and Human Services (HHS)
EXPIRED
MOLECULAR LIBRARIES SCREENING CENTERS NETWORK (MLSCN)
RELEASE DATE: April 21, 2004
RFA Number: RFA-RM-04-017 (see NOT-RM-04-016 and NOT-RM-04-011)
(also see addenda NOT-RM-04-014 and NOT-RM-04-012)
EXPIRATION DATE: August 25, 2004
Department of Health and Human Services (DHHS)
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
(http://www.nih.gov)
This RFA is developed as an NIH Roadmap initiative (http://nihroadmap.nih.gov).
All NIH Institutes and Centers participate in Roadmap initiatives. The RFA will
be administered by the National Institute of Mental Health (NIMH) on behalf of
the NIH.
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: 93.389
LETTER OF INTENT RECEIPT DATE: July 26, 2004 (see change NOT-RM-04-016)
APPLICATION RECEIPT DATE: August 24, 2004 (see change NOT-RM-04-016)
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Background
o Technical Assistance Workshop
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
PURPOSE OF THIS RFA
The Institutes and Centers (ICs) of the NIH invite applications from
investigators interested in participating in an NIH Roadmap pilot program to
establish the Molecular Libraries Screening Centers Network (MLSCN). The MLSCN
will be a national resource capable of providing innovative high throughput
molecular screening (HTS) approaches for the identification of small organic
molecules (compounds) that are active in biological assays, and synthetic
chemistry to improve the utility of these molecules as bioactive probes for in
vitro, and potentially in vivo, studies of normal and abnormal physiology of
cells, organs, model systems, and/or organisms.
The over-arching goal of the MLSCN is to screen large numbers of compounds to
identify and subsequently optimize small molecules that selectively interact with
specific biological targets so that they may be used as probes to understand the
function of newly characterized proteins, and to analyze physiological processes,
cellular phenomena, and disease mechanisms. NIH’s primary objective for this new
public sector screening effort is to identify compounds that will constitute a new
set of research tools for use by scientists in both the public and private sector.
In addition, it is anticipated that some of these compounds will be used by both
public and private sector scientists as chemical platforms that may lead to new
therapeutics. Accordingly, NIH intends that all of the data and information
generated by the MLSCN will be made publicly available in a new database to be
known as PubChem. In this regard, NIH recognizes that there are significant issues
concerning intellectual property rights with respect to patentable inventions
developed during the MLSCN program. This subject is discussed more fully below.
Within this context however, it is NIH’s hope that inventors will exercise any
intellectual property rights retained on inventions developed as part of the MLSCN
program in a way that will promote wide accessibility to and further development of
the resources that are generated.
Applications are invited from groups that have the interest and capabilities to
develop and/or expand their assay development/optimization, screening, and
synthetic chemistry operations as well as groups with established capabilities in
these domains.
BACKGROUND
The NIH Roadmap is a series of new initiatives designed to pursue major
opportunities and gaps in biomedical research that no single NIH institute could
tackle alone but which the agency as a whole can address to make the biggest impact
possible on the progress of medical research and to catalyze changes that will
serve to transform new scientific knowledge into tangible benefits for public
health (http://nihroadmap.nih.gov/). The Molecular Libraries and Imaging
Initiative is one of the components comprising the Roadmap theme of New Pathways
to Discovery , the goal of which is to build a better toolbox to use in
understanding the many interconnected networks of molecules that comprise cells and
tissues, their interactions, regulation, and the combination of molecular events
that lead to disease. This Initiative will offer a publicly available database of
biological information on small organic molecules, and public access to these
molecules by the scientific community, to promote their use as chemical probes to
study cellular pathways in greater depth and to provide new ways to explore the
functions of major components of the cell in health and disease. It is anticipated
that the Molecular Libraries and Imaging Initiative will: 1) produce research
tools (molecular probes and novel assays) to facilitate studies of biology and
pathophysiology, and that these tools will enable and catalyze the identification
of novel targets for therapeutic intervention; and 2) accelerate the discovery of
biomarkers to monitor disease progression and predict treatment response
(http://nihroadmap.nih.gov/molecularlibraries/index.asp).
The MLSCN is a major component of the Molecular Libraries Initiative. Other
components include: 1) the NIH Small Molecule Repository, a publicly available
repository of 100,000-500,000 chemically diverse small organic molecules of both
known and unknown activities
(see http://grants.nih.gov/grants/guide/notice-files/NOT-RM-04-003.html);
2) PubChem, a public sector database that will archive
the chemical structures and biological data generated by the MLSCN; and 3) the
development of related technologies. The technology development initiatives will:
(a) enhance the chemical diversity of small molecules; (b) facilitate the
development and adaptation of innovative target- and phenotype-based assays that
can be automated and considered for screening at the MLSCN; (c) develop new
robotics and instrumentation for screening; and (d) stimulate the development of
predictive ADME/toxicology (absorption, distribution, metabolism, and
excretion/toxicology) assays and algorithms. The MLSCN also interacts with the
Molecular Imaging Initiative
(http://nihroadmap.nih.gov/molecularlibraries/index.asp).
An overview of how the MLSCN interacts with the other components of the
Molecular Libraries and Imaging Initiative, and with interrelated activities in
the public and private sector is shown in Figure 1,
http://www.nimh.nih.gov/grants/rm04017fig1.pdf.
TECHNICAL ASSISTANCE WORKSHOP
NIH staff will conduct a technical assistance and information-sharing workshop in
Bethesda, MD in May or early June of 2004. This workshop will allow potential
applicants to discuss and clarify any issues or questions related to this RFA with
NIH staff. The NIH is also seeking public comments regarding the potential use of
a deviation to the standard patent rights clause to limit the rights of MLSCN
center investigators to retain title to certain subject inventions involving the
use of proprietary compounds in order to access and assemble the largest collection
of compounds as possible for this project. The proposed deviated clause would
provide title or exclusive rights to the provider of the proprietary compounds (see
below). To accommodate individuals who cannot attend the meeting, the meeting will
be webcast and made available for viewing on the Roadmap website. If you plan to
attend the workshop, please contact Dr. Linda Brady (e-mail lbrady@mail.nih.gov or
phone 301-443-5288) to register to attend. Potential applicants are encouraged to
submit their questions to the email address listed above in advance of the meeting.
Detailed information about the time and location of the meeting will be available
on the NIH Molecular Libraries and Imaging Roadmap web page under Grants and
Funding Opportunities (http://nihroadmap.nih.gov/molecularlibraries/grants.asp).
RESEARCH OBJECTIVES
The NIH wishes to facilitate the use of HTS approaches within the academic
community to speed the discovery of molecular research tools (e.g., ligands,
imaging probes, and new activities of existing drugs) in the public sector. It is
anticipated that the MLSCN effort will catalyze scientific breakthroughs that will
contribute to the identification of molecular entities or molecular classes that
may have potential benefit for the development of therapeutics by the private
sector. Through this approach, NIH wishes to stimulate research in the following
areas: 1) discovery of novel biological targets that can inform studies of cell
function and disease pathophysiology; 2) discovery, validation, and application of
assays (screens) and disease models to evaluate the activity of novel small
molecules; and 3) use of chemical genomic approaches to characterize the biology of
genes of interest, cellular processes, and proteins associated with disease
processes.
The public sector has not taken advantage of the considerable potential of HTS to
improve the understanding of biology and disease mechanisms because access by
academic scientists to automated screening facilities and diverse compound
libraries is very limited. The NIH Molecular Libraries Initiative is intended to
create and provide access to such resources and to facilitate the broad application
of HTS in research in the public sector. The MLSCN effort differs from HTS efforts
in private industry in several ways. First, because the NIH’s interest is not
limited to the identification of compounds with therapeutic effect, the range of
the MLSCN effort is much broader. The MLSCN effort will screen small molecules in
assays that encompass a broad range of novel biological targets and activities. If
successful, the MLSCN will result in the identification, by the academic community,
of a very large number of compounds for use as chemical probes to study many
cellular pathways and the functions of major components of the cell in health and
disease. Second, the biological screening data, assay protocols, and chemical
structures for compounds tested in the MLSCN will be publicly available via the
PubChem database, allowing data mining to obtain structural information about small
molecules and the biological targets with which they interact. Third, the NIH
Roadmap Initiative does not include plans to engage in the much more extensive
aspects of drug development.
