PHASED APPLICATION AWARDS IN CANCER PROGNOSIS AND PREDICTION RELEASE DATE: April 8, 2003 PA NUMBER: PAR-03-098 (see replacement PA-04-102) EXPIRATION DATE: December 12, 2003, unless reissued National Cancer Institute (NCI) (http://www.nci.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.394 LETTER OF INTENT RECEIPT DATES: May 14, 2003 and November 13, 2003 APPLICATION RECEIPT DATES: June 11, 2003 and December 11, 2003 This Program Announcement (PA) replaces PAR-01-061, which was published in the NIH Guide on March 1, 2001. THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanisms of Support 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 Award Criteria o Receipt and Review Schedule o Required Federal Citations THIS PROGRAM ANNOUNCEMENT (PA) INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE OF THIS PA The Cancer Diagnosis Program of the National Cancer Institute invites applications for research projects to evaluate the utility and pilot the application of new strategies for determining prognosis or predicting response to therapy. This will provide tools to improve clinical decision-making in the care of cancer patients. This Program Announcement (PA) provides support for a first phase (R21) for technical development and a second phase (R33) for application and evaluation of clinical utility. The first phase should produce data to demonstrate the technical feasibility of the study design proposed for the second phase, including the analytic performance of the assay or test system on samples comparable to those that will be used in the second phase. The second phase should be designed to test whether application of the strategy will provide clinical benefit to a defined set of cancer patients. Small businesses are encouraged to consider a parallel program announcement of identical scientific scope PAR-03-099 at (http://grants.nih.gov/grants/guide/pa-files/PAR-03-099.html) that utilizes the SBIR and STTR award mechanisms. RESEARCH OBJECTIVES Background The number of clinical laboratory assays currently in routine use in oncology is very small. For example, estrogen and progesterone receptor status of breast cancers is used to predict response to hormonal therapy. Blood levels of prostate specific antigen and human chorionic gonadotropin in prostate cancer and germ cell cancer, respectively, are used to assess the effectiveness of treatment and to detect recurrence. Patients whose tumor cells exhibit over-expression or amplification of the Her2/neu gene may be offered trastuzumab, forerunner of a new class of therapeutic agents directed against specific molecular targets. These markers are the exception, not the rule. During the past five years the College of American Pathologists, ASCO Expert Panels and the American Joint Committee on Cancer have carefully considered many new markers proposed for use in managing breast, colon and prostate cancer, but have found none with proven clinical utility sufficient to justify their adoption for routine practice. Recently the NCI has sought to encourage the rapid appraisal of new candidate prognostic and predictive markers through a series of program announcements soliciting exploratory (R21) studies. An increasing number of publications have described new molecules, new patterns of gene expression and new aspects of tumor cell growth that appear to be correlated with known prognostic factors. But very few markers progress beyond the stage of an initial promising result. Studies to move the development of a new diagnostic test beyond the exploratory stage require large numbers of patient samples with associated clinical data, a robust, efficient assay technique, and substantial statistical input. The transition from an exploratory marker study to initial confirmatory testing in a clinical setting may involve additional developmental work. For example, the study design may change from a retrospective to a prospective analysis or from a single institution to a multi-institutional setting. Frequently an assay format must be modified, which may require the generation and characterization of additional reagents. Procedures for standardization between collaborating laboratories may be needed. These tasks will usually fall outside the scope of an initial R21 grant, but without this preliminary work it may be difficult for the investigator to establish the feasibility of a larger project. The phased innovation award, introduced by the NCI initially to support technology development, provides an appropriate mechanism to support the development of new prognostic and predictive markers. The R21/R33 phased innovation award permits an investigator to perform initial developmental work in the R21 phase, to demonstrate feasibility by meeting a set of quantitative, peer-reviewed milestones and then to move directly into the clinical study in the R33 phase. Investigators with sufficient preliminary data to demonstrate feasibility can apply directly for an R33 award. Research Goals and Scope This program is intended to accelerate the translation of new discoveries into clinical practice by enabling investigators to apply new diagnostic strategies to clinical problems. The desired outcome will be studies with sufficient statistical power using efficient assay techniques that are conclusive enough to support the initiation of larger clinical trials designed to influence practice recommendations or to pursue FDA approval of a new device or analytic reagent. Applications involving collaborations with industrial partners either through this PAR or the parallel SBIR/STTR solicitation PAR-03-099 at (http://grants.nih.gov/grants/guide/pa-files/PAR-03-099.html) are encouraged. Applicants should justify their proposals on the strength of the study proposed in the R33 component. Applicants who can provide sufficient preliminary data are encouraged to apply for R33 grants. The R21 component of an R21/R33 application will be considered