GLUCOSE SENSORS IN THE TREATMENT OF TYPE 1 DIABETES NIH Guide, Volume 26, Number 38, November 21, 1997 RFA: DK-98-008 P.T. National Institute of Diabetes and Digestive and Kidney Diseases National Center for Research Resources Letter of Intent Receipt Date: February 19, 1998 Application Receipt Date: March 19, 1998 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Center for Research Resources (NCRR) invite investigator-initiated research grant applications to develop a glucose sensor or to create a closed- loop system for regulating blood glucose. Commercial development of needle-based sensors and minimally invasive sensors is underway. Several optical approaches are appealing and are worthy of further development but are unlikely to yield a functioning sensor in the near future. This Request for Applications (RFA) is intended to stimulate the application of advances in chemistry, engineering, cell biology, biochemistry and endocrinology to the development of novel technologies (which may include a combination of cellular and mechanical approaches) to reliably and accurately measure glucose levels as part of a system to maintain euglycemia. This RFA allows for the submission of applications for two-year pilot and feasibility grants, regular research project grants, and interactive research project grants, which will support the efforts of several independent investigators working in a collaborative manner. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Glucose Sensors in the Treatment of Type 1 Diabetes, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone: 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Support of this program will be through the National Institutes of Health (NIH) Research Project Grants (R01), Interactive Research Project Grants (IRPG), and Exploratory/Developmental Research Grants (R21) award mechanisms. Guidelines for preparing IRPG applications are available from the program official or from the internet at: https://grants.nih.gov/grants/guide/pa-files/PA-96-001.html. The R21 awards are to demonstrate feasibility of a concept and to generate sufficient preliminary data to pursue it through other funding mechanisms. These grants are intended to (1) provide initial support for new investigators; (2) allow exploration of possible innovative new leads or new directions for established investigators; and (3) stimulate investigators from other areas to lend their expertise to research within the scope of this solicitation. Applicants for the R21 must limit their requests to $100,000 direct costs per year and are limited to two years. Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Applicants anticipating submitting IRPG applications or applicants requesting more than $500,000 in direct costs per year for any year should consult with the NIDDK Program Official listed under "INQUIRIES" at an early opportunity. Applicants for the R01 mechanism must receive permission from the NIDDK prior to the submission of an application requesting more than $500,000 in direct costs per year for any year of the proposed study. NIDDK staff will coordinate consideration and acceptance of such large applications by the staff of the appropriate Institute. The total requested project period for an application submitted in response to this RFA may not exceed three years. Budget escalations in future years are be limited to 3% of recurring costs. The anticipated award date is September 30, 1998. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Awards will be administered under Public Health Service (PHS) grants policy as stated in the PHS Grants Policy Statement. FUNDS AVAILABLE For FY 1998, $4 million will be committed to fund applications submitted in response to this RFA. It is anticipated that 16 to 18 awards will be made. However, this funding level is dependent upon the receipt of a sufficient number of applications of high scientific merit. The award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Diabetes mellitus affects approximately 16 million people in the United States. Individuals with type 1 diabetes mellitus have lost their ability to produce insulin due to the immune destruction of their pancreatic beta cells, which secrete insulin in response to a glucose challenge. Individuals with type 2 diabetes mellitus have lost their ability to over-produce insulin to maintain euglycemia in the presence of insulin resistance. Thus, both major forms of diabetes mellitus demonstrate a loss of sufficient insulin production by the beta cell. On September 4 and 5, 1997, the NIH sponsored a workshop entitled "Diabetes Mellitus: Challenges and Opportunities." This workshop highlighted research opportunities in several areas. One of the most important areas identified was the need to develop a glucose sensor to create a closed-loop system for regulating blood glucose. Intensive treatment of type 1 diabetes, although effective in improving long-term outcome, is labor intensive and difficult to implement for many patients with type 1 diabetes, and does not achieve euglycemia. Using currently available intensive treatment methods, the level of glycemic control achieved, as measured by glycated hemoglobin (HbA1c), is at best 4-5 standard deviations above the mean value for the nondiabetic population. The implementation of intensive therapy is limited by the accompanying increased frequency of severe hypoglycemia. In addition, weight gain that accompanies intensive therapy has resulted in an increasing prevalence of overweight patients with type 1 diabetes. Finally, currently available methods are particularly problematic in children and adolescents, which is especially distressing since our best clinical data support early intervention as being most effective. Glucose sensors for the treatment of diabetes hold great promise for improving metabolic control and quality of life for persons with diabetes. The single greatest change in the management of both type 1 and type 2 diabetes in the past two decades has been the introduction and widespread implementation of reliable, accurate, and relatively "user-friendly" self-glucose monitoring devices. At present, state-of-the-art technology cleanly divides mechanical delivery devices and glucose sensing technology; however, the ultimate goal would be to develop a "closed-loop" delivery system by combining the two technologies. Scope and Objectives Despite the enormous success of self-glucose monitoring, the technical challenges of developing methods for continuous monitoring of blood glucose and several highly publicized industry failures have overshadowed recent progress in the field of glucose sensing. Several approaches for continuous glucose measurement are close to clinical applicability. Various glucose sensor designs are in development. Designs that utilize an enzyme electrode (such as glucose oxidase) and either a hydrogen peroxide or an oxygen detection system appear to be the most successful to date. These electrodes can be placed subcutaneously or intravenously. Other glucose sensor designs being examined include acute microdialysis systems, transdermal extraction of tissue fluids for glucose assay, and non- invasive technologies. Future designs may incorporate glucose sensing/alarm systems that are operational in vivo, such as isolated islet electrical activity as a sensor. These designs require more basic research before demonstration of feasibility and subsequent development. This RFA invites applications to improve or test sensors currently under examination and to develop new approaches. In this regard, understanding the molecular mechanism by which ambient glucose concentrations elicit cellular responses may yield new approaches to measuring glucose with potential applications for glucose monitoring. These can include the molecular events leading to cellular recognition of hypo- or hyperglycemia. The intended application of a specific sensor must be clearly defined, since it specifies the required technology. Also, the reproducibility of a sensor may be related to its fabrication method especially whether each sensor is individually made or mass-produced. In fact, mass production methods may need to be developed in hand with the clinical verification of a glucose sensor. Important functions to be included in the design and verification of a sensor are hypoglycemic alarm, continuous or frequent measurement of glucose levels, algorithms for converting glucose data to insulin dose requirements, and finally, linking glucose determinations to direct insulin delivery via a closed-loop system. The movement of glucose sensors into the clinical arena requires ascertainment of their longevity, the need for re-calibration, and the relationship between blood and subcutaneous glucose concentrations especially during exercise and hypoglycemia. The latter issue includes the evaluation of the lag-time from changes in blood glucose levels to changes in the subcutaneous tissue glucose levels, which may be affected by local physiologic factors, such as tissue architecture, microvascular perfusion, tissue oxygen distribution, movement, implant biocompatibility and wound healing. Assessment of this information requires further animal studies for certain devices, but other devices are ready to move into studies on normal volunteers and on volunteers with diabetes. The scope of the present solicitation includes the further development of glucose sensors to determine their clinical value and constraints; development and verification of fabrication methods; establishment of miniaturization procedures for the sensor and for control units; evaluation of the usefulness of the sensor in individuals with type 1 diabetes; and development of a closed-loop system with an accurate glucose sensing device, a controller, and an insulin delivery system. Relevant topics listed below are examples and should not be construed as required or limiting. o Development of glucose sensors o Investigation of relationship between blood glucose levels and dynamics in different tissues, including relative concentrations, characteristics of lag- times, determinants of partitioning o Innovative, speculative approaches which incorporate cellular and mechanical technologies into the development of a glucose sensor o Development of fabrication and/or miniaturization methods applicable to glucose sensors o Examination of noninvasive or optical approaches to ascertain proof of concept and reliability especially related to variables affecting the path length and to inter-individual variability conferred by different skin types o Independent assessment of clinical utility of a glucose sensor o Integration of sensor, control and delivery systems and creation of a true artificial pancreas, which may include examination of appropriate parameters for control of glycemia with insulin, delivered peripherally or intraperitoneally o Analysis of safety considerations of a closed-loop system with particular emphasis on the risk of over- or under-treatment o Development of algorithms, telemetry, etc., to link the glucose sensor to the insulin delivery system o Development of self-regulating implantable systems that are responsive to blood glucose levels INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23, Number 11, March 18, 1994. Investigators may also obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by February 19, 1998, a letter of intent that includes a descriptive title of the proposed research; the name, address, and telephone number of the Principal Investigator; the identities of other key personnel and participating institutions; and the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIH staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Disease 45 CENTER DRIVE, Room 6AS-37F, MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@od.nih.gov. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. As indicated under "Mechanism of Support," if a collaboration of individual investigators is planned, it is necessary to identify one of the investigators as the group coordinator and to cite this individual in all applications on page 2 of the form PHS 398 (rev. 5/95). Applicants who have entered into a collaboration may submit the applications individually with a cover letter noting their involvement and listing the other members of the collaboration. Submit a signed, typewritten original of the application, including the Checklist, plus three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Disease 45 CENTER DRIVE, Room 6AS-37F, MSC 6600 BETHESDA, MD 20892-6600 Applications must be received by March 19, 1998. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council of the assigned Institute/Center. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written review, comments on the following aspects of the application will be made in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in the assignment of the overall score. o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? o Appropriateness of the proposed budget and duration in relation to the proposed research. o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects, and the safety of the research environment. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. o For those applications that propose collaborative efforts between several applicants, additional factors to be considered during the review would include the efficacy of the collaboration, the commitment of the participants to the collaboration, the design and responsibilities of the coordinating center and the cost effectiveness of the collaborative effort. R21 applications will have the additional review criteria: o Potential for novel and innovative approaches that clearly require additional preliminary data for their value to be established. IRPG applications will have these additional review criteria: o Each component R01 of the IRPG will be reviewed as above for its independent scientific merit. o The reviewers will assess the intended IRPG interactions, including the effectiveness and feasibility of the proposed IRPG group interactions, whether or not they enhance the prospects for reaching the stated objectives of the group, and the extent of synergy among the various projects. AWARD CRITERIA The anticipated date of award is September 30, 1998. The factors that will be used to make award decisions include: o scientific and technical merit as determined by peer review, o availability of funds, and o programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Joan T. Harmon, Ph.D. Diabetes Research Section National Institute of Diabetes and Digestive and Kidney Disease 45 CENTER DRIVE, Room 5AN-18G, MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8808 FAX: (301) 480-3503 E-mail: Joan_Harmon@nih.gov Dov Jaron, Ph.D. Biomedical Technology National Center for Research Resources 6705 Rockledge Drive Room 6160 MSC 7965 Bethesda, MD 20892-7965 Telephone:(301) 435-0775 FAX: (301) 480-3659 Email: BTAdir@ep.ncrr.nih.gov Direct inquiries regarding fiscal and administrative matters to: Nancy C. Dixon Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Disease 45 CENTER DRIVE MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8854 FAX: (301) 480-4237 E-mail: dixonn@extra.niddk.nih.gov Louise Amburgey Office of Grants Management National Center for Research Resources 6705 Rockledge Drive Room 6086 MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0844 Email: louisem@ep.ncrr.nih.gov SCHEDULE Letter of Intent Receipt Date: February 19, 1998 Application Receipt Date: March 19, 1998 Initial Review: June/July 1998 Second Level Review: September 1998 Anticipated Date of Award: September 30, 1998 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 (Diabetes, Endocrinology and Metabolism Research) and 93.371. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American People.
Return to NIH Guide Main Index
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||