The MLSCN centers will vastly increase the ability of investigators in both the
public and private sectors to use small molecules in basic biological research, and
to translate the resulting findings into novel ligand discovery, and ultimately
into therapeutics development in many disease areas through traditional routes of
drug development. With respect to the latter, while drug development is not part
of the Molecular Libraries and Imaging Initiative, individual Institutes and
Centers at the NIH may, as they always have, subsequently decide to pursue certain
drug development projects, particularly those that may not be attractive to the
private sector for economic reasons (e.g., the Spinal Muscular Atrophy Project,
http://www.smaproject.org). The sharing of small molecules, assays, and screening
data with the larger scientific community represents a new paradigm that promises
to: facilitate the understanding of basic biological mechanisms; identify new
biological targets and test them in disease models; and shorten the timeline for
ligand and tool discovery. Potentially, the open sharing of these resources will
also facilitate therapeutics development by the private sector with resulting
benefits to public health, especially for rare or marginalized disorders.
The first phase of the MLSCN program is being implemented through this RFA as a 3-
year pilot program that will support 6 or more pilot centers to develop sufficient
capability, by the end of the three-year funding period, to screen a minimum of
100,000 compounds in 20 assays that have been adapted for HTS within each center
per year. The NIH anticipates that this pilot program will lay the groundwork for
a subsequent solicitation for a smaller number of fully operational HTS centers.
Thus, the specific goal of this RFA is to support the establishment of a network of
pilot Molecular Libraries Screening Centers that have or can develop the
capabilities to: 1) implement a diverse array of both target-based and cell- or
model organism-based phenotypic assays obtained from investigators in the public or
private sector to HTS format; 2) screen a large number of compounds in the NIH
Small Molecule Repository for biological activity in these assays; 3) provide
synthetic chemistry to optimize screening hits into useful in vitro and/or in vivo
biological probes; and 4) provide informatics support to track compounds, assays,
and screening data. The MLSCN will make all biological screening data and assay
protocols freely available to the public through the PubChem database.
In order to meet the goals and objectives of this Roadmap initiative, NIH is
considering the use of a deviation to the standard patent rights clause in the
Terms and Condition of Award. If a Determination of Exceptional Circumstances
(DEC) were implemented herein, this clause deviation would serve to protect the
pre-existing and future patent rights of suppliers of proprietary compounds for HTS
in the MLSCN centers. The proposed clause deviation would be narrowly tailored to
apply only to discoveries resulting from HTS of proprietary compounds, and would
provide, for example, title or exclusive rights to new use inventions to the
provider of the proprietary compounds, or otherwise dispose of the title and rights
in a way that would encourage the provision of proprietary compounds to the
centers. Furthermore, the MLSCN centers would have the right to ask for greater
rights, as defined in the clause, if the supplier of the proprietary compound were
not interested in the subject invention. The NIH is seeking public comments
regarding the potential use of a deviation to the standard patent rights clause at
the Technical Assistance Workshop; applicants are encouraged to submit their
comments to lbrady@mail.nih.gov in advance of the meeting.
Note: Because the 3-year goal of screening 100,000 compounds in 20 assays may be
an under- or over-estimate, this goal will be re-assessed annually by the MLSCN,
the External Scientific Panel, and the NIH Project Team.
ORGANIZATIONAL STRUCTURE OF THE MLSCN
During the pilot phase, the MLSCN will be comprised of 6 or more extramural
(academic and/or private sector) pilot centers and the NIH Chemical Genomics Center
(NCGC, a screening center that is being established in the Intramural Research
Program at NIH). The MLSCN will be established as a collaborative research network
of centers with complementary abilities that will enable the network to address a
wide range of biological opportunities.
It is envisioned that each center will bring to the MLSCN a specific set of
expertise and skills in the areas of assay optimization, HTS, and synthetic
chemistry to improve the biological utility of compounds identified as hits in
biochemical, cell-based, and phenotypic assays. The focus of the MLSCN will be on
implementing HTS-based assays for classes of proteins within different gene
families and cell-based phenotypic assays rather than on specific human disorders
or therapeutic areas. The rationale for this approach is that such a network will
be the best way of serving the diverse needs and interests of the many NIH
Institutes and Centers that participate in the Roadmap Initiative.
Each center within the MLSCN will be expected to include each of five critical
functions:
(1) Assay Implementation, to optimize and automate target-based and cell-based
phenotypic assays obtained from the scientific community for HTS, including the
ability to obtain and produce cells, proteins, vectors, and other resources
required;
(2) HTS, to screen appropriate/relevant set(s) of compounds, which are housed in
the NIH Small Molecule Repository, in the optimized assays and to identify and
confirms initial positive candidate compounds ( hits );
(3) Synthetic Chemistry and Probe Development, to apply rational strategies for the
initial modification of candidate compounds to improve their ability to be used as
in vitro and/or in vivo research tools, and to produce and screen second-generation
libraries;
(4) Informatics, to address a number of different needs that the centers will have,
including: automation and management of laboratory operations (e.g., compound
tracking, control of robotic processes, data capture, and assay protocols) through
a LIMS (laboratory information management system); procedures for data
analysis/management and deposition of screening results and assay protocols to
PubChem; and structure-activity analysis (SAR) of hits; and
(5) Administration and Management, to provide a structure for organization and
integration of the required activities across the center, capabilities for key
decision-making in the strategies employed for assay automation, screening, hits
optimization and characterization, and establishment of efficient on-going
operation of the center’s screening activities.
NIH does not specify how these functions are to be organized. The applicant may
choose to organize the proposed centers in terms of separate Cores or in any other
manner deemed appropriate for the implementation of an effective pipeline.
However, the application must clearly address how the proposed organization of the
center will ensure that each of these functions is effectively accommodated.
Each of the functions is described in more detail below.
1. Assay Implementation. The goal of the MLSCN is to establish innovative
biochemical, biophysical, and cell-based assays for biological targets or processes
for which no highly specific and potent small molecule activator or inhibitor is
broadly available to the public. However, the initial design and development of
assays will not be the responsibility of the MLSCN centers. Rather, investigators
in the broader scientific community will submit requests in response to an NIH
Guide Notice that solicits biological assays to be optimized for HTS by the MLSCN,
and those assay applications will be evaluated through a competitive process
described below. The MLSCN centers will then be responsible for importing and
adapting specific assays selected for implementation within the MLSCN.
The following list of target-based and phenotypic assays is intended to give a
number of examples of assays that will potentially be of interest to the NIH,
rather than to be exhaustive or prescriptive. Target-based assays may include
those for G-protein coupled receptors (GPCRs), ion channels, transporters, orphan
GPCRs, nuclear receptors, and kinases. Assays focusing on a broader range of
functions could include those for macromolecular interactions using a variety of
detection approaches such as mass spectrometry, nuclear magnetic resonance, or
optical technologies, and molecular-level functional screens using enzymatic
activity or reporter gene assays. Examples of non-traditional targets of interest
include transcription factors, nucleic acids, multimeric proteins, membrane
proteins, and polymorphic gene products, and subcellular processes such as
molecular trafficking and translocation, post-transcriptional editing or splicing
of gene products, and protein or RNA stabilization. Phenotypic assays could
include cellular processes (e.g., proliferation or apoptosis) or could utilize
model organisms (e.g., yeast, worms, zebrafish, etc). Other assays of interest
include those for metabolism, bioavailability, toxicity, blood-brain barrier
permeability, or other phenomena that are not typically available in the academic
community.
The proposed goal of the pilot centers will initially be to screen 10,000 compounds
in 10 or more assays in the first year of the MLSCN program using 96- or 384-well
plates, with an eventual goal of screening 100,000 or more compounds in a minimum
of 20 assays in the third year. Applicants should clearly address a plan for
adapting assays for HTS (e.g., assay miniaturization and automated processing) in
order to achieve the proposed target goals for the first and third years (as
indicated above), and discuss criteria for determining when an assay is
sufficiently optimized to allow HTS at the anticipated scales of throughput.
