From owner-sci-resources@net.bio.net Sun Mar 02 22:00:00 1997 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NSF - Summary of new documents on STIS, 1 March 1997 Date: 2 Mar 1997 23:28:00 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 105 Sender: daemon@net.bio.net Approved: biosci-help@net.bio.net Distribution: world Message-ID: <5fdui0$7e0@net.bio.net> NNTP-Posting-Host: net.bio.net This message contains a summary of the documents added to the NSF STIS system for the week ending March 1, 1997. Reference material concerning STIS follows the summary. ------------------------------------------------------------------------ ** NEW DOCUMENTS ON STIS ** Document Type: Bulletin Title: NSF March Bulletin Vol 24; No 7 File size (bytes): 48132 STIS Filename: bul9703.txt Document Type: Press Release Title: "BAKED ALASKA" MUD VOLCANO DISCOVERED IN NORTH ATLANTIC File size (bytes): 5789 STIS Filename: pr9717.txt Document Type: Program Guideline Title: NSF 97-44 - Operational Methods in Semiconductor Manufacturing File size (bytes): 17345 STIS Filename: nsf9744.txt Title: NSF 97-62 -- CHALLENGES IN COMPUTER AND INFORMATION SCIENCE AND ENGINEERING File size (bytes): 22688 STIS Filename: nsf9762.txt Document Type: Recruit Title: Program Director, AD-4 File size (bytes): 6653 STIS Filename: vex974a1.txt Title: Program Analyst, GS-343-13 File size (bytes): 7516 STIS Filename: vgs9739.txt ------------------------------------------------------------------------ ** UPDATES TO EXISTING STIS DOCUMENTS ** Document Type: Bulletin Title: NSF March Bulletin Vol 24; No 7 File size (bytes): 48132 STIS Filename: bul9703.txt Document Type: Phone Book Title: NSF Alphabetical List File size (bytes): 114263 STIS Filename: phnalpha.txt Also available: phnalpha.dlm Title: NSF Organization Directory File size (bytes): 128207 STIS Filename: phnorg.txt Document Type: Program Guideline Title: NSF 96-06 DATABASE ACTIVITIES IN THE BIOLOGICAL SCIENCES File size (bytes): 36465 STIS Filename: nsf9606.txt Also available: nsf9606.doc ------------------------------------------------------------------------ ** FOR YOUR REFERENCE (updated 8/23/96) ** ------------------------------------------------------------------------ HOW TO OBTAIN DOCUMENTS We are currently migrating to a completely Web-based information dissemination system. Please visit our Web site at the following URL: http://www.nsf.gov/ The above files refer to the STIS system, which is being replaced. If you are familiar with STIS, you can use the information above to retrieve these files: Documents via E-mail: Send a message to stisserve@nsf.gov Use the "STIS Filename" shown above in the "get" command. For example, to retrieve nsf9606.txt, the text of your message should be as follows: get nsf9606.txt Anonymous FTP: FTP to stis.nsf.gov. Use the "STIS Filename" shown above to retrieve a file. For example, to retrieve nsf9606.txt, you would enter: ftp> get nsf9606.txt If you want a *printed* copy of a document: Send your name and postal mailing address, and the document title and number to "pubs@nsf.gov". If you have problems with the above procedures: Send a message to "stis@nsf.gov". From owner-sci-resources@net.bio.net Mon Mar 03 22:00:00 1997 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NIH MAIL No Eguide on 2/28 Date: 4 Mar 1997 11:34:41 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 6 Sender: daemon@net.bio.net Approved: biosci-help@net.bio.net Distribution: world Message-ID: <5fhtgh$9ac@net.bio.net> NNTP-Posting-Host: net.bio.net $$MAIL BEGIN *********************************************************** The NIH Guide for Grants & Contract will not be published on February 28, 1997, the next issue of the NIH Guide will be March 7, 1997. Thank you. $$MAIL END************************************************************** $$MAIL END************************************************************** From owner-sci-resources@net.bio.net Sat Mar 08 22:00:00 1997 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NIH GUIDE - PAR-97-042 - V26(07) 03/07/97 Date: 9 Mar 1997 15:15:04 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 342 Sender: daemon@net.bio.net Approved: biosci-help@net.bio.net Distribution: world Message-ID: <5fvg9o$cdl@net.bio.net> NNTP-Posting-Host: net.bio.net INNOVATION GRANT PROGRAM FOR APPROACHES IN HIV VACCINE RESEARCH NIH GUIDE, Volume 26, Number 7, March 7, 1997 PA NUMBER: PAR-97-042 P.T. 34; K.W. 0715008, 0765033, 0755020, 079000 National Institute of Allergy and Infectious Diseases Application Receipt Date: May 23, 1997 PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID) gives special consideration for funding to scientifically meritorious applications in response to our program announcements (PAs). PAs identify current areas of ongoing research emphasis for the NIAID. The NIAID, National Institutes of Health (NIH) on the recommendation of the AIDS Vaccine Research Committee (AVRC), seeks to implement a new program aimed at rapidly exploiting new scientific opportunities to broaden the base of scientific inquiry in areas related to vaccine discovery and development. This program announcement represents the first step in establishing the INNOVATION Grant Program. The NIAID invites applications, including those from researchers previously outside the field of AIDS research, for research projects that involve a high degree of innovation, risk and novelty-- as well as a clear promise of helping to improve vaccine design or evaluation-- in the following three general areas: 1) the structure/function of HIV envelope protein; 2) creation/improvement of animal models for vaccine evaluation and pathogenesis studies; and 3) mechanisms of directing antigen processing in vivo. This INNOVATION Grant Program utilizes a grant mechanism which provides the resources to carry out preliminary tests of feasibility for new research hypotheses, and a rapid and streamlined review and award process. This approach will be evaluated by the AVRC for suitability and responsiveness following this initial offering. If successful, other announcements may be made in the future. 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 PA, Innovation Grant Program for Approaches in HIV Vaccine Research, is related to the priority areas of HIV infection, and immunization and infectious diseases. 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) through the Superintendent of Documents, government Printing Office, Washington, DC 20402-0325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, foreign for-profit and non-profit organizations, both 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 Research projects will be supported with the exploratory/developmental research grant mechanism (R21). This mechanism provides short-duration support for preliminary studies of a highly speculative nature which are expected to yield, within this time frame, sufficient information upon which to base a well-planned and rigorous series of further investigations. Applicants may request up to two years of support and up to $150,000 per annum in direct costs, although with compelling justification exceptions can be made if specific costly reagents, animals, specimens or laboratory modifications are needed to perform these studies. Program staff may be able to advise prospective applicants concerning NIAID-sponsored resources which may be available to them. Please contact the program staff listed under INQUIRIES for further information. The award is non-renewable; however, applicants may elect to seek continuing support for this research through the R01 mechanism. RESEARCH OBJECTIVES After an initial examination of the state of the art of HIV vaccine discovery, the National Institute of Allergy and Infectious Diseases and the AIDS Vaccine Research Committee seek to broaden the base of scientific inquiry in three key scientific areas related to HIV vaccine discovery and development. o The structures of HIV envelope proteins as they relate to their function as immunogens. Examples of areas of interest include, but are not limited to: - Understanding the oligomeric structure of the envelope protein both free and on the virion; - Novel approaches to a detailed understanding of the structure of Env as it interacts with cellular receptors upon virus entry; - Development of methods to preserve native structure and evaluate different protein forms as immunogens; o Creation of new animal models for vaccine evaluation and pathogenesis studies, or innovations to improve existing animal models. Examples of areas of interest include, but are not limited to: - Methods to produce populations of primates that can accept grafts of hematopoietic cells (e.g., populations of macaques that are twins, or clonally-derived or otherwise rendered MHC-compatible); - Novel small animal models produced with transgene that render them sensitive to HIV infection. - Creation or study of SCID mice, or other animals, that would allow for analysis of protective cellular immune responses through passive transfer of cells from infected immunized, or exposed and uninfected humans or primates. o Mechanisms of directing in vivo antigen processing to maximize immune response. Examples of areas of interest include, but are not limited to: - Defining and comparing pathways of processing various HIV/SIV vaccine classes (e.g., subunit, recombinant, whole killed, live attenuated, DNA) by various antigen processing cells (e.g., APC subsets, macrophages, B cells); - Developing methods to expand, in vitro, each of the processing and/or presenting cells such that they can be charged with SIV/HIV vaccine candidates, ex vivo. - Developing assays to test the APC subsets for their ability to stimulate TH1, TH2, CTL and B cell responses; - Identifying cytokines and/or other molecules that improve APC functions; - Evaluating vaccine-charged APCs for their ability to induce relevant immunity, in vivo, (e.g., clearance of HIV infected cells, development of appropriate humoral/mucosal immunity). To help meet the research objectives defined by the AIDS Vaccine Research Committee, research applications intended to produce preliminary data or precedent for an idea or a concept are particularly encouraged. 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 are provided that inclusion is inappropriate with respect to the health of the subjects of the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 28, 1994 (FR. 59 14508- 14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. APPLICATION PROCEDURES Applications are to be submitted on form PHS 398 (rev. 5/95), the standard application form for research grants. 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: ASKNIH@odrockm1.od.nih.gov. Application kits may also be obtained electronically via the WWW at http://www.nih.gov/grants/phs398/phs398.html. Applicants must adhere to the format and requirements specified in the PHS 398 application kit, except as noted below. A modular budget application format will be pilot tested, in which budgets and justifications are simplified. Applicants may apply for up to two years of support at up to $150,000 per annum, and total direct costs may be requested in modular increments of $10,000. The form, ~Detailed Budget for Initial Budget Period (page 4 of the PHS 398 application kit, rev. 5/95),~ is not required and will not be accepted at the time of application. Applicants should use the form, ~Budget for Entire Proposed Period of Support (page 5 of the PHS 398 application kit, rev. 5/95),~ leaving blank the categorical budget table and providing only the requested total direct costs for each year and total direct costs for the entire proposed period of support. The budget justification should begin in the space provided, using continuation pages as necessary, and should justify the requested budget on the basis of overall requirements, scientific aims and scope of the proposed research. All project personnel (salaried or unsalaried) should be listed by name, role on project and per cent effort, and a narrative justification provided for each person based on his/her role on the project and proposed level of effort. All consultants should be identified by name and organizational affiliation and the services they will perform should be described. A narrative justification should be provided for any major budget items, other than personnel, which would be considered unusual for the scope of research; otherwise, no specific costs for items or categories should be shown. Applications exceeding $150,000 in requested total direct costs will also require a special justification, identifying the specific costly reagents, animals, specimens or laboratory modifications which are required. Key personnel and their level of effort must be specified, and biosketches provided. If consortium/contractual costs are requested, the percentage of the subcontract total costs (direct and indirect) relative to the total direct cost of the overall project should be specified. The subcontract budget justification should be prepared according to the instructions provided above. The research plan shall be limited to 10 pages, and any appendices to 10 pages. For purposes of identification and processing the application, mark ~YES~ in item 2 on the face page and enter the PA number PAR-97-042 and the title ~INNOVATION Grant Program for Approaches in HIV Vaccine Research.