exploratory, so that extensive preliminary data from the applicant's own laboratory are not required. However, the project must be based on a strong rationale, and the applicant should provide evidence that the initial clinical evaluation of the proposed diagnostic strategy is promising. The R21 phase provides time for necessary preliminary work such as, for example, the substantial modification of an assay format. An application that includes an R21 component may use results obtained during a previous R21 award to support a proposal in response to this PAR. Applicants for R21/R33 projects need to provide information in the application or to propose milestones that will demonstrate the feasibility of the R33 phase. Milestones must be designed to permit a straightforward decision as to whether or not the applicant is ready to initiate the R33 phase of the project. Milestones should also be provided to show that the assay format to be used in the R33 phase meets necessary performance standards for sensitivity, specificity, and reproducibility. For example, milestones could be used to demonstrate the feasibility of the R33 project in the following ways: o Establish assay conditions: types of specimens, fixation processes, antigen retrieval methods, reagents and other components of the assay system, detection system, positive and negative controls, etc. o Define procedures for scoring and for reporting data. o Demonstrate that the assay or test system proposed for use in the R33 phase has the required sensitivity, specificity and reproducibility. o Establish procedures for standardization and demonstrate that comparable results can be obtained from assays performed at multiple sites. o Estimate the prevalence of the marker on a pilot set of specimens of the same type (fixed, frozen, etc.) and the same patient characteristics as the set proposed for the R33 study. o Provide evidence that the number of participants or specimens required by the study design in the R33 phase can be accrued. This list is intended for illustration, and is not meant to prescribe or to limit the milestones an application may include. See below (SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION AWARD APPLICATION) for examples. Milestones will be negotiated and may be modified in response to reviewers' recommendations (see below, AWARD CRITERIA). The R33 phase of the study must be described in sufficient detail to permit reviewers to assess the significance and innovation of the proposed work and the strength of the experimental design. Applicants are expected to provide promising evidence of clinical utility for their proposed diagnostic strategy and to show how their new test or procedure will aid the process of clinical decision-making for a specific group of patients. Applicants should plan to report correlations between the new diagnostic test and other measures used in the same clinical setting. Investigators who propose prospective studies must clearly describe the arrangements for collection and analysis of patient outcome data, especially if follow-up will be required beyond the end of the award period. Proposals will be evaluated on the strength of the scientific rationale, the significance of the problem to be addressed, the adequacy of the proposed statistical design, the feasibility of accrual of study participants or human tissue specimens and the choice of assay format and analytic performance criteria. Investigators may apply for either an R21/R33 or an R33 award, but not for an R21 alone under this PAR. Applicants who are interested in R21 projects without an R33 phase should consider NCI Program Announcements such as PA-03-003 (Exploratory Studies in Cancer Detection, Diagnosis and Prognosis) or PA-03-064 (Correlative Studies Using Specimens from Multi-Institutional Prevention and Treatment Trials. Exploratory studies focused on cancer imaging, including new imaging modalities, agents and analysis methods, are more appropriate for PA-01-030 (Exploratory Developmental Grants for Diagnostic Cancer Imaging or PAR-01-101 (Development of Novel Technologies for In Vivo Imaging: Phased Innovation Award), both sponsored by the NCI Biomedical Imaging Program. Summary Applicants should clearly describe the clinical question that their new test or procedure is intended to address: for example, diagnosis, prognosis, prediction of response to therapy, disease monitoring, etc., in a specific group of patients. Applicants should describe what additional information beyond standard clinical parameters that the new test is expected to provide. They should also demonstrate that the proposed assay has the sensitivity or accuracy adequate to answer the clinical question and that the proposed R33 study has the necessary statistical power. The R21 phase is available, if necessary, to accomplish the development or refinement of an assay. MECHANISMS OF SUPPORT This PA will use the National Institutes of Health (NIH) Exploratory/Developmental Research Grant (R21) and the Exploratory/Developmental Research Grant Phase 2 (R33). The R33 is a NIH grant mechanism to provide a second phase for the support of innovative exploratory and development research initiated under the R21 mechanism. Transition of the R21 to the R33 phase will be expedited and is dependent on completion of negotiated milestones. Applicants will be solely responsible for planning, directing, and executing the proposed project. The NIH Grants Policy Statement applies to all awards. Under this PA, applicants can submit either a combined R21/R33 application (Phased Innovation Award application) or the R33 application alone, if feasibility can be documented, as described in the APPLICATION PROCEDURES section of this program announcement. Applications for R21 support alone will not be accepted. The total project period for an application submitted in response to this PA may not exceed the following duration: R33, 4 years; combined R21/R33 application, 5 years. In the combined application, the R21 phase cannot extend beyond 2 years. For combined R21/R33 applications, the R21 phase may not exceed $100,000 direct costs per year. R21 budgets can exceed this cap to accommodate indirect costs to subcontracts to the project. The combined R21/R33 application offers two advantages over the regular application process: 1. Single submission and evaluation of both the R21 and the R33 as one application. 