candidates for this topic, nor are viral delivery platforms for RNAi. The RNAi-nanoparticle constructs under development may incorporate additional functionalities to supplement or enhance the therapeutic RNAi. Such functionalities may include, but are not necessarily limited to, the following: • Novel nanoparticle delivery vehicles • Constructs involving novel tumor targeting • Novel RNAi loading and releasing schemes • Nanoparticle constructs capable of crossing the blood-brain barrier, penetrating pancreatic stroma, overcoming multi-drug resistance, or treating metastatic cancer • Combination therapies utilizing multiple RNAi payloads (e.g., RNAi-based Logic Circuits) • Other combination therapies utilizing at least one RNAi therapeutic and one conventional chemotherapeutic agent (i.e., non-nucleic acid agent) Phase I Activities and Expected Deliverables • Provide a detailed experimental strategy to develop and deliver the RNAi/nanotherapeutic, and identify an appropriate cancer indication(s) for the nanoconstruct containing the RNAi(s) • Encapsulate and/or attach the selected RNAi therapeutic agent(s) to the nanoparticle • Demonstrate nanoconstruct stability in vitro, and demonstrate controlled release of the RNAi therapeutic agent(s) from the nanoconstruct • Perform in vitro efficacy studies in the relevant cancer cell line(s): (a) quantitate knockdown of the target gene transcript(s) and demonstrate a ≥70% reduction in the corresponding protein product(s) (knockdown of multiple gene products is encouraged but not required); and (b) evaluate appropriate correlative endpoints / phenotypic effects (e.g., cell death, cell cycle arrest, cell differentiation) Establish specificity of the RNAi therapeutic and its phenotypic effects using appropriate controls (e.g., mutational substitution, cDNA rescue, scrambled RNAi sequences) • Perform a small in vivo efficacy study in a relevant animal model of cancer: (a) quantitate knockdown of the target gene transcript (i.e., at least one gene) and demonstrate a ≥70% reduction in the corresponding protein product; (b) evaluate appropriate correlative endpoints / phenotypic effects Phase II Activities and Expected Deliverables (include at least three of the following) • Provide a plan and timeline to complete preclinical development for the RNAi/nanotherapeutic, culminating in the filing of an IND with the FDA • Demonstrate in vivo preclinical efficacy (properly powered studies) • Demonstrate acceptable safety (i.e., toxicity in rodents and/or large animals) • Demonstrate acceptable pharmacokinetics and pharmacodynamics • Conduct process development to support clinical manufacturing (e.g., scale-up feasibility) • Conduct other R&D activities needed to complete an IND application, carried out in a suitable pre-clinical environment
Keywords: NCI
314: Development of Human Tissue Culture Systems that Mimic the Tumor Microenvironment
Description: There is a critical need to improve the accuracy of preclinical drug efficacy screening and testing through the development of in vitro culture systems that more effectively mimic the in vivo environment. Currently, two-dimensional (2D) in vitro culture systems or in vivo animal models are the primary tools used to test cancer cell responses to drugs. However, drug sensitivity data obtained via 2D culture systems can be misrepresentative, while animal models are expensive, time-consuming, and not always predictive of the effects on human tumors in their native environment. Three-dimensional (3D) culture systems that mimic the tumor microenvironment using human tissue could be a better tool for drug screening by providing a more accurate, in vivo-like structure and organization than 2D culture systems, without the cost and time associated with using animal models. In addition, culture systems using human tissue may produce responses more predictive of humans than animal models. Advances in bioengineering and 3D cell culture models have led to in vitro systems that better replicate the structure, physiology, and function of tissues seen in vivo. 3D models more accurately mimic the in vivo milieu than current 2D in vitro culture systems by recreating the morphology and arrangement of individual cells, concentration gradients of signaling molecules and therapeutic agents, and the composition, structure, and mechanical forces of extracellular matrix around cells. The use of 3D systems that recreate the human tumor microenvironment could improve drug development in at least two ways: 1) speed decision-making for whether a particular therapeutic agent is worth pursuing in an animal model, reducing the time and cost of development; 2) lead to fewer clinical trial failures because of earlier, more relevant results from human tissue. Properly representing the tumor microenvironment is particularly critical for testing the effectiveness of anti-cancer therapeutic agents. For example, extravascular transport in solid tumors is a fundamental determinant of the efficacy of both locally and systemically administered cancer agents. Large diffusion distances in tumor tissues, elevated interstitial fluid pressure, and interactions between anti-cancer drugs, tumor tissue, and normal tissue are factors that significantly limit drug diffusion in the extravascular compartment. Additionally, due to rapid proliferation and poor blood supply to tumor cells, the tumor microenvironment is often acidic and hypoxic, which can lead to the resistance of tumor cells to both drug and radiation therapy. Thus, systems to properly recreate the tumor microenvironment are essential to advance the discovery and development of effective anti-cancer agents. Project Goals The focus of this topic is the development of 3D human tissue model culture systems that accurately mimic the tumor microenvironment, including factors affecting tumor cell responses such as vascularization and interactions with heterogeneous cell types. The project goal is to produce a system that is validated against known effective anti-cancer agents to demonstrate the system’s utility as a predictive tool and screening assay. It is anticipated that the development of 3D systems representative of human tumor microenvironments will lead to an increase in the quality of and reduction in the timelines and costs associated with screening drugs, and enhancement in efficacy information for regulatory decisions. Essential characteristics of an in vitro tumor microsystem should include all or some of the following features: 1) multicellular architecture that represents physiologically relevant characteristics of the tumor and tissue of origin; 2) reproducible and viable operation with simple and clear protocols; 3) ability to examine multiple aspects of cancer, such as tumor growth, angiogenesis, cell proliferation, migration, and/or invasion; and 4) compatibility with high content screening platforms that include multiple molecular read-outs, such as genomic, proteomic, metabolomic, or epigenomic analyses. System development should permit scale-up production such that the system can be reliably reproduced at a cost with reasonable expectation for market success. An eventual goal for such systems may include the ability to incorporate individual patient tumor biopsies to test patient-specific responses to available agents. It is important to note that full 3D tumor microenvironment systems will consist of more than just an extracellular matrix containing tumor cells and will facilitate the inclusion of various cell types to mimic tumor cell interaction with surrounding normal cells and their effects on cancer aggressiveness and response to anti-cancer drugs. Examples include stromal cells that can induce chemoresistance and encourage metastasis, as well as endothelial cells that can carry therapeutics to the cancer. This topic is not intended to fund microphysiological organ systems for the study of toxicity, though tumor culture systems developed under this topic may be combined as a module with systems such as those being developed through the collaborative program between NIH, FDA, and DARPA: http://www.ncats.nih.gov/research/reengineering/tissue-chip/tissue-chip..... Phase I Activities and Expected Deliverables • Develop 3D culture system prototype that incorporates human tumor cells o System should include: • Co-culture with multiple cell types, such as stromal cells, endothelial cells, etc. • Components to address cell-cell or cell-extracellular matrix (ECM) adhesion • Method to deliver and control necessary growth factors o Use a tumor cell line or biopsy tissue that is readily available and well characterized o Model should be developed using or easily adapted for use with high content screening platforms for sample analysis o Develop standardized protocol to enable reproducible culture of tumor cells in 3D microenvironment o Recapitulate tissue-tissue interfaces, spatiotemporal chemical gradients (e.g. oxygen, nutrients, and/or growth factors), and mechanical context of tumor microenvironment • Submit a statement to NCI that specifies metrics used and criteria for prediction of clinical efficacy prior to demonstration of accurate prediction of clinical efficacy o Identify specific biomarkers (e.g. gene expression patterns, cell surface proteins) that characterize cell types and tumors used o Specify criteria for assessing whether the tumor microenvironment is representative of human physiological environment o Specify markers of tumor activity o Specify metrics that will be used to evaluate efficacy and milestones for desired efficacy • Demonstrate accurate prediction of clinical efficacy in the developed prototype o Test at least one anti-cancer agent with a known clinical profile using the developed prototype (e.g., agent used may be from the NCI Developmental Therapeutics Program [DTP] Approved Oncology Drugs Set) (http://dtp.cancer.gov/branches/dscb/oncology_drugset_explanation.html) o Benchmark performance in developed system against 2D (e.g., NCI-60 Human Tumor Cell Line), and currently available 3D culture systems (e.g., tumor spheroids, hollow-fiber bioreactors) Phase II Activities and Expected Deliverables • Benchmark performance in developed system against applicable in vivo animal model(s) and known clinical performance o Test multiple agents with known clinical profiles in the developed prototype • Test at least one agent that has proven efficacious in animal trials but not in clinical trials o Assess genomic, proteomic, metabolomic, and epigenomic profile of the tumor system • Use validated markers and/or evaluative criteria from in vivo histologic analysis • Genomic data may be compared to The Cancer Genome Atlas (http://cancergenome.nih.gov) o Compare dose-response relationships of known anti-cancer agents • Demonstrate the ability to scale-up the system for use in high-throughput therapeutic agent screening assays o Demonstrate the ability to perform high-throughput quantitative analysis on samples, such as simple harvesting and/or automated imaging.
