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Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
This RFA is developed as an NIH Roadmap initiative (http://nihroadmap.nih.gov ). All NIH Institutes and Centers participate in roadmap initiatives. The RFA will be administered by the National Institute of Mental Health and the National Human Genome Research Institute on behalf of the NIH. http://www.nimh.nih.gov, http://www.nhgri.nih.gov

Title: Molecular Libraries Probe Production Centers Network (MLPCN) (U54) Limited Competition

Announcement Type
New

Request For Applications (RFA) Number: RFA-RM-08-005

Catalog of Federal Domestic Assistance Number(s)
93.310

Key Dates
Release Date: November 9, 2007
Letters of Intent Receipt Date: December 13, 2007
Application Receipt Date: January 10, 2008
Peer Review Date: March 2008
Council Review Date: May 2008
Earliest Anticipated Start Date: July 1, 2008
Additional Information To Be Available Date (Url Activation Date): Not Applicable
Expiration Date: January 11, 2008

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

A. Background:

The NIH Roadmap is a series of trans-NIH research programs designed to foster new ways of doing research, to fill fundamental knowledge gaps, and to encourage risk taking to solve complex problems. The overarching criterion for Roadmap programs is that they are expected to transform the way research is conducted across the spectrum of health research (http://nihroadmap.nih.gov/ ). The Molecular Libraries and Imaging Initiative (MLI) is one of the components currently comprising the Roadmap theme of New Pathways to Discovery, the goal of which is to build better tools to use in studying the many interconnected networks of molecules that comprise cells and tissues, their interactions, regulation, and the combination of molecular events that lead to disease. In the initial pilot phase, the primary objective of the Molecular Libraries Initiative was to introduce chemical genomics as a major new approach for public sector research. In the production phase, the MLI will become the Molecular Libraries Program (MLP) with a focus on probe discovery and development.

A1. Molecular Libraries Program: Pilot Phase. The MLI was begun in FY 2004 to pilot a set of components aimed at developing selective and potent chemical probes for use in basic research. The three main components were data production, data dissemination, and technology development. Data production in the pilot phase involved: (a) the Molecular Libraries Small Molecule Repository (MLSMR) to establish and provide access to a unique and diverse library of compounds; (b) support of assay implementation through the Solicitation of Assays for High Throughput Screening (HTS) in the Molecular Libraries Screening Centers Network initiatives, PAR-06-545 (R03) and PAR-06-259 (X01), and the Guide Notice NOT-RM-07-012 announcing Fast Track entry to the MLSCN; and (c) the Molecular Libraries Screening Center Network (MLSCN) to implement assays provided by the wider research community and generate chemical probes for the scientific community. Data dissemination was supported by PubChem, the primary portal through which the screening and chemistry results of the MLSCN are made public. Technology development supported advances in a number of aspects of the probe generation process, including: (a) Chemical Diversity development with the Pilot Scale Libraries (PSL) for High-Throughput Screening (RFA-RM-06-003 (P41)) a program to support the development of pilot-scale chemical diversity libraries for screening in the MLSCN and New Methodologies for Natural Products Chemistry (RFA-RM-05-013 (R01)) a program to develop new methods for natural products chemistry; (b) Assay Development for High Throughput Screening (RFA-RM-07-008 (R21)) a program to support the development of novel bioassays that have the potential to advance scientific discovery, emphasizing assay novelty and the current availability of probes; (c) Molecular Libraries Screening Instrumentation (RFA-RM-04-020 (R01)) a program to support the development of breakthrough instrumentation technologies; (d) the Exploratory Centers for Cheminformatics Research (ECCRs) (RFA-RM-05-012 (P20)) with multiple roles including high-level data analysis and dissemination with a focus on developing new understanding of cellular processes (genes and pathways); (e) Novel Preclinical Tools for Predictive ADME/Toxicology (RFA-RM-04-023 (R21)); (f) Molecular Imaging and Contrast Agent Database (MICAD) which contained imaging probe information; (g) High-Specificity/High-Sensitivity Molecular Imaging Probes (RFA-GM-08-009 (R01)), RFA-GM-07-234 (R01)) program to develop imaging agents for basic or clinical applications with an emphasis on enhancing the specificity and resolution of the agents by an order of magnitude and (h) the Imaging Probe Development Center (IPDC) an NIH intramural center effort that offers the production of known imaging probes for the research community. The expired FOAs for these components can be found at https://mli.nih.gov/mlscn/index.php .

In the pilot phase, the MLSCN comprised a network of nine extramural and one NIH intramural screening centers. Each screening center has implemented innovative HTS approaches to identify compounds that are active in biochemical, cell-based or model organism assays using multiple screening formats including target-based, reporter and phenotypic screens. To date, the MLSMR has acquired and maintains a unique and diverse collection of nearly 200,000 compounds obtained from both commercial and academic sources as a screening library for the MLSCN. Active compounds identified through initial screening of the library are further developed within the MLSCN through a combination of structure-activity analysis and synthetic chemistry to obtain useful bioactive probes. The centers have adopted an eleven-step process to provide consistent, high quality data on compound structures, screening data, and assay protocols to the public through the PubChem database (see chemical probe development path, https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm). Information in PubChem is available to all researchers for use in biological and biomedical research studies (http://pubchem.ncbi.nlm.nih.gov/ ).

B. Molecular Libraries Program: Production Phase.

With the end of the MLI pilot phase, this FOA solicits applications that will implement the transition of the MLP to a full-scale production phase where the program emphasis will be on the generation of high quality probes and biological-chemical data for high-value targets. It is expected that all applicants will be at full production rate defined in this FOA for each type of center no later than the end of the first grant year.

B1. Program Objectives. The long-term goal of the MLP is to develop new small molecule probes that will be used as research tools in the identification and analysis of protein function, signaling and metabolic pathways and cellular function important to the maintenance of human health, with the expectation that increased knowledge and wider understanding of probe chemistry will accelerate the development of new therapeutics. The major programmatic goal is to establish a valuable community resource/repository of compounds, probes and biochemical data for furthering research to benefit the public health. As a central component of the MLP, the MLPCN program will continue to offer HTS resources to the scientific community under its Data Sharing and Intellectual Property (IP) policies (see NIH Policy on Data Sharing and IP in the MLP, http://www.nimh.nih.gov/about/organization/dnbbs/the-mlscn-project-team-policy-on-data-sharing-and-ip-in-the-mlscn-program.pdf). These policies are designed to speed the dissemination of screening results and new molecular research tools (e.g., ligands, imaging probes, and new activities of existing drugs) to the public sector for their immediate use. The MLP also intends to stimulate research in the following areas: 1) discovery of novel probes directed against biological targets that can inform studies of cell function and disease mechanisms; 2) development, validation, and application of screening assays and disease models to evaluate the activities of novel small molecules; and 3) use of chemical genomic approaches to characterize the biology of genes of interest, cellular processes, and proteins associated with disease processes.

The NIH anticipates that the MLPCN will have sufficient capacity to screen the MLSMR library (a minimum of 300,000 and as many as 500,000 compounds as the library expands in size) each year in 100 assays that have been adapted for automated screening. Thus, the specific goal of this FOA is to announce a limited competition that is the second phase of the solicitation process that began with PAR-07-368 (X02). Invited applicants may submit applications to participate in the production phase of the MLP that, overall, will have the capabilities to: 1) implement a diverse array of both target-based, and phenotypic assays obtained from investigators in the public or private sector; 2) screen a large number of compounds that comprise the screening collection in the MLSMR for biological activity in these assays; 3) employ medicinal chemistry (synthetic and computational) to optimize screening hits into useful in vitro and/or in vivo biological probes; and 4) provide informatics support to track compounds, assays, screening and chemistry data. The MLPCN will make all biological screening data, assay and text descriptions of reaction protocols, and structures of chemical probes and related chemical data such as structure-activity relationships (SAR) freely available to the public through the PubChem database.

B2. Core Capabilities of the MLPCN. The MLPCN will be established as a collaborative research network of Comprehensive Centers and Specialized Screening and Chemistry Centers with complementary abilities that will enable screening of diverse types of assays and generation of chemical probes to address a wide range of biological opportunities. It is envisioned that each center will bring to the network a specific set of expertise and skills in the main functions/cores appropriate to the type of center (i.e., assay development, assay adaptation/implementation, HTS, informatics, (SAR)/cheminformatics and chemistry); see link for definition of terms, https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm. It is also envisioned that the organization of the centers into a functioning network will allow the MLPCN to achieve synergies and thereby (1) advance the state of the art in chemical genomics more rapidly than if the same centers functioned in isolation and (2) effect the uptake of chemical genomics by the wider scientific community as a new approach that will enable the biomedical research enterprise to provide scientific validation of critical drug targets and accelerate development of new therapeutics to improve the health of the public.

One of the primary goals of the MLPCN is the production of new and useful chemical probes for biomedical research. The minimum characteristics that a probe compound will need to have to be a useful research tool has been determined by the MLPCN Steering Committee and the MLP Project Team. According to the definition currently used by the MLSCN, these characteristics include <100 nM affinity, >10-fold selectivity against related targets, and solubility in aqueous solutions (possibly including a low concentration of DMSO). Most importantly, a chemical probe must represent an improvement over existing probes for the designated target (https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm). NIH recognizes that whatever the characteristics of the probes, further modification may be necessary to produce compounds that are useful for in vivo studies. However, such additional efforts are outside of the activities called for in this FOA. It is the desire of NIH that during the production phase, all probes and all related biological and chemical data will be made available to all researchers.

B3. Program Changes for the Production Phase. The production phase of the Molecular Libraries Probe Production Center Network (MLPCN) will differ from the pilot phase (MLSCN) in several strategic ways based on knowledge and on experience gained during the pilot phase.

C. Types of MLPCN Centers.

The three types of centers for which applications are being solicited are: Comprehensive Centers each with the capability to screen 300,000-500,000 compounds against at least 20-25 assays per year and provide SAR analysis and medicinal chemistry to identify potent and selective chemical probes; Specialized Screening Centers each with the expertise and experience to successfully implement complex and technically difficult assays that may not be amenable to HTS (e.g., high content screening, phenotypic assays, ion channel screening, whole organism screening); and Specialized Chemistry Centers each with outstanding capabilities in applying medicinal chemistry in order to advance early hits to chemical probe status. As an integral part of the network, the Specialized Chemistry Centers will actively participate with both types of screening centers to generate probes. Further details on the integration of the probe pipeline, center cores and the overlapping roles of the comprehensive and specialized centers can be seen under Center Infrastructure at https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm).

