kristoff@GENBANK.BIO.NET (Dave Kristofferson) (02/22/91)
MINORITY DISSERTATION RESEARCH GRANTS IN AGING, 1991 RFA AVAILABLE: AG-91-07 P.T. 34, FF; K.W. 0710010, 0720005 National Institute on Aging Application Receipt Date: April 29, 1991 PURPOSE Small grants (R03) to support doctoral dissertation research will be available in 1991 for underrepresented minorities.(1) Grant support is designed to aid the research of new minority investigators and to encourage individuals from a variety of academic disciplines and programs to study problems in aging. (1) Underrepresented minority investigators are defined as individuals belonging to a particular ethnic or racial group that has been determined by the grantee institution to be underrepresented in biomedical or behavioral research at that institution. The National Institute on Aging (NIA) will give priority to projects from African-Americans, Native Americans, Hispanics, Pacific Islanders, or other ethnic or racial group members who have been found to be underrepresented in geriatric and gerontology research nationally. Grants to support dissertation research will provide no more than $25,000 in total direct costs. Dissertation research grants will be administered in accordance with the U.S. Code Annotated, Title 42, Part B, Section 284. Awards will depend on the availability of funds. NIA expects to fund up to 20 dissertation research projects in 1991. ELIGIBILITY The applicant investigator applying for a dissertation research grant must be an individual from an underrepresented minority group enrolled in an accredited doctoral degree program in the biomedical, social, or behavioral sciences and must have approval of the dissertation proposal by a named committee. The student must also be conducting or intending to conduct dissertation research on issues related to aging. Research topics should fit within one or more of the areas described below for each individual program (see National Institute on Aging Contacts below). The applicant must be a registered doctoral candidate in resident or nonresident status. All requirements for the doctoral degree other than the dissertation must be completed by the time of the award. This information must be verified in a letter of certification from the thesis chairperson and submitted with the grant application (see Application Procedures). The applicant institution must be domestic and will administer the grant on behalf of the proposed investigator. The applicant investigator for dissertation research grant support must be a citizen of the United States or hold a permanent resident visa. The performance site may be domestic or foreign. SCOPE OF AWARDS Applicant investigators should request support for the amount of time necessary to complete the dissertation. However, a dissertation research grant usually is awarded for a period of 12 months or less but may be awarded for up to 24 months. Investigators who need the 24 months to complete the research project will be required to submit a continuation application for support beyond the first 12 months. Continuation support may be awarded if satisfactory progress is being made, but the total direct costs of the entire project may not exceed $25,000. A proposal that exceeds this amount will be returned. An applicant who receives support for dissertation research under a grant from NIA may not at the same time receive support under a predoctoral or fellowship grant awarded by any other Federal agency, nor be supported under any other research project grant. ALLOWABLE COSTS Expenses usually allowed under PHS research grants will be covered by NIA dissertation research grants, but may not exceed $25,000 for the project. Allowable costs include the investigator's salary (not to exceed $10,000); direct research project expenses such as travel, data processing, and supplies; and dissertation costs. Any level of effort that is less than full time must be fully justified. No tuition nor permanent equipment is allowed. Small equipment requires special justification. NATIONAL INSTITUTE ON AGING CONTACTS Interested applicants should request the full Request for Applications (RFA), additional guidelines for preparing the application, and discuss the suitability of the mechanism by letter or by telephone with the first person named below. The applicant will then be referred to the relevant program director, named below, to discuss the suitability of the research topic. Phyllis B. Eveleth, Ph.D. Deputy Associate Director and Training Officer Office of Extramural Affairs National Institute on Aging Building 31, Room 5C02 Bethesda, MD 20892 Telephone: (301) 496-9322 Geriatrics Program The program supports research on clinical problems that occur predominantly among older persons or that are associated with increased morbidity and mortality in older people. Areas of interest include cardiovascular-pulmonary diseases, infectious diseases, osteoporosis, digestive diseases, rehabilitation and physical function, and performance in older persons. Evan Hadley, M.D., Associate Director Geriatrics Program Building 31, Room 5C27 Bethesda, MD 20892 Telephone: (301) 496-6761 Neuroscience and Neuropsychology of Aging The program supports research on the structure and function of the aging nervous system and the behavioral manifestations of the aging brain. Areas of special interest include age- related changes in the nervous system, especially as these affect sensory processes, learning, cognition, memory, and sleep. The study of Alzheimer's disease and