CENTERS OF EXCELLENCE IN CHEMICAL METHODOLOGIES AND LIBRARY DEVELOPMENT RELEASE DATE: December 17, 2002 RFA: GM-03-004 (Reissued as RFA-GM-08-007) National Institute of General Medical Sciences (NIGMS) (http://www.nigms.nih.gov) LETTER OF INTENT RECEIPT DATE: January 24, 2003 APPLICATION RECEIPT DATE: February 20, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this RFA is to reannounce and to update the National Institute of General Medical Sciences (NIGMS) program of "Centers of Excellence in Chemical Methodologies and Library Development" (CMLD Centers), last issued as RFA-GM-01-006 in June 2001. The goal of this program is to stimulate the establishment of multi- investigator research centers whose mission will be to develop efficient, general, state-of-the-art methodologies for the design, synthesis, analysis, and handling of chemical diversity libraries. The CMLD Centers will feature collaborations and team approaches that otherwise would not be established, including individuals from various subdisciplines within the field of chemistry and/or from cognate fields, that will develop novel enabling methodologies. Each Center will establish a library synthesis core facility that will serve two purposes. First, the library synthesis core will validate newly-developed methodologies for application to diversity-oriented synthesis (also known as combinatorial chemistry). Second, the library synthesis core will apply newly-developed chemical methodologies and strategies to the generation of chemical diversity libraries for high- throughput biological screening. This will provide "real world" tests of the utility of new methodologies and will also facilitate the study of complex biological phenomena. Each Center must develop a plan for outreach to the biology research community. The essential goals of the CMLD Centers program are to discover and to implement fundamental new chemistry that will facilitate access to high-quality libraries of expanded diversity. RESEARCH OBJECTIVES Background Consistent with the stated mission of NIGMS, which is to support "basic biomedical research that is not targeted to specific diseases, but that increases understanding of life processes...," the rationale behind this RFA is that advances in fundamental, enabling methodologies for chemical diversity libraries will produce lasting benefits for all of biomedical science, including biology and medicine. Until recently, the predominant approach to drug discovery has involved in vivo and/or in vitro testing of individual, purified compounds, both natural and synthetic, for physiological properties such as cytotoxicity or antibiotic activity. These screens have tended to be labor-intensive, slow, and expensive. However, the last decade has witnessed major breakthroughs in the identification of genes, gene products, metabolic pathways, and signaling pathways, as well as progress in miniaturization and automation technologies. These advances have led to the development of highly specific, mechanism- based biological assays that are rapid, inexpensive, and compatible with automation. The new assays have, in turn, revolutionized the discovery of small molecules with powerful physiological effects. Not surprisingly, the ability to screen massive numbers of compounds quickly using these new technologies has stimulated the demand for collections of structurally diverse molecules. Historically, most drug leads have been either isolated from natural sources (e.g., plants, marine organisms, or microorganisms), synthesized individually from inexpensive starting materials, or obtained by chemical modification of natural products. Molecules obtained from natural sources exhibit tremendous structural diversity as well as a great variety of bioactivities. However, the collection of source materials and the isolation, separation, and purification of the constituent bioactive principles are relatively labor-intensive and time-consuming. De novo synthesis of individual natural product (or natural product-derived) molecules is similarly demanding. Concurrent with the aforementioned developments in bioactivity screening, pioneering advances have been made in strategies and techniques for diversity-oriented synthesis. Diversity-oriented synthesis (also referred to as combinatorial chemical synthesis) is a process by which multiple compounds (chemical libraries) are generated simultaneously, in a predictable fashion, by using techniques that involve parallel chemical transformations. Diversity-oriented synthesis may use solid- or solution-phase reaction and product isolation techniques. A library may be small (e.g., a few compounds) or large (e.g., thousands or even millions of compounds), and it may focus on a narrow or wide range of "diversity space." When subjected to high-throughput biological screening, chemical diversity libraries offer unprecedented opportunities for the rapid identification of small molecules with significant physiological effects. The early success of this new strategy has led quickly to its widespread adoption, particularly in the pharmaceutical industry, where it has become a major approach for drug lead identification. Now, however, limitations are becoming apparent. At this relatively early stage in the development of diversity-oriented synthesis, the tools for planning, synthesizing, encoding, and chemically analyzing libraries are proving to be limited in both number and sophistication. Significantly, many synthetic reactions that work well under more standard conditions are not effective under the conditions that are used for diversity-oriented synthesis, particularly if the library components (or the reagents) are attached to a solid support. As a simple example, catalytic hydrogenation using palladium on charcoal is a common, high-yielding method for reducing olefins; however, catalytic hydrogenation does not work well if the olefin is attached to a solid support. Also, owing to the substantial, unique challenges that attend separation and purification procedures in diversity-oriented