C1. Comprehensive Centers. The Comprehensive Centers will provide rapid screening of a broad diversity of assays (e.g. enzymes/proteases, G-protein coupled receptors, kinases, cytotoxicity, protein-protein interactions, protein misfolding/degradation, high-content screening, transcription/expression, etc) using a number of detection platforms. These large, ultrahigh-throughput screening centers will contain all the necessary functions to take a project through the complete chemical probe development process from creation of a Chemical Probe Development Plan and assay development to chemical synthesis of potent and selective probe compounds. The key functionalities or cores required by these centers are: assay development, assay adaptation/implementation, HTS, informatics, SAR/cheminformatics and chemistry. All centers will be expected to apply process management methods of planning, monitoring and evaluating of process performance as part of their management of their portfolio of assays and probe development projects over the lifetime of the grant period. Each Comprehensive Center will be expected to define a set of specific center milestones, including production rate, program efficiency and costs; these will be useful management tools for the PI as well as allow careful monitoring by NIH program staff. Each center is expected to be able to screen a library of 300,000-500,000 compounds per assay, process 20-25 or more assays per year, and undertake 20-25 or more probe projects per year in order to deliver 10-15 new probes per year once the discovery pipeline is at full capacity. To be competitive for funding under this FOA, the application must demonstrate that the proposed center can achieve this production capacity at the time the award is made or no later than the end of the first year of funding. Each center also will be required to develop an active outreach program to (1) increase awareness of the biomedical community in the goals of the MLP and more generally, the value of chemical genomics to biomedical research, (2) to solicit investigators to submit assays to the MLPCN and (3) to provide support to aid assay submitters in preparing a competitive X01 or R03 Assay Solicitation application. A Comprehensive Center will be responsible for all three of the following operational stages in the probe generation pipeline:

a. Hit identification: The identification of hits will require the centers to have the capability for assay development, assay adaptation/implementation, HTS and informatics to accept assays into the center, modify and implement them for automated HTS; for screening the MLSMR library of compounds; and for confirming initial hits by re-screening. The first step in implementing an assay is the creation of a Compound Probe Development Plan (CPDP) by the project team composed of center staff, the assay provider and a NIH Network Science Officer assigned to the assay project. The CPDP outlines the projected probe development path for the specific assay, assigns tasks to each member of the project team and predicts appropriate milestones and timelines (see link for example of a CPDP (https://mli.nih.gov/resources/MLPCN_U54_FAQ.htm). Applicants should describe how they will incorporate the CPDP into their hit identification process.

b. Hit characterization: Fresh compound samples of initial hits will be selected (cherry-picked) by the MLSMR and sent to the centers for further characterization. Working with the assay provider, valid hits should be characterized in an alternative assay to that used in the primary screen. This provides additional verification that the hit is acting on the target of interest. Depending on the assay and target, the assay implementation and HTS cores may choose to develop counter-screens to determine the selectivity and specificity of the hits for the target. All secondary screens (alternative, concentration dependent and counter screens) will be the responsibility of the screening center. The informatics and chemistry cores will analyze the data for correlations between compound structure and the observed biological activity (SAR analysis). All assay data on hit characterization will be promptly deposited into PubChem.

c. Hit to probe optimization: To optimize initial hits, the assay implementation, informatics and chemistry cores will work together with the assay provider through successive rounds of synthesis and testing of new compounds to improve the potency and selectivity of the original hits. New compounds for testing in this phase often begin with the purchase of analogs structurally related to the hit, if they are available. In many instances, a compound may not be found by purchase that meets the probe criteria defined in the CPDP. In those instances, the center will need to provide sufficient synthetic chemistry to generate a library of structurally related analogs to identify compounds of improved affinity, specificity and solubility. The center should expect to continue hit optimization until a compound is identified with the appropriate properties of a probe or determine by analysis that the structure series under investigation will be unproductive. This may involve testing anywhere from <20 to a few hundred analogs; the application should describe the center’s process for making a go/no go decision for further chemistry activities. If confirmed hits are flagged as compounds provided by compound contributors to the MLSMR, the contributors may be invited to consult with the project team. If the project team decides on starting a chemistry campaign, the contributor may be asked as part of the project team to provide medicinal chemistry support in the development of a probe. Each center may expect to undertake 25 or more probe projects per year and deliver 10-15 new probes per year once the discovery pipeline is at full capacity.

C2. Specialized Screening Centers: Certain types of assays requiring multiple steps or specialized instrumentation (e.g. phenotypic imaging assays, multiplexed flow cytometry, ion channel assays) may not fit well in the comprehensive center format due to their special requirements and slower screening rates. However, these more difficult assays for screening large compound sets may represent the only technology available for newly discovered targets and pathways. Assays of this type are windows to important biological phenomena and are, accordingly, an important objective of the MLP. To address these needs and opportunities, the MLP has introduced the concept of Specialized Screening Centers in the production phase. The Specialized Screening Centers will be smaller in scope, but similarly expected to apply novelty and innovation to specific types of assays or platforms. These centers will need to have assay development, assay adaptation/implementation, screening and informatics functional cores. Each center is expected to try to screen a library of 300,000-500,000 compounds per primary assay and process 5 or more assigned assay projects per year. NIH understands, however, that some assays might not be amenable to screening with such a large screening library, and therefore will be willing to consider approving use of subsets of the library on a case by case basis. If the applicant anticipates that this may be an issue, s/he should describe how such a problem would be identified and the approach that would be taken to determine an appropriate screening set recognizing the importance NIH places on the development of biological profiles for each compound in the MLSMR that derive from screening of the complete library and deposition of the screening data in PubChem. In collaboration with a Specialized Chemistry Center or the chemistry core of a Comprehensive Center that can provide cheminformatics and chemistry resources, the Specialized Screening Center is expected to deliver 2-3 new probes per year once the discovery pipeline is at full capacity. Each center is encouraged to develop an active outreach program to (1) increase awareness in the biomedical community of the goals of the MLP, (2) to solicit investigators to submit assays to the MLPCN and (3) to provide support to aid the assay submitter in preparing a competitive X01 or R03 Assay Solicitation application. A Specialized Screening Center will be responsible for Hit identification , Hit characterization and, in collaboration with a Specialized Chemistry Center or the chemistry core of a Comprehensive Center, Hit to probe optimization stages in the probe generation pipeline. All centers will be expected to apply process management methods of planning, monitoring and evaluating process performance as part of their management of their portfolio of assays and probe development projects over the lifetime of the grant period. Specific center metrics including production rate, program efficiency and costs will be carefully monitored by NIH program staff.

a. Hit identification: The Specialized Screening Centers will run a primary screen, perform confirmatory assays and analyze all the data before deposition into PubChem. The throughput of many of these assays will be relatively low because the emphasis of the Specialized Center’s component of the MLPCN is not screening rate but the opportunity to include other medium and low throughput screening methods for difficult assays or assays not amenable to present HTS methods (i.e., inaccessible targets or complex phenotypes). Complete screening of the MLSMR library is expected, but this will be anticipated to occur over a longer time span than an assay campaign in the Comprehensive Centers. Applicant’s will need to provide information on the center’s capability for assay development, assay adaptation/implementation, HTS and informatics functional cores and describe how the center will accept, modify and implement assays for automated HTS, screen the MLSMR library and confirm initial hits. Explain how the project team will be formed for each assigned assay project and how the CPDP will be created and used to guide the probe development process.

b. Hit characterization: Immediately following completion of the primary screen, fresh compound samples of initial hits (cherry-picked) will be provided by the MLSMR for hit confirmation and secondary screens. Working with the assay provider, valid hits will need to be characterized in an alternative assay to verify that the compound is target specific. Depending on the assay and target, the center will develop counter-screens to determine the selectivity and specificity of the hits for the target. All secondary screens (alternative, concentration dependent and counter screens) will be the responsibility of the screening center.

c. Hit to probe optimization: At an early stage in hit characterization, the Specialized Screening Center will identify within the MLPCN a Specialized Chemistry Center or the chemistry core of a Comprehensive Center capable of providing chemistry resources (both synthetic and cheminformatics) for hit-to-probe optimization. In this collaborative effort, the Specialized Screening Center will provide all follow-up assays on the compound analogs. To optimize initial hits, the biologists, chemists and cheminformaticians will work together with the assay provider through successive rounds of synthesis and testing of new compounds to improve the potency and selectivity of the original hits. New compounds for testing in this phase should begin with the purchase of analogs structurally related to the hit, if they are available. If a probe cannot be found by compound purchase that meets the probe criteria defined in the CPDP, the center providing chemistry resources will generate a library of structurally related analogs to identify compounds of improved affinity, specificity and solubility. Before synthesis is attempted, the participating MLPCN centers working with the NIH Network Science Officer and the assay provider will update the CPDP to clearly identify all relevant go/no-go criteria and appropriate milestones and timelines. If confirmed hits are flagged as compounds provided by compound contributors to the MLSMR, the contributors may be invited to consult with the project team. If the project team decides on starting a chemistry campaign, the contributor may be asked as part of the project team to provide medicinal chemistry support in the development of a probe.

