INNOVATIVE TECHNOLOGIES FOR MOLECULAR ANALYSIS OF CANCER RELEASE DATE: December 17, 2003 RFA Number: RFA-CA-05-002 (This RFA has been reissued, see RFA-CA-06-002) (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 Requirements 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 proposing the development of highly innovative cancer relevant technologies. Technology encompasses methods and tools that enable research, including, but not limited to, instrumentation, techniques, and devices. Technology is distinct from resources such as databases, reagents, and tissue repositories. Applications for support of such resources will not be considered responsive to this RFA. Technologies solicited include, but are not necessary limited to, those that are suitable for the detection of alterations and instabilities of genomic DNA; measurement of the expression of genes and gene products, including proteins; analysis and detection of gene and/or cellular products, including post-translational modification and function of proteins; identification and characterization of exogenous infectious agents in cancer; and assaying the function of major signal transduction networks involved in cancer. Developing technologies would include those that will support molecular analysis in vitro, in situ, or in vivo in discovery processes as well as in pre-clinical models and clinical research. This initiative is part of a broader technology development program within the NCI to harness technology in the fight against cancer. The NCI technology program underscores the desire of NCI to develop and integrate novel and emerging technologies in the support of cancer research, diagnosis, and treatment. In the research continuum of discovery, development, and delivery, this program accelerates development and delivery. This specific initiative will serve as the discovery tool of the larger program by soliciting and funding highly innovative, high risk and cancer-relevant technology development projects associated with the molecular analysis of cancer. This initiative 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 technology development projects. Technologies developed or adapted for sample preparation methodology may be most suitable for RFA CA-05-004, Innovations in Cancer Sample Preparation (http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-05-004.html). Research projects to evaluate 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 RFAs for each IMAT initiative, which utilize the SBIR and STTR grant mechanisms (see MECHANISM OF SUPPORT). Researchers who emphasize the assessment of in vivo imaging technologies as the primary focus of their grant applications should contact the Cancer Imaging Program (http://www3.cancer.gov/bip/) for information on appropriate funding opportunities. Researchers focusing on applying new bioinformatics or statistical techniques as the primary focus of their applications should consider one of the BISTI initiatives (http://www.bisti.nih.gov/bistic_funding.cfm). RESEARCH OBJECTIVES Background In order to meet the goal of eliminating death and suffering due to cancer, the NCI will continue to support the development of creative methods to understand, prevent, diagnose, and treat cancer. In the past several decades, basic discovery research has revealed that cancer is a complex disease involving myriad molecular and cellular processes, and that cancers arise as the result of the gradual accumulation of genetic changes in specific cells. Identifying which subset of the genes encoded within the human genome can contribute to the development of cancer remains a challenge. Even more challenging is the subsequent understanding of the proteins and other functional products encoded by these genes. The identification and characterization of these cancer genes and their associated gene products remains a high priority in cancer research. New technologies and approaches not only address specific questions in basic research and clinical practice but are also beneficial in uncovering and developing new directions and paradigms in cancer research. Taken together, these points highlight the leading and critical role technological advances play throughout the NCI’s mission. The Innovative Molecular Analysis Technologies (IMAT) program was originally designed in 1999 with three objectives: to focus technology development on cancer, to solicit highly innovative technology development projects, and to accelerate the rate of maturation of meritorious technologies from feasibility through development of the technology. Through solicitation, outreach, and communication with the investigator community, the IMAT program has been successful in focusing a diverse spectrum of new and emerging technologies onto cancer applications. The program has focused on both the inception and development of cancer-related technologies. Some of the technologies originally generated with IMAT funding have gone on to support the acquisition of basic knowledge about cancer, which feeds the discovery pipeline. Other IMAT supported technologies have been applied to questions of clinical importance. Through the R21/33 Phased Innovation Award, originally invented and piloted by this program, IMAT has also been successful in accelerating meritorious technology development projects by minimizing the funding gap between feasibility and development phases. While the overall NCI technology program maintains these general goals, this initiative will be more focused on the R21 or high-risk portion of an investigator’s scientific effort, with emphasis on the extent to which the idea is novel and innovative. Therefore, this RFA will not support the Phased Innovation Award (combined R21/R33), but only R21 alone and R33 alone applications, as outlined in the Mechanisms of Support section. This solicitation is intended to support the development of molecular analysis tools that will not only allow for the more careful examination of the molecular basis and profiles of cancer but will also provide the ability to identify the molecular characteristics of individuals that influence cancer development and prognosis. These tools will allow for an examination of genetic factors that influence individuals risk of developing cancer or their ability to respond to damaging external agents such as radiation, carcinogens, and therapeutic regimes. In order to fully understand cancer and define the molecular responses of the host to cancer, it will be