APPLICATIONS OF INNOVATIVE TECHNOLOGIES FOR THE MOLECULAR ANALYSIS OF CANCER: PHASED INNOVATION AWARD Release Date: May 31, 2001 PA NUMBER: PAR-01-106 (see replacement RFA-CA-05-003) National Cancer Institute Letter of Intent Date: June 15, 2001, October 17, 2001, February 14, 2002, June 10, 2002, October 18, 2002, February 14, 2003, and June 16, 2003 Application Receipt Date: July 20, 2001, November 21, 2001, March 21, 2002, July 22, 2002, November 22, 2002, March 21, 2003, and July 21, 2003 This Program Announcement (PA) replaces PAR-99-102, which was published in the NIH Guide on May 14, 1999. THE PA INCLUDES MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. THIS PA DOES NOT USE THE MODULAR GRANT CONCEPT. PURPOSE The National Cancer Institute (NCI) invites applications for research projects to evaluate the utility and pilot the application of molecular analysis technologies in studies relevant to cancer research. Molecular analysis technologies of interest include those that are entirely novel, or emerging but not currently in broad scale use where the technologies have not yet been demonstrated to be robust or reproducible in supporting molecular analysis in cancer research, or technologies currently in use for one application or set of applications, that are being evaluated for utility for alternative applications. The Program Announcement (PA) provides support for a first phase for technology evaluation and a second phase for pilot application of the technology in a study of biological interest to cancer research. The first (evaluation) phase should include proof of principle experiments that will demonstrate the utility of the technology on samples comparable to those that will be used in the second phase study. Applicants will be expected to demonstrate the utility of all components of the process required for a fully integrated system, including sample preparation, molecular analysis assay, and data capture and analysis. The second (application) phase supports the transition of the technology optimized in the first (evaluation) phase to pilot application in a study of biological interest to cancer research. The design of the second phase study should allow the demonstration that the technology can reproducibly obtain molecular data from the selected sample type and produce information of biological interest to cancer research. Studies might appropriately target analysis of precancerous, cancerous, or metastatic cells, or host derived samples, from model cancer systems, preclinical or clinical research, or from population based research. Technologies suited for this solicitation, include those that enable the detection of alterations and instabilities of genomic DNA, measurement of expression of genes and gene products, analysis and detection of gene and or cellular products including differential expression, quantitation, post translational modification, and function of proteins, identification of exogenous infectious agents in cancer, and assaying the function or major signal transduction networks involved in cancer. Additionally, technologies that will support molecular analysis in vitro, in situ, or in vivo (by imaging or other methods) are suitable for this PA. Technologies are defined as instrumentation, techniques, devices and analytical tools (e.g., computer software) but are distinct from resources such as databases, reagents, and tissue repositories. This PA will expire on July 22, 2003, unless reissued. BACKGROUND Rapid molecular analysis tools will expedite the molecular characterization of normal cells, precancerous, cancerous, and metastatic cells, as well as, expand our understanding of the biological basis of cancers. Comprehensive analysis of cancers at the molecular level will facilitate cancer detection and diagnosis, as well as identify new targets for therapeutic and preventative agents. The definition of the molecular alterations in cancer will require the continued development and dissemination of comprehensive molecular analysis technologies as well as identification of all of the molecular species encoded in genomes of cancer and normal cells. The National Cancer Institute implemented the Cancer Genome Anatomy Project (CGAP) to create an information infrastructure of the molecular changes associated with cancer development, and to develop technological tools to support the analysis of molecular profiles of cancer cells and their normal counterparts. The current CGAP program comprises Tumor Gene Indices for the human and mouse (hTGI and mTGI), a Genetic Annotation Initiative (GAI) and the Cancer Chromosome Aberration Project (cCAP). The TGI and GAI, are focused toward building a catalog of annotated genes associated with cancer. The third component, cCAP, is developing resources to catalog and facilitate the molecular characterization of cancer-related chromosomal aberrations. Complete information about CGAP can be found at http://cgap.nci.nih.gov. The NCI is also targeting support for the development and dissemination to basic, preclinical, and clinical researchers of novel technologies that will allow high- throughput analysis of genetic alterations, expression of genome products, and monitoring of signal transduction pathways in cancers. A complimentary program on "Innovative Technologies for the Analysis of Cancer" to support technology development was announced in May 1998 and has recently been reissued for the next two years. This initiative, "Applications of Innovative Technologies for the Molecular Analysis of Cancer" is intended to support the demonstration that newly developed and emerging technologies have matured and are suitable for use in cancer research, followed by the initial application of these technologies in well-defined studies of biological interest to cancer research using model cancer systems, preclinical or clinical samples, or in population research. The routine use of improved