C3. Specialized Chemistry Centers: The hit-to-probe optimization stage in the probe development process may require special tools, expertise, and resources that are frequently in short supply in a screening center. Specialized Chemistry Centers will apply innovative and novel approaches of cheminformatics and medicinal chemistry to advance active compounds identified by the Specialized Screening Centers or, in some instances, by the Comprehensive Centers. It is essential that compounds identified as research tools for the investigation of particular targets and biological processes by the MLPCN are reliable and capable of providing valid information on the activity of their intended targets. The probe compounds produced by the centers will need to be usable by the research community for in vitro and/or in vivo studies. In most cases, compounds identified by initial screening ( hits ) will not be ideal as research tools. It is likely that properties such as affinity, specificity, and solubility will need to be improved using the chemistry resources of the Specialized Chemistry Center. Specific center metrics including production rate, program efficiency and costs will be carefully monitored by NIH program staff.

a. Hit to probe optimization: Probe leads identified from screens in the Screening Centers will require further optimization through chemistry. A joint effort will begin during the hit characterization stage by formation of a project team that includes the screening center, the chemistry center, the assay provider and the NIH Network Science Officer for hit-to-probe optimization. This joint effort will match the rich chemistry resources of the Specialized Chemistry Center with the counter-screen and follow-up screens of the Screening Center in a close collaboration. New compounds for testing in this phase usually are obtained first by purchase of analogs structurally related to the hit before considering the more expensive approach of synthesis of new analogs. If a probe can not be found by compound purchase that meets the probe criteria defined in the CPDP, the Chemistry Center will provide sufficient synthetic chemistry to generate a library of structurally related analogs to identify compounds of improved affinity, specificity and solubility. The center should be expected to continue hit optimization until a compound is identified with the properties defined in the CPDP. Before synthesis is attempted, the project team will update the CPDP to clearly identify all relevant go/no-go criteria and appropriate milestones and timelines. In this collaborative effort, the screening center will provide all follow-up assays on the compound analogs. If confirmed hits are flagged as compounds provided by compound contributors to the MLSMR, the contributors may be invited to consult with the project team. If the project team decides on starting a chemistry campaign, the contributor may be asked as part of the project team to provide medicinal chemistry support in the development of a probe. Each Specialized Chemistry Center can expect to undertake 10 or more probe projects per year from the combined hits from both Specialized Screening Centers and Comprehensive Centers and deliver 4-6 new probes per year once the discovery pipeline is at full capacity.

Note: Because the goal of screening 300,000 compounds in 100 assays annually may be an under- or over-estimate, this goal will be re-assessed by the MLPCN, the External Scientific Panel (ESP), and the MLP Project Team at the Mid-course Review.

D. Center-driven research projects.

The MLP is included in the NIH Roadmap because of its potential to transform the way in which biomedical research is done by introducing the capacity for high-throughput probe development into public sector research and advancing the potential offered by chemical genomics. As the focus of the MLP, the MLPCN centers can contribute not only through the process of screening individual investigator-submitted assays. By virtue of their insight into the-probe development process, the centers have the opportunity to explore and develop truly revolutionary advances that a more comprehensive approach to chemical genomics could provide. To stimulate potentially high impact advances in chemical genomics, NIH will offer to applicants the opportunity to include research component in the center applications. NIH invites applicants to include proposals for highly creative, innovative research projects that could make major contributions to 1) the advancement of chemical genomics as an important new discipline for public sector research that is widely available to the academic research community, and 2) enhancement of the ability of public sector researchers to regularly use small molecules as investigative tools. Applicants may request support for up to 6 years for research based on a well articulated vision advancing the use of small molecules by the academic biomedical research community for the investigation of important unmet challenges. The proposal for this center-driven program should describe a broad vision of the current state of the art, identify the opportunities that new capabilities in chemical genomics offers, and describe a research program that would lead to high impact advances in biology and biomedicine. The research proposal must clearly identify a set of specific aims that would lead to the realization of the vision and a project or series of projects by which those aims would be achieved. For example, applicants could identify one or more major restriction(s) or bottleneck(s) in the high-throughput technologies for chemical genomics, in the design and synthesis of new small molecules based on initial hits, or in application of chemical genomics to important biomedical research problems and then describe one or more inventive research projects that would address the bottleneck and provide high impact, broadly enabling advances in the development of methods and tools to study the protein networks and cellular processes important in the molecular events that lead to disease. These aims can include projects that are biologically, chemically or computationally driven either alone or in an integrated fashion.

In developing their plans for the center-driven component, applicants are advised to propose high impact/high payoff projects that leverage the unique strength(s) of their proposed center. Up to 30% of the maximal allowed budget per year may be requested for the center-driven research project(s). To provide the MLP with the maximum flexibility to pursue exciting new directions offered through progress of these center-driven efforts, the center-driven programs will be evaluated at specific times during the project period, and the outcome of this assessment may result in changes in the level of funding (see Section IIF2, Requirements for Center-driven Research Project). The evaluation will be conducted by NIH staff with the assistance of outside experts and members of the External Scientific Panel. The evaluation will be based on effort, scientific progress and continued relevance of the project(s) to the articulated vision and specified aims.

The center awardees' yearly milestones for the user-driven and center-driven components will be provided to the Project Scientists(s), the MLP Project Team, the MLIIG Working Group, and the ESP. It is expected that the milestones will be adjusted annually at the award anniversary dates, both to incorporate the group's scientific accomplishments and progress, as well as to reflect any recommendations of the MLP Project Team and the ESP. Following the review of milestones, the MLP Project Team may recommend reducing or withholding funds for any center/center project that substantially fails to meet its milestones or, if the situation warrants, augmenting any center/center project. However, simply meeting milestones may not be considered sufficient accomplishment for maintaining funding at the initially committed level for the user-driven and center-driven components. Failure to remain at state-of-the-art will also be considered grounds for reduction in funding levels.

E. Organizational Structure of the MLPCN

Applications for the three types of centers will need to address two separate program components: 1) the core capabilities appropriate to the specific type of center defined as the user-driven component (designated as F1a-d below) and 2) the center-driven research project. These components require separate sets of specific aims, milestones, timelines and detailed descriptions of quantitative measures for monitoring progress.

The user-driven component is required and describes the service oriented function of the center to provide identification and development of probes and probe generation data. The applicant may request up to 70% of the maximal allowed budget be dedicated to the service function for assays submitted by the scientific community through the assay development and the HTS-ready assay solicitation sub-initiatives of the MLP. Assays for this component will also come from the center’s own outreach efforts that will include expert assistance to outside investigators in the development of their assays. The majority of funds for this component must be committed to providing service and not to center development.

The center-driven component allows the applicant to propose a 6 year plan that may be comprised of one or more projects that will advance the overall objectives of the network and contribute to maintaining a current and competitive network environment to deliver state of the art tools and knowledge to benefit the scientific community. Applicants may request that up to 30% of the maximal allowed budget be dedicated to this center-defined research component to pursue creative, highly innovative research project(s) whose aim is to advance the overall objectives of the network and contribute to maintaining a current and competitive network environment to enhance its mission to deliver state of the art tools and knowledge to the scientific community. The requested budget for the center-driven component cannot exceed 30% of the allowable budget for each type of center.

F. Center Core Capabilities:

F1a. Assay Development and Adaptation (applicable to Comprehensive and Specialized Screening Centers). The goal of the MLPCN is to establish innovative biochemical, biophysical, and cell-based assays for biological targets or processes for which no highly specific and potent small molecule activator or inhibitor is broadly available. However, the initial design and development of assays is not within the scope of this FOA and will not be the responsibility of the MLPCN centers. Rather, investigators in the broader scientific community will submit applications in response to NIH Guide program assay solicitation announcements (e.g., PAR-08-006 R03, and PAR-08-007 X01). These assay applications will be evaluated through a competitive process as described below. The MLPCN centers will then be responsible for importing, adapting and optimizing specific assays selected for implementation within the MLPCN. The first step in implementing an assay is the creation of a CPDP by a project team composed of center staff, the assay provider and an NIH Network Science Officer assigned to the assay project. The CPDP outlines the projected probe development path for the specific assay. The plan assigns tasks to each member of the project team and predicts appropriate milestones and timelines. Importantly, the CPDP defines the specific criteria that a compound must meet to be considered a probe for the project. During the hit characterization stage (or earlier) the CPDP should be updated to include SAR around chemotype/structural series along with a synthetic plan.

The proposed goal of the production center network will initially be to screen the MLSMR library of 300,000 compounds in 100 or more assays in the first year of the MLPCN program using 96-well, 384-well or 1536-well plates, with an expected goal of screening up to 500,000 compounds as the MLSMR expands in a minimum of 100 assays by the third year of the production phase. Although the majority of assays will be HTS-ready, applicants should clearly describe a plan for handling assays that need some modification for HTS (e.g., assay miniaturization and automated processing) and discuss criteria for determining when an assay is sufficiently optimized to allow HTS or when an assay cannot be implemented in HTS. Applicants should describe the assay development and implementation capabilities that they currently have or plan to have by the start of the award to accept a variety of assays from the scientific community and adapt them to a high throughput format. Issues such as experience with assay optimization, throughput, reproducibility, validation, cell culture, protein or vector production, and other relevant capabilities should be discussed. Prior experience of the center PD/PI with performing successful HTS on assays generated outside the center PD/PI’s laboratory should also be described. Screening centers should have the capability to provide scale up of reagents for HTS as this requirement is often beyond the means of assay providers. This would include methods to purify protein and the necessary equipment to grow large numbers of cells in culture.

F1b. HTS Implementation (applicable to Comprehensive and Specialized Screening Centers). A production center will need to be able to successfully carry out HTS using robotic technologies and high throughput detection systems capable of measuring a variety of readouts (e.g., absorbance, fluorescence, luminescence, FRET, BRET, SPA, etc.). Given the number of compounds to be screened, 96-, 384- and/or 1536-well plate reader capabilities will be required. Centers will need to be able to validate HTS-based assay results using appropriate statistical controls, positive and negative controls, and ways to limit and identify false positives and false negatives. In most cases, hit-confirmatory assays and at least one secondary screen (submitted by the referring investigator) will need to be run to identify true positives that would be candidates for further development as probes. Applicants should justify each of the HTS component technologies proposed for inclusion in the screening center in terms of how each one will be utilized as an integral component of the center’s HTS capabilities. Applicants should also present a coordinated, viable plan for monitoring costs accurately, reducing the use of reagents and MLSMR compounds and, when appropriate, for implementing advances in detection, miniaturization, and robotics required to maintain the center at state of the art and to meet the growing increase in screening demand as the MLSMR continues to expand the screening library.