Keywords: NCI
315: Development of Companion Diagnostics: Enabling Precision Medicine in Cancer Therapy
Description: The demand for companion diagnostics has greatly increased with the recognition that matching the right patient to the right drug at the right time can improve patient care and may decrease health care costs. More than a dozen companion diagnostic tests have been approved by the FDA to guide the prescription of products in oncology, cardiovascular disease, and infectious disease. Among them, tests of the Philadelphia chromosome, tumor-associated EGFR overexpression, and HER2 protein overexpression have been identified by the FDA as “required” for the identification of candidate cancer patients to receive Gleevec, Erbitux (cetuximab), and Herceptin (trastuzumab), respectively, for certain indications. In 2011, the FDA approved two pairs of new oncology drugs and their companion diagnostic tests simultaneously. These decisions suggest that the era of companion diagnostics has arrived. Despite initial success, many therapies in the cancer arena (both primary and adjuvant treatments) still lack prediction and guidance from companion diagnostics. Many patients die from recurrence and metastasis as a result of unpredicted resistance to drugs or radiation developed during therapy, or due to pre-existing tumor insensitivity to the drugs or radiation therapy. Guidance towards effective and safe therapy is greatly needed and can be provided by companion diagnostics, which include tests developed after a drug has come to market, tests developed in conjunction with the development of a therapeutic agent, and tests to predict the interaction of novel agents with existing standard of care therapies, such as radiation or cytotoxic chemotherapy. This topic seeks to stimulate research, development, and commercialization of innovative tests and technology platforms for all types of companion diagnostic applications. Companies with advanced biomarkers are particularly encouraged to apply. Project Goals The goal of this contract topic is to develop companion diagnostic assays that identify patients for which a particular therapeutic regimen, including radiation therapy, existing drugs, and drugs in clinical development will be safe and effective. Tests for monitoring the response to treatment for the purpose of adjusting treatment (e.g., schedule, dose, discontinuation) to achieve improved safety or effectiveness are also acceptable under this contract topic. Though the examples mentioned above are for targeted therapies, tests may also encompass therapeutics outside of this class. These tests include, but are not limited to, tumor RNA/protein expression or overexpression, gene mutation or deletion/insertion, allelic variation, and enzymatic deficiency. Noninvasive and minimally invasive sampling methods (e.g., body fluids and mouth swab) are preferred. Other sampling methods are also acceptable if they provide significantly improved predictive value, accuracy, and clinical applicability. This topic is not intended to support the development of assays that do not provide predictive/prognostic information for a therapy. For example, the development of an assay for the sole purpose of measuring whether the drug hits its intended target (e.g., pharmacodynamic assay) would not be considered responsive under this contract topic. A novel test/device providing information that is useful in cancer diagnostics or prognostics, but not a determining factor for the safe and effective use of a therapeutic product, would also not be considered responsive. Phase I Activities and Expected Deliverables • Develop a working companion diagnostic test that meets the criteria described above • Characterize the variation, reproducibility, and accuracy of the test, and implement a QA/QC plan • Demonstrate the suitability of the test for use in the clinic, and conduct benchmarking studies against current tests (if available);algorithms must be tested with datasets other than those used for their development • In cases where the drug for which the companion diagnostic test being developed is not yet commercially available (i.e., approved for marketing), the applicant must provide proof of collaboration or partnership with the entity that is developing the therapeutic agent or with an established diagnostic company • All offerors must establish a collaboration or partnership with a diagnostic and/or pharmaceutical company and/or clinical/research institution that can provide relevant clinical trial specimens; offerors must provide a letter of support from the partnering organization in the Phase II application • Deliver the SOP of the working test to NCI for evaluation Phase II Activities and Expected Deliverables • Demonstrate clinical utility and value by testing sufficient numbers of patients from multiple sites to unequivocally prove statistical significance with regards to patient selection for the therapy • If the primary conclusions reached during the Phase I studies were based on animal experiments or ex vivo modeling, then a correlation study between these models and treatment in human subjects is expected • Establish marketing partnership or alliance with the company developing the therapy, unless the therapy is already approved for marketing • It is preferred that the test be performed in at least one independent CLIA-certified laboratory • Deliver the final SOP to NCI for evaluation
Keywords: NCI
316: Development of CTC Isolation Technologies Enabling Downstream Single Cell Molecular Analysis
Description: Summary Circulating tumor cells (CTCs) are cancer cells shed from either the primary tumor or its metastases and are circulating in the peripheral blood. While metastases are directly responsible for the majority of cancer deaths, CTCs may constitute seeds for metastases and may be instrumental for the spread of the disease. Many studies have shown that the presence of CTCs in peripheral blood or bone marrow is of prognostic significance in different types of solid tumors, and that the number and molecular changes of CTCs may help predict or monitor response to treatment. An increasing number of studies have shown large molecular and cellular heterogeneity of CTCs from the same types of cancer and even from CTCs from the same patient. This phenomenon has made the interpretation of cancer status very difficult. Current FDA-approved CTC analysis is based on immunological capture of CTCs by magnetic beads. This method does not capture all types of CTCs, and the recovery of the captured cells for subsequent molecular or cellular analysis is limited; hence, it is important to develop improved methodologies for CTC isolation that enable subsequent genomic, proteomic, or metabolomic analysis at the single cell level in order to understand the origin and role of these subpopulations of CTCs in cancer progression and treatment response. Enabling CTC analysis at the single-cell level will significantly contribute to cancer research and the selection of treatment options for patients based on changes in CTC numbers and molecular characteristics before and during treatment. Project Goals The long-term goal of the project is to integrate new or established technologies to enable molecular characterization and analysis of individual CTCs isolated from blood or bone marrow. An ideal system will be a modular platform combining a CTC capture and separation module with several other modules for downstream molecular analysis such as genomic, metabolomic, proteomic and mutation analysis at the individual cell level. Non-modular systems will also be acceptable. The short-term goal is to demonstrate the technical viability of the proposed technology to isolate and analyze CTCs at the single-cell level in an experimental setting. If molecular analysis is not performed with the proposed device, a detailed description about compatible downstream analysis technology(/ies), including manufacturers and model numbers, is required. Acceptable studies include but are not limited to: • CTC isolation and enrichment technologies such as magnetic separation, microfluidics, size separation, and negative or positive selection • Integrated CTC devices which combine CTC capture and molecular analysis • Viable CTC cell isolation and/or culturing for treatment assessment • Low-cost multichannel scanning, imaging, flow cytometry, spectral analysis or equivalent technologies for CTC molecular analysis with the potential to combine with innovative single-cell isolation (e.g. micro dissection) • Non-separation-based technologies for CTCs that enable molecular analysis Phase I Activities and Expected Deliverables • Develop a method for CTC isolation or identification amenable to downstream single-cell analysis • The technology/device should be able to isolate or identify CTCs from samples with CTC counts as low as one cell/ml of blood (for Phase I, seeding experiments are acceptable) • The technology/device should be able to perform single-cell molecular analysis (or whole genome amplification) for more than 100 CTCs, or isolate more than 100 CTCs individually in a format and volume that is compatible with existing downstream single-cell molecular analysis o In the latter case, please specify the format, volume, and intended downstream analysis • Characterize the variation, reproducibility, and accuracy of the method; the method must demonstrate at least 80% recovery and 70% purity • When applicable (e.g., when downstream analysis is gene expression), determine the viability of CTCs • Demonstrate feasibility that the device (including imaging, spectral analysis or equivalent technologies) can provide CTCs for molecular analysis at the single-cell level, and at least 10 biomarkers (including markers to confirm that the isolated cells are CTCs) can be measured (preferably simultaneously) for the same cell • Implement a QA/QC plan • The establishment of a collaboration or partnership with established diagnostic or pharmaceutical companies is strongly encouraged • Provide the NCI with SOPs, including sample collection, shipping, storage conditions, consumables used, and molecular analysis, for evaluation • Provide the NCI detailed design specifications (including components) and estimations of the cost of producing the proposed devices and/or reagents, including an analysis/breakdown of vendors and/or sources of raw materials Phase II Activities and Expected Deliverables • Develop a prototype of the device incorporating the technology demonstrated in Phase I with at least two of the applications below or other applications with significant clinical utility: o Single CTC whole genome sequencing o Single CTC molecular phenotyping o Single CTC proteomic analysis o Single CTC metabolomic analysis o Single CTC targeted multiplex gene expression analysis o Single CTC targeted multiplex mutation analysis o Single CTC targeted multiplex epigenetic analysis o Culture of individual CTCs with sufficient percent of viable cells for ex vivo analysis (e.g. drug treatment) • Test the device with a sufficient number of patient samples to demonstrate clinical utility and advantages, with appropriate consideration of statistical significance • Establish a marketing partnership or alliance with an established diagnostic or device company
