| ID | Title | Body | Facebook Description | Facebook image | Facebook Title | Facebook Video | Twitter Description | Twitter Image | Twitter Title | Meta tags |
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| 322 | Clinical Research Efficiency | In the clinical stage of the translational process, medications, devices, diagnostic products and other treatment regimens developed in the preclinical stage are tested for safety and effectiveness in humans, disseminated to broader patient populations, and studied for their capacity to improve public health. Like those before it, this stage is fraught with scientific uncertainties and operational inefficiencies that limit our ability to test new treatments in humans and deliver interventions to patients more quickly. NCATS is directly addressing clinical translation problems in a system-wide manner by developing, demonstrating and disseminating more efficient collaborative approaches to the clinical enterprise. The aim is to improve procedures in areas such as clinical training, institutional review board operations and patient recruitment methods for multisite studies, and evaluation and accountability of investigators. Streamlining these processes can accelerate the transformation of laboratory discoveries into new treatments for patients. NCATS’ Clinical and Translational Science Awards Program and Rare Diseases Clinical Research Network aim to improve clinical research efficiency. Learn more about other translational issues NCATS aims to address: Predictive efficacy and toxicology De-risking therapeutic development Collaboration and partnerships Data transparency and release | ||||||||
| 321 | Submission of Prior Approval Requests | NCATS grantees are required to adhere to the NIH Grants Policy Statement, unless the Notice of Award states otherwise. Detailed guidance on the submission requirements for the most common NIH prior approval requests is provided below. All prior approval requests must be submitted in writing (including submission by email) to NCATSPriorApprovalRequest@mail.nih.gov with a copy to the named Grants Management Specialist (GMS) and Program Officer (PO) no later than 30 days before the proposed change and signed by the Authorized Organizational Representative. NCATS recommends that grantees follow NIH guidance for the electronic submission of requests for administrative supplements and change of grantee organization: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) (PA-20-272) Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-21-268) Successor-in-Interest (Type 6 Parent Clinical Trial Optional) (PA-20-275) Change in Key Personnel Prior approval is only required for a change in effort for the Program Director/Principal Investigator (PD/PI) or other senior/key personnel specifically named in the Notice of Award. Extensions An extension is a request for additional time to complete originally approved scope of work beyond the end date of the approved project period. An extension period should not be utilized to expand and/or increase the originally approved scope of work. Unobligated Funds/Carryover Unobligated funds are appropriated funds that are unspent and/or uncommitted by the end of a budget period. Unobligated funds remaining at the end of a budget period may be used as carryover or offset by the federal government. Carryover is the process by which unobligated (unspent) funds remaining at the end of a budget period may be carried forward to a subsequent budget period to cover allowable costs in that budget period. An offset is the use of the unobligated funds to partially or fully fund a future budget period. Foreign Components Prior approval is required for an award recipient to add or change a foreign component under a grant to a domestic or foreign award. Change in Key Personnel Prior approval is only required for a change in effort for the PD/PI or other senior/key personnel specifically named in the Notice of Award. Process for Submitting a Change in Key Personnel NIH prior approval is required for any reduction of effort of 25 percent or more from the level that was approved at the time of the initial competing year award, or a change of 25 percent or more from a previously approved reduction in effort level as reflected in a revised Notice of Award. All requests must be made via email to NCATSPriorApprovalRequest@mail.nih.gov with a copy to the GMS and PO assigned to the grant and signed by the Authorized Organization Representative (AOR) from the grantee institution. Requests should be submitted 30 days prior to the proposed change and must include the following information: Statement indicating the previous approved level of effort and the requested new level of effort reflected in person months Description of the remaining work that needs to be accomplished on the grant and statement that the requested level of effort is sufficient to complete the remaining work Justification for the change Statement indicating whether the change is related to concerns about safety and/or work environment (Refer to NOT-OD-20-124 for details) Start date for the change Budget changes resulting from the proposed change, if any Updated Other Support page, incorporating the requested change in effort, explaining how this change in effort affects the overall level of effort on other grants If a new individual is being added to the grant, a biographical sketch, current other support information, proposed effort level and certification of human subjects training (if applicable) is required for the proposed individual. If the change involves the reduction, addition or removal of a PI, signatures of the current PI/ PIs and the proposed replacement PI, if applicable, are required. If all of the above documentation is provided, the review process should take no more than 30 days from receipt to notification of a decision. Process for Submitting a Change in Multi-PD/PI Multiple PD/PI awards are an opportunity for multidisciplinary efforts and collaboration through a team of scientists under a single grant award. All PD/PIs share equally