F1c. SAR Analysis and Medicinal Chemistry (applicable to Comprehensive and Specialized Chemistry Centers). It is essential that compounds identified as research tools for the investigation of particular targets and biological processes by the MLPCN are reliable and capable of providing reproducible and accurate information on the activity of their intended targets. The probe compounds produced by the centers will need to be usable by the research community for in vitro studies. In most cases, compounds identified by initial screening ( hits ) will not be ideal as research tools. It is likely that properties such as affinity, specificity, and solubility will need to be improved before a useful compound is obtained. Therefore, applications for the Comprehensive and Specialized Chemistry Centers should describe a plan for the development or acquisition of sufficient computational and synthetic chemistry capability to generate a library of structurally related compounds around a confirmed hit and how to test those compounds in the appropriate assays to identify derivatives with improved affinity, specificity, solubility, and bioavailability. It is also likely that hits would need to be re-synthesized at the center before structure-activity work is undertaken. Chemistry efforts could include optimization of SAR via directed library synthesis and structure-guided design or other appropriate methods. The minimum characteristics for a probe compound to be a useful research tool will be determined by the MLPCN Steering Committee and the MLP Project Team; it is anticipated that such characteristics will include <100 nM affinity, >100-fold selectivity against related targets, and solubility in aqueous solutions or in a low concentration of DMSO. NIH recognizes that whatever the characteristics of the probes, further modification may be necessary to produce compounds that are useful for in vivo studies (although such further modification is outside the scope of this FOA). For this reason, it is the desire of NIH that during the production phase, all probes and all related biological and chemical data will be made available to all researchers. The centers will be expected to provide 10-15mg quantities of probes and the analogs developed in the hit to probe optimization phase to the MLSMR. NIH is working to develop a process outside the MLPCN intended to facilitate general access to probes by the biomedical community.

F1d. Screening Informatics (applicable to Comprehensive and Specialized Screening Centers) and Cheminformatics (applicable to Comprehensive and Specialized Chemistry Centers). Adequate informatics capabilities will be critical to multiple components of the center. Depending on the type of center, automation, sample tracking, laboratory procedures, quality control, data management, deposition of screening data, assay protocols, and other relevant information to PubChem, and data analysis all depend on sufficient informatics capabilities and resources. Applicants should present a clear set of operational plans for ensuring that, as appropriate, the screening and cheminformatics needs of the center are addressed, and demonstrably contribute to the efficiency of the center s operation. Issues that should be addressed include plans for acquisition and analysis of primary screening data, and data generated from screening of a second-generation library of structurally related compounds generated around a confirmed hit. Comprehensive Center and Specialized Chemistry Center applicants should additionally describe their capabilities for computational chemistry, and cheminformatics to fully support the hit-to-probe work. In preparing the screening and/or cheminformatics plan, the applicant should take into account that once the MLPCN is established, the MLPCN Steering Committee will address issues of possible standardization of operating procedures across centers such as quality control and quality assessment for assay and screening procedures, and data deposition practices for submission of screening data, assay protocols, and standards of information transfer to PubChem. Applicants will be expected to demonstrate a high degree of flexibility and willingness to adopt uniform policies and procedures recommended by the MLPCN Steering Committee.

All screening data and descriptions/protocols for assays optimized for HTS by the MLPCN are required to be deposited immediately in the public domain (via PubChem) after they have been confirmed for accuracy. The procedures for the deposition of screening data and assay protocols to PubChem will be jointly managed by the MLPCN network, PubChem and NIH program staff. For chemical structure data, PubChem currently supports multiple formats such as SDF or MOL files. For chemical synthesis descriptions of small molecules in the Repository, PubChem supports deposition of text descriptions and citations. Centers performing chemical synthesis are welcome to propose solutions for establishing an online database of reaction protocols.

F1e. Administration and Management. Each MLPCN center must have a well-conceived and implemented management plan and a significant commitment of effort by the PI of the project. The PI of an MLPCN center is expected to devote at least 25% effort to the project. The application should describe the management plan for the proposed center, and how the plan will support its proposed goals. It should describe the organization of the proposed center and its management structure, and should address the integration of the functional components to form an efficient assay optimization, screening, and/or hit optimization chemistry pipeline for generating small molecule research tools. The plan should specifically address interactions between key personnel and reporting relationships. Applicants must discuss the ways in which close working interactions will be promoted and maintained in cases where the key personnel on a given project will be at geographically distinct performance sites (as will always be the case for Specialized Screening or Chemistry Centers). Recruitment and training of personnel should be discussed. The plan should specifically address how any collaborations or subcontracts will be managed. The PI is strongly encouraged to propose a project manager for the center to manage the day-to-day operations. All center applicants are expected to apply process management methods for planning, monitoring and managing the portfolio of assays and probe development projects (as appropriate) over the lifetime of the grant period and are expected to communicate this to NIH program staff upon request.

The management plan should also address the interactions of the proposed center with the other components of the MLPCN (e.g., MLSMR, the MLPCN Steering Committee, the NIH program staff; these components are described in more detail below) and how the center would structure collaboration with the assay providers and in certain circumstances, compound contributors.

NIH does not specify how core functions are to be organized within the center. The applicant may choose to organize the proposed center in terms of separate functional cores or in any other manner deemed appropriate for the implementation of an effective pipeline. However, the application must clearly address how the proposed organization of the center will ensure that each of the core functions is effectively accommodated. Each of the functions is described in more detail below.

F2. Requirements for Center-driven Research Project. Each type of center is invited to propose a creative, highly innovative research program of up to 6 years with a well articulated vision for advancing the ability of the academic biomedical community to create and use small molecules for the investigation of important and unmet challenges in biomedical research. The proposed projects must be distinct from investigator-provided assays and must not be merely an extension of on-going research work in the applicant’s laboratory. Both the vision and the proposed high impact/high payoff projects should leverage the unique strength(s) of the particular center.

Proposals for the center-driven projects must provide the following information: a) a clearly stated vision of what will be achieved at the end of the funding period; b) a clear articulation of how the success of the vision will have a broad impact on molecular and cellular biology and on the increased use of small molecules as probes of biomolecular systems; c) a description of how the proposed project(s) and their specific aims address the vision; d) a defined plan for the proposed project(s) and sub-projects with timelines that have milestones with sufficient detail for evaluation and monitoring purposes; e) one or more alternative approaches as a back-up if the initial plan were to fail; and f) a description of a method to measure progress and milestone achievements quantitatively and qualitatively over the course of the research project(s). Applicants may request up to 30% of the maximal allowed budget per year be dedicated to this center-defined research project over the grant period of 6 years.

In addition to the customary NIH annual progress reports, the center-driven programs will be evaluated at two-year increments. Evaluation of both project progress and continuing importance of the original program goals will be carried out by the ESP and NIH program staff, with input from outside experts as appropriate, at the end of the second year and the fourth year into the grant period. Funding for the center-driven components of the U54 cooperative agreement may be adjusted annually and on the basis of the outcome of that review.

In addition, the center-driven and user-driven components of each center will be evaluated as part of the overall MLP Mid-course Review that will occur near the end of the third year of the grant period. These evaluations and outcome of the mid-course review will be crucial in establishing a specific, concrete and successful set of outcomes for the MLPCN over the 6 year project period.

G. Other Considerations.

In addition to the functions described above, there are a number of other issues important to the successful operation of the MLPCN that should be addressed separately in the application:

G1. Acquisition of Assays and Outreach. The function of the MLPCN centers will be to receive assays that have been developed by members of the scientific community, adapt them for high-throughput implementation, and use them to screen the compound collection provided by the MLSMR to identify and confirm compounds that have the desired effect in the assay. Proposals for innovative assays for screening center implementation will be solicited from the scientific community through FOAs in the NIH Guide. Applications will be peer reviewed for scientific merit, including suitability for high-throughput implementation, by a Committee convened by the CSR.

The MLPCN screening centers have a key role to play in the acquisition of high quality assays by the Probe Production Center Network by mounting an active outreach effort about the opportunities provided by the Network to the larger scientific community. Applicants for Comprehensive or Specialized Screening Centers should address the issue of evaluating and adapting assays for high-throughput implementation and should present a clear plan for doing so. All center applicants should also provide an aggressive plan to reach out to the scientific community to encourage investigators to access the resources of the MLPCN. Success of this Roadmap initiative is dependent on the awareness and participation of the scientific community. The screening centers should describe plans to increase awareness of the MLP through meetings, presentations, networking and other means. Assays that are brought into the network through assay development collaborations (Assay Development for HTS, R21 program) with a center improve the chances for a successful X01 or R03 peer review and insure that the highest quality assays are screened in the MLPCN. Chemistry centers should provide an outreach plan to increase awareness in the chemistry community of the chemistry opportunities of the MLPCN and NIH’s interest in obtaining novel and unique compounds for its screening collection.

The results of the X01 and R03 reviews and information about available capacity and expertise at each center should form the basis for assay prioritization and assignment decisions. The information will be provided on a regular basis to the MLPCN Steering Committee, which will make recommendations about assay assignments. The MLP Project Team will provide a second level of review of the decisions of the Steering Committee and give final approval for assay assignments on a time frame suitable to the screening schedules of the centers. The previous interaction of a center, through its outreach component, with an assay provider will be taken into account in assigning the assay of interest.

The MLPCN centers will not have a privileged position relative to the rest of the scientific community with respect to access to HTS services. Should the PI or any outreach participant in an MLPCN center wish to implement his/her own assays, s/he will have to submit that assay for review and prioritization according to the process described previously for the scientific community. Should such an assay be placed on the priority list, the MLP Project Team will take the PI s interest into account in assigning that assay to the requested center.

G2. Data Release. A major benefit provided by the MLPCN to the scientific community is the rapid dissemination of screening data. It is expected that MLPCN centers will quickly release data (i.e., screening data and assay descriptions) to PubChem as soon as the data have been determined to be reliable. It is anticipated that the MLPCN Steering Committee will develop guidelines for standardizing the reliability/validation of screening data for different types of assays across centers. Responses to this RFA should include a statement of willingness to abide by the immediate data release policy for submission of screening data to PubChem. MLPCN members will submit data to PubChem in the formats adopted by the MLPCN Steering Committee working with NIH program staff and PubChem staff at NCBI. These formats will leverage current practices and standards developed and/or adopted during the pilot phase of this Roadmap initiative (http://www.nimh.nih.gov/about/organization/dnbbs/the-mlscn-project-team-policy-on-data-sharing-and-ip-in-the-mlscn-program.pdf). For chemical structure data, it is anticipated that PubChem will support, among others, existing formats such as SDF or MOL files. For screening assay descriptions and results, it is anticipated that PubChem will support depositions based on best current technologies including XML exchange specifications. Upon submission to PubChem, all data will be made freely available to the entire research community in a form that would allow for redisplay and reanalysis, so that maximal utility of this research resource will be realized.