molecular analysis tools will lead to a better understanding of the molecular basis of cancer, and will facilitate the identification of molecular characteristics of individuals, that influence cancer development and prognosis. Molecular analysis technologies of interest include those that will support: --A more complete understanding of the biological basis of cancer. --The identification of molecular variations between normal, precancerous, cancerous, and metastatic cells that can serve as targets for the detection, diagnosis, therapy, and prevention. --An examination of genetic factors that influence an individual"s likelihood to develop cancer or their ability to respond to external damaging agents, such as radiation and carcinogens. --The molecular correlation between individuals with therapeutic or toxic responses to treatment and prevention measures and genetic factors that influence the efficacy and safety of these strategies and agents (pharmacogenomics). --Identification of molecular markers in the individual that correlate with the body"s response to the onset or clearance of disease and the development of biomarkers to track and even image the efficacy of therapy (therametrics) and prevention, as well as the onset of secondary cancers. --Tracking of the damage to the genome from exogenous agents such as carcinogens, radiation and existence of exogenous infectious agents resident in cancer cells. The comprehensive molecular analysis of cancer will require: --High through put analysis strategies to elucidate the processing and expression of genetic material in the cell. --Detection of molecular changes in the cell without preconceived ideas about which information will be most valuable to monitor. --Adequate adaptations to accommodate technical issues specific to the study of cancer in vitro and in vivo, such as limited cell number, sample heterogeneity, and heterogeneity of specimen types (i.e., bodily fluids and waste, tissues, cells). --Adaptation of novel technologies for use in cancer research, including use on tumor specimens, in patient imaging, and in population research. --Integration of sample preparation components that maintain the efficiencies of the assay system and effectively accommodate human tumor specimens. --Data analysis tools for interpreting the information from highly multiplexed molecular analyses. Novel technologies for comprehensive molecular analysis are being developed. Many of these technologies have not yet been demonstrated to have utility or cost effectiveness in application to cancer model systems, cancer specimens, or in population-based research. It will be necessary to demonstrate that relevant technologies have adequate sensitivity to discriminate differences between tumors and normal tissues, and tumors of different stages. Therefore, the need exists to demonstrate the ability of emerging molecular analysis technologies to provide routine assay performance, adequate sensitivity and discrimination, and associated robust data analysis tools, that can be adapted to basic, pre-clinical, and clinical research settings for the purpose of cancer research. Translation of new in vitro technologies for the multiplexed analysis of molecular species in clinical specimens will require a multidisciplinary team approach with broad expertise in a variety of research areas. Such varied expertise, potentially including but not limited to, expertise in pathology, specimen acquisition and preparation, informatics and biostatistics exists in ongoing cancer centers and clinical trials cooperative groups. The coordination and collaboration of investigators from these various disciplines to demonstrate the utility and applicability of new analytical tools in clinical and population based studies is considered to be a high priority. Existing technologies for molecular analysis are also largely restricted to in vitro analysis. While these systems are suitable for discovery and many basic and clinical research questions, they are limited in their ability to offer information relative to molecular changes in real time and in the appropriate context of the intact cell or body. Imaging in situ or in vivo is becoming increasingly important for extending molecular analysis of early cancer formation. The application of high-resolution imaging at the cellular or molecular levels to, tissue samples, pre-clinical models, or human investigations is therefore considered to be an important extension of molecular analysis methods. Similarly, the application of molecular probes for imaging molecular events is also of interest for pre-clinical and human investigations. Finally, the use of molecular contrast enhancement techniques, such as contrast modifications of gene expression are considered critical to improve the sensitivity of detection of molecular changes in vivo. The molecular imaging methodologies proposed, including hardware and software, are specifically understood as being within the context of molecular analysis tools. They include specialized high resolution or microscopic imaging methods dedicated to detection and analysis of molecular events related to cancer formation or as applied to pre-clinical drug discovery. Improvements in these areas will bring capabilities for real time molecular analysis at whole body levels. Investigations of tumor models that do not target molecular species are not responsive to this application. Investigators are encouraged to contact NCI program staff for further information. RESEARCH OBJECTIVE The National Cancer Institute (NCI) invites applications for research projects to evaluate the utility and pilot the application of newly developed molecular analysis technologies in studies relevant to cancer research. The Program Announcement (PA) provides support for a first phase for technology evaluation and a second phase for pilot application of the technology in a study of biological interest to