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 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), (http://www.nigms.nih.gov) on behalf of the NIH.

Title:  New Methodologies for Natural Products Chemistry (R01)

Announcement Type
This is a reissuance of RFA-RM-05-013, which was previously released on November 17, 2004.

Update: The following update relating to this announcement has been issued:

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424 (R&R) Application Guide

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).

A registration process is necessary before submission, and applicants are highly encouraged to start the process at least four weeks prior to the grant submission date. See Section IV.

Request for Applications (RFA) Number: RFA-RM-08-004

Catalog of Federal Domestic Assistance Number(s)
93.310

Key Dates
Release/Posted Date: November 15, 2007
Opening Date:  December 23, 2007  (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): December 23, 2007
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization). 
Application Submission/Receipt Date(s):  January 23, 2008
Peer Review Date(s): June-July 2008
Council Review Date(s): August 2008
Earliest Anticipated Start Date(s): September 1, 2008
Additional Information To Be Available Date (Activation Date): Not Applicable
Expiration Date: January 24, 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 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. Request Application Information

2. Content and Form of Application Submission
3. Submission Dates and Times
    A. Submission, Review, and Anticipated Start Dates
          1. Letter of Intent
    B. Submitting an Application Electronically 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 Contacts
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, administered by the NIH Office of Portfolio Analysis and Strategic Initiatives (OPASI), is a collection 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 become 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 Molecular Libraries Program (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 (notably, 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 houses approximately 200,000 compounds obtained from both commercial and noncommercial 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 MLSMR and the biological data generated by the MLSCN/MLPCN (http://pubchem.ncbi.nlm.nih.gov/
); and 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.  There is no requirement that compounds in the MLSMR be Rule of Five-compliant.  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 the potential for development into therapeutics.  The benefits to public health, especially for rare or marginalized disorders, are evident.

Until the latter part of the 20th century, nature generally was regarded as the most prolific source of bioactive small-molecules. Indeed, according to an article published by National Cancer Institute scientists [J. Nat. Prod., 66, 1022 (2003), as paraphrased in the October 13, 2003 issue of Chemical and Engineering News; http://pubs.acs.org/cen/coverstory/8141/8141pharmaceuticals.html], ”61% of the 877 small-molecule new chemical entities introduced as drugs worldwide during 1981–2002 can be traced to or were inspired by natural products. These include natural products (6%), natural product derivatives (27%), synthetic compounds with natural-product-derived pharmacophores (5%), and synthetic compounds designed on the basis of knowledge gained from a natural product (that is, a natural product mimic; 23%). In certain therapeutic areas, the productivity is higher: 78% of antibacterials and 74% of anticancer compounds are natural products or have been derived from, or inspired by, a natural product.” The utility of nature as a source of bioactive small-molecules is readily rationalized, as these molecules have evolved in order to enhance the survival of the organisms that produce them.

Notably, over the past 12-15 years, during which HTS has become the dominant strategy for the discovery of bioactive small-molecules (particularly in the private sector), scientists have turned away from natural products (NP) chemistry. Instead, high-throughput chemical synthesis (often referred to as combinatorial chemistry, combichem, or diversity-oriented synthesis) is now the predominant source of structurally diverse molecules for HTS. [High-throughput synthesis is a process by which multiple compounds (chemical libraries) are generated simultaneously, in a predictable fashion, by techniques that involve parallel chemical transformations.]

The reasons for this paradigm shift are largely economic. NP chemistry (i.e., isolation, purification, and structure elucidation) has tended to be labor-intensive and time-consuming and not easily adapted to a high-throughput format.  Also, bioactive NPs may not be readily available in substantial quantities (from natural sources or by chemical synthesis), as would be needed for drug manufacturing or even for investigational studies.  For instance, highly bioactive NPs may occur only in minute concentrations in the organisms that make them; some NP-producing organisms (e.g., marine invertebrates or higher plants) may not lend themselves to laboratory cultivation; or the producing organism may be rare (perhaps an endangered species) or may no longer produce the compound of interest.  In addition to the foregoing, many NPs are less readily derivatized than are synthetic compounds that are designed with an eye toward the generation of analogs.

Objectives of the Project

The goal of this FOA is to stimulate the development of a new generation of methods for NP chemistry, and in doing so, to reinvigorate the investigation of nature as a prolific source of small molecules that have the potential to interact with all of the proteins that participate in cellular processes.  As novel, bioactive NPs are discovered, they will be incorporated into HTS collections, enabling their evaluation for a wide range of biological activities.

