Full Text CA-96-001 PREVENTION CLINICAL TRIALS UTILIZING INTERMEDIATE ENDPOINTS AND THEIR MODULATION BY CHEMOPREVENTIVE AGENTS NIH GUIDE, Volume 24, Number 37, October 20, 1995 RFA: CA-96-001 P.T. 34 Keywords: Cancer/Carcinogenesis Clinical Trial Chemopreventive Agents National Cancer Institute Letter of Intent Receipt Date: November 21, 1995 Application Receipt Date: January 18, 1996 PURPOSE The Division of Cancer Prevention and Control (DCPC), National Cancer Institute (NCI), invites applications for cooperative agreements to support clinical trials that are directed toward examining the role of various chemopreventive agents and/or diet in the prevention of cancer. This is a follow-up to earlier RFAs that requested grant applications, and then later, applications for cooperative agreements in this area. 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 Application (RFA), Prevention Clinical Trials Utilizing Intermediate Endpoints and Their Modulation by Chemopreventive Agents, 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, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the cooperative agreement mechanism (U01). The cooperative agreement is an assistance mechanism in which substantial NIH programmatic involvement with the recipient during performance of the planned activity is anticipated. The nature of the Program Director's involvement is described in the section on SPECIAL REQUIREMENTS, A.2. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant/awardee. However, there will be government involvement with regard to (1) assistance in securing an Investigational New Drug (IND) approval from the Food and Drug Administration (FDA), (2) coordination and assistance in obtaining the chemopreventive agent, (3) monitoring of safety and toxicity, and (4) quality assurance of the clinical chemistry aspects of the study. If an investigator anticipates requiring considerable assistance in obtaining the chemopreventive agent and/or in securing an IND permit from the FDA, such assistance must be sought, in writing, from the Program Director, and assistance approved by the Program Director, prior to submitting the application. Awards will not be made until all arrangements for obtaining the IND and the agent are completed. Final awards will also consider the cost of the clinical trial, and the cost of the agent and, if necessary, its formulation. This RFA will be reissued annually for two years. Future unsolicited continuation applications will compete with all other investigator-initiated research applications and be peer reviewed by a study section in the Division of Research Grants. However, should the NCI determine that there is a sufficient continuing program need, NCI may invite all funded recipients to submit competing continuation applications. FUNDS AVAILABLE Approximately $1.5 million in total costs for the first year will be committed to specifically fund applications submitted in response to this RFA. It is anticipated that three to five awards will be made annually. This number of awards is dependent on the receipt of a sufficient number of applications of high scientific merit. The total project period for an application submitted in response to the present RFA may not exceed five years. The earliest feasible start date for the initial awards will be September 30, 1996. Although this program is provided for in the financial plans of the NCI, awards made pursuant to this RFA will be contingent upon the continued availability of funds for this purpose. RESEARCH OBJECTIVES Background The primary objective of this solicitation is to encourage cancer chemoprevention clinical trials that utilize biochemical and biological markers to identify populations at risk and/or to provide intermediate endpoints that may predict later reduction in cancer incidence rates. These studies may be developed in phases, including a pilot phase, which could later proceed to a full scale intervention. The main emphasis should be on small, efficient intervention studies aimed at improving future research designs of chemoprevention trials, providing further biologic understanding of the trial results, or providing better, more quantitative and more efficient endpoints for these trials. After successful completion of the pilot phase (i.e. demonstrated modulation of marker endpoints by the intervention), subsequent studies could include a definitive clinical trial monitoring the test system, a cancer incidence or mortality endpoint, and a designated agent. Investigators may apply at this time for the pilot phase, or submit an application for both the pilot and definitive trial studies. However, if the application is for the pilot phase only, it must include a description of its relevance to a broad clinical application including the chemopreventive agent, marker test system, and study population which would be the subject of a full scale, randomized, cancer risk reduction clinical trial. Applications should be prepared and submitted in accordance with the aims and requirements described in the following sections: A number of compounds and/or dietary components have been associated with the inhibition of carcinogenesis in animal models, in vitro systems, and/or epidemiologic investigations. Results from these studies suggest that chemopreventive