PREVENTION OF INSULIN DEPENDENT DIABETES MELLITUS BY IMMUNOMODULATION NIH GUIDE, Volume 21, Number 12, March 27, 1992 PA NUMBER: PA-92-60 P.T. 34 Keywords: Diabetes Disease Prevention+ Immunotherapy National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Allergy and Infectious Diseases National Institute of Child Health and Human Development PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institute of Child Health and Human Development (NICHD) are seeking applications for clinical studies designed to test the hypothesis that immunomodulation will prevent insulin-dependent diabetes mellitus (IDDM) in high-risk populations. 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 program announcement, Clinical Trials to Prevent Insulin Dependent Diabetes Mellitus by Immunomodulation, 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 "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by public and private, foreign and domestic, for-profit and non- profit organizations, such as universities, colleges, hospitals and laboratories, units of State and local governments, and authorized units of the Federal Government. Women and minority investigators are encouraged to apply. MECHANISM OF SUPPORT The mechanism for support for this program will be the individual research grant (R01). The application may include subcontracts or consortia with several institutions. Due to fiscal constraints, the NIDDK does not anticipate being able to provide more than $500,000 in total costs to any one application. RESEARCH OBJECTIVES Background Over the past 10 years, significant progress has been made in defining the autoimmune etiology and pathophysiology of IDDM. Several clinical trials of general immunosuppressive agents in patients with newly diagnosed IDDM have induced a temporary clinical remission of this disease. These observations have led to the hypothesis that immunomodulatory interventions may be effective in the prevention of this disease in individuals who are asymptomatic but who are in an earlier period of the autoimmune process. A workshop on Clinical Trials of Immunosuppression for Prevention of IDDM was held on April 19-20, 1990, in Bethesda, Maryland. This workshop was sponsored by the NIDDK, NIAID, and NICHD. It was the charge of this group to assess the status of scientific and medical knowledge necessary to initiate a clinical trial of immunomodulatory intervention for the prevention of IDDM. Participants for the meeting were drawn from the diabetes and immunology research communities and were chosen to provide a broad range of insight and judgment in these areas. Several major issues were extensively discussed, and consensus was reached in some areas while others remained open for continued examination, evaluation, and debate. There was general consensus based on the published literature and discussion on the following important issues: o IDDM in humans is an autoimmune disease and, as such, should be amenable to immunotherapeutic intervention; o There are measurable parameters that can identify a group of individuals at high risk for the development of IDDM; and o Further clinical studies in high-risk individuals to explore the ability of immunomodulation to alter the natural history of IDDM are timely and warranted. Concerns were expressed by several of the participants that applicants utilizing pediatric populations must strongly justify the risks and benefits to the trial participants. A summary of this workshop is available from the NIDDK staff listed under INQUIRIES. Goal and Scope The goal of this program announcement is to stimulate clinical research that will evaluate the effectiveness of immunomodulatory therapies for the prevention of IDDM in high-risk populations. The research scope of this program will encompass a range of basic and clinical research disciplines, such as immunology, endocrinology, genetics, biochemistry, pharmacology, physiology, and pediatrics. Some examples of relevant research areas to be addressed by these clinical studies include: o Identification and characterization of markers that have value in predicting remission or progression in pre- IDDM individuals on long-term immunotherapy; o Using presently available markers, determine the natural history of high-risk individuals; and o Evaluation of the effect of immunomodulatory interventions in high-risk individuals including efficacy in prevention of progression of the autoimmune process and parameters such as dosage, duration, and deleterious side effects. These recommendations are not necessarily all inclusive and any new ideas with credible hypotheses that would appropriately fall within the scope of this announcement may be the basis for an application. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDIES NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 in Section 2, 1-4 of the Research Plan and summarized in Section 2, E, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventative strategies), diagnosis, or treatment or diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES Applicants are to use the research grant application form PHS 398 (rev. 9/91). If application kits are not available at the institution's business office or central application control office, a copy may be obtain from the Office of Research Grants, National Institutes of Health, Division of Research Grants, 5333 Westbard Avenue, Room 449, Bethesda, MD, 20892, telephone 301-496-7441. In order to identify the application as a response to this program announcement, check "yes" on Item 2a of the application face page with the title, "Prevention of IDDM by Immunomodulation, PA-92-60." Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center of Research Resources may wish to identify the Center as a resource for conducting the proposed research. In such a case, a letter of agreement from the GCRC Program Director must be included in the application material. REVIEW PROCEDURES Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications in response to this solicitation will be reviewed in accordance with the usual NIH peer review procedures. Applications will first be reviewed for scientific and technical merit by a review group composed mostly of non-Federal scientific consultants (study section). Secondary reviews will be by an appropriate national advisory council. AWARD CRITERIA Applications recommended for further consideration will compete for available funds with all other applications assigned to the Institutes. However, because the NIDDK, NICHD, and NIAID and their Advisory Councils have identified this research area to be of particular program interest, applications responsive to this announcement will be brought to the special attention of these Advisory Councils. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review; availability of funds; and program balance among research areas of the announcement. INQUIRIES Potential applicants are encouraged to discuss their plans with any of the following NIH program staff: Dr. Joan T. Harmon Executive Director, Diabetes Research Program National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 622 Bethesda, MD 20892 Telephone: (301) 496-7731 Dr. Howard B. Dickler Chief, Clinical Immunology Branch National Institute of Allergy and Infectious Diseases Solar Building, Room 4A-19 Bethesda, MD 20892 Telephone: (301) 496-7104 Dr. Gilman D. Grave Chief, Endocrinology, Nutrition and Growth Branch National Institute of Child Health and Human Development Executive Plaza North, Room 637 Bethesda, MD 20892 Telephone: (301) 496-5593 AUTHORITY AND REGULATION This program is described in the Catalog of Federal Domestic Assistance No. 93.847, Diabetes, Endocrinology and Metabolism Research; 93.855, Immunology, Allergic and Immunologic Disease Research; 93.865, Research for Mothers and Children. 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. .
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