other disorders associated with the aging nervous system, including the causes, diagnosis, epidemiology, treatment, and management of such disorders are of special interest. Zaven Katchaturian, Ph.D., Associate Director Neuroscience and Neuropsychology of Aging Program Building 31, Room 5C35 Bethesda, MD 20892 Telephone: (301) 496-9350 Behavioral and Social Research The program supports research on social and psychological aging processes and the place of older people in society and its social institutions. The emphasis is on promoting health, effective functioning, productivity, and independence throughout the middle and later years. Areas of special interest include health and behavior; cognitive functioning; long-term care; work, retirement and productivity; family and intergenerational relationships; aging demographics; and minorities, women, oldest old rural and retarded older adults. Matilda Riley, Ph.D., Associate Director Behavioral and Social Research Program Building 31, Room 5C32 Bethesda, MD 20892 Telephone: (301) 496-3136 Biology of Aging The program supports studies that focus on diseases associated with increasing age and the basic mechanisms involved in aging processes. The overall objectives of the program are related to understanding normal functions and alterations in them that can be induced by interaction with the environment and disease processes as aging proceeds. The program interests are in molecular and cellular biology, genetics, immunology, basic nutrition, and endocrinology. Richard Sprott, Ph.D., Associate Director Biology of Aging Program Building 31, Room 5C15 Bethesda, MD 20892 Telephone: (301) 496-4996 APPLICATION PROCEDURES Application form. The full RFA and special guidelines for dissertation grant applications are available from the Office of Extramural Affairs (see address above). The application must be submitted on form PHS 398 (revised 10/88, reprinted 9/89) available from most university research offices and the Division of Research Grants, 5333 Westbard Avenue, Westwood Building, Room 449, Bethesda, Maryland 20892, telephone (301) 496-7441. The special instructions described here and in the application kit must be followed. Write "Minority Dissertation in Aging" under Item 2 of the face page. The mailing label in the application kit must be glued to the envelope and the RFA label stapled to the face page of the original application or processing and review of the application may be delayed. Applications will be assigned to the NIA for review and possible funding. Closing date. Applications must be received by April 29, 1991. Application materials must be sent directly to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Copies required. The applicant must submit the original and four copies of the completed application, which includes a detailed narrative project description (not to exceed 10 pages) and letters. An additional two copies should be sent to: Grants and Contracts Management Office National Institute on Aging Building 31, Room 5C07 Bethesda, MD 20892 Attn: Minority Dissertation Additional Material. A letter from the faculty committee or university official directly responsible for supervising the development and progress of the dissertation research must be submitted with the application. The letter must (1) fully identify the members of the committee and certify their approval of the dissertation proposal; (2) certify that all requirements for the doctoral degree, except the dissertation, are completed (or will be completed by the time of the grant award); and (3) note that the university official or faculty committee expects the doctoral candidate to proceed with the approved project proposal with or without NIA support. In addition, the application should include a statement of the applicant's career goals to be placed under "Background". Although not required, identification of the applicant's minority group would be helpful so effectiveness of the program can be evaluated. Conformity. A proposal that does not conform to the instructions, including additional guidelines, will be returned. The information in the required narrative project description must be presented in a form suitable for detailed scientific and technical review. Resubmission. Resubmissions will not be considered. SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Section 2, A-D of the Research Plan AND summarized in Section 2, E, Human Subjects. Applicants/offerors are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. REVIEW PROCESS Dissertation research grants are competitive. A mail review will be conducted by NIA. Applications may first receive a preliminary review by a subcommittee to establish those applications deemed to be competitive. Reviewers will be selected on the basis of their accomplishments and knowledge in aging research and their experience in research career development. All elements of the application will be considered in the review process. Emphasis will be given to the scientific merit, feasibility, relevance of the project to aging research, and to the qualifications of the candidate. Review results and funding decisions will be announced within 5 months after the submission date. Review criteria, funding decisions, and continuation of support are described below. Review Criteria Review criteria include significance of problem, relationship of proposed research to NIA mission, research design, research methods, personal qualifications of the candidate, supervision of the candidate, institutional