~ The completed, signed original and three (3) legible, single sided copies of the application must be sent or delivered to: Division of Research Grants, National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817-7710 (for express/courier service) At the same time, two complete copies of the application and all five copies of any appendices must be sent or delivered to: Dr. Dianne E. Tingley National Institute of Allergy and Infectious Diseases Solar Building, Room 4C07 6003 Executive Boulevard Rockville, MD 20852-7610 Telephone: (301) 496-2550 REVIEW CONSIDERATIONS Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the Division of Research Grants, NIH, and for responsiveness to the goals of the PA by NIAID staff. Incomplete applications will be returned to the applicant without further consideration. Applications will be evaluated for scientific and technical merit by appropriately constituted Scientific Peer Review Group(s) convened by the NIAID, in accordance with standard NIH review policies. As part of the initial merit review, all applications may undergo a process in which only those applications deemed to have the highest scientific merit will be assigned a priority score and receive a second level review by the National Advisory Council of the National Institutes of Allergy and Infectious Diseases. Review Criteria The Scientific Peer Review Group(s) will consider and score each application according to the following three dimensions of scientific merit, and will also assign an overall priority score for the application. Impact: The quality (e.g. innovativeness, significance, importance) of the idea/hypothesis and the relevance of the idea/concept to understanding host/pathogen interactions and vaccine development; Approach: The appropriateness of the methods, subjects, and materials chosen to produce data addressing the hypothesis; Feasibility: Prospects for accomplishing the objectives, given the requested budget and term of award, the qualifications and research experience of the Principal Investigator and staff, and the access to necessary resources. The Scientific Peer Review Group(s) also will examine the provisions for the protection of human and animal subjects, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to NIAID. The following will be considered in making funding decisions: the scientific and technical merit of the proposed project as determined by peer review, and the availability of funds. In the final selection of applications to be funded, consideration will be given to the ability to achieve balanced coverage of the scientific areas of emphasis recommended by the AIDS Vaccine Research Committee. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Carole A. Heilman., Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases Solar Building, Room 2A16 MSC 7620 6003 Executive Boulevard Bethesda, MD 20892-7610 Telephone: (301) 496-0545 FAX: (301) 402-1505 Email: ch25v@nih.gov Direct inquiries regarding fiscal matters to: Jane Unsworth Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, 4B25 6003 Executive Blvd. Rockville, MD 20892-7610 Telephone: (301) 402-6824 Fax: (301) 480-3780 Email: ju3a@nih.gov Direct inquiries regarding review matters to: Dianne Tingley, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, 4C07 MSC 7610 6003 Executive Blvd. Rockville, MD 20892-7610 Telephone: (301) 496-2550 Fax: (301) 402-2638 Email: dt15g@nih.gov AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301(c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citation is both (No. 93.855 - Immunology, Allergy, and Transplantation Research and No. 93.856 - Microbiology and Infectious Disease Research ). Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems 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. From owner-sci-resources@net.bio.net Sat Mar 08 22:00:00 1997 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NIH GUIDE - PAR-97-041 - V26(07) 03/07/97 Date: 9 Mar 1997 15:14:47 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 394 Sender: daemon@net.bio.net Approved: biosci-help@net.bio.net Distribution: world Message-ID: <5fvg97$cbs@net.bio.net> NNTP-Posting-Host: net.bio.net PILOT GRANTS IN GERIATRICS NIH GUIDE, Volume 26, Number 7, March 7, 1997 PA NUMBER: PAR-97-041 P.T. 34; K.W. 0710010, 0710030 National Institute on Aging Application Receipt Dates: March 17, July 17, November 17, 1997 PURPOSE The Geriatrics Program of the National Institute on Aging (NIA) is seeking small grant (R03) applications to stimulate and facilitate research in underdeveloped topics in specific areas of aging research. This Small Grant (R03) Program provides support for pilot research that is likely to lead to a subsequent individual research project grant (R01) or a First Independent Research Support and Transition (FIRST) (R29) award application and/or a significant advancement of aging research. These R03 projects include, but are not limited to, research which is innovative and/or high risk. 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 PA, Pilot Grants in Geriatrics, is related to the priority area of chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-11474-0 or Summary Report: Stock No. 017-001-11473-1) 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, 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. Foreign organizations and institutions are not eligible. Participation in the program by investigators at minority institutions is strongly encouraged. To be eligible for this award, the proposed Principal Investigator must, at a minimum, be an independent investigator at the beginning of her/his research career as defined by the eligibility requirements for a FIRST (R29) award. That is, they should be genuinely independent of a mentor. Individuals in the final stages of training may apply, but individuals can not be in a training status at the time the award is made. Established investigators proposing research unrelated to a currently funded research program are also eligible to apply for these grants. MECHANISM OF SUPPORT Applicants may request up to $50,000 (direct costs) for one year through the small grant (R03) mechanism. However, the grants will be awarded under Expanded Authorities and are eligible for a single one-year no cost extension. These awards are not renewable. Before completion of the R03, investigators are encouraged to seek continuing support for research through a research project grant (R01) or FIRST (R29) award. Salary support may be requested along with other costs and is included in the $50,000 (direct costs). Replacement of the Principal Investigator on this award is not permitted. RESEARCH OBJECTIVES The Small Grant program is designed to support new, junior, and established investigators interested in conducting research on underdeveloped topics in geriatrics and aging research. Collection of new data or secondary analysis of existing data are allowed. Topics of interest are limited to those listed below and applications not on these topics will be returned to the applicant without review. o Preliminary studies needed for epidemiologic research projects on genetic factors affecting longevity, active life expectancy, or rate of progression of age-related pathologies. Examples of such preliminary studies include, but are not limited to: analyses of existing familial, demographic, and/or epidemiologic data for feasibility and power calculations; pilot testing of proband-identification and recruitment strategies; identifying, determining the frequency of, and estimating the relative risk associated with specific polymorphisms at one or more loci of interest. (See also related program announcement on "Small Research Grants (R03) Program: Secondary Analysis in Demography and Economics of Aging," NIH Guide, Vol. 26, No. 3, January 31, 1997.) Direct inquiries on this topic to Dr. Evan Hadley at the address listed under INQUIRIES. o Preliminary clinical studies to explore potential benefits, feasibility, and/or risks of administering gonadal or adrenal androgens (e.g., testosterone, DHEA) or their analogs or secretagogues, to older persons whose levels of these factors are diminished or dysregulated relative to younger persons (either chronically or acutely) or to test other potential therapeutic benefits or risks of administering these agents to older people. Direct inquiries on this topic to Dr. Sherry Sherman at the address listed under INQUIRIES. o Clinically related studies focusing on a systems physiology or integrative approach in defining age-associated changes in the cardiovascular system and how these changes increase the risk of cardiovascular disease. Direct inquiries on this topic to Dr. Andre Premen at the address listed under INQUIRIES. o Preliminary clinical studies designed to contribute to the improvement of vaccines for use in elderly populations. This may include studies of methods to improve the immune response in older persons including alternate immunization schedules with existing vaccines or the use of new vaccines. Clinical studies designed to characterize immunosenescence in older human populations are also appropriate as they may contribute to the identification of potentially correctable deficiencies. Direct inquiries on this topic to Dr. Stanley Slater at the address listed under INQUIRIES. 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 are provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. APPLICATION PROCEDURES The submission, review, and award schedule for the Small Grant Program for 1997/1998 is: Application Receipt Dates: Mar 17 Jul 17 Nov 17 Institute Committee Review: Jun-Jul Oct-Nov Feb-Mar Earliest Funding: Sep 97 Jan 98 May 98 Only one Small Grant application may be submitted by a Principal Investigator per receipt date. Applicants may not submit R01 or R29 applications on the same topic concurrent (to be considered at the same review cycle) with the submission of a Small Grant application. Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and prepared according to the directions in the application packet, with the exceptions noted below. 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, e-mail: asknih@odrockm1.od.nih.gov. On the face page of the application: Item 2 Type "Pilot Grants (R03) in Geriatrics." Check the "YES" box. Sections 1-4: Do not exceed a total of ten pages for the following sections: specific aims, background and significance, progress report/preliminary studies, and experimental design and methods. Tables and figures are included in the ten page limitation. Applications that exceed the page limitation or PHS requirements for type size and margins (Refer to PHS 398 application for details) will be returned to the investigator without review. The ten page limitation does not include Sections 5-9 (Human Subjects, Consortia, Literature cited). "Just-in-time" (JIT) is an initiative of the National Institutes of Health (NIH) Extramural Reinvention Laboratory under the auspices of the National Performance Review and government-wide efforts to create a government that works better and costs less. JIT postpones the collection of certain information that currently must be included in all competing applications when submitted. The information for the applications with a likelihood of funding is submitted "just-in-time" for awards to be made. This program announcement is incorporating JIT procedures as described below. 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 your application receives a priority score in the fundable range. Form DD - Page 4 - DETAILED BUDGET PLAN FOR INITIAL BUDGET PERIOD Do not complete this form on page 4 of the PHS 398 (rev. 5/95). It is not required nor will it be accepted at the time of the application. Form EE - Page 5 - BUDGET FOR THE ENTIRE PROPOSED PROJECT Do not complete the categorical budget table form on page 5 in the PHS 398 (rev. 5/95). Only the requested total direct costs for each year and total direct costs for the entire proposed period of support should be shown. Begin the budget justification in the space provided, using continuation pages as needed. Budget Justification o List the name, role on project, and percent effort for all project personnel (salaried or unsalaried) and provide a narrative justification for each person based on his/her role on the project and proposed level of effort. o Identify all consultants by name and organizational affiliation and describe the services to be performed. o Provide a narrative justification for any major budget items, other than personnel, that are requested for the conduct of the project that would be considered unusual for the scope of the research. No specific costs for items or categories should be shown. o Indirect costs will be calculated at the time of the award using the institution's actual indirect cost rate. Applicants will be asked to identify the indirect cost exclusions prior to award. o If consortium/contractual costs are requested, provide the percentage of the subcontract total costs (direct and indirect) relative to the total direct costs of the overall project. The subcontract budget justification should be prepared following the instructions provided above. Biographical Sketch - A biographical sketch is required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. o Complete the education block at the top of the form page; o List current position(s) and those previous positions directly relevant to the application; o