New Methodologies for Natural Products Chemistry

RFA Number: RFA-RM-05-013

Part I Overview Information

Department of Health and Human Services

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

Components of Participating Organizations
This RFA is developed as an NIH Roadmap Initiative. All Institutes and Centers participate in Roadmap Initiatives. The RFA will be administered by the National Institute of General Medical Sciences (NIGMS), http://www.nigms.nih.gov, on behalf of the NIH.

Announcement Type
New

Update: The following updates relating to this announcement have been issued:

Catalog of Federal Domestic Assistance Number(s)
93.859

Key Dates

Release Date: November 17, 2004
Letters Of Intent Receipt Date: January 3, 2005
Application Receipt Date: January 24, 2005
Peer Review Date: June-July 2005
Council Review Date : August-September 2005
Earliest Anticipated Start Date: September 15, 2005
Expiration Date: January 25, 2005

Due Dates for E.O. 12372
Not Applicable

Executive Summary

The Institutes and Centers (ICs) of the NIH invite applications for funding from the NIH Molecular Libraries Roadmap program for the development of novel methodologies related to natural products chemistry. The goal of this RFA is to stimulate the development of a new generation of methods for natural products chemistry, and in doing so, to reinvigorate the investigation of nature as a prolific source of small-molecules with the potential to interact with all of the proteins that participate in cellular processes in health and disease. Examples of topics that would be appropriate for investigation under this RFA might include (but 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 natural products from a variety of natural sources. Ideally, one or more such systems would be developed for the expression of natural products from eukaryotic as well as prokaryotic organisms.

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

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
    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
      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
    3. Merit Review Criteria
      A. Additional Review Criteria
      B. Additional Review Considerations
      C. Sharing Research Data
      D. Sharing Research Resources

  Section VI. Award Administration Information
    1. Award Notices
    2. Administrative Requirements
    3. Award Criteria
    4. Reporting

  Section VII. Agency Contacts
    1. Scientific/Research Contact
    2. Peer Review Contact
    3. Financial or Grants Management Contact

  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 is a series of initiatives designed to pursue major opportunities in biomedical research and 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 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 is a component of the “New Pathways to Discovery” theme of the Roadmap. The goal of this initiative is to augment the toolbox for understanding the functionally interconnected networks of molecules that comprise cells and tissues, their interactions and regulation, and the combinations of molecular events that maintain health and lead to disease. 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, highly specific, mechanism-based biological assays. The new assays have, in turn, revolutionized the discovery of small molecules with powerful physiological effects. While high-throughput screening (HTS) of small-molecule libraries is widespread in the pharmaceutical industry, the goal of the Molecular Libraries (ML) Roadmap Initiative is to facilitate the use of HTS and chemical libraries within the academic community. It is anticipated that the ML initiative will produce research tools (including novel small-molecule modulators of cellular function and phenotypic assays) to facilitate studies of biology and pathophysiology. Among the possible outcomes, it is anticipated that such tools will 1) promote the identification of novel targets for therapeutic intervention and 2) accelerate the discovery of biomarkers to monitor disease progression and to predict treatment response (http://nihroadmap.nih.gov/molecularlibraries/index.asp).

For the most part, the academic community has not availed itself of the considerable potential of HTS to improve the understanding of biology. This is because most academic scientists have limited access to automated screening facilities and to libraries of structurally diverse compounds. The ML Initiative will establish and provide access to such resources and thus facilitate the broad application of HTS to research in the public sector.

The ML effort differs from HTS efforts in private industry in several ways. First, the NIH's interest is not limited to the identification of compounds with therapeutic properties. The range of the effort is much broader and will involve screening a greater diversity of small molecules in assays that will encompass a broader range of novel biological targets and activities. If successful, the ML Initiative will result in the identification of a very large number of compounds for use as probes to study cellular processes in health and disease. Second, the biological screening data, assay protocols, and chemical structures for compounds tested in the Molecular Libraries Screening Center Network (see below) will be publicly available for data mining via the PubChem database. Data-sharing with the larger scientific community represents a new paradigm that promises to: facilitate the understanding of basic biological mechanisms; identify new biological targets for evaluation in disease models; and shorten the timeline for ligand and tool discovery. Third, the ML Roadmap Initiative does not include plans to engage in the much more extensive aspects of drug development. It is anticipated that the initiative will complement private sector drug development efforts by contributing to the identification and validation of novel drug targets, as well as molecular structure classes with potential for development into therapeutics. The benefits to public health, especially for rare or marginalized disorders, are evident.