facilities and support structure, and budgetary appropriateness. Funding Decisions Reviewers will recommend that an application be approved, disapproved, or approved for funding with specific modifications. Final funding decisions are based on the recommendations of the reviewers, the relevance of the project to NIA priorities, and the availability of funds. Continuation of Support Grantees who have been funded for 12 months of a project requiring 24 months or more must submit a continuation application with a progress report 10 months after the study begins. Decisions concerning support beyond 12 months are based on the availability of funds and on evidence of acceptable progress. Grant Conditions The following conditions apply to dissertation grants: o Work on the funded project must be initiated within 3 months after the date of the award. o An awardee may be invited to participate in a meeting or presentation of other NIA dissertation awardees. o A Principal Investigator who discontinues or suspends a project during the grant period must inform the NIA Grants and Contracts Management Office immediately in writing. NIA may suspend or terminate the grant as requested by the Principal Investigator or on its own initiative. o The dissertation constitutes the final report of the grant. Two copies of the dissertation must be submitted. The dissertation must be officially accepted by the faculty committee or university official responsible for the candidate's dissertation and must be signed by the responsible officials. o The requirements of Executive Order 12372, "Intergovernmental Review of Federal Programs," are not applicable to NIA research grant programs. REQUEST FOR COOPERATIVE AGREEMENT APPLICATIONS RFA: CA-91-08 PREVENTION CLINICAL TRIALS UTILIZING INTERMEDIATE ENDPOINTS AND THEIR MODULATION BY CHEMOPREVENTIVE AGENTS P.T. 34; K.W. 0755015, 0740018, 0715035, 0710095 National Cancer Institute Letter of Intent Receipt Date: April 1, 1991 Application Receipt Date: May 24, 1991 I. INTRODUCTION The Division of Cancer Prevention and Control (DCPC), National Cancer Institute (NCI), invites applications for cooperative agreements to support clinical trials directed toward examining the role of various chemopreventive agents and/or diet in the prevention of cancer. This is a follow-up to earlier Requests for Applications (RFAs) that had requested grant applications, and then later, cooperative agreement applications in this area. 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, Cooperative Agreements for Prevention Clinical Trials Utilizing Intermediate Endpoints and Their Modulation for Chemopreventive Agents, is related to the priority area of cancer. The primary objective of this solicitation is to encourage cancer chemoprevention clinical trials that utilize biochemical and biological markers to identify populations at risk and/or to provide intermediate endpoints that may predict later reduction in cancer incidence rates. These studies may be developed in phases, including a pilot phase, that could later proceed to a full-scale intervention. The main emphasis should be on small, efficient studies aimed at improving future research designs of chemoprevention trials, providing further biologic understanding of the trial results, or providing better, more quantitative and more efficient endpoints for these trials. After successful completion of the pilot phase (i.e., demonstrated modulation of marker endpoints by the intervention), subsequent studies can include Phase III clinical trials involving the designated agent, the utilization of the monitoring test system, and a cancer incidence or mortality endpoint. Investigators may apply at this time for the pilot phase or submit an application for both phases. However, if the application is for the pilot phase only, it must include a description of its relevance to a broad clinical application including the chemopreventive agent, marker test system, and study population that would be the subject of a full-scale, randomized, cancer risk reduction clinical trial. Applicants funded under this RFA will be supported through the cooperative agreement mechanism. An assistance relationship will exist between NCI and the awardees to accomplish the purpose of the activity. As more fully described later in this announcement, 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, (3) monitoring of safety and toxicity, and (4) quality assurance of the clinical chemistry aspects of the study. Awards will not be made until all arrangements for obtaining the IND and the agent are completed. Final awards will also consider not only the cost of the clinical trial but also the cost of the agent and, if necessary, its formulation. This RFA solicitation represents a single competition with a specified deadline, May 24, 1991, for receipt of applications. All applications received in response to the RFA will be reviewed by the same NCI Initial Review Group. Applications should be prepared and submitted in accordance with the aims and requirements described in the following sections: II. BACKGROUND INFORMATION A number of compounds and/or dietary components have been associated with the inhibition of carcinogenesis in animal models, in vitro systems, and/or epidemiologic investigations. Results from these studies suggest that chemopreventive agents, including dietary components, affect the later stages of carcinogenesis. The best approach to confidently address the efficacy and safety, as well as the applicability and