cancer research. The first (evaluation) phase should include proof of principle experiments that will demonstrate the utility of the technology on samples comparable to those that will be used in the second phase study. Applicants will be expected to demonstrate the utility of all components of the process required for a fully integrated system, including sample preparation, molecular analysis assay, and data capture and analysis. The second (application) phase supports the transition of the technology optimized in the first (evaluation) phase to pilot application in a study of biological interest to cancer research. The design of the second phase study should allow the demonstration that the technology can reproducibly obtain molecular data from the selected sample type and produce information of biological interest to cancer research. Studies might appropriately target analysis of precancerous, cancerous, or metastatic cells, or host derived samples, from model cancer systems, preclinical or clinical research, or from population based research. The application of new tools that support the comprehensive molecular characterization of normal, precancerous, cancerous, and metastatic cells, as well as the identification of new targets for detection, diagnosis, preventative, and therapeutic strategies, is needed to support the basic discovery process and the translation of basic discoveries to pre-clinical and clinical research. Application of improved molecular analysis technologies will also allow a more thorough examination of the variations that influence predisposition to cancer, and individual variability in response to therapeutic and prevention agents as well as the identification of exogenous infectious agents that may be associated with the development of cancer. Examples given below are not intended to be all-inclusive, but are illustrative of the types of molecular analysis capabilities that are of interest for evaluation and pilot application in response to this solicitation. --In vitro identification and characterization of sites of chromosomal aberrations, which arise from inherited 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, detecting rare variants in mixed populations, or identifying infrequently represented mutations in mixed populations of DNA molecules. --Detection and characterization of nucleic acid sequences of novel exogenous infectious agents including viruses, bacteria or other microscopic forms of life that may be etiologic factors or co-factors in the initiation and/or progression of human cancers. New technologies are demonstrating that microorganisms may play a more important role in the initiation of malignancies than was previously appreciated. -- In vitro scanning for and identification of sites of mutations and polymorphisms which reflect inherited aberrations or variations, or somatic alterations resulting from aging or oxidation, or exposure to radiation or carcinogens, including those that are suitable for scaling for screening whole genomes, detecting DNA adducts, of identifying infrequently represented mutations in mixed populations of DNA molecules. -- Highly specific and sensitive detection of specific mutations in multiplexed high through put analysis. -- Detection of mismatch and recombinational DNA repair anomalies related to cancer susceptibility, cancer progression, and drug sensitivity. -- In vitro multiplexed analysis of the expression of genes. -- Computer assisted quantitation of gene expression. --In vitro detection of expression of proteins and their post- translationally 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. --Assaying 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 members of a complete genetic pathway. Translation of the utility of the technologies described above and basic research findings into tools for pre-clinical and clinical applications requires additional technological innovation with regard to sample preparation, enhanced sensitivity, and expanded data analysis tools. Of interest is the application of technologies suitable for: -- Detection, quantification and analysis of DNA mutations and polymorphisms and functional proteins in clinical specimens (e.g. tissue, serum, plasma, nipple aspirates, bronchioalveolar lavage, sputum, urine, pancreatic juice, colonic wash, and bladder wash). --Imaging in situ or in vivo in order to extend molecular analysis to early cancer formation. The application of high-resolution imaging at the cellular or molecular levels to, tissue samples, pre-clinical models, or clinical investigations are therefore considered to be an important extension of molecular analysis methods. Similarly, the application of molecular probes for imaging molecular events is also of interest for pre-clinical and human investigations. Finally, the use of molecular contrast enhancement techniques, such as contrast modifications of gene expression are considered critical to improve the sensitivity of detection of molecular changes in vivo. The molecular imaging methodologies proposed, include hardware and software, are specifically understood as being within the context of molecular analysis tools. They include specialized high resolution or microscopic imaging methods dedicated to detection and analysis of molecular events related to cancer formation or as applied to pre- clinical drug discovery. Improvements in these areas will bring capabilities for real time molecular analysis at whole body levels. The R21 proposal supports a first phase for technology evaluation. Applicants should describe proof of principle experiments that will demonstrate the utility of the technology. The applicant should: --Demonstrate performance of the selected technology on samples comparable to those to be used in the proposed study in the R33 phase. --Have a detailed plan to optimize and troubleshoot the technology for complete adaptation of the technology for the R33 