INNOVATIVE TECHNOLOGIES FOR THE MOLECULAR ANALYSIS OF CANCER: PHASED INNOVATION AWARD Release Date: May 31, 2001 (see addendum NOT-CA-03-007) PA NUMBER: PAR-01-104 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-99-100, 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 develop novel technologies that will support the molecular analysis of cancers and their host environment in support of basic, clinical, and epidemiological research. Technology encompasses methods and tools that enable research including, but not limited to, instrumentation, techniques, devices, and analysis tools (e.g., computer software). Technology is distinct from resources such as databases, reagents, and tissue repositories. Applications for support of such resources will not be considered to be responsive to this Program Announcement (PA). Technologies solicited include those that are suitable for the detection of alterations and instabilities of genomic DNA; measurement of the expression of genes and gene products; analysis and detection of gene and or cellular products including post translational modification, and function of proteins; identification and characterization of exogenous infectious agents in cancer; and assaying the function of major signal transduction networks involved in cancer. This PA is intended to support the development of all required components of fully integrated systems for analysis including front end preparation of sample materials from cells, bodily fluids, and tumor specimens; novel chemistries or contrast agents; molecular detection systems; data acquisition methods; and data analysis tools. Technologies under consideration include those that will support molecular analysis either in vitro, in situ, or in vivo (by imaging or other methods) in the discovery process, as well as in pre-clinical models and clinical research. This PA will expire on July 22, 2003 unless reissued. BACKGROUND In the past several decades it has become clear that cancer is not one disease but many, and that cancers arise as the result of the gradual accumulation of genetic changes in single cells. Identifying which subset of the genes encoded within the human genome can contribute to the development of cancer remains a challenge. The identification of these cancer genes and their associated gene products remains a high priority in cancer research. 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. The definition of the molecular profiles of cancer will require the development and dissemination of enhanced molecular analysis technologies, as well as elucidation 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 the 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. Products of this PA are intended to contribute to this goal. This solicitation is intended to support the development of molecular analysis tools that will allow for the more careful examination of the molecular basis and profiles of cancer, and also provide the ability to identify the molecular characteristics of individuals that influence cancer development and prognosis. These tools will allow for an examination of genetic factors that influence an individual’s likelihood to develop cancer or their ability to respond to damaging external agents, such as radiation, carcinogens, and therapeutic regimes. Correlating the molecular variations between individuals with therapeutic or toxic responses to treatment and prevention measures should define genetic factors that influence the efficacy and safety of these strategies and agents (pharmacogenomics). Identification of molecular markers in the individual that characterize the body’s response to the onset or clearance of disease will allow for the development of biomarkers to track and even image the efficacy of therapy (therametrics) and prevention, as well as the onset of secondary cancers. The ability to completely screen the genome for variations should enable tracking of the damage to the genome from exogenous agents such as carcinogens, infectious agents, radiation, and therapeutic regimes. Products of this PA such as molecular imaging in situ are intended to contribute to this goal. Modern molecular technology can contribute to 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. New molecular analysis tools resulting from this initiative are intended to contribute to this goal. In order to fully understand cancer and define the molecular response of the host to cancer, it will be critical to not only have knowledge at the DNA level, but to have a complete understanding of the processing of genetic information in cellular function. Current discoveries indicate that alterations in many of the cellular processes, pathways, or networks may contribute to the genesis of cancer and could be exploited for therapeutic or prevention intervention. Therefore, it is important to put in place technologies that can detect molecular changes in the cell without preconceived ideas about which information will be most valuable to monitor or which technologies will have the greatest impact. It is currently possible to monitor very specific changes in the expression and function of genes and gene products at the DNA, RNA, or protein level. However, many existing technologies do not adequately address technical issues specific to the study of cancer in vitro and in vivo, such as limited cell number, sample heterogeneity, heterogeneity of specimen types (i.e. bodily fluids and waste, tissues, cells), and cost effectiveness. Adaptation of novel technologies to support use in cancer research, including use on tumor specimens, and in patient imaging, is encouraged. In the discovery phase, it will be of great utility to have technologies that can effectively scan variations or function, in many or all members of the populations of DNA, RNA or protein molecules present in cells through highly multiplexed analysis. Current technologies for the multiplexed analysis of molecular species are at a stage where the greatest utility exists for the analysis of large numbers of relatively homogeneous cell populations that can be assayed in vitro. While many of the existing technologies have relatively sophisticated multiplexing capability in the assay format of the system, none of the existing systems is comprehensive for any particular molecular species (DNA, RNA or protein). In addition, none of the existing systems for in vitro analysis have well integrated sample preparation components that maintain the cost efficiencies of the assay system and effectively accommodate human tumor specimens. Similarly, data analysis tools for interpreting the information from highly multiplexed molecular analyses have not been sufficiently developed and tested for use in the context of basic, preclinical, and clinical cancer research questions. Therefore, the opportunity exists for further development to insure that resulting technologies provide enhanced assay potential, adequate sensitivity and discrimination, robust data analysis tools, and are easily adapted to the basic, preclinical, and clinical research settings. 