PAR-98-071: SMALL GRANTS IN DIGESTIVE AND NUTRITIONAL DISORDERS

Department of Health
and Human Services (HHS)

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SMALL GRANTS IN DIGESTIVE AND NUTRITIONAL DISORDERS Release Date: May 15, 1998 PA NUMBER: PAR-98-071 P.T. National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The Division of Digestive Diseases and Nutrition (DDDN), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), began using the small grants (R03) mechanism in 1995 to support short-term clinical studies related to digestive diseases and nutritional disorders. This mechanism helps to stimulate the translation of promising and potentially relevant new developments from the laboratory to the clinical setting. This program announcement (PA) supersedes and expands upon the PAR-95-078, which was published in the NIH Guide, Vol. 24, No. 27, July 28, 1995. It is specifically to encourage the submission of applications for pilot studies leading to full-scale clinical trials and epidemiological studies relating to digestive diseases and nutritional disorders. The small grants (R03) may be used as planning grants for full-scale multi-center clinical trials or clinical trial pilot studies that could lead to full-scale multi-center clinical trials designed to provide evidence for or against changes in the current standard of care. Such trials may use pharmacological, dietary, surgical, or behavioral interventions given for disease therapy or prevention. Pilot epidemiological studies are encouraged that could lead to more extended research that would provide evidence for or against changes in health policy, especially as related to disease prevention. It is expected that these R03 grants will serve as a basis for planning future multi-center research project grant applications (R01) or cooperative agreement (U01) awards. New and experienced investigators in relevant fields and disciplines may apply for these small grants. Investigators are encouraged to take advantage of recent laboratory developments. In addition, the small grant is a good mechanism for new and experienced investigators to become better equipped to perform clinical and epidemiological research. Areas of special interest in this PA are non-alcoholic steato-hepatitis (NASH) and chronic liver disease associated with hepatitis C. There is continuing interest in gastroesophageal reflux disease, prevention and treatment of Barrett"s esophagus, inflammatory bowel diseases (IBD), complications of Helicobacter pylori infection, medical and behavioral interventions in functional bowel syndromes (FBS), non-ulcer dyspepsia, and chronic constipation, celiac disease, prevention of recurrence of diverticulitis, biliary atresia and neonatal hepatitis, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, gallstone disease, chronic and familial pancreatitis, obesity, binge eating disorders, anorexia nervosa and bulimia. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," in a PHS-led national activity for setting priority areas. This PA, Small Grants for Clinical Trials in Digestive Diseases and Nutritional Disorders, is related to the priority area of 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 for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, and laboratories, units of State and local governments, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. Applications may be from a single institution or several institutions (collaborating institutions or consortia), if appropriate. Planned full-scale clinical trials should be multi center. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT Support for this Program Announcement will be through the NIH small grant (R03) mechanism. Specific application instructions have been modified to reflect streamlining efforts. It is hoped that these changes will relieve the burden for the applicants, reviewers, and institute staff. The small grants research program provides limited funds (maximum of $50,000 direct costs per year) for short-term (up to two years) research projects. Only limited budget information will be requested and the Initial Review Group can make budget recommendations concerning level of effort (e.g., if the SRG recommends reduction of personnel, those funds could be shifted to other categories). Instructions for completing the Biographical Sketch have also been modified. In addition, NIDDK Staff will request Other Support information and the application Checklist page upon consideration for an award. These grants are non-renewable and continuation of projects developed under this program will be through the regular research grant program. Applicants will be responsible for the planning, direction, and execution of the proposed project. Applications submitted in response to this PA will compete for funds with all other R03 and regular research project grant (R01) applications assigned to NIDDK. The direct cost should not exceed $50,000 in each of the two budget periods (for a total of not more than $100,000 in direct costs) and the grant must be short term (not to exceed two years). Indirect costs will be awarded based on the negotiated rate at the time of each award. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the National Center for 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. Applicants are encouraged to collaborate with the Directors of the Silvio O. Conte Digestive Diseases Centers, Clinical Nutrition Research Centers, and Obesity/Nutrition Research Centers for consultation in experimental design, intervention, and methodology, as well as usage of core facilities appropriate for carrying out their projects. Information describing the centers and their cores can be requested from the person listed in INQUIRIES. The award of grants in response to this PA is also contingent upon the availability of funds. Awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement (rev. 4/94). Projects with substantial scientific merit that are not funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) are eligible for support by the American Digestive Health Foundation (ADHF). Principal investigators will be responsible for forwarding copies of their summary statements and applications to the ADHF for consideration for this award mechanism. The amount of ADHF support will be determined by project scope and duration of funding will be limited to two years. No funds for indirect costs will be provided. RESEARCH OBJECTIVES Background This PA supersedes PAR-95-078 published in 1995 at the inception of the small grants program for clinical trials in digestive diseases and nutritional disorders. The DDDN plans to continue the small grants program by broadening the scope of the original program announcement. New areas of special interest in this PA are non-alcoholic steato-hepatitis (NASH) and chronic liver disease associated with hepatitis C: Chronic liver disease associated with hepatitis C: The hepatitis C virus (HCV) is a major cause chronic liver disease. In the United States, hepatitis C accounts for approximately 60-70% of chronic viral