and Human Services (HHS)
EXPIRED
Department of Health and
Human Services
Participating Organizations
National Institutes of
Health (NIH), (http://www.nih.gov/)
Components of Participating Organizations
This FOA is developed as an
NIH Roadmap initiative (http://nihroadmap.nih.gov).
All NIH Institutes and Centers participate in Roadmap initiatives. The
FOA will be administered by the National Institute of General Medical Sciences
(NIGMS/NIH), (http://www.nigms.nih.gov)
on behalf of the NIH.
Title: Pilot-Scale Libraries (PSL) for High-Throughput
Screening (P41)
Announcement Type
This is a reissuance of RFA-RM-05-014,
which was previously released on November 18, 2004 and of RFA-RM-06-003,
which was previously released on December 8, 2005.
Update: The following update relating to this announcement has been issued:
Request For Applications (RFA) Number: RFA-RM-08-003
Catalog of Federal Domestic Assistance Number(s)
93.310
Key Dates
Release Date: November
15, 2007
Letters of Intent Receipt
Date(s): December
12, 2007; December 12, 2008
Application Receipt Date(s): January 15,
2008; January 8, 2009
Peer Review Date(s): May-June 2008; May-June 2009
Council Review Date(s): August 2008; August2009 - (New Date October 2009 per NOT-RM-09-005)
Earliest Anticipated Start
Date: September 2008;
September 2009 - (New Date December 1, 2009 per NOT-RM-09-005)
Additional Information To Be
Available Date (Url Activation Date): N/A
Expiration Date: January 9, 2009
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
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
Background
The NIH Roadmap, overseen by the NIH Office of Portfolio Analysis and Strategic Initiatives (OPASI), is a series of initiatives designed to pursue major opportunities in biomedical research, as well as gaps in current knowledge that cannot be addressed by any single NIH institute or center on its own, but that must be addressed by the agency as a whole. The ultimate goal is to enable the rapid transformation of new scientific knowledge into tangible benefits for public health (http://nihroadmap.nih.gov/). The Molecular Libraries and Imaging Initiative (MLI) (http://nihroadmap.nih.gov/molecularlibraries/) is a component of the New Pathways to Discovery theme of the Roadmap (http://nihroadmap.nih.gov/newpathways/). The MLI will be known as the Molecular Libraries Program (MLP) in the production (i.e., post-pilot) phase.
The last decade has witnessed major breakthroughs in the identification of genes, gene products, metabolic pathways, and signaling pathways, as well as progress in miniaturization and robotics, enabling the development of high-throughput, mechanism-based biological assays. The new assays have, in turn, facilitated the discovery of small molecules with powerful physiological effects. While high-throughput screening (HTS) of small-molecule libraries is a standard approach in the pharmaceutical industry, the goal of the MLP is to facilitate the use of HTS and chemical libraries within the academic and nonprofit community. It is anticipated that the ML initiative will produce research tools (including novel small-molecule modulators of biological function) for the study of fundamental biology. It also will continue to yield large amounts of data, in a publicly-accessible format, enabling scientists to test hypotheses that correlate biological function with specific regions of chemical structure space. (http://nihroadmap.nih.gov/molecularlibraries/index.asp; http://www.nature.com/horizon/chemicalspace/index.html).
This particular FOA is part of the Chemical Diversity Technology Development effort, which is a major component of the MLP. Other components of the MLP currently include:
1) the Molecular Libraries Screening Center Network (MLSCN), which provides innovative HTS capacity for implementing assays that are submitted by the research community. The MLSCN also conducts medicinal chemistry to optimize these molecules as biological probes (http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-017.html). In the Production Phase of the MLP, the MLSCN will be phased out, and HTS and medicinal chemistry will be conducted via the Molecular Libraries Probe Production Centers Network (MLPCN).