Keywords: NCI
317: Wound Healing Preparations Incorporating Nitric Oxide-Releasing Materials (NIH Technology Transfer)
Description: Summary Non-healing wounds can pose significant problems for cancer patients (e.g., in cases where multiple operations are required for local recurrence, when large wounds are slow to close, and especially when patients receive radiation at sites requiring surgery). In addition, the effects of chemotherapy, nutritional deficits along with co-morbidities (e.g., diabetes), and infections can complicate wound healing. Therefore, the cancer patient population has the potential for non-healing wounds due to the nature and effects of the oncologic disease process and its treatments (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2206003/). Improved methods are thus needed for treating non-healing wounds that often result in lengthy hospital stays, application of multiple types of dressings and ointments, and hyperbaric methods. Nitric oxide (NO) is an important bio-signaling molecule whose role has been extensively recognized in the body’s endogenous immune, inflammatory, and tissue regenerative responses. Therapeutic application of exogenous topical NO-generating agents has been shown to provide powerful, broad-spectrum antimicrobial action, and NO is capable of providing numerous wound-healing benefits if delivered at the proper concentrations. However, since NO is an easily oxidized gas, controlled topical delivery of NO to a desired area is difficult. The National Cancer Institute (NCI) has developed a family of polymers based on poly(acrylonitrile) that are capable of storing NO bound in a stable chemical functionality, called a diazeniumdiolate group, and releasing NO under aqueous conditions. The next logical step in the utilization of these materials for biomedical applications is the incorporation of these NO-releasing poly(acrylonitrile)-based compositions into suitable, biocompatible dressings for application to wounds to fight infection, modulate inflammation, and promote angiogenesis and collagen synthesis in order to accelerate wound closure and/or otherwise improve functional outcomes. This invention is the subject of issued patents US 7,968,664 and US 8,093,343, and HHS Reference Number E-188-2004. Project Goals The ultimate goal of this effort is to develop a commercially viable wound-healing dressing, utilizing this NCI-developed technology, to alleviate the suffering and costs caused by non-healing wounds, thereby establishing a precedent for supportive care for cancer while quickly creating a product of merit. The short-term goal of this project is to develop a prototype of such a dressing and to provide data that clearly demonstrate the potential of this stable NO-releasing material/formulation. The work scope may include design and fabrication of the material with in vitro evaluation (e.g., product stability testing) and preliminary in vivo assessment of its efficacy and final prototype development. These data will support the continued development of the experimental medical device to the point of filing an Investigational Device Exemption (IDE). The long-term goal of this topic is to enable a small business to bring a fully developed product incorporating NCI’s NO-releasing polymer technology to the clinic and the market. The dressing to be developed under this contract should demonstrate the ability to maintain the stability of the diazeniumdiolate group during storage and sterilization, and to release NO when triggered by any mechanism related to wound contact (e.g., thermal or aqueous stimuli, biochemical interaction, etc.), or triggered by the health care provider (e.g., light source, chemical mixing, etc.). Since one of the major potential benefits of sustained and controlled release of therapeutic NO is the reduced frequency with which the care provider must contact the wounded skin to apply therapeutics and change the dressing, any stable, NO-releasing formulation will be considered including, but not limited to, fabric-based “traditional” dressings incorporating poly(acrylonitrile) as one of the textile components, hydrogels, creams, gels, nanomaterials, meshes, films, coatings, etc. This is an NIH TT (Technology Transfer) contract topic from the NCI. This is a program whereby inventions from the NCI Intramural Research Program (Center for Cancer Research, CCR) are licensed to qualified small businesses with the intent that those businesses develop these inventions into commercial products that benefit the public. The contractor funded under this contract topic shall work closely with the NCI CCR inventors of this technology. The inventors will provide assistance in a collaborative manner with reagents and discussions during the entire award period. Between the time this contract topic is published and the time an offeror submits a contract proposal for this topic, no contact will be allowed between the offeror and the NCI CCR inventors. However, a pre-submission public briefing and/or webinar will be given by NCI staff to explain in greater detail the technical and licensing aspects of this program (for further information, see http://sbir.cancer.gov/news/upcoming/). In addition, a list of relevant technical, invention, and licensing-related questions and answers (including those from the public briefing) will be posted, maintained, and updated online (http://sbir.cancer.gov/news/upcoming/) during this time period. The awarded contractor will automatically be granted a royalty-free, non-exclusive license to use NIH-owned and patented background inventions only within the scope and term of the award. However, an SBIR offeror or SBIR contractor can apply for an exclusive or non-exclusive commercialization license to make, use, and sell products or services incorporating the NIH background invention. Offerors submitting an SBIR contract proposal in response to this topic are strongly encouraged to submit concurrently an application for a commercialization license to such background inventions. Under the NIH NCI TT program, the SBIR contract award process will be conducted in parallel with, but distinct from, the review of any applications for a commercialization license. To apply for a commercialization license to develop this NIH invention, an SBIR offeror or contractor must submit a license application to the NIH Licensing and Patenting Manager: Betty Tong Ph.D., tongb@mail.nih.gov or 301-594-6565. A license application and model license agreements are available at http://www.ott.nih.gov/pdfs/LicApp.pdf and http://www.ott.nih.gov/forms_model_agreements/forms_model_agreements.asp.... This license application provides NIH with information about the potential licensee, some of the terms desired, and the potential licensee's plans for development and/or commercialization of the invention. License applications will be treated in accordance with Federal patent licensing regulations as provided in 37 CFR Part 404. A further description of the NIH licensing process is available at http://www.ott.nih.gov/licensing_royalties/intra_techlic.aspx. NIH will notify an SBIR offeror who has submitted an application for an exclusive commercialization license if another application for an exclusive license to the background invention is received at any time before such a license is granted. Any invention developed by the contractor during the course of the NIH TT contract period of performance will be owned by the contractor subject to the terms of Section 8.5. Phase I Activities and Expected Deliverables • Prepare one or more dressings or other formulations incorporating NO-releasing poly(acrylonitrile) materials • Produce a prototype product meeting minimum essential characteristics o Quantifiable NO release durations should range from acute time periods (minutes) to 24 hours or longer to support an adequate therapeutic window o NO storage and release should be quantified via standard electrochemical or chemiluminescent assays routinely used in characterizing NO-based materials • Characterize the material’s: o total NO release potential o triggered NO release kinetics • Conduct proof of concept in vitro studies in the appropriate models and environments • Conduct in vivo efficacy studies to demonstrate potential therapeutic benefit of the lead candidate NO-releasing preparation in an appropriate model Phase II Activities and Expected Deliverables • All studies in Phase II shall be conducted with the ultimate aim of producing a product acceptable to the FDA, and shall thus follow the recommendations contained in the FDA document “Guidance for Industry: Chronic Cutaneous Ulcer and Burn Wounds-Developing Products for Treatment” published June 2006 and available for download from the FDA website: (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati...) • Conduct appropriate stability studies, including thermal stability at sterilization temperatures and shelf life characterization • Provide quantitative evidence of improved wound healing over the current standard-of-care • Demonstrate capability for commercial production of the product • Demonstrate capability to manufacture and sterilize the lead candidate in an industrial setting • Prototype should demonstrate the ability to provide medical benefit, robust stability, and commercial potential
Keywords: NCI
318: Test to Predict Effectiveness of Docetaxel Treatment for Prostate Cancer (NIH Technology Transfer)
