Full Text CA-94-013 CHEMOPREVENTION CLINICAL TRIALS INVOLVING MODULATION/FUNCTION OF GENES AND/OR GENE PRODUCTS NIH GUIDE, Volume 23, Number 27, July 22, 1994 RFA: CA-94-013 P.T. 34 Keywords: Chemoprevention 0765014 Growth Factors Chemotherapeutic Agents Letter of Intent Receipt Date: October 15, 1994 Application Receipt Date: November 23, 1994 PURPOSE The Chemoprevention Branch, Division of Cancer Prevention and Control (DCPC), National Cancer Institute (NCI), invites applications for cooperative agreements to encourage coordinated submissions of projects from investigators dedicated to chemoprevention clinical trials of agents that may effect gene expression and cellular growth. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Chemoprevention Clinical Trials Involving Modulation/Function of Genes and/or Gene Products, is related to the priority area of chemoprevention. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). 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 or local governments, and eligible agencies of the Federal government. Applications from minority and women investigators are encouraged. Each application will be considered on its own merit as an individual research project. Applicants for "Chemoprevention Clinical Trials Involving Modulation/Function of Genes and/or Gene Products" MAY NOT concurrently submit R01 applications that represent significant duplication of efforts. MECHANISM OF SUPPORT This RFA will use the cooperative agreement (U01) mechanism. The cooperative agreement is an assistance mechanism in which substantial NCI programmatic involvement with the recipient during performance of the planned activity is anticipated. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant/awardee. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section, "Terms and Conditions of Awards." The total project period for an application submitted in response to the present RFA may not exceed five years. The anticipated award date is July 1, 1995. 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. This RFA is a one-time solicitation for applications for new awards. Future unsolicited competitive 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 (DRG), NIH. However, if it is determined that there is a sufficient continuing need, the NCI will invite recipients of awards made in FY '95 under this RFA to submit competitive continuation applications for review according to procedures described below under APPLICATION PROCEDURES and REVIEW CONSIDERATIONS. FUNDS AVAILABLE Approximately $2.0 million in total costs per year for five years will be committed to specifically fund applications that are submitted in response to RFA. It is anticipated that three to six awards will be made. This number of awards is dependent on the receipt of a sufficient number of applications of high scientific merit. The earliest feasible start date for the initial awards will be July 1, 1995. 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 A. Background Evolving understanding of molecular mechanisms brings unprecedented opportunities for advances in the prevention of cancer based especially on the identification of specific gene products and the modulation of their effects at the molecular level with chemopreventive agents. New developments in the understanding of cellular function and cellular metabolites are occurring that provide information on cell growth, proliferation, differentiation and neoplastic transformation. In vitro, in vivo, and animal model systems and the chemoprevention decision network have identified a number of potential chemopreventive agents and have resulted in a rational approach to cancer preventive agent development and testing. The endpoints for cancer treatment trials are usually a measured reduction in tumor size or statistically measured survival in a population whose survival is limited. For chemopreventive interventions, no such easily measured endpoints exist. For a clinical endpoint, the primary endpoint is incidence reduction, which occurs years later. Complex biostatistical and epidemiological strategies are necessary in measuring study populations in order to prove efficacy. Another approach is to develop surrogate endpoints to measure effect and for the study of the carcinogenesis process in humans. Inhibition of the post initiation phases of carcinogenesis is an emerging strategy for the prevention of cancer. Recent understanding of the role of oncogenes and tumor suppressor genes in cancer development suggests several strategies. Specifically, gene products appear to act at various points in the intracellular pathway utilized by growth factors, cell surface receptors, GTP-binding proteins, protein kinases, and transcription factors in stimulating cell proliferation. A common characteristic of these genes is that they encode components of the signal transduction system. This system refers to the biochemical mechanisms that permit complex changes in the cytoplasm and in gene expression in the nucleus which are often controlled by extracellular ligands that act through receptors, second messenger molecules and protein kinases. Clinical trials of agents effecting gene expression or gene products are being sought. Initially, knowledge of genes involved in carcinogenesis will provide tools for screening and diagnosis. The challenge will be to move as rapidly as possible from structural defects evident in disease alleles to improved methods of compensation for these defects. This will involve the development of pharmaceuticals that will inhibit the function of these altered gene products in the carcinogenesis process. The identification of oncogenes and tumor suppressor genes opens up a number of opportunities or targets for their study in precancers and will result in improved capabilities for drug screening and rationale drug design. The major types of cancer appear to be polygenic. This means that