2) the NIH Molecular Libraries Small-Molecule Repository (MLSMR; http://mlsmr.glpg.com/MLSMR_HomePage/identify.html), which currently possesses approximately 150,000 compounds obtained from both commercial and academic sources. Ultimately it will house a collection of up to 500,000 chemically diverse small organic molecules (http://grants.nih.gov/grants/guide/notice-files/NOT-RM-04-003.html).
3) PubChem: a public sector database that provides information on the biological activities of small molecules, including the compounds in the SMR and the biological data generated by the MLSCN/MLPCN (http://pubchem.ncbi.nlm.nih.gov/).
4) the development of related technologies.
The ML effort differs from HTS efforts in private industry and others in academic settings in several ways. First, the purpose of this NIH program is not the identification of compounds with therapeutic properties but the identification of a very large number of compounds for use as probes to study cellular processes. This involves screening a greater diversity of small molecules in assays encompassing a broader range of novel biological targets and phenotypes. Second, the biological screening data, assay protocols, and a minimal amount of chemical data for compounds tested in the MLSCN/MLPCN (see below) are publicly accessible via the PubChem database. Data-sharing with the larger scientific community represents a new paradigm that leverages the MLP’s investment and empowers the scientific community broadly. Third, the MLP facilitates, but does not engage in, the much more difficult and expensive process of drug development. The MLP complements private sector drug development efforts by contributing to the identification and validation of novel drug targets, as well as small molecule classes with potential for development into therapeutics. The benefits to public health, especially for rare or marginalized disorders, are evident.
Objectives of the Project
The goal of this FOA is to solicit applications for chemical library generation, in order to increase the diversity and the uniqueness of the collection in the MLSMR.
The pilot-scale libraries (PSL) generated under this FOA will be submitted to the MLSMR and then to the MLSCN/MLPCN for HTS evaluation. When a PSL exhibits an encouraging pattern of biological activity, a decision may be made to more fully explore the pertinent region of chemical structure space. It is likely that grantees under this initiative will be given the opportunity to participate in followup studies of compounds that they submit that show up as actives in HTS.
Since the goal of the MLP is to identify novel small molecule effectors of biological function, it is crucial that library designs be driven by biological considerations rather than by chemical methodologies. Design motifs for synthetic libraries must be supported by objective criteria such as computational evaluation or preliminary biological testing of representative examples. Such supporting data need not have been generated by the applicant but may come from the literature.
Furthermore, since the goal is to identify effectors of truly novel biological phenotypes and mechanisms, it is important that the compounds produced under this FOA represent chemotypes that are distinct from what is available commercially and from those that are already in the MLSMR. The applicant must describe procedures that will be used to assess the uniqueness of the proposed libraries.
In contrast to the NIGMS Centers of Excellence in Chemical Methodologies and Library Development (CMLD; http://www.nigms.nih.gov/Initiatives/CMLD), the focus of this RFA is on the generation and provision to NIH of novel libraries rather than on methodology development.
Approaches Being Sought to Achieve the Objectives
This FOA does not specify the means by which the libraries are to be assembled. In fact, various approaches may be envisioned, including: 1) high-throughput (HT) synthesis (often referred to as combinatorial chemistry, combichem, or diversity-oriented synthesis); 2) isolation and purification of compounds from living organisms (natural products), including compounds isolated from their natural sources, as well as natural products and their analogs made by use of genetic engineering or semisynthesis; and 3) target-oriented synthesis (including the synthesis of analogs of a natural product or other lead compound).
HT synthesis is a process by which multiple compounds (chemical libraries) are generated simultaneously, in a predictable fashion, by techniques that involve parallel chemical transformations. HT synthesis may use solid- and/or solution-phase reaction and product isolation techniques. A library produced by HT synthesis may be small (e.g., a few compounds) or large (e.g., thousands or even millions of compounds), and it may focus on a narrow or wide range of "chemical diversity space.
Natural products may come from microorganisms or from higher organisms such as plants or marine invertebrates. There is general agreement that most natural products have evolved as chemical defense substances, enhancing the survival of the organisms that produce them. Thus, it is not surprising that a great number of approved drugs are themselves natural products, are derived from natural products, or were inspired by natural products.