List selected peer-reviewed publications directly relevant to the proposed project, with full citation; o Provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. Title, principal investigator, funding source, and role on project must be provided. Other Support - Do not complete the other support page (format page 7 of the PHS 398 (rev. 5/95)). Information on active support for key personnel will be requested prior to award. Checklist - Do not submit the checklist page. For amended applications, applicants must complete the block in the upper right corner of the face page to indicate the previous grant number. A completed checklist will be required prior to award. Submit a signed original of the application, including the checklist, and three exact photocopies in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 -MSC-7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/overnight service) In addition, to expedite the review of the application, submit two additional exact photocopies of the application directly to: Chief, Scientific Review Office National Institute on Aging Gateway Building Suite 2C212, MSC 9205 7201 Wisconsin Avenue Bethesda, MD 20892-9205 In order not to delay review, it is important that applicants comply with this request. REVIEW CONSIDERATIONS Small grant applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be reviewed for scientific and technical merit by a review committee of the National Institute on Aging, in accordance with the standard NIH peer review procedures. Applications will be evaluated with respect to the following criteria: o Importance of the area to aging research o Feasibility of the proposed exploratory research o Likelihood of the proposed pilot project leading to the development of an R01/R29 grant application, or significant advancement of aging research. o Adequacy of approach and scientific originality and significance o Appropriateness of the proposed budget and timetable in relation to the scope of the proposed research o Qualifications and research experience of the principal investigator. o Availability of resources necessary for the research, including any needed to supplement the budget. o The adequacy of the proposed means for protecting against or minimizing potential adverse effects upon humans, animals, or the environment. o Adequacy of adherence to guidelines for including gender and minority representation in any study population. AWARD CRITERIA Applications will compete for available funds with all other scored 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: Evan Hadley, M.D. Geriatrics Program National Institute on Aging Gateway Building, Room 3E327 Bethesda, MD 20892-9205 Telephone: (303) 435-3044 FAX: (301) 402-1784 Email: hadleye@gw.nia.nih.gov Sherry Sherman, Ph.D. Endocrinology and Musculoskeletal Branch National Institute on Aging Gateway Building, Room 3E327 Bethesda, MD 20892-9205 Telephone: (301) 496-3048 FAX: (301) 402-1784 Email: shermans@gw.nia.nih.gov Andre Premen, Ph.D. Cardiovascular Research Program National Institute on Aging Gateway Building, Room 3E327 Bethesda, MD 20892-9205 Telephone: (301) 496-6761 FAX: (301) 402-1784 Email: premena@gw.nia.nih.gov Stanley L. Slater, M.D. Geriatrics Program National Institute on Aging Gateway Building, Room 3E327 Bethesda, MD 20892-9205 Telephone: (301) 496-6761 FAX: (301) 402-1784 Email: slaters@gw.nia.nih.gov Direct inquiries regarding fiscal matters to: Mr. David Reiter Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 7201 Wisconsin Avenue MSC 9205 Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: David_Reiter@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.866. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. From owner-sci-resources@net.bio.net Sat Mar 08 22:00:00 1997 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NIH GUIDE - PAR-97-040 - V26(07) 03/07/97 Date: 9 Mar 1997 15:14:28 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 402 Sender: daemon@net.bio.net Approved: biosci-help@net.bio.net Distribution: world Message-ID: <5fvg8k$car@net.bio.net> NNTP-Posting-Host: net.bio.net NIA PILOT RESEARCH GRANT PROGRAM IN NEUROSCIENCE AND BIOLOGY NIH GUIDE, Volume 26, Number 7, March 7, 1997 PA NUMBER: PAR-97-040 P.T. 34; K.W. 1002030, 1002006, 0710010 National Institute on Aging Application Receipt Dates: March 17, July 17, November 17, 1997 PURPOSE The National Institute on Aging (NIA) is seeking small grant (R03) applications to: (1) stimulate and facilitate the entry of promising new investigators into the neuroscience and biology of aging and (2) encourage established investigators to enter new targeted, high priority areas in these research fields. This Small Grant (R03) Program provides support for pilot research that is likely to lead to a subsequent individual research project grant (R01) or a First Independent Research Support and Transition (FIRST) (R29) award application and /or a significant advancement of aging research. 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, NIA Pilot Research Grant Program in Neuroscience and Biology, is related to the priority areas of unintentional injuries, diabetes and chronic disabling conditions, and immunization and infectious diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-11474-0 or Summary Report: Stock No. 017-001-11473-1) 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, 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. Foreign organizations and institutions are not eligible. Participation in the program by investigators at minority institutions is strongly encouraged. Pilot project grants awarded through this Program Announcement may not be used to support thesis or dissertation research. To be eligible for this award as a new investigator in aging, the proposed Principal Investigator (PI) should be an independent investigator at the beginning of her/his career. If the applicant is in the final stages of training, it is permissible to apply for an R03 but awards cannot be made to anyone still in training status at the time of award. Established investigators proposing research unrelated to a currently funded research program are also eligible to apply for these grants. MECHANISM OF SUPPORT Applicants may request up to $50,000 (direct costs) for one year through the small grant (R03) mechanism. However, the grants will be awarded under Expanded Authorities and are eligible for a single one-year no cost extension. These awards are not renewable. Before completion of the R03, investigators are encouraged to seek continuing support for research through a research project grant (R01) or FIRST (R29) award. The award may not be used for salary support for the principal investigator, but may be used to support the costs of technicians or fellows to carry out the research. Replacement of the Principal Investigator on this award is not permitted. Revisions of applications previously reviewed under this initiative but unfunded are not permitted. RESEARCH OBJECTIVES The Small Grant program is designed to support independent basic and clinical scientists who are interested in entering the research fields of the neuroscience or biology of aging. Targeted aims For 1997, investigators may apply for a small grant to support research on one of the following topics relevant to aging research: o Age-related factors in HIV infection, latency, progression and severity; and the susceptibility of the aging nervous system to HIV infection and AIDS-associated opportunistic infections. o Immunobiology of aging including cellular and molecular approaches, as well as neural and neuroendocrine mechanisms and pathways modulating the aging immune system. o Molecular mechanisms regulating age-related alterations in gene expression including transcriptional, post-transcriptional, and translational processes and protein structural or conformational changes in either neural or non-neural tissues. o Development of novel biological resources for aging research (e.g., animal models, other models, molecular reagents and probes). o Basic underlying mechanisms of musculoskeletal aging (muscle, bone, cartilage). o Molecular basis of cardiovascular aging. o Nutritional factors and aging. o Biology of age-related prostate growth. o Mechanisms underlying changes in sleep and circadian processes in older organisms. o Neural mechanisms of age-related changes in attention and frontal lobe executive processes. o Mechanisms underlying changes in sensory and motor processing in the aging nervous system. o Novel tract-tracing procedures to identify age-related changes in neuronal connections and degeneration in post-mortem tissues. o Investigations into neuroglia function in aging that examine cellular and molecular factors controlling glial cell activation, death, neurotransmitter receptor and transport functions, and mitochondrial and other abnormalities leading to neuronal oxidative damage. Applications for support in areas other than those stated will be returned to the proposed Principal Investigator without review. The National Institute on Aging will modify the selected topic areas annually by reissuing the program announcement. Information on other initiatives supported by NIA may be found at the following internet address: http://www.nih.gov/nia . 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 are provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and prepared according to the directions in the application packet, with the exceptions noted below. 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: ASKNIH@ODROCKM1.OD.NIH.GOV. On the face page of the application: Item 2 Type "NIA PILOT RESEARCH GRANT PROGRAM IN NEUROSCIENCE AND BIOLOGY". Check the "YES" box. Only one Small Grant application may be submitted by a principal investigator per receipt date. Applicants may not submit R01 or R29 applications on the same topic concurrent (to be considered at the same review cycle) with the submission of a Small Grant application. The submission, review, and award schedule for this Small Grant Program for 1997 is: Application Receipt Dates: Mar 17 Jul 17 Nov 17 Institute Committee Review: Jun-Jul Oct-Nov Feb-Mar Earliest Funding: Sep 97 Jan 98 May 98 In a cover letter, identify the specific research topic relevant to your research from the bulleted items in the RESEARCH OBJECTIVES section of this program announcement. Also indicate whether you are a new investigator to aging or an established investigator entering a new area of aging research. Sections 1-4: Do not exceed a total of ten pages for the following sections: specific aims, background and significance, progress report/preliminary studies, and experimental design and methods. Tables and figures are included in the ten page limitation. Applications that exceed the page limitation or PHS requirements for type size and margins (Refer to PHS 398 application for details) will be returned to the investigator. The ten page limitation does not include Sections 5-9 (Human Subjects, Consortia, Literature cited). "Just-in-Time" Instructions: "Just-in-Time" (JIT) is an initiative of the National Institutes of Health Extramural Reinvention Laboratory under the auspices of the National Performance Review and government-wide efforts to create a government that works better and costs less. JIT postpones the collection of certain information that previously was included in all competing applications when submitted. The information for the applications with a likelihood of funding is submitted "just-in-time" for awards to be made. This delayed exchange of information significantly relieves the administrative burden for the 75 to 80 percent of applicants who will not receive an award. In addition, the information that is exchanged "just-in-time" for award will be current, rather than several months old as is currently the case (which often necessitates a request for updated information, e.g., for other support). Detailed Budget for Initial Budget Period - Do not complete form page 4 of the PHS 398 (rev. 5/95). It is not required nor will it be accepted at the time of application. In some cases it may be requested prior to award. Budget for Entire Proposed Period of Support - Do not complete the categorical budget table on form page 5 in the PHS 398 (rev. 5/95). Only the requested total direct costs for each year and total direct costs for the entire proposed period of support should be shown. Begin the budget justification in the space provided, using continuation pages as needed. Budget Justification o List the name, role on project and percent effort for all project personnel (salaried or unsalaried) and provide a narrative justification for each person based on his/her role on the project and proposed level of effort. o Identify all consultants by name and organizational affiliation and describe the services to be performed. o Provide a narrative justification for any major budget items, other than personnel, that are requested for the conduct of the project that would be considered unusual for the scope of research. No specific costs for items or categories should be shown. o Indirect costs will be calculated at the time of the award using the institution's actual indirect cost rate. Applicants will be asked to identify the indirect cost exclusions prior to award. o If consortium/contractual costs are requested, provide the percentage of the subcontract total costs (direct and indirect) relative to the total direct costs of the overall project. The subcontract budget justification should be prepared following the instructions provided above. Biographical Sketch - Biographical sketches are required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. o Complete the education block at the top of the form page; o List current position(s) and those previous positions directly relevant to the application; o List selected peer-reviewed publications directly relevant to the proposed project, with full citation; o Provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. Title, principal investigator, funding source, and role on project must be provided. Other Support - Do not complete the other support page (format page 7 of the PHS 398 (rev. 5/95)). Information on active support for key personnel will be requested prior to award. Checklist - Do not submit the checklist page. A completed checklist will be required prior to award. Submit a signed, original of the application, including the checklist, and three exact photocopies in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC-7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/overnight service) In addition, to expedite the review of the application, submit two additional exact photocopies of the application directly to: Chief, Scientific Review Office National Institute on Aging Gateway Building Suite 2C212, MSC 9205 7201 Wisconsin Avenue Bethesda, MD 20892-9205 In order not to delay review, it is important that applicants comply with this request. Amended applications will not be allowed. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be reviewed for scientific and technical merit by a review group of NIA, in accordance with the standard NIH peer review procedures. Applications will be evaluated with respect to the following criteria: o Importance of the area to aging research. o Feasibility of the proposed exploratory research. o Likelihood of the proposed pilot project leading to the development of an R01/R29 grant application, or significant advancement of aging research. o Adequacy of approach and scientific originality and significance. o Potential for high gain, perhaps with high risk. o Appropriateness of the proposed budget and timetable in relation to the scope of the proposed research. o Qualifications and research experience of the principal investigator. o Availability of resources necessary for the research, including any needed to supplement the budget. o The adequacy of the proposed means for protecting against or minimizing potential adverse effects upon humans, animals, or the environment. o Adequacy of adherence to guidelines for including gender and minority representation in any study population 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: Dr. David B. Finkelstein Biology of Aging Program Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: BAPquery@gw.nia.nih.gov Dr. Judy Finkelstein Neuroscience and Neuropsychology of Aging Program Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: NNAquery@gw.nia.nih.gov The address and general E-mail address for all the above is: National Institute on Aging Gateway Building, Suite 2C212 7201 Wisconsin Avenue MSC 9205 Bethesda, MD 20892 Email: NIAPILOT@gw.nia.nih.gov Direct inquiries regarding fiscal matters to: Robert Pike Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 7201 Wisconsin Avenue MSC 9205 Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: pikeR@gw.nia.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance No. 93.866. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. From owner-sci-resources@net.bio.net Sat Mar 08 22:00:00 1997 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NIH GUIDE - RFA CA-97-014 - V26(07) 03/07/97 Date: 9 Mar 1997 15:14:12 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 883 Sender: daemon@net.bio.net Approved: biosci-help@net.bio.net Distribution: world Message-ID: <5fvg84$ca3@net.bio.net> NNTP-Posting-Host: net.bio.net PIVOTAL CLINICAL TRIALS FOR CHEMOPREVENTION AGENT DEVELOPMENT NIH GUIDE, Volume 26, Number 7, March 7, 1997 RFA: CA-97-014 P.T. 34; K.W. 0715035, 0755015, 0740018 National Cancer Institute Letter of Intent Receipt Date: April 3, 1997 Application Receipt Date: May 22, 1997 PURPOSE The Division of Cancer Prevention and Control (DCPC), National Cancer Institute (NCI) invites applications to further the drug development efforts of the Chemoprevention Branch by carrying out intermediate-sized Phase II/III efficacy trials of promising chemopreventive agents in major cancer target organs, particularly prostate, breast, lung, colon, and bladder. Currently, most NCI-sponsored Phase II clinical trials enroll fewer than 100 participants and evaluate a spectrum of potential SEBs as study endpoints over a relatively brief study period (2 weeks 6 months). This is in contrast to the large Phase III clinical chemoprevention trials with tamoxifen, finasteride (Proscar), and aspirin conducted under the direction of the Community Oncology & Rehabilitation Branch or the Chemoprevention Branch which are enrolling 10,000 22,000 participants and evaluating clinical parameters, such as cancer incidence reduction, over many years. This comparison emphasizes the need for Phase II/III chemoprevention clinical trials of intermediate size and duration which are designed to establish the efficacy of promising agents and the validity of the most promising histopathologic and laboratory-based SEBs currently held to be "reasonably certain" predictors of cancer prevention. Because of the critical nature of the biomarkers used in Phases I IIb of clinic al chemopreventive drug development, the careful scientific conduct of these biomarker assessments is considered essential to progress in chemoprevention. Measurement of these biomarkers is crucial. It is anticipated that biomarkers validated through these intermediate Phase II/III studies could be used in future efficacy evaluations of new chemopreventive compounds and in clinical and regulatory decision-making. As described above, the intermediate-sized clinical trials supported through this RFA are a pivotal decision point in the NCI chemoprevention drug development program. The consensus view of a Working Group from the NCI and the FDA acknowledges that "the interim analysis of a validated surrogate endpoint of cancer incidence may facilitate the timely and cost-effective marketing of efficacious drugs (Kelloff et al., Cancer Epidemiol. Biomark. Prev. 4: 1-10, 1995)." Thus the efficacy and safety data from these studies potentially supports FDA marketing approval (NDA applications) for chemoprevention indications, and certainly facilitates decisions regarding the most appropriate recommendations for subsequent large, community-based efficacy studies. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000", a PHS-led national activity for setting priority areas. This RFA, Pivotal Clinical Trials for Chemoprevention Agent Development, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Applications from minority and women investigators are encouraged. For those respondents affiliated with the Community Clinical Oncology Program (CCOPs), it is suggested that proposals be submitted through the CCOPs mechanism. MECHANISM OF SUPPORT This RFA will use the cooperative agreement (U01) mechanism. The cooperative agreement is an assistance mechanism in which substantial involvement of the NCI with the recipient is anticipated during the performance of the planned activity. The nature of the NCI's involvement is described under SPECIAL REQUIREMENTS, 2. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant/awardee. The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date is September 1997. This RFA is a one-time solicitation. Future unsolicited competitive continuation applications will compete with all other investigator-initiated research applications and be peer reviewed by a study section in the Division of Research Grants (DRG), NIH. However, if it is determined that there is a sufficient continuing need, the NCI will invite recipients of awards made under this RFA in FY 97 to submit competitive continuing applications for review according to procedures described below under APPLICATION PROCEDURES and REVIEW CONSIDERATIONS. FUNDS AVAILABLE Approximately $3 million in total costs for the first year of support for the program will be committed specifically to fund applications submitted in response to this RFA. It is anticipated that 3-4 awards will be made. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of the awards will vary also. Awards and the level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI, awards made pursuant to this RFA will be contingent on the continued availability of funds for this purpose. RESEARCH OBJECTIVES Background The purpose of this initiative is to enhance clinical cancer prevention research. This RFA seeks to build on information from Chemoprevention Branch contract-supported agent identification, preclinical testing, and Phase I and early Phase II clinical studies of promising agents by supporting their continued systematic development in longer, intermediate-sized Phase II/III clinical trials. The goals for these pivotal clinical studies comprise (1) expansion and refinement of information from the smaller Phase II trials on efficacy, participant recruitment and retention, adverse effects, and acceptability of treatment over time; (2) validation of surrogate endpoint biomarkers (SEBs) selected from experience in the Phase II studies; and (3) diversification of the target populations for the chemopreventive interventions. Results of these pivotal clinical trials may support New Drug Applications (NDAs) to the FDA, where appropriate, for chemoprevention indications and larger community-based cancer prevention clinical trials with incidence reduction endpoints. As our understanding of carcinogenesis increases, preventive interventions become increasingly practical for many primary cancer sites. While prevention of carcinogen exposures and lifestyle changes may eventually alter cancer incidence, pharmacologic interventions offer an attractive approach with the potential for more immediate results. The drug development process for these chemopreventive agents, in contrast to that for cancer therapy drugs, has unique requirements because of the generally good health status of their target populations, the anticipated long duration of use, and the low level of acceptable toxicity. The NCI's chemoprevention drug development program has the mission of identifying safe and effective chemical agents for preventing human cancer. This program is an applied drug development science effort with clinical trials as its endpoint. It begins with the identification of candidate agents for development and the characterization of these candidates for efficacy using in vitro and animal screens. Promising agents are then further tested in animal models to explore their potential for clinical application, with regard to both safety and efficacy. The most successful agents then progress to clinical trials. The ultimate goal of this process is to achieve accurate and reliable information on long-term efficacy and safety that will support marketing approval and widespread clinical use. In contrast to the development of therapeutic agents, the identification and validation of biomarkers characterizing the neoplastic process are key aspects of the chemoprevention drug development process. SEBs are defined as measurable and modulatable biological or chemical properties that are highly correlated to cancer incidence and that may serve as indicators of the likely incidence or progression of cancer. While traditional Phase I drug development studies focus on pharmacokinetics and tolerability of the investigational agent, Phase I chemoprevention studies are designed to develop and evaluate biologic markers of drug effect and SEBs, besides obtaining required pharmacokinetic and safety information. Phase II chemoprevention studies characterize dose-biomarker response and more common chronic toxicities, to identify safe and effective doses for further studies. When clearly defined and standardized biomarkers are not known, Phase IIa dose-response studies are undertaken to evaluate the feasibility of candidate biomarker measurements (for drug effects and/or SEBs) and to standardize assay conditions and develop quality control procedures. Phase IIb chemoprevention studies are done subsequently to establish the dose-response relationship of SEB modulation and the toxicities associated with chronic administration in order to select a safe and effective dose for Phase III clinical trials. Scope and Objectives This RFA will support Phase II/III randomized, placebo-controlled clinical trials to evaluate the chemopreventive efficacy of selected agents or regimens in target populations consistent with the Clinical Development Plans of the DCPC Agent Development Committee (see Journal of Cellular Biochemistry Supplement 20, 1994 and Supplement 26, 1996). Investigators may propose any cohort, intervention, or drug for which justification and developmental support can be provided. The following list is provided as an example only but for which preclinical, early clinical, drug supply, and regulatory support may be available: 1. Prevention of colorectal adenomas in patients having a history of colorectal adenomas or early stage colon carcinoma using selected nonsteroidal antiinflammatory drugs (NSAIDs, including less toxic derivatives), 2-difluoromethylornithine (DFMO), Oltipraz, or the combinations of calcium with vitamin D or an NSAID and of DFMO with an NSAID; 2. Prevention of prostatic intraepithelial neoplasia (PIN), its progression, and cancer incidence by antiandrogens (e.g., flutamide or bicalutamide), vitamin E, selenium, the combination of vitamin E with selenium, fluasterone (DHEA analog 8354), selected retinoids [e.g., all-trans-N-(4-hydroxyphenylretinamide) (4-HPR) or 9-cis-retinoic acid], or 5`-reductase inhibitors (e.g., finasteride); 3. Prevention of bronchial dysplasia, its progression, or second primary upper aerodigestive cancer in patients with a history of resected early stage NSCLC or laryngeal cancer by retinoids (e.g., 4-HPR, 9-cis-retinoic acid or all-trans retinoic acid, possibly in aerosolized formulations), Oltipraz, N-acetyl-l-cysteine (NAC), or the combinations of Oltipraz with NAC or 4-HPR; 4. Modulation of biomarkers (including mammographic patterns) and new proliferative or precancerous lesions in patients with atypical ductal or lobular hyperplasia or lobular carcinoma in situ by anti-estrogens, retinoids (e.g., 4-HPR or 9-cis-retinoic acid), fluasterone or low-dose DHEA, DFMO, or the combination of vitamin E with selenium; 5. Prevention of dysplastic oral leukoplakia, its progression, and oral cancer by Oltipraz (in chronic smokers), 4-HPR, DFMO or curcumin; 6. Prevention of cervical intraepithelial neoplasia (CIN II/III), its progression, and cervical cancers by 4-HPR, DFMO, Oltipraz, or selected NSAIDs; 7. Prevention of recurrence or new lesions in patients with Ta/T1 bladder carcinoma with or without TIS (post-BCG) by 4-HPR, DFMO, or selected NSAIDs; 8. Prevention of precancerous lesions in Barrett's esophagus, their progression, and esophageal cancers by DFMO, retinoids, or Oltipraz. 