agents, including dietary components, affect the later stages of carcinogenesis. The best approach to confidently address the efficacy and safety as well as the applicability and effectiveness for these agents is through the conduct of clinical trials. A variety of parameters have become available and may be used to identify or evaluate risk modulation in selected target populations by chemopreventive agents. Examples include reversal of abnormal cytology, prevention or reversal of nuclear aberrations (micronuclei), ornithine decarboxylase and/or prostaglandin synthetase inhibition, DNA ploidy alterations, changes in colonic mucosal proliferation (histology, tritiated thymidine labelling indices), decreases in fecal mutagens, and oncogene suppression tests. Markers of precancerous lesions may also be useful to define populations that may benefit from chemoprevention trials; however, more information is required concerning the ability of such markers to predict and/or modulate cancer incidence. The development of sensitive and accurate intermediate endpoints should greatly enhance the ability to design effective cancer risk reduction trials. Chemoprevention clinical trials involve a spectrum of subjects in various categories of risk. These might involve normal human subjects, subjects at high risk due to prior exposure to carcinogens, subjects with precancerous lesions, patients having been treated for a primary cancer now free of disease, and patients treated for primary cancer with alkylating agents or radiation who are at high risk for developing second cancers. Methods for identification of populations at risk and assessment of their risk of developing cancer is therefore a major goal of the chemoprevention program. These studies are expected to augment the efficient experimental design of clinical trials leading to lesser number of subjects required to achieve adequate statistical power. The tests used for risk identification are also of value because of the multi-step nature of cancer induction and the different mechanisms by which chemopreventive agents are known to inhibit the carcinogenic process. Thus, it is useful to have tests that measure genotoxic exposure as well as tests which indicate that subjects are in the later (e.g. promotional, progressional) phase of the carcinogenic process. It should be emphasized that protocols that propose use of assays/methods for risk identification must also include assays that measure biochemical or biological intermediate markers of cancer endpoints (in the pilot phase) or measurement of the intermediate endpoints themselves (in the later definitive trials). Studies of Special Interest Short term chemoprevention clinical trials that evaluate the effect of innovative biomedical monitoring tests in high risk populations are sought. These tests might be useful to determine an intermediate endpoint, serve as a basis to assess cancer risk status or to assess response to a chemopreventive agent. The modulation of effects by a chemopreventive agent on tests which are indicative of neoplastic progression may be an early indicator of its efficacy. Examples of such tests might include classical cytological techniques, suppression of oncogene protein products, etc. Modulation of a biological marker by a chemopreventive agent might be highly significant in relation to ultimate cancer prevention. A series of one or more tests would be included in the chemoprevention intervention clinical trial, initially to determine baseline parameters and later as a follow- up after administration of the chemopreventive agent. Biological fluids including urine, blood, sputum, etc. would have to be obtained from participants for analysis. Priority would be given for studies with biological monitoring procedures which do not overlap or duplicate currently funded projects. The pilot phase should attempt to detect the clinical activity of the chemopreventive agent rapidly, efficiently, and in reasonably accurate fashion with a relatively small number of subjects. In vivo or in vitro assays are acceptable if of particular and direct relevance to clinical trials. The pilot phase is not expected to give a definite answer to the ultimate value of the chemopreventive agent, which is the purpose of a larger Phase III study. It is expected, however, that upon completion of a pilot study, it should be possible to make a judgement regarding the effectiveness of the agent to modulate the marker test system (which will be correlated with modulation of the cancer endpoint in the definitive trials). Additionally, the pilot phase is expected to give an indication of the nature of any short term adverse effects related to the particular dose schedule, information on patient compliance, ability to measure the agent in body fluids and any other factors related to the subsequent clinical trial. These factors may provide further clarification on the need for a large, full scale study. Intervention populations of interest might include: individuals at high risk at selected cancer sites, individuals with precancerous lesions, or individuals presently free of cancer but at risk for second cancers. Intermediate marker studies of breast cancer chemoprevention are especially encouraged. SPECIAL REQUIREMENTS A. Terms and Conditions of Award Under the cooperative agreement, a partnership will exist between the recipient of the award and NCI, with assistance from NCI in carrying out the planned activity. The following terms and conditions pertaining to the scope and nature of the interaction between NCI and the investigators will be incorporated in the Notice of Award. These terms will be in addition to the customary programmatic and financial negotiations which occur in the administration of cooperative agreements. The "Terms and Conditions of Award" described in this section are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines; DHHS grant administration regulations 45 CFR 74 and 92; other DHHS, PHS, and NIH grant administration policy statements; and other NCI administrative terms of award. 