Traditionally, natural products are isolated directly from their natural sources. However, recent developments have led to alternative sources of some natural products and natural product analogs. For instance, certain microbial metabolites may be produced by engineered organisms, including heterologous hosts. Similarly, by genetic manipulation of the genes that encode the biosynthetic machinery, pathways may be adapted so as to yield natural product analogs.
It is anticipated that libraries of natural products will be an especially rich source of bioactive small molecules with potentially broad utility as probes of biological mechanisms. Furthermore, it is expected that unique source organisms will give rise to new structural classes of natural products with unprecedented bioactivities. Libraries of such compounds should be especially valuable for HTS by the MLSCN/MLPCN. Obtaining libraries of natural products and natural product analogs is a high priority for the NIH.
In addition to providing a platform for the development of new chemical methodologies, a prime motivation for the synthesis of complex molecules is the investigation of biological activities. Accordingly, many synthetic strategies are devised so as to be short (i.e., relatively few reaction steps), efficient (i.e., high-yielding and highly specific), and readily adaptable to the synthesis of key analogs. Potential applicants under this FOA should note that it is the desire of the NIH to obtain substantial numbers of novel small molecules via this FOA. Additionally, the ease of resupply and ready access to analogs are important considerations.
Experts have estimated that "chemical diversity space" may encompass 10^60 small-molecule structures (i.e., molecular weights up to 500). By comparison, fewer than 10^8 small-molecules have ever been synthesized or isolated from natural sources. Given the tiny fraction of chemical diversity space that thus far has been probed for biological activity, it is important that library design be underpinned by a strong biological rationale. Applicants should describe the process by which regions of chemical diversity space will be selected for study, as well as the general rationale for design of their pilot-scale libraries. Structural complexity per se, or synthetic accessibility will not suffice in the absence of a compelling biological rationale. For synthetic libraries, the biological rationale must be supported by objective criteria such as computational modeling or preliminary biological screening of representative or related molecules.
Note that PubChem or other chemical databases may be useful for gauging the need for libraries representing particular regions of chemical diversity space. The applicant must discuss the specific approach to be used for assessing the uniqueness of proposed libraries. While libraries submitted in response to this initiative need not be drug-like in the usual sense (since the goal of the MLP is not drug discovery), chemical stability under both HTS and storage conditions is very important. Also, compounds with inherently reactive functional groups e.g., potent alkylating or acylating agents (see http://mlsmr.glpg.com/MLSMR_HomePage/pdf/MLSMR_Excluded_Functionality_Filters_200605121510.pdf) as well as compounds that are prone to nonspecific aggregation (see, for example, J. Med. Chem. 2003, 46, 4265-4272) are undesirable.
In the context of this FOA, a typical PSL might include 10-30 compounds. This will afford (a) adequate structural diversity for evaluation of the library design concept; and (b) a minimal amount of structure-activity relationship (SAR) information, so as to provide a basis for deciding whether further exploration of the particular region of chemical diversity space is warranted. In certain cases for example, natural products from rare organisms, where there is a high probability of discovering unprecedented chemical structures and bioactivities smaller libraries may be justified.
NIH is not specifying the total number of compounds to be submitted over the course of the project. As is the case for library size, in certain cases for example, natural products from rare organisms, where there is a high probability of discovering unprecedented chemical structures and bioactivities but great effort may be required to produce and isolate these compounds smaller numbers may be adequate.
The MLSMR will accept only discrete, well characterized compounds. While racemates are acceptable, mixtures (including mixtures of diastereomers) cannot be accepted. This is due to the additional effort that would be required to deconvolute HTS hits (i.e., identify which component of a mixture is responsible for a hit) as well as the challenges of carrying out routine quality control in the MLSMR (see below).
Samples are to be submitted as dry films or powders, and bar coded sample vials will be provided by the MLSMR. The grantee should verify in good faith that none of the compounds submitted to the MLSMR has restrictions that will impair the distribution and use of the compounds by the MLPCN.