synthesis, only reactions that proceed cleanly, give high yields, and are extremely tolerant of structural variations in the substrates are truly useful. This severely limits the number of reactions that may be employed reliably. Even for reactions that do work for library synthesis, extensive time and effort must be invested in process development and optimization prior to synthesis of the actual library. Significantly, although screening of chemical diversity libraries is firmly established for the identification of drug leads in the pharmaceutical industry, relatively few novel library-related methodologies are being published by industrial chemists. While this may be due, in part, to intellectual property concerns, the pharmaceutical industry's focus on discovering and developing commercial drug products limits the resources that are available for more basic types of research. Thus, the emphasis in industry is on the screening of both existing libraries and libraries that can be synthesized rapidly by a limited number of currently available methodologies. Another factor that limits library diversity is that practitioners tend to reuse the small number of core scaffolds that have been used successfully in the past. This is because (a) the derivatization chemistry is well understood and (b) these scaffolds are known to have acceptable biological properties. Furthermore, the vast majority of the libraries that have been synthesized include molecules based upon a single core structure per library, with the structural variations confined to peripheral substituents. There are very few strategies and synthetic methods that will lead in a predictable fashion to multiple scaffold structures in a given library. In contrast to the well-established use of retrosynthetic analysis for designing "target-oriented" syntheses of individual molecules, the strategies for planning diversity-oriented syntheses are not well developed. Through retrosynthetic analysis, a synthesis is planned in reverse, beginning with the final product. The investigator identifies a reaction that could afford a particular product and then deduces the structure of the required starting material. This process is repeated until a set of easily-procured starting materials is identified that can be converted, by using an appropriate sequence of reactions, to a complex target structure. Since diversity-oriented synthesis produces multiple products, it is not possible to use retrosynthetic analysis, at least in its current form. While the development of novel methodologies is a major goal of academic chemists, the academic chemistry community has not generally embraced the development of methods that are specifically applicable to diversity-oriented synthesis. Similarly, few academic chemistry labs routinely synthesize libraries for screening by biology collaborators. The reasons for the limited involvement of academic chemists may include the burdensome nature of process development, the high cost of equipment for making large libraries, and the unfamiliarity of strategies for diversity-oriented versus traditional target-oriented organic synthesis. The limitations of current methodologies clearly restrict the degree of structural complexity, the diversity, and the quality of libraries. It has been suggested that the theoretically accessible "chemical diversity space" is defined by approximately 10(E60) "small" molecular structures (i.e., molecular weights of 500 or lower). Even today's largest libraries sample only a tiny fraction of this potential chemical diversity space. Leaders in the pharmaceutical industry (where diversity-oriented synthesis is used extensively) view the limitations of current methodology as a problem of considerable urgency and a significant impediment to the identification of drug candidates in new classes and with new mechanisms of action. Clearly, the same concerns would apply to the use of libraries by academic biologists who seek to discover new, specific, mechanism-based small molecule probes of fundamental biological processes. Thus, it is evident that reliance on current techniques for producing and evaluating chemical libraries will limit the ability to capitalize on the plethora of new targets that will be uncovered through research in proteomics and functional genomics. The goal of the CMLD initiative is to address these limitations by attracting the best academic chemists to the development of a wide range of versatile, dependable library-related methodologies. A workshop sponsored by NIGMS focusing on the needs and opportunities in diversity-oriented synthesis affirmed the importance, timeliness, and feasibility of stimulating further research in this area. There was agreement that improvements in chemical methodology for the development of chemical diversity libraries are necessary for this approach to realize its full potential to benefit biomedical science and human health. A summary of the August 19, 2000 workshop at NIGMS may be found on the NIGMS web site at: http://www.nigms.nih.gov/news/reports/chemical_diversity.html. Elements and Organization of a CMLD Center of Excellence A CMLD Center must be an integrated, coordinated project, with interdependent subprojects that are described fully and justified in the grant application. Collaborations and consortia are strongly encouraged, and the interactive nature of the proposed research is a key factor that will be evaluated in peer review. The benefits to be achieved through the establishment of multidisciplinary teams and novel collaborations, as opposed to working independently, should be described fully. The applicant should identify clearly in the abstract, and more fully in the research plan, the new capabilities that are proposed to be developed, or what specific questions are to be studied, as a result of the establishment of the Center. The minimum requirements for a CMLD Center will be three research projects, three faculty-level participants (but not necessarily one per project), and a library synthesis