effectiveness, for these agents is through the conduct of clinical trials. A variety of parameters have become available and may be used to identify or evaluate risk modulation in selected target populations by chemopreventive agents. Examples include reversal of abnormal cytology, prevention or reversal of nuclear aberrations (micronuclei), ornithine decarboxylase and/or prostaglandin synthetase inhibition, DNA ploidy alterations, changes in colonic mucosal proliferation (histology, tritiated thymidine labelling indices), decreases in fecal mutagens, and oncogene suppression tests. Markers of precancerous lesions may also be useful to define populations that may benefit from chemoprevention trials; however, more information is required concerning the ability of such markers to predict and/or modulate cancer incidence. The development of sensitive and accurate intermediate endpoints should greatly enhance the ability to design effective cancer risk reduction trials. Chemoprevention clinical trials involve a spectrum of subjects in various categories of risk. These might involve normal human subjects, subjects at high risk due to prior exposure to carcinogens, subjects with precancerous lesions, patients having been treated for a primary cancer now free of disease, and patients treated for primary cancer with alkylating agents or radiation who are at high risk for developing second cancers. Methods for identification of populations at risk and assessment of their risk of developing cancer is, therefore, a major goal of the chemoprevention program. These studies are expected to augment the efficient experimental design of clinical trials leading to lesser number of subjects required to achieve adequate statistical power. The tests used for risk identification are also of value because of the multi-step nature of cancer induction and the different mechanisms by which chemopreventive agents are known to inhibit the carcinogenic process. Thus, it is useful to have tests that measure genotoxic exposure as well as tests that indicate when subjects are in the later (e.g., promotional, progressional) phase of the carcinogenic process. It should be emphasized that protocols proposing use of assays/methods for risk identification must also include assays that measure biochemical or biological intermediate markers of cancer endpoints (in the pilot phase) or measurement of the intermediate endpoints themselves (in the later Phase III trials). III. RESEARCH GOALS AND SCOPE The purpose of this RFA is to solicit applications from qualified investigators interested in developing and implementing cancer prevention clinical trials using biological markers. These trials, which may be designed in two phases, will examine the role of chemopreventive agents alone, diet modification alone, or a combination of these interventions. A. STUDIES OF SPECIAL INTEREST Short-term chemoprevention clinical trials that evaluate the effect of innovative biomedical monitoring tests in high- risk populations are sought. These tests might be useful to determine an intermediate endpoint, serve as a basis to assess cancer risk status or to assess response to a chemopreventive agent. The modulation of effects by a chemopreventive agent on tests that are indicative of neoplastic progression may be an early indicator of its efficacy. Examples of such tests might include classical cytological techniques and suppression of oncogene protein products. Modulation of a biological marker by a chemopreventive agent might be highly significant in relation to ultimate cancer prevention. A series of one or more tests would be included in the chemoprevention intervention clinical trial, initially to determine baseline parameters and later as a followup after administration of the chemopreventive agent. Biological fluids, including urine, blood, and sputum, would need to be obtained from participants for analysis. Priority would be given for studies with biological monitoring procedures that do not overlap or duplicate currently funded projects. The pilot phase should attempt to detect the clinical activity of the chemopreventive agent rapidly, efficiently, and in reasonably accurate fashion with a relatively small number of subjects or in an in vivo or in vitro assay. The pilot phase is not expected to give a definite answer to the ultimate value of the chemopreventive agent. That is the purpose of a larger Phase III study. It is expected, however, that upon completion of a pilot study, it should be possible to make a judgement regarding the effectiveness of the agent to modulate the marker test system (which will be correlated with modulation of the cancer endpoint in the Phase III studies). Additionally, the pilot phase is expected to give an indication of the nature of any short- term adverse effects related to the particular dose schedule, information on patient compliance, ability to measure the agent in body fluids, and any other factors related to the subsequent clinical trial. These factors may provide further clarification on the need for a large, full- scale study. Intervention populations of interest might include: individuals at high risk at selected cancer sites, individuals with precancerous lesions, and individuals presently free of cancer but at risk for second cancers. SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research dosing and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Section 2, A-D of the Research Plan AND summarized in Section 2, E, Human Subjects. Applicants/offerors