In order to minimize false positives in HTS assays, a high premium will be placed on analytical purity. Applicants should state specifications for acceptable levels of purity (ordinarily, at least 90%) and should describe analytical as well as preparative methods. Unless a compelling justification is provided, preparative chromatographic purification (or purification by another method that will remove chromatographic baseline impurities) of all samples is required.
In order to streamline the process of sample acceptance into the MLSMR and distribution to the screening centers, PSL grantees will be required to submit up-to-date analytical data to document the structures and the purities of the samples that they submit. Analytical data must be submitted along with the samples and must have been obtained in the 90 day period prior to sample submission.
The MLSMR will perform analytical chemistry/quality control (QC) on all compounds entering the collection and periodically will perform QC on a representative sampling of compounds already in the collection. The MLSMR s standard protocols for evaluation of weight, solubility, identity, and purity are as follows, although improved procedures will be implemented, as appropriate. These procedures are designed to provide maximum versatility and accuracy, consistent with the demands of building and maintaining a large sample collection. Commercial solvents (chloroform, methanol, DMSO, etc.) are used by the MLSMR without any additional purification. Solvent specifications may be obtained from the MLSMR.
Weight: Each sample will be dried to a constant mass under vacuum (pressure < 5 millibar) at 25 35 C and weighed. Dried samples must meet the minimum weight requirement in order to be accepted.
Solubility: Each 10 mg sample will be mixed with 2 mL of a solvent mixture comprising 90:10 chloroform:methanol; samples that dissolve completely will be accepted. If the sample does not dissolve completely then it will be concentrated to dryness and mixed with DMSO; only samples that dissolve completely will be accepted. If the compound provider believes that there is a possibility that the compounds will be incompatible with chloroform:methanol, samples can be solubilized directly in DMSO. Samples that are dissolved in DMSO will not be concentrated to dryness for long-term storage but will be maintained in DMSO solution.
Identity and Purity: For samples that are soluble in 90:10 chloroform:methanol, an aliquot of the chloroform:methanol solution corresponding to approximately 0.05 mg of the solute will be concentrated to dryness. The residue will be dissolved in 200 microliters of a solvent mixture consisting of 97:3 methanol:DMSO and analyzed by LC-MS. Samples that are insoluble in 90:10 chloroform:methanol but soluble in DMSO will be sampled for LC-MS directly from the DMSO solution. Sample molecular weight will be determined using (at MLSMR’s discretion but after discussion with the compound provider) electrospray, chemical ionization, or photoionization in positive ion mode or negative ion mode or both. Purity will be determined by relative area under the curve (AUC) using UV (214 nm) and evaporative light scattering detection (ELSD). The MLSMR will accept samples for which the molecular ion is correctly identified to within 0.5 amu and for which the sample purity is at least 90% by UV and/or ELSD. The default LC modifier is trifluoroacetic acid (TFA); MLSMR will employ basic modifiers (ammonium carbonate or ammonium acetate) when specified by the supplier at the time of sample submission.
Applicants should indicate in their proposals whether any aspects of this quality control process are likely to be incompatible with the proposed libraries and, where possible, should discuss appropriate, alternative analysis methods.
Compounds in the MLSMR will be subjected to a large number of HTS assays, and so unless there is a compelling justification to the contrary, each compound must be supplied in a quantity of no less than 10 mg. When HTS assay results call for it, additional quantities and/or analogs may be needed. While supply of these additional materials is not a specific goal of this RFA, it is highly desirable that resupply of compounds and the generation of analogs be readily achievable. Thus, compounds submitted to the MLSMR must be accompanied by documentation indicating their origin, such as synthesis protocols.
Analogs of synthetic compounds may be substantially easier to make than analogs of natural products. However, since natural products have evolved for their biological activity, it is likely that minimal SAR optimization will be required to generate useful biological probes. For this reason, the ease of generating analogs will not be a major factor in the evaluation of natural product libraries.
