BARRETT’s ESOPHAGUS, GASTROESOPHAGEAL REFLUX DISEASE AND ADENOCARCINOMA OF THE ESOPHAGUS Release Date: September 17, 2001 RFA: RFA-DK-02-015 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) National Cancer Institute (http://www.nci.nih.gov/) Letter of Intent Receipt Date: February 20, 2002 Application Receipt Date: March 20, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE This initiative is designed to stimulate and solicit studies to broadly address the problem of Barrett’s esophagus and its etiology and relationship to gastroesophageal reflux disease (GERD) and its link to the rising incidence of adenocarcinoma of the esophagus. The specific areas of emphasis of this initiative will include novel approaches for molecular characterization of Barrett’s metaplasia and dysplasia in comparison to normal squamous and intestinal epithelium, identification of esophageal stem cells and the factors responsible for specific differentiation pathways into either squamous or intestinal epithelium, regeneration of squamous mucosa, the molecular precursors or predictors of dysplasia, identification of serum biomarkers of metaplasia or dysplasia, development of suitable animal models to study pathogenesis, chemoprevention or treatment strategies, and clinical studies aimed at revealing environmental or genetic risk factors or the role of gastroesophageal reflux in Barrett’s esophagus. In addition to hypothesis-driven R01 projects, this initiative will encourage development of new research tools through Exploratory/Developmental Grants (R21). HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This Request for Applications (RFA), Barrett’s Esophagus, Gastroesophageal Reflux Disease, and Adenocarcinoma of the Esophagus, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and nonprofit 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 exploratory research grant (R21) mechanisms. Except as otherwise noted in this announcement, awards will be administered under policies as stated in the NIH Grants Policy Statement. R01 applications submitted in response to this RFA may not request a total project period of more than five years. The maximum budget request for R01 applications should be limited to $250,000 in direct costs for each budget year. Exploratory research grant (R21) applications may not exceed two years for the total project period. The maximum budget request for R21 applications may not exceed $100,000 in direct costs for each budget year. The R21 grant mechanism may be used by new investigators or experienced investigators to develop pilot and feasibility studies for new and innovative approaches. R21 applications generally are expected to have little preliminary data and are reviewed based on the development of hypotheses and supporting literature. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH"s 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 customary peer review procedures. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The anticipated award date is September 30, 2002. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE The NIDDK and NCI intend to commit approximately $2.5 million in FY 2002 to fund approximately six new research project grants (R01) and six new exploratory research grants (R21) in response to this RFA. Although the financial plans of the NIDDK and NCI 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. RESEARCH OBJECTIVES Background Barrett’s esophagus (BE) is a pre-malignant condition of the esophagus characterized by the presence of specialized intestinal metaplasia in the esophagus that is normally lined by squamous epithelium. The prevalence of BE is significantly increased in patients with long-standing gastroesophageal reflux disease (GERD), one of the most common gastrointestinal disorders. Furthermore, in some patients BE undergoes neoplastic transformation into dysplasia and esophageal adenocarcinoma, a disease of high morbidity and mortality that has a rapidly rising incidence in the United States. At the present time there are many unanswered questions about BE suitable for further research that are the subject of this solicitation. A number of studies have attempted to define the epidemiology of BE. It is found in about 1% of the older population and in 3% to 5% of patients with gastroesophageal reflux, which is the primary risk factor associated with BE. However, the great majority of patients with BE remain undiagnosed, as patients with BE are more likely to have clinically silent gastroesophageal reflux. Accurate population based data on the prevalence, incidence, and long-term natural history of BE are currently unavailable. At the present time the only clinically accepted method to diagnose BE is by endoscopy and biopsy, which entails high cost, patient and provider time, and potential risks. The diagnosis is complicated by concerns about non uniform endoscopic and histologic criteria for diagnosis. The etiologic factor(s) and pathophysiological steps responsible for transformation of the normal squamous lined esophagus into BE are unknown. There are no accepted animal models that faithfully reproduce the human condition that are suitable for pathophysiological studies. The major factors controlling the extent, progression or potentially, regression of BE are similarly unknown. The major health care concern regarding BE is the predisposition for transformation into dysplasia and adenocarcinoma. The factors and pathophysiological steps responsible for transformation of metaplasia into dysplasia or into invasive carcinoma are unknown. Molecular techniques have identified candidate molecular markers that may characterize dysplasia and carcinoma. However, there are no accurate predictive factors that distinguish patients who are likely to progress to adenocarcinoma vs. patients with a benign course, which is the most common outcome. As for diagnosis of BE, the only currently accepted procedure for identification of dysplasia and/or adenocarcinoma is endoscopy and biopsy. The risk/benefit estimates for surveillance in patients with known BE have led to guidelines for repeated endoscopic surveillance. However, many patients with BE remain undiagnosed and for those with the diagnosis, surveillance for dysplasia and cancer remain imperfect. Most patients presenting with adenocarcinoma have not had a prior diagnosis of BE or surveillance. At the present time, no medical therapy has proved effective in preventing the development of BE or the progression