The NIH has identified the MLPCN as a community resource project as defined by the Fort Lauderdale meeting (http://www.genome.gov/Pages/Research/WellcomeReport0303.pdf), and accordingly expects that users of the data will respect the legitimate interests of the producers to analyze and publish their results by treating the data as unpublished information, until otherwise indicated. As with any unpublished data, it is expected that users will provide proper citation of the source of the data. It is our further expectation that publications that result from this unpublished data be approved by the contributors of the assay and non-commercial compound providers of active compounds who may elect to be part of the team of collaborators This includes the crafting/approving of the manuscript and co-authorship. The individual investigators within the MLPCN may publish the results of their own screening efforts. Neither these individual publications nor any MLPCN network publications should delay the other’s publications. The MLPCN network may publish global analyses of the results of the screening effort. MLPCN members will fully disclose algorithms, software source code, and experimental methods to the other members of the network for purposes of scientific evaluation and will be strongly encouraged to make them available to the broad research community.

G3. Cost Sharing This program encourages, but does not require cost-sharing with the applicant institution, biotechnology, pharmaceutical, or disease foundations to support infrastructure and reagent costs, especially in the transition phase of the program, as defined in the current NIH Grants Policy Statement. NIH is aware that a number of institutions have already established such activities and have already committed institutional funds to them. Cost sharing will not be a review criterion; any comments that reviewers might make will be reported in an administrative note for consideration by program staff.

G4. Transition Plan A fundamental objective of the NIH Roadmap for Biomedical Research is to transform the way in which biomedical research is done in the future because while the opportunities for discoveries have never been greater, the complexity of biology remains a daunting challenge. The Molecular Libraries Initiative, now Program, was implemented to effect a major change in academic and public-sector biomedical research by making the power of chemical genomics broadly available outside of the pharmaceutical sector. The role of the NIH Roadmap in this effort has been to provide the incubator space for this major initiative to develop and mature, and it has been appropriate, therefore, to provide the initial funding for the growth of chemical genomics capability through the Common Fund from which Roadmap projects are supported.

However, the planning of Roadmap projects includes the eventual transition of support from the Common Fund to individual NIH institutes and more traditional sources of funding as the transformative effects of the Roadmap project are realized. For the MLP, this transition will begin in the fifth year of the Program. The first four years of the Production Phase will be fully supported by the Common Fund; there will then be a two-year transition period in which the Common Fund contribution will decrease.

Therefore for purposes of the present FOA, applicants should provide a budget request for years -05 and -06 sufficient to support probe production at the same levels as in years -01 to -04. However, applicants should realize that the award of the two-year transition phase will be based on program priorities, on the availability of funds, and on successful completion of negotiated scientific milestones as determined by NIH staff in the context of the NIH Midcourse review.NIH staff will work with MLP awardees to identify additional funding sources that will allow continued support for the MLP. At the same time, applicants are well-advised to begin planning during the first few years of the award for other mechanisms of support, such as fee for service and/or private funding.

Notes: Other considerations including data sharing, cost sharing and transition plan will not be review criteria; any comments that reviewers might make will be reported in an administrative note for consideration by program staff and by the applicant.

Because of the complexity of the MLPCN, it is anticipated that program staff from NIH may visit each MLPCN center periodically to conduct an administrative site visit. Each center should also plan for hosting at least one meeting of the MLPCN Steering Committee and should budget appropriately.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This FOA will use the NIH U54 Specialized Center Cooperative Agreement award mechanism. In the cooperative agreement mechanism, the PI retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the PI, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

2. Funds Available

The NIH Roadmap intends to commit approximately $70 million per year from the Common Fund for the first four years of the six year funding period (2008-2013) to support 6-10 centers. The earliest anticipated start date for awards under this funding opportunity is July 1, 2008.

The MLP anticipates awarding up to 2-4 Comprehensive Centers, 2-3 Specialized Screening Centers, and 2-3 Specialized Chemistry Centers. Comprehensive Center applicants may request up to $10 million direct costs annually; Specialized Screening Center applicants may request up to $2.1 million direct costs annually; Specialized Chemistry Center applicants may request up to $2.85M direct costs annually. The total project period for an application submitted in response to this FOA may not exceed six years. Funding of the MLP program beyond the initial 4-year production phase will be determined by successful completion of negotiated scientific milestones as determined by NIH, by the outcome of the NIH Midcourse review of the overall MLP program, and on the availability of funds.

Costs for equipment may be included in year one, up to $500,000. There will be no limit on equipment costs in the following years but should be well justified to meet the goals of the network.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size of each award will also vary. Although the financial plans of the NIH 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.

Section III. Eligibility Information

1. Eligible Applicants

This NIH Roadmap RFA is a limited competition for those who on the basis of peer review of PAR-07-368 (X02) applications have been invited to submit full U54 applications.

1.A. Eligible Institutions

For PAR-07-368 (X02) an organization with any of the following characteristics were eligible:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI was eligible to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities were, as always encouraged to apply for NIH support. Foreign investigators can serve as a PD/PI on a core, a member, or consultant for a center.

The timeline for the program is given below.

October 2007 Invitations are made for the U54 applications

January 10, 2008 Submission date for U54 full application

March, 2008 Scientific merit review for full application

May 2008 National Advisory Council review of application

June 2008 Awards announcement

July 1, 2008 Starting date for the Production Phase of the MLPCN


2. Cost Sharing or Matching

This program does not require cost-sharing as defined in the current NIH Grants Policy Statement

3. Other-Special Eligibility Criteria

Limited eligibility for the U54 applications in response to this FOA: Investigators interested in participating in the MLPCN must have submitted a pre-application (X02), as described in PAR-07-368 Preapplication for the Molecular Libraries Probe Production Centers Network (MLPCN) [X02] . Successful applicants have been invited to submit a U54 cooperative agreement application in response to this FOA. It is expected that the PD/PI for the X02 pre-application also will be the PD/PI of the U54 application. The U54 application can be submitted by a single institution or by a consortium of institutions. Only applicants who successfully competed in the pre-application process are eligible to compete for the MLPCN.

An individual can participate as the PD/PI of the center in only one application. There are no limits on the number of applications that can be submitted by one organization.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact Grants Info, Telephone (301) 710-0267, Email: [email protected].

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Applications From federal Agencies

The requests from federal agencies, including the NIH intramural program, will not include any salary and related fringe benefits for career, career conditional or other federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative costs).

In general, the budget requests will be limited to the incremental costs required for carrying out the proposed work. These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. While support for extramural collaborators may be requested in a separate grant application, funds can be requested for services by an external investigator or contractor as a subcontract/consortium including the applicable indirect (F&A costs) of the contractor/collaborating institution.

Justification must be provided for all requested support and for the Federal employees who will be committed to the project although no funds are requested in the application.

Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date: December 13, 2007
Application Receipt Date: January 10, 2008
Peer Review Date: March 2008
Council Review Date: May 2008
Earliest Anticipated Start Date: July 1, 2008

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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 IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Ingrid Y. Li, Ph.D.
NIH Molecular Libraries & Imaging Roadmap
National Institute of Mental Health, NIH
6001 Executive Boulevard, Room 7192, MSC 9641
Bethesda, MD 20892-9641
Telephone: (301) 443-7099
FAX: (301) 402-4740
Email: [email protected]

Applicants are strongly encouraged to send the letter of intent by Email. Please do not submit the same letter by multiple routes (e-mail, FAX, or hard copy)

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and five signed copies, as well as all of the appendix material are to be sent to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

Using the RFA Label: The RFA label available in the PHS 398 application instructions 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/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by NIH Roadmap staff. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the PI in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

Applications are to be submitted on Form PHS 398 (http://grants.nih.gov/grants/funding/phs398/phs398.html). All instructions and guidelines accompanying the PHS 398 are to be followed, with the exception of the sections modified by the specific instructions described below.

Research Plan Component for the U54 application:

It is recognized that the applications in response to this FOA will be longer and more complex than many other NIH applications. In order to ensure an effective review, the application should be clearly laid out and well organized into sections, the main function/center cores (See Section II.I.1.F1a-e) and the Center-driven research Project (see Section II.I.1.D and F2). The number of functional cores is determined by the type of center (see MLPCN Centers, Section II.I.1.C); http://mli.nih.gov/resources/MLPCN_X02_FAQ.htm).

a) Comprehensive Centers should describe five functional cores (1. Assay Development, Adaptation and Implementation, 2. HTS, 3. Chemistry, 4. Informatics, 5. Administration and Management, see Section II.I.1.C1) and the optional Center-driven Research component (Section II.I.1.D and F2).

b) Specialized Screening Centers should describe four functional cores (1. Assay Development, Adaptation and Implementation, 2. HTS, 3. Informatics, 4. Administration and Management, see Section II.I.1.C2) and the optional Center-driven Research component (Section II.I.1.D and F2)

c) Specialized Chemistry Centers will need three functional cores (1. Informatics, 2. Chemistry, 3. Administration and Management, see Section II.I.1.C3) and the optional Center-driven Research Project (Section II.I.1.D and F2). The informatics core must be able to interpret the data coming from the screening centers and use computational chemistry resources to provide a full SAR to support the medicinal chemistry development of probe leads.

Organization of the Application:

Applicants must construct the Research Plan component as a single document. The total page number for a Specialized Center application is 35 pages and the total for a Comprehensive Center application is 50 pages (in both cases, including the introductory overview). It is recommended that the Research Plan be divided into separate sections for the user-driven and center-driven components and the user-driven component be further subdivided into sections corresponding to the center cores with an average of 4-5 pages for each core. It is also recommended that the center-driven section not exceed 15 pages for a Comprehensive Center or 7-8 pages for a Specialized Center. Additional sections should address how the center will collaborate with members of the network, the plan for outreach to the research community, data sharing, cost sharing and the transition plan for additional mechanisms of funding for the center beginning in year 5.

The application should be organized as follows:

1. Form Page 1: Face Page

2. Form Page 1 continued: N/A

3. Form Page 2: Description, Performance Sites, and Key Personnel.

4. Form Page 3: Table of contents

5. Form Page 4: Detailed budget for initial budget period.

6. Form Page 5: Budget for entire proposed project period.

7. Biographical Sketch Format Page: Should be provided for each of the key personnel.

8. Resources Format Page:

9. Continuation Form: Use this form for the Research Plan pages, including introductory overview, background and significance specific aims, preliminary studies/progress report, research designs and methods for each of the proposed functional cores.