1. Awardee Rights and Responsibilities a. Safety and Toxicity Review Each awardee institution and principal investigator agree to comply with the recommendations of the safety and protocol review to assure that all FDA requirements are satisfied. b. Quality Control and Adverse Reaction Reporting (1) The awardee will be required by the NCI Program Director to set up mechanisms for quality control. Some or all of the following may be relevant: compliance with protocol requirements for eligibility; treatment and follow-up; laboratory data; dietary data; pathological materials; and operative reports. (2) The awardee agrees to perform the study according to the approved protocol. Any proposed changes in the protocol must receive the advance permission of the NCI Program Director for this award. (3) The awardee is required to conform to NCI guidelines for the use of investigational drugs including investigator registration (FDA Form 1573), maintaining a record of drug receipt and reporting of adverse drug reactions. Life threatening or unexpected toxicity MUST be reported by the investigator IMMEDIATELY by telephone to the NCI Program Director shown on the Notice of Award and confirmed with details in writing within two weeks. The investigator will be responsible for amending protocols and consent forms based on new toxicity information sent to the investigators by NCI staff. c. Informed Consent; IRB Approval Approval by the Institutional Review Board (IRB) must be obtained by awardees on all protocols because of the involvement of human subjects. d. Data Management and Reporting Requirements Data acquisition and analysis is the responsibility of the investigator. Investigators will be required to submit reports to NCI using the following schedule and format: (1) Semi-annual Reports Semi-annual scientific reports should report on the progress of the project during the previous six months and the cumulative progress of the study. (a) Individual Study Information. The summary is required to include the following information for each study: The title of the study (with any appropriate study identifiers such as protocol number), its purpose, a brief statement identifying the patient population and the inclusion of women and minorities, and a statement as to whether the study is completed. The total number of subjects initially planned for inclusion in the study, the number entered into the study to date, the number whose participation in the study was completed as planned, and the number who dropped out of the study for any reason. If the study has been completed, or if interim results are known, a brief description of the study results. (b) Summary Information. Information obtained during the previous six months' clinical and nonclinical investigations, including: A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system. A list of subjects who died during participation in the investigation, with the cause of death for each subject. A list of subjects who dropped out during the course of the investigation in association with any adverse experience, whether or not thought to be drug related. A brief description of what, if anything, was obtained that is pertinent to an understanding of the drug's actions, including for example, information about dose response, information from controlled trials, and information about bioavailability. A list of the preclinical studies (including animal studies) completed or in progress during the past year and a summary of the major preclinical findings. (c) A description of the general investigational plan for the coming year to replace that submitted one year earlier. (d) A description of any significant pilot trial protocol modifications made during the previous year and not previously reported to the IND in a protocol amendment. (e) A brief summary of significant foreign marketing developments with the drug during the past year, such as approval of marketing in any country or withdrawal or suspension from marketing in any country. Grantees are responsible for initialing corrective plans if the progress of studies reported in non-competing renewal applications indicate that patients are not being accrued as originally proposed. Grants can be terminated for failure to accrue adequate numbers of both genders. Each progress report must describe accrual by gender and racial/ethnic group. Due Dates for Reports January 1 and July 1 for the semiannual report. (2) Final Study Report The final report of a completed study shall consist of detailed analyses of results and toxicity, plans for publications, a comprehensive list of all previous publications related to the project, and plans for archiving and storing the study records. 