are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissue from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. B. PREPARATION OF THE PROPOSAL The instructions contained in the grant application form PHS 398 (revised 10/88, reprinted 9/89) are to be used in preparing cooperative agreement applications. Because of the Terms of Cooperation included as Section V, it is important that applicants indicate in the Research Plan how they will meet the requirements stated in the RFA for staff involvement. To ensure that the cooperative agreement remains the appropriate instrument, awardees submitting competing continuation and supplemental applications must describe how they have met the established terms and conditions. The following items apply to new as well as to competing continuing proposals: 1. The study must clearly address Phase I, and optionally II. Phase I must involve the application of a biological and/or biochemical marker and its modulation by the study agent. Phase II involves the implementation of a full-scale randomized, double-blind, risk reduction, prevention clinical trial. For applicants seeking to conduct only Phase I, the study must describe relevance to a clinical trial application including a marker, agent, and target group that might be appropriate for a full-scale intervention after completion of the pilot study. 2. The applicant should provide a rationale for selection of the biological or biochemical marker, its relevance to risk identification or modulation, and its relevance to the intervention agent and the target population. 3. The applicant should provide the rationale for selection of the proposed intervention agent. This should include relevant epidemiologic and laboratory data. Preclinical and clinical data on any potential untoward effects of the intervention agent should also be presented. In circumstances where there might be some doubt as to the availability or the safety of the agent, the applicant may wish to consult with the pharmaceutical company and the NCI Program Director prior to preparing the application. The applicant should thus present a reasonable case for the "readiness" of the proposed intervention agent for a clinical trial. 4. The applicant should provide a rationale for selection of a specific target group and provide an estimate of the number of participants required for the completion of the study. Criteria and calculations used to estimate sample size should be included. The applicant should provide a description of the target population or group chosen and should justify the selection of this group. The group 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 to its possible prevention by the designated inhibitor(s). The 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. The applicant should clearly indicate the clinical chemistry and biologic aspects of the study to include collection, storage, handling, analysis, and quality control of biological or biochemical samples. The methods and equipment to be used and the technical qualifications and experience of the personnel involved must be addressed. If these aspects of the study 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. The applicant should elucidate any known or potential safety or toxicity considerations, the techniques and procedures to monitor and report any adverse health effects, and appropriate dose modifications based on toxicity monitoring. 7. The applicant should specify the methods to be used to document nutrient intake, if indicated, and adherence to the prescribed intervention during the course of the trial. 8. The applicant must indicate a willingness to work cooperatively with the assistance of the Program Director in the implementation and conduct of the study. IV. MECHANISM OF SUPPORT This RFA will use the cooperative agreement mechanism. The cooperative agreement is an assistance mechanism in which limited NIH programmatic involvement with the recipient during performance of the planned activity is defined. The nature of Program Director's involvement is described in Section V. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant/awardee. Except as otherwise stated in this RFA, awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1, 1990. This RFA will be issued annually for three years. However, should the NCI determine that there is a sufficient continuing program need, NCI may invite all funded recipients to submit competing continuation applications. Approximately $1 million in total costs per year for 3 to 5 years will be committed to specifically fund applications that are submitted in response to this RFA. It is anticipated that 3 to 5 awards will be made annually. This funding level is dependent on the receipt of a sufficient number of applications of high scientific merit. The total project period for applications submitted in response to the present RFA should not exceed 5 years. The earliest feasible start date for the initial awards will be December 1, 1991. Although this program is provided for in the financial plans of the NCI, awards made pursuant to this RFA will be contingent upon the continued availability of funds for this purpose. Non-profit and for-profit institutions are eligible to apply. Foreign as well as domestic institutions are eligible. V. TERMS OF AWARD These special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant regulations 45 CFR 74 and other Health and Human Services, Public Health Service, and NIH grants administration policy. The NCI will provide appropriate