hepatitis. Chronic hepatitis C infection is the second most common cause of cirrhosis of the liver. In 1995, it accounted for 30% of all transplants making it the single major indication for liver transplantation in adults. At least 70% of persons infected with this virus develop chronic infection. Chronic hepatitis C is typically insidious and asymptomatic, but leads to cirrhosis and end-stage liver disease in 20-30% of persons, usually over the course of 2 to 3 decades. Worldwide 1-2% of individuals are chronic carriers of the virus. The natural history and prognosis of persons infected with hepatitis C are not well understood. Infection appears to resolve spontaneously in a small proportion of infected individuals. In chronically infected patients, cirrhosis develops in a minority of patients and this may be only after decades of infection. Many other individuals appear to have no clinically significant liver disease, despite many years of infection. Also uncertain is the basis for the apparent inconstancy of disease activity as indicated by liver enzyme fluctuations in many infected individuals. Periods of relative dormancy may be interrupted by intense inflammatory activity and liver injury. An important need is to identify the viral host, and exogenous factors and their interactions that determine the natural history of hepatitis C. Particularly needed are studies that can identify common, modifiable risk factors, such as the potential importance of moderate alcohol consumption on disease progression. There is a major need for safe and effective means of treating chronic hepatitis C. Clinical research studies are needed to assess current and future therapeutic approaches to ameliorating chronic liver disease associated with hepatitis C. Thus, the role of iron status, alcohol use, drug abuse, and other environmental factors needs to be addressed. The long term natural history of hepatitis C needs to be better defined to address the critical factors in progression of this disease. NASH: The causes of non-alcoholic steato-hepatitis are unknown. NASH is common in diabetics and in obese patients, but also occurs in non-obese and non-diabetic patients. The similarities between NASH and alcoholic liver injury suggest a common pathogenesis such as mitochondrial injury due to disturbances in intracellular metabolism, insulin action or cytokine effects. The prevalence of NASH is unknown and its natural history has not been defined. NASH is frequently cited as a cause of abnormal serum aminotransferases but is rarely mentioned as a cause of cirrhosis, end-stage liver disease or as an indication for liver transplantation. Even less is known about therapy or management of NASH. While weight loss is usually suggested for patients with NASH, the efficacy of this approach in altering the disease manifestations or natural history has not been evaluated. Other diseases or disorders: Diseases of the gastrointestinal tract, liver and pancreas are major causes of morbidity and mortality. Gastrointestinal diseases of focus in this PA include gastroesophageal reflux disease, prevention and treatment of Barrett’s esophagus, inflammatory bowel diseases (IBD), complications of Helicobacter pylori infection, medical and behavioral interventions in functional bowel syndromes (FBS), non-ulcer dyspepsia, and chronic constipation, celiac disease, and prevention of recurrence of diverticulitis. Liver diseases warranting clinical investigation include biliary atresia and neonatal hepatitis, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, and gallstone disease. Pancreatic diseases of interest in this PA are chronic and familial pancreatitis. Nutritional disorders and conditions constitute major health risks and remain challenges for medical management. Nutritional disorders of focus in this program announcement include obesity, binge eating disorders, anorexia and bulimia. 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 new 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 also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. NIH POLICY AND GUIDELINES ON THE 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 APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits 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 301-435-0714, Email: Grantsinfo@nih.gov. The program announcement title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Mail the signed, original, single-sided application, along with five exact, single-sided copies and five collated sets of appendix materials 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) SPECIAL INSTRUCTIONS FOR THE COMPLETION OF THE PHS 398 APPLICATION In responding to the program announcement, the following are specific instructions for sections of the PHS 398 application form (rev. 5/95) that should be completed differently from usual. Some sections are modified and others in the application do not need to be completed for the submission of the application but WILL be requested if the application receives a priority score in the fundable range. For all other items in the application, follow the usual instructions on pages 5-20 of the PHS 398 booklet. FACE PAGE (Form AA) - The title and number of the PA must be typed in Item 2. Failure to do so could result in delayed processing of the application such that it may not reach the review committee in time for review. FORM DD - PAGE 4 - DETAILED BUDGET PAGE FOR INITIAL BUDGET PERIOD Enter the following information without the associated costs: o Personnel and level of effort only should be itemized in the Personnel section. o In addition, generally list consultants, equipment, supplies, travel (especially for personnel assisting in preparation of the Manual of Procedures), patient care activities, and other expenses as appropriate. No costs should be associated with these individual items or categories. Enter only the total direct costs. APPLICANTS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS PA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. Form EE - Page 5 - BUDGET FOR ENTIRE PROPOSED PROJECT PERIOD - Do not complete this page. The second budget period will be the same as the first. Form FF - Page 6 - BIOGRAPHICAL SKETCH - For each KEY person only, provide a two-page biographical sketch. Name, Position Title, Education - Identify your research background and experience relevant to the research proposed. Specifically, provide: o A list of previous research positions that are felt to be of significance or relevance for the review of the proposed research, o Complete references, titles, and authors on all peer-reviewed publications representative of your research career or pertinent to the research proposed. o The title and funding source of all active research grants or contracts on which you are principal investigator, co-investigator, or project leader. Indicate current percent effort for each award. o The title and length of service on any peer review group, council, or program advisory committee. The significance of this section is to demonstrate the following as briefly as possible. o Professional credentials of the organizers indicating experience in such areas as: o The problem under study o Clinical trial administration o Methodology o Adequate and similar participant recruitment o The proposed procedures. o Professional credentials of the participating center investigators in the clinical problem and in clinical trial participation. Verification of the cooperating investigators and their institutions will be required later if considered for funding. Form GG - Page 7 - OTHER SUPPORT - Do not complete. Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Updated information will be requested by NIDDK staff from only those applicants being considered for funding. Form HH - Page 8 - RESOURCES - Complete item(s) only if proposed research requires specialized resources unique for the proposed research. RESEARCH PLAN (Booklet Pages 15-19) o Applications in response to this PA should be concise and substantially shorter than regular grant applications. Items a-d may not exceed a total of 16 pages. (a) - Specific Aim - Within one page, list in order of priority, the broad, long-range objectives. Describe concisely and realistically the hypothesis to be tested and what the specific research described in this application is intended to accomplish. (b) - Background and Significance - Within three pages, describe (1) how the proposed research will contribute to meeting the goals and objectives of the PA, and, (2) explain the rationale for the selection of the general methods and approaches proposed to accomplish your specific aims. (c-d) - Preliminary Studies/Progress Report, Research Design and Methods - Within twelve pages, complete as instructed on pages 16-17 of the PHS 398 (rev. 5/95) booklet with the modification that the clinical protocol(s) and up to three publications, manuscripts submitted or accepted for publication, patents, or invention reports can be included in the Appendix (see below). Investigator may use this section to address, even though briefly, issues such as the following: o Merit of the study design. o Appropriateness of intervention groups. o Plans to minimize bias through randomization, stratification, choice of controls, and masking of treatment or results. o Identification of appropriate primary and secondary outcomes for the trial. o Recognition of possible problems inherent in the design and the adequacy of plans for dealing with them. o Quality of plans (even if broadly described) for recruitment and retention of patients, identification of eligibility and exclusion criteria, and standardization and maintenance of quality control among participating centers. o Patient protection, including informed consent and monitoring data for safety and efficacy. Plans for early termination if it becomes necessary. o Documentation of potential availability of patients at each of the participating centers. o Plans for the preparation of a Manual of Procedures that must be submitted with any future application for actual conduct of the randomized controlled trials. o Preliminary studies pertinent to the application. o The study group"s suitability for providing the necessary supporting data for preliminary studies. o The feasibility of the study group, particularly in conducting preliminary studies. o Rationale and hypothesis for the clinical trial and laboratory studies such as: - Clinical importance of the disease or condition being studied. - Rationale for therapy being applied. - Ethical considerations of treatment. - General methods that will be utilized, provide specific details for those techniques which are unique or where a significant departure from a generally accepted technique is important for reviewers to know. - Plans for the rigorous data management and verification of research data including rationale and validity of sample size and general methods to be used for data analyses. - Potential pitfalls in the experimental design and alternative studies that will be done if the proposed experiments fail. (e-f) - Human Subjects, Vertebrate Animals - Complete as described on pages 17-18. State clearly the plans for early detection of and protection against adverse effects on human subjects. (g) - Literature Cited - Within two pages, give full literature citations including the title of the article. (h) - Consortium/ Contractual Arrangements - Within one page, provide a brief explanation of the programmatic, fiscal, and administrative arrangements made with collaborating organizations. (i) - Consultants - Biographical sketches should conform to the brief format described previously for key personnel on Form FF. APPENDIX (Page 19) - Up to three publications, manuscripts submitted or accepted for publication, patents, invention reports should be provided. Clinical protocol(s) must be included in this section. Other than this change, complete as instructed. CHECKLIST (Form II and JJ) - Do not complete. Information will be requested by NIDDK staff from only those applicants being considered for funding. If the applicant or the institutional business office have any questions regarding these instructions, contact program staff listed under INQUIRIES. REVIEW CONSIDERATIONS Applications that are complete 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, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Specific clarifications pertinent to the review of R03s (small grants): o Pilot trials are encouraged. An important question to ask is whether the pilot is likely to lead to a full-scale efficacy trial or epidemiological study. o Planning grants including or not including a pilot are encouraged. The Institute encourages interactions of investigators, including face-to-face meetings, to develop important elements of a larger study, such as a common protocol, data collection forms, and a procedure manual. An important question to ask is whether the planning grant is likely to lead to a full-scale efficacy trial or epidemiological study. 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 method? 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, 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. 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. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Tommie Sue Tralka Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AN/12K, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8879 Email: tralkat@extra.niddk.nih.gov Direct inquiries regarding specific epidemiological programmatic issues to: James Everhart, M.D., M.P.H. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AN/12J, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8878 Email: vjy@cu.nih.gov Direct inquiries regarding fiscal matters to: Ms. Donita Marconi Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AN/44K, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8860 Email: marconid@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848. 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 Public Health Service (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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