INNOVATIONS IN CANCER SAMPLE PREPARATION RELEASE DATE: December 17, 2003 RFA Number: RFA-CA-05-004 (This RFA has been reissued, see RFA-CA-06-004) (see NOT-CA-04-013) Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Cancer Institute (NCI) (http://www.nci.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.392, 93.393, 93.394, 93.395, 93.396. LETTER OF INTENT RECEIPT DATES: January 16, 2004; May 17, 2004; September 17, 2004 APPLICATION RECEIPT DATES: February 17, 2004; June 17, 2004; October 18, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirement o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Cancer Institute (NCI) invites applications for research projects involving the development and significant enhancement or adaptation of sample preparation methodologies and technologies, the development of assays to assess sample quality, and studies designed to elucidate the criteria by which to judge sample quality. The outcome will be products and methods designed to optimize sample utility. Samples may originate from residual material not necessary for patient care or from cell lines, model organisms, or other sources relevant to cancer research. The development of new and/or improved cancer sample preparation methodologies and technologies, the development of assays to assess sample quality, and studies to elucidate the criteria needed to judge sample quality covers a wide range of project sizes and innovation levels. This RFA will allow the submission of applications involving R21, R21/R33, and R33 mechanisms. R21 applicants may propose small, highly innovative feasibility studies or small, short-term exploratory studies to meet one of the RFA goals. R21/R33 applicants should propose projects that require a small feasibility study followed by a well-defined development plan. Successful completion of the R21 feasibility study and the resulting transition to the R33 phase will be judged by NCI staff per NCI R21/R33 policy. Projects for which feasibility has already been established may be proposed as R33 applications. Feasibility means that some preliminary experiments have been performed and that there is sufficient technical data to support proof-of- principle of the technology/hypothesis. This initiative is part of a broader technology development program within the NCI. That program underscores the desire of NCI to develop and integrate novel technologies focused on the molecular analysis of cancers and their micro-environment in support of cancer research, diagnosis, and treatment. In the research continuum of discovery, development, and delivery, this program thus emphasizes the link between development and delivery. This specific initiative aims to foster the development of sample preparation techniques and methodologies that are essential for effective research, technology development, and validation that will eventually lead to clinical applications. This RFA capitalizes on both the success and intent of the original NCI sponsored Innovative Molecular Analysis Technologies (IMAT) program in bringing together a multi-disciplinary group of scientists and engineers to work on cancer and the expansion of interest in technology development across the NCI and other NIH institutes. This continuation of the IMAT program consists of the following three initiatives: Innovative Technologies for the Molecular Analysis of Cancer; Innovations in Cancer Sample Preparation; and Application of Emerging Technologies for Cancer Research. This RFA is designed to support research focused on sample preparation methods. Projects focused on the development of novel technologies may be most suitable for RFA CA-05-002, Innovative Technologies for the Molecular Analysis of Cancer (http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-002.html). Projects focused on evaluating emerging technologies that are ready for initial clinical or biological application in cancer research may be most suitable for RFA CA-05-003, Application of Emerging Technologies for Cancer Research (http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-003.html). Applicants from small businesses are encouraged to submit applications to the parallel RFA for each IMAT initiative, which utilizes the SBIR and STTR grant mechanisms (see MECHANISMS OF SUPPORT). RESEARCH OBJECTIVES Background High quality sample preparations are the foundation for effective technology validation as well as for meaningful biological and clinical research. Sample preparation covers the spectrum from preparation of molecules to cells to tissues. Preparation of the highest quality samples can be hampered by technical issues, lack of standards by which to judge quality, and lack of standard practices. Sample preparation methods vary. Researchers often develop sample preparation methodologies in an ad hoc fashion as part of other projects. This lack of information and standardization affects the quality and comparability of data across all fields of cancer research and across all technological platforms. Objectives and Scope Sample preparation methods and technologies may be developed for sample collection, processing, isolation, storage, purification, preservation, and, in the case of stored tissues, reversal of adverse events resulting from storage and preservation. Methods may be for preparation of molecules, fluids, tissues, or any other samples necessary for cancer research. Researchers may propose to develop methods to isolate cells or sub-cellular components, such as classes of molecules, organelles, or sub-cellular structures. They may propose to isolate specific classes of molecules, such as membrane-bound proteins. They may also propose studies to determine the effects of collecting, processing, and storage on molecular components of interest in stored specimens. The goal is to develop products and methodologies that maximize the quality and utility of samples for research and, in the case of human specimens, maximize the quality of the samples for research and clinical needs without compromising patient care. Sample preparation methods may impact the results or interpretation of biological studies. Investigators may apply different methods of sample