Introductory Overview/Specific Aims/Background and Significance (2-5 pages):

Clearly identify the type of center for which the applicant requests funding (Comprehensive Center, Specialized Screening Center, or Specialized Chemistry Center). Provide an overview of the proposed center and describe how it can contribute to the MLPCN to achieve the overall goals of the MLP. List specific aims and milestones for the first year and projected milestones for subsequent years of the program. In subsequent years, milestones will be reconsidered each year in negotiation with NIH program staff. Specific Aims of Overall Center: Describe the center goals. Explain the proposed contribution of each of the functional cores in achieving the objectives of the center. The Overview must contain a Summary Table with all of the functional cores in the Center. This section should also address the data sharing and willingness to collaborate with the MLSMR, assay provider, compound provider, other centers, etc.

For each Center Core include the following:

Provide a brief overview of each functional unit, its activities, and how the key personnel will interact and coordinate with the other functional cores.

Preliminary Studies/Progress Report.

For screening centers, the Preliminary Studies/Progress Report section of the Research Plan should provide a summary data table providing information on the center’s progress in the last two years. Provide information in two columns for the period September 2005 to August 2006 and September 2006 to August 2007. This information should include the number of assays implemented, number of compounds screened in each assay, the number of probe projects undertaken and number of analogs generated for each project, the chemical probes generated, deposition of data to PubChem or similar public database, and any resulting publications. Provide additional detail on one or more assay(s)/probe project(s) to illustrate the current capability and capacity of the center. Screening Center applicants should describe the capabilities that they currently have to import a variety of assays and adapt them to run on the center’s high throughput screening platform and the ability of the informatics core to accept, analyze and store large amounts of screening data. For Specialized Screening Centers, in addition to the above information, define areas of expertise and describe advantages of the center’s screening program to handle unique and/or difficult assays.

For Specialized Chemistry Centers, describe expertise with different types of chemistry, provide examples of hit optimization campaigns, describe plans for accepting and processing hits and plan for the communication and transfer of material and information with the screening centers. Describe experience in meeting milestones. For centers that were funded as part of the MLSCN, describe milestones met and compliance with the MLP data sharing and IP policy.

Research Designs and Methods.

Identify each proposed functional core by title and provide detailed information on each core, including those that are found to be underdeveloped for HTS. Provide current production rates and established QC, QA standards. Describe each core’s activities, and how the key personnel from that core will interact and coordinate with the other functional cores. What criteria will be used to determine if an assay should undergo further development at the center or be rejected and what steps will be required to determine rejection of the assay or modification to enable HTS? Explain the proposed contribution of each of the functional cores in achieving the objectives of the center.

Identify the center-driven component by title and provide detailed information on each proposed project. Clearly state the following points.

Letters of Support.

Include a letter documenting institutional commitment to the MLPCN program, including provision of funding, space, faculty positions, and/or commitments for construction or renovation. A letter from an appropriate institutional official, generally a dean or provost, should follow the Research Plan. If multiple institutions are involved in the center application, a letter should come from each institution.

Appendix:

NIH has published new limitations on grant application appendix materials to encourage applications to be as concise as possible while containing the information needed for expert scientific review. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-018.html

The following materials may be included in the Appendix

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the relevant policies and procedures may be delayed in the review process.

7. Plan for Sharing Research Data

During the pilot phase, the MLSCN/MLPCN developed a policy in consultation with the research community on data sharing and IP applicable to achieving the goals of the MLI (i.e., the NIH Policy on Data Sharing and IP in the MLP, http://www.nimh.nih.gov/dnbbs/datasharing-ip.pdf). During the production phase, the MLP Project Team expects that the existing policies will be followed. Consistent with such policy, all data generated by the MLPCN will be deposited into PubChem upon data verification. For this, the term data will include, but will not be limited to, assay descriptions, protocols and/or links to published assays implemented in the MLPCN; performance data for assays and compounds; primary data from HTS and data generated in the secondary screen (e.g., EC50s, IC50s, AC50s, counter screens); chemical structures, links to published or unpublished synthesis protocols for chemical analogs of non-commercial hits, or probes, and the biological activities of analogs and chemical probes.

All applicants are expected to include a statement of willingness to abide by the NIH Data Sharing and IP policy in the MLP and include a plan for sharing any other types of research data in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

8. Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources other than those addressed in the NIH Policy on Data Sharing and IP in the MLP (http://www.nimh.nih.gov/about/organization/dnbbs/the-mlscn-project-team-policy-on-data-sharing-and-ip-in-the-mlscn-program.pdf) will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans in meeting the programmatic goals will be considered by the MLP Project Team and MLIIG when making funding decisions (see Part I, Section IV, 2.A.2).

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

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 CSR in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

The following will be considered in making funding decisions:

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria 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 in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? For applications designating multiple PDs/PIs, is the leadership approach, including the designated roles and responsibilities, governance, and organizational structure, consistent with and justified by the aims of the project and the expertise of each of the PDs/PIs?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the PD/PIs and other key personnel appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level(s) of the principal investigator(s) and other researchers? Do the PD/PIs and investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Do(es) the scientific environment(s) in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment(s), or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Review Criteria for Overall Center

The center will receive an overall priority score that reflects the synergy and strength of the center as a whole; the scientific merit of the user-driven (cores); and the scientific merit of the center-driven research program.

The overall center will be assessed according to the following criteria:

1. Significance: 1). Does the center address an important problem? 2) If the aims of the application are achieved, how will scientific knowledge be advanced? 3) What will be the effect of these studies on the concepts, methods, and technologies that drive this field? 4) Does the center have the potential for impact in automated screening and probe development?

2. Center as a whole: 1). What is the potential for impact? 2). Degree of synergy, i.e., does the center as a whole serve a purpose greater than the sum of the individual components? 3). What is the effectiveness of the proposed center in meeting the goals of the MLP. 4) Does the center (comprehensive or specialized screening) have the current capacity to screen the MLSMR collection of 300,000 compounds, or reach the capacity to do so for each primary assay by the end of the first year? Does the center have the current capacity to undertake the estimated number of probe projects and deliver new probes by the end of the first year (i.e., 25 probe projects/10-15 new probes for the comprehensive centers, 10 probe projects/4-6 new probes for the specialized chemistry centers)? 5).Quality of the outreach program and potential to contribute to the success of the network. 6). The quality of the facilities or services provided by center (including procedures, techniques, and quality control). 7). The qualifications, experience, and commitment of the personnel involved. 8) The potential for impact of the center-driven research project.

3. Data Management: 1). Are data management and support procedures developed sufficiently to allow tracking of compounds, assays, and screening data? 2) Are procedures in place for quality control and quality assessment for assay and screening procedures?

4. Program Administration and Management: 1). Does the PD/PI have the scientific and organizational vision and experience to serve effectively as the center Director? 2). Is there evidence of sufficient management capabilities for the center that include fiscal administration, procurement, property and personnel management, planning, and budgeting?

5. Facilities: 1). Are facilities adequate for the overall functions of the center and to implement the goals of the MLPCN?

6. Institutional Commitment: 1). Is there evidence for institutional commitment to the program, including provision of funding, space, faculty positions, and/or commitments for construction or renovation? 2). Are the research environment and resources, including equipment and facilities, adequate? 3). Is there potential for interaction with scientists from other departments and components?

7. Interaction: 1) Are there adequate plans for ensuring effective communication, interaction, and coordination among the PI, Core PIs, network of MLPCN centers, assay providers, compound contributors, and NIH staff? 2) Do the investigators state their willingness to collaborate extensively and share information fully? 3) Do the investigators state their willingness to abide by the policies stated in the Terms and Conditions of the Cooperative Agreement?

Review Criteria for Cores

Each core will be assessed according to the following criteria and will receive a priority score:

Approach: Are the concepts or framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? How effective is the overall organization of the cores in relation to the center's goals? Will each core enhance collaborative and/or interdisciplinary research within the center and the wider research community? Are procedures in place for quality control and quality assessment for assay, screening, and synthetic chemistry/computational chemistry procedures? Are data management and support procedures developed sufficiently to allow tracking of compounds, assays, and screening data?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the PD/PI(s), project manager, and other key personnel 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? Does the PD/PI(s) and investigative team bring complementary and integrated expertise to the project (if applicable)? What are the qualifications, experience, and commitment of the personnel involved in the cores? Does the PI have the scientific and organizational vision and experience to serve effectively as the center Director? Is there evidence of sufficient management capabilities for the center that include fiscal administration, procurement, property and personnel management, planning, and budgeting?

Environment: Do(es) the scientific environment(s) in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support? What are the quality of the facilities or services provided by this functional unit (including procedures, techniques, and quality control)? Are facilities adequate for the overall functions of the center and to implement the goals of the MLP? Is there evidence for institutional commitment to the program, including provision of funding, space, faculty positions, and/or commitments for construction or renovation? Are the research environment and resources, including equipment and facilities, adequate? Is there potential for interaction with scientists from other departments and components?

Review Criteria for Center-driven Research Component

The center-driven component will be assessed according to the following criteria and will receive a priority score:

Significance and innovation will be the primary determinants of the score. The approach will be evaluated for general feasibility (probability of success, well defined metrics and milestones). Lack of preliminary data will not preclude the center-driven component from receiving an outstanding priority.

Significance: 1) Does the center-driven project(s): a) address an important scientific problem, restriction, or limitation in screening and probe generation? b) explain why this is a restriction and why removal of this restriction would be of major impact to the scientific community? 2) If the aims of the application are achieved, how will scientific knowledge be advanced?

Innovation and Impact: 1) Does the project(s) challenge existing paradigms or develop new tools, methodologies, or technologies? 2) Does the center have the potential for impact in automated screening and/or probe development?

Approach: Does the center-driven component: a) clearly define a plan to investigate and overcome the restriction?; b) describe project(s) based on the plan that could lead to a resolution of the problem; c) describe an alternative approach if the first plan were to fail; and d) describe clearly a method to quantitatively measure progress and milestone achievements over the course of the research project.