pilot application. --Discuss how they will evaluate cost effectiveness of the technology relative to existing and competing technologies. --Specifically address approaches to sample preparation, molecular analysis assays, data collection, and data management. Applicants must include in a separate section the milestones to be accomplished in the first phase of the application. Milestones are separate from specific aims. They provide a clear measure of the success of the R21 application which is necessary to proceed to the second phase, therefore they should be clearly stated and presented in a manner that is easily quantifiable. The R33 study is intended to support the pilot application of technology evaluated and refined in the R21 proposal, to a study of biological interest to cancer research. Technology developers are strongly encouraged to seek collaborations with qualified cancer researchers. In the R33 phase the applicants should: --Describe how they will assess the performance of the technology in providing useful molecular data relative to existing technologies. --Address plans to refine study design parameters based on R21 results. --Provide a more refined plan detailing the biological questions to be asked by the study and how the forthcoming data will be translated, either directly or indirectly, into information relevant to the study of cancer. --Comment in detail on the suitability of the study design (i.e. numbers, types of samples) for asking the biological questions posed by the study. This should be discussed in the context of information and data to be obtained from R21 studies. The study design parameters (i.e. number of samples, data analysis, etc.) should be of a scale to reflect that this is a pilot application of the technologies. --Clearly define what is considered to be a high quality sample for the technology to be used. --Document a strategy for obtaining access to high-quality samples that will be needed to carry out the study. --Discuss the ease of transition of the technology from R21 to R33 application with respect to scaling up the technology and implications related to sample cost, availability, and sample through-put. Effective data management and analysis will be critical to the successful and productive application of the proposed technology. Therefore applications must: --Address the ability to acquire, store, analyze, and extract information from data collected through the course of the study. --Demonstrate capabilities to capture the data and to perform the complex multiplex analysis on data a acquired through the course of the study. --Describe bioinformatics, other analytical systems, and approaches that will be used to interpret data obtained from the study. Applicants are encouraged to discuss potential strategies for making resulting molecular data sets available to the cancer research community in both peer reviewed-publications as well as in complete electronically accessible data sets. MECHANISM OF SUPPORT Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Except as otherwise stated in this program announcement, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, March 2001, available at: http://grants.nih.gov/grants/policy/nihgps_2001/. Hard copies are not available. 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 development research initiated under the R21 mechanism. Transition of the R21 to the R33 phase will be expedited and is dependent on completion of negotiated milestones. Under this PA, applicants can submit either a combined R21/R33 application (Phased Innovation Award application) or the R33 application alone, if feasibility can be documented, as described in the APPLICATION PROCEDURES section of this program announcement. Applications for R21 support alone will not be accepted. The total project period for an application submitted in response to this PA may not exceed the following duration: R33, 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. R33 applications requesting in excess of $500,000 dollars direct costs in any single year of the grant period require prior approval before submission. It is strongly recommended that applicants contact NCI staff at an early stage of application development to convey critical information, such as potentially large budget requests or to discuss programmatic adherence to the guidelines of the proposed project. Early contact with NCI staff is particularly critical relative to this PA because it uses an expedited review procedure. Refer to the INQUIRIES sections of this program announcement for NCI staff contacts. The combined R21/R33 application offers two advantages over the regular application process: 1. Single submission and evaluation of both the R21 and the R33 as one application. 2. Minimal or no funding gap between R21 and R33. The award of R33 funds will be based on program priorities, on the availability of funds and on successful completion of negotiated scientific milestones as determined by NCI staff in the context of peer review recommendations. To be eligible for the Phased Innovation Award, the R21 phase must include well-defined quantifiable 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 quantifiable 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 (http://grants.nih.gov/grants/guide/pa-files/PAR-01-107.html) that will utilize the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) mechanisms. ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and not-for-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Carol A. Dahl, Ph.D. Office of Technology and Industrial Relations National Cancer Institute 31 Center Drive, Room 11A03 Bethesda, MD 20892-2590 Telephone: (301) 496-1550 FAX: (301) 496-7807 Email: carol_dahl@nih.gov Direct inquiries regarding fiscal matters to: Ms. Kathleen J. Shino Grants Administration Branch National Cancer Institute 6120 Executive Blvd. Room 243 Bethesda, MD 20892-7150 Telephone: (301) 846-1016 FAX: (301) 846-5720 Email: shinok@gab.nci.nih.gov Direct inquiries regarding review matters to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8326 Bethesda, MD 20892-8326 Rockville, MD 20852 (for express/courier service) Telephone (301) 496-3428 Fax: (301) 402-0275 Email: tf12w@nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by the dates listed on the first page of this PA, a Letter of Intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the PA in response to which the application may be submitted. 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 to Dr. Carol Dahl, listed under INQUIRIES, by the Letter of Intent receipt date. APPLICATION PROCEDURES 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. Application kits are available at most institutional offices of sponsored research and on the Internet at: http://grants.nih.gov/grants/funding/phs398/phs398.html. 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, quantifiable and scientifically justified. A discussion of the milestones relative to the progress of the R21 phase, as well as, the implications of successful completion of the milestones for the R33 phase should be included. This section should be indicated in the Table of Contents. Applications lacking this information as determined by 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 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., section a-d and milestones for the R21 and sections a-d for the R33 phase must be contained within the 25 page limit.) In preparing the R21/R33 application, investigators should consider the fact that applications will be assigned a single priority score. In addition, as discussed in the REVIEW CONSIDERATIONS section, the initial review panel has the option of recommending only the R21 phase for support. However, a Phased Innovation Award Application with an R33 Phase that is so deficient in merit that it is not recommended for support will reflect upon the judgement 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 judgement of the applicant in this proposal. 1. Face Page of the application: Item 2. Check the box marked YES and type the number and title of this program announcement. Also indicate if the application is a R21/33 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 provide a detailed budget for Initial Budget Period (form page 4), for each of the initial years of the R21 and R33 phases as well as a budget for the entire proposed period of support (form page 5). Form pages should indicate which years are R21 and R33. All budgets should include a written justification. An annual meeting of all investigators funded through this program will be held to share progress and research insights that may 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. 4. Research Plan: Item a., Specific Aims. The applicants must present specific aims that the applicant considers to be scientifically appropriate for the relevant phases of the project. The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Since the goal of this PA is to support the pilot application of innovative technologies, hypothesis testing per se may not be the driving force in developing such a proposal and, therefore, may not be applicable. Furthermore for R21 grant applications, preliminary data are not required, although they should be included when available. For both the R21 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 this section are essential. Studies pursuing comprehensive analysis in particular may result in hypothesis generation, rather than hypothesis testing. Item b: Background and Significance Elaborate on the innovative nature of the proposed research. Clarify how the technology proposed for evaluation 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. Describe the significance of the second phase pilot biological study in terms of relevance to cancer research. Item c., Preliminary Studies/Progress Report While preliminary data are not required for submission of the R21 phase, this section should provide current thinking or evidence in the field to substantiate feasibility of the R21 phase. The R33 need not repeat information already provided in the R21. In the event that an applicant feels that technology is too proprietary to disclose, applicants at a minimum should provide a demonstration (results) of the capabilities of the proposed technology. Item d., Research Design and Methods Follow the instructions in the PHS 398 booklet. In addition, for the R21 phase only, the following information must be included as a final section of Item d: Applications must include a specific section labeled Milestones following the Research Design and Methods of the R21 phase. Milestones should be well described, quantifiable, and scientifically justified and not be simply a restatement of the specific aims. A discussion of the milestones relative to the success of the R21 phase, as well as the implications of successful completion of the milestones for the R33 phase and the page number of the milestones section should be listed. This section should be indicated in the Table of Contents. Applications lacking this information as determined by the NCI program staff, will be returned to the applicant without review. 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 PREPARATION OF THE R33 APPLICATION WHEN SUBMITTED WITHOUT THE R21 PHASE. Applications for R33 grants are to be submitted on the grant application form PHS 398 and prepared according to the instructions provided unless specified otherwise within items 1-5 below. Application kits are available at most institutional offices of sponsored research and on the Internet at: http://grants.nih.gov/grants/funding/phs398/phs398.html. 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. 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 pilot biological study in which the technology will be applied. 