transformation is not due to a single mutation, but from multiple mutations and can result from a composite number of different mutagenic events. Although this has many disadvantages, it also has the advantage that there may be many targets for chemopreventive activity. Currently, there is no method to rationalize these events or to predict them a priori. By correlating differences in responses to various inhibitors with variations at the DNA level, investigators may be able to develop a predictive ability for assessing risk and its modulation by using a battery of DNA based tests. What is the most promising is a possibility for the utilization of a number of different preventive agents utilized in combinations. At the preclinical level, the screening of agents with transgenic mice with gene knockouts will be helpful. The prospect of collecting and understanding responsiveness to various agents is likely to be a major aspect of future cancer prevention research. Oncogene abnormalities might be used as markers for the detection of high risk groups, and markers for the study and evaluation of precancer progression. Mutant oncogene products could be utilized as major targets for the development of new molecular forms designed to specifically inhibit to alter the function of effected pathways. At this time, targeting gene products and their function is a most advantageous strategy for chemopreventive interventions. For example, the technology might be used with extracellular molecules such as surface receptors which would not require the compound to enter the cells. Failure to permeate cells might also reduce the potential side effects. Several examples of types of studies that might be considered are as follows: Ras oncogenes have been detected in 90 percent of human pancreatic cancers, 50 percent of colorectal tumors, 30 percent of lung cancers, and 10 to 40 percent of numerous other cancers, making them the most prevalent oncogenes in human cancer. It has been known that ras proteins interact with the inner surface of the plasma membrane, where they play a role in signal transduction. In cancer cells, a single mutation in the ras oncogene impairs the ability of the ras protein to turn off the signal and continues to stimulate the cell to grow. GTP binding is one of the two requirements that the ras protein must meet to be active. The other is that the protein must be anchored to the cell membrane. This involves binding to farnesyl pyrophosphate. Blocking farnesylation with chemopreventive agents might block the ras protein attachment and, therefore, its activity. Isoprenylation of the protein can be blocked by intermediates in the cholesterol biosynthesis pathway. For example, a compound L731,735 has been developed by Merck which inhibits one of the enzymes, farnesyl transferase, in the cholesterol biosynthesis pathway. A number of other inhibitors of farnesyl protein transferase have been identified. These include the monoterpene, limonene, a major constituent of orange peel oil. The mechanism of action appears related to inhibition of isoprenylation of a 21-26 Kda protein, which is associated with cell growth. Lovastatin, a cholesterol biosynthetic inhibitor has been shown to be effective earlier in the pathway. This compound may be a model for less toxic derivatives that may be equally effective in inhibiting ras activation. The compound, Riverstatin, has inhibited the pathway with a 100-fold greater potency than Lovastatin. Other potential compounds are available and could be evaluated in clinical trials. A widely accepted general model for colorectal tumorigenesis suggests that an early and critical step in carcinogenesis is the development of altered DNA methylation, the most common form of which is global hypomethylation. This is frequently accompanied by over-expression of the c-myc proto-oncogene, as well as by genomic mutations in other proto-oncogenes and anti-oncogenes such as K-ras and p53, DCC (deleted in colon cancer), and MCC (mutated in colon cancer), respectively. Because strong associations exist between DNA hypomethylation, mutations in the above mentioned oncogenes and the evolution of colonic adenomas, these biochemical indices are considered to be excellent candidates for intermediary markers of colonic carcinogenesis. Folate is an essential cofactor in the production of S-adenosylmethionine (SAM), the primary methyl donor in the body. The SAM dependent methylation of specific DNA cytosine bases to form 5 methylcytosine may block ras gene expression and abnormalities in DNA methylation. Its deficiency may contribute to the loss of normal control of proto-oncogene expression. In rats, a chronic dietary deficiency of methyl donors (i.e., choline and methionine) and methyl transfer factors (i.e., folate and vitamin B12) lowers the concentration of SAM, increases DNA methyltransferase activity, and reduces methylation of DNA cytosine and increases the incidence of liver cancer. Several clinical reports point to the possibility that diminished folate status might also result in altered cell proliferation and neoplasia. The colonic epithelium is among the list of epithelia where epidemiological studies have established an association between diminished folate status and an enhanced risk of dysplasia and cancer. Epidemiologically, this principle applies to individuals who have an underlying predisposition to colonic dysplasia as well as to the general population. It has recently been observed that among individuals with ulcerative colitis, the prevalence of colonic dysplasia in those receiving folate supplements was about on-half that of these receiving no supplements. Two epidemiologic studies in the general population have established a significant association between diminished dietary folate intake and an enhanced risk of colon and/or rectal cancer. Adenomatous polyps, especially those that are multiple, greater than 1 cm. in