This particular RFA is part of the Chemical Diversity Technology Development effort, which in turn is a major component of the ML Initiative. Other components of the ML Initiative include: 1) the Molecular Libraries Screening Center Network (MLSCN): a national resource that will provide innovative HTS approaches for the identification of small, bioactive organic molecules, as well as synthetic chemistry to optimize these molecules as biological probes (see http://grants1.nih.gov/grants/guide/rfa-files/RFA-RM-04-017.html); 2) the NIH Small-Molecule Repository, which will house a collection of ca. 500,000 chemically diverse small organic molecules (see http://grants2.nih.gov/grants/guide/notice-files/NOT-RM-04-003.html); 3) PubChem: a public sector database that will archive the chemical structures and biological data generated by the MLSCN; and 4) the development of related technologies. In addition to this RFA, other technology development initiatives will aim to: (a) obtain pilot-scale libraries of small molecules for HTS (RFA-RM-05-014); (b) facilitate the development and adaptation of innovative target- and phenotype-based assays that can be considered for use in screening by the MLSCN (see http://grants1.nih.gov/grants/guide/rfa-files/RFA-RM-04-012.html); (c) develop new robotics and instrumentation for screening (see http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-020.html); and (d) stimulate the development of predictive ADME/toxicology (absorption, distribution, metabolism, and excretion/toxicology) assays and algorithms (see http://grants1.nih.gov/grants/guide/rfa-files/RFA-RM-04-023.html) .

The ability to screen massive numbers of compounds quickly using HTS technologies continues to stimulate the demand for collections of novel small molecules. This demand is expected to increase markedly as the MLSCN becomes operational. However, meeting this demand in an efficient, intelligent manner is a major challenge. Ideally, one would like to discover at least one small-molecule modulator of each function of each unique protein encoded by the human genome (as well as each unique protein from non-human sources that affect human health). Humans elaborate at least 100,000 unique proteins, and so the required number of small-molecule modulators should be on the order of 1,000,000. On the other hand, experts have estimated that the theoretically accessible extent of "chemical diversity space" is 10(E60) small-molecule structures (i.e., molecular weights up to 500), and it is certain that fewer than 10(E8) small-molecules have ever been synthesized or isolated from natural sources. Vast regions of chemical diversity space remain unexplored, and it will be critical that scientists have the tools available with which to predict potentially useful structure types as well as to efficiently obtain representatives of those structure types.

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.

However, over the past 10-15 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 chemistry. Instead, high-throughput chemical synthesis (HTSyn; commonly referred to as combinatorial chemistry, combichem, or diversity-oriented synthesis) is now the predominant source of structurally diverse molecules for HTS. [HTSyn 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. Natural products chemistry (i.e., isolation, purification, and structure elucidation) is labor-intensive and time-consuming and is not easily adapted to a high-throughput format. Also, bioactive natural products 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 natural products may occur only in minute concentrations in the organisms that make them; these 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 have mutated to a form that no longer makes the compound of interest. In addition to the foregoing, many natural products 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 RFA is to stimulate the development of a new generation of methods for natural products chemistry, and in doing so, to reinvigorate the investigation of nature as a prolific source of small-molecules with the potential to interact with all of the proteins that participate in cellular process in health and disease. As novel, bioactive natural products are discovered, they will be incorporated into HTS collections, enabling evaluation for a wide range of activities.

NIH expects that in the course of method development and validation studies, grantees will discover a certain number of useful, new natural products. Accordingly, a second goal of this RFA is to expand the NIH small-molecule collection by the addition of these new compounds, which will be available for high-throughput screening in a wide variety of bioassay systems, via the MLSCN.

Please note that throughout this RFA, the term “natural product” refers to a single chemical compound that is produced by a living organism. It is not used to describe mixtures or extracts isolated from natural sources.

Approaches Being Sought to Achieve the Objectives

Natural products may come from microorganisms or from higher organisms such as plants or marine invertebrates. 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 analogs of certain natural products. Examples of topics that would be appropriate for investigation under this RFA might include (but not be limited to) novel, general, and efficient methods to effect the following:

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

Sharing New Compounds with NIH

NIH expects that in the course of developing new methods, grantees will isolate, purify, and characterize a certain number of structurally novel natural products. In keeping with the mission of the ML Roadmap, grantees will be required to provide samples of these new compounds (up to 20 mg per compound) for the NIH small-molecule collection.

Project Oversight

As part of the larger Molecular Libraries and Imaging Roadmap Initiative, projects that are 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 the 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 will be the operational governing body for the initiative and will include NIH staff from various Institutes and Centers who are actively involved in the management and implementation of this Roadmap initiative. The Project Team will report to the MLIIG.