Description: Summary Over the past two years, medical oncologists have added three new therapies to the therapeutic arsenal against Castration-Resistant Prostate Cancer (CRPC): abiraterone, Sipleucel-T, and cabazitaxel. Before approval of these agents, docetaxel was the only life-extending therapeutic option for men with CRPC, and docetaxel remains the standard of care for men who can tolerate chemotherapy. Moreover, there are several promising agents that are likely to be FDA-approved for CRPC in coming years (i.e., MDV-3100, EPI-001, and TOK-001). Therefore, the commercial availability of a method to determine which CRPC patients will have a superior response to docetaxel therapy (and which CRPC patients will not respond), will allow medical oncologists to consider other approved options in certain patients, thereby “personalizing” CRPC therapy. The National Cancer Institute (NCI) has developed a genotype test that can indicate the duration of survival following docetaxel therapy in men with CRPC. The test detects a genetic variant in cytochrome P450 1B1 (CYP1B1*3; 4326C>G) that encodes a leucine-to-valine amino acid substitution, L432V, in the translated protein. This genetic polymorphism causes P450 1B1 *3 to synthesize higher than normal concentrations of a reactive estrogen species (e.g., estradiol-3,4-quinone [E2-3,4Q]) that reduces docetaxel activity via two distinct mechanisms. Firstly, E2-3,4Q binds directly to docetaxel at biological pH, thereby reducing docetaxel potency. Secondly, E2-3,4Q antagonizes the mechanism of action of docetaxel (i.e., microtubule stabilization), by destabilizing the interaction between tubulin thiol groups that are required to form microtubules. Therefore, a simple genotypic test can determine whether or not a patient will respond to docetaxel, or whether treatment with other newly-approved anticancer agents is warranted. The genetic marker CYP1B1*3 could be used as a prognostic tool to predict survival rate and propensity to respond to docetaxel treatment. This invention is the subject of filed patent applications US20100280084A1 and EP1943358, and HHS Reference Number E-307-2005/0. Project Goals The focus of this topic is to advance development of this genetic test which would provide rapid and useful a priori predictions of the clinical outcome of docetaxel patients and guide the therapeutic strategy for each patient. The short-term goals of this project are to: (i) develop a rapid and reproducible assay for the CYP1B1*3 variant; (ii) provide additional preclinical evidence necessary for carrying the CYP1B1*3 genotype test into the clinical setting; and (iii) determine if cabazitaxel activity is related to the CYP1B1*3 allele and reactive estrogen species. The long-term goal of this project is obtain FDA approval for the test, to establish broader utility for the CYP1B1*3 test in treatment of other cancer types, implement the test in conjunction with alternate therapeutics that act via modulation of this estrogen responsive pathway, and to further translate the utility of the genotype test to wider clinical use. This technology, once demonstrated in the field of prostate cancer, could be applied to breast and lung cancer genetic markers that have clinical application in defining the chemotherapeutic treatment schedules for individual patients. Phase I deliverables include technique development, further demonstration of the mechanism of CYP1B1*3 interference, validation that genotype is related to survival using retrospective CRPC patient samples, and identification of the percentage of samples with the variant. A future Phase II SBIR award would include a genotype-directed prospective clinical trial with docetaxel and/or cabazitaxel to demonstrate improved taxane outcomes in genotyped patients. This is an NIH TT (Technology Transfer) contract topic from the NCI. This is a program whereby inventions from the NCI Intramural Research Program (Center for Cancer Research, CCR) are licensed to qualified small businesses with the intent that those businesses develop these inventions into commercial products that benefit the public. The contractor funded under this contract topic shall work closely with the NCI CCR inventor of this technology. The inventor will provide assistance in a collaborative manner with reagents and discussions during the entire award period. Between the time this contract topic is published and the time an offeror submits a contract proposal for this topic, no contact will be allowed between the offeror and the NCI CCR inventor. However, a pre-submission public briefing and/or webinar will be given by NCI staff to explain in greater detail the technical and licensing aspects of this program (for further information, see http://sbir.cancer.gov/news/upcoming/). In addition, a list of relevant technical, invention, and licensing-related questions and answers (including those from the public briefing) will be posted, maintained, and updated online (http://sbir.cancer.gov/news/upcoming/) during this time period. The awarded contractor will automatically be granted a royalty-free, non-exclusive license to use NIH-owned and patented background inventions only within the scope and term of the award. However, an SBIR offeror or SBIR contractor can apply for an exclusive or non-exclusive commercialization license to make, use, and sell products or services incorporating the NIH background invention. Offerors submitting an SBIR contract proposal in response to this topic are strongly encouraged to submit concurrently an application for a commercialization license to such background inventions. Under the NIH NCI TT program, the SBIR contract award process will be conducted in parallel with, but distinct from, the review of any applications for a commercialization license. To apply for a commercialization license to develop this NIH invention, an SBIR offeror or SBIR contractor must submit a license application to the NIH Licensing and Patenting Manager: Sabarni Chatterjee, Ph.D., chatterjeesa@mail.nih.gov or 301-435-5587. A license application and model license agreements are available at http://www.ott.nih.gov/pdfs/LicApp.pdf and http://www.ott.nih.gov/forms_model_agreements/forms_model_agreements.asp.... This license application provides NIH with information about the potential licensee, some of the terms desired, and the potential licensee's plans for development and/or commercialization of the invention. License applications will be treated in accordance with Federal patent licensing regulations as provided in 37 CFR Part 404. A further description of the NIH licensing process is available at http://www.ott.nih.gov/licensing_royalties/intra_techlic.aspx. NIH will notify an SBIR offeror who has submitted an application for an exclusive commercialization license if another application for an exclusive license to the background invention is received at any time before such a license is granted. Any invention developed by the contractor during the course of the NIH TT contract period of performance will be owned by the contractor subject to the terms of Section 8.5. Phase I Activities and Expected Deliverables • Develop a simple array-based genotyping technique for CYP1B1*3 in which a genotype call is conferred to the patient within two days following the receipt of a blood sample • Extend the proof-of-concept that CYP1B1*3 interferes with docetaxel activity via formation of estrogen quinones using cellular assays and/or tumor-bearing mice • Validate that the genotype is related to survival in retrospective samples obtained from patients with CRPC undergoing therapy with docetaxel (The NCI intramural laboratory can aid in getting samples) • Identify the percentage of patient samples with the CYP1B1*3 variant • Determine if cabazitaxel is subject to the same interaction with E2-3,4Q (The NCI intramural laboratory has synthesized frozen E2-3,4Q and can provide some of the quinone estrogen species; it is unlikely that the NCI laboratory could provide any retrospective samples) • Deliver data to the NCI Phase II Activities and Expected Deliverables • Conduct a genotype-directed prospective clinical trial with docetaxel and/or cabazitaxel to demonstrate improved taxane outcomes in genotyped patients (The NCI may provide samples from retrospective studies and assist with getting more samples) • Identify the percentage of patients with the CYP1B1*3 variant • Translate the test to the commercial clinical setting in a manner sufficient to pass CLIA certification • Develop a commercially-viable prototype
Keywords: NCI
319: Technology to Generate Anti-Peptide Capture Reagents for Affinity-Enriched Proteomic Studies
Description: Summary Anti-peptide capture reagents can be used to identify and quantify proteins containing a target peptide sequence with a number of applications in biological research and bioassay development. For instance, they are used routinely in techniques such as immunoprecipitation, Western blot, and immunohistological identification and protein localization. A recently-developed application of such reagents is Stable Isotope Standards and Capture by Anti-Peptide Antibodies (SISCAPA), which utilizes antibodies to enrich peptides from complex matrices for quantitation of proteins by stable isotope dilution mass spectrometry. SISCAPA has the potential for simultaneous quantification of multiple targets from a given sample. There is growing interest in the development of such multiplex protein assays, including large-scale biomarker candidate verification studies and analyses of targeted biological pathways. Concurrent quantification of multiple protein analytes is highly desirable in these applications to minimize sample requirements, handling, and assay costs per analyte, while maximizing throughput. Project Goals The goal of this project is to develop new technologies that generate reproducible, well-characterized anti-peptide capture reagents for use in affinity-enriched proteomic studies for the cancer research community. An important characteristic of the desired reagents is the ability to immunoprecipitate their target peptide with high affinity. These reagents should be comparable or superior to ELISA-based antibody technologies in terms of specificity, affinity, and sensitivity and be reproducibly generated in a cost-effective and efficient (e.g. renewable) manner. Currently, mice are often used to generate monoclonal antibodies or alternative capture reagents, but peptides do not always elicit a potent immune response, which can result in low yield of antibodies to effectively immunoprecipitate the target peptides. The desired technology will likely be one that produces a strong immune response to peptide antigens, and may include the use of species other than mice for the generation of antibodies, since other species may have more diverse epitope recognition and improved immune response to small-size epitopes. The development of these affinity capture reagents will be done in coordination with NCI's Clinical Proteomic Technologies for Cancer (CPTC) (http://proteomics.cancer.gov). A list of proteins or proteotypic peptides derived from cancer biomarker candidates may be requested from CPTC. Furthermore, these capture reagents must be made available as a resource to the scientific community. The suggested choices of performance platforms that the affinity reagents must be compared to include mass spectrometry-based quantitative assays, immunoprecipitation, ELISA-based assays, Western blot, and immunohistochemistry. In addition, other considerations should include sensitivity/specificity/affinity information for the reagents, and method comparison with gold standard practices, precision, and LOD/LOQ. Phase I Activities and Expected Deliverables • Develop proof-of-concept strategies and/or technologies that reliably generate anti-peptide capture reagents that can immunoprecipitate the target peptides; this includes, but is not limited to, strategies/technologies that can produce stronger immune responses to peptide antigens than current technologies • Demonstrate that the capture reagents developed through this technology can repeatedly and reproducibly immunoprecipitate the target peptides • Work with the Clinical Proteomic Technologies for Cancer (CPTC) community (http://proteomics.cancer.gov), private and public sector to identify appropriate minimum characterization criteria for validation of the assays • In coordination with CPTC program staff, select and generate affinity reagents to at least ten proteotypic peptides and demonstrate high affinity (Kd of10-9 M or better), specificity and immunoprecipitation performance • If requested, be prepared to make available to NCI sufficient reagents to perform 10 test runs for each of the ten peptides for independent evaluation • Present findings to an NCI CPTC Evaluation Panel and demonstrate any additional characteristics (e.g. capture of corresponding full-length protein) and how the capture reagents have improved cost effectiveness and throughput capabilities in production and method feasibility of screening of large numbers of hybridomas while conserving time and resources • Propose quantitative feasibility milestones Phase II Activities and Expected Deliverables • Implement the new fully functional anti-peptide capture reagent development strategies/technologies and project plan for development of at least 100 anti-peptide capture reagents capable of immunoprecipitation in coordination with CPTC program staff o Reagents should be able to capture the target peptides of interest from complex biological mixtures such as blood, plasma, or tissue • Demonstrate whether the antibodies can immunoprecipitate full-length proteins • Test performance criteria against affinity, specificity, immunoprecipitation and affinity-enriched SRM-MS (Selected Reaction Monitoring-Mass Spectrometry) platforms or clinical-grade ELISA tests if available • Work with CPTC to integrate capture reagents into proteomic research platforms
Keywords: NCI
320: High Quality Cancer-Related Standards for Metabolomics Research
Description: Summary The metabolome is a measure of the output of biological pathways and, as such, is often considered more representative of the functional state of a cell than other ‘omics measures such as genomics or proteomics. In addition, metabolites are conserved across various animal species, facilitating the extrapolation of research findings in laboratory animals to humans. Despite early promise, challenges remain before the full potential of metabolomics can be realized – including the limited availability of high quality metabolite standards and of companies/core facilities that provide metabolomics services. The NIH Common Fund is currently developing a multi-component program to help increase metabolomics research capacity. SBIR contracts that focus on identifying and synthesizing reliable metabolite standards will complement this effort by attracting current and emerging small businesses to develop these much needed tools – which in turn will contribute towards achieving an important NIH Common Fund goal of increasing the repertoire of high quality and authentic standards for identification, characterization and quantization of metabolites. Entities that wish to compete for such contracts must be cognizant of the current cost and intellectual property rights challenges that have restricted the use of said tools in basic, pre-clinical, and translational research alike and consequently make reasonable efforts to make said standards and corresponding product sheets widely accessible to the metabolomics community at large. Project Goals The short and long-term project goals involve the development of both isotopically labeled (i.e., 15N, 13C or 2H) and unlabeled metabolite standards for use with mass spectrometry (MS) and/or nuclear magnetic resonance spectroscopy (NMR), respectively. Compounds need to be synthesized in GLP labs with ISO 9000 certification, and purified by either chromatographic methods or crystallization to >95% purity. Classes of metabolites that require standards for metabolite identification include, but are not limited to: 1. Glycolytic and other energy intermediates 2. Amino acid metabolism 3. Lipids (phospholipids, glycerolipids, sphingolipids, glycolipids, oxylipins) 4. Acylcarnitines and acylglycines 5. Secondary drug metabolites 6. Secondary food metabolites 7. Fatty acids Offerors should focus their proposals on developing at least one set of metabolite standards, where all compounds in the set are linked to one cancer-related metabolic pathway Phase I Activities and Expected Deliverables • Synthesize, as appropriate for any given metabolic pathway, a range of 10-1000 labeled or unlabeled compounds under GLP conditions on a pilot scale sufficient to run at least 10 MS or NMR analyses • Verify structures of the synthesized compounds • Purify compounds using either chromatographic methods or crystallization to >95% purity • Investigate formulation issues and whether the compounds in the metabolite standards set can stably be packaged together versus separately • Run pilot MS or NMR validation tests of the metabolite standards set to evaluate its performance Phase II Activities and Expected Deliverables • Scale up of synthesis, purification, and formulation/packaging/chemical stability of Phase I deliverables to allow for more extensive product validation. • Validate the metabolite standards set for reproducible performance in MS or NMR as appropriate. • Provide letters of interest from potential customers, and later letters of commitment from customers to purchase the product developed under this contract.
Keywords: NCI
321: Chemically Defined Glycan Libraries for Reference Standards and Glycomics Research (Joint NCI-NIGMS Program)
Description: Summary Glycans play important roles in cell recognition, motility, signaling processes, cell differentiation, cell adhesion, microbial pathogenesis, and immune recognition. Carbohydrate-based high throughput assays (e.g. glycan microarrays, nanoparticles) hold great promise for the rapid analysis of carbohydrate binding proteins (CBPs), elucidation of CBP biology, and the development of diagnostics, vaccines, and therapeutics for a number of diseases, including cancer. However, the utility of these high throughput assays is limited by the paucity of robust biologically relevant glycan libraries available for screening. Glycan standards are also needed to perform structural analysis, especially for monitoring changes in glycosylation that can significantly affect protein function and the safety and efficacy of bio-therapeutics. NCI participates in trans-NIH initiatives to further glycomics research as part of the Alliance of Glycobiologists for Detection of Cancer, which partners with NCI’s Early Detection Research Network, as well as the Glycomics and Glycotechnology Biomedical Technology Research Centers and the Consortium for Functional Glycomics which are funded by NIGMS. Small businesses that develop new glycan libraries for defining the specificities of CBPs, probing the immune response, screening for cancer-associated glycan biomarkers, and enabling glycan structural analysis will more rapidly advance the field of glycomics. Contract offerors must be cognizant of the current cost and intellectual property rights challenges that have restricted the use of chemical libraries in basic, preclinical, and translational research, and be willing to abide by NIH policies pertaining to the sharing and dissemination of unique research resources developed with NIH funding. Abiding by the NIH Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources will ensure that libraries and data generated from them will be deposited into existing repositories and databases that will serve as resources for the entire glycobiology community for non-commercial research purposes. Project Goals The goals of this program are to support the synthesis and commercial distribution of robust, well-characterized new carbohydrate libraries that are amenable to being functionalized/linkered for use in high throughput assays, are useful as standards in mass spectrometry (MS) and nuclear magnetic resonance (NMR) applications, and can be used to expand existing screening platforms, structural assays, and additional tool development. These libraries would need to be made with appropriate quality control documentation, and at reasonable cost. The Expanding the Chemical Space for Carbohydrates: Roadmap to Automated Synthesis workshop report, presented to the NIGMS National Advisory Council in 2011, highlights the critical need for comprehensive chemically-defined glycan libraries for: development of screening platforms with sufficient numbers of structures and diversity to cover the major sectors of mammalian glycomes, use as analytical standards, use as substrates for enzymology, and use as building blocks to increase the glycan chemical space with newly identified enzymes. For analytical standards, biologically relevant groups of related structures with emphasis on isomers will be most useful. Compound collections that provide a basis for development of MS or NMR-based experimental conditions for differentiation of closely related structures are highly desirable. Based on current literature, a 10k-12k glycan collection is needed to represent the functional human glycome, and populate a comprehensive glycan array in a manner that would significantly move the field of glycomics forward. Presently, estimates suggest that only 1000 or so glycans have been synthesized for research purposes, and of these, only a few hundred