NIH expects that in the course of methods development and validation studies, grantees will isolate and purify significant quantities of a certain number of useful NPs.  Accordingly, a second key goal of this FOA is to expand the NIH small molecule collection by the addition of these compounds, which will be made available for high-throughput screening in a wide variety of bioassay systems, via the MLPCN.

Please note that throughout this FOA, the term “natural product” refers to a single discrete chemical compound that is produced by a living organism.  It is not used to describe mixtures or extracts isolated from natural sources.  The goal of this FOA is to solicit applications for methods development, in order ultimately to increase the diversity and the uniqueness of the collection in the MLSMR. 

Approaches Being Sought to Achieve the Objectives

NPs may come from microorganisms or from higher organisms such as plants or marine invertebrates.  Traditionally, NPs are isolated directly from their natural sources.  However, recent developments have led to alternative sources of some NPs and NP analogs.  For instance, certain microbial metabolites may be produced by engineered organisms, including heterologous hosts.  Similarly, by manipulation of the genes that encode the biosynthetic machinery, pathways may be adapted so as to yield analogs of certain NPs.  Examples of topics that would be appropriate for investigation under this FOA might include (but would not be limited to) novel, general, and efficient methods to effect the following:

A topic of particular interest to the NIH is the development of one or more “universal” expression systems. A universal expression system would enable the convenient, high-yield expression of a wide range of NPs from a variety of natural sources. Ideally, one or more such systems would be developed for the expression of NPs from eukaryotic as well as prokaryotic organisms.

Examples of topics that would not be appropriate (i.e., would be unresponsive) to the current FOA would include (but not be limited to):

NIH is not specifying the number of NP samples to be submitted each year by a grantee under this FOA.  On the one hand, it is a goal of the MLP to assemble a large number of unique, potentially bioactive small molecules for the MLSMR.  While a substantial rate of compound submission is desirable, it is critical that the NPs submitted under this FOA be well-characterized and provided in good quantity (ordinarily, 10-20 mg; 5 mg minimum).  The following are examples of topics that should be addressed by the applicant:

Project Oversight

As part of the larger Molecular Libraries and Imaging Roadmap Initiative, projects funded under this FOA 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 NATURAL PRODUCTS METHODOLOGIES PROJECT TEAM. The Project Team is the operational governing body for the initiative and 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 FOA 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 public and private sources for the MLSMR.  While it is likely that samples 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 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 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 of Support

This Funding Opportunity Announcement (FOA) will use the NIH Research Project Grant (R01) award mechanism.   

The applicant will be solely responsible for planning, directing, and executing the proposed project.  

This FOA uses “Just-in-Time” information concepts. It also uses the modular as well as the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application through a U.S. organization with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 5.4, “Modular Budget Component,” of the Application Guide). 

Ordinarily, a maximum of $250,000 (direct costs) per year may be requested.  A larger budget request may be considered, if there is a sufficiently compelling justification, and if funds are available.

U.S. applicants requesting more than $250,000 in annual direct costs and all foreign applicants must complete and submit budget requests using the Research & Related Budget component found in the application package for this FOA. See NOT-OD-06-096, August 23, 2006.

Both new and competing renewal applications will be accepted under this FOA.  It is not known at this time whether this FOA will be reissued.

2. Funds Available

With funds provided by the NIH Roadmap, the National Institute of General Medical Sciences (NIGMS) intends to award up to $2.5 million per year, to support approximately six new or competing renewal grants. 

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the Institutes and Centers (ICs) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

Ordinarily, the total project period for an application submitted in response to this FOA will be three years.  Requests for four years of support will be considered if there is a sufficiently compelling justification, and if funds are available. 

NIH grants policies as described in the NOT-OD-05-004, November 2, 2004.  

Section III. Eligibility Information


Failure of an applicant to meet an eligibility criterion by the time of an application deadline may result in the return of the application without review.  Alternatively, even though the application may be reviewed, failure to meet an eligibility criterion may preclude the agency from making an award.