2. NCI Staff Responsibilities a. Study/Protocol Plan The NCI Program Director will assist the awardee in the study and protocol design by providing information regarding a) the nature of concurrent studies in the area of research, pointing out possible duplication of effort, b) safety and toxicity of proposed regimens, and c)availability of necessary drugs. The NCI Program Director may also offer advice regarding the scientific rationale, priority, design and implementation of the proposed studies. A safety and protocol review will be undertaken by the NCI Program Director on all clinical trials from proposals which are ultimately funded. Such a review is legally required by the Food and Drug Administration to assure that all safety, toxicity, monitoring, and reporting issues are in conformance with Investigational New Drug guidelines. The awardee institution and principal investigator must agree to comply with the recommendations of the review. b. Data Access The NCI Program Director will have access to the data to review toxicity and safety aspects of the project, prepare IND applications and monitor any trial aspects required by other federal agencies. This information is necessary to satisfy FDA regulations with regard to Code of Federal Regulations (CFR) 21. The NCI Program Director may encourage and facilitate sharing of data between investigators when this is in the mutual interest of the investigators and the NCI. c. Investigational New Drug (IND) The NCI will have the option to cross file or independently file an IND on investigational drugs evaluated in trials supported under the cooperative agreements. The NCI will advise investigators of specific requirements and changes in requirements concerning investigational drug management for compliance with NCI and the FDA guidelines and regulations. Investigators conducting trials under cooperative agreements will be expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents, for reporting adverse reactions, and for maintaining necessary records of drug receipt and distribution. d. Assistance with Obtaining or Purchasing Investigational Drugs If an investigator anticipates requiring considerable assistance in obtaining the chemopreventive agent and/or in securing an Investigational New Drug (IND) permit from the Food and Drug Administration (FDA), such assistance must be sought in writing to the Program Director, and assistance approved by the Program Director, prior to submitting the application. Awards will not be made until arrangements for obtaining the agent are complete. Final awards by the NCI will also consider not only the cost of the trial but also the cost of the agent, including its formulation, encapsulation and packaging, if these costs are to be borne by the Government. e. Protocol Modification No protocol modifications may be implemented without approval from the NCI Program Director, and also from the FDA, if indicated. f. Protocol Termination The NCI Program Director may request that a protocol study be terminated. Reasons for this request may be a) insufficient accrual, b) further accrual will not add information of scientific value, and/or c) consideration of patient safety. The NCI will not provide drugs or IND sponsorship for a study after requesting termination. Investigators who wish to challenge protocol termination may do so according to the arbitration process described below. In addition, the NCI may withdraw funding for such a protocol if the grounds for termination are patient safety and toxicity. h. Clinical Trials Progress Review Progress will be evaluated semi-annually by the Program Director from material presented in the awardee's semi-annual report (as described in Section V.B.4.A. below). Recommendations of the Program Director will be communicated by letter to the investigator to which he/she is expected to respond. Insufficient numbers of patients accrued to attain the stated delta value (d=difference between treatments to be detected divided by standard deviation), unsatisfactory progress, or non- compliance with terms of award may result in a reduction of the budget, withholding of support, suspension or termination of the award. i. Quality Assurance (1) The NCI has established a clinical chemistry quality assurance program with the National Institutes of Standards and Technology, Gaithersburg, Maryland which will provide chemical standards for some of the agents that will be used and assayed for in the clinical trials. These standards will contribute to the quality control of selected laboratory determinations. The awardee will participate in the laboratory quality control activity when so notified. (2) Periodically, the NCI Program Director will review the mechanisms established by each awardee for quality control of clinical studies. These mechanism must conform with Food and Drug Administration (FDA) regulations. j. The awardees will retain custody of and primary rights to their data. k. Other Terms Patient enrollment may not begin without the prior written approval of the NCI Program Director for this cooperative agreement including submission to and approval by the FDA of an IND application and satisfactory response to the recommendations of the safety and protocol review. 