Investigators: Are the qualifications of the PD/PI and key personnel appropriate for undertaking a high impact, potentially high risk center-driven project? Is the work proposed appropriate to the experience level of the center director and key personnel?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

Milestones and timeline: Quantitative milestones should be included for assessing progress and success achieved by user-driven and center-driven components of the Center for each year. The description may be accompanied by a graphic representation (timeline). The reasonableness of the proposed milestones and timeline will be evaluated during review and will be used in the future to assist the NIH in evaluating progress toward the project's goals. Applicants should present explicit, quantitative milestones.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

The willingness of applicants to abide by the NIH Data Sharing and IP in the MLP (http://www.nimh.nih.gov/dnbbs/datasharing-ip.pdf) and the reasonableness of the plan for sharing any other types of research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

2.D. Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131).

Investigators responding to this announcement should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans in meeting the programmatic goals will be considered by NIH staff in making the awards.

3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement U54, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator (PI) of the center will coordinate project activities scientifically and administratively at the awardee institution. The PI will have primary responsibility for defining the details for the projects within the guidelines of this FOA, and for performing all scientific activities. The PI will agree to accept the close coordination, cooperation, and participation of the NIH staff (MLPCN Program Officials, Project Scientists, the Network Science Officers, the Project Team Leader, and the MLP Project Team) in those aspects of scientific and technical management of the project as described below.

Specifically, the PI of this MLPCN center will:

1. Determine experimental approaches, design protocols, set project milestones, conduct experiments, and analyze and interpret research data.

2. Provide goals for assay optimization, screening throughput, quality, and cost to the NIH Program Official and Project Scientist as requested (usually at the outset of the award and in six-month progress reports, but also at other times as requested by the Program Official and Project Scientist).

3. Serve on the MLPCN Steering Committee, and participate, along with critical staff, in the MLPCN Steering Committee meetings held three times annually, at least one time/year in the metropolitan Washington, DC area.

4. Adhere to MLPCN policies regarding data release, IP, publications, and other policies that might be established, as agreed upon by the MLPCN Steering Committee and the MLP Project Team.

5. Ensure that primary and secondary screening data, assay protocols and chemical data on compound probes and analogs are deposited in a centralized public database (e.g., PubChem or other, as specified by the NIH Program Official and Project Scientist) according to the timeline agreed upon by the MLPCN Steering Committee and the MLP Project Team, and that resources developed as a part of this project (e.g., information about assays and chemical probes) are made publicly available according to MLPCN policies.

6. Accept and implement all scientific, practical, and policy decisions approved by the MLPCN Steering Committee and the MLP Project Team.

7. Submit data for quality assessment in any manner specified by the MLPCN Steering Committee, MLP Project Team, or ESP.

8. Submit periodic (e.g., six-month and annual) progress reports in a standard format, as agreed upon by the MLPCN Steering Committee and MLP Project Team.

9. Share research resources, tools, and data of interest with other MLPCN centers, as agreed upon by the MLPCN Steering Committee and MLP Project Team.

10. Agree not to disclose confidential information obtained from other members of the MLPCN network.

11. Be prepared for annual administrative site visits by NIH staff.

2.A.2. NIH Responsibilities

An MLPCN Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

Project Scientist Responsibilities The MLPCN Project Scientists are NIH extramural program scientists who will have substantial scientific involvement during the conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants. This includes facilitating the partnership relationship between NIH and the MLPCN centers funded under this RFA, helping to maintain the overall scientific balance in the program commensurate with new research and emerging research opportunities, and ensuring that the activities of the MLPCN centers are consistent with the mission of the NIH MLP. However, the role of the Project Scientist will be to facilitate and not to direct. Each MLPCN center will have one designated Project Scientist, and a given Project Scientist may be assigned to multiple centers.

The MLPCN Project Scientists will have the following substantial involvement:

1) Provide ongoing coordination and tracking of the activities of individual MLPCN centers.

2) Provide relevant scientific expertise and overall knowledge.

3) Assist in the integration of the individual MLPCN centers into a research network, including coordinating regular conference calls for sharing of approaches and fostering inter-center collaborations.

4) Develop a plan for distribution of assays to specific centers within the Network on the basis of peer review of assay proposals received in response to PAR-06-545(R03) and PAR-06-259(X01), through the Fast Track process for completed Assay Development awardees (RFA-RM-04-023 (R21)) and future HTS assay solicitations, the MLP Project Team’s prioritization of assays acceptable for implementation, and information about available capacity and expertise of each center.

5) Participate, as a voting member, with the other MLPCN Steering Committee members in the group process of setting research priorities and milestones, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Project Scientist will assist and facilitate the group process and not direct it.

6) Develop, with input from the MLPCN Steering Committee and the MLPCN Project Team, progress report formats (six-month and annually) for both individual centers and for the Network.

7) Participate in the ESP meetings.

8) Serve as scientific liaison between the awardees, other NIH program staff, and the MLPCN Project Team.

9) Report periodically (e.g., monthly) on the progress of the MLPCN program to the MLPCN Project Team.

10) Assist in developing timelines for the wide distribution of screening data to the scientific community in accordance with the decisions of the MLPCN Steering Committee and the Project Team.

11) Assist in avoiding unwarranted duplication of effort across the MLPCN network, and help coordinate collaborative research efforts that involve multiple centers.

12) Review and comment on critical stages of MLPCN development for presentation to the MLPCN Project Team and External Scientific Panel before subsequent stages are implemented.

13) Retain the option to recommend, with the advice of the External Scientific Panel, additional research endeavors within the constraints of the approved research and negotiated budget to the MLPCN Project Team.

14) Retain the option to recommend, with the advice of the External Scientific Panel, re-allocation of NIH support among awardees, as scientific goals evolve.

15) To help carry out these duties, Project Scientists may consult with non-NIH experts in the field.

Network Science Officer Responsibilities The MLPCN Network Science Officers are NIH extramural program staff who will work as a team with the MLPCN Project Scientists to: 1) provide a broad base of scientific expertise to assist in oversight of the MLPCN research network in areas such as HTS approaches, detection platforms, assays, lead optimization chemistry, cheminformatics, and compound management of the repository at the programmatic management level; and 2) serve as a resource to other NIH extramural staff about the procedures and progress of the MLPCN program.

The MLPCN Network Science Officer will have the following involvement:

1) Assist the awardees, in conjunction with the Project Scientists, as needed.

2) Provide relevant scientific expertise and overall knowledge about specific aspects of MLPCN operations to the Project Scientists.

3) Serve as subject matter experts to assist other NIH program staff in providing advice to investigators about the MLPCN program.

4) Assist the Project Scientists in reviewing critical stages of development in the research program for presentation to the Project Team and ESP to make determinations regarding the implementation of subsequent stages.

5) Facilitate interactions between the awardee and investigators at other institutions.

6) Work with the center and the assay provider in the development of the CPDP.

7) Provide information about ongoing NIH-supported research and resources, and recommend the development of MLP-related initiatives to the Project Team.

8) Participate with the other MLPCN Steering Committee members in the group process of setting research priorities and milestones, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted in a non-voting liaison member role.

9) Two representatives of the Network Science Officers will participate in External Scientific Panel meetings to review and evaluate the progress of the centers in meeting their individual and collective milestones as non-voting liaison members.

Program Official Responsibilities: The MLPCN Program Official is an NIH program staff member who will have responsibility for normal program oversight and stewardship of the MLPCN centers on behalf of the MLPCN Project Team.

The Program Official will have the following involvement:

1) Approval of progress reports and support for out-years, on behalf of the Project Team, for the U54 cooperative agreements that comprise the MLPCN network.

2) Have the option to recommend, following consultation with the Project Scientists, the Project Team Leader, the Project Team, and the ESP, the withholding or reduction of support from any center that substantially fails to achieve its goals according to the milestones agreed to at the time of the award fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award for either the user-driven or the center-driven components.

3) Have the option to recommend, following consultation with the Project Scientists, the Project Team Leader, the Project Team, and the ESP, an increase in support for any center that substantially exceeds its goals according to the milestones agreed to at the time of the award and substantially improves state-of-the-art capabilities for either the user-driven or the center-driven components.

4) Participate in the MLPCN Steering Committee meetings as an ex officio (non-voting) member.

5) Carry out continuous review of all activities to ensure objectives are being met.

Project Team Leader Responsibilities The MLPCN Project Team Leader is an NIH program staff member who will have responsibility for coordinating the activities of the MLPCN Project Team and interactions with the MLPCN centers. The Project Team Leader may also serve as a Program Official.

The MLPCN Project Team Leader will have the following responsibilities:

1) Chair the MLP Project Team.

2) Participate in the MLPCN Steering Committee meetings as an ex officio (non-voting) member. Provide materials to the ESP needed to review and evaluate the progress of the centers in meeting their individual and collective milestones.

3) Ensure that a concise summary of the ESP meetings is provided to the panel members, center PIs, Program Officials, Project Scientists, Network Science Officers, and MLP Project Team.

4) Carry out continuous review of all activities to ensure objectives are being met.

MLPCN Coordination Working Group (CWG) The Coordination Working Group (CWG) will be established by NIH to provide a range of important services to the MLPCN. Working Group membership will be NIH program staff. The Working Group will assist in the organization and administration of the network functions and operations provided by the centers and report its findings and proposals to the MLP Project Team.

The Coordination Working Group will have the following involvement:

1) Identify best practices for network integration of center operations and communication.

2) Assist in the resolution of Network problems and provide administrative support for the MLPCN Steering Committee meetings and Steering Committee Work Group meetings.

3) Provide tracking of activities of the MLPCN, its component screening centers and investigator provided assays through the intra-network Common Assay Reporting System (CARS).

4) Maintain CARS and a MLPCN website that will provide up-to-date information on assays accepted for implementation in specific MLPCN centers, compounds accepted for entry into the MLSMR, overall progress of the network towards meeting its milestones and goals, list of new Network probes and notable data depositions to PubChem.

5) Provide monthly updates to the NIH Project Team and the MLIIG on Network status and the progress of each network center.

6) Oversee assignment of assays from the research community to the MLPCN centers.

MLP Project Team Responsibilities The MLP Project Team will serve as the trans-NIH body overseeing and coordinating MLPCN activities. Project Team membership will include one or more representative(s) from each of the NIH Institutes and Centers (IC) participating in the Molecular Libraries. Program Officials, Project Scientists and Network Science Officers can be members of the MLP Project Team. Each participating NIH IC will have a single vote on the Project Team, no matter how many members from the NIH IC are involved. The Project Team Leader will chair meetings and serve as the Project Team Leader of the MLPCN centers on behalf of the MLP Project Team. The Project Team will receive recommendations from the MLPCN Steering Committee and will be overseen by the MLIIG.