preparation using the same measurement technology. In many cases of measuring biological response, no gold standard exists by which to compare research results obtained from the different sample preparation methods. There is a need for methods to assess the quality of samples prepared using different methodologies. This RFA will support methods to assess sample quality and studies that elucidate the criteria needed to judge sample quality under different conditions. This RFA will also support the development of technologies to make these assessments, such as the development of sample reference materials that can be used to calibrate the effectiveness of new fixatives or new detection methodologies. It is expected that many investigators who developed successful cancer sample preparation techniques under previous IMAT initiatives or under the new RFA (Innovative Technologies for Molecular Analysis of Cancer, RFA CA-05-002) (http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-002.html) will propose projects for this RFA. However, this RFA is not limited to techniques developed under the IMAT program. Investigators are encouraged to use any sample preparation methodologies or techniques relevant to cancer. For all projects proposed, it will be important to substantiate the ultimate value of the innovation for analyzing samples, optimizing analysis, and/or evaluating sample quality for the purpose of research and eventually clinical applications. Also of importance is the potential for ultimately transferring knowledge, technologies, and/or methodologies to other laboratories or the clinic. In the case of technologies intended for use on clinical specimens or in patients, applications from or collaborations with investigators involved in the clinical research of cancer are encouraged. MECHANISMS OF SUPPORT This RFA will use NIH Exploratory/Developmental Research Grant (R21), Exploratory/Developmental Phase II (R33), and the Phased Innovation Award (R21/R33) mechanisms. Applicants will be solely responsible for planning, directing, and executing the proposed projects. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is seven to nine months after the receipt date. Applications that are not funded in the competition described in this RFA may be resubmitted as amended applications for the receipt dates listed in this RFA and its future issuances, if any. This RFA uses just-in-time concepts. It also uses both the modular budgeting as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise, follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. The total project period for an application submitted in response to this RFA may not exceed the following durations: R21, 2 years; R33, 3 years; combined R21/R33 application, 4 years. In the combined application, the R21 phase cannot extend beyond 2 years. For R21 and 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. 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, and to discuss programmatic adherence of the proposed project to the RFA guidelines. Refer to the INQUIRIES sections 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 phases as one application. 2. Minimal or no funding gap between 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. An R21/R33 application must contain, within the R21 phase, well-defined quantitative milestones that will be used to judge the success of the proposed research, as well as a credible plan for the pilot application of the proposed technology in the R33 phase. These must be presented in a section labeled Milestones at the end of the Research Plan of the R21 application. A discussion of the suitability of the proposed milestones for assessing the success in the R21 phase, and a discussion of the implications of successful completion of these milestones for the proposed R33 study, should also be presented in this section. This program will run in parallel with a program of identical scientific scope RFA CA-05-008 that will utilize the Small Business Innovation Research (SBIR, R43 and R44) and Small Business Technology Transfer (STTR, R41 and R42) mechanisms. FUNDS AVAILABLE NCI intends to commit approximately $1,000,000 in FY 2005 to fund four to eight new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to two years for an R21, up to three years for an R33, and up to four years for a combined R21/R33 of which the R21 portion may be no more than 2 years. An applicant may request a budget for direct costs of up to $100,000 per year for R21 and the R21 portion of R21/R33 applications. Budgets for R33 and the R33 portion of R21/R33 grant applications should be appropriate for the science proposed. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/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 REQUIREMENT An annual meeting of all investigators funded through this program will be held to share progress and research insights that may lead to further progress in the program. 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 inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into four areas: scientific/research, intellectual property, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Gregory J. Downing, D.O., Ph.D. Office of Technology and Industrial Relations National Cancer Institute Building 31, Room 10A52 Bethesda, MD 20892 Telephone: (301) 496-1550 FAX: (301) 496-7807 Email: downingg@mail.nih.gov o Questions regarding intellectual property management plans should be directed to: Wendy Patterson, J.D. National Cancer Institute Technology Transfer Branch 6120 Executive Boulevard, EPS Room 450 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-0477 Email: pattersw@mail.nih.gov o Direct your questions about peer review issues to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) 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. Catherine Blount Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, EPS Room 243 Bethesda, MD 20892-7150 Rockville, MD 20852 (express/courier service) Telephone: 301-496-3179 Fax: 301-496-8601 Email: blountc@mail.