It is desirable for each center to have an identifiable theme or concept around
which it is initially organized (e.g., targets and detection approaches) and a plan
to acquire the expertise and capability to import and optimize a broad range of
biochemical or biophysical target-based assays and cell- or organism-based
phenotypic assays during the three-year pilot phase. As indicated previously, the
theme for a center should not be based on specific human diseases or therapeutic
areas.
Applicants should describe the capabilities that they currently have or will
develop to import a variety of assays from the scientific community and adapt them
to a high throughput format. Issues such as experience with assay optimization,
throughput, reproducibility, validation, cell culture, protein or vector
production, and other relevant capabilities should be discussed.
2. HTS Implementation. A pilot center will need to be able to successfully carry
out HTS using robotic technologies and high throughput imaging systems capable of
detecting a variety of readouts (e.g., absorbance, fluorescence, luminescence,
FRET, BRET, SPA, and biophysical readouts). Given the number of compounds to be
screened, 96-, 384- and eventually 1536-well plate reader capabilities will be
required. Centers will need to be able to validate HTS-based assay results, using
for example Z scores, unbiased statistical approaches, positive and negative
controls, and ways to limit and identify false positives and false negatives. In
most cases, confirmatory assays of hits, and at least one secondary screen
(submitted by the referring investigator) will need to be run to identify true
positives that would be candidates for further development as probes.
Applicants should justify each of the HTS component technologies proposed for
inclusion in the pilot center in terms of how each one will be utilized as an
integral component of the center’s HTS capabilities. Applicants should also
present a coordinated, viable plan for scaling up the HTS activities and, when
appropriate, for implementing advances in detection, miniaturization, and robotics
required for optimal high throughput implementation of assays to achieve the target
capacity by the end of the pilot phase.
Synthetic Chemistry and Probe Development. It is essential that compounds
identified as research tools for the investigation of particular targets and
biological processes by the MLSCN are reliable and capable of providing reliable
information on the activity of their intended targets. The probe compounds
produced by the centers will need to be usable by the research community for in
vitro and/or in vivo studies. In most cases, compounds identified by initial
screening ( hits ) will not be ideal as research tools. It is likely that
properties such as affinity, specificity, and solubility will need to be improved
before a useful compound is obtained. Therefore, applicants should describe a plan
for the development or acquisition of sufficient synthetic chemistry capability to
generate a library of structurally related compounds (~100-300) around a confirmed
hit and to test those compounds in the primary assay to identify derivatives with
improved affinity, specificity, solubility, and bioavailability. Chemistry efforts
could include optimization by structure-activity relationships (SAR) when a
pharmacophore can be identified, including directed library synthesis and
structure-guided design. The minimum characteristics that a probe compound will
need to have to be a useful research tool will be determined by the MLSCN Steering
Group and the NIH Project Team; it is anticipated that such characteristics will
include <100 nM affinity, >100-fold selectivity against related targets, and
solubility in aqueous solutions or in a low concentration of DMSO. NIH recognizes
that whatever the characteristics of the probes, further modification will be
necessary to produce compounds that are useful for in vivo studies. For this
reason, all probes, as well as the data and hits from which they are derived, will
be made available to all researchers. Support for such projects will be through
Roadmap-related Program Announcements or other NIH funding mechanisms.
4. Informatics. Adequate informatics capabilities will be critical to multiple
components of the center. Automation, sample tracking, laboratory procedures,
quality control, data management, deposition of screening data, assay protocols,
and other relevant information to PubChem, and data analysis all depend on
sufficient informatics capabilities and resources.
Applicants should present a clear set of operational plans for ensuring that the
informatics needs of the center are addressed, including the issue of integration
to the extent that it contributes to the efficiency of the center’s operation.
Issues that should be addressed include plans for acquisition and analysis of
primary screening data, and data generated from screening of a second-generation
library of structurally related compounds generated around a confirmed hit.
Applicants should describe their capabilities or plans to acquire resources for
computational chemistry, pharmacophore modeling, and SAR analysis of new leads
(e.g., QSAR, CoMFA, Sybil software).
In preparing the informatics plan, the applicant should take into account that once
the MLSCN is established, the MLSCN Steering Group will address issues of possible
standardization of operating procedures across centers such as quality control and
quality assessment for assay and screening procedures, and data deposition
practices for submission of screening data, assay protocols, and other information
to PubChem. Although the proposed informatics plan will be evaluated for adequacy
by the review committee, once the centers network is established, the MLSCN
Steering Group will identify opportunities and develop guidelines for increasing
the inter-operability of the centers. Applicants will be expected to have a high
degree of flexibility and be willing to adopt uniform policies and procedures
recommended by the MLSCN Steering Group.
All screening data and descriptions/protocols for assays optimized for HTS by the
MLSCN are required to be deposited immediately in the public domain (via PubChem)
after they have been certified for accuracy. The procedures for the deposition of
screening data and assay protocols to PubChem will be coordinated directly with the
National Center for Biotechnology Information (NCBI), the lead on the PubChem
initiative. PubChem staff at NCBI will suggest specific formats for data
deposition and will work with MLSCN centers as necessary to ensure accurate
transmission. For chemical structure data, it is anticipated that PubChem will
support, among others, existing formats such as SDF or MOL files. For screening
assay descriptions and results, it is anticipated that PubChem will support
depositions based on best current technologies including XML exchange
specifications. For chemical synthesis descriptions of small molecules in the
Repository, PubChem will support deposition of text descriptions and citations.
5. Administration and Management. The management of a MLSCN center will require a
well-conceived and implemented management plan and a significant commitment by the
PI of the project. The PI of an MLSCN center funded under this RFA is expected to
devote at least 25% effort to the project. The application should describe the
management plan for the proposed center, and how the plan will support its proposed
goals. It should describe the organization of the proposed center and its
management structure and should address the integration of the functional
components to form an efficient assay optimization, screening, and hits
optimization chemistry pipeline for generating small molecule research tools. The
plan should specifically address interactions between key personnel and reporting
relationships. Recruitment and training of personnel should be discussed. The
plan should specifically address how any collaborations or subcontracts will be
managed.
The management plan should also address the interactions of the proposed center
with the other components of the MLSCN Network (e.g., the Small Molecule
Repository, the MLSCN Steering Group, the Coordinating Center, and the NIH Project
Team; these components are described in more detail below in the Definitions
section). The PI is strongly encouraged to consider proposing a project manager
for the center. It is also expected that each MLSCN center will have a Center
Steering Committee (CSC) that includes key center personnel, external advisors, and
an NIH Science Officer (defined below). The CSC should meet at least on an annual
basis to review progress and provide advice on strategies for assay automation,
screening, hits optimization and characterization. Plans for organizing a CSC
should be described in the application, but potential members of the CSC should not
be contacted until after an award has been made, and the names of potential members
should not be listed in the application.
Note: Because of the complexity of the MLSCN, program staff from NIH expect to
visit each MLSCN center periodically to conduct an administrative site visit. U54
centers should be prepared for annual visits and should budget appropriately
(including travel for collaborators and other necessary costs).
In addition to the functions described above, there are a number of other issues
important to the successful operation of the MLSCN that should be addressed
separately in the application:
1. Governance Structure of the MLSCN. The Molecular Libraries and Imaging
Initiative consists of multiple interacting components, many of which contribute
activities that are directly related to the successful operation of the MLSCN
centers. The coordination of these separately funded activities is one of the
primary reasons why the NIH will fund the MLSCN using the cooperative centers
(U54) mechanism. To facilitate the coordination, the NIH Project Team proposes
the following governance structure for the MLSCN and related Molecular Libraries
and Imaging Initiative activities. For additional details, see the Definitions
section in the RFA, and Figure 2, http://www.nimh.nih.gov/grants/rm04017fig2.pdf.
o Each MLSCN center will have an individual CSC as described above.
o The MLSCN Steering Group will consist of the PIs for each center within the
MLSCN network, including the NCGC center located in the Intramural Research Program
at NIH, and the NIH Science Officers. The PI of the Small Molecule Repository, the
PI of the Coordinating Center, and a representative from PubChem will be ex officio
members. The MLSCN Steering Group will be responsible for the overall coordination
of the screening center network, and the group through which the centers will
interact with the NIH Project Team and other components of the Roadmap Initiative.