As stated, the goal of the MLP is to produce large numbers of novel small molecule probes for studies of fundamental and applied biology. It is expected that hits identified through HTS will be insufficiently potent and/or selective to qualify as probes, thus necessitating additional optimization via medicinal chemistry. In order to optimize the use of medicinal chemistry resources within the MLP, PSL grantees should expect to be asked to participate in the optimization of compounds that they provide to the MLSMR. The MLP will benefit from the experience and skills of the PSL grantees, and the grantees will have the opportunity to participate in a larger scientific undertaking, with joint publication a likely outcome.
NIH is not specifying the number of libraries to be submitted each year by a PSL grantee. It is a goal of the MLP to assemble a large number of unique, potentially bioactive small molecules for the MLSMR. However, it is critical that the libraries submitted under this RFA be thoughtfully designed, well characterized, and provided in good quantity (vide supra). An applicant should provide a clear and well-justified estimate of the total number of compounds and the number of unique libraries to be submitted to the MLSMR each year. These estimates will provide a basis for evaluation of the grant application as well as a benchmark for evaluating the actual output of each grantee. It is likely that libraries submitted to the MLSMR by grantees under this FOA will be accepted into the NIH small-molecule collection; however, this may not always be the case. For example, if a new library falls largely in a region of chemical diversity space that already is adequately represented in the collection, then it is unlikely that the new library will be accepted.
Applicants must discuss their proposed methodologies and strategies for the generation of high-quality libraries. The following are examples of topics that should be addressed:
basis
for predicting biological activity in proposed libraries;
methods for
assessing structural uniqueness;
chemical synthesis
strategies;
ease of
production of second generation analogs;
purification;
sample handling;
qualitative and
quantitative analysis of libraries and individual compounds;
sample storage;
archiving of
analytical data; and
plans for public
dissemination of information on the methodologies that are used.
Project Oversight
As part of the larger Molecular Libraries and Imaging Roadmap Initiative, projects funded under this RFA are subject to oversight and evaluation of each aspect of the effort.
THE MOLECULAR LIBRARIES AND IMAGING IMPLEMENTATION GROUP (MLIIG). The MLIIG comprises the directors of the National Human Genome Research Institute (NHGRI), the National Institute of Mental Health (NIMH), and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) as well as NIH staff who coordinate the major components of the Molecular Libraries and Imaging Roadmap Initiative. The MLIIG will provide overall guidance.
THE MLPCN PROJECT TEAM. The MLPCN Project Team, which is comprised of NIH staff, is the operational governing body for the network, reviewing and, upon concurrence, implementing guidelines and policies for the MLPCN. The MLSCN Project Team acts as a second-level of review for the distribution of assays to each of the screening centers and the acquisition of compounds for the MLSMR. The MLPCN Project Team reports to the MLIIG.
THE PILOT LIBRARIES PROJECT TEAM. The Project Team is the operational governing body for this initiative. It includes NIH staff from various Institutes and Centers who are actively involved in the management and implementation of this Roadmap initiative. The Project Team reports to the MLIIG.
Grantees under this RFA also will interact with the MLPCN Compound Acquisition Working Group. This group assists in oversight of MLSMR operations and in the development of the NIH Small-Molecule Collection. It also evaluates proposals for the acquisition of small molecules from commercial and noncommercial sources for the MLSMR. Recommendations on which of the libraries generated under this FOA will be accepted by the MLSMR may be made by this working group and will be communicated to the Pilot Libraries Project Team. As mentioned above, while it is likely that libraries submitted under this FOA will be accepted into the MLSMR, acceptance will not be automatic. Also, compounds may be eliminated from the collection if they are deemed expendable or if they are found to have properties that are incompatible with HTS.
Grantees under this RFA will be expected to use a Material Transfer Agreement (MTA) approved by the NIH MLPCN Project Team for transfer of compounds and any associated materials to the MLSMR for screening in assays selected for implementation within the MLPCN centers. For an example of the data sharing and IP terms used to transfer assays to the MLPCN centers, see the Material Transfer Agreement Model for Transferring Assays Selected for Implementation in the MLSCN (http://mli.nih.gov/collateral/13.pdf).