are commercially available. A number of NIH institutes (NIGMS, NCI, NIAID, NHLBI) support specific efforts in glycomics and several others (NIDDK, NIDCR, NICHD, NIAMS) also have interests in glycobiology. Discovery labs in The Alliance of Glycobiologists for Detection of Cancer (http://glycomics.cancer.gov), supported by NCI have a current need for libraries of glycans to facilitate structural studies and high-throughput analysis of carbohydrates derived from biological sources. SBIR contracts focused on synthesis of chemically defined glycan libraries that represent important subsets of the human glycome including representative N- and O- linked glycan libraries, glycan structures found on glycosphingolipids, and libraries of glycosaminoglycan oligomers, would speed progress towards a comprehensive mammalian glycan library. Ready access to these reagents is expected to speed progress in the emerging field of glycomics. Compounds must be synthesized and purified utilizing best practices to >98% purity as established by NMR. It is recommended that offerors focus their proposals on developing at least one robust glycan library of significant complexity. Libraries of free, reducing-end glycans required include, but are not limited to: Hybrid-type and complex N-glycan core structures with various multiples of antennae • Hybrid-type N-glycans with all combinations of mannose cores • Complex-type N-glycans with basic structures of bi-, tri- tetra-antennary, and bisected versions of those, terminating in either sialic acid, galactose, or N-acetylglucosamine. Further elaboration of antennae might include lactosamine extensions, fucosylation, or sulfation. Variability of these features in the antennae is also required to distinguish topological isomers. • High mannose-type glycans and isomers. O-glycans • O-glycan Cores 1 and 2, as well as O-glycans bearing fucosylated and sialylated lactosamines of various lengths and degrees of internal fucosylation. Human Blood Group Antigens • ABO blood group (N-Acetylgalactosamine, galactose) antigens (ABO(H) and their variations - A1, A2, H-type 1, H-type 2, H-type 3, H-type 4, etc.). • Lewis blood group (human fucose-containing) antigens (sLex, Lex , Lea, sLea, repeating Lex, etc., on glycolipid, N- and O-glycan backbones, etc.). Glycosphingolipid head groups • Ganglioside-, globoside-, lactosamine-, and neo-lactosamine-based core structures Phosphorylated mannose glycans • P-Man-R and GlcNAc-P-Man-R Glycosaminoglycans (GAGs) • Glycosaminoglycan fragments (especially heparan sulfate oligosaccharides) of 4 to 8 saccharides with/without defined sulfation. Glycopeptides • O-linked core structures on building blocks (such as Fmoc, Ser, or Thr) that can be utilized in peptide synthesis. Phase I Activities and Expected Deliverables • Synthesize a defined library of free reducing-end glycans (20-50 compounds) representative of a sector(s) of the mammalian glycome that is not presently commercially available, under GLP conditions on a pilot scale (~ 200 μg/compound) • Purify these compounds using best practices to >98% purity • Verify structures of the synthesized compounds by NMR • Investigate any packaging issues for the compounds • Provide samples (~50 μg) of all synthesized compounds to an NIGMS-designated screening center for printing on glycan arrays, appropriate validation testing, and subsequent use in NIGMS-funded screening assays • Provide the spectra used to confirm each glycan’s structure as part of product information • Expand the reducing glycan libraries representative of a sector(s) of the mammalian glycome and not presently commercially available to at least 100 compounds • Verify structures of the synthesized compounds by NMR • Scale up the synthesis, purification, structural verification, and packaging of all compounds in the libraries • Provide the spectra used to confirm each glycan’s structure as part of product information • In collaboration with an NIGMS-designated screening center: provide ~ 50 μg of each of the newly synthesized compounds made to expand the libraries for printing on glycan arrays, appropriate validation testing, and subsequent use in NIGMS-funded screening assays • Provide letters of interest from potential customers to purchase the product developed under this contract
Keywords: NCI NIGMS
322: Real-Time Integration of Sensor and Self-Report Data for Clinical and Research Applications
Description: Summary Wireless sensors, and mobile devices and applications are increasingly marketed for health monitoring or interventions in consumer and clinical settings for prevention or management of chronic disease. A rapidly expanding market segment of technologies are focused on objective measures of health related behaviors (e.g., physical activity, sleep, diet, medication adherence, etc.). These mobile health technologies offer the capability to collect tremendous volumes of high quality health data, with continuous monitoring or event recording functions, in near real time. The expanding use of behavioral monitoring technologies, applications and mobile messaging provides new opportunities within consumer health, clinical care, and research. However, meaningful interpretation of the high volume of data generated from monitoring technologies is a challenge for the patient, care team and the researcher. Further, health monitoring technologies are often criticized for lacking additional contextual data to facilitate their interpretation. Added to data from sensors and monitoring technology, self-reported measures can provide invaluable psychosocial, contextual, and environmental health-related information. Patient-reported outcomes in physical, mental or social health domains include physical abilities, fatigue, pain, depression, and social interactions. The expanded use of smartphone technologies lends itself to private, convenient, real-time data collection of self-reported measures. However, development or optimization of cross-platform mobile applications and scalable, efficient, cloud-based server platforms for rapid and real-time self-reporting and monitoring of these measures is needed. Real-time integration of objective and patient-reported data could improve understanding and clinical management of acute and time-varying symptoms such as fatigue, pain, or depression experienced by cancer and other chronic disease patients. The integrated collection of objective and self-reported data can stimulate innovation within clinical and research settings, including clinical trials, clinical care, case-management, interventions, surveillance, and epidemiologic studies. For example, temporal integration of medication monitoring technologies, such as smart pill cases and sensor-based activity and sleep data, with patient-reported measures of depression, fatigue, or pain could enhance pharmaceutical clinical trial results. However, efficient systems and platforms for the capture, storage, integration, visualization, and reporting of these data streams are extremely limited or non-existent. Project Goals This topic’s short-term goal is the development of innovative, secure, privacy-compliant mobile applications and paired analytic systems to control the collection, transfer, integration, analysis and reporting of objective and self-reported health-related measures. Longer term goals include the integration of these data systems and layers in health care and research settings to support customized monitoring and feedback loops, alerts, or alarms for consumers, patients, or members of the health care team. Responses to this topic are expected to address the development of efficient methods and platforms to: 1. Collect data from behavioral health monitoring technologies and self-reported behavioral, psychosocial, environmental, and contextual measures. 2. Demonstrate integration with various wireless sensors. 3. Appropriately secure data at each stage of collection, transfer, and storage. 4. Temporally integrate information from multiple data sources. 5. Visualize data using customizable tools. 6. Analyze and report on (patient identified or de-identified) individual or group level data using customizable tools and reporting systems. 7. Maintain compliance with HIPAA, privacy, and consent management protocols as required for platform specific applications. The resulting platform’s utility extends from consumer health to clinical care and research settings for behavioral monitoring and prevention or management of disease. This topic encourages development of innovative, secure, privacy compliant mobile applications and 2-way mobile messaging techniques to facilitate and control the collection and transport of temporal data inputs from behavioral health monitoring technologies, self-reported measures, and associated metadata. The data acquisition systems described above must be paired with efficient, scalable back-end systems for data importation, storage, integration, visualization, analyses, and output reporting. Data elements may include (but are not limited to) wireless physical activity or sleep sensors/monitors, physiologic sensors, adherence monitors, sensor-based measures of stress or fatigue, dietary intake measures, geospatial location tags or linkages, images, text based annotations, speech recording and recognition; and self-reports of behavioral, psychosocial, environmental, and contextual data. An essential task for each proposal is the development of transparent and customizable analytic tools for temporal data integration, visualization, and summary reporting of individual or group level measures. Recommended short term targets for system outputs are to provide reports to patients/participants, clinicians/researchers, and health systems; with longer term targets to provide reports directly to electronic medical records and public health surveillance systems. Recommended reports are consistent with current health outcomes policy priorities and objectives in the Meaningful Use Matrix for electronic health records established by the Health Information Technology Policy Committee (see http://healthit.hhs.gov/portal/server.pt). Phase I Activities and Expected Deliverables • Establish a project team including proven expertise in: sensor technology for behavioral and physiological monitoring, wireless sensor integration with mobile devices (smartphones, tablets, etc.), self-reported and/or sensor-based psychosocial, environmental, and contextual measures, secure wireless transport of health data using standards based protocols, secure cloud-based computing models, data visualization, and systems