core. NIGMS is not specifying a maximum number of projects or participants; rather, the size of a CMLD Center should be a function of the science as well as the available funds (see below). Additional cores (e.g., an administrative core) or shared resources may be proposed as appropriate to each Center. The anticipated effectiveness of the proposed Center structure will be a criterion of the peer review evaluation prior to an award and will be monitored after an award is made. a. Research projects on methodology development Examples of topics that would be appropriate for investigation within a CMLD Center might include (but not be limited to) the following: o chemical reactions that will increase the diversity and/or quality of chemical libraries; o new core scaffolds; o methods for chemically derivatizing scaffolds; o solid supports and linkers; o new strategies for generating structural diversity; o fractionation, purification, and reagent scavenging techniques; o assessment of library purity and diversity; o strategies and/or instrumentation for automation of library synthesis; o methods of sample preparation for biological screening of libraries; o encoding and identification of the structures of active compounds within libraries; o storage and maintenance of libraries; or o managing data on chemical diversity libraries. It is clear that innovations in one aspect of library methodology research will stimulate complementary advances in others. For instance, new polymeric supports may prompt developments in linker or sample purification technology; new core scaffolds may influence the development of linkers as well as derivatization chemistry; and new reaction methodologies may lead to changes in library design strategies. Thus, for maximum impact, Centers should feature broadly- diversified research teams. While chemists from any subdiscipline may participate in a CMLD Center, collaborations that cross traditional subdisciplinary boundaries (e.g., organic, inorganic, analytical, physical, computational, and polymer chemistry) and that feature complementary (i.e., nonredundant) skills are particularly encouraged. Participants in a CMLD Center may come from the same or different departments of a single academic institution or from different institutions, and they may come from industry as well as academia. However, industry participants must be willing to abide by the CMLD guidelines, including data sharing and handling of intellectual property. Applicants should describe collaborative research projects as well as mechanisms for promoting scientific interactions among the participants. Plans must be presented for effective team communication and coordination of effort that covers the development, implementation, and conduct of all aspects of the research program. The degree of synergy among the participating research groups and the benefits that may be expected to result from these interactions will be major criteria in peer review and in NIGMS funding decisions. It is essential to justify the proposed Center in terms of the "value added" beyond what would be expected from a set of independent R01-style projects. b. Library synthesis core facility Each Center must establish a core facility for the synthesis of high- quality chemical libraries. The purpose of this core will be two-fold. First, it will validate newly-developed methodologies in the context of chemical diversity libraries. Second, it will apply these new chemical methodologies and strategies to the generation of actual libraries for high-throughput biological screening. This will provide "real world" tests of the utility of new methodologies and will also promote new approaches for studying complex biological phenomena. The staff of the core synthesis facility must have the administrative and technical skills to ensure smooth operation for the validation and optimization of new methodologies, as well as for the application of new methodologies to the synthesis of libraries for screening. Applicants should describe the scientific function of the library synthesis core, including the approaches to be used for optimizing and validating new methodologies; the design strategies and methods that will be used for the synthesis, purification (as necessary), sample handling, and analysis of actual libraries; and protocols to be used for archiving and analyzing both the data and the compounds that are generated by the library synthesis core. Funding for process validation studies and for most library syntheses will be included in the P50 Center budget. As the focus of the CMLD Centers program is on chemical methodology rather than biology, biological screening will best be accomplished via interdisciplinary collaboration involving the library synthesis core. Such collaborations must merge innovative chemistry with innovative and significant biology. Applicants should describe the management plan for the library synthesis core. There must be representation by the biological research community in the administration and/or oversight of the core, and a strategy should be presented for outreach to the biological research community in order to develop collaborative projects. The administrative plan should indicate how requests for libraries will be prioritized, in the event that the demand outstrips the capacity to produce libraries. c. Administration and management Due to the inherent complexity of the Center structure, including both interdependent research projects as well as shared resources, a well thought-out and carefully described management plan that ensures that the interests of all CMLD participants are represented will be required. Whether or not an administrative core is specified, plans must be presented for the proper administration of the Center. The P50 grant application should specify the administrative and organizational structure(s) that will be used to support the research, and the synergies enabled by those structures. The PI will be responsible for ensuring that scientific goals are met, and for