The MLP Project Team will have the following involvement:

1) Review and implement MLPCN guidelines and policies based on recommendations from the MLPCN Steering Committee.

2) Communicate, through its chair, policy information to the MLPCN Steering Committee, Small Molecule Repository, PubChem, and the MLIIG.

3) Select HTS assays for assignment to the MLPCN centers on the basis of scientific merit, significance of the biological target or cellular phenotype, need for small molecule probes, and program priorities.

4) Monitor the progress of HTS and probe development for individual assays to determine the appropriateness of the use/continued use of MLPCN resources (e.g., for implementing particularly difficult assays, or developing chemical probes)

5) Oversee the addition of new compounds to the MLSMR.

6) Evaluate progress of the MLPCN program in consultation with the ESP and the CWG.

7) Attend the ESP meetings and MLPCN Network meetings.

2.A.3. Collaborative Responsibilities

MLPCN Steering Committee Functions The MLPCN Steering Committee is the operational group responsible for coordination of the activities of the MLPCN centers and the committee through which the Project Team interacts with the MLPCN Network. The MLPCN Steering Committee will identify scientific and policy issues that need to be addressed at the Network level, develop recommendations to the Project Team for addressing such issues, coordinate the primary recommendations for assay distribution within the Network, and coordinate the dissemination of screening data, assay protocols, and other materials with the wider scientific community.

The MLPCN Steering Committee membership will include the PI of each of the centers, the Project Scientists, and two representatives of the Network Science Officers. The PI of the MLSMR, the PubChem designee, Program Officials, and the Project Team Leader will be ex officio (non-voting) members.

The PI of each center (or designee) will have one vote on the MLPCN. The Project Scientists and Network Science Officers may vote, but the total votes will count as a maximum of one-third of the total MLPCN votes. Membership on the Steering Committee becomes effective upon issuance of the Notice of Award. The MLPCN Steering Committee may establish additional subcommittees or workgroups for specific tasks. No NIH staff member may chair any committee or subcommittee.

The MLPCN Steering Committee will:

1) Convene at least three times per year. The purpose of these meetings is to assess scientific progress, identify new research opportunities, establish priorities, consider policy recommendations, and discuss strategies. One of the meetings will be in conjunction with the annual meeting of the ESP to allow the MLPCN center Directors to meet directly with the ESP.

2) Make decisions by a majority vote of a quorum, with an attempt for a consensus. A quorum will be the presence of a majority of the center PIs or their designees, at least one Project Scientist, one Program Official, and the Project Team Leader. Outside consultants/experts may be asked to participate in these discussions as nonvoting advisors.

3) Establish a chair, or workgroups for specific tasks; the Program Officials, Project Scientists, Network Science Officers, and Project Team Leader may not chair any committee or workgroup.

4) Hold conference calls of the full committee and any workgroups as needed; monthly calls are anticipated in the first year of the program.

5) Develop recommendations for guidelines and policies for quality control and quality assurance of assay validation, screening, data reliability and quality, and chemical probe optimization; implement and monitor quality control/quality assurance procedures to assure consistency across centers.

6) Develop recommendations for a set of minimal characteristics that will have to be met in order to designate a compound as a chemical probe, which is operationally defined as the final product of the MLPCN center’s activity in the context of the MLP program.

7) Develop recommendations for guidelines for optimization of candidate compounds within the goals of the MLPCN program.

8) Develop recommendations for guidelines for standardizing the reporting of screening data and protocols for different types of assays to PubChem; develop policies to facilitate the timely deposition of screening data and protocols to PubChem in accordance with the MLP data release policy.

9) Serve as a venue for coordination on improving the state-of-the-art HTS in the academic sector by reporting progress, disseminating best practices, and collectively evaluating new procedures, resources, and technologies.

10) Identify opportunities to increase the inter-operability of centers in the Network; centers will be expected to have a high degree of flexibility and be willing to adopt uniform policies and procedures recommended by the Steering Committee and approved for implementation by the MLP Project Team.

11) Develop recommendations for guidelines for publication of screening data, assay protocols, chemical probe optimization, HTS technology development, and global data analyses, etc. resulting from the MLPCN effort.

12) Address recommendations made by the External Scientific Panel and approved for implementation by the MLP Project Team.

13) Each MLPCN Center will be expected to use the model agreement language approved by the MLPCN Steering Committee for transfer of assays, compounds, and materials into the individual MLPCN Centers.

External Scientific Panel (ESP): The ESP will be responsible for reviewing and evaluating the progress of the MLPCN centers in meeting their individual and collective milestones and goals, and making recommendations about the progress and directions of the MLPCN network and individual centers to the MLP Project Team and the MLIIG Working Group. The ESP will be composed of 6-8 senior non-federal scientists who are not directly involved in the activities of the MLPCN. The MLP Project Team will appoint members to the ESP. The MLP Project Team will select one member as chair. The MLPCN Program Officials, Project Scientists, Project Team Leader, Network Science Officers, and MLP Project Team members may attend the External Scientific Panel meetings as non-voting participants.

The ESP will have the following involvement:

1) The chair will schedule, develop agendas, and oversee the annual meetings and conference calls. The membership of the Panel may be enlarged permanently, or on an ad hoc basis by action of the original members.

2) The External Scientific Panel will meet in person at least once a year and by conference call quarterly. During part of this meeting, there will be a joint meeting with the MLPCN Steering Committee to allow the Panel members to interact directly with the MLPCN center PIs, and the PIs of the MLSMR, and PubChem.

3) The ESP will review progress of the MLPCN network and individual centers, and make recommendations regarding any changes that may be needed in the direction of the MLPCN program to the MLP Project Team and the MLIIG Working Group.

4) The ESP will be consulted by the Project Scientists and Project Team Leader when changes in a center’s funding level are being considered because of either outstanding or poor technical performance, or for other reasons.

5) Any MLPCN center PI who considers a MLPCN Steering Committee decision unacceptable may appeal to the ESP.

6) ESP members will be invited to attend as observers to the thrice-annual meetings of the MLPCN Steering Committee.

2.A.6. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. The three members will be: a designee of the MLPCN Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. In the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

3.A. Progress Reviews/Milestones and Evaluations

The progress of the MLPCN centers will be reviewed periodically by the NIH Program

Official(s) and the MLP Project Team to assure that satisfactory progress is being made in achieving the project objectives. During the first year of funding, and during subsequent years if deemed necessary by the Program Officer(s) and the MLP Project Team, reviews may be more frequent. The adherence of the MLPCN centers to the approved data sharing plan and IP plans, which will be part of the Terms and Conditions of award, will also be reviewed annually. Should problems arise in the conduct of the study, the NIH Program Official(s) may require that the center awardee submit more frequent reports on progress and fiscal matters.

The progress report will have two components. The first will be the standard NIH progress report (Form 2590). The second will be a more specialized report that will be developed by the MLPCN Steering Committee in collaboration with the MLP Project Team. This specialized report should be included as an attachment to the standard progress report and will go to the NIH Program Officer(s) and the MLP Project Team. The contents or the report may be changed according to programmatic needs, based on discussion between NIH Program Officers, the center PI, and the MLPCN Steering Committee.

The center awardees' yearly milestones will be provided to the Project Scientists(s), the MLP Project Team, the MLPCN Steering Committee, the MLIIG Working Group, and the ESP. It is expected that the milestones will be adjusted annually at the award anniversary dates, both to incorporate the group's scientific accomplishments and progress, as well as to reflect any recommendations of the MLP Project Team and the ESP. Following the review of milestones, the MLP Project Team may recommend reducing or withholding funds for any center/center project that substantially fails to meet its milestones or, if the situation warrants, augmenting any center/center project. However, simply meeting milestones may not be considered sufficient accomplishment for maintaining funding at the initially committed level for the user-driven and center-driven components. Failure to remain at state-of-the-art will also be considered grounds for reduction in funding levels.

The center-driven programs will be evaluated at two-year increments in addition to the customary NIH annual progress reports. Evaluation of both project progress and continuing importance of the original program goals will be carried out by the ESP and NIH program staff, with input from outside experts, at the end of year 2 and 4 of the grant period. Funding for the center-driven components of the U54 cooperative agreement may be adjusted on the basis of the outcome of that review. In addition, the center-driven component as well as the user-driven component of each center will be part of the overall MLP Mid-course Review that will occur near the end of the third year of the grant period. These evaluations and the mid-course review will be crucial in establishing a specific, concrete and successful set of outcomes for the MLPCN over the project period.

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

1. Scientific/Research Contacts:

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: Direct your questions about scientific/research issues to:

Ingrid Li, Ph.D.
NIH Molecular Libraries & Imaging Roadmap
National Institute of Mental Health
6001 Executive Blvd, Room 7192, MSC 9641
Bethesda, MD 20892-9641
Telephone: (301) 443-7099
Fax: (301) 402-4740
Email: [email protected]

Carson Loomis, Ph.D.
NIH Molecular Libraries & Imaging Roadmap
National Human Genome Research Institute, NIH
Division of Extramural Research
5635 Fishers Lane, Ste. 4076, MSC 9305
Bethesda, MD 20892-9306
Tel: 301-594-5936
Fax: 301-480-2770
Email: [email protected]

2. Peer Review Contacts:

Direct your questions about peer review issues to:

Joseph G. Rudolph, Ph.D.
Scientific Review Officer
Integrative, Functional and Cognitive Neuroscience IRG
Center for Scientific Review
National Institutes of Mental Health
6701 Rockledge Drive, MSC 7844
Bethesda, MD 20892-7844
Tel: 301-435-2212
Email: [email protected]

3. Financial or Grants Management Contacts:

Direct your questions about financial or grants management matters to:

Victoria Carper
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6118, MSC 9605
Bethesda, MD 20892-9604
Tel: 301-443-3858
Email: [email protected]

Monika Christman
Grants Administration Branch
National Human Genome Research Institute
5635 Fishers Lane, Suite 4076, MSC 9306
Bethesda, MD 20892-9306
For overnight courier service use Rockville, MD 20852
Telephone: (301) 435-7860
Email: [email protected]

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

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 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 funding opportunity 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.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for 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 at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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