architecture that will effectively address all objectives of the current topic • Provide a report including detailed description and/or technical documentation of the proposed: o Database structure for the proposed system’s self-reported and sensor-based data inputs and metadata requirements o Data standards for collection, transport, importation, and storage of self-reported and sensor-based data inputs o Data types for exchange of health-related behaviors such as physical activity, sleep, diet, and medication adherence between mobile platforms and secure servers o Data integration approaches to leverage multiple data input streams o Data visualization, feedback, and reporting systems for population or clinical monitoring and research applications o Expected sensor(s), mobile platform(s) and mobile device(s) compatibility matrix for front- end mobile application and back-end server systems to be developed • Develop a functional prototype system that includes: o Front-end mobile application(s) to facilitate and control the collection and transport of self-reported and sensor-based data inputs and any associated metadata used within the system o Integration with several wireless sensors including wireless physical activity monitors and other physiologic, geospatial, indoor location, proximity, environmental, or compliance related sensors o Automated data screening and importation protocols for data transferred from the mobile application to the back-end server systems o Software systems user interface (web- or computer-based) o Back-end user-interface controls for custom data integration and visualization for individual or group-level data • Provide a report detailing output reporting systems feasibility, proposed timelines, data standards, and communication architecture for reporting summary outputs to patients/subjects, clinicians/researchers, electronic medical records, and health surveillance systems • Finalize database formats and structure, data collection, transport, and importation methods for targeted data inputs • Include funds in budget to present Phase I findings and demonstrate the final prototype to an NCI evaluation panel Phase II Activities and Expected Deliverables • Beta-test and finalize front-end mobile applications developed in Phase I • Beta-test and finalize automated file transfer, screening, and database importation protocols and systems • Develop, beta-test, and finalize data integration and visualization tools developed in Phase I • Develop, beta-test, and finalize care team/researcher user-interface systems • Develop and beta-test output reporting systems capabilities for multiple system output targets listed above • Demonstrate system compatibility with sensor(s), mobile platform(s), and mobile device(s), included in the Phase I compatibility matrix • Perform regression testing for both front-end and back-end system functions • Conduct usability testing of consumer/patient-facing mobile applications and any associated web portals and care team/researcher-facing user interface features including system management, analyses, and reporting applications • Develop systems documentation where applicable • In the first year of the contract, provide the program and contract officers with a letter(s) of commercial interest • In the second year of the contract, provide the program and contract officers with a letter(s) of commercial commitment
Keywords: NCI
323: Development of Radiation Modulators for Use During Radiotherapy
Description: Summary Radiotherapy is employed in the treatment of over half of all cancer patients. Many of those patients suffer adverse effects during and/or after treatment. Additionally, tumors recur in approximately half the patients treated with curative intent. Enhancing specific tumor killing and minimizing normal tissue damage from radiotherapy would improve tumor control and patient quality of life. An ideal intervention would both enhance radiation effects in tumors and protect the normal tissues. Radiosensitizers are agents that are intended to enhance tumor cell killing while having a minimal effect on normal tissues. Recently, two new radiation sensitization drugs have proven clinically effective: Temozolomide treatment with radiotherapy for glioblastoma and Cetuximab treatment combined with radiation for head and neck squamous cell cancers. There is significant potential for further development of novel radiosensitizing agents. Conventionally, radioprotectors are defined as agents given before radiation exposure to prevent or reduce damage to normal tissues, while mitigators refer to those agents given during or after a patient’s prescribed course of radiation therapy to prevent or reduce imminent damage to normal tissues. Both radioprotectors and mitigators are also being developed as potential countermeasures against radiological terrorism and several have shown promise in pre-clinical testing. In order for these to be developed and useful in clinical radiation therapy applications, it is imperative to demonstrate that they do not protect cancer cells. The importance of developing agents that sensitize tumor cells, protect or mitigate radiation-induced damage in normal tissue, improve survival, quality of life, and palliative care in cancer patients was emphasized in a recent NCI workshop on Advanced Radiation Therapeutics - Radiation Injury Mitigation held on January 25th 2010 (Movsas B, et al. Decreasing the adverse effects of cancer therapy: National Cancer Institute guidance for the clinical development of radiation injury mitigators. Clin Cancer Res. 2011 Jan 15;17(2):222-8. Epub 2010 Nov 3. PMID: 21047979), and in a workshop on Radiation Resistance in Cancer Therapy: Its Molecular Bases and Role of the Microenvironment on its Expression held Sept 1-3, 2010. Prior workshops have dealt with sensitization, protection, or radiation effects assessment (Colevas AD, et al. Radiation Modifier Working Group of the National Cancer Institute. Development of investigational radiation modifiers. J Natl Cancer Inst. 2003 May 7;95(9):646-51. Review. PMID:12734315; Stone HB, et al. Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003. Radiat Res. 2004 Dec;162(6):711-28. PMID: 1554812.) This contract topic encourages the development of innovative and promising radioprotectors, mitigators, or sensitizers that either selectively protect normal tissues (but not tumors) against ionizing radiation or selectively sensitize tumors, thereby increasing the therapeutic ratio of radiation. Proposals for radiation modulators are solicited that include preclinical and/or early phase clinical studies demonstrating safety, efficacy, dose, schedule, pharmacokinetics (PK), pharmacodynamics (PD), and metabolism. Proposals should also demonstrate a clear understanding of regulatory requirements, and should include a regulatory plan including key steps such as a pre-IND meeting with FDA, submission of an investigational new drug (IND) application, approval of clinical trial design, and ultimately drug registration. Project Goals The goal is to stimulate collaborations among academic institutions, small businesses, and contract research organizations in order to promote the rapid development of innovative radioresponse modifiers that will decrease normal tissue injury and/or enhance tumor killing, thereby improving radiotherapy outcomes. The long-term goal is to enable small businesses to fully develop, license, and/or market radioresponse modifiers for clinical use. The contract proposal must describe: Phase I • A quantitative estimate of the patient population that will benefit from the availability of such radioresponse modifiers. • A plan for generating evidence that the proposed compound(s) protects at least one relevant normal tissue from radiation-induced injury, and/or sensitizes at least two relevant tumor models. • Either: 1. A plan for generating evidence that the proposed radioprotector(s)/mitigator(s) does not significantly protect cancer cells, OR 2. A plan for generating evidence that the proposed radiosensitizer(s) does not significantly sensitize normal cells and tissues. • The plans must include the methodologies proposed to evaluate the preferential effects on normal tissues or tumors by the compound(s) in vivo (including appropriate biomarkers and endpoints as determined during early interactions with the FDA). • Determination of the optimal dose and schedule in vivo based upon preclinical pharmacodynamic and pharmacokinetic studies. • Statistical validation of the proposed study endpoints including where appropriate, power calculations and rationale for proposed sample sizes. Phase II • The approach to early-phase human trials designed to take into account relevant molecular pathways and targets, and aim to gather pharmacodynamic and pharmacokinetic data to confirm the compound’s observed behavior in animal studies. The approach and experiments to assess the safety and efficacy of the compound(s) in early-phase human trials employing, as appropriate, physician-reported endpoints as well as patient-reported outcomes. Deliverables Phase I may include primarily preclinical studies. Phase II or Fast-Track proposals must contain a section entitled "Regulatory Plan" detailing plans for early involvement of the FDA. There should be a description of how the applicant plans on meeting the requirements to: 1) define suitable biomarkers and endpoints, 2) file IND and 3) design and perform phase 0-2 clinical trials in preparation for product transition to phase 3 clinical trials by groups such as the Radiation Therapy Oncology Group (http://www.rtog.org/). Where cooperation of other partners is critical for implementation of the proposed methodology, the applicant should provide evidence of such cooperation (through partnering arrangement, letters of support, etc.). The following deliverables may be required depending on a compound’s maturity in the developmental pipeline: Phase I • Selection and approval of cell line panels for in vitro testing • Demonstration of drug solubility and uptake using cultured normal and transformed cells • Study design for determining clonogenic survival or approved alternative tailored to the mechanism of each tested compound • Clonogenic survival data or approved alternative validating lack of drug toxicity in normal cells, efficacy and specificity of radioprotection for normal cells and/or efficacy and specificity of radiosensitization for tumor cells • Preliminary evidence for lack of in vivo toxicity in normal cells or organisms • Documentation providing a top-level description of the protocols and the testing results should be provided to NCI as part of the Phase I progress report Phase II For advanced pre-clinical work: • Design of NCI and Institutional Animal Care and Use Committee (IACUC)-approved in vivo experimentation plan including statistical validation of experimental design, and sample size determination including power calculations • Selection and approval of tumor cell panel and normal tissues for in vitro testing • Demonstration of bioavailability PK and PD in rodent model • For radiation protectors/mitigators: demonstration by physiologic testing and histological assessment that irradiated normal tissues are spared over a 6-month period • Demonstration of effects (sensitization or lack of protection as appropriate) on tumors using in vivo radiation regrowth delay assays • Collection of data validating lack of drug toxicity, efficacy, and specificity for normal cells over tumor cells in the case of radiation protectors/mitigators • Documentation of the testing protocol and testing results should be provided to NCI as part of the Phase II progress report for pre-clinical studies For proposals advancing to early-phase human trials: • Identify GMP drug source • Obtain IND approval • Provide evidence of established clinical collaboration • Submit protocol for IRB approval • Define suitable clinical endpoints and patient-oriented outcomes