In addition to these oversight committees, grantees under this RFA will interact with the

MLSCN Compound Acquisition Working Group (which will report to the MLIIG). This group will oversee the operation of the Repository and the management of the NIH Small-Molecule Collection. It also will evaluate proposals for the acquisition of small-molecules from public and private sources for the Repository. Recommendations on which of the libraries generated under this RFA will be accepted by the Small-Molecule Repository will 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 RFA will be accepted into the Repository, acceptance will not be automatic. Also, the NIH collection will be dynamic, and compounds may be eliminated from the collection if they are deemed expendable.

Section II. Award Information

1. Mechanism of Support

This funding opportunity will use the NIH R01 Research Project Grant award mechanism. The R01 mechanism may be used to support either single-investigator projects or collaborative projects. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Any future, unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures.

This funding opportunity uses just-in-time 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 with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions. Otherwise follow the instructions for non-modular research grant applications.

2. Funds Available

On behalf of the NIH Roadmap, the National Institute of General Medical Sciences intends to commit up to $3 million dollars in FY 2005 to fund approximately 8-10 new grants in response to this RFA. An applicant may request a project period of up to three years.

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 IC(s) 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 highly meritorious applications.

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:

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his/her institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

2. Cost Sharing
N/A

3. Other-Special Eligibility Criteria
N/A

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. 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

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 11/2004). Applications must have a Dun and Bradstreet (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. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

See Section VI.2 Administrative Requirements for additional information.

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.

3. Submission Dates

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: January 3, 2005
Application Receipt Date(s): January 24, 2005
Peer Review Date: June-July 2005
Council Review Date: August-September 2005

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

The letter of intent is to be received by January 3, 2005 .

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) 594-5560
FAX: (301) 480-2802
Email: schwabj@nigms.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. Submit a signed, typewritten original of the application, including the checklist; five signed photocopies; and all copies of appendix material 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)

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 listed in the heading of this funding opportunity. If an application is received after that date, it will be returned to the applicant without review. Applications will be evaluated for completeness by CSR.

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

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the National Institute of General Medical Sciences and the Natural Products Methodologies Project Team. Incomplete applications will not be reviewed.

If the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All 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 (See also Section VI.3. Award Criteria)

6. Other Submission Requirements

Specific Instructions for Modular Grant Applications:

Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget format. The modular budget format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 11/2004) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular budgets. Additional information on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

Plan for Sharing Research Data

Since the inception of the ML Roadmap, NIH has emphasized that in order to maximize the benefit, all physical and intellectual research resources should be publicly available. There are strong scientific arguments supporting this position.

Small-molecule probes that selectively interact with biological targets are key research tools for understanding the functions of proteins and for elucidating biological pathways. A collection of such probes that would allow the comprehensive study of all of the proteins and other gene products encoded by the human genome would be an invaluable contribution to biomedical research. It will take the combined efforts of researchers in the public and private sectors many years of using small-molecule probes to completely characterize the biology of genes and proteins in health and disease, and then to use that information to develop approaches that will improve public health. Clearly, the open sharing of data, research tools, and resources will lead more rapidly to the identification and validation of novel targets for drug discovery, and will facilitate the rapid development of therapeutics by both the private and public sectors, with resulting benefits to public health, especially for rare or marginalized disorders.

All applicants must include a plan for sharing research data in their application. 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 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

Guidance for Community Resources:

The following data and materials generated or developed through the ML Roadmap initiative are expected to be community resources: (1) primary data from HTS and from secondary screens; (2) protocols for assays implemented in the MLSCN; (3) the chemical structures of compounds tested in the MLSCN; and (4) the optimization chemistry protocols for probe development conducted within the MLSCN centers. In keeping with this approach, NIH expects that (1) all libraries and individual compounds submitted to the NIH under this RFA; (2) data derived from biological screening of these compounds; and (3) protocols for obtaining these compounds (via synthesis, biosynthesis, or by isolation from biological sources) will be made readily available and accessible, consistent with other facets of the ML Roadmap.

It is well-established in the scientific community that hits in random HTS of chemical libraries such as those in the NIH small-molecule collection almost invariably require extensive medicinal chemistry optimization in order to be useful for in vivo investigational, much less for human therapeutic, purposes. NIH is concerned that patents on compounds that give rise to early-stage HTS hits would be premature, could have a chilling effect on the development of future substantive inventions, and thus could interfere with the broad utilization of early-stage biological and chemical information, which is the purpose of the ML initiative. Consistent with this concern, discussions with investigators in both the public and private sectors have indicated that those who otherwise might be interested in optimizing and developing these compounds with therapeutic intent might not utilize them if they were patented. It is the NIH's opinion that the objectives of the ML program would be served best by facilitating future innovation based on the compounds in the NIH collection and their use in biological systems, enabling the production of small-molecule probes with more advanced properties. To the extent that early patent filing and restrictive licensing could interfere with this scenario, such approaches would not be consistent with NIH's intent for the ML program.