It will develop criteria and implement procedures for data quality assessment,
consider standard operating procedures across centers, and develop and recommend
policies for data release (e.g., the exchange of screening data, assay protocols,
and other materials with the wider scientific community) for concurrence by the NIH
Project Team. The MLSCN Steering Group will develop a plan for assignment of
assays to specific centers within the network after considering the evaluation of
assay proposals by the MLSCN Assay Access Committee (see definitions below); the
Steering Group will then recommend the assay distribution plan to the NIH Project
Team for concurrence. The MLSCN Steering Group will consider each center’s
proposed strategy for optimization of candidate compounds ( hits ). In the event
that the number of candidate compounds identified by a specific center exceeds its
capacity for chemical optimization, the MLSCN Steering Group will develop a plan
for re-distribution of probe development within the network and will recommend the
plan to the NIH Project Team for concurrence.
o The Coordinating Center will provide a range of important services to the MLSCN.
The Coordinating Center will assist in coordinating and tracking the activities of
the MLSCN and its component screening centers, and will maintain a website that
will provide up-to-date information on assays accepted for implementation in
specific MLSCN centers, compounds accepted for entry into the Small Molecule
Repository, confirmed hits within the network, and data depositions to PubChem.
The Coordinating Center will also provide administrative support to the MLSCN Assay
Access Committee, which will evaluate proposals from the research community for
assays to be implemented by the MLSCN, and to the MLSCN Compound Acquisition
Committee, which will evaluate requests for compounds to be incorporated into the
Repository. The Coordinating Center will be implemented as a contract with a
Request for Proposals (to be issued shortly).
o The NIH Project Team will be composed of NIH staff who are actively involved in
the management and implementation of this Roadmap Initiative. The Project Team
will be the operational governing body for the network that reviews and, upon
concurrence, implements the guidelines and policies recommended by the MLSCN
Steering Group, and will act as a second-level of review for the distribution of
assays to each of the screening centers and the acquisition of compounds for the
Small Molecule Repository.
o The Molecular Libraries and Imaging Implementation Group (MLIIG) will be
composed of the Directors of NHGRI, NIMH, and NIBIB and the lead NIH staff for each
of the components of the Roadmap Initiatives. The MLIIG will provide overall
guidance for all components of this Roadmap Initiative.
2. Acquisition of Assays. The function of the MLSCN centers will be to receive
assays that have been developed by members of the scientific community, adapt them
for high-throughput implementation, and use them to screen the compound collection
provided by the NIH Small Molecule Repository to identify and confirm compounds
that have the desired effect in the assay. Proposals for innovative assays for
screening center implementation will be solicited from the scientific community
through notices in the NIH Guide and in scientific journals. Applications will be
reviewed for scientific merit, including suitability for high-throughput
implementation, by an MLSCN Assay Access Committee convened by NIH. The results of
the reviews and information about available capacity at each center will form the
basis for assay prioritization and assignment decisions. The information will be
provided on a regular basis to the MLSCN Steering Group, which will make
recommendations about assay assignments. The NIH Project Team will provide a
second level of review of the decisions of the Steering Group and give final
approval for assay assignments on a time frame suitable to the screening capacity
and expertise of the centers. Applicants for this MLSCN RFA-RM-04-017 should
assume, therefore, a continuous and regular supply of new assays for
implementation, and do not need to address assay acquisition in their applications.
The applications should address the issue of evaluating and adapting assays for
high-throughput implementation and should present a clear plan for doing so.
The MLSCN centers will not have a privileged position relative to the rest of the
scientific community with respect to access to HTS services. Should the PI or any
other participant in an MLSCN center wish to implement an assay of their own
devising, they will have to submit that assay for review and prioritization
according to the process described in the previous paragraph. Should such an assay
be placed on the priority list, the NIH Project Team will take the PI’s interest
into account in assigning that assay to the requesting center.
3. Data Release. The MLSCN will function opening by making all data available to
the scientific community. It is expected that MLSCN centers will immediately
release data (i.e., screening data and assay descriptions) to PubChem as soon as
the data have been determined to be reliable. It is anticipated that the MLSCN
Steering Group will develop guidelines for standardizing the reliability/validation
of screening data for different types of assays across centers. Responses to this
RFA should include a statement of willingness to abide by the immediate data
release policy for submission of screening data to PubChem.
o MLSCN members will submit data to PubChem in the format specified by NCBI, the
lead on the PubChem initiative. PubChem staff at NCBI will suggest specific
formats for data deposition and will work with MLSCN centers as necessary to ensure
accurate transmission. For chemical structure data, it is anticipated that PubChem
will support, among others, existing formats such as SDF or MOL files. For
screening assay descriptions and results, it is anticipated that PubChem will
support depositions based on best current technologies including XML exchange
specifications. For chemical synthesis descriptions of small molecules in the
Repository, PubChem will support deposition of text descriptions and citations.
o Upon submission to PubChem, all data will be made freely available to the entire
research community in a form that would allow for redisplay and reanalysis, so that
maximal utility of this research resource will be realized. It is NIH’s
expectation that users of these data will respect the legitimate interests of the
producers to analyze and publish their results by treating the data as unpublished
information, until otherwise indicated. As with any unpublished data, it is
expected that users will provide proper citation of the source of the data.
o The individual investigators within the MLSCN may publish the results of their
own screening efforts. Neither these individual publications nor any MLSCN network
publications should delay the other’s publications.
o The MLSCN network may publish global analyses of the results of the screening
effort. The MLSCN Steering Group, with guidance from the External Scientific Panel
and the NIH Project Team, will establish a timeframe once the MLSCN has been
launched and there is a better understanding of the timeframe and scope of the
project.
o MLSCN members will fully disclose algorithms, software source code, and
experimental methods to the other members of the network for purposes of scientific
evaluation and will be strongly encouraged to make them available to the broad
research community.
4. Cost Sharing. Cost sharing by applicant institutions is not a requirement of
this RFA. NIH is aware that potential applicants will be in different stages of
their development of a Molecular Libraries Screening Center. Indeed, one of the
reasons that the MLSCN is being initiated as a pilot center phase is to provide
interested investigators and institutions with the opportunity to get involved in
HTS screening. At the same time, NIH is aware that a number of institutions have
already established such activities and have already committed institutional funds
to them. Cost sharing will not be a review criterion; any comments that reviewers
might make will be reported in an administrative note for consideration by program
staff.
In summary, the minimal features of a center within the MLSCN are:
o A specific set of expertise and skills in molecular screening.
o A capacity to implement innovative cell-based biochemical, biophysical, and
functional assays for biological targets and cell- or model organism-based
phenotypic assays.
o A plan with explicit milestones and timelines for achieving the three-year goal
of an annual capacity to screen 100,000 compounds in 20 different assays.
o An ability to adapt and modify HTS approaches, HTS-based assay protocols,
optimization chemistry, and computational chemistry as the technology and demands
on the center change.
o A capability to provide sufficient informatics to support LIMS, compound
tracking, data analysis, data handling, and data deposition to PubChem.
o A statement of the proposed center’s willingness to abide by the immediate data
release requirement for submitting screening data to PubChem.
o A sharing plan for access to any research resources generated by the proposed
centers.
o A plan for addressing if and how the proposed center will exercise intellectual
property rights, should any intellectual property be generated under a center
award, while making such research resources available to the broader scientific
community in accordance with the goals of the Roadmap Initiative.
o A technology development capability that will facilitate the integration of
technology improvements (e.g., robotics, assay miniaturization, chemistry, and
protocols) to increase the efficiency and decrease the cost of the center’s
screening capacity.
o A plan for center management addressing how the functional units will be
integrated and how key personnel will interact.
o A plan for implementing adequate quality control procedures including the
reproducibility of assay data, and carrying out effective quality assessment.
o A high degree of flexibility and ability to interact with other centers within
the MLSCN, the Coordinating Center, the Small Molecule Repository, PubChem, the NIH
Project Team and the proposed governance for the MLSCN, and with other entities
with whom it may be necessary to interact in order to make a maximum contribution
to the Roadmap Initiative.