diameter, and/or have villous or tubule-villous components, are widely regarded as early neoplastic lesions that will progress to frank invasive cancer if left untreated. They also serve as markers to identify individuals who are at increased risk of developing invasive colon cancer. Such patients receive regular screening colonoscopy and are an ideal target group for chemoprevention studies with folate or SAM that would include studies to evaluate the modulation of gene expression. Studies to evaluate aberrant methylation (both hypt and hyper) in oncogene activation or tumor suppressor gene inactivation might be considered. With recent results from human clinical trials, it is of interest to examine whether the effects of Sulindac and aspirin occur as a result of alterations of gene expression. It is believed that aspirin reduces DNA transcription primarily through acetylation of the serine residue of cyclooxygenase. An appropriate panel of genes implicated in colonic carcinogenesis has been identified. The rationale for the selection of biological markers, the various agents associated with colorectal cancer and adenomas and the agents that might effect the prostaglandin pathway are known. Specifically, measuring the steady state levels of RNA transcribed from adenomatous polyposis coli (APC), deleted in colon cancer (DCC), mutated in colon cancer (MCC), ras, and ornithine decarboxylase (OPC) genes in response to chemopreventive agents is possible. In addition, examining the inhibition of cyclic AMP second messenger systems which might effect the expression of colon genes could be undertaken. These types of experiments may provide further understanding of the role of NSAID drugs in the inhibition of colon neoplasia. Such projects are timely and studies of the effects of chemopreventive agents on gene expression and function are of intense interest. B. Scope and Objectives The emphasis is on the development of short-term clinical trials that will evaluate the modulation/function of genes or gene products by chemopreventive agents. The studies should be developed in phases that may include a pilot phase in humans that could later proceed to a full-scale intervention. One or more biomarkers endpoints might be initially evaluated to determine baseline parameters and, subsequently, to serve as a follow-up after the administration of the prevention measure or the chemopreventive agents in vivo and/or in vitro. The main emphasis should be on small, efficient studies aimed at improving future research designs, providing a molecular basis for the action of the chemopreventive agent(s), or providing improved intermediate endpoint biomarkers. After successful completion of the pilot phase (i.e., demonstrated modulation of endpoint biomarkers), subsequent studies could include a clinical trial monitoring the test system, a cancer incidence or mortality endpoint, and a designated agent. Studies that develop and evaluate biotechnologies for the identification of new genes, gene products and DNA probes to identify human disease or to identify individuals at high risk or predisposition to cancer are also encouraged. For the initial human phase, the proposed study might describe the relevance of the marker test system to clinical or public health cancer prevention, the rationale for the selection of the study population, and the potential intervention agent or procedure. The project could result later in the markers and agent being evaluated in a full-scale, double-blind, randomized, risk reduction clinical trial. SPECIAL REQUIREMENTS The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator, as well as the institutional official at the time of award. Terms and Conditions of Award These special Terms and Conditions of Award are, in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines Federal grant administration policy statements and regulations. A. Awardee Rights and Responsibilities 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 NCI scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NCI's 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 awardee(s) and the NCI Program Director. 1. Safety and Toxicity Review Each awardee institution and principal investigator agree to comply with the recommendations of the safety and protocol review conducted by the Program Director to assure that all FDA requirements are satisfied. 2. Quality Assurance and Adverse Reaction Reporting (a) 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. (b) 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. (c) The awardee is required to adhere to NCI guidelines for the use of investigational drugs, including investigator registration (FDA Form 1573), and maintaining a record of drug receipt. Adverse drug reactions, whether 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. 3. Data Management and Reporting Requirements Data acquisition and analysis is the responsibility of the investigator. Each awardee institution 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. Investigators will be required to submit semi-annual and annual reports to NCI using the following schedule and format as required by FDA Investigational Drug Regulations. (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: o 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. o 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. o 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: o A narrative or tubular summary showing the most frequent and most serious adverse experiences by body system. o A list of subjects who died during participation in the investigation, with the cause of death for each subject. o 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. o 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. o A list of 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 trial protocol modifications made during the previous year and not previously reported to the FDA 