INNOVATIVE TECHNOLOGIES FOR THE MOLECULAR ANALYSIS OF CANCER: PHASED INNOVATION AWARD Release Date: May 8, 1998 PA NUMBER: PAR-98-067 P.T. National Cancer Institute Letter of Intent Receipt Dates: July 2, November 5, 1998 and March 5, 1999 Application Receipt Dates: August 7, December 10, 1998 and April 9, 1999 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 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, monitoring of the expression of genes and gene products, analysis and detection of the cellular localization, post-translational modification, and function of proteins, and monitoring 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 clinical application. This program will utilize the Phased Innovation Award mechanisms (R21 and/or R33) to allow expedited review of applications and expedited transition of successful technology research to an expanded development phase. Small businesses are encouraged to consider a parallel program announcement (PAR-98-066) of identical scientific scope that utilizes the SBIR and STTR mechanisms with accelerated review and transition, as well as cost and duration requirements comparable to the Phased Innovation Awards. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This PA, 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 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202- 512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and non- 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 MECHANISM OF SUPPORT Support for this program will be through the National Institutes of Health (NIH) Exploratory/Developmental Research Grant (R21) and the Exploratory/Developmental Research Grant Phase 2 (R33). The R33 is a newly established NIH grant mechanism to provide a second phase for the support of innovative exploratory and development research initiated under the R21 mechanism. Conversion of the R21 to the R33 phase will be expedited and based 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. Although the R33 application has no official budgetary limit, 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 responsiveness of the proposed project. Early contact with NCI staff is particularly critical relative to this PA since it utilizes a new grant mechanism (R33) as well as 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 release 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 measurable milestones that will be used to judge the success of the proposed research, as well as a credible development plan for phase R33. In place of a Preliminary Studies/Progress Report, the R33 application must include a discussion of the R21 milestones and their implications for the R33. Through a separate program announcement, (PA-98-066) the NCI is inviting applications for SBIR and STTR support, focusing on the identical research areas as described in the RESEARCH OBJECTIVES section of this solicitation. For SBIR/STTR solicitation, the expedited NCI review and cost allowance policies and procedures will be identical to this PA. Qualified applicants are strongly encouraged to consider responding to the SBIR/STTR program announcement. SBIR and STTR application information is available on the web at: http://www.nih.gov/grants/funding/sbir.htm Potential applicants who believe that they may be eligible for the SBIR/STTR award should discuss their eligibility with NCI staff listed under INQUIRIES. 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 PHS grants policy as stated in the PHS Grants Policy Statement, DHHS Publication No (OASH) 90-50,000 revised April 1, 1994 RESEARCH OBJECTIVES 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" 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. To this end, the NCI has established the Cancer Genome Anatomy Project (CGAP), which will put in place the tools that will allow deciphering of the molecular anatomy of a cancer cell at the DNA, RNA and protein levels. The NCI is currently targeting two objectives in the CGAP. The first is the establishment of an index (Tumor Gene Index) identifying genes that are expressed in normal, precancerous, and cancerous cells. This project is well under way and further information about the Index can be found at: http://www.ncbi.nlm.nih.gov/ncicgap/. The second objective is the support for the development and dissemination to basic 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. Improved molecular analysis tools will not only allow for the more careful examination of the molecular basis and profiles of cancer, but will also provide the ability to identify the molecular characteristics of individuals that influence cancer development and prognosis. These tools will allow for an examination of genetic factors that influence an individual"s likelihood to develop cancer or their ability to respond to damaging external agents, such as radiation and carcinogens. 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 and radiation. 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. 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 both basic 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 both the basic 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 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. Therefore, the development of technologies such as imaging that will support the in situ and in vivo monitoring of molecular activity is considered to be essential. Objectives and Scope 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 epidemiologic 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 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 -- Highly specific and sensitive detection of specific mutations -- Detecting mismatch and recombinational DNA repair related to cancer susceptibility -- In vitro multiplexed analysis of the expression of genes -- Computer assisted quantitation of gene expression in histological samples -- 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 in vitro tools for clinical research and clinical application 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. -- Detecting DNA mutations and polymorphisms, and functional proteins in biologic fluids such as serum, plasma, nipple aspirates, bronchioalveolar lavage, sputum, urine, pancreatic juice, colonic wash, and bladder wash. During the basic discovery process, enhanced capability is needed to determine the influence of various molecular alterations or factors in the context of viable whole cells or whole body analysis of model organisms. Similarly, substantial opportunity exists for improvements in approaches to monitor molecular events non-invasively in humans in support of both clinical research and patient care. Of interest are technologies suitable for: -- Delineating molecular expression or function in situ including imaging technologies related to the energy source-detector, contrast agents, and data analysis tools. -- Delineating molecular expression or function at the cellular level in the context of the whole body, including imaging technologies related to the energy source-detector, contrast agents, and 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 demonstrating the utility of the technology is appropriate. 