See Section VIII, Other Information - Required Federal
Citations, for policies related to this announcement.
Section
II. Award Information
1. Mechanism(s) of Support
This funding opportunity
will use the P41 award mechanism.
As an applicant, you
will be solely responsible for planning, directing, and executing the proposed
project.
This funding opportunity
uses the just-in-time budget concepts. It also uses the non-modular budget
format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).
A detailed categorical budget for the "Initial Budget Period" and the
"Entire Proposed Period of Support" is to be submitted with the
application.
2. Funds Available
On behalf
of the NIH Roadmap, the National Institute of General Medical Sciences (NIGMS)
intends to make two sets of awards under this RFA, one in Fiscal Year 2008, and
the other in Fiscal Year 2009. For each round, up to $2.5 million per
year will be committed, to fund approximately six new and/or competing renewal
grants in response to this FOA. An applicant may request a project period of up to three years and a budget for direct costs up to $250,000 dollars per year.
Although the financial
plans of NIGMS and the MLP provide support for this program, awards pursuant to
this funding opportunity are contingent upon the availability of funds and the
receipt of a sufficient number of meritorious applications.
Facilities and
administrative costs requested by consortium participants are not included in
the direct cost limitation, see NOT-OD-05-004.
Section
III. Eligibility Information
1. Eligible Applicants
1.A. Eligible Institutions
You may submit (an)
application(s) if your organization has any of the following characteristics:
Foreign
institutions are not eligible to apply and may not be included as
subcontractors or funded collaborators, as per the NIH Grants Policy Statement
(http://grants1.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600262)
1.B. Eligible Individuals
Any individual with the
skills, knowledge, and resources necessary to carry out the proposed research
is invited to work with their institution to develop an application for
support. Individuals from underrepresented racial and ethnic groups as well as
individuals with disabilities are always encouraged to apply for NIH support.
2. Cost Sharing or Matching
This
program does not require cost sharing as defined in the current NIH Grants Policy Statement.
The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing
3. Other-Special Eligibility Criteria
Applicants
may submit more than one application, provided each application is
scientifically distinct. Applications for new grants as well as competing
renewals and applications for supplementation of existing projects all are
eligible to compete. Resubmissions (formerly referred to as
revised applications ) of unfunded applications submitted in
response to previous versions of this FOA are welcome.
The NIH will allow applicants and their institutions to identify more than one
Principal Investigator (PI). The decision to apply for a single PI or a
multiple PI grant will be the responsibility of the investigators and the
applicant organization. Those decisions should be consistent with and
justified by the scientific goals of the project. As described in the
Background section below and on the Multiple Principal Investigator website at http://grants.nih.gov/grants/multi_pi/index.htm,
the NIH expects the availability of the Multiple PI option to encourage
interdisciplinary and other team approaches to biomedical research. For
additional information, see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-017.html.
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 GrantsInfo, 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(s): December 12,
2007; December 12, 2008
Application
Receipt Date(s): January 15,
2008; January 8, 2009
Peer Review
Date(s): May-June 2008; May-June 2009
Council Review
Date(s): August 2008; August2009
Earliest
Anticipated Start Date(s): September 2008; September 2009
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 at the beginning of this document.
The letter of intent
should be sent to:
John M. Schwab, Ph.D.
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
45 Center Drive, Room 2As.43A
MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-3827
FAX: (301) 480-2802
Email: [email protected]
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 photocopies
in one package 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 CSR and responsiveness by NIGMS (on behalf of the MLP). 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, resubmissions (formerly referred to as
revised applications ) of unfunded applications submitted in
response to previous versions of this particular FOA are welcome.
Information on the status of an application should be
checked by the Principal Investigator 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
This
funding opportunity uses the just-in-time budget concepts. It also uses the
non-modular budget format described in the PHS 398 application instructions
(see http://grants.nih.gov/grants/funding/phs398/phs398.html).