the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the applicant organization, or as appropriate to a collaborating organization, for the proper conduct of the project or program, including the submission of all required reports. The presence of more than one PD/PI on an application or award diminishes neither the responsibility nor the accountability of any individual PD/PI. NIH prior approval is required for any change in multi-PD/PI including a change from a single PD and/or PI to a multiple PD and/or PI model and vice versa. All requests must be made via email to the GMS and PO assigned to the grant and signed by the AOR from the grantee institution. Requests should be submitted 30 days prior to the proposed change and must include the following information: Statement indicating the previous approved level of effort and the requested new level of effort reflected in person months Description of the remaining work that needs to be accomplished on the grant and statement that the requested level of effort is sufficient to complete the remaining work Justification for the change Start date for the change Budget changes resulting from the proposed change, if any Updated Other Support page, incorporating the requested change in effort, explaining how this change in effort affects the overall level of effort on other grants If a new individual is being added to the grant, a biographical sketch, current other support information, proposed effort level and certification of human subjects training (if applicable) is required for the proposed individual. If the change involves the reduction, addition or removal of a PD and/or PI, signatures of the current PD and/or PIs, and the proposed replacement PD and/or PI, if applicable, are required. A revised multi-PD/PI Leadership Plan, including a conflict resolution plan If all of the above documentation is provided, the review process should take no more than 30 days from receipt to notification of a decision. Extensions An extension is a request for additional time to complete an originally approved scope of work beyond the end date of the approved project period. An extension period should not be utilized to expand or increase the originally approved scope of work. NCATS currently considers First No-Cost Extensions, Subsequent No-Cost Extensions and Cost Extensions. First No-Cost Extension Within 90 days prior to the project period end date, grantees may extend the final budget period of the competitive segment one time for up to 12 months beyond the original expiration date shown in the Notice of Award via eRA Commons, if— No term of award or IMPAC II status specifically prohibits the extension; No additional funds are required to be obligated; and The project’s originally approved scope will not change. If a grantee misses the deadline to submit a first no-cost extension in the Commons, the request should be submitted as a subsequent no-cost extension request, as described below. Subsequent No-Cost Extension Any additional project period extension requires NIH prior approval. A second or third extension must be submitted via email by an AOR to NCATSPriorApprovalRequest@mail.nih.gov,with a copy to the GMS and PO at least 30 days before the end of the project period. The written request must include the following information: Amount of funds remaining (estimated unobligated balance), in U.S. dollars; Detailed budget reflecting the proposed plans to use the remaining funds during the extension; Level of effort for Key Personnel during the extended period (Reminder that for NIH awards, the PD/PI and other key personnel named in the Notice of Award must devote a measurable level of effort. Many NCATS grant programs include effort level requirements in the relevant funding opportunity announcements [FOAs].); Scientific rationale for continuing the project; Scope of work to be completed during the extension; Updated certifications and assurances, including institutional review board (IRB) and institutional animal care and use committee (IACUC) approvals; Detailed explanation of why the project could not be completed within the originally approved end date; and Explanation of how the project will be completed in this final extension or how it will proceed without additional funds. NOTE: The fact that funds remain at the end of the project period is not sufficient justification for a subsequent extension. NCATS rarely approves third extensions and does so only with extraordinary scientific justification and approval from the PD and Director, Division of Extramural Activities. If approved, this would be the FINAL extension for the grant. Cost Extension (CE) A cost extension is a one-time request for an extension of the original final budget period of a project with a minimal amount of funds, for a period of up to 12 months. The purpose of a cost extension is to provide an orderly completion/closeout of critical activities or a temporary continuation of support to prevent loss of research resources or hardship of personnel. Additional funding support is contingent on the availability of NCATS resources and funding. To ensure a CE is the most appropriate path, PD/PIs are strongly encouraged to consult with their POs prior to initiating the CE prior approval process. CE requests must be submitted at least 30 days before the original project period is scheduled to expire. Requests must be submitted electronically in response to the NIH Parent Announcement for Administrative Supplements to Existing NIH Grants and Cooperative Agreements. A CE cannot be submitted if the recipient has not initiated their optional automatic first time No Cost Extension (NCE) via the Commons. The NCE link becomes available 90-days before the project period ends. Prior to submitting a CE request, award recipients must ensure that the most current Federal Financial Report (FFR) has been submitted via the Payment Management System and accepted by NIH, and ensure the NCE has been initiated via the eRA Commons. NOTE: NCATS will return any CE request if the most current FFR has not been submitted and accepted. The CE request must include all the following