9. Progression of precancerous lesions of the skin, their progression, and skin cancer by DFMO, retinoids or Curcumin. Study endpoints should include changes in the most promising SEBs (such as those in preinvasive disease or proliferative disease), the development of new premalignant lesions, and, as appropriate, the occurrence of new invasive cancers. This emphasis on SEBs requires that the research team include strong collaborative support from the areas of pathology, biochemistry and molecular biology, and cancer biology and carcinogenesis. The clinical trial design should include an adequate number of participants and should be of sufficient duration to assure statistical power to address the study questions of chemopreventive efficacy, long-term safety and acceptability, and SEB validation. To this end, biostatistics and clinical trial design expertise should be included from the first efforts in study planning and design. Study size and duration will vary according to specific study hypotheses, target population, agent(s), and SEBs and other endpoints. SPECIAL REQUIREMENTS General Currently, most NCI-sponsored Phase II clinical trials enroll fewer than 100 participants and evaluate a spectrum of potential SEBs as study endpoints over a relatively brief study period (2 weeks 6 months). This is in contrast to the large Phase III clinical chemoprevention trials with tamoxifen, finasteride (Proscar ), and aspirin conducted under the direction of the Community Oncology and Rehabilitation Branch or the Chemoprevention Branch which are enrolling 10,000 22,000 participants and evaluating clinical parameters, such as cancer incidence reduction, over many years. This comparison emphasizes the need for Phase II/III chemoprevention clinical trials of intermediate size and duration which are designed to establish the efficacy of promising agents and the validity of the most promising histopathologic and laboratory-based SEBs currently held to be "reasonably certain" predictors of cancer prevention. Because of the critical nature of the biomarkers used in Phases I IIb of clinic al chemopreventive drug development, the careful scientific conduct of these biomarker assessments is considered essential to progress in chemoprevention. Measurement of these biomarkers is crucial. It is anticipated that biomarkers validated through these intermediate Phase II/III studies could be used in future efficacy evaluations of new chemopreventive compounds and in clinical and regulatory decision-making. As described above, the intermediate-sized clinical trials supported through this RFA are a pivotal decision point in the NCI chemoprevention drug development program. The consensus view of a Working Group from the NCI and the FDA acknowledges that "the interim analysis of a validated surrogate endpoint of cancer incidence may facilitate the timely and cost-effective marketing of efficacious drugs (Kelloff et al., Cancer Epidemiol. Biomark. Prev. 4: 1 10, 1995)." Thus the efficacy and safety data from these studies potentially supports FDA marketing approval (NDA applications) for chemoprevention indications, and certainly facilitates decisions regarding the most appropriate recommendations for subsequent large, community-based efficacy studies. Applications funded under this RFA will be supported through the cooperative agreement (U01) mechanism. An assistance relationship will exist between NCI and the awardees to accomplish the research objectives. As described more fully below, the recipients will have primary responsibility for the development and performance of the activity. However, there will be government involvement with regard to (1) assistance in securing an Investigational New Drug (IND) approval from the Food and Drug Administration (FDA), (2) coordination and assistance in obtaining the chemopreventive agent, and (3) monitoring of study safety and conduct. If an investigator anticipates requiring considerable assistance in obtaining the chemopreventive agent and/or in securing an IND permit from the FDA, such assistance should be sought in writing to and approved by the NCI Program Director, prior to submitting an application. Awards will not be made until all arrangements for obtaining the IND and the agent are completed. Cost of agent and necessary formulation should be included in the budget. Definitions Program Director - the NCI Program Staff official (see INQUIRIES section of this RFA) responsible for the stewardship and monitoring of the award. The Program Director may also function as the Staff Collaborator. Staff Collaborator - the NCI Program Staff Collaborator responsible for contributing expert advice on the scientific design and conduct of the research. Data Safety and Monitoring Committee - the committee composed of external, non-participating scientists appointed by the Principal Investigator to monitor patient safety, conduct data audits, and document progress to the NCI Program Director. Terms and Conditions of Award A. Applicability. These special Terms and Conditions of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS grant administration regulations in 45 CFR part 74 and 92, and other HHS, PHS and NIH grant administration policy statements. The administrative and funding instrument used shall be a cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NCI scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NCI purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with the above concept, the dominant role and prime responsibility for the activity reside with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Staff Collaborator Under the cooperative agreement, a relationship will exist between the recipient of these awards and the NCI, in which the performers of the activities are responsible for the requirements and conditions described below, and agree to accept program assistance from a named NCI Staff Collaborator in achieving project objectives. Failure of an awardee to meet the performance requirements, including these special terms and conditions of award, or significant changes in the level of performance, may result in a reduction of budget, withholding of support, suspension and/or termination of the award. B. Awardee Rights and Responsibilities. The Awardee is responsible for: 1. Research design and protocol development, including definition of objectives and approaches, planning, implementation, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results. 2. Establishing an external Data Safety and Monitoring Committee to review data. The Principal Investigator will name external, non-participating investigators to serve as members on a Data Safety and Monitoring Committee and schedule meetings periodically. The NCI Staff Collaborator will be a non-voting member. 3. Designating Protocol Chairs. The Principal Investigator shall designate a single Protocol Chairperson (if the P.I. does not assume this role). The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for developing and monitoring the protocol. All proposed protocol modifications will be submitted by the Chair through the Principal Investigator to the NCI Program Director, for review and approval, subject to negotiation with the awardee. 4. Implementing the data collection method and strategy. 5. Establishing mechanisms for quality control and monitoring. Awardees are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense; and (3) sufficiently staffed. 6. Submitting interim progress reports, when requested, to the NCI Program Director including as a minimum, summary data on protocol performance. The Data Safety and Monitoring Committee may require additional information. Such reports are in addition to the annual awardee noncompeting continuation progress report. 7. Establishing procedures, where applicable, to comply with FDA regulations of 21 CFR Part 312 for studies involving investigational agents and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects. For IND's sponsored by the NCI, the Principal Investigator is responsible for obtaining approval from both the Institutional Review Board and the NCI Program Director to enroll patients and to change the protocol. The Principal Investigator is also responsible for all aspects of investigational drug acquisition, formulation, distribution, etc. 8. Cooperating in the reporting of the study findings. The NCI will have access to and may periodically review all data generated under an award. Where warranted by appropriate participation, plans for joint publication with NCI of pooled data and conclusions are to be developed by the Principal Investigator, as applicable. NIH policies governing possible co-authorship of publications with NCI staff will apply in all cases. In general, to warrant co-authorship, NCI staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; and (c) preparation and authorship of pertinent manuscripts. The awardee(s) will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS and NIH policies. C. NCI Staff Responsibilities It is expected that the dominant role and prime responsibility for the activity will reside with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Staff Collaborator who will provide expert advice to the awardee(s) on specific scientific and/or analytic issues as described below. The NCI Staff Collaborator will be named later based upon the subject matter of the award. However, the NCI Program Director will retain overall programmatic responsibility for the award and will be the contact point for all facets of interaction with the awardee related to stewardship and monitoring of the award. NCI Program Staff responsibilities will include: 1. Interacting with the Principal Investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the Principal Investigator and staff, periodic site visits for discussions with awardee research team, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Data Safety and Monitoring Committee and related meetings. The NCI retains, as an option, the right to act as Sponsor for an IND filed to support the clinical research and to conduct periodic external review of progress. 2. Participating in the Data Safety and Monitoring Committee meetings. The NCI Staff Collaborator will be an invited attendee and participant of the Data Safety and Monitoring Committee and, if applicable, subcommittees, but will not have a vote on any committee. 3. Serving as a resource with respect to other ongoing NCI activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort. 4. Involvement assisting in the design and coordination of research activities for awardees as elaborated below: a. Assisting by providing advice in the management and technical performance of the investigations, coordinating clearances for investigational agents held by NCI. The NCI reserves the right to crossfile or independently file an Investigational New Drug Application form with the FDA. b. Through participation in meetings/correspondence of the research team, with the agreement of the Principal Investigator, the NCI Staff Collaborator may assist in the design, development, and coordination of the research or clinical protocol, in the statistical evaluations of data, in the preparation of questionnaires and other data recording forms, and in the publication of results. c. Reviewing and approving protocols to insure they are within the scope of peer review and for safety considerations, as required by Federal regulations. The NCI Program Director will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. The NCI will not permit further expenditures of NCI funds for a study after requesting closure (except for patients already on-study). d. Reviewing and providing advice regarding the establishment of mechanisms for quality control and study monitoring. 