2. Minimal or no funding gap between R21 and R33. The award of R33 funds will be based on program priorities, on the availability of funds and on successful completion of negotiated scientific milestones as determined by NCI staff in the context of peer review recommendations. Through a separate program announcement PAR-03-099 at (http://grants.nih.gov/grants/guide/pa-files/PAR-03-099.html), the NCI is inviting applications for SBIR and STTR support, focusing on the identical research areas as described in the RESEARCH OBJECTIVES section of this solicitation. For the SBIR/STTR solicitation the review, and cost allowance policies and procedures will be identical to this PA. Qualified applicants are strongly encouraged to consider responding to the SBIR/STTR program announcement. SBIR and STTR application information is available on the web at: http://grants.nih.gov/grants/funding/sbir.htm Potential applicants who believe that they may be eligible for the SBIR/STTR award should consult the PHS SBIR and STTR Omnibus Solicitation prior to discussions of their eligibility with NCI staff listed under INQUIRIES. ELIGIBLE INSTITUTIONS Applications may be submitted by: 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 organizations 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 An annual meeting of all investigators funded through this program will be held to share results and research insights that may accelerate progress. Applicants should request travel funds in their budgets for the principal investigator and one additional senior investigator to attend this annual meeting. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity 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: Tracy G. Lugo, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035A Bethesda, MD 20892 Telephone: (301) 496-1591 FAX: 301-402-7819 Email: lugot@mail.nih.gov (for general inquiries and for projects specifically related to breast cancer, gynecologic cancers, gastric cancer, pancreatic cancer or brain tumors) Magdalena Thurin, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035A Bethesda, MD 20892 Telephone: (301) 496-1591 FAX: 301-402-7819 Email: thurinm@mail.nih.gov (for projects related to colon cancer, skin cancers including melanoma, sarcomas, or acute leukemias) James V. Tricoli, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035A Bethesda, MD 20892 Telephone: (301) 496-1591 FAX: 301-402-7819 Email: tricolij@mail.nih.gov (for projects related to prostate cancer, renal or bladder cancer, liver cancer, lymphomas or chronic leukemias) Barbara Conley, M.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035A Bethesda, MD 20892 Telephone: (301) 496-1591 FAX: 301-402-7819 Email: conleyb@mail.nih.gov (for projects related to lung cancer, head and neck cancer or esophageal cancer) 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: ncirefof@dea.nci.nih.gov o Direct your questions about financial or grants management matters to: Ms. Eileen Natoli Section Chief Grants Administration Branch National Cancer Institute 6120 Executive Blvd. EPS – Room 243 Bethesda, Maryland 20892 Phone: (301) 496-8791 Fax: (301) 496-8601 E-mail: 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 PA 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: Tracy G. Lugo, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035A Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-1591 FAX: 301-402-7819 Email: lugot@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001 or most recent version). 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. This PA does not use the "modular grant" application process. It is strongly recommended that applicants contact NCI staff at an early stage of application development to convey critical information, such as potentially large budget requests, or to discuss programmatic adherence to the guidelines of the proposed project. Early contact with NCI staff is particularly critical relative to this PA because it uses the R33 grant mechanism as well as special receipt dates and an expedited transition procedure. Refer to the INQUIRIES sections of this program announcement for NCI staff contacts. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted by the receipt dates listed on the first page of this program announcement. SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION AWARD APPLICATION: (See below for instructions for preparing an R33 application without the R21 phase.) R21/R33 applications must include specific aims that are relevant to each phase as well as feasibility milestones that would justify transition to the R33 phase. Applications must include a specific section labeled Milestones following the Research Plan of the R21 phase. Milestones should be well described, quantifiable and scientifically justified and should not be simply a restatement of the R21 specific aims. A discussion of the implications of successful completion of the milestones for the R33 phase should be included. This section should be indicated in the Table of Contents. Applications lacking this information, as determined by CSR or NCI staff, will be returned to the applicant without review. The R21/R33 application must be submitted as one application with one Face Page. Although it is submitted as a single application, it should be clearly organized into two phases. To accomplish a clear distinction between the two phases, applicants are directed to complete Sections a-d of the Research Plan twice: one write-up of Sections