information: Reason for request Amount of additional funds being requested Amount of time being requested (maximum period of up to 12 months) Amount of funds remaining (most current expenditure report listing direct and indirect costs), in U.S. dollars Detailed justification of why the current unobligated balance cannot be re-budgeted to cover requested costs Scientific rationale for continuing the project; ensure including the following, as applicable: A detailed description of the scope of work to be performed during the extension Orderly closeout plan Project completion plan Potential loss of research resources, including personnel Detailed budget and budget justification associated with proposed plans for parent and subaward sites; including the following: Level of effort to be devoted by each staff member , as well as a detailed description of their role and responsibility during the orderly closeout phase Identify any changes to key personnel Detailed justification for any direct cost greater than $1,000 Facilities and administrative rate for parent and subaward sites Checklist page for parent and subaward sites Updated Other Support for Key Personnel, if applicable Updated certifications and assurances, including IRB and IACUC approvals for completion of ongoing projects that involve human subjects or vertebrate animal subjects (NOTE: No new projects and/or research testing/methodologies may be initiated during the CE period.) Detailed sustainability plan describing how the program will continue without expectation of securing federal grant funds If requesting a CE in the final budget period, ensure that the AOR initiates a No-Cost Extension via the eRA Commons before the project period is scheduled to expire. NOTE: No support or additional time may be requested for new activity and/or expansion of the currently approved scope of work. New and/or expanded activity would include, but is not limited to, new and/or additional scholar/trainee appointments, pilot projects, research methodologies, testing, etc. NCATS will not approve requests if the primary purpose of the proposed extension is to permit the use of unobligated balances of funds or if the recompeting application for the currently funded award was submitted late and resulted in a lapse in grant support beyond a 12-month no-cost extension. NCATS rarely approves subsequent cost extensions and does so ONLY in rare circumstances with extraordinary scientific justification. NCATS will not consider a subsequent cost extension if the primary purpose is to stay afloat until future federal grant support is acquired. Unobligated Funds/Carryover Unobligated funds are appropriated funds that are unspent and/or uncommitted by the end of a budget period. Unobligated funds remaining at the end of a budget period may be used as carryover or offset by the federal government. Carryover is the process by which unobligated (unspent) funds remaining at the end of a budget period may be carried forward to a subsequent budget period to cover allowable costs in that budget period. An offset is the use of the unobligated funds to partially or fully fund a future budget period. Prior Approval Requirements Most grants have automatic carryover authority, meaning grantees do not have to request approval from NIH in order to carry over funds from one budget period to the next. Grantees that do not have automatic carryover authority are required to provide a written prior approval request to gain access to those funds. The following mechanisms typically do not have automatic carryover and require NIH prior approval: Cooperative Agreements (U) Program Centers (P30, P50, P60) Awards to Individuals, including Fellowships (F) Non-Fast-Track, Phase 1 (one-year) SBIR (R43) and (one-year) STTR (R41) Training Grants (T) Clinical Trials (regardless of activity code) Before Submitting a Carryover Request Prior to submitting a carryover request, the grantee is encouraged to discuss it with his or her PO and GMS. In addition, the grantee must ensure that the Federal Financial Report for the last (and all prior) budget period(s) have been submitted AND accepted by the NIH Office of Financial Management. Process for Submitting a Carryover Request Carryover requests must be limited to actual needs for the current budget period, must be expended before the end of the current budget period, must meet an immediate need and must not result in re-occurring costs. All carryover requests must be made in writing (via email) to NCATSPriorApprovalRequest@mail.nih.gov with a copy to the GMS and PO assigned to the grant and signed by the AOR from the grantee institution. Requests must be submitted 30 days prior to the proposed use of the funds and must include the following information: Grant number and PI name Amount of funds to be carried over Explanation for the unobligated balance Plan for expenditure, including a description of activities to be carried out during the carryover period, and how the activities relate to the aims of the project Detailed budget and justification for all items, including detailed budget pages for any subcontract costs Clarification as to why current funding cannot be re-budgeted to cover the expenses. Identification of the requested Facilities and Administrative (F&A) costs, including F&A rate, for the prime grantee and any subcontracts Justification for the request (See below.) When preparing a justification for a carryover request, grantees should answer the following questions: Why were the funds not spent in the past year? What additional work will be performed during the current grant year that is not possible with the budget currently allotted to this year? Thought must be given to how the work will be accelerated; for example, will more staff be hired, effort increased or more assays run? Is the request essential? Are costs reasonable, allowable, necessary and in line with the existing budget? Are there new costs that were previously unforeseen? How will the work be affected if the funds are not carried over? Can the carryover funds be expended prior to the end of the current budget