On the other hand, it is NIH's hope and expectation that the analysis of HTS data from the MLSCN (which will be freely available 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 RFA would not be subject to any special IP considerations as described herein. Rather, NIH would encourage appropriate intellectual property (IP) protection of compounds at those later stages of development.

It is NIH's understanding that the utility of the resources and data generated by the ML initiative will be maximized if they are treated as community resources and made broadly available, consistent with achieving the goals of the ML Roadmap. While NIH recognizes that under the Bayh-Dole Act, awardees have the right to elect title to subject inventions and seek appropriate IP protection, the data sharing and IP plans should take all of the above considerations into account. Applicants should provide clear explanations and rationales for their plans, especially for any proposed plan that involves principles differing from those described in this RFA. Guidance for IP and Accessibility of Technology Development Resources A separate component of the IP plan should address any other data and resources that are expected to be generated by the grantees under this RFA. These may include, but are not limited to: chemical methodology, instrumentation, or software. NIH encourages applicants to consider inclusion of "non-assert" language in IP plans for all potentially patentable inventions to ensure that, while an institution might apply for a patent on an invention, the institution would not attempt to enforce that patent against organizations utilizing the technology for research purposes. IP and International Interests Specific to Natural Products NIH recognizes that certain international agreements may be in conflict with specific aspects of the data and resource sharing requirements as described in this RFA. Clarifications or modifications to the policies in this RFA may be announced in a subsequent issue of the NIH Guide. Review of Plans The data sharing and IP plans in the application will be evaluated by the Scientific Review Group using the principles and expectations detailed in this RFA, but will not be considered in the priority score. Following the review, in the case of those applications being considered for funding, program staff will negotiate a final version of plans for data sharing and IP to ensure accessibility of research resources. Applicants' plans for maximizing the public use of the data and resources generated under this RFA will be a major award criterion. Finalized plans will be included in the terms and conditions of any grant awarded under this RFA. If the goals of the ML Roadmap are not being met using this approach, NIH will consider using a determination of exceptional circumstances (DEC) under future awards to restrict or eliminate the right of parties to elect title to subject inventions. NIH policy requires that grant awardees make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication, as per the NIH Grants Policy Statement (http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). 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 the MLIIG and Program staff of NIGMS 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. Award Criteria.

Section V. Application Review Information

1. Criteria
N/A

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIH Center for Scientific Review in accordance with the review criteria stated below.

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

In addition to technical merit, programmatic considerations such as the diversity of experimental approaches may enter into funding decisions made under this RFA.

3. Merit Review Criteria

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.

1. 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?

2. 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? How likely are the proposed methodologies to be of general utility, rather than specific to a limited class of natural products?

3. 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?

4. 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)?

5. 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?

3.A. Additional Review Criteria:
N/A

3.B. Additional Review Considerations

Budget: The appropriateness 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.

3.C. Sharing Research Data

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

3.D. Sharing Research Resources

NIH policy requires that grant awardees 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/archive/archive/grants/policy/nihgps_2003/index.htm 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. Reviewers will be asked if the applicants have addressed intellectual property issues in their proposals, in order to prevent interference with (1) the progress of research; (2) sharing of information with the research community; and (3) provision of compounds to the NIH Small-Molecule Repository for high-throughput screening by the MLSCN, with dissemination of compound structures and screening data via PubChem.

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 Principal Investigator 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. Award Criteria.

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

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/archive/grants/policy/nihgps_2003/index.htm.

A formal notification in the form of a Notice of Grant Award (NGA) will be provided to the grants official at the applicant organization, electronically via the NIH Commons, via e-mail, or via U.S. mail, depending upon the capabilities of the applicant organization. The notice of award signed by the grants management officer is the authorizing document.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

2. Administrative Requirements

All NIH Grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the notice of grant award. 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/archive/grants/policy/nihgps_2003/index.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/archive/grants/policy/nihgps_2003/index.htm.

3. Award Criteria

The following will be considered in making funding decisions:

4. 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 Contact:

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: schwabj@nigms.nih.gov

2. Peer Review Contact:

John L. Bowers, Ph.D.
Chief, Biological Chemistry and Macromolecular Biophysics 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 4178
Bethesda, Maryland 20817-7806
Telephone: (301) 435-1725
FAX: (301) 480-2327
Email: BowersJ@csr.nih.gov

3. Financial or Grants Management Contact:

Ms. Antoinette Holland
Grants Management Office
National Institute of General Medical Sciences
National Institutes of Health
45 Center Drive, Room 2AN.50B MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-5132
FAX: (301) 480-2554
Email: hollanda@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, 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.

Public Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA 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


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.