of BE to dysplasia or carcinoma, short of esophagectomy, a radical surgical procedure with high potential morbidity and mortality. A variety of experimental procedures exist with the potential for elimination of BE or dysplasia, but the long term outcomes of these approaches are currently unknown. Research Scope This initiative encourages further basic and clinical investigation aimed at a broad range of problems, including epidemiology, mechanisms responsible for BE, it progression, diagnosis, mechanisms of transformation to dysplasia and adenocarcinoma, diagnosis, treatment and prevention. Research aimed at fundamental biological and physiological processes in the esophagus that might be relevant to BE are also appropriate subjects for this solicitation. This solicitation specifically excludes applications for clinical trials of esophageal cancer therapy, which should be submitted through other mechanisms. Areas of particular focus for R01 grant applications include, but are not limited to: o Identification of the cell of origin of BE metaplasia, the nature of esophageal stem cells, and factors that determine differentiation into mature squamous epithelium. o Molecular characterization of BE and dysplasia. o Validation of animal models suitable for research on BE involving pathogenesis, prevention or treatment. o Identification of genetic risk factors for BE, dysplasia or adenocarcinoma. o Identification and validation of biomarkers for BE, dysplasia or early adenocarcinoma. o Identification of the pathophysiological steps leading from GERD to BE metaplasia, factors controlling injury and repair relevant to BE. o Identification of alternative strategies for diagnosis of BE or surveillance strategies for dysplasia in patients with known BE. o Epidemiological studies of incidence, prevalence, natural history and risk factors of BE and factors determining progression to dysplasia or adenocarcinoma that provide important new insights that can be achieved within the budget and time constraints of this solicitation. o Identification of novel environmental risk factors for BE, dysplasia, or adenocarcinoma. In addition to hypothesis-driven R01 applications, this initiative will support exploratory/ developmental efforts using the R21 mechanism that seek to explore highly innovative and potentially high risk approaches for the study of BE for which there may be limited preliminary data. This mechanism would be acceptable for new investigators entering the field or established investigators not currently working in the field of BE who wish to apply novel technologies or approaches to this problem. 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 are provided indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. 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://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the officials listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLS IN GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit, by February 20, 2002, 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 and NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable PDF format. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. All application instructions outlined in the PHS 398 application kit are to be followed. All applications will use the MODULAR GRANT and JUST-IN- TIME concepts, with direct costs requested in $25,000 modules. The following requirements apply specifically to R21 applications: 1. R21 applications may request up to $100,000 per year in total direct costs. 2. Although preliminary data are not required for an R21 application, they may be included. 3. Sections a-d of the Research Plan of the R21 application may not exceed 15 pages, including tables and figures. 4. R21 appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution. The following materials may be included in the appendix: o Up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, or other printed materials directly relevant to the project. These may be stapled as sets. o Surveys, questionnaires, data collection instruments, and clinical protocols. These may be stapled as sets. o Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the 15 page limit of items a-d of the research plan SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a signed, typewritten original of the application, including the Checklist, and 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: Francisco O. Calvo, Ph.D. Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. 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 Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK and NCI. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with review criteria stated below. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by appropriate National Advisory Council/Board. 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. 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 applicant employ novel tools, 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: 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 reasonableness of the proposed budget and duration to the proposed research will also be reviewed. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. 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. SCHEDULE Letter of Intent Receipt Date: February 20, 2002 Application Receipt Date: March 20, 2002 Peer Review Date: July, 2002 Council Review: September, 2002 Earliest Anticipated Start Date: September 30, 2002 AWARD CRITERIA 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 priorities. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Frank Hamilton, M.D., M.P.H. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 663 Bethesda, MD 20892-5458 Telephone: (301) 594-8877 FAX: (301) 480-8300 E-mail: fh14e@nih.gov Ellen Richmond, M.S., R.N., C.S. Division of Cancer Prevention National Cancer Institute Executive Plaza North 6130 Executive Boulevard, Room 2148 Bethesda, MD 20892 Telephone: (301) 435-2466 FAX: (301) 435-6344 E-mail: richmone@mail.nih.gov Direct inquiries regarding NIDDK fiscal and administrative matters to: Ms. Carolyn Kofa Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Room 727 Bethesda, MD 20892 Telephone: (301) 594-7687 FAX: (301) 480-3504 E-Mail: ck104i@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848 and No 93.393. Awards are 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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.


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