period? NOTE: Carryover requests for scholar and trainee slots will only be considered in rare circumstances; carryover requests for scholar/trainee-related expenses and travel could be considered. If the request is approved, a revised Notice of Award will reflect the additional authorized funds for the current budget period. If carryover is denied, you will receive correspondence from the GMS. If all of the above documentation and justifications are provided, the carryover process should take no more than 30 days from receipt to notification of a decision. Managing Unobligated Balances Appropriations law requires all federal agencies to abide by the Bona Fide Needs Rule. This rule mandates that a fiscal year’s appropriations only be obligated to meet a legitimate or bona fide need arising in the fiscal year for which the appropriation is made. In accordance with the Bona Fide Needs Rule and the NIH Grants Policy Statement Section 8.4.1.5.4, NIH is required to manage any reported unobligated balances as part of our fiduciary responsibility for proper stewardship of federal funds. Unobligated funds are expected to be used before newly awarded funds. Accordingly, the Grants Management Officer (GMO) will compare the total of any unobligated balance shown and the funds awarded for the current budget period with the NIH share of the approved budget for the current budget period. If the funds available exceed the NIH share of the approved budget for the current budget period, the GMO may offset the current award or a subsequent award by an amount representing some or all of the excess. NCATS is governed by the following guiding principles: Balances greater than 100 percent of the Total Costs to be awarded will be used as an offset for current fiscal year grant activities. Balances reported on grants in their final year of the project period also may be used as an offset for the current fiscal year grant activities. However, in general, a balance of up to 25 percent of the Total Costs (TC) of the last award is considered reasonable to maintain for unexpected needs, closeout and/or necessary acceleration due to recycling. In cases in which it is known that a new competing segment will be funded, NCATS may leave less than 25 percent of the TC of the last award, as it is anticipated the new award will provide necessary costs for the activity. Balances reported on all other grants may be used as necessary for overarching program needs and management. Again, a balance of up to 25 percent of the TC of the last award is considered reasonable to maintain for unexpected needs, closeout, and/or necessary acceleration. In no case does the offsetting of an award constitute the reduction of the current budget period award in that the total authorized level of federal activity remains the same. However, that activity is “paid for” by a combination of prior fiscal year funds and current fiscal year funds. Foreign Components NCATS provides notification to award recipients on the eligibility of foreign institutions in the applicable funding opportunity announcement (FOA) under Section III, Eligibility Information. NCATS award recipients under FOAs that permit foreign participation must request prior approval to add or change a foreign component. Exceptions to obtaining NCATS prior approval cannot and will not be granted. In accordance with the NIH Grants Policy Statement, a foreign component is defined as performance of any significant element or segment of the project outside the United States, either by the recipient or by a researcher employed by a foreign organization, whether or not grant funds are expended. Activities that would meet this definition include, but are not limited to, the following: The involvement of human subjects or vertebrate animals at a foreign site; Extensive foreign travel by recipient project staff for the purpose of data collection, surveying, sampling and similar activities; and/or Any activity of the recipient that may have an impact on U.S. foreign policy through involvement in the affairs or environment of a foreign country. Examples of other grant-related activities that may be considered significant include the following: Collaborations with investigators at a foreign site that are anticipated to result in co-authorship; Use of facilities or instrumentation at a foreign site; and/or Receipt of financial support or resources from a foreign entity. Examples of grant-related activity that is not considered a foreign component include the following: Foreign travel exclusively for consultation and/or conference attendance. Conference grant (R13/U13) support of travel exclusively for conference attendance. (Support for international conferences and/or individuals who may contribute significantly to the program may require prior approval.) In cases where all grant-related research is being conducted in the United States and involves a researcher or other project team member who has support from a foreign source. (NOTE: This non-U.S.-based resource must be reported as Other Support.) Prior Approval Requirements Adding, changing or transferring work to a foreign component under a grant to a domestic or foreign award requires NCATS prior approval. This includes the addition of a performance site or research project in a country other than that specified in the competing application and/or a change in the performance site within a foreign country. The transfer of work by a domestic award recipient to a foreign entity also requires NCATS prior approval. Submission of a Prior Approval Award recipients are highly encouraged to contact the assigned PO and GMS to discuss any plans for adding or changing a foreign component before submitting a prior approval request. All requests must be submitted by the AOR from the grantee institution via email to NCATSPriorApprovalRequest@mail.nih.gov with a copy to the PO and GMS assigned to the grant. Requests should be submitted at least 30 days prior to the proposed change and must include all of the following information: Description of the planned activity to be conducted in a foreign