developing and managing a decision-making structure and process that will allow resources to be allocated in order to meet those scientific goals. "Centers-without-walls" (i.e., Centers that involve participants from more than one physical site) are welcome under this solicitation. If any of the components is physically separated from the others (e.g., different departments or institutions), the applicant should describe how interactions will be facilitated. If the team includes investigators from more than one institution, a "letter of intent to collaborate with the applicant organization" signed by the appropriate institutional official from each participating organization must be included in the application. Projects of the anticipated degree of complexity, both scientific and managerial, will require a substantial investment of the PI's effort. The PI will be required to devote sufficient effort to ensure successful leadership and implementation of the goals of the Center. A timeline for the project should be presented. This timeline should outline how the project's goals can be met within the time frame of a CMLD grant. The timeline will also assist the investigators, NIGMS, and its advisors in evaluating progress toward the project's goals. d. External scientific advisory committee Each CMLD Center should have an external advisory committee of research scientists who are not involved in the Center, to provide independent assessment and advice to the PI and staff. This committee should be appointed by the PI and confer at least twice each year. In order to maximize the pool of possible reviewers, the potential members of the advisory committee should not be contacted or selected until after an award has been made. Nevertheless, the applicant should describe the criteria to be used in selecting the members of the external advisory committee. MECHANISM OF SUPPORT This RFA, which is a one-time solicitation, will use the NIH P50 award mechanism. Awards are expected to be made during September 2003 or early in FY 2004. Diversity-oriented synthesis is a rapidly developing field, and it is anticipated that most projects that can be initiated now will have a limited lifetime during which support from NIGMS will be appropriate, either because the project goals will have been accomplished or the Center will have developed to the point that support can be derived from other sources. Therefore, the total length of support for any P50 Center under this program will be no more than ten years (an initial five-year award followed by a single five-year renewal). The applicant will be solely responsible for planning, directing, and executing the proposed project. FUNDS AVAILABLE NIGMS intends to commit approximately $6 million in FY 2003 to fund up to two new grants in response to this RFA. Up to two additional grant awards, totaling approximately $6 million, may be made in early FY 2004, if the funds are available. An applicant may request a project period of up to five years and a budget for direct costs (not counting capital equipment and F&A costs for subcontracts) of up to $1.1 million per year per Center. Inflationary increases in subsequent years (up to a total of five years) will be allowed at a rate of up to 3% per year. Because the library synthesis core may require significant capital equipment, a well-justified request for an additional allowance (up to $1.25 million) for the acquisition of capital equipment in the first year of the project will be considered. The budget should be fully justified and should include funds for attending the annual meeting (see below). Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of NIGMS provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government Foreign institutions are not eligible to apply for research center grants. However, subcontracts to foreign institutions are allowable, with sufficient justification. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his or her institution to develop an application for support. Individuals from underrepresented racial and ethnic groups, as well as individuals with disabilities, are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS NIGMS has adopted several policies that are applicable to the CMLD research centers. Applicants must present plans for implementing these policies, where appropriate. Intellectual property: The NIH has an interest in ensuring that the new inventions, including methods, technologies, strategies, and computer software, that are developed through this program become available to the research community conveniently and in a timely fashion. It is expected that these inventions will be readily and broadly applicable to research and to the development of products and knowledge that will benefit public health. For this reason, applicants should develop and propose specific plans for sharing the data, materials, and software generated through the grant, taking into consideration the recent Guidance issued by NIH (http://www.nih.gov/od/ott/RTguide_final.htm). The results of CMLD projects should be freely available for use by the entire research community, consistent with the terms of the Bayh-Dole Act (http://www.ucop.edu/ott/bayh.html). The initial review group will comment on the proposed plan for data sharing and release, including publication of results and product licensing (where appropriate). The adequacy of the plan will also be considered by NIH staff as one of the award criteria. The proposed sharing plan, after negotiation with the applicant when necessary, will be made a condition of the award. Evaluation of renewal applications will include assessment of the effectiveness of data, materials, and software release. Applicants are also reminded that the grantee institution is required to disclose each subject invention to the Federal Agency providing research funds within two months after the inventor discloses it in writing to the grantee institution personnel who are responsible for patent matters. Annual meeting: Applicants should plan to attend an