a-d and milestones for the R21 phase and Sections a-d again for the R33 phase. The Form 398 Table of Contents should be modified to show Sections a-d for each phase as well as the milestones. There is a page limit of 25 pages for the combined text. (i.e., Section a-d and milestones for the R21 and Section a-d for the R33 phase must be contained within the 25 page limit.) Background material or preliminary data presented in the R21 research plan need not be repeated in the plan for the R33. Sections e (Human Subjects) and f (Vertebrate Animals, if applicable) should be included for each phase; the page limits do not apply to these sections, but be concise. In preparing the R21/R33 application, investigators should consider the fact that applications will be assigned a single priority score. For these reasons, the clarity and completeness of the R21/R33 application with regard to feasibility milestones and specific goals for each phase are critical. The presentation of milestones that are not sufficiently scientifically rigorous to be valid for assessing progress in the R21 phase will reflect upon the scientific judgment of the applicant. 1. FACE PAGE OF THE APPLICATION: Item 2. Check the box marked "YES" and type the NUMBER AND TITLE of this PA. Also, indicate that the application is submitted as an R21/R33. Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT: For the R21 phase of the combined R21/R33 application, direct costs are limited to a maximum of $100,000 per year for up to two years and the award may not be used to supplement an ongoing project. The requested budgets can exceed this cap to accommodate indirect costs to subcontracts to the project. Insert the total costs requested for first year of R21 support in item 7a. Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT: The R21 phase may be either one or two years in duration. For the R21 phase, direct costs requested for the proposed period may not exceed $200,000 for two years of support. The requested budgets can exceed this cap to accommodate indirect costs to subcontracts to the project. Insert the sum of all years of requested support (R21 plus R33) in item 8a. 2. PAGE 2 - DESCRIPTION: As part of the description, identify concisely the diagnostic strategy to be developed, the specific clinical question to be addressed, the relationship to presently available capabilities for cancer prognosis or prediction and the expected impact on patient care. 3. BUDGET: The application should provide a DETAILED BUDGET for Initial Budget Period (form page 4), for each of the initial years of the R21 and R33 phases as well as a budget for the entire proposed period of support (form page 5). Form pages should indicate which years are R21 and R33. All budgets should include a justification for each item requested. The modular budget format is NOT to be used. 4. RESEARCH PLAN: Item a: Specific Aims: The applicant must present specific aims that the applicant considers to be scientifically appropriate for each of the two phases of the project. The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Since the goal of this PA is to develop new methods for cancer prognosis and prediction, clearly state the clinical questions to be addressed. Identify the patient population(s) to be studied and the assay(s) or test system(s) to be employed. Item b: Background and Significance: Clarify how the prognostic or predictive strategy proposed for evaluation in this project is a significant addition to existing approaches. Explain the potential of the proposed technology for a broad impact on patient care and improvement in patient outcomes. Clearly identify how the project, if successful, would result in new capabilities for cancer prognosis or prediction. If preliminary data from the applicant's own laboratory are not available, this section must provide current evidence from the literature or from other investigators to substantiate the potential clinical utility of the proposed strategy. Item c: Preliminary studies/Progress report: While preliminary data are not required for the R21 phase, easily understandable data that provide relevant information to aid review should be included when available. An applicant may use preliminary data obtained with the support of a previous R21 award. The R33 section of the application need not repeat information already provided in the R21. Applicants are encouraged to include all information required for adequate evaluation by reviewers. However, in the event that assays and technology are not yet patent protected and the applicant does not wish to include complete details, the application should at a minimum provide a demonstration (results) of the capabilities of the proposed approach. Item d: Research Design and Methods: Instructions for PHS 398 should be followed. In addition, for the R21 phase only, the following information must be included as a final section of Item d: Applications must include a specific section labeled Milestones following the Research Design and Methods of the R21 phase. Milestones should be well described, quantifiable, and scientifically justified and not be simply a restatement of the specific aims. A discussion of the milestones relative to the success of the R21 phase, as well as implications of successful completion of the milestones for the R33 phase should be provided. The page number of the Milestones section should be listed in the Table of Contents. Applications lacking this information, as determined by NIH staff, will be returned to the applicant without review. The following examples are provided to illustrate the recommended level of detail for milestones, but should not be considered an exhaustive list of potentially appropriate milestones. Nor is this list intended to recommend the use of specific statistical tests. You should apply those methods that are most appropriate for your data. o Assay conditions will be optimized to achieve conditions