country, detailed budget (if any funds will be provided) and timeline of planned activities. (NOTE: Funds for grant awards are paid in U.S dollars; NIH will not adjust/compensate for currency exchange fluctuations after award. Additionally, the maximum facilities and administrative costs for an international consortium is 8 percent of the modified total direct costs, exclusive of tuition and related fees, direct expenditures for equipment, and subawards in excess of $25,000.) Identification of countries with which international cooperative activities are planned. Description of special resources or characteristics of the research project (e.g., human subjects, animals, disease, equipment and techniques), including the reasons the facilities or other aspects of the proposed project are more appropriate than a domestic setting. Description of how the scientific environment in which the research will be done contributes to the probability of success (e.g., institutional support, physical resources and intellectual rapport). Discussion of ways the proposed studies will benefit from unique features of the scientific environment or from unique subject populations, or how studies will employ useful collaborative arrangements. Specific explanation of why this activity cannot be completed in the United States. For training requests: the name of the scholar/trainee and a detailed justification for the foreign training, including the reasons the facilities, the mentor, the timeline and/or other aspects of the proposed experience are more appropriate in a foreign setting. The justification is evaluated in terms of the scientific advantages of the foreign training as compared to the training available domestically. Foreign training will be considered for funding only when the scientific advantages are clear. (See: 11.2.2.5 Sponsorship, Foreign Sponsorship in the NIH Grants Policy Statement. If human/animal research, select agents and/or highly pathogenic agents are involved: a description of the plans for ensuring appropriate research protocol review and approval. If multiple performance sites are involved: a description of the resources available at each site. Review Process and Approval Notification Award recipients must not begin any foreign component activity until official NCATS prior approval is received via a revised Notice of Award or formal approval documentation provided by the NCATS Division of Extramural Activities. Engaging in foreign component activity prior to receiving NCATS prior approval will result in non-compliance enforcement action. Upon receipt of the prior approval request, NCATS Program and Grants Management Staff will review the request to determine eligibility, allowability and appropriateness of the activity to the approved scope of work. If there is a determination to move forward with the request, NCATS staff will proceed with necessary secondary reviews through the NIH Fogarty International Center and/or U.S. Department of State. (NOTE: Due to the requirements for additional review and oversight for foreign components, award recipients should anticipate significant delays.) | ||||||||
| 320 | Small Molecule Treatment for Rheumatoid Arthritis | Rheumatoid arthritis is a disease in which the body’s own immune system mistakenly attacks tissues in the joints. The condition causes pain, swelling, stiffness and damage to the joints, making it hard to move and reducing quality of life. No cure for rheumatoid arthritis currently exists. The investigators are developing a drug that, when applied to the skin, blocks the production of a chemical called glutamate, which is thought to contribute to joint pain and swelling. This treatment can relieve pain for 24 hours or more. The aim of the project is to continue preparing the drug to make it available for testing in human clinical trials. Scientific Synopsis Kemmx Corp. is developing 6-diazo-5-oxo-L-norleucine (DON) as a topical analgesic for rheumatoid arthritis sufferers. The investigator has discovered that DON can block glutamate production in arthritic sensory nerves of the skin and locally produce pain relief that lasts for 24 hours or more. Kemmx will continue research and development on topical formulation, drug stability and the analgesic dose response for DON. The outcome of the above objectives will allow the company to pursue pharmacokinetic and toxicology studies, an Investigational New Drug (IND) filing with the Food and Drug Administration (FDA), and phase I clinical trials for DON. The investigator’s goal is to receive FDA approval and enter clinical trials with a highly innovative topical analgesic for rheumatoid arthritis sufferers. Lead Collaborator Kemmx Corp., Sapulpa, Oklahoma Kenneth Miller, Ph.D. Public Health Impact Kemmx Corp. is developing 6-diazo-5-oxo-L-norleucine as a topically applied pain reliever for rheumatoid arthritis sufferers. A partnership between Kemmx and NIH will help bring forward the drug for FDA approval. Outcomes Work on this project is complete. Project Details Synthesis of non-Good Manufacturing Practice (GMP) material IND-directed toxicology | ||||||||
| 319 | Single-Chain Urokinase Plasminogen-Activating Factor | The pleural cavity is the space between the exterior membrane of the lungs and the interior membrane of the body cavity containing the lungs. This space normally contains a small amount of liquid. In diseases such as pneumonia or tuberculosis, the membranes become inflamed and the pleural cavity can fill up with substantially more liquid, putting pressure on the lungs and causing a variety of symptoms, such as coughing, difficulty with breathing and fever. This occurs in as many as half of hospitalized pneumonia cases and may affect 1 million patients each year in the United States. Treatment often involves surgery, which can have significant complications, or multiple doses of a drug to reduce the inflammation and thickening of the membranes, which can be impractical. These researchers are developing an alternative medical treatment for this condition that may be more effective in a single dose because of its ability to