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent at least one month prior to the targeted receipt date. The receipt dates and respective letter of intent dates are listed at the beginning of this document. The letter of intent should be sent to: Gregory J. Downing, D.O., Ph.D. Office of Technology and Industrial Relations National Cancer Institute Building 31, Room 10A52 Bethesda, MD 20892 Telephone: (301) 496-1550 FAX: (301) 496-7807 Email: downingg@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone: (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 APPLICATION Applications for R21/R33 grants are to be submitted on the grant application form PHS 398 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 quantitative feasibility milestones that would, if successfully completed, 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, quantitative, and scientifically justified. For funded applications, completion of the R21 negotiated milestones (potentially modified in the light of peer review and further discussion with the Program Director to whom the application is assigned) will elicit an NCI expedited review that will determine whether or not the R33 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 review may result in additional negotiations of award. The R21/R33 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 and milestones for the R21 phase and sections a-d again for the R33 phase. The Table of Contents form page in the PHS 398 instructions 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 sections a-d and milestones for the R21 phase and sections a-d for the R33 phase. In preparing the R21/R33 application, investigators should consider the fact that applications will be assigned a single priority score. In addition, the initial review panel has the option of recommending only the R21 phase for support. However, an R21/R33 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, and the quality of the feasibility milestones for the R21 phase, are critical. The presentation of milestones that are judged not to be sufficiently scientifically rigorous 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 request for applications. Also indicate if the application is an R21 only, a combined R21/R33, or an 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. 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, both R21 and R33 years, in item 8a 2. Page 2 - Description: As part of the description, identify concisely and completely the technology or methodology to be applied, its innovative nature, its relationship to presently available capabilities, and its expected impact on the molecular analysis of cancer, as well as the study in which the technology will be applied. 3. Budget: The application should contain a modular budget for the Initial Budget Period (form page 4), for each of the initial years of the R21 and R33 phases (or a detailed budget for R33 years that exceed $250,000 direct costs), 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. 4. Research Plan: Item a: Specific Aims The applicant must present specific aims that the applicant considers to be scientifically appropriate for the relevant 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 RFA is to support the pilot application of innovative technologies, hypothesis testing per se may not be the driving force in developing such an application and, therefore, may not be applicable. Furthermore, for R21 grant applications, preliminary data are not required, although they should be included when available. For both the R21 phase and the R33 phase, research that supports the pilot application of new technologies is likely to require the application of principles of fields such as engineering, materials science, physics, mathematics, and computer science. Clear statements of these underlying principles are essential. In particular, studies pursuing comprehensive analyses may result in hypothesis generation rather than hypothesis testing. 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, quantitative, and scientifically justified and they should 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 the implications of successful completion of the milestones for the R33 phase should be provided. 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 funded applications, completion of the R21 negotiated milestones will elicit an NCI expedited review 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 milestones, program priorities, and on the availability of funds. The expedited review may result in additional negotiations of award. SPECIFIC INSTRUCTIONS FOR PREPARING THE R21 APPLICATION (WITHOUT AN R33 PHASE) 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 RFA is to develop innovative technologies, hypothesis testing per se may not be the driving force in developing such an application and, therefore, may not be applicable. Furthermore, preliminary data are not required, although they should be included when available. Item d: Research Design and Methods Follow the instructions in the PHS 398 booklet. In addition to sections a-d, a one page section entitled Technical Vision should be included describing the potential application of the proposed technology. The R21 application must also include the quantitative feasibility milestones that, when accomplished, would justify a future continuation to an R33 phase. The milestones and Technical Vision sections must be contained within the standard 25 page limit for sections a-d text for an R21 application. Applications lacking these sections, as determined by the NCI program staff, will be returned to the applicant without review. SPECIFIC INSTRUCTIONS FOR PREPARING THE R33 APPLICATION (WITHOUT AN R21 PHASE). Applications for R33 grants are to be submitted on the grant application form PHS 398 and prepared according to the instructions provided unless specified otherwise within the items below. 1. Face Page of the application: Item 2. Check the box marked a YES and type the number and title of this program announcement and indicate R33. 