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. The NCI Executive Committee states that there must be gender equality in all NCI funded clinical trials absent scientific justification for gender underrepresentation of a single sex study. The Grants Administration Branch will not issue an award that fails to meet this criterion. Program staff are responsible for reviewing actual accrual reported on non-competing renewal applications. Investigators will be required to initiate corrective plans if studies are not accruing as originally proposed. Each progress report must describe accrual by gender and racial/ethnic group. Due Dates for Reports January 1 and July 1 for the semi-annual report. (f) 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. B. NCI Staff Responsibilities 1. Study/Protocol Plan The NCI Program Director (see INQUIRIES) will assist the awardees 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, and (b) availability of necessary pharmacological agents. The NCI Program Director will 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 (IND) guidelines. The awardee institutions and principal investigator must agree to comply with the recommendations of the review. 2. 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 the Code of Federal Regulations (CFR) 21. The awardees, however, will retain custody of, and primary rights to, their data. 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. 3. Investigational New Drug (IND) The NCI will have the option to cross-file or independently file an IND on investigational drugs evaluated in trials supported under this cooperative agreement. The NCI will advise investigators of specific requirements and changes in requirements concerning investigational drug management for compliance with NCI and the FDA guidelines and regulations. Investigators conducting trials under cooperative agreements will be expected, in cooperation with the NCI, to comply with all FDA monitoring and reporting requirements for investigational agents, for reporting adverse reactions, and for maintaining necessary records of drug receipt and distribution. 4. Assistance with Obtaining or Purchasing Investigational Drugs If an investigator anticipates requesting considerable assistance in obtaining the chemopreventive agents and in securing the Investigational New Drug (IND) permit from the Food and Drug Administration (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 agent are complete. Final awards by the NCI will also consider not only the cost of the trial, but also the cost of the agent, including its formulation, encapsulation and packaging, if these costs are to be borne by the Government. 5. Protocol Modification No protocol modifications shall be implemented without approval from the NCI Program Director, consistent with FDA requirements. 6. 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. The Arbitration Mechanism is described in C. below. 7. Clinical Trials Progress Review Progress will be evaluated semi-annually by the NCI Program Director from material presented in the awardee's semi-annual report (as described above). Recommendations of the NCI Program Director will be communicated by letter to the investigator to which he/she is expected to respond. 8. Quality Assurance (1) The NCI has established a clinical chemistry quality assurance program with the National Institute of Standards and Technology, Gaithersburg, Maryland, which may provide chemical standards for some of the agents being used and assayed in clinical trials. These standards will contribute to the quality control of selected laboratory determinations. If available, 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 mechanisms must conform with Food and Drug Administration (FDA) regulations. 9. Other Terms No patients may be enrolled in this study without the prior written approval of the NCI Program Director for this cooperative agreement. Such approval is contingent upon submission to, and approval by, the FDA of an IND application and satisfactory response to the recommendations of the safety and protocol review. C. Arbitration When mutually acceptable agreements on the safety of research protocols, protocol disapproval or protocol termination cannot be obtained between investigators and the NCI Program Director, as described above, 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. STUDY POPULATIONS 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 10-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women 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 subject 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 below. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by October 15, 1994, a letter of intent that includes a descriptive title of the proposed research, the name, address and telephone number of the principal investigator, the names of other key personnel, the participating institutions, and the number and title of the RFA in response to which the application 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 and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Winfred F. Malone at the address listed under INQUIRIES. APPLICATION PROCEDURES The regular research grant application form PHS 398 (rev. 9/91) is to be used in applying for cooperative agreements. These forms are available at most institutional offices of sponsored research, from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267, and from the NCI Program Director listed under INQUIRIES. The RFA label available in form PHS 398 (rev. 9/91) 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 title of the application, "Chemoprevention Clinical Trials Involving Modulation/Function of Genes and/or Gene Products," and the RFA number, CA-94-013, must be typed in line 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact, clear, and single-sided photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At 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 6130 Executive Boulevard, Room 636 Rockville, MD 20852 (if hand-delivered or delivery service) Bethesda, MD 20892 (if using U.S. Postal Service) Applications must be received by November 23, 1994. No addenda or appendix materials will be accepted after the receipt date. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG 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. Preparation of the Application The general instructions provided for the preparation of the applications contained in the Grant Application Form PHS-398 are to be used in preparing Cooperative Agreement applications. Because of the award terms and conditions included in the section under SPECIAL REQUIREMENTS, Terms and Conditions of Award, it is important that applicants indicate in the Research Plan how they will meet the requirements stated in the RFA. To ensure that the cooperative agreement remains the appropriate instrument, awardees submitting competing continuation and supplemental applications must describe how they have met the established terms and conditions. The following items apply to all applications: 1. The study should 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 should provide a rationale for selection of the biological or biochemical marker, its relevance to risk identification or modulation, and its relevance to the intervention agent and the target population. 3. The applicant should provide the rationale for selection of the proposed intervention agent. This should include relevant epidemiologic and laboratory data. Preclinical and clinical data on any potential untoward effects of the intervention agent should also be presented. In circumstances where there might be some doubt as to the availability or the safety of the agent, the applicant may wish to consult with the pharmaceutical company and the NCI Program Director prior to preparing the application. If an investigator anticipates requiring considerable assistance in obtaining the chemopreventive agents or in securing the Investigational New Drug (IND) permit from the Food and Drug Administration, such assistance must be sought in writing from the Program Director, prior to submitting the application. 4. The applicant should provide a rationale for selection of a specific target group and provide an estimate of the number of participants required for the completion of the study. Criteria and calculations used to estimate sample size should be included. The applicant should provide a description of the target population or group chosen and should justify the selection of this group. The group should be defined, as appropriate, by age, sex, race, dietary customs, education, geographic location, occupational or lifestyle risk factors, and 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 proposal should 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. 5. The applicant should clearly indicate the clinical chemistry and biologic aspects of the study to include collection, storage, handling, analysis, and quality control of biological or biochemical samples. The methods and equipment to be used and the technical qualifications and experience of the personnel involved must be addressed. If these aspects of the study are to be conducted by groups other than at the applicant's institution, a letter from the cooperating institutions indicating their willingness to participate should be included. 6. The applicant should elucidate any known or potential safety or toxicity considerations, the techniques and procedures to monitor and report any adverse health effects and appropriate dose modifications based on toxicity monitoring. 7. The applicant should specify the methods to be used to document nutrient intake, if indicated, and adherence to the prescribed intervention during the course of the trial. 8. The applicant must indicate a willingness to work cooperatively with the assistance of the NCI 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. 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 NCI staff find that the application is not responsive to the RFA, it will be returned 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 NCI in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be promptly notified. 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) that 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, intervention agents, etc., procedures for their collection and analysis, and assurances of their accessibility. 7. Adequacy of plans for NCI program staff involvement with the proposed studies. 8. Adequacy of plan for inclusion of women and minorities. 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 the initial awards will be July 1, 1995. In addition to the technical merit of the applications, the NCI will consider how well the applicant institutions meet the goals and objectives of the program as described in the RFA, availability of resources, and study populations, in making funding decisions. INQUIRIES Written and telephone inquiries concerning the RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues and address the letter of intent to: Winfred F. Malone, Ph.D., M.P.H. Division of Cancer Prevention and Control National Cancer Institute Executive Plaza North, Room 218 Bethesda, MD 20892-4200 Telephone: (301) 496-4664 FAX: (301) 402-0553 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 Number 93.399, Cancer Control. Awards will be made under the authority of the Public Health Service Act, Title IV, Section 301 (Public Law 78-410; 42 U.S.C. 241, and Section 412, as amended by Public Law 99-158, 42 U.S.C. 258a-1), and administered under Federal regulations 42 CFR Part 52 and grant policies 45 CFR Part 74 and 92. This program is not subject to the intergovernmental review requirement of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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