resist deactivation by the plasminogen activator inhibitor, PAI-1, which reduces the effectiveness of the currently used medication. Scientific Synopsis Pleural loculation is a serious, common complication that can arise in both pediatric and adult patients with parapneumonic effusions. The current standard of care can involve surgery, which is associated with significant morbidity, or the use of low-molecular-weight urokinase (Abbokinase) or tissue plasminogen activator (tPA; Genentech) that is given through a chest tube or intrapleurally in multiple doses. A recent study demonstrated that the use of Abbokinase (no longer marketed or commercially available) for treating loculations associated with pleural effusions in pediatric patients was equivalent to surgery in terms of efficacy but entailed significantly less morbidity. We recently demonstrated that the zymogen form of high-molecular-weight urokinase (single-chain urokinase; scuPA) is superior to Abbokinase in resolving pleural loculations in a model of tetracycline-induced pleural effusion. In this study, scuPA was given as a single intrapleural dose and although not statistically significant, also exhibited a trend of being superior to tPA. Pleural loculations are characterized by increased fibrin deposition due to high levels of the endogenous plasminogen activator inhibitor, PAI-1, which would immediately inactivate enzymatically active lysins such as tPA and Abbokinase. We hypothesize that scuPA, which is in its zymogen form and therefore not immediately inactivated by PAI-1, can reach the fibrin and be activated locally, leading to its superior activity in our studies and providing a basis for a single dose’s (in contrast to Abbokinase, for example, which is given multiple times) being sufficient to resolve pleural loculations. Our affirmative studies provide a strong rationale for the development of this potentially superior fibrinolysin for intrapleural use. Our objective is to secure program support to assist us in getting this drug to the clinic. Lead Collaborators University of Texas Health Science Center at Tyler Steven Idell, M.D. Scott & White Clinic, Central Texas Arthur Frankel, M.D. Attenuon, LLC, San Diego Andrew Mazar, Ph.D. Public Health Impact A more effective pharmacotherapeutic approach to treating pleuritis would represent a significant advantage over the current standard of care, which is surgery or repetitive administration of active fibrinolysins subject to rapid inactivation, in terms of reducing cost and morbidity. Outcomes Work on this project is complete. Project Details Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies Investigational New Drug (IND)-directed toxicology | ||||||||
| 318 | Grantee Information | The links below provide more details about the current federal budget and how it affects NCATS’ funding and grant award policies: NCATS Funding Policy NIH Extramural Financial Operations Funding Decisions & Award Policies The decision to award a contract, grant application or cooperative agreement occurs after it has been recommended favorably by an initial scientific review group and by the NCATS Advisory Council, which provides a second level of review. Funding decisions are made according to the Center’s funding policy and based upon the following considerations: Scientific and technical merit of the proposed project as determined by scientific peer review. Availability of funds. Relevance of the proposed project to program priorities in support of the NCATS mission. NCATS adheres to established NIH funding policies when making grant awards: NIH Grants Policy and Guidance Salary Limitation on Grants, Cooperative Agreements and Contracts (NOT-OD-17-087) Submission of Prior Approval Requests Communicating and Acknowledging Federal Funding NIH Grants Policy Changes NIH regularly issues updates to its grants policies. The links below provide more information: NIH Clinical Trial Requirements for Grants and Contracts Reminder: NIH & AHRQ Grant Application Changes for Due Dates On or After January 25, 2016 (NOT-OD-16-058) NIH Implementation of Final Research Performance Progress Reports (Final RPPR) (NOT-OD-17-022) ASSIST Now an Option for All NIH Competing Grant Applications and Some Post-award Administrative Actions (NOT-OD-16-042) Reminder: NIH Requires the Research Performance Progress Report (RPPR) for All Type 5 Progress Reports (NOT-OD-15-014) Reporting Publications in the Research Performance Progress Report (RPPR) (NOT-OD-15-091) NIH RPPR Overview and Technical Assistance NIH RPPR Instruction Guide (PDF - 4MB) Guidance for Correcting Human Subjects RPPR Submission Validation Errors (PDF - 798KB) | ||||||||
| 317 | Safety Pharmacology Studies for Beta Thalassemia | Beta thalassemia is a rare, inherited blood disorder that causes severe anemia and damage to organs. Another type of genetic blood disease, hemoglobinopathies, includes sickle cell disease (SCD). About 70,000 Americans and millions around the world are affected by SCD. Red blood cells carry a protein called hemoglobin, which transports oxygen from the lungs to the rest of the body. People with SCD have an abnormal form of hemoglobin that causes red blood cells to take on a crescent (sickle) shape instead of being round. Because of their irregular shape, sickle cells cannot easily move through blood vessels, and they slow blood flow to limbs and organs. This blockage causes pain and organ damage, and it can lead to infection. No widely available cure exists for either disease. Both beta thalassemia and SCD are caused by gene defects that lead to abnormal forms of hemoglobin. In both disorders, a gene necessary to produce of a type of hemoglobin called fetal hemoglobin is turned off. Fetal hemoglobin is thought to prevent cells from becoming sickle-shaped and blocking blood flow in SCD, and fetal hemoglobin can replace deficient hemoglobin in beta thalassemia. The investigators are developing a drug that increases production of fetal hemoglobin to treat these diseases. The project’s goal is to continue preparing the drug for testing in human clinical trials. Scientific