5. Making recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Data Safety and Monitoring Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements. D. Collaborative Responsibilities In addition to the interactions defined above, NCI Staff and Awardees shall share responsibility for the following activities: 1. Data Safety and Monitoring Committee. A Committee organized by the Principal Investigator will be the main oversight body of the clinical trial. The Data Safety and Monitoring Committee has primary responsibility to review progress, monitor patient accrual, data management, and patient safety, and cooperate on the publication of results. The Data Safety and Monitoring Committee will document progress in written reports to the NCI Program Director, and will provide periodic supplementary reports to designated NCI staff upon request. The Data Safety and Monitoring Committee will be composed of external, non-participating peer Investigators, including those of data coordinating/statistical centers, if any, and the NCI Staff Collaborator. An initial meeting of the Data Safety and Monitoring Committee will be convened early after award by the Principal Investigator. The final structure of the Data Monitoring Committee will be established at the first meeting; the Principal Investigator will not be a member or routine attendee of the Committee after the first meeting. The NCI Staff Collaborator will have nonvoting membership on the Committee, and as appropriate, its subcommittees. Such a Committee usually will meet at least yearly. A Chairperson, other than the NCI representative, will be selected by a vote of the members. The Chairperson is responsible for coordinating the Committee activities, for preparing meeting agendas, and for scheduling and chairing meetings. E. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NCI may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the awardee, a second member selected by NCI, and the third member selected by the two prior selected members. These special arbitration procedures in no way affect the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is NIH policy 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 10-43) and supersedes and strengthens previous policies (Concerning the Inclusion of Women in Study Populations), which have been in effect since 1990. All investigators proposing research involving human subjects should read the "NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register, March 28, 1994 (59 FR 14508-14513) and in the NIH GUIDE FOR GRANTS AND CONTRACTS, March 18, 1994, Volume 23, Number 11. LETTER OF INTENT Prospective applicants are asked to submit, by April 3, 1997, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the names of other key personnel, the participating institutions, and the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, it is requested to provide an indication of the number and scope of applications and to avoid conflict of interest in the review. The letter of intent is to be sent to: Gary J. Kelloff, M.D. Division of Cancer Prevention and Control National Cancer Institute 6130 Executive Boulevard, Suite 201 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier services) Telephone: (301) 496-8563 FAX: (301) 402-0553 Email: kelloffg@dcpcepn.nih.nci.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/95) is to be used for these cooperative agreements. Applications 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: ASKNIH@odrockm1.od.nih.gov. The RFA label available in PHS-398 must be affixed to the bottom of the face page. Failure to use this label could delay processing of the application such that it may not reach the review committee in time for review. Additionally, the title of the RFA, PIVOTAL CLINICAL TRIALS FOR CHEMOPREVENTION AGENT DEVELOPMENT and the RFA number CA-97-014, must be typed in line 2 of the face page and the YES box must be marked. A signed, typewritten original of the application, including the Checklist and three signed, clear, and single-sided photocopies must be submitted in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the same time, two additional copies of the application must also be sent to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Applications must be received by May 22, 1997. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG 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. Preparation of the Application The general instructions provided in PHS-398 for the preparation of applications must be used. Because the Terms and Conditions of Award (discussed in the SPECIAL REQUIREMENTS Section), will be included in all awards issued as a result of this RFA, it is critical that each applicant provide specific plans for responding to the terms and conditions of award and requirements stated in the RFA. Plans must take into account NCI staff involvement as well as how all the responsibilities of awardees will be fulfilled. The following items apply to all applications: 1. Clinical trial designs should include an adequate number of participants and should be of sufficient duration to assure statistical power to address the study questions of chemopreventive efficacy, long-term safety and acceptability, and surrogate endpoint biomarker (SEB) validation. To this end, biostatistics and clinical trial design expertise should be included from the first efforts in study planning and design. 2. A discussion of the evaluation of SEBs, including relevance to the test agent and target population should be provided. 3. A rationale for each test agent should be provided, including relevant epidemiological and laboratory data. Preclinical and clinical toxicity data should also be presented. Where the availability or safety of the agent are in doubt, the applicant should consult with the NCI Program Director or the manufacturer prior to preparing the application. As noted above, applicants anticipating the need of considerable assistance in obtaining the chemopreventive agent(s) to be studied or in securing IND approval, e.g. with respect to adequate preclinical toxicology data, should seek this assistance from the NCI Program Director in writing. The request should be made to the Program Director prior to submission of the application. 4. A rationale for selection of the target patient cohort and an estimate of the number of participants required to complete the clinical studies should be provided. Criteria and calculations used to estimate sample size should be included. The patient cohort should be described and its selection justified. The cohort should be defined, as appropriate by age, sex, race, dietary customs, education, geographic location, occupational or lifestyle risk factors, and relevance to a specific cancer problem or its prevention by the test agent. Accrual rate should be estimated. If multiple institutions are involved, the proposal should include verification of the co-investigators' willingness to participate, and pertinent additional information regarding the cooperating institutions' staff qualifications, resources, research plans, including patient availability and data flow, as well as corresponding budget requirements. 5. Clinical chemistry and biologic aspects of the studies should be completely described, including sample collection, storage, handling, analysis, and quality control. The methods and equipment to be used and the technical qualifications and experience of the personnel involved should be addressed. If these aspects of the studies are to be conducted by groups other than at the applicant's institution, a letter from the cooperating institutions indicating their willingness to participate should be included. 6. Any known or potential toxicity considerations should be described, along with the techniques and procedures to monitor any adverse events and dose modifications to be made based on toxicity. 7. Methods to monitor patient compliance and, as appropriate, methods to document nutrient intake should be specified. 8. A willingness to work cooperatively with the NCI Program Director in the implementation and conduct of the study should be indicated. 9. Applicants from institutions which have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC Program Director or Principal Investigator could be included with the application. REVIEW CONSIDERATIONS A. Review Procedures Upon receipt, applications will be reviewed by the Division of Research Grants (DRG) for completeness and by the NCI for responsiveness. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the Request for Applications will be evaluated for scientific and technical merit in accordance with the review criteria stated below by an appropriate peer review group convened by the NCI. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Cancer Advisory Board. The review group will assess the scientific merit of the studies using the following review criteria: B. Review Criteria Review Criteria for the Proposed Clinical Trial o Scientific merit of the proposed research. This includes design, methodology (including considerations of toxicity, quality assurance, endpoint analyses, and power), and the clinical study protocol. o The significance and importance of the objectives. Basic and clinical scientific significance, as well as originality of the proposed research. Particularly important are the definition of the high-risk target populations and the evaluation biomarkers relative to clinical interventions. o Documentation of relevant prior successful accrual. o The qualifications of the Principal Investigator to serve as both the scientific and administrative leader of the proposed research. The Principal Investigator should be an established scientist with a substantial record of independent research. o The adequacy of the commitment (percent effort) of the Principal Investigator to the proposed research. There should be a specific commitment to both the scientific and administrative aspects of the proposed research though it is not mandatory that the Principal Investigator be a project leader of an individual research project. o The qualifications of Co-Investigators and support personnel. o The presence of an organizational and administrative structure appropriate for effective attainment of the proposed research objectives. o The mechanisms for internal quality control of the research. o The institutional environment in which the research is conducted, including the availability of space, equipment and patients as well as the physical proximity of participants. For applications involving more than one institution, the mechanisms for assuring close coordination and interaction are evaluated. o The adequacy of the proposed means for early detection of and protection against potential adverse effects upon humans and the environment. o The appropriateness of the statistical design and mechanism for the rigorous management and verification of research data. Adequacy of methods for data and tissue collection and analysis. Documentation of validated bioanalytical procedures (method sensitivity, specificity, quality control, etc.) and of prior experience with endpoints to-be-evaluated. o Adequacy of adherence to guidelines for including gender and minority representation in any study population. o The appropriateness of the budget. A realistic budget reflects the project leader's understanding of the scope of work. o Adequacy of plans for NCI Program staff involvement with the proposed research. AWARD CRITERIA The earliest feasible start date for the initial awards will be September 1997. Besides technical merit, NCI will base funding decisions on how well the applicant institutions meet the goals and objectives of the program described in the RFA, as well as on availability of resources and study populations. INQUIRIES Written and telephone inquiries concerning the RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Gary J. Kelloff, M.D. Division of Cancer Prevention and Control National Cancer Institute 6130 Executive Boulevard, Suite 201 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8563 FAX: (301) 402-0553 Email: kelloffg@dcpcepn.nih.nci.gov Inquiries regarding fiscal matters may be addressed to: Ms. Carolyn Mason Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Suite 243 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-7800 Ext. 259 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Number 93.399, Cancer Control. Awards will be made under authority 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 258); and administered under PHS grant policies and Federal Regulations 42 CFR Parts 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirement 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. From owner-sci-resources@net.bio.net Sat Mar 08 22:00:00 1997 Path: biosci!biosci!not-for-mail From: BIOSCI Administrator Newsgroups: bionet.sci-resources Subject: NIH GUIDE - RFA CA-97-005 - V26(07) 03/07/97 Date: 9 Mar 1997 15:13:55 -0800 Organization: BIOSCI International Newsgroups for Molecular Biology Lines: 886 Sender: daemon@net.bio.net Approved: biosci-help@net.bio.net Distribution: world Message-ID: <5fvg7j$c9a@net.bio.net> NNTP-Posting-Host: net.bio.net CHEMOPREVENTION IN GENETICALLY-IDENTIFIED HIGH-RISK GROUPS: INTERACTIVE RESEARCH AND DEVELOPMENT PROJECTS NIH GUIDE, Volume 26, Number 7, March 7, 1997 RFA: CA-97-005 P.T. 34; K.W. 0740018, 0745003, 0715035, 0411005, 0710030 National Cancer Institute Letter of Intent Receipt Date: April 3, 1997 Application Receipt Date: May 22, 1997 PURPOSE The purpose of this initiative is to establish integrated, multidisciplinary research programs that define and evaluate chemopreventive strategies in asymptomatic subjects at high risk for cancer. This Request for Applications (RFA) seeks programs with administrative core functions supporting at least three independent but integrated research projects that share a common focus directed at designing and evaluating chemopreventive strategies in high-risk cohorts. This includes groups with on-going administrative clinical trials core functions and laboratory support such as cooperative groups, CCOP Research Bases and NCI designated cancer centers. At least two of the individual projects must involve Phase I/II or Phase II clinical chemoprevention trials or translational research needed for chemoprevention applications. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Chemoprevention in Genetically-Identified High-Risk Groups: Interactive Research and Development Projects, is related to the priority area of cancer. 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, laboratories, units of state and local governments, and eligible agencies of the Federal government. Applications from minority and women investigators are encouraged. For those respondents affiliated with the Community Clinical Oncology Program (CCOPs), it is suggested that applications be submitted through the CCOPs mechanism. MECHANISM OF SUPPORT This RFA will use the research program cooperative agreement (U19) mechanism. The U19 is essentially the cooperative agreement version of the P01 (Program Project Grant) funding mechanism. Therefore the applicant should use the NCI P01 guidelines in preparing the application. The P01 guidelines are available from the NCI Referral Officer (Ms. Toby Friedberg), listed under APPLICATION PROCEDURES. The cooperative agreement is an assistance mechanism in which substantial involvement of the NCI program with the recipient is anticipated during the performance of the planned activity. The nature of the NCI's involvement is described under SPECIAL REQUIREMENTS and in the TERMS AND CONDITIONS section. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the awardee. The U19 cooperative agreement builds on the leadership of a key Principal Investigator and the interaction of the participating investigators to integrate the individual projects in a way that accelerates the acquisition of knowledge beyond that expected from the same projects conducted separately, without combined leadership or a common theme. Individual investigators may apply their specialized research capabilities to basic, developmental, and clinical aspects, as they relate to the focused, central theme of the overall project. This grant mechanism also offers a way to achieve economy of effort through the sharing of personnel, facilities, equipment, data, ideas, and concepts. The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated award date is September 1997. This RFA is a one-time solicitation. Future unsolicited competitive continuation applications will compete with all other investigator-initiated research applications and be peer reviewed by a study section in the Division of Research Grants (DRG), NIH. However, if it is determined that there is a sufficient continuing need, the NCI will invite recipients of awards made under this RFA in FY 97 to submit competitive continuing applications for review according to procedures described below under APPLICATION PROCEDURES and REVIEW CONSIDERATIONS. FUNDS AVAILABLE Approximately $3 million in total costs for support of the first year of the program will be committed specifically to fund applications submitted in response to this RFA. It is anticipated that three to four awards will be made. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated the sizes of awards will vary also. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI, awards made pursuant to this RFA will be contingent on the continued availability of funds for this purpose. RESEARCH OBJECTIVES Background High risk for cancer may be attributable to inherited or acquired genetic lesions, lifestyle or environmental factors, or combinations of these parameters. Program components include, but are not limited to (1) definition of cohorts, (2) identification and characterization of early precancerous lesions/biomarkers that may contribute to defining cohorts, serve as endpoints for clinical studies, or both, and (3) clinical studies to evaluate the chemopreventive strategies. Successful programs will require expertise in general and molecular cancer epidemiology, genetics, molecular biology, descriptive and quantitative pathology, pharmacology, oncology, and clinical science with attendant capabilities in biostatistics, bioanalytical methodologies, data management and clinical trials management. Support of the translational research needed to bring relevant basic research findings to clinical application in the high-risk cohorts is a major objective. Increasing knowledge of the 20 40 year process of human carcinogenesis is providing many new opportunities for early intervention and prevention, and, specifically, for chemoprevention. A significant part of this knowledge is the association of increased cancer risk with inherited or acquired genetic lesions. Genetic predisposition includes well-characterized germline mutations, many of which are associated with lost tumor suppressor function. Examples are APC (familial adenomatous polyposis leading to colorectal cancer), BRCA1 and BRCA2 (breast and ovarian cancers), and p53 mutations resulting in Li-Fraumeni syndrome (multiple cancers including breast, colorectal, brain and leukemia). Other cancer-predisposing genes such as MLH1 and MSH2 (both linked to hereditary nonpolyposis colon cancer) cause defective DNA repair. Also, recent cancer epidemiology and pharmacogenetic studies have suggested the importance of genetic polymorphisms affecting the ability to detoxify carcinogens e.g., glutathione S-transferase (GSTM1, GSTM2, GSTP1), N-acetyltransferase (NAT1, NAT2), cytochrome P450 (CYP450IAI), and steroid 5 alpha-reductase type II (SRD5A2). Mutations and changes in expression of tumor suppressors acquired during carcinogenesis are also important. Similarly, oncogenes and growth factors activated by mutation or overexpressed during carcinogenesis (e.g., ras, EGFR, c-erbB2) are significant genetic lesions in cancer as are mutations in cyclin and cyclin-related genes implicated in cell cycle control. Besides these specific genetic lesions, general indicators of genetic susceptibility have been developed, for example, mutagen sensitivity as measured by bleomycin-induced DNA break frequency. Although it is not likely that any of these lesions will be eradicated by chemopreventive agents, their presence and activity may be decreased by damping the signal transduction pathways in which they participate, thereby selecting against proliferation of progeny cells containing the lesions or inducing apoptosis in these cells. Environmental, hormonal, lifestyle and other etiological factors contribute to cancer risk and may enhance the risks from genetic predisposition. It is estimated that while approximately 5 percent of cancers are due to genetic predisposition and 15 percent occur spontaneously, the remaining 80 percent are attributable to the environment and environmental-genetic interactions. Chemoprevention strategies should be useful in these situations to reduce mutational frequency and clonal evolution. For example, smokers who are continually exposed to gene-damaging agents may be good candidates for chemopreventive intervention with antimutagens. Also, women at high risk for breast cancer may benefit from chemopreventive intervention that controls breast cell proliferation. Scope and Objectives The purpose of this initiative is establishment of integrated, multidisciplinary research programs that define and evaluate chemopreventive strategies in subjects at high risk for cancer. This RFA is seeking programs with administrative core functions supporting at least three independent research projects which share a common focus directed at designing and evaluating chemopreventive strategies in high-risk cohorts. Program components might include, but are not limited to groups with on-going administrative clinical trials core functions and laboratory support such as cooperative groups, CCOP Research Bases and NCI designated cancer centers. The programs should be directed to further characterizing and defining high-risk cohorts for major cancers, such as those listed above. High-risk may be defined by clinical and epidemiological criteria, linkage analysis or DNA testing or combinations of these parameters. Applications using clinical criteria or linkage analysis should include provisions for tissue collection and storage for future DNA testing. Applicants are strongly encouraged to pursue research objectives consistent with the Clinical Development Plans for chemopreventive agents published by the NCI, DCPC Agent Development Committee (see Journal of Cellular Biochemistry Supplement 20, 1994 and Supplement 26, 1996) for which preclinical efficacy and toxicity information has been developed and for which IND support and drug are available. However, applications should reflect the interests and insights of the investigators. Examples of theme areas for which projects may be proposed, for the purpose of illustration only, might include the following: 1. Women at high risk for breast cancer with atypical epithelial hyperplasia or epithelial hyperplasia and one or more of aneuploidy, elevated PCNA, EGFR or hormone receptors, or mutated p53 by baseline fine-needle aspiration cytology might be randomized to chemopreventive treatment and placebo groups. Primary endpoints of treatment might include cytology, nuclear/nucleolar morphometry, PCNA, EGFR or hormone receptors, p53, and apoptosis (bcl-2/bax). Additional areas of investigation could include genetic analysis of BRCA-1, -2 relative to function and penetrance, LOH at 11q12-13, methylation, other risk factor analysis (e.g., hormone receptor types), and surveillance (e.g., as related to DCIS, LCIS, and ovarian cancer), or other basic research questions explored using animal model or cell culture techniques. Correlative studies using NMR, digital imaging mammography, sonoelastography, neoangiogenesis MRI, etc. could also be undertaken. 2. Patients with familial adenomatous polyposis coli who are found at baseline colonoscopy endoscopic biopsy to have 100 or more colorectal adenomas or APC truncation mutation and 10 or more colorectal polyps of which two or more are adenomas might be randomized to chemopreventive treatment (or compare treatments) and placebo groups. Primary endpoints of treatment might include colon polyp incidence, colon crypt proliferation kinetics, and apoptosis. Additional areas of investigation could include translational research involving the MIN and MSH mouse models and analysis of COX2 modulation through MIN and MOM pathways, analysis of aberrant crypt formation and zonal proliferation, and other areas relevant to HNPCC and mutational spectra. 