2. Research Plan: Item c: Preliminary Studies/Progress report This section must document that feasibility studies have been completed, and progress achieved, equivalent to that expected through the support of an R21 project. The applicant must clearly describe how the exploratory/developmental study is ready to be scaled up to an expanded application stage. In the event that an applicant feels that the technology is too proprietary to disclose, the applicant must at a minimum provide a demonstration (results) of the capabilities of the proposed technology. Preliminary data relevant to both the technology evaluations and the pilot biological study should be presented. FOR ALL APPLICATIONS Appendix: All instructions in the Form 398 application kit apply. INTELLECTUAL PROPERTY MANAGEMENT PLAN: Certain research plans will require collaboration and coordination between investigators at different institutions, some of whom may not be NIH funding recipients and who may have pre-existing intellectual property obligations to third parties. It is anticipated that commercial embodiments of the results of such research may incorporate single inventions shared by several institutions, or multiple inventions each from a separate institution. Therefore, prior to funding, R33 grant applicants must address how they will coordinate patent prosecution and licensing activities, if necessary to enable a licensee to access the bundle of intellectual property needed to take a product to market on commercially viable terms. Suggested strategies include: (1) assigning intellectual property rights to related inventions to an invention management firm; (2) designating one organization to take the lead on patenting and licensing related inventions; and (3) agreeing in advance that if multiple parties are to independently license related inventions, the total of stacked royalties will not exceed a predetermined percentage rate. The technology transfer/intellectual property management/licensing officer or equivalent of the principal investigator’s institution is to submit an intellectual property management plan including at least those elements above. Alternatives to the suggested strategies, which accomplish the same goals, will be considered. Intellectual property management plans are a just-in-time requirement; it is not necessary to include the plan in the grant application but plans will be required before an R33 grant can be awarded. The applicant’s institution should avoid exclusively licensing those inventions that are research tools, unless either: (1) the field of use of the exclusive license is restricted to commercial use, or (2) the exclusive licensee will make the research tool available on reasonable terms. Applicants are directed to the NIH policy on the dissemination of biological research resources ( research tools ), which can be found at http://www.ott.nih.gov/policy/rt_guide_final.html. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) Appendices should be comprised of single-sided, unbound materials, with separators between documents. 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 policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html). APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. 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. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. This does not preclude the submission of a substantial revision of an unfunded version of an application already reviewed, but such an application must include an Introduction addressing the previous critique. An application through this RFA that is unsuccessful may be resubmitted as amended at the next subsequent receipt date. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NCI. Incomplete and/or non-responsive applications will not be reviewed. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities of the NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: 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 Receive a written critique; and o 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. In the written comments, reviewers will be asked to evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The 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, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 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? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 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? 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)? 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: MILESTONES: In the cases of R21 alone and R21/R33 applications, are appropriate and quantitative scientific milestones included that will show, when completed by the end of the R21 period, whether or not the project has shown feasibility to pursue the R33 portion of the project? 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. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research will be assessed after the determination of the priority score. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Dates: January 16, 2004; May 17, 2004; September 17, 2004 Application Receipt Dates: February 17, 2004; June 17, 2004; October 18, 2004 Peer Review Dates: June 2004; November 2004; March 2005 Council Reviews: September 2004; February 2004; June 2005. Earliest Anticipated Start Dates: December 2004; April 2005; July 2005. AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review); o Availability of funds; and o Programmatic priorities. 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. See http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm. DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II); and efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety 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/. SHARING RESEARCH DATA: Starting with the October 1, 2003, receipt date, investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing). Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state, and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 "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 is 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/. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at 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 the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. 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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