Synopsis The beta thalassemias and hemoglobinopathies are types of genetic diseases with early mortality caused by molecular mutations affecting the beta globin chain of adult hemoglobin A. Reactivating expression of developmentally silenced fetal globin genes, which can functionally substitute for deficient beta globin in beta thalassemia and inhibit sickling in the sickle syndromes, is one accepted approach to therapy. Short chain fatty acids (SCFAs) stimulate fetal globin gene expression in experimental models, including patients’ cultured cells, transgenic mice and baboons. In clinical trials, prototype SCFA therapeutics have induced fetal globin and improved total hemoglobin levels, demonstrating proof-of-concept. However, the prototype drugs are metabolized rapidly, necessitating prolonged IV infusion or large oral doses, and their administration must be limited for antiproliferative effects on erythroid cells. An orally active SCFA compound with a more favorable pharmacokinetics (PK) profile and proliferative actions is needed for many patients. With NIH support, the investigators have evaluated two libraries of SCFA candidates for stimulation of fetal globin production and identified a few compounds that also prolong erythroid cell survival and increase cell proliferation through alteration of Bcl-family proteins. This activity is particularly important in beta thalassemia, as thalassemic erythroid cells undergo rapid apoptosis early during cell development. One SCFA (sodium ST20) with these dual beneficial actions has favorable oral PK in baboons and an acceptable safety profile. Accordingly, sodium ST20 was selected for clinical development. Good Manufacturing Practice (GMP) synthesis, formulation, mutagenicity testing and preclinical toxicology studies in two species have been performed on sodium ST20. At a pre-Investigational New Drug (IND) meeting, two standard safety pharmacology studies were requested by the Food and Drug Administration before initiating human clinical trials of ST20. The goal of this project is to conduct two preclinical studies required for an IND for sodium ST20 for potential treatment of beta thalassemia and sickle cell disease. Lead Collaborator Boston University School of Medicine Susan P. Perrine, M.D. Public Health Impact NIH investment would allow translation of basic science to be brought into clinical trials in three patient populations (beta thalassemia, sickle cell anemia, and potentially myelodysplastic syndromes). These disorders are not a focus of large pharmaceutical companies, primarily because of their orphan status in the United States. Outcomes The investigator successfully filed an IND application using NIH Rapid Access to Intervention Development program data (now known as the BrIDGs program). Seven clinical trials have been conducted, including Phase II trials in patients with beta thalassemia and sickle cell anemia. Project Details Formulation development Bioanalytical method development IND-directed toxicology Publication Short-Term Toxicity Study of ST-20 (NSC-741804) by Oral Gavage in Sprague-Dawley Rats • Toxicology & Pathology • May 10, 2011 | ||||||||
| 316 | De-Risking Therapeutic Development | Preclinical research, which connects basic scientific discoveries with initial testing of therapies in humans, is a failure-prone stage of translation. Innovations in drug discovery and development and management of development programs can substantially reduce the risks, time delays and costs of advancing basic research breakthroughs into treatments, an approach known as “de-risking.” Preclinical programs at NCATS are designed both to develop new technologies to make this translational stage more predictive and efficient, and also to de-risk targets and disease projects so that they will be more attractive to potential partners. NCATS works with academic, nonprofit and industry investigators and with patient groups to provide preclinical drug development expertise and resources to advance their research and, in addition, assists in generating data needed for regulatory approval. Using expertise in preclinical drug development, NCATS scientists apply innovative approaches to advance potential treatments to the point of attracting external partners who would be interested in investing in completing clinical development, manufacturing and marketing. NCATS’ goal is to improve success rates in the crucial preclinical stage of development. NCATS’ Therapeutics for Rare and Neglected Diseases and Bridging Interventional Development Gaps programs aim to de-risk drug development and provide access to NCATS expertise and contract resources to conduct crucial preclinical studies necessary for regulatory approval of first-in-human trials. Learn more about other translational issues NCATS aims to address: Predictive efficacy and toxicology Clinical research efficiency Collaboration and partnerships Data transparency and release | ||||||||
| 315 | Redox Encrypted Therapeutics for Treatment of Friedreich’s Ataxia | Friedreich’s ataxia is a rare inherited disease that causes damage to the nervous system and worsening muscle coordination over time, often beginning in childhood. It affects about 1 in 50,000 people of both sexes. People with the disease must use a wheelchair within 10 to 20 years of diagnosis and in later stages can be totally incapacitated. Life expectancy may be shortened, and heart disease is the most common cause of death. Friedreich’s ataxia has no cure or effective treatment, but the symptoms can be treated to allow optimal functioning for as long as possible. The disease is caused by mutations in the FXN gene, which codes for frataxin, a protein essential for assembling iron and sulfur molecules. The researchers are developing a drug for the treatment of Friedreich’s ataxia. This drug acts as an antioxidant to help counter the oxidative destruction of brain, spinal cord and muscle cells seen in patients with this disease. Scientific Synopsis Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative and cardiodegenerative disorder caused by decreased function of the protein