APPLICATION OF EMERGING TECHNOLOGIES FOR CANCER RESEARCH RELEASE DATE: December 17, 2003 RFA Number: RFA-CA-05-003 (This RFA has been reissued, see RFA-CA-06-003) (see NOT-CA-04-013) Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) ( COMPONENT OF PARTICIPATING ORGANIZATION: National Cancer Institute (NCI) ( 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 to evaluate the usefulness of emerging technologies that are ready for initial application to clinical or biological questions in cancer research. Projects should be designed to demonstrate that the technology is robust and yields reproducible measurements. Projects should also be designed to gather preliminary data to support the use of the technology in a future project(s) with a clinical or biological focus. It is expected that some refinement or adaptation of the technology may be appropriate in the initial phase of the project, but projects requiring significant technology development effort are not appropriate. In addition, applications that propose the use of commercially available technology under standard conditions, or any technology that is already commonly accepted for the proposed use, are not appropriate. (Applicants proposing projects focused on biological or clinical questions are encouraged to contact their program director to discuss appropriate funding opportunities). 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 will serve as a tool to develop emerging technologies in an appropriate biological or clinical context. 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 replace and expand on the Applications of Innovative Technologies for the Molecular Analysis of Cancer (PAR-01-106). It will support studies which start with an unproven technology, adapt or refine the technology slightly as needed, and begin to generate biological data to assess the relative robustness of the technology in the chosen biological or clinical context. Projects requiring significant technology development may be most suitable for RFA CA-05-002, Innovative Technologies for the Molecular Analysis of Cancer ( Technologies developed or adapted for sample preparation methodology may be most suitable for RFA CA-05-004, Innovations in Cancer Sample Preparation ( 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 MECHANISM OF SUPPORT). Applications of in vivo imaging technologies and projects with bioinformatics or statistics as their primary focus are not included under this RFA. Researchers who emphasize the assessment of in vivo imaging technologies as the primary focus of their grant application should contact the Cancer Imaging Program ( ) for information on appropriate funding opportunities. Researchers focusing on applying new bioinformatics or statistical techniques as the primary focus of their application should consider one of the BISTI initiatives ( 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 and application 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. 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 developments highlight the leading and critical role technological advances play throughout the NCI’s mission. Identifying the molecular alterations that distinguish any particular cancer cell from a normal cell will ultimately help to define the nature and predict the pathologic behavior of that cancer cell as well as the responsiveness to treatment of that particular tumor. By understanding the profile of molecular changes in any particular cancer, it will become possible to correlate the resulting phenotype of that cancer with molecular events. Resulting knowledge will offer the potential for a better understanding of cancer biology; the discovery of new tools and biomarkers for detection, diagnosis, and prevention studies; and new targets for therapeutic development. Assessing the usefulness of emerging technologies applied in biologically or clinically relevant settings is crucial to moving these technologies from the hands of the technology developer into the hands of biological and clinical researchers. As new technologies and experimental approaches develop, focus gradually shifts from assessment of technical feasibility toward application to biological and clinical research questions. Novel technologies are invented and refined until technical feasibility has been demonstrated. These new technologies (together with existing technologies which can be modified or adapted for new uses) then pass into a developmental phase. It is during this phase that the technologies are first applied to the research or clinical uses for which they are intended. If successful, this developmental phase produces two deliverables: a robust and reproducible tool and the preliminary supporting data resulting from its initial application. Both of these deliverables form the basis for new biological or clinical research projects enabled by the new technologies. Objectives and Scope: This RFA is intended to support projects to evaluate the usefulness of emerging technologies in appropriate biological contexts in order to assess reproducibility and produce preliminary data toward a biological or clinical question. Technologies proposed for this RFA should be sufficiently advanced in development to be applied in a relevant clinical or biological context. (Applicants proposing to use technologies that still require significant development before they can be applied to the analysis of biological materials should consider applying to the Innovative Technologies for the Molecular Analysis of Cancer, RFA CA-05-002, Researchers may propose, in the R21 phase, to continue minor refinement of newly developed technologies or minor adaptations of existing technologies to new uses. The R33 phase should be used for applying the technology in a relevant setting to generate the preliminary biological data to prove that the technology functions reproducibly and effectively in the chosen biological context. These projects should provide investigators with sufficient data to demonstrate the capabilities of the technology in a biologically relevant setting. These data may then be used by the investigator or by others to propose new projects using the technology to answer biological or clinical questions, through other existing program announcements (for example, see and or as investigator initiated R01 applications. The data generated may also be used by technology developers in partnership with clinical or biological investigators with questions that the new technology could elucidate or to partner with industry to further refine the technology into a commercial product. It is expected that investigators who developed successful cancer-relevant technologies under previous IMAT initiatives or under the new RFA CA-05-002 (Innovative Technologies for the Molecular Analysis of Cancer) will propose projects for this RFA. However, this RFA is not limited to technologies developed under the IMAT program. Investigators may propose to begin to utilize any emerging cancer-relevant technology. Areas of emerging technologies of interest to be applied in these projects include, but are not limited to, those technologies that enable: o In vitro scanning for and identification of the sites of chromosomal aberrations which reflect inherited aberrations or somatic alterations resulting from aging or 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 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 with 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 projects 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. Inherent in this early technology application is the potential for ultimately transferring knowledge gained, technology and/or methodology 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 R21/R33 Phased Innovation Award and the R33 Exploratory/Developmental Phase II award mechanisms. Applicants will be solely responsible for planning, directing, and executing the proposed project. 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 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 the RFA and its future issuances, if any. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see 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 Under this RFA, applicants can submit either a combined R21/R33 (Phased Innovation Award) application or the R33 application alone, if feasibility can be documented, as described in the SUPPLEMENTARY INSTRUCTIONS section of this RFA. Applications for R21 support alone will not be accepted. The total project period for an application submitted in response to this RFA may not exceed the following duration: R33, 3 years; combined R21/R33 application, 4 years. In the combined application, the R21 phase cannot extend beyond 2 years. For combined R21/R33 applications, the R21 phase may not exceed $100,000 direct costs per year. R21 budgets can exceed this cap to accommodate indirect costs to subcontracts to the project. It is strongly recommended that applicants contact NCI staff at an early stage of application development to convey critical information, such as potentially large budget requests or to discuss programmatic adherence to the guidelines of the proposed project. Early contact with NCI staff is particularly critical relative to this RFA because it uses an expedited review procedure for the transition from the R21 to the R33. 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: o Single submission and evaluation of both the R21 and the R33 as one application; and o Minimal or no funding gap between R21 and R33. The award of R33 funds will be based on program priorities, on the availability of funds and on successful completion of negotiated scientific milestones as determined by NCI staff in the context of peer review recommendations. To be eligible for the Phased Innovation Award, the R21 phase must include 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 technology for the R33 phase. The Phased Innovation Award must have a section labeled Milestones at the end of the Research Plan of the R21 application. This section must include well-defined quantitative milestones for completion of the R21 part of the 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. This program will run in parallel with a program of identical scientific scope (RFA CA-05-007) that will utilize the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) mechanisms. FUNDS AVAILABLE NCI intends to commit approximately $3,000,000 in FY 2005 to fund six to eight new and/or competitive continuation grants in response to this RFA. An applicant may request a project period, up to 3 years for an R33, and up to 4 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 the R21 portion of R21/R33 applications. Budgets for R33 grant applications 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 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: 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: 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: 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 Rockville, MD 20852 (for express/courier service) Bethesda, MD 20892-7150 Telephone: 301-846-1017 Fax: 301-496-8601 Email: 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: 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 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 in an interactive format. For further assistance contact GrantsInfo, Telephone: (301) 710-0267, Email: SUPPLEMENTARY INSTRUCTIONS SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION AWARD 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 feasibility milestones that would justify transition to the R33 phase. Applications must include a specific section labeled milestones following the Research Plan of the R21 phase. Milestones should be well described, quantitative, and scientifically justified. For funded applications, completion of the R21 negotiated milestones 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 Phased Innovation Award application must be submitted as a single application, with one face page. Although it is submitted as a single application, it should be clearly organized into two phases. To accomplish a clear distinction between the two phases, applicants are directed to complete Sections a-d of the Research Plan twice: one write-up of Sections a-d and milestones for the R21 phase and sections a-d again for the R33 phase. The Form 398 Table of Contents should be modified to show sections a-d for each phase as well as the milestones. There is a page limit of 25 pages for the composite a-d text (i.e., sections a-d and milestones for the R21 and sections a-d for the R33 phase must all be contained within the 25 page limit.) In preparing the R21/R33 application, investigators should consider the fact that applications will be assigned a single priority score. In addition, the initial review panel has the option of recommending only the R21 phase for support. However, a Phased Innovation Award application with an R33 Phase that is so deficient in merit that it is not recommended for support will reflect upon the judgment of the applicant. For these reasons, the clarity and completeness of the R21/R33 application with regard to specific goals and feasibility milestones for each phase are critical. The presentation of milestones that are not sufficiently scientifically rigorous to be valid for assessing progress in the R21 phase will reflect upon the scientific judgment of the applicant. 1. Face Page of the application: Item 2. Check the box marked YES and type the number and title of this request for applications. Also indicate if the application is a R21/R33 or 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 for 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 in item 8a. 2. Page 2 - Description: As part of the description, identify concisely 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 Applicants must present specific aims that are 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/R33 grant applications, preliminary data are not required, although they should be included when available. For both the R21 and 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 within the specific aims section are essential. Studies pursuing comprehensive analysis in particular 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 after 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 not be simply a restatement of the specific aims. Discuss 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. 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 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 R33 APPLICATION WHEN SUBMITTED WITHOUT THE 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 application must clearly describe why and how the exploratory/developmental study is ready to scale up to an expanded application stage. In the event that an applicant feels that the technology is too proprietary to disclose, applicants at a minimum should 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 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 includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at 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: 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.) ( 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 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 held until the next announced receipt date. 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. Applications that are not funded in the competition described in this RFA may be resubmitted as amended applications for the receipt dates listed in the RFA and its future issuances, if any. 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 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: MILESTONES: In the case of an R21/R33 application, are appropriate scientific milestones included that will show, if completed, at the end of the R21 period whether or not the project has shown feasibility to pursue the R33 portion of the project? Are the milestones as quantitative as possible to assess feasibility? 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 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. 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: 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: 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: Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available: SHARING RESEARCH DATA: Starting with the October 1, 2003, receipt date, investigators submitting an NIH application seeking more than $500,000 in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. 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 (; a complete copy of the updated Guidelines are available at 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 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 A continuing education program in the protection of human participants in research is available online at: HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see 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 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 ( 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 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 AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at 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 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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