and Human Services (HHS)
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Department of Health and Human Services
Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)
Components of Participating Organizations
This RFA is developed as an NIH roadmap initiative (http://nihroadmap.nih.gov). All NIH Institutes and Centers participate in roadmap initiatives. The RFA will be administered by the
National Institute of General Medical Sciences (NIGMS/NIH), (http://www.nigms.nih.gov) on behalf of the NIH.
Title: Pilot-Scale Libraries for High-Throughput Screening (P41)
Announcement Type
This is a reissuance of RFA-RM-05-014 which was previously released on November 18, 2004.
Update: The following update relating to this announcement has been issued:
Part I Overview Information
Part II Full Text of Announcement
Section I. Funding Opportunity Description
1. Research Objectives
Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available
Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria
Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements
Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates
Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
3. Reporting
Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)
Section VIII. Other Information - Required Federal Citations
1. Research Objectives
Background
The NIH Roadmap is a series of initiatives designed to pursue major opportunities in biomedical research, as well as gaps in current knowledge that cannot be addressed by any single NIH institute or center on its own, but that must be addressed by the agency as a whole. The 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 (http://nihroadmap.nih.gov/molecularlibraries/) is a component of the New Pathways to Discovery theme of the Roadmap (http://nihroadmap.nih.gov/newpathways/).
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 and nonprofit 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 (http://nihroadmap.nih.gov/molecularlibraries/index.asp).
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 provides innovative HTS capacity for the identification of small, bioactive organic molecules using assays submitted by the research community, as well as medicinal chemistry to optimize these molecules as biological probes (see http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-017.html); 2) the NIH Molecular Libraries Small-Molecule Repository (MLSMR), which ultimately will house a collection of ca. 500,000 chemically diverse small organic molecules (see http://grants.nih.gov/grants/guide/notice-files/NOT-RM-04-003.html); 3) PubChem: a public sector database that provides information on the biological activities of small molecules, including the compounds in the SMR and the biological data generated by the MLSCN (see http://pubchem.ncbi.nlm.nih.gov/); and 4) the development of related technologies. In addition to this RFA, other technology development initiatives aim to: a) 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://grants.nih.gov/grants/guide/rfa-files/RFA-RM-05-011.html); b) develop new robotics and instrumentation for screening (see http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-020.html); and c) stimulate the development of assays and algorithms for predictive ADME/tox (absorption, distribution, metabolism, and excretion/toxicology; see http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-023.html).
The ML effort differs from HTS efforts in private industry in several ways. First, the purpose of this NIH program is not the identification of compounds with therapeutic properties. Rather, the range of this effort is much broader and will involve screening a greater diversity of small molecules in assays encompassing 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. Second, the biological screening data, assay protocols, and minimal chemical data for compounds tested in the MLSCN (see below) will be publicly accessible 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 intends to facilitate, but does not intend to engage in, the much longer term and more expensive process of drug development. The ML initiative will complement private sector drug development efforts by contributing to the identification and validation of novel drug targets, as well as small molecule classes with potential for development into therapeutics. The benefits to public health, especially for rare or marginalized disorders, are evident.
Objectives of the Project
The goal of this RFA is to solicit applications for chemical library generation, in order to increase the diversity and the uniqueness of the collection in the MLSMR.
The pilot-scale libraries generated under this RFA will be submitted to the MLSMR and then to the MLSCN for HTS evaluation. When a pilot-scale library exhibits an encouraging pattern of biological activity, a decision may be made to more fully explore the pertinent region of chemical structure space. Constructing these secondary libraries will fall outside the scope of this RFA.
Since the goal of the ML Roadmap is to identify novel small molecule effectors of biological function, it is crucial that library designs be driven by biological considerations, rather than by chemical methodologies. Furthermore, since the goal is to identify effectors of truly novel biological phenotypes and mechanisms, it is important that the compounds produced under this RFA represent chemotypes that are distinct from what is available commercially and in existing compound collections.