MECHANISM OF SUPPORT
This RFA will use the NIH U54 award mechanism. As an applicant you will be solely
responsible for planning, directing, and executing the proposed project. The
anticipated award date is March 2005.
The U54 is a cooperative agreement award mechanism. In the cooperative agreement
mechanism, the Principal Investigator retains the primary responsibility and
dominant role for planning, directing, and executing the proposed project, with NIH
staff being substantially involved as a partner with the Principal Investigator, as
described under the section "Cooperative Agreement Terms and Conditions of Award".
This RFA uses just-in-time concepts. It also uses the non-modular budgeting
format. This program does not require cost sharing as defined in the current NIH
Grants Policy Statement at
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.
The NIH intends to issue a subsequent RFA to establish a MLSCN of three to five
larger-scale, fully operational centers with state-of-the art capabilities and with
a higher level of throughput than specified as the third-year goal of the pilot
MLSCN program (i.e., an annual capacity to screen 100,000 compounds in 20 different
assays optimized for HTS within the center per year). This future RFA will allow
funded pilot centers to apply for a competitive renewal award and will likely allow
applications from potential new centers. The initial period of support for a U54
center under the current RFA is expected to be three years.
FUNDS AVAILABLE
The NIH intends to commit approximately $20 million in FY2005 to fund approximately
6 or more new awards in response to this RFA. An applicant should request a
project period of 3 years. The budget (direct costs, excluding equipment) may not
exceed $1,000,000 in the first year, $2,000,000 in the second year, or $3,000,000
in the third year. The F&A costs (sometimes known as indirect costs) of
subcontractors will not count against these dollar limits. Costs for equipment may
be included in year one, up to $500,000; these costs will not count against the
$1,000,000 direct cost limit, but should be well justified. No limit is placed on
the allowable costs for equipment in the second and third years. Because the
nature and scope of the proposed research will vary from application to
application, it is anticipated that the size of each award will also vary.
Although the financial plans of the NIH provide support for this program, awards
pursuant to this RFA are contingent upon the availability of funds and the receipt
of a sufficient number of meritorious applications.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the following
characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals, and
laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic institutions/organizations
o Foreign institutions are not eligible to apply for an MLSCN center but can
participate as a subcontract within a center.
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
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.
DEFINITIONS
COORDINATING CENTER. A Coordinating Center will be established by NIH through a
contract, and will provide a range of important services to the MLSCN. The
Coordinating Center will assist in coordinating and tracking the activities of the
MLSCN and its component screening centers, and will maintain a website that will
provide up-to-date information on assays accepted for implementation in specific
MLSCN centers, compounds accepted for entry into the Repository, confirmed hits
within the network, and data depositions to PubChem. The Coordinating Center will
also provide administrative support to the MLSCN Assay Access Committee, which will
evaluate proposals from the research community for assays to be implemented by the
MLSCN, and to the MLSCN Compound Acquisition Committee, which will evaluate
requests for compounds to be incorporated into the Small Molecule Repository.
EXTERNAL SCIENTIFIC PANEL. The External Scientific Panel will be composed of 6-8
senior non-federal advisors who are not directly involved in the activities of the
MLSCN and who will be appointed by the NIH Project Team with concurrence from the
MLIIG. The External Scientific Panel will collectively provide expertise in
molecular screening and the needs of academic scientists who will utilize the
resources generated by the MLSCN, and will review the overall MLSCN program on a
regular basis and provide feedback and recommendations to the NIH Project Team and
the MLIIG.
MLSCN ASSAY ACCESS COMMITTEE. An NIH committee that will evaluate assay proposals
for scientific merit and feasibility. The Scientific Review Administrator (SRA)
for this panel will be an NIH review staff member and the panel members will be
primarily non-federal scientists approved by the NIH Project Team. Recommendations
of the MLSCN Assay Access Committee will be communicated to the NIH Project Team
and to the MLSCN Steering Group.
MLSCN COMPOUND ACQUISITION COMMITTEE. An NIH committee that will evaluate
proposals for the acquisition of small molecules from public and private sources
for the Small Molecule Repository. The SRA for this panel will be an NIH review
staff member and the panel members will be approved by the NIH Project Team.
Recommendations of the MLSCN Compound Acquisition Committee will be communicated to
the NIH Project Team and to the MLSCN Steering Group.
MOLECULAR LIBRARIES AND IMAGING IMPLEMENTATION GROUP (MLIIG). An oversight group
composed of the Directors of NHGRI, NIMH, and NIBIB, who are the chairs for the
Molecular Libraries and Imaging Roadmap Initiative, and the lead NIH staff for each
component of the Roadmap. The group will provide overall guidance for the MLSCN
program, coordination with other components of the Initiative, and resolution for
cases in which consensus cannot be reached by the MLSCN Steering Group and the NIH
Project Team. NIH Science Officers will not be voting members of the NIH Project
Team or the MLIIG.
MLSCN STEERING GROUP. The Steering Group for the overall MLSCN consisting of the
Director (PI) of each of the extramural screening centers, the PI of the NIH
Chemical Genomics Center (NCGC, the center housed in the NIH Intramural Research
Program), and the NIH Science Officer for each extramural center (defined below).
The NIH Science Officers may vote, and their total votes will count 1/2 as much as
the total votes of the MLSCN center PIs. The PI of the of the Small Molecule
Repository, the PI of the Coordinating Center, and the designated lead for PubChem
will be ex officio members. The Steering Group will be the primary operational
governing board of the MLSCN. The functions of this group include: 1)
recommending the assignment and scheduling of assays and tasks in conjunction with
the NIH Project Team; 2) developing guidelines to standardize the validation of
screening data in different types of assays across centers; 3) developing uniform
procedures and policies for assay validation, data quality measures, assessment
procedures, and annotation conventions for data depositions in conjunction with the
NIH Project Team and NCBI PubChem designee; 4) serving as a venue for coordination
on improving the state-of-the-art HTS in the academic sector by reporting progress,
disseminating best practices, and collectively evaluating new procedures,
resources, and technologies; 5) monitoring, developing, and implementing quality
control procedures that assure consistency across centers; 6) facilitating the
timely release of data in the format and on the schedule recommended by the MLSCN
Steering Group and implemented by the NIH Project Team; and 7) developing and
recommending progress report formats for both individual centers and for the MLSCN
Program as a whole to the NIH Project Team.
NIH PROJECT TEAM. The NIH Project Team will serve as the governing body that
coordinates and oversees the interaction of NIH with the centers and the MLSCN
Steering Group. The NIH Project Team is composed of representatives from each of
the NIH Institutes and Centers participating in the Molecular Libraries Initiative
and will be overseen by the MLIIG. The functions of the NIH Project Team include:
1) setting guidelines and policies for the MLSCN based on recommendations from the
MLSCN Steering Group; 2) nominating a rotating chair to communicate policy
information to the MLSCN Steering Group and Coordinating Center; 3) providing the
second level of review of the recommendations of the Assay Review Panel and the
Compound Review Panel; 4) overseeing the assignment of assays to specific centers
within the MLSCN; 5) overseeing the addition of new compounds to the Small Molecule
Repository; and 6) communicating information about the progress of each center and
the functions of the MLSCN Steering Group to the External Scientific Panel. NIH
Science Officers will not be voting members of the NIH Project Team or the MLIIG.
PUBCHEM. The NCBI database for the deposition of primary and secondary screening
data for compounds in the Small Molecule Repository that are tested in assays
optimized for HTS in the MLSCN, accession numbers for compounds in the NIH
repository, description of the assays and assay protocols implemented at each
center, depositor-supplied references to synthesis and/or isolation protocols for
the compounds, depositor-supplied references to sources and/or suppliers, and
computationally derived Lipinski parameters, if available. LinkOuts may be
established to capture additional biological data obtained in follow-up screening
carried out in the public or private sector (see
http://www.ncbi.nlm.nih.gov/entrez/linkout/).
SCREENING CENTER STEERING COMMITTEES (CSC). The Steering Committee for each
individual screening center (intramural and extramural centers) consisting of key
center personnel, external advisors, and the NIH Science Officer.