3. Former smokers (30 or more pack years) with moderate/severe bronchial dysplasia on fluorescence bronchoscopy and random bronchial biopsy might be randomized to chemopreventive treatment and placebo groups. In addition to the primary endpoint of treatment, bronchial dysplasia grade, investigations might include nuclear polymorphism, ploidy, LOH at 3p and 5q, p53, rb, CDKN2, microsatellite instability, PCNA, telomerase, apoptosis, and GST. These investigations might be undertaken in biopsy material and in the context of developing transgenic animal models for lung dysplasia/cancer showing high frequencies of tumor mutations. At least two of the individual projects must be Phase I/II or Phase II clinical chemoprevention trials or translational research needed for chemoprevention applications. Phase II studies should include molecular biomarkers or other intermediate biomarkers as surrogate endpoints for cancer incidence (cancer incidence may be beyond the scope and/or duration of this initiative for most clinical situations). Translational research projects will primarily involve the characterization, quantitation and evaluation of the early molecular biomarkers that identify high-risk cohorts and serve as surrogate endpoints for cancer incidence in chemoprevention trials in these populations. The programs will build on existing resources for identifying and recruiting participants to the clinical studies (e.g., genetic testing programs, risk registries). The NCI will conduct a safety and protocol review of the studies prior to their initiation. This review is required to assure that all safety, conduct, monitoring, and reporting conform to FDA IND guidelines. The awardee institutions and Principal Investigators must agree to comply with the recommendations of the review. Core functions provided in the programs might include (1) tissue storage for later analysis, (2) a data management system with validated statistical and quality assurance procedures, and (3) safety and conduct monitoring of clinical trials with oversight by scientists with expertise in genetic and epidemiological research. SPECIAL REQUIREMENTS General High risk for cancer may be attributable to inherited or acquired genetic lesions, lifestyle or environmental factors, or combinations of these parameters. This initiative is to establish integrated, multidisciplinary research programs around a theme in an area of defining and evaluating chemopreventive strategies in subjects at high risk for cancer, including but not limited to, the definition of cohorts, the identification and characterization of early precancerous lesions/biomarkers for both cohort identification and endpoint analysis, and the clinical evaluation of chemopreventive strategies. This RFA is seeking programs with administrative core functions supporting at least three independent but integrated research projects which share a common focus directed at designing and evaluating chemopreventive strategies in high-risk cohorts. Studies may involve multiple institutions. This includes groups with on-going administrative clinical trials core functions and laboratory support such as cooperative groups, CCOP Research Bases and NCI designated cancer centers. At least two of the individual projects must involve Phase I/II or Phase II clinical chemoprevention trials or translational research needed for chemoprevention applications. Applications funded under this RFA will be supported through the cooperative agreement (U19) mechanism. An assistance relationship will exist between NCI and the awardees to accomplish the research objectives. It is expected that each submission will describe plans for a mixture of basic, developmental, and clinical research activities, all directed to the meet the objectives of this RFA. As described more fully below, the recipients will have primary responsibility for the development and performance of the research activities. However, there will be government involvement, particularly on clinical studies, with regard to (1) assistance in securing an Investigational New Drug (IND) approval from the Food and Drug Administration (FDA), (2) coordination and assistance in obtaining the chemopreventive agent, and (3) monitoring of study safety and conduct. If an investigator anticipates requiring considerable assistance in obtaining the chemopreventive agent and/or in securing an IND perm it from the FDA, documentation of such assistance from the NCI should be obtained, prior to submitting an application. Awards will not be made until all arrangements for obtaining the IND and the agent are completed. Cost of agent and necessary formulation should be included in the budget. Definitions Program Director - the NCI Program Staff official (see INQUIRIES section if this RFA) responsible for the stewardship and monitoring of the award. The Program Director may also function as the Staff Collaborator. Staff Collaborator - the NCI Staff Collaborator responsible for contributing expert advice on the scientific design and conduct of the research. Advisory Committee - the committee composed of external, non-participating scientists appointed by the Principal Investigator to oversee the research activities and provide advice to the Principal Investigator who is responsible for reporting progress to the NCI Program Director. Data Safety and Monitoring Committee - Composed of external, non-participating scientists assigned by the NCI Program Director to monitor patient safety, conduct data audits, and document progress to the NCI Program Director and Advisory Committee. Terms and Conditions of Award A. Applicability. These special Terms and Conditions of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS grant administration regulations in 45 CFR part 74 and 92, and other HHS, PHS and NIH grant administration policy statements. The administrative and funding instrument used shall be a cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NCI scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NCI purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with the above concept, the dominant role and prime responsibility for the activity reside with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Staff Collaborator. Under the cooperative agreement, a relationship will exist between the recipient of these awards and the NCI, in which the performers of the activities are responsible for the requirements and conditions described below, and agree to accept program assistance from a named NCI Staff Collaborator in achieving project objectives. Failure of an awardee to meet the performance requirements, including these special terms and conditions of award, or significant changes in the level of performance, may result in a reduction of budget, withholding of support, suspension and/or termination of the award. B. Awardee Rights and Responsibilities. The Awardee is responsible for: 1. Research design and protocol development, including definition of objectives and approaches, planning, implementation, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results. 2. Establishing an external Advisory Committee to oversee projects and review data. The Principal Investigator will name external, non-participating investigators to serve as members on an Advisory Committee and schedule meetings periodically. The NCI Staff Collaborator will be a non-voting member. 3. Designating Clinical Study Protocol Chairs. The Principal Investigator shall designate a single Protocol Chairperson (if the P.I. does not assume this role) for each protocol within the described research plan. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for developing and monitoring the protocol. All proposed protocols and modifications will be submitted by the Chair through the Principal Investigator to the NCI Program Director, for review and approval, subject to negotiation with the awardees. 4. Implementing the data collection method and strategy. 5. Establishing mechanisms for quality control and monitoring. Awardees are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense; and (3) sufficiently staffed. 6. Submitting interim progress reports, when requested, to the NCI Program Director including as a minimum, summary data on protocol performance. The Advisory Committee may require additional information. Such reports are in addition to the annual awardee noncompeting continuation progress report. 7. Establishing procedures, where applicable, to comply with FDA regulations of 21 CFR Part 312 for studies involving investigational agents and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects. For IND's sponsored by the NCI, the Principal Investigator is responsible for obtaining approval from both the Institutional Review Board and the NCI Program Director to enroll patients and to change the protocol. The Principal Investigator is also responsible for all aspects of investigational drug acquisition, formulation, distribution, etc. 8. Cooperating in the reporting of the study findings. The NCI will have access to and may periodically review all data generated under an award. Where warranted by appropriate participation, plans for joint publication with NCI of pooled data and conclusions, are to be developed by the Principal Investigator or Advisory Committee, as applicable. NIH policies governing possible co-authorship of publications with NCI staff will apply in all cases. In general, to warrant co-authorship, NCI staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; and (c) preparation and authorship of pertinent manuscripts. The awardee(s) will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS and NIH policies. C. NCI Staff Responsibilities It is expected that the dominant role and prime responsibility for the activity will reside with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Staff Collaborator who will provide expert advice to the awardee on specific scientific and/or analytic issues as described below. The NCI Staff Collaborator will be named later based upon the subject matter of the award. However, the NCI Program Director will retain overall programmatic responsibility for the award and will be the contact point for all facets of interaction with the awardee related to stewardship and monitoring of the award. NCI Staff responsibilities will include: 1. Interacting with the principal investigator(s) on a regular basis to monitor study progress Monitoring may include: regular communications with the principal investigator and staff, periodic site visits for discussions with awardee research teams, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Advisory Committee and related meetings. The NCI retains, as an option, the right to act as Sponsor for an IND filed to support the clinical research and to conduct periodic external review of progress. 2. Participating in the Advisory Committee meetings. The NCI Staff Collaborator will be an invited attendee and a participant on the Advisory Committee and, if applicable, subcommittees, but will not have a vote on any committee. 3. Serving as a resource with respect to other ongoing NCI activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort. 4. Involvement assisting in the design and coordination of research activities for awardees as elaborated below: a. Assisting by providing advice in the management and technical performance of the investigations, coordinating clearances for investigational agents held by NCI. The NCI reserves the right to crossfile or independently file an Investigational New Drug Application form with the FDA. b. Through participation in the Advisory Committee and with the agreement of the Principal Investigator, the NCI Staff Collaborator may assist in the design, development, and coordination of the research or clinical protocol, in the statistical evaluations of data, in the preparation of questionnaires and other data recording forms, and in the publication of results. c. Reviewing and approving protocols to insure they are within the scope of peer review and for safety considerations, as required by Federal regulations. The NCI Program Director will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. The NCI will not permit further expenditures of NCI funds for a study after requesting closure (except for patients already on-study). d. Reviewing and providing advice regarding the establishment of mechanisms for quality control and study monitoring. 5. Making recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Advisory Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements. D. Collaborative Responsibilities In addition to the interactions defined above, NCI Staff and Awardees shall share responsibility for the following activities: 1. Advisory Committee. An Advisory Committee organized by the Principal Investigator will be the main oversight body of the proposed research. The Advisory Committee has primary responsibility to oversee research activities and provide advice to the Principal Investigator. The Principal Investigator will document progress in written reports to the NCI Program Director, and will provide periodic supplementary reports upon request. The Advisory Committee will be composed of external, non-participating peer Investigators, including the NCI Staff Collaborator. An initial meeting of the Advisory Committee will be convened early after award by the Principal Investigator. The final structure of the Advisory Committee will be established at the first meeting. The NCI Staff Collaborator will attend and participate in the Advisory Committee, and as appropriate, its subcommittees but will not be a voting member of any committee. Such a committee usually will meet at least yearly. 2. Data Safety and Monitoring Committee. The NCI Program Director will facilitate and the awardee shall allow for interim data auditing and patient safety monitoring. The Data Safety and Monitoring Committee may assist in clinical protocol coordination and IND submission, subject to discussion with the Principal Investigator, and will review interim results periodically and report to NCI and the Advisory Committee, as appropriate. E. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NCI may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the awardee, a second member selected by NCI, and the third member selected by the two prior selected members. These special arbitration procedures in no way affect the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is NIH policy 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 10-43) and supersedes and strengthens previous policies (Concerning the Inclusion of Women in Study Populations), which have been in effect since 1990. All investigators proposing research involving human subjects should read the "NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register, March 28, 1994 (59 FR 14508-14513) and in the NIH GUIDE FOR GRANTS AND CONTRACTS, March 18, 1994, Volume 23, Number 11. LETTER OF INTENT Prospective applicants are asked to submit, by April 3, 1997, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the names of other key personnel, the participating institutions, and the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of subse