Much of the chemical methodology to achieve the goals of this RFA exists currently, and libraries need only be designed and produced. In other cases, new methodology may be required. In contrast to the NIGMS Centers of Excellence in Chemical Methodologies and Library Development (CMLD; http://www.nigms.nih.gov/Initiatives/CMLD), the focus of this RFA is on the generation of novel libraries rather than on methodology development. Nevertheless, the ability to develop novel, library-related methodologies may be important for success in meeting the goals of this RFA.
Approaches Being Sought to Achieve the Objectives
This RFA does not specify the means by which the libraries are to be assembled. In fact, various approaches may be envisioned, including: 1) high-throughput synthesis (HT synthesis; often referred to as combinatorial chemistry, combichem, or diversity-oriented synthesis); 2) isolation and purification of compounds from living organisms (natural products), including compounds isolated from their natural sources, as well as natural products and their analogs made by use of genetic engineering; and 3) target-oriented synthesis (including the synthesis of analogs of a natural product or other lead compound).
HT synthesis is a process by which multiple compounds (chemical libraries) are generated simultaneously, in a predictable fashion, by techniques that involve parallel chemical transformations. HT synthesis may use solid- and/or solution-phase reaction and product isolation techniques. A library may be small (e.g., a few compounds) or large (e.g., thousands or even millions of compounds), and it may focus on a narrow or wide range of "diversity space.
Natural products may come from microorganisms or from higher organisms such as plants or marine invertebrates. There is general agreement that most natural products have evolved as chemical defense substances, enhancing the survival of the organisms that produce them. Thus, it is not surprising that a great number of approved drugs are themselves natural products, are derived from natural products, or were inspired by natural products. It is anticipated that libraries of natural products will be an especially rich source of bioactive small molecules with potentially broad utility as probes of biological mechanisms. Furthermore, it is expected that unique source organisms will give rise to new structural classes of natural products with unprecedented bioactivities. Libraries of such compounds should be especially valuable for HTS by the MLSCN.
Traditionally, natural products are isolated directly from their natural sources. However, recent developments have led to alternative sources of some natural products and natural product analogs. For instance, certain microbial metabolites may be produced by engineered organisms, including heterologous hosts. Similarly, by genetic manipulation of the genes that encode the biosynthetic machinery, pathways may be adapted so as to yield natural product analogs.
Target-oriented (total) synthesis of complex molecules, particularly natural products, long has been a dominant theme in organic chemistry. The rationale for total synthesis is rooted in the fact that until the latter part of the 20th century, natural product structures only could be deduced from a preponderance of indirect evidence, primarily from chemical degradation. Given the indirect nature of this process, as well as the sometimes unanticipated outcomes of the degradation reactions, the ultimate proof would be the de novo synthesis of the proposed structure and demonstration that the natural and synthetic materials were identical. However, during the last 40 years, spectroscopic and crystallographic techniques have evolved to the point that total synthesis rarely is required to complete or to confirm a structure proof.
Today, in addition to providing a platform for the development of new chemical methodologies, a prime motivation for the synthesis of complex molecules is the investigation of biological activities. Accordingly, many synthetic strategies are devised so as to be short (i.e., relatively few reaction steps), efficient (i.e., high-yielding and highly specific), and readily adaptable to the synthesis of key analogs. Ideally, such analogs allow mechanistic hypotheses to be addressed and/or allow pharmacophore characterization. Potential applicants under this RFA should note that it is the desire of the NIH to obtain substantial numbers of novel small molecules via this RFA. Additionally, the ease of resupply as well as the generation of analogs are important considerations.
Experts have estimated that "chemical diversity space" may encompass 10(E60) small-molecule structures (i.e., molecular weights up to 500). By comparison, fewer than 10(E8) small-molecules have ever been synthesized or isolated from natural sources. In view of the challenge, applicants should describe the process by which regions of chemical diversity space will be selected for study, as well as the general rationale for planning their pilot-scale libraries. Note that PubChem or other chemical databases may be useful for gauging the need for libraries representing particular regions of chemical diversity space. While libraries submitted in response to this initiative need not be drug-like in the usual sense (since NIH’s goal is not drug discovery), chemical stability under both HTS and storage conditions is very important. Also, compounds with inherently reactive functional groups (e.g., potent alkylating or acylating agents) as well as compounds that are prone to nonspecific aggregation (see, for example, J. Med. Chem. 2003, 46, 4265-4272) are undesirable.