1. Eligible Applicants

1.A. Eligible Institutions

You may submit an application(s) if your institution/organization has any of the following characteristics:

1.B. Eligible Individuals

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited 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 are always encouraged to apply for NIH support.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a “team science” approach that clearly does not fit the single-PD/PI model. Additional information on the implementation plans and policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a single PD/PI or multiple PD/PI grant is the responsibility of the investigators and applicant organizations and should be determined by the scientific goals of the project. Applications for multiple PD/PI grants will require additional information, as outlined in the instructions below. The NIH review criteria for approach, investigators, and environment have been modified to accommodate applications involving either a single PD/PI or multiple PDs/PIs. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PD/PIs will be factored into the assessment of the overall scientific merit of the application.  Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

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

Applications for competing renewal of existing projects are eligible, as are applications for new awards. Resubmissions (formerly known as “Revisions”) of unsuccessful applications originally submitted in response to RFA-RM-05-013 will not be accepted but may be submitted as new applications, with suitable modifications.  

Applicants may submit more than one application, provided each application is scientifically distinct.

Section IV. Application and Submission Information


To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, link to http://www.grants.gov/applicants/apply_for_grants.jsp and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

PDs/PIs should work with their institutions/organizations to make sure they are registered in the eRA Commons.

Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:

1) Organizational/Institutional Registration in Grants.gov/Get Registered

2) Organizational/Institutional Registration in the eRA Commons

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

Both the PD/PI(s) and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.

Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

For further assistance, contact GrantsInfo: Telephone 301-435-0714, Email: GrantsInfo@nih.gov.

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

2. Content and Form of Application Submission

Prepare all applications using the SF424 (R&R) application forms and in accordance with the SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, although not marked as mandatory, are required by NIH (e.g., the “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”

The SF424 (R&R) application has several components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY includes all applicable components, required and optional. A completed application in response to this FOA includes the data in the following components:

Required Components:

SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist

PHS398 Modular Budget or Research & Related Budget, as appropriate (See Section IV.6., “Special Instructions,” regarding appropriate required budget component.)  
Research & Related Budget (required for foreign applications)

Optional Components:

PHS398 Cover Letter File
Research & Related Subaward Budget Attachment(s) Form

Foreign Organizations (Non-domestic (non-U.S.) Entity)

NIH policies concerning grants to foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600260.

Applications from foreign organizations must:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

SPECIAL INSTRUCTIONS  

Applications with Multiple PDs/PIs

When multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the "Contact” PI, who will be responsible for all communication between the PDs/PIs and the NIH, for assembling the application materials outlined below, and for coordinating progress reports for the project. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PDs/PIs, but has no other special roles or responsibilities within the project team beyond those mentioned above.

Information for the Contact PD/PI should be entered in item 15 of the SF424 (R&R) Cover component. All other PDs/PIs should be listed in the Research & Related Senior/Key Person component and assigned the project role of “PD/PI.” Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the “Credential” field of the Research & Related Senior/Key Person component. Failure to include this data field will cause the application to be rejected.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership of the project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled “Multiple PD/PI Leadership Plan” (Section 14 of the Research Plan Component in the SF424 (R&R)), must be included. A rationale for choosing a multiple PD/PI approach should be described.  The governance and organizational structure of the leadership team and the research project should be described, including communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators. 

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan.  In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.

Applications Involving a Single Institution

When all PDs/PIs are within a single institution, follow the instructions contained in the SF424 (R&R) Application Guide.

Applications Involving Multiple Institutions 

When multiple institutions are involved, one institution must be designated as the prime institution and funding for the other institution(s) must be requested via a subcontract to be administered by the prime institution. When submitting a detailed budget, the prime institution should submit its budget using the Research & Related Budget component. All other institutions should have their individual budgets attached separately to the Research & Related Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R) Application Guide for further instruction regarding the use of the subaward budget form. 

When submitting a modular budget, the prime institution completes the PHS398 Modular Budget component only. Information concerning the consortium/subcontract budget is provided in the budget justification. Separate budgets for each consortium/subcontract grantee are not required when using the Modular budget format. See Section 5.4 of the Application Guide for further instruction regarding the use of the PHS398 Modular Budget component.

Applications Involving 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

See Section IV.3.A. for details.

3.A. Submission, Review, and Anticipated Start Dates

Opening Date: December 23, 2007 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): December 23, 2007
Application Submission/Receipt Date(s): January 23, 2008
Peer Review Date(s): June-July 2008
Council Review Date(s): August 2008
Earliest Anticipated Start Date(s): September 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:

John M. Schwab, Ph.D.
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
National Institutes of Health
45 Center Drive, Room 2As.43A
MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-3827
FAX: (301) 480-2802
Email: schwabj@nigms.nih.gov

3.B. Submitting an Application Electronically to the NIH

To submit an application in response to this FOA, applicants should access this FOA via http://www.grants.gov/applicants/apply_for_grants.jsp  and follow steps 1-4. Note:  Applications must only be submitted electronically.  PAPER APPLICATIONS WILL NOT BE ACCEPTED. 