SPECIAL REQUIREMENTS
A. Public Domain of Data
The overall goal of the MLSCN program is to make biological screening data,
compounds, and assays readily available and accessible to the scientific community
for use in research. Restricted availability of unique research resources, upon
which further studies are dependent, can impede the advancement of research. The
NIH is interested in ensuring that the research resources developed through this
funding agreement become readily available to the broader research community in a
timely manner for further research, development, and application, in the
expectation that this will lead to products and knowledge of benefit to the public
health. It is expected that resources to be shared will include, among others, the
screening data, assay protocols, and materials.
To address the interests of the government in the availability of, and access to,
the results of publicly funded research, NIH requires applicants who respond to
this RFA to propose detailed plans for sharing the research resources generated
through the grant. It is expected that the resources to be shared include all
materials (e.g., screening data, and assay protocols) developed in projects funded
under the RFA. The investigator’s intent to make screening data available
immediately for deposition in PubChem, after certification for accuracy, should
also be specified in the application and will be considered during the review of
the plan for sharing.
The NIH proposes the following for applicants to consider for sharing data and
research resources:
1. HTS of non-proprietary compounds in the Small Molecule Repository. Compounds
identified as hits (initial positive candidate compounds) may not be considered
to be patentable because they would not likely be immediately useful as research
tools or a final product. These screening data should be made available
immediately for deposition in PubChem, after certification for accuracy. However,
under exceptional circumstances, if a non-proprietary compound were well-enough
developed to support the filing of a use invention, a waiver of the requirement for
immediate deposition of screening data would be considered by the NIH Project Team
and the MLSCN Steering Group. In such cases, a 60-day (calendar days) delay for
the deposition of the select screening data to PubChem by the MLSCN may be
acceptable to allow the MLSCN center applicant to file a patent on specific
compounds.
2. Synthetic chemistry and probe development. The generation of secondary
libraries around a confirmed, non-proprietary hit is likely to result in compounds
with enhanced affinity, specificity, and solubility in the target assay. Some of
these novel compounds may be valuable leads for further commercial development. In
such cases, and under exceptional circumstances, a 60-day (calendar days) delay for
the deposition of the select screening data to PubChem by the MLSCN may be
acceptable to allow the MLSCN center applicant to file a patent on specific
compounds if desired.
3. Assay implementation. Optimization of assays for HTS by the MLSCN centers may
require close interaction with the investigator who originally developed the assay.
In such cases, it should be recognized that co-inventorship of improved assay
inventions may result, dependent on the inventive contributions of the parties
involved. In cases where a patent would be filed for an assay, the requirement for
immediate deposition of screening data and assay description would be reconsidered
by the NIH Project Team and MLSCN Steering Group on a case-by-case basis, again
under exceptional circumstances. In such cases, a 60-day delay (calendar days) for
the deposition of the select screening data to PubChem by the MLSCN may be
acceptable to allow the MLSCN center applicant to file a patent on specific
compounds.
The investigator should also include a sharing plan for access to any other
research resources (e.g., HTS methods, development of technology to automate
and/or miniaturize assays for HTS, data analysis software, etc.) that are
expected to be generated by the proposed centers. It is important that
research resources and materials be made readily available to investigators
in the scientific community for research purposes. Research resources and
materials may also be made available to investigators for commercial purposes
with appropriate restrictions and licensing terms as the applicant and their
institution deem necessary. The plans for the development of resources for
use by the biomedical community should have the appropriate timeliness and
mileposts. In the development of the sharing and intellectual property
plans, applicants should confer with their own institution's office(s)
responsible for handling technology transfer related matters and/or their
sponsored research office. If applicants or their representatives require
additional guidance in preparing these plans, they are encouraged to make
further inquiries to the program contact listed below for such matters.
All awards made under this RFA are subject to the Final NIH Statement on Sharing
Research Data (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html)
and the Principles and Guidelines for Recipients of NIH Research Grants and
Contracts on Obtaining and Disseminating Biomedical Research Resources
(http://www.ott.nih.gov/policy/rt_guide_final.html).
The scientific review group will evaluate the adequacy of the proposed plan for
sharing and data access. Comments on the plan and any concerns will be presented in
an administrative note in the Summary Statement. These comments will not affect the
priority score of the application. The adequacy of the plan will be considered by
NIH program staff and will be a factor in determining whether the cooperative
agreement shall be awarded. The sharing plan approved by program staff, after
negotiation with the applicant when necessary, will become part of the terms and
conditions of the award. NIH program staff will evaluate the compliance with the
sharing plan and scientific progress in the non-competing continuation application;
such compliance will be a criterion for continued funding of the award.
B. Intellectual Property Rights and Accessibility of Research Resources
NIH is interested in ensuring that the research resources developed through this
RFA become readily available to the research community. NIH will convene a meeting
in May/June 2004 to further discuss intellectual property issues associated with
the Molecular Libraries and Imaging Probes Roadmap Initiative. Subsequent to that
meeting, NIH will develop a set of intellectual property guidelines for the
Initiative, and will post these guidelines in the NIH Guide prior to the receipt
date for this RFA. Applicants are expected to comply with the intellectual
property guidelines adopted by NIH for the MLSCN RFA.
Applicants who respond to this RFA should include a plan addressing if, or
how, they will exercise their intellectual property rights, should any
intellectual property be generated under a center award, while making such
research resources available to the broader scientific community for research
purposes consistent with the goals of the NIH Molecular Libraries and Imaging
Initiative. It is important that research resources and materials be made
readily available to qualified investigators in the scientific community for
research purposes. A reasonable time frame for release of materials should
be specified in the sharing plan and will be considered during the review.
Furthermore, transfers of research resources must be made consistent with the
NIH Research Tools Policy (http://www.ott.nih.gov/policy/rt_guide_final.html)
and other NIH sharing policies. In the development of the sharing and
intellectual property plans, applicants should confer with their own
institution's office(s) responsible for handling technology transfer related
matters and/or their sponsored research office. If applicants or their
representatives require additional guidance in preparing these plans, they
are encouraged to make further inquiries to the appropriate contacts listed
below for such matters.
As described previously, the NIH will be seeking public comments regarding
intellectual property issues at the Technical Assistance Workshop. Potential
applicants and other interested parties are invited to present comments as well as
provide alternative approaches that would serve to meet the objectives/goals of
this Initiative without the use of the deviation. All comments will be considered
and discussed at the meeting. Intellectual property issues will also be discussed
at a separate NIH meeting to be held in May/June. Both meetings will be used to
guide NIH policy for the MLSCN centers. If a Determination of Exceptional
Circumstances (DEC) were implemented, this clause deviation would serve to protect
the pre-existing and future patent rights of suppliers of proprietary compounds for
HTS in the MLSCN centers. If used, the proposed clause deviation would be narrowly
tailored to apply only to discoveries resulting from HTS of proprietary compounds,
and would provide, for example, title or exclusive rights to new use inventions to
the provider of the proprietary compounds, or otherwise dispose of the title and
rights in a way that would encourage the provision of proprietary compounds to the
centers. Furthermore, the MLSCN centers would have the right to request greater
rights if the supplier of the proprietary compound is not interested in the subject
invention.
The scientific review group will evaluate the adequacy of the proposed plan for
handling intellectual property rights. Comments on the plan and any concerns will
be presented in an administrative note in the Summary Statement. These comments
will not affect the priority score of the application. NIH program staff, in
determining whether the application shall be awarded, will consider the adequacy of
the proposed plan. The plan as approved, after negotiation with the applicant when
necessary, will be part of the terms and conditions of the award. Evaluation of
non-competing continuation applications will include assessment of the center
awardee's adherence to the proposed plan, and will be a criterion for continued
funding of the award.
Applicants also are reminded that the grantee institution is required to disclose
each subject invention to NIH within two months after the inventor discloses it in
writing to grantee institutional personnel responsible for patent matters. The
awarding Institute reserves the right to monitor awardee activity in this area to
ascertain if patents or patent applications on automation of biological assays,
genetically encoded reporters, cell lines, and vectors used in HTS-based assays, or
other patentable subject matter are adversely affecting the goals of this RFA.