A typical pilot-scale library might include 20-100 compounds, in order to afford (a) adequate structural diversity for evaluation of the library design concept; (b) a minimal amount of structure-activity relationship (SAR) information, so as to provide a basis for deciding whether further exploration of the particular region of chemical diversity space is warranted. In certain cases for example, natural products from rare organisms, where there is a high probability of discovering unprecedented chemical structures and bioactivities smaller libraries may be justified.
In order to minimize false positives in HTS assays, a high premium will be placed on analytical purity. Applicants should state specifications for acceptable levels of purity (ordinarily, at least 90%) and should describe analytical as well as preparative methods. Analytical data must accompany submissions to the MLSMR.
The preferred format for submission will be determined through discussions with the MLSMR. In all likelihood, it will be dry films or powders, or solutions in dimethylsulfoxide (DMSO), and sample vials will be provided by the MLSMR. The grantee should verify in good faith that none of the compounds submitted to the MLSMR has restrictions that will impair the distribution and use of the compounds by the MLSCN.
The MLSMR will perform analytical chemistry/quality control for submitted compounds. Currently, the protocols for evaluation of weight, solubility, identity, and purity are as follows, although improved procedures will be implemented, as appropriate.
Weight: Each sample will be dried to a constant mass under vacuum (pressure < 5 millibar) at 25 35 C and weighed. Dried samples must meet the minimum weight requirement in order to be accepted.
Solubility: Each 10 mg sample will be mixed with 2 mL of a solvent mixture comprising 90:10 chloroform:methanol; only samples that dissolve completely will be accepted.
Identity and Purity: An aliquot of the chloroform/methanol solution corresponding to approximately 0.05 mg of the solute will be dried. The residue will be dissolved in 200 microliters of a solvent mixture consisting of 97:3 methanol:dimethylsulfoxide and analyzed by LC-MS. Molecular weight will be determined using electrospray in either positive or negative ion mode (negative ion mode will be employed when certain acidic functional groups are present); purity will be determined by relative area under the curve (AUC) using UV (214 nm) and evaporative light scattering detection (ELSD). The MLSMR will accept samples where the molecular ion is correctly identified within 0.5 amu and where the sample purity is at least 90% by UV or ELSD or both.
Applicants should indicate in their proposals whether any aspects of this quality control process are likely to be incompatible with the proposed libraries, and where possible, should discuss appropriate, alternative analysis methods.
Compounds in the MLSMR will be subjected to a large number of HTS assays, and so unless there is a compelling justification to the contrary, each compound must be supplied in a quantity of no less than 10 mg. When HTS assay results call for it, additional quantities and/or analogs may be needed. While supply of these additional materials is not a specific goal of this RFA, it is highly desirable that resupply of compounds and the generation of analogs be readily achievable. Thus, compounds submitted to the MLSMR must be accompanied by documentation indicating their origin, such as synthesis protocols. It is recognized that making analogs may be substantially easier for synthetic compounds than for natural products, and so the uniqueness of natural product libraries as well as a compelling rationale for novel biological activity may be considered as compensating factors.
NIH is not specifying the number of libraries to be submitted each year by a grantee. On the one hand, it is a goal of the ML Roadmap to assemble a large number of unique, potentially bioactive small molecules for the MLSMR. An applicant should provide a well-justified estimate of the total number of compounds and the number of unique libraries to be submitted to the MLSMR each year. These estimates will provide a basis for evaluation of the grant application as well as a benchmark for evaluating the actual output of each grantee. While a substantial rate of library submission is desirable, it is critical that the libraries submitted under this RFA be thoughtfully designed, well-characterized, and provided in good quantity (vide supra). It is likely that libraries submitted to the MLSMR by grantees under this RFA will be accepted into the NIH small-molecule collection; however, this will not always be the case. For example, if a new library falls largely in a region of chemical diversity space that already is adequately represented in the collection, then it is unlikely that the new library will be accepted.
