PHASED APPLICATION AWARDS IN CANCER PROGNOSIS AND PREDICTION Release Date: March 1, 2001 (see replacement PAR-03-098) PA NUMBER: PAR-01-061 National Cancer Institute Letter of Intent Date: May 9, 2001, November 6, 2001, May 2, 2002, and November 7, 2002 Application Receipt Date: June 13, 2001, December 11, 2001, June 11, 2002, and December 11, 2002 THIS PROGRAM ANNOUNCEMENT (PAR) INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PAR. PURPOSE 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 (PAR) 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. This solicitation will utilize the newly created Phased Application Award Mechanism (R21/R33). Specific features of this mechanism include: o Single submission and evaluation of both the R21 and R33 as one application. o Expedited transition from feasibility phase to application phase. o Flexible budgets. o Flexible staging of feasibility and application phases. Small businesses are encouraged to consider a parallel program announcement (http://grants.nih.gov/grants/guide/pa-files/PAR-01-062.html) of identical scientific scope that utilizes the SBIR and STTR mechanisms with accelerated transitional review, as well as cost and duration requirements, comparable to the Phased Application Awards. 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 Herceptin7, 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 format 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 application 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 application 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 (http://grants.nih.gov/grants/guide/pa-files/PA-01-062.html) are encouraged. Applicants should justify their proposals on the strength of the study proposed in the R33 component. Applications that include an R21 component 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. Applicants who can provide sufficient preliminary data are encouraged to apply for R33 grants. 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-01- 010 (Exploratory Studies in Cancer Detection, Prognosis and Prediction) or PA- 01-015 (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-00-089 (Development of Novel Imaging Technologies-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. Examples of possible milestones include: 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 MECHANISM OF SUPPORT Responsibility for the planning, direction and execution of the proposed project will be solely that of the applicant. Except as otherwise stated in this program announcement, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, rev. March 2001. Support for this program will be through the National Institutes of Health (NIH) Exploratory/Developmental Research Grant (R21) and the Exploratory/Developmental Research Grant Phase 2 (R33). The R33 is a newly established NIH grant mechanism to provide a second phase for the support of innovative exploratory and developmental 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. Because of the combined use of the R21/R33 the modular grant instructions will not apply to these applications. Under this PAR, applicants can submit either a combined R21/R33 application (Phased Application 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. The NIH Grants Policy Statement applies to all awards. 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 F&A costs to subcontracts to the project. Although the R33 application has no official budgetary limit, applications requesting in excess of $500,000 dollars direct costs in any single year of the grant period require prior approval before submission. 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 responsiveness of the proposed project. Early contact with NCI staff is particularly critical relative to this PAR because it uses a new grant mechanism (R33) as well as an expedited transition procedure. Refer to the INQUIRIES section of this program announcement for NCI staff contacts. 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 funded R21 and R33 grants. 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. To be eligible for the Phased Application Award, the R21 phase must include milestones that will be used to judge the feasibility of the research proposed for the R33 phase. The Phased Innovation Award must have a section labeled "Milestones" at the end of the Research Plan of the R21 application. This section must include well-defined quantifiable milestones that are to be completed by the end of the R21 part of the proposed project and a discussion of the suitability of the proposed milestones for assessing the prospects for success in the proposed R33 study. Through a separate program announcement (PAR-01-062), 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 expedited NCI review and cost allowance policies and procedures will be identical to this PAR. 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. ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Tracy G. Lugo, Ph.D. Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room 6042 Rockville, MD 20892 Telephone: (301) 496-1591 FAX: (301) 402-7819 Email: TL82S@nih.gov Direct inquiries regarding fiscal matters to: Ms. Kathleen J. Shino Grants Administration Branch National Cancer Institute 6120 Executive Blvd., EPS Room 243 Bethesda, MD 20892-7150 Telephone: (301) 846-1016 FAX: 301-846-5720 Email: shinok@gab.nci.nih.gov Direct inquiries regarding review matters to: Ms. Toby Friedberg Referral Officer National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for overnight/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: tf12w@nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by the dates listed on the first page of this PAR, a letter of intent that includes a descriptive title of the proposed research, the name, address and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of this PAR. 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 the NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Tracy Lugo at the address listed under INQUIRIES by the letter of intent receipt date. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov. For those applicants with internet access, the 398 kit may be found at: http://grants.nih.gov/grants/forms.htm. Applicants are strongly encouraged to call the program contacts listed in INQUIRIES above with any questions regarding the adherence of their proposed project to the goals of this PAR. All clinical trials supported or performed by NCI require some form of monitoring. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff to a data and safety monitoring board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional Review Board (IRB). For details about the Policy of the NCI for Data Safety Monitoring of Clinical Trials see http://deainfo.nci.nih.gov/grantspolicies/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. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE COMBINED R21/R33 PHASED APPLICATION AWARD APPLICATION Applications for R21/R33 grants are to be submitted on the grant application form PHS 398 (rev. 4/98) and prepared according to the instructions provided unless specified otherwise within this section. The R21/R33 application must include the specific aims for each phase and the 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. Successful completion of the milestones should establish feasibility for the proposed R33 work. This section should be indicated in the Table of Contents. Applications lacking this information, as determined by the NCI program staff, will be returned to the applicant without review. See the Research Objectives section above for examples of possible milestones. Prior to funding an application, the 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. The R21/R33 Phased Application Award application must be submitted as a single 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, followed by the 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 composite a-d text (i.e., section a-d and milestones for the R21 and sections a-d for the R33 phase must be contained within the 25 page limit.) In preparing the R21/R33 application, investigators should consider the fact that applications will be assigned a single priority score. In addition, as discussed in the REVIEW CONSIDERATIONS section, the initial review panel has the option of recommending only the R21 phase for support. However, a Phased Innovation Award Application with an R33 Phase that is so deficient in merit that it is not recommended for support will reflect upon the judgment of the applicant. For these reasons, the clarity and completeness of the R21/R33 application with regard to specific goals for each phase and feasibility milestones for the R21 phase are critical. The presentation of milestones that are not sufficiently scientifically rigorous to be valid for assessing the success of the R21 phase will reflect upon the scientific judgement of the applicant in this proposal. 1. Face Page of the application: Item 2. Check the box marked "YES" and type the number and title of this program announcement. Also indicate that the application is 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 a maximum of 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. The R21 phase may be either one or two years in duration. Insert the first year of R21 support in item 7a. Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT: For the R21 phase, direct costs requested for the proposed period may not exceed $200,000 for two years of support. The statement in item 7a above pertaining to subcontract costs also applies here. Insert sum of all years of requested support (R21 plus R33) in item 8a. 2. Budget: The application should provide a detailed budget for the 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 written justification. The Modular Budget approach is not to be used. An annual meeting of all investigators funded through this program will be held to share progress and research insights that may benefit the program. Applicants should request travel funds in their budgets for the principal investigator and one additional senior investigator to attend this annual meeting. 3. Research Plan: Item a., Specific Aims The applicant must present specific aims that are scientifically appropriate for each phase of the project. Clearly state the clinical question(s) 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 improvement over existing approaches. 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 submission of the R21 phase, they 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. Item d., Research Design and Methods Follow the instructions in the PHS 398 booklet. 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 suitability of the milestones for judging the success of the R21 phase, as well as how their successful completion establishes feasibility of the R33 phase must be included. The page number of the milestones section should be indicated in the Table of Contents. Applications lacking this information, as determined by the NCI program staff, will be returned to the applicant without review. 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 on the grant application. 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. For both the R21 and R33 phases, the Research Plans must include the following sections: Gender and Minority Inclusion for Research Involving Human Subjects - Describe the composition of the proposed study population in terms of gender and racial/ethnic group and provide a rationale for selection of such subjects. Display this proposed composition using the Inclusion Report Format provided in the PHS 398 form instructions. Participation of Children - This section should provide either a description of the plans to include children and a rationale for selecting or excluding a specific age range of child, or an explanation of the reason(s) for excluding children as participants in the research (see justifications for exclusions in the PHS 398 form instructions). 4. Human Subjects For each phase of the project provide a separate description of the participation of human subjects in the research, addressing the six points in the application form instructions. 