CHEMOPREVENTION IN GENETICALLY-IDENTIFIED HIGH-RISK GROUPS: INTERACTIVE RESEARCH AND DEVELOPMENT PROJECTS Release Date: April 1, 1998 RFA: CA-98-012 P.T. National Cancer Institute Letter of Intent Receipt Date: July 15, 1998 Application Receipt Date: August 26, 1998 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 at least three independent but integrated research projects and the associated administrative core functions that share a common focus directed at designing and evaluating chemopreventive strategies in high-risk cohorts. This includes groups with on-going clinical trials, core functions and laboratory support such as cooperative groups, CCOP Research Bases, NCI designated cancer centers, genetic testing programs and risk registries. 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 Request for Applications (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 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. 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 Interim Guidelines for the Program Project Grant of the National Cancer Institute dated February 1998 in preparing the application. The P01 guidelines are available from the NCI Referral Officer 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 an application submitted in response to this RFA may not exceed five years. The anticipated award date is March, 1999. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all other investigator-initiated research applications and be reviewed according to customary peer review procedures. 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 99 to submit competing 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 to 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. Applicants should include preclinical in vitro or in vivo data to support their proposal. If no preliminary data is available, they might consider including a small pilot study (Phase IIa) prior to the initiation of a Phase IIB trial. 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 interested in receipt of applications relevant to either inherited or acquired genetic lesions. 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 application 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 permit from the FDA, documentation of 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 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 as defined in the terms and conditions. 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 appointed by the Principal Investigator 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. Program Director 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. 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). 3. 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. Staff Collaborator responsibilities will include: 1. 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. 2. 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. 3. 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. d. Reviewing and providing advice regarding the establishment of mechanisms for quality control and study monitoring. D. Collaborative Responsibilities In addition to the interactions defined above, NCI Staff and Awardees shall share responsibility for the following activities: 1. Advisory Committee. The 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 annually. 2. Data Safety and Monitoring Committee. The Principal Investigator shall appoint a Data Safety and Monitoring Committee for the study. 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 Advisory Committee, a second member selected by NCI, and the third member selected by the two prior selected members. This special arbitration procedures in no way affects 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. 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 have been 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. Copies may be obtained from the Program Staff listed under INQUIRIES. Program Staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by July 15, 1998, a letter of intent that includes a descriptive title of the proposed research and a list of titles for the anticipated components of the U19. The name, address, and telephone number of the Principal Investigator, other key personnel and participating institutions, the number and title of the RFA in response to which the application is being submitted, and the projected approximate costs for each year. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information allows NCI staff to estimate the potential review workload 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.nci.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying 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 301/710-0267, email: ASKNIH@od.nih.gov. The RFA label available in PHS-398 application must be affixed to the bottom of the face page of the application. Failure to use this label could delay processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title "CHEMOPREVENTION IN GENETICALLY-IDENTIFIED HIGH-RISK GROUPS: INTERACTIVE RESEARCH AND DEVELOPMENT PROJECTS" and number must be typed in line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must also be sent to: Referral Officer 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 August 26, 1998. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revision of application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. APPLICATION PROCEDURES The general instructions provided in PHS-398, in conjunction with the NCI P01 guidelines (available from the NCI Referral Officer listed in the APPLICATION PROCEDURES section of this RFA), are to be used for the preparation of applications. 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 genetic lesions and SEBs, including relevance to the test agent and target population should be provided for the basic research and clinical components of the projects. 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. Particularly, the genetic lesion under study should be carefully described and characterized. 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 that 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. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator could be included with the application. REVIEW CONSIDERATIONS A. Review Method Upon receipt, applications will be reviewed by the CSR 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 Peer review emphasizes a synthesis of two major aspects of the program project application: 1) review of the program as an integrated research effort focused on a central theme and 2) review of the merit of individual research projects and core components in the context and environment of the proposed program. In arriving at an overall score for the program project, reviewers will consider the likelihood that the proposed research will have a substantial impact on the scientific field. As of October 1, 1997, the review criteria for both overall program and the individual projects are Significance, Approach, Innovation, Investigators and Environment (NIH Guide, Vol. 26, Number 22, June 27, 1997). The sections below give more detail about how these five criteria are applied to the overall program and the individual projects. A. Review Criteria for the Overall Program o Significance: The significance of the program overall and its potential to advance scientific knowledge in the field. o Approach: The adequacy and quality of the experimental approaches proposed in the projects and the overall design of the program project. o Innovation: The degree to which the overall program applies novel concepts and innovative approaches. o Investigators: The qualifications of the Principal Investigator and the program leadership. o Environment: Scientific, organizational and administrative environment. o The adequacy of the commitment (percent effort) of the Principal Investigator to the program project. There should be a specific commitment to both the scientific and administrative aspects of the program project. Though desirable it is not mandatory that the Principal Investigator be a project leader of an individual research project. o The ability of the Principal Investigator to select individual projects for both scientific excellence and relatedness to the theme of the program project (as demonstrated by the included projects) and actively promote interactions and collaborations. Components not recommended for further consideration impact negatively on the evaluation of the program leadership skills and scientific judgment of the Principal Investigator. o The mechanisms for internal quality control of the research. o The anticipated synergy of the program project above that provided by a collection of separate research grants. o The appropriateness of the proposed project budget and the duration, the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, and the safety of the research environment. B. Program as an Integrated Effort o The coordination, interrelationship and synergy among the meritorious research projects and core component as related to the common theme of the program project. o The advantages of conducting the proposed research as a program project rather than through separate research efforts. o The mechanisms for regular communication and coordination among investigators. o For competing renewals, evidence of productive collaborations. C. Review Criteria for Projects o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Innovation: Does the project employ novel concepts, approaches of methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigators: Is the project leader appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the project leader and other researchers (if any)? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? (NOTE: Synergy and thematic relatedness between the projects and cores, and the significance of the project for the program as a whole, will be described and evaluated under Program as an Integrated Effort and/or in the Overall Critique sections.) D. Review Criteria for Core(s) o The utility of the core to the program project. Each core must provide essential facilities or services for two or more projects judged to have substantial merit. o The quality of the facilities or services provided by this core (including procedures, techniques, and criteria for prioritization). o The qualifications, experience, and commitment of the personnel involved in this core. o Appropriateness of the budget. Accountability for distribution of costs to projects. A realistic budget reflects the core director’s understanding of the score of the work. AWARD CRITERIA The earliest feasible start date for the initial awards will be March 1999. Applications recommended by the NCI Advisory Board will be considered for award based upon (a) scientific and technical merit, (b) program balance, including in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood, and (c) availability of funds. SCHEDULE Letter of Intent Receipt: July 15, 1998 Application Receipt Date: August 26, 1998 Review by NCAB Advisory Board: January 1999 Anticipated Award Date: March 1999 INQUIRIES Written and telephone inquiries concerning the RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues 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.nci.nih.gov Direct inquiries regarding fiscal matters 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 Direct inquiries regarding review matters to: Referral Officer Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636 Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Number 93.399, Cancer Control. 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 grant policies and Federal Regulations 42 CFR Parts 52 and 45 CFR Part 74 [and Part 92 when applicable for State and Local governments]. 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.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices



NIH Office of Extramural Research Logo
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy
NIH... Turning Discovery Into Health®



Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.