Applicants must discuss their proposed methodologies and strategies for the generation of high-quality libraries. The following are examples of topics that should be addressed:
Project Oversight
As part of the larger Molecular Libraries and Imaging Roadmap Initiative, projects funded under this RFA are subject to oversight and evaluation of each aspect of the effort.
THE MOLECULAR LIBRARIES AND IMAGING IMPLEMENTATION GROUP (MLIIG). The MLIIG comprises the directors of the National Human Genome Research Institute (NHGRI), the National Institute of Mental Health (NIMH), and the National Institute of Biomedical Imaging and Bioengineering (NIBIB) as well as NIH staff who coordinate the major components of the Molecular Libraries and Imaging Roadmap Initiative. The MLIIG will provide overall guidance.
THE MLSCN PROJECT TEAM. The MLSCN Project Team, which is comprised of NIH staff, is the operational governing body for the network, reviewing and, upon concurrence, implementing guidelines and policies for the MLSCN. The MLSCN Project Team acts as a second-level of review for the distribution of assays to each of the screening centers and the acquisition of compounds for the MLSMR. The MLSCN Project Team reports to the MLIIG.
THE PILOT LIBRARIES 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 RFA also will interact with the MLSCN Compound Acquisition Working Group. This group will assist in oversight of MLSMR operations and in the development of the NIH Small-Molecule Collection. It also will evaluate proposals for the acquisition of small molecules from public and private sources for the MLSMR. Recommendations on which of the libraries generated under this RFA will be accepted by the MLSMR may be made by this working group and will be communicated to the Pilot Libraries Project Team. As mentioned above, while it is likely that libraries submitted under this RFA will be accepted into the MLSMR, 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.
Grantees under this RFA will be expected to use a Material Transfer Agreement (MTA) approved by the NIH MLSCN Project Team for transfer of compounds and any associated materials to the MLSMR for screening in assays selected for implementation within the MLSCN centers. The MTA for transferring compounds to the Small Molecule Repository for use in the MLSCN program is under development and will be made available as an addendum to this RFA. For an example of the data sharing and IP terms used to transfer assays to the MLSCN centers, see the Material Transfer Agreement Model for Transferring Assays Selected for Implementation in the MLSCN (http://www.nimh.nih.gov/dnbbs/73-mcrm.cfm).
See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.
Section II. Award Information1. Mechanism(s) of Support
This funding opportunity will use the NIH Biotechnology Resource Grant (P41) award mechanism. This mechanism is used to support the development of research resources that will be available to qualified investigators without regard to the scientific disciplines or disease orientations of their research activities. The maximum award duration will be three years.
As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.
This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.
2. Funds Available
On behalf of the NIH Roadmap, the National Institute of General Medical Sciences (NIGMS) intends to make two sets of awards under this RFA. For each round, up to $2.5 million per year will be committed, to fund approximately six new grants. 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 also will vary. Although the financial plans of NIGMS 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.
FY 2006 awards will begin on or about September 2006, and FY 2007 awards will begin during the summer of 2007.
Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.
Section III. Eligibility Information1. 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 their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.
2. Cost Sharing or Matching
Not applicable
3. Other-Special Eligibility Criteria
Not applicable
1. Address to Request Application Information
The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: 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 most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.
The title and number of this funding opportunity must be typed on line 2 of the face page of the application form, and the YES box must be checked.
3. Submission Dates and Times
Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.
3.A. Receipt, Review and Anticipated Start Dates
Letter of Intent Receipt Dates: January 27, 2006; September 1, 2006
Application Receipt Dates: February 22, 2006; September 22, 2006
Peer Review Dates: June-July 2006; February-March 2007
Council Review Dates: August-September 2006; May 2007
Earliest Anticipated Start Dates: September 2006; July 2007
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 to plan the review.