frataxin. Frataxin is important for the assembly of iron-sulfur clusters in mitochondrial respiratory-chain complexes. Although the biochemical basis of FRDA is being further elucidated, current knowledge allows the development of new therapeutic approaches for effective treatment. Despite the diverse functions that mitochondria carry out, genetic defects that are nonlethal manifest themselves with relatively common biochemical phenocopies. Hallmarks of many of these diseases include decreased ATP product, increased oxidative stress and increased lactate formation. These biochemical alterations are most remarkable in respiratory chain diseases. Considerable evidence suggests that redox-coupling defects underlie the observed biochemical manifestations of select mitochondrial diseases, including FRDA. Specifically, evidence suggests that genetic defects giving rise to structural changes within the respiratory chain may alter the physical-chemical properties of redox centers, impairing electron flux and giving rise to the aforementioned observations. As a means to develop new therapeutic approaches to the treatment of mitochondrial diseases, we hypothesized that compounds that restore electrochemical coupling between defective redox centers may result in (partial) restoration of redox flux and improvement. EPI-A0001, a redox encrypted bioisostere of CoQ10, has been identified through a proprietary biodesign-guided chemical mining approach and evaluated in functional assays of FRDA. The preliminary developability assessment of EPI-A0001 is favorable. Lead Collaborators University of Pennsylvania, Philadelphia Robert B. Wilson, M.D., Ph.D. Friedreich’s Ataxia Research Alliance, Downington, Pennsylvania Ron Bartek Public Health Impact There are currently no approved drugs for Friedreich’s ataxia, a life-shortening, highly debilitating disease. The market is such that this disease, with an orphan designation, has not warranted sufficient commercial interest on the part of large pharmaceutical companies. Inroads into therapeutic development in Friedreich’s ataxia are likely to benefit other, larger affected patient populations, such as Parkinson’s disease patients, that possess potential shared disease mechanisms. Outcomes Work on this project is complete. The investigator successfully filed an Investigational New Drug (IND) application using BrIDGs data and initiated clinical testing. EPI-A0001 eventually entered Phase II clinical trials in patients with Friedreich’s ataxia. Project Details Synthesis of Good Manufacturing Practice (GMP) and non-GMP material Formulation development Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies Investigational New Drug (IND)-directed toxicology | ||||||||
| 314 | Cures Acceleration Network | The Cures Acceleration Network (CAN) was authorized (PDF - 133KB) to advance the development of high-need cures and reduce significant barriers between research discovery and clinical trials. To achieve these objectives, CAN gives NCATS new flexibilities in its funding authorities. Under CAN, NCATS may make large grant awards of up to $15 million per fiscal year, partnership awards that require 1:3 matching funds, and flexible research awards using the special funding mechanism called other transactions (OT), which allows projects to be actively and aggressively managed by using mechanisms similar to those used by the Defense Advanced Research Projects Agency at the U.S. Department of Defense. CAN investments are guided by the CAN Review Board (CAN RB). Launched in 2019, the CAN RB Real-World Applications for Mature Programs working group is developing recommendations to the CAN RB on real-world use and practice of mature CAN programs. At NCATS, CAN funds a variety of initiatives designed to address scientific and technical challenges that slow down translational research, based on available funds each fiscal year. CAN currently is supporting projects through the Tissue Chip for Drug Screening, Biomedical Data Translator and 3-D Tissue Bioprinting programs. 2012 CAN Workshop As requested by Congress, NCATS contracted with the Institute of Medicine (IOM) in 2012 to host a two-day workshop focused on discussion of the funding authorities provided to NCATS under CAN. “Maximizing the Goals of the Cures Acceleration Network to Accelerate the Development of New Drugs and Diagnostics: A Workshop” took place June 4–5, 2012. Review the workshop summary (PDF - 601KB) or visit the National Academy of Medicine (formerly the Institute of Medicine) website for more information about this event. | ||||||||
| 313 | Predictive Efficacy and Toxicology | Predicting the biological effects of drugs, chemicals and interventions is fraught with hazard. Many candidate drugs fail in human clinical trials because they are found to be unsafe or ineffective, despite promising preclinical studies in animal and cell models. NCATS is developing model systems for drug and toxicity testing that more closely resemble human physiology and more accurately reflect how our bodies will react to an experimental compound. Such advances could save enormous amounts of time and expense by preventing people in clinical studies from being exposed to potentially harmful or ineffective candidate drugs. Scientists also can use these models to study the basic biology of disease, predict toxicity or other physiological processes, and evaluate environmental chemicals. The model systems support NIH’s position that non-animal model approaches can reduce the need for animals in research but will require further improvement to completely replace them. Several NCATS programs and initiatives — including Assay Development and Screening Technologies, Early Translation Branch, Tissue Chip for Drug Screening and Toxicology in the 21st Century — are designed to address the translational issue of predictive efficacy and toxicology. Learn more about other translational issues NCATS aims to address: De-risking therapeutic development Clinical research efficiency Collaboration and partnerships Data transparency and release |
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