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 subpopulations 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 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 "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. 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. NIH POLICY AND GUIDELINES ON THE 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. Therefore, the policy does not apply to applications submitted on the August 7, 1998 receipt date. 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://www.nih.gov/grants/guide/notice-files/not98-024.html LETTER OF INTENT Prospective applicants are asked to submit, by the dates listed at the beginning of this program announcement, 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 avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Carol Dahl at the address listed under INQUIRIES. 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 (rev. 5/95) 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 may be obtained from the Division of Extramural Outreach and Information Resources, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: grantsinfo@nih.gov. The R21/R33 application must include the specific goals for each phase and the feasibility milestones that would justify expansion to the R33 phase. 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 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 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 writeup of Sections a-d for the R21 phase and again for the R33 phase. The Form 398 Table of Contents should be modified to show sections a-d for each phase. There is a page limit of 25 pages for the composite a-d text (i.e., Sections a-d for both the R21 and 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. 1. Face Page of the application: Item 2. Check the box marked "YES" and type the number and title of this program announcement.. 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. 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. 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, the immediacy of the opportunity and its expected impact on the molecular analysis of cancer. 3. Research Plan: Item a., Specific Aims. The applicants must present scientific milestones that the applicant considers to be scientifically appropriate for determining proof of feasibility and warrants expansion of the R21 to the R33 development phase. The instructions in the PHS 398 booklet for this section of research grant applications suggest that the applicant state "the hypotheses to be tested." Since the goal of this 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 In Item c of the R33 phase, a description of the scientific milestones can be included in lieu of preliminary studies. 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 (rev. 5/95) 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 may be obtained from the Division of Extramural Outreach and Information Resources, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: grantsinfo@nih.gov. 1. Face Page of the application: Item 2. Check the box marked "YES" and type the number and title of this program announcement 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." Since 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. FOR ALL APPLICATIONS Appendix: All instructions in the Form 398 application kit apply. The completed original application and three legible copies must be sent or delivered 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 6130 Executive Boulevard, Room 636a, MSC 7405 Bethesda, MD 20892-7405 Rockville, MD 20852 (for overnight/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Applications must be received by the receipt dates listed at the beginning of this PA. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed by the CSR for completeness and by NCI program staff for responsiveness. Applications not adhering to application instructions described above and those applications that are incomplete or non-responsive as determined by CSR or by NCI program staff will be returned to the applicant without review. Applications will be reviewed for scientific and technical merit by an initial review group convened by the NCI Division of Extramural Activities. Following scientific-technical review, the applications will receive a second-level review by the National Cancer Advisory Board. As part of the initial merit review, a process may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the PA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. 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 field 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? What is the immediacy of the research opportunity? 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? How appropriate are the proposed milestones against which to evaluate the demonstration of feasibility for transition to the R33 development phase? 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 For the R21/R33 Phased Innovation Award Application, the initial review group will evaluate the specific goals for each phase and the feasibility milestones which 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"s specific goals and the feasibility milestones justifying expansion to the R33 phase. Deletion of the R33 phase by the review panel 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 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. In addition, for applications submitted for the December 10, 1998 and April, 9 1999 receipt dates, reviewers will address the adequacy of plans for including children as appropriate for the scientific goals of the research, or justification for exclusion. (See section on NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS). AWARD CRITERIA Applications will compete for available funds with all other approved 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. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Carol Dahl, Ph.D. Office of Technology and Industrial Relations National Cancer Institute Building 31, Room 11A03 31 Center Drive, MSC 2590 Bethesda, MD 20892-2590 Telephone: (301) 496-1550 FAX: (301) 496-7807 Email: carol_dahl@nih.gov Direct inquiries regarding fiscal matters to: Ms. Theresa Mercogliano Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243, MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-7800 ext. 243 FAX: (301) 496-8601 Email: mercoglt@gab.nci.nih.gov Direct inquiries regarding review matters to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636 Bethesda, MD 20892-7150 Telephone: (301) 496-3428 FAX: (301) 402-0275 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.394. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and part 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 and contract 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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