3. Research Plan: Item a., Specific Aims. The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state the hypotheses to be tested. Because the goal of this program announcement is to pilot the application of innovative technologies, hypothesis testing per se may not be the driving force in developing such a proposal and, therefore, may not be applicable. Studies pursuing comprehensive analysis in particular may result in hypothesis generation rather than hypothesis testing. Item b: Background and Significance Elaborate on the innovative nature of the proposed research. Clarify how the technology proposed for evaluation 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, and how these proposed technologies would differ from existing technologies. Discuss the significance of the pilot biological application to be undertaken in terms of relevance for cancer research. 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 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. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040 - MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) To expedite the review process, at the time of submission, send two additional copies of the application to: Ms. Toby Friedberg Referral Officer National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8326 Bethesda, MD 20892-8326 Rockville, MD 20852 (for overnight/courier service) Applications must be received by the receipt dates listed at the beginning of this PA. The Center for Scientific Review (CSR) will not accept any application in response to this PA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the CSR for completeness and by NCI program staff for adherence to the guidelines. Applications not adhering to application instructions described above and those applications that are incomplete as determined by CSR or by NCI program staff will be returned to the applicant without review. Applications that are complete and adhere to the guidelines of this PA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI in accordance with the review criteria stated below. As part of the initial merit review, all applicants will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit generally the top half of the applications will be discussed, assigned a priority score, and receive a second level review by the National Cancer Advisory Board (NCAB). Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a technology forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? To what degree does the technology support the needs of the targeted research community? For systems intended for clinical research the additional criteria will be considered: to what degree is the analysis system appropriate for clinical research and likely to have utility for the analysis of clinical specimens or patients? 2. 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? 3. Innovation. Does the project employ novel concepts, approaches, or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? What is the throughput and cost effectiveness of the proposed technology? What additional uses can be projected for the proposed technology? 4. 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)? 5. 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 Considerations Milestones. How appropriate are the proposed milestones against which to evaluate the demonstration of feasibility for transition to the R33 development phase? For the R21/R33 Phased Innovation Award Application, the initial review group will evaluate the specific goals for each phase and the feasibility milestones that would justify expansion to the R33 phase. A single priority score will be assigned to each scored application. As with any grant application, the initial review group has the option of recommending support for a shorter duration than that requested by the applicant, and basing the final merit rating on the recommended portion of the application. For the R21/R33 application, this may result in a recommendation that only the R21 phase be supported, based on concerns related to the applicant specific goals and the feasibility milestones justifying expansion to the R33 phase. Deletion of the R33 phase by the review panel or inadequate milestones will affect the merit rating of the application. The initial review group will also examine: the appropriateness of the proposed project budget and duration, the adequacy of plans to include both genders and minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to the NCI. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. SCHEDULE Letter of Intent Receipt Dates: June 15, 2001, October 17, 2001, February 14, 2002, June 10, 2002, October 18, 2002, February 14, 2003, and June 16, 2003 Application Receipt Dates: July 20, 2001, November 21, 2001, March 21, 2002, July 22, 2002, November 22, 2002, March 21, 2003, and July 21, 2003 NCAB Review Dates: February 2002, May 2002, September 2002, February 2003, May 2003, September 2003, February 2004 Earliest Anticipated Award Date: April 1, 2002, July 1, 2002, November 1, 2002, April 1 2003, July 1, 2003, November 1, 2003, April 1, 2004 INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the NIH policy on education in the protection of human research participants now required for all investigators, which is published in the NIH Guide for Grants and Contracts, June 5, 2000 (Revised August 25, 2000), available at the following URL address http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program on the protection of human participants in research is now available online at http://cme.nci.nih.gov/. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS led national activity for setting priority areas. This PA, Applications of Innovative Technologies for the Molecular Analysis of Cancer, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.394. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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