A detailed categorical budget for the "Initial Budget Period" and the
"Entire Proposed Period of Support" is to be submitted with the
application.
It is likely that grantees under this RFA will be invited to attend one meeting
per year of the MLPCN Steering Committee, for discussions among PSL grantees as
well as with MLPCN personnel. Applicants are advised to include
appropriate travel costs in their budgets.
Plan for Sharing Research Data
All applicants are
expected to include a plan for sharing research data in their applications. The
data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing.
All investigators responding to this funding opportunity should include a
description of how final research data will be shared, or explain why data
sharing is not possible.
The precise content of
the data-sharing plan will vary, depending on the data being collected and how
the investigator is planning to share the data. Applicants who are planning to
share data may wish to describe briefly the expected schedule for data sharing,
the format of the final dataset, the documentation to be provided, whether or
not any analytic tools also will be provided, whether or not a data-sharing
agreement will be required and, if so, a brief description of such an agreement
(including the criteria for deciding who can receive the data and whether or
not any conditions will be placed on their use), and the mode of data sharing
(e.g., under their own auspices by mailing a disk or posting data on their
institutional or personal website, through a data archive or enclave).
Investigators choosing to share under their own auspices may wish to enter into
a data-sharing agreement. References to data sharing may also be appropriate in
other sections of the 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.
For the
purpose of this FOA, the relevant data to be shared will include analytical
data as well as experimental protocols for sample preparation (e.g., chemical
synthesis, growth of producing organisms, compound isolation, purification).
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),
consistent with the programmatic goals of the MLP. Investigators responding to
this funding opportunity should include a plan for sharing research resources
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 will be considered by Program staff of the funding
organization when making recommendations about funding applications. The
effectiveness of the resource sharing will be evaluated as part of the
administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm).
See Section VI.3. Reporting.
It is
NIH's understanding that the utility of the resources and data generated by the
MLP will be maximized if they are treated as community resources and made
broadly available. To this end, and consistent with achieving the goals
of the MLP, NIH expects that (1) protocols for obtaining all libraries and
individual compounds that are submitted to the NIH under this FOA (via
synthesis, biosynthesis, or isolation from biological sources) will be made
readily available by publication in the scholarly literature and/or by posting
on the PSL grantee’s publicly accessible website; (2) data derived from biological
screening of these compounds by the MLPCN will be made readily available and
accessible via the PubChem database; and (3) molecular structures will be
uploaded to PubChem by the MLSMR immediately upon acceptance of samples into
the MLSMR.
It is NIH’s expectation that access to the MLPCN’s HTS data (via PubChem) will spur efforts to develop second-generation compounds with practical value, such as more advanced tools for biological investigation, or drug leads. Optimized, second generation compounds that are pursued independent of this FOA would not be subject to any special IP considerations. NIH recognizes that under the Bayh-Dole Act, awardees have the right to elect title to subject inventions and seek appropriate IP protection, and NIH would encourage appropriate intellectual property (IP) protection of compounds at those later stages of development.
Data sharing and IP plans should take all of the above considerations into account, consistent with achieving the programmatic goals of the MLP. Applicants should provide clear explanations and rationales for their plans, especially for any proposed plan that involves principles differing from those described in this FOA.
Grantees
under this FOA will be expected to use a Material Transfer Agreement (MTA)
approved by the NIH MLPCN Project Team for transfer of compounds and any
associated materials to the MLSMR for screening in assays selected for
implementation within the MLPCN centers. For an example, see http://mli.nih.gov/collateral/13.pdf.
Section
V. Application Review Information
1. Criteria (Update: Enhanced review criteria have been issued for the evaluation of research applications received for potential FY2010 funding and thereafter - see NOT-OD-09-025).
The following will be
considered in making funding decisions:
2. Review and Selection Process
Applications that are
complete and responsive to the FOA will be evaluated for scientific and
technical merit by an appropriate peer review group convened by the NIH Center for Scientific
Review (CSR) in accordance with the review criteria stated below.