annual meeting of CMLD awardees, in order to present results and to discuss issues of common interest or concern. For the purpose of preparing an appropriate budget, it should be presumed that two representatives of each Center will attend this annual meeting at the NIH campus in Bethesda, MD. Post-award management: During the grant period, experimental technologies will improve, and the rate of progress and the focus of work supported by the grant may change. It is expected that the PI will make any necessary adjustment in direction to accommodate a changing scientific environment, keeping the NIGMS staff informed if significant changes are made. In order to ensure that each Center remains focused on appropriate goals, features truly integrated approaches to science, incorporates new technological advances, and makes sufficient progress, scientific and administrative visits to the grantee may be conducted by NIGMS staff. NIGMS may include outside consultants in the annual progress review and may reduce or withhold funds in the case of limited progress toward the goals of the CMLD program. A report by the NIGMS program director on each Center's progress and recommendations to modify funding may be made annually to the National Advisory General Medical Sciences Council. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: John M. Schwab, Ph.D. Division of Pharmacology, Physiology, and Biological Chemistry National Institute of General Medical Sciences National Institutes of Health Building 45, Room 2AS.43A 45 Center Drive, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-5560 FAX: (301) 480-2802 Email: schwabj@nigms.nih.gov o Direct your questions about peer review issues to: Helen R. Sunshine, Ph.D. Chief, Office of Scientific Review National Institute of General Medical Sciences National Institutes of Health Building 45, Room 3AN.12P 45 Center Drive, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-2881 FAX: (301) 480-8506 Email: sunshinh@nigms.nih.gov o Direct your questions about financial or grants management matters to: Ms. Antoinette Holland Grants Management Office National Institute of General Medical Sciences National Institutes of Health Building 45, Room 2AN.50B 45 Center Drive, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-5132 FAX: (301) 480-2554 Email: hollanda@nigms.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIGMS staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: John M. Schwab, Ph.D. Division of Pharmacology, Physiology, and Biological Chemistry National Institute of General Medical Sciences Bldg. 45, Room 2As.43A 45 Center Drive, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-5560 FAX: (301) 480-2802 Email: schwabj@nigms.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: The application should include: (a) a single face page for the entire application; (b) abstract; (c) key personnel listing; (d) table of contents; (e) the consolidated budget for the entire CMLD grant [summarizing budgets for the component parts and core(s)]; (f) individual project and core budgets; (g) biographical sketches for all key personnel; (h) other sources of research support (both current and pending) for all key personnel (see http://grants.nih.gov/grants/funding/phs398/instructions2/p3_other_support.htm); (i) resources and facilities (including major instruments and special program resources); (j) institutional support; (k) project overview (including a description of the overall scope and objectives; (l) justification of the P50 Center mechanism, including a description of the synergy among the components of the Center and a discussion of how the scientific goals will be furthered via the P50 Center grant mechanism in ways that would not be readily attainable through individual research project grants; (m) plans for administrative management; (n) plans for project management; (o) plans for handling intellectual property issues; (p) project descriptions; (q) description(s) of core(s); (r) letters of collaboration; etc. Section (h) must also detail the relationship of other support to the proposed Center and describe anticipated modifications to that support in the event of funding (e.g., folding in support for related, funded research). Each project description should include (in the following order) a cover page, an abstract, budget pages, and a detailed research plan. The research plan should be organized as specified in the PHS 398 application form; i.e., it should include specific aims, background and significance, preliminary studies, and research design and methods, and the usual 25 page limit will apply. The special benefits (to the project) of being associated with the Center must also be addressed. Each core facility should be described in no more than 20 pages, in addition to the budget pages for that particular core. Separate sections describing and justifying the core resource(s) should be included. Sections (j) through (o) of the application (see above) should be presented in no more than 30 pages. Note that there is no requirement to submit the maximum number of pages; instead, concise, articulate applications are strongly encouraged. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form, and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten or machine printed original of the application (including the Checklist) and three signed photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application, including all appendices, must be sent to: Helen R. Sunshine, Ph.D. Chief, Office of Scientific Review National Institute of General Medical Sciences Building 45, Room 3AN.12P 45 Center Drive, MSC 6200 National Institutes of Health Bethesda, MD 20892-6200 APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIGMS. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIGMS in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique. It is also possible that applications will undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score. Finally, all applications will receive a second level review by the National Advisory General Medical Sciences Council. It is unlikely that site visits or applicant interviews will be performed as part of the initial review. You should not assume that they will be conducted; therefore, you must present a complete and well-justified written proposal. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals, the reviewers will be asked to discuss in their written comments the following aspects of your application: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Separate scores will not be assigned for each subproject; however the scientific merit of each subproject will be assessed, based on its merit as an independent effort and its potential importance/contribution to the success of the overall effort. Core facilities and resources will be assessed for their quality, cost-effectiveness, and utility to the overall effort. (1) SIGNIFICANCE: How likely is it that any proposed methodologies, research tools, software, strategies, etc., will have a broad impact on the production of high-quality, highly diverse chemical libraries? Will these new methodologies substantially enhance the availability of chemical diversity libraries for high-throughput biological screening? Are the proposed strategies and technologies likely to be readily exportable? How important are the proposed research areas and topics being explored, and how relevant are these research areas and topics to furthering the state of the art in developing high-quality chemical diversity libraries? What is the likely effect of the proposed research on the field, and what is the likely impact on the larger scientific community? If the aims of the application are achieved, how will scientific knowledge be advanced? (2) APPROACH: How strong is the scientific research plan? What is the likelihood that the proposed research plan will achieve the stated aims? Are the conceptual framework, design, methods, analyses, techniques, and technologies adequately developed, well integrated, and appropriate to the aims of the project? Are potential problem areas acknowledged and alternative tactics proposed? How much interplay and synergy are there among the projects and among the key personnel? Are the interactions among the key personnel critical to achieving the stated goals? Is the proposed structure of the library synthesis core facility (including staffing, procedures, management, and equipment) appropriate for meeting the goals of the core--to validate new methodologies and to produce high-quality libraries for biological screening? (3) INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are the scientific training, background, and expertise of the Principal Investigator and key personnel appropriate to achieving the specific aims and overall goals of the proposed research? Do the skills of the key personnel complement one another in a manner that is appropriate to an integrated, team-oriented project? Does the Principal Investigator have the appropriate management and administrative skills to lead and coordinate the activities, and to develop and implement the management plan, as required for the project's success? Are the library synthesis core personnel qualified for their role in the Center? Are the levels of effort of the key personnel adequate? (5) ENVIRONMENT: Does the scientific environment in which the work will be done, including space, equipment, services, infrastructure, and facilities, contribute to the probability of success? Does the proposed research Center take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support, including any needed expansion of facilities, improvement of infrastructure, and relief from other academic duties, where necessary? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the application will also be reviewed with respect to the following: o MANAGEMENT AND ADMINISTRATION: The suitability and quality of the management plan, including the management structure; the plan for deployment of equipment and human resources to attain the research aims and overall Center goals; the organization and coordination of the personnel; plans for making critical decisions or choices about overall research direction; o OUTREACH: The plans for outreach to the biomedical research community, including solicitation of interest in using chemical diversity libraries; and making libraries available for screening; o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application; o DATA SHARING: The adequacy of the proposed plan to share data; the plan for addressing intellectual property issues, including the dissemination of intellectual and material products of this research, as well as mechanisms for the licensing of CMLD-supported inventions that are patented by a CMLD grantee; o BUDGET: The appropriateness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: January 24, 2003 Application Receipt Date: February 20, 2003 Peer Review Date: June/July 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 15, 2003 AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to NIGMS. Awards will be made on or before September 30, 2003. The following factors will be considered in making funding decisions: o responsiveness to the goals and objectives of the RFA; o scientific merit, as determined by peer review; o overall contribution of the project to the knowledge and experience required to advance the state of the art in the planning, generation, and/or analysis of chemical diversity libraries; o program priority of research in this area and other areas of NIGMS interest; o plans for rapid and effective dissemination of the results and information on technological developments; and o availability of funds. REQUIRED FEDERAL CITATIONS PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures, given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review, because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.859, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. http://grants.nih.gov/grants/guide/pa-files/PA-02-015.html.


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