The letter of intent is to be sent by the date listed at the beginning of this document.
The letter of intent should be sent to:
John M. Schwab, Ph.D.
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
45 Center Drive, Room 2As.43A
MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-3827
FAX: (301) 480-2802
Email: schwabj@nigms.nih.gov
3.B. Sending an Application to the NIH
Applications must be prepared using the research grant application and instructions described above. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).
At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:
Helen R. Sunshine, Ph.D.
Chief, Office of Scientific Review
National Institute of General Medical Sciences
45 Center Drive, Room 3AN.12E
MSC 6200
National Institutes of Health
Bethesda, MD 20892-6200
Telephone: (301) 594-3663
FAX: (301) 480-8506
Email: sunshinh@nigms.nih.gov
Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form, and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.
3.C. Application Processing
Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the National Institute of General Medical Sciences and the Pilot Libraries Project Team. Incomplete and non-responsive applications will not be reviewed.
The NIH will not accept any application in response to this funding opportunity that is essentially the same as one that is 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.
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 NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.
Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.
The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.
6. Other Submission Requirements
Data and Resource Sharing
Since the inception of the ML Roadmap, NIH has emphasized that in order to yield the maximum 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 a large number of the gene products encoded by the human genome would be an invaluable contribution to biomedical research. It will take 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 facilitate the identification and validation of novel targets for drug discovery, as well as the rapid development of therapeutics, with resulting benefits to public health.
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, resource 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, chemical instrumentation, software, etc. 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.
Review of Plans. The Scientific Review Group will consider the data sharing and IP plan in the application using the principles and expectations detailed in this RFA; however, the reviewers will not factor the plan into the determination of the scientific merit or the priority score. Following the review, in the case of those applications being considered for funding, program staff will negotiate a final version of the plan for data sharing and IP so as to ensure accessibility of research resources. The applicant’s plan for maximizing the public use of the data and resources generated under this RFA will be a major award criterion. The finalized sharing plan approved by NIGMS, after negotiation with the applicant when necessary, will become part of the terms and conditions of any grant awarded under this RFA. As part of the administrative review of each non-competing Grant Progress Report (see Section VI.3: Reporting), NIGMS and ML Roadmap program staff will evaluate the effectiveness of resource sharing, compliance with the sharing plan, and scientific progress.
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.
Plan for Sharing Research Data
Each applicant must include a plan for sharing research data in his or her application, regardless of the level of funding that is being requested. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing, and answers to frequently asked questions (FAQ) are provided at http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm. 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 will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of the scientific merit or the priority score.
The types of data to be covered by the research data sharing plan will include (1) detailed protocols for producing the compounds in the libraries provided to the NIH, including (as appropriate) procedures for synthesis, biosynthesis, isolation from natural sources, purification; and (2) analytical characterization, both qualitative and quantitative, of the compounds provided to the NIH.
Sharing Research Resources
Investigators conducting biomedical research frequently develop unique research resources, such as synthetic compounds, engineered organisms, cell lines, viruses, cell products, and cloned DNA, as well as DNA sequences, mapping information, crystallographic coordinates, and spectroscopic data. Specific examples include specialized or genetically defined cells; microbial cells and products; recombinant nucleic acid molecules; DNA probes; nucleic acid and protein sequences; and intellectual property such as computer programs.
NIH considers the sharing of such unique research resources (also called research tools) an important means to enhance the value of NIH-sponsored research. Restricting the availability of unique resources can impede the advancement of further research. Therefore, when these resources developed with NIH funds and the associated research findings have been published or after they have been provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community.
NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared.
The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of NIGMS and the ML Roadmap when making recommendations about funding applications. Program staff may negotiate modifications of the resource sharing plan with the awardee before recommending funding of an application. As mentioned above, as part of the administrative review of each non-competing Grant Progress Report (see Section VI.3: Reporting), NIGMS and ML Roadmap program staff will evaluate the effectiveness of resource sharing, compliance with the sharing plan, and scientific progress.
Intellectual Property. It is well established in the scientific community that hits in random HTS of chemical libraries such as those in the MLSMR almost invariably require extensive medicinal chemistry optimization in order to be useful for in vivo investigational use, much less for human therapeutic applications. NIH is concerned that enforcement of 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 pursue projects where there is prior patenting. 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 be inconsistent with NIH's intent for the ML program.
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 even drug leads. Optimized, second generation compounds that are pursued independent of this RFA would not be subject to any special considerations as described herein. NIH would encourage appropriate intellectual property (IP) protection of compounds at those later stages of development.
For additional information, refer to the data sharing and IP terms described in the MLSCN Project Team Policy on Data Sharing and IP in the MLSCN Program (http://www.nimh.nih.gov/dnbbs/73-mcrm.cfm).
1. Criteria
The following will be considered in making funding decisions:
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 National Institute of General Medical Sciences 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, or technologies that drive this field? How likely are the proposed strategies to result in the discovery of small molecules with novel and significant bioactivities?
Approach: Are the conceptual 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? Will the proposed approach afford compounds in acceptable quantities (ordinarily, at least 10 mg/compound) and acceptable purities (ordinarily, at least 90%)? Are the proposed analytical methodologies adequate for demonstrating the quality (i.e., identity and purity) and the quantity of the compounds to be submitted to the NIH? Is there an adequate plan to ensure that compounds submitted to the NIH will be physically and chemically compatible with high-throughput screening? Are issues of resupply and producing analogs dealt with adequately? Will a substantial number of unique libraries and new compounds be provided, and is the applicant's estimate well-justified? Will the design of each library be based upon a sound and insightful rationale? Are the proposed methods for sample handling and storage adequate?
Innovation: How original and innovative is the project? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?
Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?
Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or employ useful collaborative arrangements? Is there evidence of institutional support?
2.A. Additional Review Criteria:
In addition to the above criteria, the following 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: The reasonableness of the proposed budget and the requested period of support (three years, maximum) in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.
2.C. Sharing Research Data
Data Sharing Plan: The reasonableness of the data sharing plan (see Section III.6, above) 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 data sharing plan will be approved by NIH staff and will be included in the terms and conditions of the award. NIGMS and ML Roadmap staff will be responsible for monitoring the data sharing policy.
2.D. Sharing Research Resources
As described in Section III.6 (above), NIH policy requires that grant awardees make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication. Investigators responding to this funding opportunity must include a sharing research resources plan addressing how unique research resources will be shared.
The adequacy of the resources sharing plan will be considered by NIH Program staff when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.
3. Anticipated Announcement and Award Dates
Fiscal Year 2006 awards will be announced in September 2006, with grants to begin on or about September 2006. Fiscal Year 2006 awards will be announced in June-July 2006, with grants to begin in July-August 2006
1. Award Notices
If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.
Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5, Funding Restrictions.
2. Administrative and National Policy Requirements
All NIH grant awards include the NIH Grants Policy Statement as part of the Notice of 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/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).
Terms and Conditions dealing with intellectual property as well as data sharing and resource sharing will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.
3. Reporting
Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.
We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:
1. Scientific/Research Contacts:
John M. Schwab, Ph.D.
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
45 Center Drive, Room 2As.43A MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-3827
FAX: (301) 480-2802
Email: schwabj@nigms.nih.gov
2. Peer Review Contacts:
Helen R. Sunshine, Ph.D.
Chief, Office of Scientific Review
National Institute of General Medical Sciences
45 Center Drive, Room 3AN.12P MSC 6200
National Institutes of Health
Bethesda, MD 20892-6200
Telephone: (301) 594-2881
FAX: (301) 480-8506
Email: sunshinh@nigms.nih.gov
3. Financial or Grants Management Contacts:
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
Required Federal Citations
Sharing Research Data:
Investigators should seek guidance from their institutions, on issues related to institutional policies. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.
Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.
Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.
NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.
NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.
For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools, including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_manual.htm).
URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.
Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.
Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance 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.
Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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