Principles and guidelines for recipients of NIH research awards on obtaining and
disseminating biomedical research resources can be found at
http://www.ott.nih.gov/policy/rt_guide_final.html. This document also defines
terms, parties, responsibilities, prescribes the order of disposition of rights,
prescribes a chronology of reporting requirements, and delineates the basis for and
extent of government actions to retain rights. Patent rights clauses may be found
at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page,
http://www.iedison.gov.
COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD
As part of the U54 Specialized Center Grant process, the following Terms and
Conditions of Award and details of the arbitration procedures pertaining to the
scope and nature of the interaction between the NIH staff and the participating
awardees will be incorporated into the Notice of Grant Award and provided to the
Principal Investigator and the institutional official at the time of award. These
procedures will be in addition to the customary programmatic and financial
negotiations that occur in the administration of grants.
Cooperative agreements are assistance mechanisms subject to the same administrative
requirements as grants. The special Terms and Conditions of Award are in addition
to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS
Grant Administration Regulations at 45 CFR Part 74 and 92, and other HHS, PHS, and
NIH grant administration policies and procedures. Cooperative Agreements are
subject to the administrative requirements outlined in pertinent OMB, HHS, PHS, and
NIH guidelines, with particular emphasis on HHS regulations at 42 CFR Part 52 and
45 CFR Part 74. Facilities and Administrative Cost (indirect cost) award
procedures will apply to cooperative agreement awards in the same manner as for
grants.
The administrative and funding instrument used for this program is a Cooperative
Agreement (U54), an "assistance" mechanism (rather than an "acquisition" mechanism)
in which substantial NIH scientific and/or programmatic involvement with the
awardee is anticipated during performance of the activity. Under the cooperative
agreement, the NIH purpose is to support and/or stimulate the recipient's activity
by involvement in and otherwise working jointly with the award recipient in a
partner role, but it is not to assume direction, prime responsibility, or a
dominant role in the activity. Consistent with this concept, the dominant role and
prime responsibility for the activity resides with the awardee(s) for the project
as a whole, although specific tasks and activities in carrying out the studies will
be shared among the awardees and NIH Science Officers (defined below).
Failure of the awardees to meet the performance requirements, including these
special terms and conditions of award, or significant changes in level of
performance, may result in a reduction of budget, withholding of support,
suspension and/or termination of the awards.
1. Awardee Rights and Responsibilities
The PI will coordinate project activities scientifically and administratively at
the awardee institution. The PI will have primary responsibility for defining the
details for the projects within the guidelines of this RFA RM-04-017, and for
performing all scientific activities. The PI will agree to accept the close
coordination, cooperation, and participation of the NIH Science Officer(s), the NIH
Project Team, the MLSCN Steering Group, the Molecular Libraries Coordinating
Center, and Molecular Libraries External Scientific Panel in those aspects of
scientific and technical management of the project as described below.
Specifically, the PI will:
o Determine experimental approaches, design protocols, set project milestones, and
conduct experiments.
o Propose protocol modifications as required.
o Analyze and interpret research data.
o Provide goals for assay optimization, screening throughput, quality, and cost to
the NIH Science Officer and/or Program Officer as requested, usually at the outset
of the award and in six-month progress reports, but also at other times if
requested.
o Release data according to the approved plans for timely sharing of research
resources and data generated through the award, and publish results, as agreed upon
by the MLSCN Steering Group and the NIH Project Team.
o Ensure that primary and secondary screening data and assay protocols are
deposited in a centralized database, PubChem, according to the timeline implemented
by the NIH Project Team.
o Establish a Center Steering Committee (CSC) consisting of key center personnel,
external scientific advisors, and the NIH Science Officer, and prepare a concise
summary of their meeting within 30 days.
o Serve on the MLSCN Steering Group.
o Provide information to the NIH Program Officer concerning progress, by submitting
periodic progress reports in a standard format, as agreed upon by MLSCN Steering
Group.
o Accept and implement all scientific, practical, and policy decisions approved by
the MLSCN Steering Group and the NIH Project Team.
o Share with other MLSCN facilities research resources, tools, and data of interest
to those facilities, as directed by the MLSCN Steering Group and agreed upon by the
NIH Project Team.
o Participate, along with critical staff, in the MLSCN Steering Group meetings held
twice annually in the metropolitan Washington, DC area.
o Be prepared for annual administrative site visits by NIH staff
Note: The NIH Intramural Research Program’s NIH Chemical Genomics Center (NCGC)
will participate with the same rights and responsibilities, and within the same
governing structure, as the extramural awardees.
2. Coordinating Center
A Coordinating Center will be established by NIH as a contract, and will provide a
range of important services to the MLSCN. The Coordinating Center will assist in
coordinating and tracking the activities of the MLSCN and its component screening
centers, and will maintain a website that will provide up-to-date information on
assays accepted for implementation in specific MLSCN centers, compounds accepted
for entry into the Repository, confirmed hits within the network, and data
depositions to PubChem. The Coordinating Center will also provide administrative
support to the MLSCN Assay Access Committee, which will evaluate proposals from the
research community for assays to be implemented by the MLSCN, and to the MLSCN
Compound Acquisition Committee, which will evaluate requests for compounds to be
incorporated into the Small Molecule Repository.
3. NIH Science Officers
The NIH Science Officers will be NIH program staff who will have substantial
scientific involvement during the conduct of this activity, through technical
assistance, advice, and coordination above and beyond normal program stewardship
for grants. This includes functioning as a peer with the PIs, facilitating the
partnership relationship between NIH and the facilities funded under this RFA,
helping to maintain the overall scientific balance in the program commensurate with
new research and emerging research opportunities, and ensuring that the activities
of the MLSCN centers are consistent with the mission of the NIH Molecular Libraries
and Imaging Initiative. Each MLSCN center will have a designated NIH Science
Officer, and a given individual may be the NIH Science Officer for more than one
center. The NIH Science Officers will be selected by the NIH Project Team.
The NIH Science Officers will:
o Provide relevant scientific expertise and overall knowledge.
o Assist in avoiding unwarranted duplication of effort across centers, and help
coordinate collaborative research efforts that involve multiple centers.
o Review and comment on critical stages in the research program before subsequent
stages are implemented.
o Assist in the interaction between the awardee and investigators at other
institutions.
o Provide information about ongoing NIH-supported research and resources.
o Attend Center Steering Committee (CSC) meetings as a voting member, and assist in
developing operating guidelines, quality control procedures, and consistent
policies for dealing with recurrent situations that require coordinated action in
conjunction with the MLSCN and the NIH Coordinating Center.
o Attend the MLSCN Steering Group meetings as a voting member, and assist in the
group process of setting research priorities and milestones, deciding optimal
research approaches and protocol designs, and contributing to the adjustment of
research protocols or approaches as warranted. The Science Officer will assist and
facilitate the group process and not direct it.
o Serve as scientific liaison between the awardees, other NIH program staff, and
the NIH Project Team.
o Assist in developing timelines for the wide distribution of screening data to the
scientific community.
o Retain the option to recommend additional research endeavors within the
constraints of the approved research and negotiated budget.
o Retain the option to recommend re-allocation of NIH support among awardees, as
scientific goals evolve.
o To help carry out these duties, Science Officers may consult with non-NIH experts
in the field.
4. NIH Program Officer:
The awarding Institute will appoint a Program Officer who will have responsibility
for normal program oversight and stewardship of the MLSCN centers. The Program
Officer may also serve as the designated Science Officer.
The NIH Program Officer will:
o Exercise the normal stewardship responsibilities of an NIH Program Officer.
o Carry out continuous review of all activities to ensure objectives are being met.
o Attend CSC meetings as a non-voting participant, if not also participating as a
Science Officer.
o Attend the MLSCN Steering Group meetings as a non-voting participant, if not also
participating as a Science Officer.
o Have the option to recommend, with the advice of the External Scientific Panel,
the withholding or reduction of support from any center that substantially fails to
achieve its goals according to the milestones agreed to at the time of the award,
fails to maintain state-of-the-art capabilities, or fails to comply with the Terms
and Conditions of the award.
5. NIH Project Team Responsibilities
The NIH Project Team will serve as the governing body that coordinates and oversees
the interaction of NIH with the MLSCN centers and the MLSCN Steering Group. The
Project Team membership will include representatives from each of the NIH
Institutes and Centers participating in the Molecular Libraries and Imaging
Initiative or their designated representative. Science Officers will be ex officio
(non-voting) members of the NIH Project Team. The Project Team will receive
recommendations from the MLSCN Steering Group and will be overseen by the MLIIG.
The NIH Project Team will:
o Set guidelines and policies for the MLSCN based on recommendations from the MLSCN
Steering Group.
o Nominate a rotating chair to communicate policy information to the MLSCN Steering
Group, Coordinating Center, Small Molecule Repository, and PubChem.
o Review recommendations of the MLSCN Steering Group for the distribution of assays
to each of the centers within the MLSCN and make final assignments of individual
assays to specific centers on a timetable that will ensure efficient operation of
the Network.
o Oversee the addition of new compounds to the Small Molecule Repository.
o Communicate information about the progress of each center, the MLSCN program, and
other components of the Molecular Libraries and Imaging Initiative, as well as
activities of the MLSCN Steering Group, to the External Scientific Panel.
6. Collaborative Responsibilities: MLSCN Steering Group Functions
The MLSCN Steering Group is the operational governing board responsible for overall
coordination of the MLSCN program, and the committee through which the NIH Project
Team interacts and collaborates with the individual screening centers. The MLSCN
Steering Group membership will include the PI of each of the extramural centers and
the NCGC (the NIH intramural center) and the NIH Science Officers. The PIs of the
Small Molecule Repository, Coordinating Center, and PubChem will be ex officio
(non-voting) members. The MLSCN Steering Group will coordinate the activities of
the centers and the dissemination of screening data, assay protocols, and other
materials with the wider scientific community. The External Scientific Advisory
Panel recommendations will be addressed by the MLSCN Steering Group.
The PI of each center (or designee) will have one vote on the MLSCN. The NIH
Science Officers may vote, and their total votes will count 1/2 as much as the
total votes of the center PIs. Center membership on the Steering Group becomes
effective upon issuance of the Notice of Grant Award. The Steering Group may
establish additional by-laws, subcommittees, or workgroups for specific tasks. The
NIH Science Officers may not chair any committee or subcommittee.
The MLSCN Steering Group meetings will be convened at least twice yearly; one of
these meetings will be in conjunction with the annual meeting of the External
Scientific Panel to allow the MLSCN center Directors to meet directly with the
External Scientific Panel. The purpose of these meetings is to assess scientific
progress, identify new research opportunities, establish priorities, consider
policy recommendations, and discuss strategy. MLSCN Steering Group decisions will
be made by a majority vote of a quorum, with an attempt for consensus when
possible. A quorum is the presence of a majority of the center Directors and at
least one Science Officer. The MLSCN Steering Group can convene through telephone
conference or in person. Outside consultants/experts may be asked to participate
in these discussions as nonvoting advisors. The MLSCN Steering Group may also be
used to endorse HTS methods, standard operating procedures for quality control,
assay validation, data analysis, and data deposition formats that will be used
across multiple centers.
The MLSCN Steering Group will:
o Recommend the assignment and scheduling of assays and tasks in conjunction with
the NIH Project Team.
o Develop guidelines to standardize the validation of screening data in different
types of assays across centers.
o Develop uniform procedures and policies for assay validation, data quality
measures, assessment procedures, and annotation conventions for data depositions in
conjunction with the NIH Project Team and NCBI PubChem designee.
o Serve as a venue for coordination on improving the state-of-the-art HTS in the
academic sector by reporting progress, disseminating best practices, and
collectively evaluating new procedures, resources, and technologies.
o Monitor, develop, and implement quality control procedures that assure
consistency across centers.
o Facilitate the timely release of data in the format and on the schedule
recommended by the MLSCN Steering Group and implemented by the NIH Project Team.
o Develop and recommend progress report formats for both individual centers and for
the MLSCN Program as a whole to the NIH Project Team.
Any center Director who considers a MLSCN Steering Group decision unacceptable may
appeal by following the arbitration procedure described below.
7. External Scientific Panel
The External Scientific Advisory Panel will be responsible for reviewing and
evaluating the progress of the MLSCN centers in meeting their individual and
collective milestones and goals, and make recommendations about the progress of
both the overall MLSCN Network and the individual centers to the NIH Project Team
and the MLIIG. The External Scientific Panel will provide recommendations to the
NIH Project Team and the MLIIG in relation to the evolving goals of the trans-NIH
Molecular Libraries and Imaging Initiative, and the accomplishments and progress of
the MLSCN Network.
The External Scientific Panel will be composed of 6-8 senior non-federal advisors
who are not directly involved in the activities of the MLSCN and who will be
appointed by the NIH Project Team with concurrence from the MLIIG. The NIH Project
Team will select one member to be the committee chair, after considering the
External Scientific Panel’s recommendations for chair. The chair will schedule the
first meeting, develop meeting agendas, and chair the meetings. The membership of
the Panel may be enlarged permanently, or on an ad hoc basis by action of the
original members. The Science Officer(s) will attend the External Scientific Panel
meetings as non-voting participants. Other NIH staff and MLSCN members may attend
the External Scientific Panel meetings when their expertise is required for
specific discussions. The External Scientific Panel will meet at least once a
year. During part of this meeting, there will be a joint meeting with the MLSCN
Steering Group to allow the Panel members to interact directly with the MLSCN
center Directors, including the PI of the NCGC, and the PIs of the Small Molecule
Repository, Coordinating Center, and PubChem. Annually, the External Scientific
Panel will make recommendations regarding the overall progress of the MLSCN and the
progress of the individual centers, and then provide advice regarding any changes
that may be needed in the direction of the MLSCN program to the NIH Project Team
and the MLIIG. The External Scientific Panel will also be consulted by the NIH
Science and/or Program Officer(s) in the case that changes in a center’s funding
level are being considered because of poor technical performance.
8. Public Domain of Data
All awards made under this RFA are subject to the Final NIH Statement on Sharing
Research Data (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html)
and the Principles and Guidelines for Recipients of NIH Research Grants and
Contracts on Obtaining and Disseminating Biomedical Research Resources
(http://www.ott.nih.gov/policy/rt_guide_final.html).
It is expected that research resources generated through the award will be shared
by awardees according to approved sharing plans that will include, among others,
the screening data, assay protocols, and materials. The plans for the development
of resources for use by the biomedical community will have the appropriate
timelines and mileposts. NIH program staff will evaluate the compliance with the
sharing plan and scientific progress in the non-competing progress report (Form
2590); such compliance will be a criterion for continued funding of the award.
9. Intellectual Property Rights
Awardees are expected to comply with the intellectual property guidelines adopted
by NIH for the MLSCN RFA. In the interim, awardees will comply with their approved
plan for addressing if, or how, they will exercise their intellectual property
rights, should any intellectual property be generated under a center award, while
making such research resources available to the broader scientific community
consistent with the goals of the NIH Molecular Libraries and Imaging Initiative.
The plan will include a reasonable time frame for release of materials. This plan
will also include disclosure of any pre-existing agreements involving intellectual
property rights, including options to for-profit research sponsors that are
associated with biomaterials and data that may be generated.
The majority of transfers to not-for-profit entities should be implemented under
terms no more restrictive than the Uniform Biological Materials Transfer Agreement
(UBMTA). In particular, recipients are expected to use the Simple Letter Agreement
provided at http://www.nih.gov/od/ott/RTguide_final.htm, or another document with
no more restrictive terms, to readily transfer unpatented tools developed with NIH
funds to other recipients for use in NIH-funded projects. If the materials are
patented or licensed to an exclusive provider, other arrangements may be used, but
commercialization option rights, royalty reach-through, or product reach-through
rights back to the provider are inappropriate. Similarly, when for-profit entities
are seeking access to NIH-funded tools for internal use purposes, recipients should
ensure that the tools are transferred with the fewest encumbrances possible. The
Simple Letter Agreement may be expanded for use in transferring tools to for-profit
entities, or simple internal use license agreements with execution or annual use
fees may be appropriate.
NIH program staff will evaluate the compliance with the sharing plan and scientific
progress in the non-competing progress report (Form 2590); such compliance will be
a criterion for continued funding of the award.
10. