HUMAN ISLET TRANSPLANTATION INTO HUMANS Release Date: December 11, 1998 RFA: DK-99-006 P.T. National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Allergy and Infectious Diseases Juvenile Diabetes Foundation International Letter of Intent Receipt Date: February 10, 1999 Application Receipt Date: March 10, 1999 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases (NIAID) and the Juvenile Diabetes Foundation International (JDFI) invites investigator-initiated research grant applications to investigate the potential of modulation of the immune response in humans to transplanted human islets. These applications should propose clinical studies using new methods to induce immune tolerance to prevent reoccurrence of the autoimmune destruction of the beta cells in the islet, which causes type 1 diabetes, and to prevent transplant rejection. These methods include anti-CD40 ligand antibody, CTLA4Ig and anti-B7 antibody and/or bone marrow transplantation to create lymphocyte 'chimerism.' Collaborative efforts linking expertise in tolerance induction, autoimmunity, transplantation, and islet isolation to expertise in diabetes are strongly encouraged. Applications will be submitted to the NIH and will be reviewed by the NIH according to usual NIH peer review procedures. Applicants wishing to have their application considered by the JDFI for possible funding must authorize the NIH to provide a copy of their application and NIH-prepared summary statement of the initial review to the JDFI. 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 Request for Applications (RFA), Human Islet Transplantation Into Humans, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html. 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 This RFA will use the National Institutes of Health (NIH) research project grant (R01)and Interactive Research Project Grant (IRPG) award mechanisms. Guidelines for preparing IRPG applications are available from the program official or from the internet at: http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years. This RFA is 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. The anticipated award date is September 30, 1999. It is anticipated that the award for each site of research activity will be approximately $750,000 direct costs per year. Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center of Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. FUNDS AVAILABLE The NIDDK intends to commit approximately $3 million, the NIAID intends to commit approximately $1 million and the JDFI intends to commit approximately $1 million in FY 1999 to fund 4 to 5 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of approximately $750,000 per year, excluding facilities and administrative costs on consortium arrangements. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIDDK and the NIAID provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. 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 immune system-mediated destruction of the insulin producing beta cells of the pancreas. On September 4 and 5, 1997, the NIH sponsored a conference entitled "Diabetes Mellitus: Challenges and Opportunities." This conference identified research opportunities in several areas, one of the most important being the need for innovative therapies for diabetes. It was noted that intensive treatment of type 1 diabetes, although effective in improving long-term outcome, is difficult to implement for many patients and does not achieve euglycemia. The level of glycemic control achieved using currently available intensive treatment methods is at best 4-5 standard deviations above the mean value for the nondiabetic population, as measured by glycated hemoglobin (HbA1c). Intensive therapy is also limited by the accompanying increased frequency of severe hypoglycemia and weight gain, resulting in an increasing prevalence of overweight patients with type 1 diabetes. Finally, currently available intensive therapy is particularly problematic in children and adolescents due to difficulties in getting them to comply with current treatment regimens. This is especially troublesome since current clinical data support early intervention as being the most effective treatment strategy. Thus, the results of the Diabetes Control and Complications Trial indicate that maintenance of near normal glycemic levels can reduce and delay the onset of the devastating complications of diabetes. Therefore, establishing methods to achieve and maintain euglycemia will have enormous impact on the health and quality of life of individuals with diabetes. Scope and Objectives Although the ultimate research goal is to prevent the onset of type 1 diabetes, investigators are currently developing approaches and technology to modulate blood glucose levels in patients with diabetes and to restore insulin-producing capacity through transplantation of the whole pancreas, or of islets from the pancreas. Today, the only method that offers normal blood glucose levels is pancreas transplantation. Several decades ago, islet transplantation was proposed in the hope of reducing the need for difficult surgical procedures by allowing intravenous injection of islets. Initial animal studies on islet transplantation were encouraging, but subsequent research using larger animals and humans resulted in lower success rates as defined by exogenous insulin independence. Unfortunately, the initial promise held out for islet cell transplantation has not been realized. Thus, of the 270 adult islet transplants performed by the end of 1995 in patients with type 1 diabetes, only ten percent of recipients did not require insulin injections for more than one week, and only five percent remained off exogenous insulin for more than one year. In light of these results, studies are needed to better understand what treatment regimens would allow successful islet transplantation using the least amount of immunosuppression, thereby minimizing the toxicity to the islet. For example, corticosteroids, a mainstay of immunosuppressive regimens for solid organ transplantation, interfere with the normal beta cell function to release insulin in response to elevated blood sugar levels. In addition, the recurrence of autoimmune-mediated destruction of transplanted beta cells is problematic, and many researchers are pursuing studies to abrogate the underlying autoimmunity that has led to type 1 diabetes. While the "gold standard" for transplant success has been insulin independence, clinicians are observing a beneficial effect of islet transplantation even in recipients who have not achieved insulin independence. These patients require less exogenous insulin and show an improvement in metabolic control, which equates to fewer episodes of severe hypoglycemia. This effect may also lower the risk of long-term complications. Considerable knowledge has accrued from these early studies, including: improved procedures for handling the donor pancreas to optimize islet survival; improved methods for preparing large quantities of islets; the development of standardized solutions of enzymes to dissociate the islets from the other pancreatic tissue; pre-transplant treatment methods to reduce rejection; cryopreservation procedures; and evidence of the detrimental effects of immunosuppressive therapy on islet function and survival. New clinical interventions in the autoimmune disease process, which leads to type 1 diabetes, are being developed. Currently being considered is a strategy already utilized to block the progression of several autoimmune diseases. T cell activation is inhibited with an antibody that binds to a cell membrane component (CD28 or CTLA4) of an activating T cell and prevents further T cells from being activated. For type 1 diabetes, the intent would be to employ this protocol for induction of tolerance to transplanted islets, and to prevent further autoimmune attack on the transplanted islets. The scope of this RFA includes the establishment of clinical methods for immunomodulation/tolerance induction and the establishment of hematopoietic stem cell therapies for immunomodulation. Relevant topics for study listed below are examples and should not be construed as required or limiting. o Development and evaluation of immunomodulation regimens to optimize patient safety and promote islet allograft survival o Assessment of how to prevent autoimmune destruction of the transplanted islets o Optimization of tolerance induction protocols that would allow indefinite islet survival o Determination of the optimal site for islet engraftment to minimize the immune response and maximize graft function o Determination of the optimal number of islets necessary to ensure engraftment, most efficiently o Establishment of methods to completely abrogate the non-specific inflammatory response to infused islets Although the NCI will not formally participate in this solicitation, the NCI has strong interests in studies of anti-CD40 ligand antibody, CTLA4Ig and anti-B7 antibody, blood or bone marrow transplantation to create lymphocyte 'chimerism' and other issues dealing with tolerance induction and autoimmunity. Applications addressing these areas but judged to be non-responsive to the RFA will be of interest to the NCI, commensurate with established referral guidelines. SPECIAL REQUIREMENTS Letter of Authorization Applicants should submit a brief letter to the NIDDK indicating whether or not they wish their application to be considered for funding by the JDFI. While applicants may request that their applications be considered only by the NIH and not by the JDFI, it is necessary that the record indicate the applicant's consideration of this opportunity. For those applicants who wish to have the JDFI consider their application, all materials relating to the application will be promptly forwarded to that organization and the summary statements for such applications will be shared with the JDFI when available. The NIDDK will provide no information to the JDFI related to applications from applicants who request that the JDFI not consider their application. Letters of authorization should be prepared by the principal investigator and co-signed by the official signing for the applicant organization. This letter may be combined with the Letter of Intent (see below) or may be submitted as a cover letter accompanying the application. In all cases, the NIDDK and NIAID will make their funding decisions prior to those of the JDFI. Periodic Meetings Upon initiation of this program, the NIDDK, the NIAID and the JDFI plan to sponsor periodic meetings to encourage exchange of clinical results among investigators, to foster collaborative efforts among program grantees, and to identify resources that would enhance the productivity of grantees. For this purpose, applicants should request travel funds for a two-day meeting each year, probably held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in such meetings and to cooperate with other researchers at other clinical research sites. 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 subpopulations 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 was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://www.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff 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 10, 1999, 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 the RFA in response to which the application may be submitted. 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 NIDDK 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 Diseases 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.4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: GrantsInfo@nih.gov. The RFA label available in the PHS 398 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. 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. 4/98). 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. These applications should all include the DESCRIPTION OF INTERACTIVE RESEARCH ACTIVITIES Submit a signed, typewritten original of the application, including the Checklist, and five 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) Applications must be received by the application receipt date listed in the heading of this RFA. 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 already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NIDDK and the NIAID. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NIDDK and NIAID National Advisory Councils. 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 comments reviewers will be asked to discuss the following aspects of the application 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 assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) 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? (2) 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? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) 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)? (5) 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. The initial review group will also examine the provisions for the protection of human subjects and the safety of the research environment. 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. Schedule Letter of Intent Receipt Date: February 10, 1999 Application Receipt Date: March 10, 1999 Peer Review Date: June/July 1999 Council Review: September 1999 Earliest Anticipated Start Date: September 30, 1999 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds 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. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 5AN-18G Bethesda, MD 20892 Telephone: (301) 594-8813 FAX: (301) 480-3503 Email: Joan_Harmon@NIH.GOV Stephen M. Rose, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4A14 Bethesda, MD 20892-7640 Telephone: (301) 496-5598 FAX: (301) 402-2571 Email: Steve_Rose@nih.gov Direct inquiries regarding fiscal matters to: George A. Tucker, MBA Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 6AN-38A Bethesda, MD 20892 Telephone: (301) 594-8853 FAX: (301) 480-3504 Email: firstname.lastname@example.org Pam Fleming Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C25 Bethesda, MD 20892-7610 Telephone: (301) 402-6580 FAX: (301) 480-3780 Email: email@example.com AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 and 93.855. 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 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.
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