RFA-CA-02-009: CHEMOPREVENTION OF TOBACCO-RELATED CANCERS IN FORMER SMOKERS: CLINICAL STUDIES

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CHEMOPREVENTION OF TOBACCO-RELATED CANCERS IN FORMER SMOKERS: CLINICAL STUDIES Release Date: April 19, 2001 RFA: RFA-CA-02-009 (see replacement RFA-CA-03-006) National Cancer Institute Letter of Intent Receipt Date: June 25, 2001 Application Receipt Date: July 30, 2001 PURPOSE The purpose of this initiative is to fund clinical research to develop effective chemopreventive strategies that reduce the risk of tobacco-related cancers in former smokers. This initiative will fund pilot clinical trials (phase I/II or phase II) evaluating the efficacy of chemopreventive agents in specified cohorts of former smokers and translational studies performed on specimens (such as tissue, blood, urine, etc.) derived from these clinical trials. RESEARCH OBJECTIVES Background An efficient way of identifying clinically useful chemopreventive agents is to perform short term pilot clinical studies examining the effect of interventional agents on molecular, imaging, and histologic endpoints in populations at high risk for developing invasive cancer. These studies serve to establish the safety and preliminary efficacy of the interventional strategies ( proof of principle ) in high risk, but phenotypically normal, populations and are crucial in determining which agents/strategies are safe and effective enough for further development in phase III clinical trials. Since phase III cancer prevention trials require large patient cohorts, major resources, and many years to give a definitive answer, it is imperative to prioritize promising agents before embarking on such trials. The purpose of this RFA is to stimulate phase I/II or phase II clinical trials that will identify agents suitable for definitive testing in the phase III trial context for tobacco-related cancers in cohorts of former smokers. It is estimated that smoking is responsible for more than thirty percent of all cancers, particularly cancers arising in the lung, head and neck, bladder, esophagus, kidney, pancreas, and cervix. While the risk of developing cancer (i.e., of the lung) in people who quit smoking decreases substantially compared with the risk in people who continue to smoke, former smokers continue to have significantly elevated cancer risk compared to never smokers and this increased risk is maintained for the remainder of their lives. Recent data show that genetic damage in tobacco-exposed tissues, such as the bronchial epithelium, persists for decades after stopping smoking. Currently almost one-half of all new cases of lung and bladder cancer occur in former smokers. Therefore, the identification of molecular and imaging markers of risk and early neoplasia, and the testing of agents that can prevent the development of clinical cancer in this group are of high public health importance. Increasing understanding of the lengthy process of human carcinogenesis is providing many new opportunities for prevention and early intervention. The identification of genotypic and phenotypic abnormalities that occur frequently during tobacco-induced carcinogenesis in the aerodigestive or urothelial epithelia, for instance, provides markers for risk of developing cancer as well as potential targets for intervention in the process of carcinogenesis. For instance, the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are frequently expressed in tobacco related malignancies as well as in preneoplastic lesions associated with these malignancies, thereby representing novel, mechanistic targets for intervention. Similarly, loss of heterozygosity at chromosomal loci such as 3p and 9p are frequent early changes occurring in lung and upper aerodigestive carcinogenesis, suggesting that the tumor suppressor genes found at these loci (i.e., FHIT at 3p) may have important roles in these early phases of carcinogenesis and thereby be reasonable mechanistic targets. Phase II clinical cancer prevention trials depend on intermediate endpoints, whether they be histologic preinvasive lesions or molecular endpoints, to determine preliminary interventional agent efficacy. Since these trials are intended to evaluate efficacy quickly, it is necessary to identify surrogates for cancer incidence/mortality to serve as trial endpoints. Examples of such surrogate or intermediate endpoints include, but are not limited to: preneoplastic lesions at high risk for progression to invasive cancer (e.g., oral leukoplakia, superficial bladder cancer, bronchial dysplasia, etc.), abnormalities in expression of specific proteins associated with cancer (e.g., proteins involved in the control of growth, differentiation, and/or apoptosis), and specific genetic or epigenetic abnormalities (e.g., microsatellite alterations, FISH abnormalities, mutations/deletions in tumor suppressor genes or oncogenes, aberrant promoter methylation). The incorporation of newer imaging technologies, such as spiral CT, PET, MRI, or combinations, into chemoprevention trials could also provide novel and important information. Several promising agents are already available for chemoprevention studies in lung, head and neck, bladder, and other tobacco-damaged organ sites. For example, members of the non-steroidal anti-inflammatory drug family (NSAIDs) have shown efficacy in animal models for multiple tobacco-related malignancies, including cancers of the lung, upper aerodigestive tract, esophagus, and bladder. Furthermore, the highly specific COX-2 inhibitor celecoxib, which has minimal gastrointestinal toxicity compared with other NSAIDs, has already been shown to be effective in reducing colorectal polyp number in patients with familial adenomatous polyposis. As mentioned above, elevated COX-2 levels have been documented in a variety of tobacco-related neoplasms, including cancers of the lung, bladder, and esophagus, as well as precursor lesions for lung cancer (atypical adenomatous hyperplasia) and for oral malignancy (oral leukoplakia). Thus, COX-2 may be one reasonable target for chemoprevention strategies, although many other targets also exists. Based on preclinical animal studies and limited human studies, the list of other potential agents to consider includes, but is not limited to, glucocorticoids, selenium, lipoxygenase