where the analytic sensitivity is at least X and the specificity is at least Y when Z samples, half of which are truly positive for the analyte, are studied. o The assay to be used in the R33 phase will perform reproducibly as defined by a coefficient of variation less than Y in a series of X test specimens. o Show that the marker, as defined by a cut-off value of X, is correlated with the outcome of interest in the patient population for the R33 phase by demonstrating that there is a difference of at least Y% in the prevalence of the marker when comparing N1 patients with outcome type 1 to N2 patients with outcome type 2. o The prognostic significance of molecular profiles defined in the training set will be demonstrated in an independent set of X specimens. This milestone will be met if values of Y% or higher are achieved for both sensitivity and specificity in predicting the clinical outcome of interest for the R33 phase. For the R33 phase, Item d of the Research Plan should include a statistical section that discusses the choice of the study design and laboratory methods. Sample sizes must be clearly stated and justified with power calculations. The statistician involved with the project should be identified and a letter of support included if no effort is requested in the budget. Plans for data management and verification of clinical research data should also be described. Collaborative arrangements should be clearly documented, and where collaborations involve NCI-sponsored clinical trials the protocol numbers should be provided. Letters of support should be included in the application to substantiate plans for collection of follow-up information beyond the period of award. Where appropriate, applicants are strongly encouraged to include a copy of the complete clinical protocol in the Appendix. Item e: Human Subjects: Refer to the instructions for the PHS 398. For each phase of the project provide a separate description of the participation of human subjects in research, and place it following item d of the Research Plan. The description for each phase must include sections that respond to the instructions in the PHS 398 for "Human Subjects Research," "Women and Minority Inclusion in Clinical Research" and the "Inclusion of Children" and "Data and Safety Monitoring" if the research involves a clinical trial. Although no specific page limits apply to these sections of the application, be succinct. Item f: Vertebrate Animals: Refer to the instructions for the PHS 398. If applicable, for each phase of the project provide a separate description of the use of vertebrate animals in the proposed research that responds to the instructions in the PHS 398. Place it following item e of the Research Plan. Although no specific page limits apply to these sections of the application, be succinct. 5. CONSULTANTS/COLLABORATORS: Include letters of support from collaborators in this section of the application. Do not place them in the Appendix. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN SUBMITTED WITHOUT THE R21 PHASE: 1. FACE PAGE OF THE APPLICATION: Item 2. Check the box marked "YES" and type the TITLE AND NUMBER of this PA. Also, indicate that the application is for an R33. 2. DESCRIPTION: As part of the description, identify concisely the diagnostic strategy to be developed, the specific clinical question to be addressed, the relationship to presently available capabilities for cancer prognosis or prediction and the expected impact on patient care. 3. BUDGET: The application should provide a DETAILED BUDGET for the Initial Budget Period (form page 4) as well as a budget for the entire proposed period of support (form page 5). Budget should include a justification of all items requested. The modular budget format is NOT to be used. 4. RESEARCH PLAN: Item a: Specific Aims: The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Since the goal of this PA is to develop new methods for cancer prognosis and prediction, clearly state the clinical questions to be addressed. Identify the patient population(s) to be studied and the assay(s) or test system(s) to be employed. Item b: Background and Significance: Clarify how the prognostic or predictive strategy proposed for evaluation in this project is a significant addition to existing approaches. Explain the potential of the proposed technology for a broad impact on patient care and improvement in patient outcomes. Clearly identify how the project, if successful, would result in new capabilities for cancer prognosis or prediction. If preliminary data from the applicant's own laboratory are not available, this section must provide current evidence from the literature or from other investigators to substantiate the potential clinical utility of the proposed strategy. Item c: Preliminary studies/Progress Report: R33 applications should clearly state how feasibility for the project has already been demonstrated. Preliminary data relevant to both the laboratory assay(s) or test system(s) and the clinical outcome measurements should be presented. This section must document that progress has been achieved which is essentially equivalent to that expected from an R21 grant. An applicant may use preliminary data obtained with the support of a previous R21 award. Item d: Research Design and Methods: Instructions for PHS 398 should be followed. Item d of the Research Plan should include a statistical section that discusses the choice of the study design and laboratory methods. Sample sizes must be clearly stated and justified with power calculations. The statistician involved with the project should be identified and a letter of support included if no effort is requested in the budget. Plans for data management and verification of clinical research data should also be described. Collaborative arrangements should be clearly documented, and where collaborations involve NCI-sponsored clinical trials the protocol numbers should be provided. Letters of support should be included in the application to substantiate plans for collection of follow-up information beyond the period of award. Where appropriate, applicants are strongly encouraged to include a copy of the complete clinical protocol in the Appendix. Item e: Human Subjects Follow all instructions in the PHS 398. Item f: Vertebrate Animals Follow all instructions in the PHS 398 if applicable. 