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 including but not limited to 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 preclinical, clinical and in 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, preclinical, 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 development of high-resolution imaging at the cellular or molecular scales in tissue samples, pre-clinical models, or human investigations is considered to be an important extension of molecular analysis methods. Similarly, the development 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 modification 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. RESEARCH OBJECTIVES The purpose of this program announcement is to encourage applications from individuals and groups interested in developing novel technologies suitable for the molecular analysis of cancers and their host environment in support of basic, clinical, and epidemiological research. Technologies to support research in the following areas are considered to be appropriate. Examples given below are not intended to be all-inclusive, but are illustrative of the types of capabilities that are of interest. New tools that allow development of a more complete molecular profile of normal, precancerous, and cancerous cells, as well as the process of carcinogenesis, are needed to support the basic discovery process. These tools 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. Of interest are technologies and data analysis tools for: --In vitro scanning of or 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. --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, or identifying infrequently represented mutations in mixed populations of DNA molecules. --Technologies for detection and characterization of nucleic acid sequences of novel exogenous infectious agents that may be present in human cancer. --Highly specific and sensitive detection of specific mutations. --Detecting mismatch and recombinational DNA repair related to cancer susceptibility 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 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. --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. Translation of the utility of the technologies described above and basic research findings into tools for preclinical, and clinical research; requires additional technological innovation with regard to sample preparation, enhanced sensitivity, and expanded data analysis tools. Of interest are technologies for: --In vitro sample and specimen preparation that is suitable for human tissues and tumor (including solid tumor) specimens that interface with molecular analysis tools of the type listed above. --Detection, quantification and analysis of DNA mutations, polymorphisms and functional proteins in clinical specimens (e.g. tissues, urine, serum, plasma, nipple aspirates bronchioalveolar lavage, sputum, pancreatic juice, colonic wash and bladder wash). During the basic discovery process enhanced capability is critically needed for the following: --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. Applications may request support for the development of individual components of the final system, for example, front-end sample preparation components for in vitro systems, molecular detection systems, data acquisition systems, and data analysis tools. Issues related to the integration of the entire analysis process should be discussed particularly in the context of the R33 application. For all technologies proposed it will be important to substantiate the ultimate value of and role for the technology in deciphering the molecular anatomy of cancer cells or analyzing the molecular profile of the individual. It is also important for applicants to discuss the ultimate potential for the transfer of ensuing technology to other laboratories or the clinic, and for more mature technologies, plans to ensure dissemination of the technology. In the case of technologies intended for use on clinical specimens or in patients, applications from or collaborations with investigators involved in the clinical research of cancer are encouraged. The focus of this Program Announcement is technology development. Support for mechanistic studies of basic questions will not be provided, although testing on biological samples or in whole organisms in the course of enhancing the utility of the technology is appropriate. Support for the pilot applications of new technologies to questions of interest to cancer research is outside the scope of this PA, but is the subject of another solicitation entitled Application of Innovative Technologies for the Molecular Analysis of Cancer. 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 development 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-01-105.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 developed, its innovative nature, its relationship to presently available capabilities, and its expected impact on the molecular analysis of cancer. 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 develop innovative technologies, hypothesis testing per se may not be the driving force in developing such a proposal and, therefore, may not be applicable. Furthermore 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 develops 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. Item b: Background and Significance Elaborate on the innovative nature of the proposed research. Clarify how the technology development proposed in this project is a significant improvement over existing approaches. Explain the potential of the proposed technology for having a broad impact on cancer research. Clearly identify how the project, if successful, would result in new capabilities for research, the immediacy of the opportunity and how these proposed technologies would differ from existing technologies. 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 developed, its innovative nature, its relationship to presently available capabilities and its expected impact on the molecular analysis of cancer. 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 develop innovative technologies, hypothesis testing per se may not be the driving force in developing such a proposal and, therefore, may not be applicable. Item b: Background and Significance Elaborate on the innovative nature of the proposed research. Clarify how the technology development proposed in this project is a significant improvement over existing approaches. Explain the potential of the proposed technology for having a broad impact on cancer research. Clearly identify how the project, if successful, would result in new capabilities for research, the immediacy of the opportunity, and how these proposed technologies would differ from existing technologies. 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 development 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. 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? What is the time frame for developing the proposed technologies and suitability of this time frame for meeting the scientific community’s needs? How easy will it be to use the proposed technology? Are the plans for proposed technology dissemination adequate? 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, Innovative Technologies for the Molecular Analysis of Cancer: Phased Innovation Award, 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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