CHEMOPREVENTION OF TOBACCO-RELATED CANCERS IN FORMER SMOKERS: CLINICAL STUDIES Release Date: March 28, 2002 RFA: CA-03-006 National Cancer Institute (NCI) (http://www.nci.nih.gov/) LETTER OF INTENT RECEIPT DATE: June 21, 2002 APPLICATION RECEIPT DATE: July 26, 2002 This RFA is a reissue of RFA-CA-02-009, which was published in the NIH Guide on 04/20/2001. THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations 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 with or without a prior history of a tobacco-related malignancy 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 populations, including phenotypically normal cohorts as well as cohorts with dysplasia/intraepithelial neoplasia, 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, bronchial dysplasia, urothelial dysplasia, superficial bladder cancer, etc.), abnormalities in expression of various proteins associated with cancer development and progression (e.g., proteins involved in the control of growth, differentiation, and/or apoptosis), and distinct 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, light scatter spectrophotometry, 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. Thus, COX-2 may be one reasonable target for chemopreventive strategies, and numerous studies evaluating NSAIDs for chemoprevention are already ongoing. Many other targets also exist. Based on preclinical animal studies and limited human studies, the list of other potential agents to consider includes, but is not limited to, glucocorticoids, lipoxygenase inhibitors, farnesyl transferase inhibitors, EGF receptor inhibitors, other novel tyrosine kinase inhibitors, immune modulators, angiogenesis modulators, soy isoflavones, vitamin D analogs, perillyl alcohol, and lycopene. Investigators are strongly encouraged to propose novel agents. 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, mouthwash, or intravesical installation) would constitute another important chemopreventive strategy. Prevention trials employing agent combinations targeting various biochemical pathways that are relevant to tobacco-induced carcinogenesis represent yet another important experimental approach. For example, preclinical studies support the use of both cyclooxygenase and lipoxygenase inhibitors for chemoprevention in various organs, suggesting that the combination of these inhibitors may prove more efficacious than either one alone by blocking both major pathways of arachidonic acid metabolism. A second example of such a strategy would be the concurrent use of inhibitors of polyamine synthesis and cyclooxygenase inhibitors for bladder cancer prevention. The use of combinations of agents should, however, be based on a strong scientific rationale. Furthermore, the feasibility of such an approach (e.g., the ability to obtain each agent from a pharmaceutical supplier for the specified purpose of a combination trial, as well as the feasibility of obtaining FDA permission for a combination trial) must be addressed prior to application. 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-03-004.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.) and to use appropriate processing and storage modalities to preserve them for future translational studies. It is anticipated that reissuance of this RFA in the future 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. Investigators must, however, demonstrate access to specific interventional agents in their applications. Investigators are strongly encouraged to integrate studies of relevant molecular and biologic markers into their clinical trial design. Assessment of various molecular markers associated with regulatory mechanisms controlling malignant transformation, proliferation, differentiation, apoptosis, and/or angiogenesis may be appropriate. Investigation of molecular profiles (mRNA- based or protein-based) could be included in a proposed study if the investigations are hypothesis-driven. Assessment of markers of drug efficacy in target tissues may also provide valuable information. Investigators are encouraged to utilize various types of specimens (e.g., tissue biopsies, brushings, lavage fluid, serum, sputum, urine, buccal smears, etc.) to investigate biomarkers and to perform relevant correlative studies. The choice of markers should be dictated by the hypotheses being addressed by each study and the relevance of each marker should be adequately addressed in each application. 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 multiple biomarkers, as appropriate, in biopsied abnormal and histologically normal tissues, bronchoalveolar lavage, and induced sputum. Subjects may also be asked to undergo spiral CT 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 multiple molecular markers performed on biopsied normal and involved tissue, as well as on sputum and buccal smears. 3. Former smokers with superficial bladder cancer (Ta, T1, Tis) who have undergone resection and remain at high risk or who received intravesical BCG treatment 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 multiple intermediate endpoints in the resected superficial bladder cancer as well as in normal-appearing mucosa pre and post treatment and in urine. Surveillance could also include marker analysis in serum, urine and bladder washings using one or more of several FDA-approved biomarkers. 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. MECHANISM OF SUPPORT This RFA will use NIH U01 award mechanism. The NIH U01 is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement 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, 2003. 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 one additional time next year. Future issuance 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 2003 to fund 3 to 5 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. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. 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. The investigator is responsible for obtaining access to the chemopreventive agent(s) prior to submitting an application to this RFA. The source of agent must be clearly identified in the application, including written documentation of support from pharmaceutical companies, if applicable. 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 Cooperative Agreement 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. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Eva Szabo, M.D. Division of Cancer Prevention National Cancer Institute 6130 Executive Blvd., Room 2132, MSC 7341 Bethesda, MD 20892 Phone: (301) 435-1595 FAX: (301) 480-3924 Email: szaboe@mail.nih.gov o Direct your questions about peer review issues to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: ncidearefof@mail.nih.gov o Direct your questions about financial or grants management 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 a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent 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 SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: 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 be sent to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8041, MSC-8329 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html) This change in practice is effective immediately. This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. 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 revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NCI program staff. 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 (DEA) at NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o 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 and assigned a priority score o Those that receive a priority score will undergo a second level review by the National Cancer Advisory Board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: June 21, 2002 Application Receipt Date: July 26, 2002 Peer Review Date: November/December, 2002 Council Review: February, 2003 Earliest Anticipated Start Date: April, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). Clinical trials supported or performed by NCI require special considerations. 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 or 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 for the NCI for Data and Safety Monitoring of Clinical trials see: http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. 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. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available: http://www.cancer.gov/clinical_trials/ INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and compelling 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 clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research in now available online at: http://cme.nci.nih.gov/ PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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. Furthermore, we caution reviewers 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 is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/ AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.393, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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