assistance, advice, and guidance as described below. The role of the NCI will be to facilitate, not to direct. A. PROGRAM STAFF INVOLVEMENT 1. STUDY/PROTOCOL PLAN Dr. Marjorie Perloff, Program Director, Chemoprevention Branch, DCPC, NCI, may assist the awardee in the study and protocol design by providing information regarding: a) the nature of concurrent studies in the area of research, pointing out possible duplication of effort; b) safety and toxicity of proposed regimens; and c) the availability of necessary drugs. The NCI Program Director may also offer advice regarding the scientific rationale, priority, design, and implementation of the proposed studies. A safety and protocol review will be undertaken on all clinical trials from applications that are ultimately funded. Such a review is legally required by the FDA to assure that all safety, toxicity, monitoring, and reporting issues conform with Investigational New Drug guidelines. The awardee institution and Principal Investigator must agree to comply with the recommendations of the review. 2. DATA ACCESS The Program Director will have access to the data to review toxicity and safety aspects of the project, prepare IND applications, and monitor any trial aspects required by other federal agencies. This information is necessary to satisfy FDA regulations with regard to Code of Federal Regulations (CFR) 21. Data generated, however, are the property of the awardee institution. The Program Director may encourage and facilitate sharing of data between investigators when this is in the mutual interest of the investigators and the NCI. 3. INVESTIGATIONAL NEW DRUG (IND) The NCI will have the option to cross file or independently file an IND on investigational drugs evaluated in trials supported under the cooperative agreements. The NCI will advise investigators of specific requirements and changes in requirements concerning investigational drug management for compliance with NCI and the FDA guidelines and regulations. Investigators conducting trials under cooperative agreements will be expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents, for reporting adverse reactions, and for maintaining necessary records of drug receipt and distribution. 4. ASSISTANCE WITH OBTAINING OR PURCHASING INVESTIGATIONAL DRUGS The NCI may assist the investigator to obtain the agent to be used in the proposed study. Once the application is approved by the peer review committee, the NCI, the National Cancer Advisory Board, and the NCI Program Director may begin discussions with the Principal Investigator and pharmaceutical industry with regard to obtaining the drug. In the event a suitable agent is not available at no cost, the NCI may proceed to purchase the agent through normal procurement mechanisms. Purchase of the agents is only undertaken after measures to obtain the drug at no cost have been exhausted. Awards will not be made until all arrangements for obtaining the agent are complete. Final awards by the NCI will also consider not only the cost of the trial but also the cost of the agent, including its formulation, encapsulation, and packaging, if these costs are to be borne by the Government. 5. PROTOCOL DISAPPROVAL Protocols may be disapproved by the NCI on the basis of patient safety and toxicity, failure to meet FDA regulations concerning NCI-sponsored investigational drugs, obvious duplications, or failure to satisfy the goals of the RFA or of the awardee applications. The Arbitration Mechanism is described in V-8 below. 6. PROTOCOL MODIFICATION No protocol modifications shall be implemented without approval from the Program Director, and also from the FDA if indicated. 7. PROTOCOL TERMINATION The Program Director may request that a protocol study be terminated. Reasons for this request may be: a) insufficient accrual, b) further accrual will not add information of scientific value, and/or c) consideration of patient safety. The NCI will not provide drugs or IND sponsorship for a study after requesting termination. Investigators who wish to challenge protocol termination may do so according to the arbitration process described below. If the request to terminate a study is upheld by the arbitration panel, but the awardee chooses to continue the study, the results of that study will be subject to careful monitoring through progress reports. In addition, the NCI may withdraw funding for such a protocol if the grounds for termination are patient safety and toxicity. The Arbitration Mechanism is described in V-8. 8. DESCRIPTION OF ARBITRATION MECHANISM When mutually acceptable agreements on the safety of research protocols, protocol disapproval, or protocol termination cannot be obtained between investigators and the NCI staff committee, as described above, an arbitration panel composed of one member of the grant recipient group nominated by the grantee, one NCI nominee, and a third member with appropriate expertise chosen by the other two members will be formed to review NCI decisions. These special arbitration procedures in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. 9. CLINICAL TRIALS PROGRESS REVIEW Progress will be evaluated semi-annually by the Program Director from material presented in the awardee's semi- annual report (as described in Section V.B.4.A. below). Recommendations of the Program Director will be communicated by letter to the investigator to which he/she is expected to respond. Insufficient numbers of patients accrued to attain the stated delta value (d=difference between treatments to be detected divided by standard deviation), unsatisfactory progress, or non-compliance with terms of award may result in a reduction of the budget, withholding of support, or suspension or termination of the award. 