Keywords: NCI
324: Novel Imaging Agents to Expand the Clinical Toolkit for Cancer Diagnosis, Staging, and Treatment
Description: Summary Medical imaging plays a key role in the clinical management of cancer patients. Cancer imaging agents are used in conjunction with medical imaging equipment, and, by highlighting the contrast between normal and malignant tissues, they allow the collection of information on cancer presence, spread, and metabolism. Recent scientific advances in nanotechnology, radiochemistry, reporter gene imaging, cancer stem cell imaging, and other fields enable the development of novel imaging agents for: • Early detection and diagnosis of cancer. • Differentiation of benign disease from malignancy. • Stratification of patients for the purpose of selecting a cancer therapy. • Surgical planning. • Evaluation of tumor response to chemotherapy and radiation therapy. • Detection of cancer recurrence. Despite significant preclinical scientific progress, very few cancer imaging agents are available in the clinic. This SBIR contract topic seeks to stimulate the commercialization of novel imaging agents, including but not limited to: nanotechnology-based imaging agents, radiopharmaceuticals for positron emission tomography (PET) and single photon emission computed tomography (SPECT), targeted contrast agents for X-ray, computed tomography (CT), and magnetic resonance imaging (MRI), optical contrast agents, and reporter gene imaging technologies. One specific area of interest under this topic is the development of single-domain antibody fragments used to target radionuclides for imaging and targeted radiotherapy of cancer. Single-domain antibody fragments are comprised of the single variable region of naturally-occurring antibodies that lack a light chain or engineered antibody fragments. This type of small protein or peptide has advantages over conventional antibodies and antibody fragments in terms of favorable and tunable clearance kinetics, ability to recognize hidden or uncommon epitopes, agent format flexibility, and ease of manufacture. Therefore, developing an imaging technology for early diagnosis of cancer at the molecular level based on single domain antibody fragments will be encouraged. Project Goals The short-term goal of this SBIR contract topic is to support research and development activity at small businesses that are developing cancer imaging agents. The imaging agent should be novel and, when appropriate, have high affinity and specificity against tumor targets. It should also display fast in vivo clearance, rapid tumor accumulation, sufficient in vivo stability and good biovailability, and low immunogenicity and toxicity. The work scope may include animal testing, formulation, GMP production, pharmacokinetic studies, pharmacodynamic studies, and toxicological studies. These data will support the rationale for continued development of the experimental medical imaging agent to the point of filing an Investigational New Drug application (IND). The long-term goal of this contract topic is to enable small businesses to bring novel classes of fully developed cancer imaging agents to the clinic and the market. Therefore, businesses are encouraged to submit applications for development of lead compounds representing novel technology platforms. Phase I Activities and Expected Deliverables Phase I activities should generate scientific data confirming the clinical potential of the proposed contrast agent. The Phase I research plan must contain specific, quantifiable, and testable feasibility milestones. Expected activities may include: • Prepare an imaging agent that produces a high signal-to-noise ratio • Demonstrate capabilities enabled by the imaging agent • Quantify imaging signals to determine agent affinity and specificity • Perform proof of concept pre-clinical studies • Perform preliminary toxicological studies • Prepare a development plan that describes in detail the experiments necessary to file an IND or an exploratory IND • Present Phase I results and development plan to NCI staff Phase II Activities and Expected Deliverables Phase II should follow the development plan laid out in the Phase I, and should further support commercialization of proposed cancer imaging agents. The Phase II research plan must contain specific, quantifiable, and testable feasibility milestones. Expected activities may include: • Complete all pre-clinical experiments according to the development plan • Demonstrate fast in vivo clearance, rapid tumor accumulation, sufficient in vivo stability, good bioavailability, and low immunogenicity/toxicity of the imaging agent • Demonstrate high reproducibility and accuracy of the imaging technology in several animal models • When appropriate, demonstrate similar or higher specificity and sensitivity of the technology compared to other imaging technologies • When appropriate, demonstrate capabilities to monitor efficacy of drugs in tumor cell lines and/or animals • Produce sufficient amount of clinical grade material suitable for an early clinical trial • If warranted, file an IND or an exploratory IND for the candidate imaging agent • Complete small-scale clinical study
Keywords: NCI
325: Innovative Radiation Sources for Advanced Radiotherapy Equipment
Description: Summary Radiation therapy is an important tool in the cancer treatment arsenal. Conventional radiotherapy with photons is currently used to treat 50% of all cancer patients. The success of radiation therapy and the risk of side effects depend heavily on the ability to concentrate radiation in the tumor while not injuring adjacent normal tissues. Recent developments in radiation therapy instrumentation have increased the ability to direct radiation energy, thereby improving the clinical utility of this treatment. Although significant progress has been made, one of the limiting factors in the development of novel radiotherapy approaches is the size and cost of radiation sources. For many types of modern advanced radiotherapy, the equipment needed to produce such radiation is bulky and extremely expensive. At the same time, continuing advances in particle acceleration approaches enable breakthrough innovations in this field. An example of such advancement is the development of technologies for charged particle acceleration using high-power lasers (laser-plasma acceleration). New technologies enable the construction of compact, cost-efficient external beam accelerators, and facilitate new applications of radiotherapy. Another potential class of applications is the development of fiber-optics-based systems for endoscopic delivery of gamma or electron beams. These and other technologies present key opportunities in enabling next-generation radiation therapy instruments. Project Goals This contract topic seeks to stimulate research, development, and commercialization of innovative radiation sources that could be used to reduce the cost and footprint of radiation treatment systems, and thus enable novel routes for radiotherapy delivery. It is expected that the proposed innovation be driven by clinical practice. Therefore, in addition to standard proposal components, the contract proposal must contain specific discussion of: 1. Evidence of an existing clinical problem that is addressed by the proposed radiation source 2. Analysis of competitive methods to address the same problem and explanation of competitive advantages of proposed system. The short-term goal of the project is to perform proof-of-principle technical feasibility demonstration of innovative radiation source or source components. The long-term goal of the project is to develop a robust, reliable radiation source and to incorporate it into a radiotherapy system. Phase I Activities and Expected Deliverables Phase I activities should support the technical feasibility of the innovative approach. • Design and build proof-of-principle prototype system • Characterize beam parameters, including energy spectra, spatial distribution, and flux • Demonstrate that the prototype has a high probability of development into a clinically-relevant radiation source in Phase II, based on measured beam parameters • Provide documentation of the prototype system design, characterization protocol, and testing results to NCI as part of the Phase I progress report Phase II Activities and Expected Deliverables Phase II activities should support development of a full-scale prototype of a radiation source with beam parameters appropriate for the clinical application. • Design and develop a prototype radiation source with parameters (e.g., beam energy, flux, stability, etc.) that are acceptable for clinical radiation oncology application • Demonstrate that the system is capable of delivering a treatment dose in a clinically acceptable period of time in an anthropomorphic phantom • Provide a data sheet detailing performance of the developed system to NCI as part of the Phase II progress report Where cooperation with other equipment manufacturers is critical for implementation of proposed technology, company should provide evidence of such cooperation (through partnering arrangement, collaboration, or letters of intent) as part of the Phase II proposal.
Keywords: NCI