As part of the initial
merit review, all applications will:
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? How likely are
the proposed strategies to result in the discovery of small molecules with
novel and significant bioactivities?
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, does the Leadership Plan ensure that
there will be sufficient coordination and communication among the
PDs/PIs? Are the administrative plans for the management of the research
project appropriate, including plans for resolving conflicts?
Will the proposed approach afford compounds in acceptable
quantities (at least 10 mg/compound) and acceptable purities (ordinarily, at
least 90%)? Are the proposed analytical methodologies adequate for
demonstrating the quality (i.e., identity and purity) of the compounds to be
submitted to the NIH? Is there an adequate plan to ensure that compounds
submitted to the NIH will be physically and chemically compatible with
high-throughput screening? Are issues of resupply dealt with
adequately? Does each of the proposed libraries have a sufficient
diversity of chemical handles to enable the exploration of structure-activity
relationships? If not, are there compelling biological considerations
that make these libraries particularly desirable? Will a substantial
number of unique libraries and new compounds be provided, and is the
applicant’s estimate well justified? Will the library design be
based upon a sound and insightful rationale? Are the proposed methods for
sample handling and storage sound and adequate? Is there an acceptable
plan to ensure that the proposed libraries will be unique and will not
duplicate structures or structure types already present in the MLSMR?
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? Are the proposed compounds novel, and does the
applicant provide adequate evidence for their novelty?
Investigators: Are the investigators
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 investigative team bring complementary and
integrated expertise to the project (if applicable)?
Environment: Does the scientific
environment 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?
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:
Resubmission
Applications (formerly revised/amended applications): Are the
responses to comments from the previous scientific review group adequate? Are
the improvements in the resubmission application appropriate?
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.
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. NIGMS and MLP staff will be responsible for monitoring the data
sharing policy.
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/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to
this funding opportunity should include a sharing research resources plan
addressing how unique research resources will be shared or explain why sharing
is not possible.
Program staff will be
responsible for the administrative review of the plan for sharing research
resources.
The adequacy of the
resources sharing plan will be considered by Program staff of the funding
organization when making recommendations about funding applications. Program
staff may negotiate modifications of the data and resource sharing plans with
the awardee before recommending funding of an application. The final version of
the data and resource sharing plans negotiated by both will become a condition
of the award of the grant. The effectiveness of the resource sharing will be
evaluated as part of the administrative review of each non-competing Grant
Progress Report (PHS 2590). See Section VI.3. Reporting.
3. Anticipated Announcement and Award Dates
Applicants
may expect to learn about the outcome of their applications, whether successful
or unsuccessful, by early September of 2008 or 2009 (for the two rounds of
funding). Grants will be awarded in September 2008 or 2009 (for the two
rounds).
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).
3. Reporting
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
We
encourage your inquiries concerning this funding opportunity 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:
1. Scientific/Research Contacts:
John M.
Schwab, Ph.D.
Division of Pharmacology, Physiology, and Biological
Chemistry
National Institute of General Medical Sciences
45 Center Drive, Room 2As.43A, MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-5560
FAX: (301) 480-2802
Email: [email protected]
2. Peer Review Contacts:
John L.
Bowers, Ph.D.
Chief, Biological Chemistry and Macromolecular Biophysics
(BCMB) IRG
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive MSC 7806
Bethesda, Maryland 20892-7806
Express/Overnight Mail:
6701 Rockledge Drive, Room 4170
Bethesda, Maryland 20817-7806
Telephone: (301) 435-1725
FAX: (301) 480-2327
Email: [email protected]
3. Financial or Grants Management Contacts:
Ms. Lisa Moeller
Grants Management Office
National Institute of General Medical Sciences
National Institutes of Health
45 Center Drive, Room 2AN.50C
MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 451-3914
FAX: (301) 480-5601
Email: [email protected]
Section
VIII. Other Information
Required Federal Citations
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.
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).
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 FOA 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.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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