10. QUALITY ASSURANCE a. The NCI has established a clinical chemistry quality assurance program with the National Institutes of Standards and Technology, Gaithersburg, Maryland, that will provide chemical standards for some of the agents that will be used and assayed in the clinical trials. These standards will contribute to the quality control of selected laboratory determinations. The awardee will participate in the laboratory quality control activity when so notified. b. Periodically, the NCI staff will review the mechanisms established by each awardee for quality control of clinical studies. These mechanism must conform with FDA regulations. 11. OTHER TERMS No patients may be enrolled in this study without the prior written approval of the Program Director for this cooperative agreement including submission to and approval by the FDA of an IND application and satisfactory response to the recommendations of the safety and protocol review. B. RESPONSIBILITIES OF AWARDEES 1. SAFETY AND TOXICITY REVIEW The awardee institution and Principal Investigator agree to comply with the recommendations of the safety and protocol review. 2. QUALITY CONTROL AND ADVERSE REACTION REPORTING a. The awardee is required to set up mechanisms for quality control. Some or all of the following may be relevant: compliance with protocol requirements for eligibility, treatment and follow-up, laboratory data, dietary data, pathological materials, and operative reports. b. The awardee agrees to perform the study according to the approved protocol and consent forms. Any proposed changes in the protocol must receive the advance permission of the NCI Program Official for this award. c. The awardee is required to conform to NCI guidelines for the use of investigational drugs including investigator registration (FDA Form 1573), maintaining a record of drug receipt, and reporting of adverse drug reactions. Life- threatening or unexpected toxicity MUST be reported by the investigator IMMEDIATELY by telephone to the NCI Program Official shown on the Notice of Award and confirmed with details in writing within two weeks. The investigator will be responsible for amending protocols and consent forms based on new toxicity information sent to the investigators by NCI staff. 3. INFORMED CONSENT; IRB APPROVAL a. Approval by the Institutional Review Board (IRB) must be obtained by awardees on all protocols because of the involvement of human subjects. b. Informed consent forms must comply with HHS Regulations and NIH guidelines and should include preclinical and clinical toxicology information as relevant. Changes in the consent forms submitted by the awardee should be reported to the NCI. c. Awardees will be responsible for amending informed consent forms if new toxicity information becomes available. 4. DATA MANAGEMENT AND REPORTING REQUIREMENTS Data acquisition and analysis is the responsibility of the investigator. Data that must be collected are listed in the protocol format available from the Program Director. Investigators will be required to submit reports to NCI using the following schedule and format: A. Semi-annual Reports Semi-annual scientific reports should report on the progress of the project during the previous six months and the cumulative progress of the study. The Semi-annual Report should include: 1. A concise narrative progress summary covering the previous six months (give dates of the six-month period covered) and the cumulative progress of the study. 2. Tabular display of: a. Accrual history of the project presented in six-month periods. In addition to total accrual, the investigator should report the number recruited but ineligible, number inevaluable, and number of study violations. b. Interim analyses of results, if appropriate. c. Toxicities, graded in severity. 3. Explanation of the following: increase or decrease in accrual, any unusual or unexpected incidence of ineligible or inevaluable participants, and any unusual or unexpected study violations. 4. Brief description of quality control measures such as review of records, on-site monitoring, and biochemical monitoring of study compliance. 5. A list of all publications related to work under this cooperative agreement. This listing should include published references, manuscripts in press or submitted. Submit two copies of each reprint. 6. Curriculum vitae should be provided if there has been a change in any of the project investigators. B. Final Study Report The final report of a completed study shall consist of detailed analyses of results and toxicity, plans for publications, a comprehensive list of all previous publications related to the project, and plans for archiving and storing the study records. VI. REVIEW PROCEDURES AND CRITERIA A. REVIEW PROCEDURE Upon receipt, applications will be reviewed (initially) by the Division of Research Grants (DRG) for completeness. Incomplete applications will be returned to the applicant without further consideration. Evaluation for responsiveness to the RFA is an NCI program staff function. Applications will be judged to determine if they meet the goals and objectives of the program as described in the RFA. Those that are judged non-responsive will be returned, but may be submitted as investigator-initiated applications at the next receipt date. Questions concerning the