3. Arbitration Mechanism 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 formed composed of one award recipient designee, one NCI designee, and a third designee with appropriate expertise chosen by the other two members of the panel. These special arbitration procedures in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Population, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research," which was reprinted in the Federal Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting errors in the earlier publication, and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by November 21, 1995, a letter of intent that includes a descriptive title of the proposed research, name, address, and telephone number of the Principal Investigator, identities of other key personnel and participating institutions, and 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 subsequent applications, it is requested in order to provide an indication of the number and scope of applications to be reviewed. The letter of intent is to be sent to: Marjorie Perloff, M.D. Division of Cancer Prevention and Control National Cancer Institute Executive Plaza North, Suite 218 Bethesda, MD 20892 Telephone: (301) 496-4664 FAX: (301) 402-0553 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these cooperative agreements. These forms are available at most institutional offices of sponsored researcher; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3032, MSC 7762, Bethesda, MD 20892-7762, telephone (301) 710-0267, email: dirg@drgpo.drg.nih.gov, and from the NCI Program Director listed under INQUIRIES. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page. 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, "Prevention Clinical Trials Utilizing Intermediate Endpoints and Their Modulation by Chemopreventive Agents," and the RFA number, CA-96-001, must be typed in block 2 of the face page of the application form. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact, clear and single sided photocopies, in one package to: DIVISION OF RESEARCH GRANTS National Institutes of Health 6701 Rockledge Drive, Room 1040 MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for courier/overnight service) At time of submission, two additional copies of the application must also be sent to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute Executive Plaza North, Room 636 6130 Executive Boulevard, MSC 7405 Rockville, MD 20852 (if hand-delivered or delivery service) Bethesda, MD 20892 (if using U.S. Postal Service) If the application submitted in response to this RFA is substantially similar to a research grant application already submitted to the NIH for review, and has been or has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. Preparation of the Application The general instructions for preparing applications contained in the grant application form PHS 398 (rev. 5/95) are to be used in preparing Cooperative Agreement applications. Because of the award terms and conditions included in the section under SPECIAL REQUIREMENTS, it is important that applicants indicate in the Research Plan how they will meet the requirements stated in the RFA for staff involvement. To ensure that the cooperative agreement remains the appropriate instrument, awardees who are invited by the NCI to submit competing continuation and supplemental applications must describe how they have met the established terms and conditions. The following items apply to new as well as to competing continuation applications: 1. The study must clearly address a pilot trial, and optionally a definitive trial. The pilot trial must involve the application of a biological and/or biochemical marker and its modulation by the study agent. The definitive trial involves the implementation of a full scale randomized, double-blind, risk reduction, prevention clinical trial. For applicants seeking to conduct only a pilot trial, the study must describe relevance to a clinical trial application including a marker, agent and target group that might be appropriate for a full scale intervention after completion of the pilot study. 2. The applicant must provide a rationale for selection of the biological or biochemical marker, its relevance to risk identification or modulation, and its relevance to the intervention agent and the target population. 3. The applicant must provide the rationale for selection of the proposed intervention agent. This should include relevant epidemiologic and laboratory data. Preclinical and clinical data on any potential untoward effects of the intervention agent should also be presented. In circumstances where there might be some doubt as to the availability or the safety of the agent, the applicant may wish to consult with the pharmaceutical company and the NCI Program Director prior to preparing the application. The applicant should thus present a reasonable case for the "readiness" of the proposed intervention agent for a clinical trial. 