critical not only to have knowledge at the DNA level but also to have a complete understanding of the processing of genetic information in cellular function. Current discoveries indicate that alterations in many of the cellular processes, pathways, or networks may contribute to the genesis of cancer and that these alterations could be exploited for therapeutic or prevention intervention. Therefore, it is important to invoke technologies that can detect molecular changes in the cell without preconceived ideas about what changes would be the most valuable to monitor. In the discovery phase, the emphasis will be on technologies that can effectively scan, through highly multiplexed analysis, structural variations or functional changes in many or all members of the populations of DNA, RNA, or proteins present in cells. Current technologies for the multiplexed analysis of molecular species are at a stage where the greatest utility exists for the analysis of large numbers of relatively homogeneous cell populations that can be assayed in vitro. While many of the existing technologies have relatively sophisticated multiplexing capabilities in the assay format, none are comprehensive for any particular molecular species (DNA, RNA, or protein). Therefore, opportunities exist for further development to insure that the resulting technologies provide enhanced assay potential, adequate sensitivity and discrimination, robust data analysis tools, and easy adaptation to the basic, preclinical, and clinical research settings. Objectives and Scope The purpose of this RFA is to encourage applications from individuals and groups interested in developing novel technologies suitable for the molecular analysis of cancers and their host environment in support of basic, clinical, and epidemiological research. Technologies to support research in the following areas are considered to be appropriate. Examples given below are not intended to be all-inclusive but are illustrative of the types of capabilities that are of interest. New tools that allow development of more complete molecular profiles of normal, precancerous, and cancerous cells, as well as the process of carcinogenesis, are needed to support the basic discovery process. The same sort of technological approaches will also be needed to examine the tumor micro-environment, including stromal and vascular interaction. These tools will also allow more thorough examination of the variations that influence predisposition to cancer and individual variability in response to therapeutic and prevention agents. Of interest are technologies and data analysis tools for: o In vitro scanning for and identification of the sites of chromosomal aberrations that reflect inherited aberrations or somatic alterations resulting from aging, oxidation, or exposure to radiation or carcinogens, including those that are suitable for scaling for use across whole genomes, detecting DNA adducts, or detecting rare variants in mixed populations; o In vitro scanning for and identification of sites of mutations and polymorphisms that reflect inherited aberrations or variations, or somatic alterations resulting from aging, oxidation, or exposure to radiation or carcinogens, including those that are suitable for scaling for screening whole genomes, detecting DNA adducts, or identifying infrequently represented mutations in mixed populations of DNA molecules; o Technologies for detection and characterization of nucleic acid sequences of novel exogenous infectious agents that may be present in human cancer; o Highly specific and sensitive detection of specific mutations; o Detecting mismatch and recombinational DNA repair related to cancer susceptibility and drug sensitivity; o In vitro multiplexed analysis of the expression of genes; o In vitro detection of expression of proteins and their modified forms, including technologies suitable for expansion to profiling of all proteins expressed in cells, detecting rare variants in mixed populations, and detecting protein adducts involved in chemical mutation; o Monitoring the function of proteins and genetic pathways, including measurement of ligand-protein complexes and technologies for monitoring protein function of all members of a class of proteins or a complete genetic pathway; o Delineating molecular expression, function, and analysis at the cellular level in the context of both the whole body and in situ, including molecular imaging technologies suitable at this scale, contrast agents, gene amplification techniques, and related data analysis tools; o Detection technologies and sensors, including signal to noise optimization and rare cell/molecule detection, of cancer and the structures and molecules important in its development and diagnosis; o Technologies to elucidate molecular modifications of macromolecules that may be indicative of and critical to the transformation process; o Delivery technologies and approaches to enable faster and more accurate delivery of molecular and cellular labels and drugs to and within cells for research and treatment, the overall goals being speed, accuracy, and biocompatibility; and/or o Development of high-throughput, quantitative assays for epigenetic alternations, e.g., acetylation and methylation, in promoter region of genes and histone proteins isolated from biological fluids and tissues. For all technologies proposed, it will be important to substantiate the ultimate value of and role for the technology in deciphering the molecular anatomy of cancer cells or analyzing the molecular profile of the individual. It is also important for applicants to discuss the ultimate potential for the transfer of ensuing technology to other laboratories or the clinic and, for more mature technologies, plans to ensure dissemination of the technology. 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. MECHANISM OF SUPPORT 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 mechanism provides a second phase for the support of innovative exploratory and developmental research that may or may not have been initiated under the R21 mechanism. Except as otherwise stated in this RFA, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, March 2001, available at: http://grants.nih.gov/grants/policy/nihgps_2001/. Hard copies are not available. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This initiative will employ separate discovery (R21) and development (R33) awarding mechanisms. The R21 application will emphasize the high risk, high innovation feasibility phase and potential impact. The development (R33) phase application will have to contain proof of the feasibility of the proposed technology. In addition, the R33 application will contain an outline of a plan for further development of the technology towards its ultimate use and application. Unlike the previous IMAT announcements of 1999 and 2002 (PAR-01-104) and the other two RFA solicitations of the current program, this RFA does not solicit and will not accept combined R21/R33 applications. Under this RFA, applicants must submit either an R21 application or a fully developed R33 application, according the guidelines below. The R21 application will emphasize the innovative and high-risk nature of the proposed research and be conceptual in nature, with no preliminary data required. In addition to the concept and discussion of the proposed technology that is common to all R21 applications, the application must also include a brief section describing the potential use and impact of the proposed technology. The specifics of the R21 application are described in the SUPPLEMENTARY INSTRUCTIONS section of this RFA. The R21 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 proposed R21 project period may be up to a maximum of 2 years funding. Under this RFA, applicants may also submit an R33 application if feasibility can be documented, as described in the SUPPLEMENTARY INSTRUCTIONS section of this RFA. R33 applicants must present detailed preliminary data in support of the feasibility of the proposed technology or approach that is proposed for development. These applications will also have the added burden of demonstrating the innovation of the particular technology or approach. The proposed R33 project period may be up to a maximum of 3 years. 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 of the proposed project to the RFA guidelines. Early contact with NCI staff is particularly critical relative to this RFA because of the kinds of funding mechanisms permitted, i.e., either R21 or R33, with R21/R33 applications not accepted. Refer to the INQUIRIES sections of this program announcement for NCI staff contacts. This program will run in parallel with a program of identical scientific scope CA-05-006 that will utilize the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) mechanisms. This RFA uses just-in-time concepts. It also uses the modular as well as non-modular budgeting format. (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 format. 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. FUNDS AVAILABLE NCI intends to commit approximately $3,000,000 in FY 2005 to fund 10 to 15 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 2 years and a budget for direct costs of up to $100,000 per year, in keeping with standard R21 mechanism guidelines, or 3 years for an R33. 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, especially in the case of R33 awards, will also vary. Budgets for R33 applications should be appropriate for the science proposed. 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 REQUIREMENTS 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: Shane Woodward Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, EPS Room 243 Bethesda, MD 20892-7150 Rockville, MD 20852 (for express/courier service) Telephone: 301-846-1017 Fax: 301-496-8601 Email: woodwars@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 ENHANCED R21 AND R33 APPLICATIONS Applications for R21 or R33 grants (no combined R21/R33 applications will be accepted under this RFA) are to be submitted on the grant application form PHS 398 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 RFA. Also indicate if the application is an R21 or R33. 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 or 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). All budgets should include a written justification. Item b: Background and Significance Elaborate on the innovative nature of the proposed research. Clarify how the technology development proposed in this project is a significant improvement over existing approaches. Explain the potential of the proposed technology for having a broad impact on cancer research. Clearly identify how the project, if successful, would result in new capabilities for research, the immediacy of the opportunity and how these proposed technologies would differ from existing technologies. SPECIFIC INSTRUCTIONS FOR PREPARATION OF AN R21 APPLICATION 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 a proposal 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. Along with 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 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. An application lacking these sections, as determined by the NCI program staff, will be returned to the applicant without review. SPECIFIC INSTRUCTIONS FOR PREPARATION OF AN R33 APPLICATION 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. 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 that 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. The applicant’s attention is 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/label-bk.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 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 submitted 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 these 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: R21 applications: the adequacy of the proposed quantitative feasibility milestones and the Technical Vision statement. R33 applications: R33 applicants must present detailed preliminary data in support of the feasibility of the proposed technology or approach that is proposed for development. They will also have the added burden of demonstrating the innovation of the particular technology or approach. 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. 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 CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share 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 2005; 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. 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); 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 more than $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 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: (if applicable) 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: (if applicable) 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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