5. CONSULTANTS/COLLABORATORS Include letters of support from collaborators in this section of the application. Do not place them in the Appendix. FOR ALL APPLICATIONS: Appendix: All instructions in the Form 398 kit apply. 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) To expedite the review process, at the time of submission, send two additional copies of the application to: Referral Officer National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for overnight/courier service) 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 (CSR) 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 receipt dates listed at the beginning of the PAR. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and for adherence to the guidelines of this PA by the NCI program staff. Applications not adhering to the guidelines of this PA, and those applications that are incomplete as determined by CSR or by NCI program staff, will be returned to the applicant without review. Applications that are complete and adhere to the guidelines of this PA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities of the 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 applications that receive a priority score will undergo a second level review by the National Cancer Advisory Board (NCAB). 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 Milestones o Innovation o Investigator o Environment The scientific review group will comment on 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 the study address an important problem? If the aims of the 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? What is the throughput and cost effectiveness of the proposed assay(s)? What will be the impact on future clinical trials or on clinical practice? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? This includes the statistical rationale for the study design and the choice of sample size. Does the applicant acknowledge potential problem areas and consider alternative tactics? Has the applicant considered how the R33 study, if promising, could proceed into eventual definitive testing of the diagnostic strategy? (3) MILESTONES: How appropriate are the proposed milestones to judge the success of the proposed R21 project and to determine whether the R33 grant should be awarded? Do they set forth specific criteria, in sufficient detail, that will permit a straightforward decision about whether or not they have been accomplished? Do the milestones establish feasibility for all aspects of the proposed R33 work? (4) INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? How is the proposed diagnostic strategy superior to existing alternatives? What additional uses can be projected from the proposed assay(s), or what additional groups of patients might benefit from the new diagnostic strategy? (5) INVESTIGATOR: Are the researchers appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and to that of other researchers, including consultants and collaborators (if any)? (6) ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Are the planned statistical and data management resources adequate? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the application will also be reviewed with respect to the following: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. OTHER: For the R21/R33 Phased Innovation Award Application, the initial review group will evaluate the specific goals for each phase and the feasibility milestones that would justify expansion to the R33 phase. A single priority score will be assigned to each scored application. As with any grant application, the initial review group has the option of recommending support for a shorter duration than that requested by the applicant and basing the final merit rating on the recommended portion of the application. For the R21/R33 application, in rare instances this might result in a recommendation that only the R21 phase be supported. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities Prior to funding an application, the NCI Program Director will contact the applicant to discuss the proposed milestones and any changes suggested by the review panel as indicated in the Summary Statement. The Program Director and the applicant will negotiate and agree on a final set of milestones. These will be the basis for judging the success of the R21 work. For funded applications, completion of the R21 milestones will elicit an expedited review by the NCI that will determine whether or not the R33 grant should be awarded. The release of R33 funds will be based on successful completion of negotiated scientific milestones, program priorities, and on the availability of funds. The expedited transitional review may result in additional negotiations of award. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Dates: May 14, 2003 and November 13, 2003 Application Receipt Dates: June 11, 2003 and December 11, 2003 NCAB Review Dates: February 18, 2004 and June 8, 2004 Earliest Anticipated Award Date: April 1, 2004 and July 1, 2004 REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving clinical trials, including Phase I and Phase II 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 is 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 PA 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. 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 PA 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. 93.394 see http://www.cfda.gov/, 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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