relevance of proposed research to the RFA should be directed to the Program Director as described in section VIII. In cases where the number of applications is large compared to the number of awards to be made, the NIH may conduct a preliminary scientific peer review to identify those which are clearly not competitive for awards. Those applications judged to be both competitive and responsive will be further evaluated, using the review criteria shown below, for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI. The second level of review by the National Cancer Advisory Board considers the special needs of the Institute and the priorities of the National Cancer Program. B. REVIEW CRITERIA The following factors will be considered in evaluating the scientific merit of each response to the RFA: 1. Extent of relevance to the overall goals and objectives of the RFA. 2. Scientific merit of the study objective(s), design, and methodology to include considerations of toxicity, safety, and quality assurance. 3. Basic and clinical scientific significance as well as originality of the proposed research. 4. Research experience and/or competence of the Principal Investigator and other key personnel to conduct the proposed studies. 5. Adequacy of time (effort) that the Principal Investigator and staff would devote to conduct the proposed studies. 6. Relevancy and appropriateness of the specific target population along with assurance as to its accessibility. 7. Identity of sources of data, tissues, fluids; procedures for their collection and analysis; and assurances as to their accessibility. 8. Availability of the chemopreventive agents or dietary factors. If an IND is held for the agent, that information should be furnished at the time of application submission. If the NCI is to assist in obtaining the IND, that information should be furnished. 9. Adequacy of plans for NCI program staff involvement with the proposed studies. The review group will critically examine the submitted budget and will recommend an appropriate budget and period of support for each approved application. VII. METHOD OF APPLYING The research grant application form PHS 398 (revised 10/88, reprinted 9/89) must be used in applying for these grants. These forms are available at most institutional business offices; from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, Maryland 20892; and from the NCI Program Director named below. The RFA label available in the revision of application form PHS 398 must be affixed to the bottom of the face page. Failure to use this label may result in delayed processing of your application such that it may not reach the review committee in time for review. In addition, the title of the application, "Prevention Clinical Trials Utilizing Intermediate Endpoints and Their Modulation by Chemopreventive Agents", and the RFA number, CA-91-08, must be typed in block 2 of the face page of the application form. Submit a signed, typewritten original of the application, including the Checklist, and four (4) signed, exact photocopies, in one package to the Division of Research Grants at the address below. The photocopies must be clear and single sided. DIVISION OF RESEARCH GRANTS National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At time of submission, two (2) additional copies of the application should also be sent to: REFERRAL OFFICER Division of Extramural Activities National Cancer Institute Room 848, Westwood Building 5333 Westbard Avenue Bethesda, MD 20892 Applications must be received by May 24, 1991. If an application is received after that date, it will not be accepted and will be returned. If the application submitted in response to this RFA is substantially similar to a research grant application already submitted to the NIH for review, but has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA that is essentially identical to one that has already been 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. VIII. LETTER OF INTENT Prospective applicants are asked to submit, by April 1, 1991, a letter of intent that includes a descriptive title of the proposed research, the name and address of the Principal Investigator, the names of other key personnel, the participating institutions, and the number and title of the RFA in response to which the application is being submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, it is requested in order to provide an indication of the number and scope of applications to be reviewed. The letter of intent must be sent to: Marjorie Perloff, M.D. Chemoprevention Branch Executive Plaza North, Suite 201 National Institutes of Health 9000 Rockville Pike Bethesda, MD 20892-4200 Telephone: (301) 496-8563 IX. INQUIRIES Written and telephone inquiries concerning the objectives and scope of this RFA and inquiries about whether or not specific proposed research would be responsive are encouraged and must be directed to the Program Director, Marjorie Perloff, M.D. at the above address. She welcomes the opportunity to clarify any issues or questions from potential applicants. This program is described in the Catalog of Federal Domestic Assistance Number 93.399, Cancer Control. Awards will be made under the authority of the Public Health Service Act, Title IV, Section 301 (Public Law 78-410,; 42 U.S.C. 241, and Section 412, as amended by Public Law 99-158, 42 U.S.C. 258a-1); and administered under PHS grant policies and Federal regulations 42 CFR Part 52 and 45 CRF Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review.