4. The applicant must provide a rationale for selection of a specific target group and provide an estimate of the number of participants required for the completion of the study. Criteria and calculations used to estimate sample size must be included. The applicant must provide a description of the target population or group chosen and must justify the selection of this group. The group should be defined, as appropriate, by age, sex, race, dietary customs, education, geographic location, occupational or life style risk factors, and relevancy to a specific cancer problem or to its possible prevention by the designated inhibitor(s). The accrual rate should be estimated. If multiple institutions are involved, the application must include verification of the coinvestigators' 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. Each project in a multiproject application must have individual budgets for the first budget period and a summary budget for all years. 5. The applicant must clearly indicate the clinical chemistry and biologic aspects of the study to include collection, storage, handling, analysis, and quality control of biological or biochemical samples. The methods and equipment to be used and the technical qualifications and experience of the personnel involved must be addressed. If these aspects of the study are to be conducted by groups other than at the applicant's institution, a letter from the cooperating institutions indicating their willingness to participate should be included. 6. The applicant must elucidate any known or potential safety or toxicity considerations, the techniques and procedures to monitor and report any adverse health effects and appropriate dose modifications based on toxicity monitoring. 7. The applicant must specify the methods to be used to document nutrient intake, if indicated, and adherence to the prescribed intervention during the course of the trial. 8. The applicant must indicate a willingness to work cooperatively with the assistance of the Program Director in the implementation and conduct of the study. 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. 10.The applicant should indicate the availability of the chemopreventive agents or dietary factors. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by the NCI. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, it will be returned without review. 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 NCI, in accordance with the review criteria stated below. 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. Review Criteria The following factors will be considered in evaluating the scientific merit of each response to the RFA: 1. Scientific merit of the study objective(s), design, and methodology to include considerations of toxicity, safety and quality assurance. 2. Basic and clinical scientific significance as well as originality of the proposed research. 3. Research experience and/or competence of the Principal Investigator and other key personnel to conduct the proposed studies. 4. Adequacy of time (effort) which the Principal Investigator and staff would devote to conduct the proposed studies. 5. Relevancy and appropriateness of the specific target population along with assurance as to its accessibility. 6. Identity of sources of data, tissues, fluids, etc., procedures for their collection and analysis, and assurances as to their accessibility. 7. Adequacy of plans for NCI program staff involvement with the proposed studies. 8. Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The review group will critically examine the submitted budget and will recommend an appropriate budget and period of support for each meritorious application. AWARD CRITERIA The earliest feasible start date for an award will be September 30, 1996. In addition to scientific and technical merit as determined by peer review, availability of funds, and programmatic priorities, funding decisions will also consider not only the cost of the clinical trial but also the cost of the agent and, if necessary, its formulation. Funding priority will be given for studies with biological monitoring procedures that do not overlap or duplicate projects currently funded by the NCI. Awards will not be made until all arrangements for obtaining the agent are complete. Funding awards by the NCI will also consider not only the cost of the trial but also the cost of the agent, including its formulation, encapsulation and packaging, if these costs are to be borne by the Government. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Marjorie Perloff, M.D. Division of Cancer Prevention and Control National Cancer Institute Executive Plaza North, Suite 218 Bethesda, MD 20892-4200 Telephone: (301)496-4664 FAX: (301) 402-0553 Email: perloffm@dcpcepn.nci.nih.gov Direct inquiries regarding fiscal matters to: Mr. Robert Hawkins Grants Administration Branch National Cancer Institute Executive Plaza South, Suite 243 Bethesda, MD 20892 Telephone: (301) 496-7800 Ext. 213 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.399, Cancer Control. Awards will be made under the authority of the Public Health Service Act, Title IV, Section 301 (Public Law 78-410,; 42 U.S.C. 241, and Section 412, as amended by Public Law 99-158, 42 U.S.C. 258a-1); and administered under and Federal regulations 42 CFR Part 52 and PHS grant policies 45 CFR Part 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 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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