inhibitors, farnesyl transferase inhibitors, EGF receptor inhibitors, and myo-inositol. Given that the same carcinogenic exposure (tobacco) is operational in a variety of target organs and that several of these agents have potential efficacy in multiple organ sites, clinical studies assessing chemopreventive efficacy in multiple tobacco damaged organs would also have great appeal. Alternatively, regional drug delivery to minimize systemic toxicity (such as by inhalation) would constitute another important chemopreventive strategy. Combination prevention trials targeting specific biochemical pathways that are relevant to tobacco-induced carcinogenesis represent yet another important experimental approach. Since preclinical data support the use of both COX-2 and lipoxygenase inhibitors for chemoprevention in various organs, the combination of a COX-2 inhibitor with a lipoxygenase inhibitor may prove more efficacious than either alone by blocking both major pathways of the arachidonic acid metabolism. Another example of a combination approach is the concurrent use of myo-inositol and glucocorticoids delivered by inhalation, as has been shown to be highly efficacious in animal lung carcinogenesis models. Multiple new agents are also expected to be identified by the companion preclinical RFA addressing chemopreventive agent development using animal studies that is being issued simultaneously with this RFA (http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-02-008.html). The appropriate preclinical screening of agents and targeted early clinical trials to identify the most promising agents are the crucial foundations for a chemopreventive strategy that should ultimately lead to a reduced cancer burden for our society. Objectives and Scope The purpose of this initiative is to establish multiple pilot short term clinical trials (phase I/II or phase II) evaluating the efficacy of chemopreventive agents in specified cohorts of former smokers. These studies should integrate the evaluation of multiple biomarkers and surrogate endpoints into the clinical trial design. Given that a significant long term goal of the NCI is the identification and validation of intermediate endpoints to replace cancer incidence and mortality as endpoints in clinical trials (and thereby significantly shorten the duration of such trials), investigators are strongly encouraged to collect and save relevant specimens (tissues, blood, urine, etc.) for future translational studies as well. It is anticipated that reissuance of this RFA in future years will include funds for independent translational studies performed on specimens collected before and after chemopreventive intervention in former smokers. The clinical trials should focus on specified target organs, well defined cohorts of former smokers, and particular chemopreventive agents or strategies as reflect the interests and expertise of the investigators. Should they so desire, investigators will have access to agents that the Division of Cancer Prevention (DCP) already has in supply and for which Investigational New Drug (IND) support is available. Alternatively, DCP will work with investigators to provide IND support for agents of their choice. Examples of clinical studies that would be appropriate for this initiative, for the purpose of illustration only, might include the following: 1. Former smokers (30 or more pack year smoking history) with bronchial dysplasia on fluorescence bronchoscopy and random bronchial biopsy might be randomized to chemopreventive treatment or placebo. In addition to the primary endpoint of treatment (number of sites and grade of bronchial dysplasia), investigators might include assessments of several of the following: promoter methylation, apoptosis (TUNEL, bcl-2/bax/bcl-x family), LOH at 3p/9p, EGFR, COX-2, Ki-67, cyclin D1, p27, and telomerase. These investigations might be performed on biopsied tissue, bronchoalveolar lavage, and induced sputum. Assessment of some of the markers may be performed on buccal smear as well. Subjects may also be asked to undergo spiral CT at the beginning of the study with appropriate follow-up if abnormalities are present. 2. Former smokers with oral leukoplakia might be randomized to chemopreventive treatment or placebo. The primary endpoints of treatment would be the size and grade of leukoplakia, but investigators might also include assessments of the following: genetic damage such as LOH at 3p, 9p, and17p, p53, RAR-beta, Ki-67, cyclin D1, p27, EGFR, COX-2, apoptosis, and telomerase. Assessments would be performed on biopsied normal and involved tissue as well as sputum and buccal smears. 3. Former smokers with superficial bladder cancer who have undergone resection and remain at high risk might be randomized to chemopreventive intervention or placebo. The primary endpoint would be recurrence of bladder cancer (superficial versus invasive), but investigators might also include assessments of the following in the resected superficial bladder cancer as well as histologically normal mucosa pre and post treatment: microsatellite instability, p53, EGFR, COX-2, Ki-67, survivin, NMP-22, DNA ploidy, apoptosis, and telomerase. Surveillance would also include marker analysis in urine and bladder washings. 4. Former smokers who have been curatively treated after a stage I or II squamous cell carcinoma of the head and neck might be randomized to treatment with a chemopreventive agent or placebo. Patients would be followed up for recurrence and development of a second tobacco-related malignancy, particularly in the aerodigestive tract. This would be a pilot study in 100 or so patients, not a definitive phase III study (for example, see Hong WK et al,. N Eng J, 323:795, 1990). Analysis of the primary tumors for relevant markers could be incorporated (i.e., if an NSAID were used, primary tumors should be examined for COX-2 expression). Surveillance could include spiral CT of the chest. 