3.C. Application Processing

Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt date(s) and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two business days to view the application image.

Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by MLP and NIGMS program staff.  Incomplete and non-responsive applications will not be reviewed.

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR receives the Grants.gov acknowledgments. The AOR and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific Review Group is also in the Commons. 

Note: Since email can be unreliable, it is the responsibility of the applicant to check periodically on their application status in the 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.

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 renewal (formerly “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 renewal 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 the
NIH Grants Policy Statement.

6. Other Submission Requirements

PD/PI Credential (e.g., Agency Login)

The NIH requires the PD/PI(s) to fill in his/her Commons User ID in the “PROFILE – Project Director/Principal Investigator” section, “Credential” log-in field of the “Research & Related Senior/Key Person Profile” component.

Organizational DUNS

The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see “Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.”

PHS398 Research Plan Component Sections

Items 2-5 of the PHS398 Research Plan component are limited to 25 pages. While each section of the Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files.  This approach will enable applicants to better monitor formatting requirements such as page limits.  All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

All application instructions outlined in the SF424 (R&R) Application Guide are to be followed, incorporating "Just-in-Time" information concepts, and with the following additional requirements:

Special Instructions for Modular Grant Applications

R01 applications from U.S. institutions/organizations requesting up to $250,000 per year in direct costs (excluding consortium F&A costs) must be submitted in a modular budget format. Additional information on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm.  When submitting a modular budget, the applicant organization will include only the PHS398 Modular Budget component.  See Section 5.4 of the SF424 (R&R) Application Guide for further instructions regarding the use of the PHS398 Modular Budget component.

Foreign organizations may not submit modular budgets. See NOT-OD-06-096

Appendix Materials

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.

Applicants must follow the specific instructions on Appendix materials as described in the SF424 (R&R) Application Guide (See http://grants.nih.gov/grants/funding/424/index.htm).

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

Note: While each section of the PHS398 Research Plan component needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan component as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to monitor better formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

Foreign Applications (Non-U.S. Entity)

Plan for Sharing Research Data

All applicants must include in their application a plan for sharing research data, regardless of the level of funding that is being requested. The 2003 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.

Since the inception of the MLI, NIH has emphasized that in order to yield the maximum benefit consistent with stated programmatic goals of the MLP, all physical and intellectual research resources should be publicly available.  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., growth of producing organisms, compound isolation, purification).

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.

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/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131), consistent with the programmatic goals of the MLP. 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.

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). 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 (e.g., via 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 

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 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 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 methodologies to be of general utility, rather than specific to a limited class of natural products and/or organisms?

Approach: Are the conceptual 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? 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 the proposed methods for sample handling and storage, as well as data handling, adequate?

Innovation:  Is the project original and innovative? For example: Does the project challenge existing paradigms; 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) 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)?

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 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:

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 and Period of Support: The reasonableness of the proposed budget and the appropriateness of the requested period of support in relation to the proposed research may be assessed by the reviewers. The priority score should not be affected by the evaluation of the budget.

Applications from Foreign Organizations: Whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources will be assessed. 

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. Staff from NIGMS and the MLP 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/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). 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.

See Section IV, Subsection 6 (above) for a detailed discussion of the guidelines for sharing of research resources.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

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), 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. Grants will be awarded in September 2008.

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 NIH 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.

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.

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 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  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Grant Progress Report (PHS 2590) annually 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 Contact(s):

John M. Schwab, Ph.D.
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
National Institutes of Health
45 Center Drive, Room 2As.43A
MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-3827
FAX: (301) 480-2802
Email: schwabj@nigms.nih.gov

2. Peer Review Contact(s):

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: BowersJ@csr.nih.gov

3. Financial/Grants Management Contact(s):

Ms. Lisa Moeller
Grants Management Officer
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:   moellerl@nigms.nih.gov

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.

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.

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) or PubMed Central (PMC) submission identification numbers must be used for publicly accessible on-line journal articles. Publicly accessible on-line journal articles or PMC articles/manuscripts accepted for publication that are directly relevant to the project may be included only as URLs or PMC submission identification numbers accompanying the full reference in either the Bibliography & References Cited section, the Progress Report Publication List section, or the Biographical Sketch section of the NIH grant application. A URL or PMC submission identification number citation may be repeated in each of these sections as appropriate. There is no limit to the number of URLs or PMC submission identification numbers that can be cited.

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 Part 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 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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