5. Vertebrate Animals For each phase of the project provide a separate description of the use of vertebrate animals in the research, addressing the five points in the application form instructions. 6. 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 Applications for R33 grants are to be submitted on the grant application form PHS 398 (rev. 4/98) and prepared according to the instructions provided unless specified otherwise within this section. 1. Face Page of the application: Item 2. Check the box marked "YES" and type the number and title of this program announcement. Also indicate that the application is an R33. 2. Budget: The application should provide a detailed budget for Initial Budget Period (form page 4) as well as a budget for the entire proposed period of support (form page 5). All budgets should include a written justification. The Modular Budget approach is not to be used. An annual meeting of all investigators funded through this program will be held to share progress and research insights that may benefit the program. Applicants should request travel funds in their budgets for the principal investigator and one additional senior investigator to attend this annual meeting. 3. Research Plan: Item a., Specific Aims Clearly state the clinical question(s) 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 improvement over existing approaches. Item c., Preliminary Studies/Progress Report This section must document that feasibility studies have been completed . Preliminary data relevant to both the laboratory assay(s) or test system(s) and the clinical outcome measurements should be presented. An applicant may use preliminary data obtained with the support of a previous R21 award. Item d., Research Design and Methods Follow the instructions in the PHS 398 booklet. 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 on the grant application. 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. The Research Plan must include the following sections: Gender and Minority Inclusion for Research Involving Human Subjects - Describe the composition of the proposed study population in terms of gender and racial/ethnic group and provide a rationale for selection of such subjects. Display this proposed composition using the Inclusion Report Format provided in the PHS 398 form instructions. Participation of Children - This section should provide either a description of the plans to include children and a rationale for selecting or excluding a specific age range of child, or an explanation of the reason(s) for excluding children as participants in the research (see justifications for exclusions in the PHS 398 form instructions). 4. Human Subjects: All instructions in the Form 398 application kit apply. 5. Vertebrate Animals: All instructions in the Form 398 application kit apply. 6. 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 application kit apply. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided 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: Ms. Toby Friedberg Referral Officer National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for overnight/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Applications must be received by the receipt dates listed at the beginning of this PA. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the CSR for completeness and by NCI program staff for responsiveness to the objectives of the PAR. Applications not adhering to application instructions as described above 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 PAR will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI in accordance with the review criteria stated below. As part of the initial merit review, all applicants will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications, will be discussed, assigned a priority score and receive a second level review by the National Cancer Advisory Board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? How is the proposed diagnostic strategy superior to existing alternatives? What will be the impact on the design of 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 for judging the success of the proposed R21 work and determining whether the R33 grant should be awarded? 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 methods or technologies? What is the throughput and cost effectiveness of the proposed assay(s)? What additional uses can be projected for the proposed assay(s), or what additional groups of patients might benefit from the new diagnostic strategy? 5. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 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 Considerations For the R21/R33 Phased Innovation Award Application, the initial review group will evaluate the specific aims for each phase and the feasibility milestones that would justify transition 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, this may result in a recommendation that only the R21 phase be supported, based on concerns related to the applicant's specific aims and the feasibility milestones justifying expansion to the R33 phase. Deletion of the R33 phase by the review panel or inadequate milestones will affect the merit rating of the application. The initial review group will also examine: the appropriateness of the proposed project budget and duration; the adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to the NCI. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. 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 are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the updated NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research, published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the policy that was published in the NIH Guide for Grants and Contracts, June 5, 2000 (Revised August 25, 2000), available at the following URL address http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-004.html). 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, Phased Application Awards in Cancer Prognosis and Prediction, is related to the priority area of cancer. 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, (use appropriate program number). Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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