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 Pricipal Investigators must agree to comply with the recommendations of the review. SPECIAL REQUIREMENTS General Applications funded under this RFA will be supported through the cooperative agreement (U01) mechanism. An assistance relationship will exist between NCI and the awardees to accomplish the research objectives. It is expected that each submission will describe plans for a clinical trial using a specified chemopreventive agent in a tobacco-damaged target organ in a well-delineated cohort of former smokers to meet the objectives of this RFA. As described below, the recipients will have primary responsibility for the development and performance of the research activities. However, there will be government involvement in 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 from the NCI should be obtained prior to submitting an application. Awards will not be made until all arrangements for obtaining the IND and the agent are completed. Cost of agent and necessary formulation should be included in the budget. Definitions Program Director the NCI Program Staff official (see INQUIRIES section of this RFA) responsible for the stewardship and monitoring of the award. The Program Director may also function as the Staff Collaborator Staff Collaborator the NCI Staff official responsible for contributing expert advice on the scientific design and conduct of the research Terms and Conditions of Award A. These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. (Part 92 applies when state and local governments are eligible to apply as a "domestic organization.") The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH 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 this concept, the dominant role and prime responsibility for the activity resides 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 DCP Project Scientist. 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. Implementing the data collection method and strategy. 3. 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) as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense, and 3) sufficiently staffed. 4. Submitting interim progress reports (twice a year) to the NCI Program Director including summary data on protocol performance. One of these progress reports will be the annual awardee noncompeting continuation progress report. 5. 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 INDs 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 ultimately responsible for all aspects of investigational drug acquisition, formulation, distribution, etc., although the NCI will provide aid for drug acquisition, IND support, etc. if requested prior to submission of application. 6. Cooperating in the reporting of the study findings. The NCI will have access to and may periodically review all data generated under an award. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. C. NCI Staff Responsibilities It is expected that the dominant role and prime responsibility for the activity will reside with the awardee (s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Staff Collaborator who will provide expert advice to the awardee on specific scientific and/or analytic issues as described below. The NCI Staff Collaborator will be named later based upon the subject matter of the award. However, the NCI Program Director will retain overall programmatic responsibility for the award and will be the contact point for all facets of interaction with the awardee related to stewardship and monitoring of the award. NCI Staff responsibilities will include: 1. Interacting with the Principal Investigator 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. The NCI retains, as an option, the right to act as Sponsor for an IND filed to support the clinical research and conduct periodic external review of progress. 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. Reviewing and approving protocols to insure they are within the scope of peer review and for safety considerations, as required by Federal regulations. The NCI Program Director will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: a) accrual rate insufficient to complete study in a timely fashion, b) accrual goals met early, c) poor protocol performance, d) patient safety and regulatory concerns, e) study results that are already conclusive, and f) emergence of new information that diminishes the scientific importance of the study question. The NCI will not permit further expenditures of NCI funds for a study after requesting closure (except for patients already on-study). c. Reviewing and providing advice regarding the establishment of mechanisms for quality control and study monitoring. d. 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., compliance with the terms of the award and reporting requirements). D. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NCI may be brought to arbitration. An arbitration panel will be composed of three members -- one selected by the awardee, a second member selected by NCI, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01) an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH 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. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed in this document under the section Terms and Conditions of Award. The total project period for applications submitted in response to the present RFA may not exceed 5 years. The anticipated award date is April 1, 2002. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that 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 Division of Cancer Prevention, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. In addition to the current RFA solicitation, it is anticipated that this RFA will be reissued two additional times at one year intervals. Future issuances will have a greater focus on translational biomarker studies on specimens collected during the course of the clinical trials supported by this RFA and will include independent funding for these translational studies separately from funding of clinical trials. If the Division of Cancer Prevention does not continue the program, awardees may submit grant applications through the usual investigator-initiated grants program. FUNDS AVAILABLE The NCI intends to commit approximately $4,000,000 in FY 2002 to fund 5 to 6 new and/or competitive supplement grants to existing cooperative agreements in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $1,000,000 per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NCI provides support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications from minority individuals, women, and persons with disabilities are encouraged. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Eva Szabo, M.D. Division of Cancer Prevention National Cancer Institute 6130 Executive Blvd., Rm 2132, MSC 7341 Bethesda, MD 20892 Phone: (301) 435-1595 FAX: (301) 480-3924 Email: szaboe@mail.nih.gov Direct inquiries regarding review issues to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8109, MSC-8326 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 Telephone (301) 496-3428 Fax: (301) 402-0275 Email: tf12w@nih.gov Direct inquiries regarding fiscal matters to: Ms. Eileen Natoli Grants Administration Branch National Cancer Institute 6120 Executive Blvd., EPS, Room 243 Bethesda, MD 20892 Telephone: (301) 496-8791 Fax: (301) 496-8601 Email: natolie@gab.nci.nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by June 25, 2001, a Letter of Intent that includes a descriptive title of the proposed research, the name, address, telephone and fax numbers, and email address of the Principal Investigator, and the number and title of the RFA in response to which the application may be submitted. Although a Letter of Intent is not required, is not binding, and does not enter into the review of a subsequent application, it allows NCI staff to estimate the potential review workload and plan the review. The Letter of Intent is to be sent to Eva Szabo, M.D. listed under INQUIRIES by the Letter of Intent receipt date. SCHEDULE Letter of Intent Receipt: June 25, 2001 Application Receipt Date: July 30, 2001 Peer Review Date: October/November 2001 Review by NCAB Advisory Board: February 2002 Earliest Anticipated Start Date: March 1, 2002 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. 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, E-mail: grantsinfo@nih.gov. For those applicants with internet access, the 398 kit may be found at http://grants.nih.gov/grants/funding/phs398/phs398.html. Additional Materials to Include in the Application 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 validation. 2. Tobacco exposure must contribute to cancers arising in the organ system(s) under study. A discussion reflecting this connection and justification for choice of target organ should be provided. 3. A discussion of the evaluation of surrogate endpoint biomarkers and their relevance to the test agent and target population should be provided. 4. A rationale for the test agent should be provided, including relevant epidemiological and laboratory data. Preclinical and clinical toxicology 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. 5. A rationale for selection of the target patient cohort (within the scope of this RFA, which requires studies to be performed in former smokers) and an estimate of the number of participants required to complete the studies should be provided. The cohort should be defined, as appropriate, by age, sex, race, occupational or lifestyle risk, etc. Accrual rates 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. 6. Laboratory 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. 7. 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. 8. Methods to monitor patient compliance and, as appropriate, to document nutrient intake should be specified. 9. All clinical trials supported or performed by NCI require some form of monitoring. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff to a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional Review Board (IRB). For details about the Policy of the NCI for Data Safety Monitoring of Clinical Trials see http://deainfo.nci.nih.gov/grantspolicies/ For phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. See NIH Guide Notice on Further Guidance on a Data and Safety Monitoring for Phase I and II Trials for additional information: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 (20817 for express service) At the time of submission, two additional copies of the application must also be sent to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8109, MSC-8326 Rockville, MD 20852 (express courier) Bethesda, MD 20892-8329 Applications must be received by July 30, 2001. 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 announcement 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 a substantial revision of an application already reviewed, but such an application must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the National Cancer Institute. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities of the National Cancer Institute in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed assigned a priority score, and receive a second level review by the National Cancer Advisory Board. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. 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? 2. 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? 3. Innovation. Does the project employ novel concepts, approaches, or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers (if any)? Is there adequate commitment (percent effort) on the part of the Principal Investigator to the proposed research? 5. 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? Are there adequate patient numbers to meet accrual goals? The initial review group will also examine: the appropriateness of proposed project budget and 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, the adequacy of plans for including children as appropriate for the scientific goals of the research, or justification for exclusion, the provisions for the protection of human subjects, and the safety of the research environment. AWARD CRITERIA Applications recommended by the National Cancer 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 clinical research program a reasonable likelihood, and (c) availability of funds. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups, if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the policy that was published in the NIH Guide for Grants an Contracts, June 5, 2000 (Revised August 25, 2000), and is available at the following URL address http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA, Chemoprevention of Tobacco- Related Cancers in Former Smokers: Clinical Studies, is related to priority area of tobacco use. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.393 (for Cancer Cause and Prevention Research). Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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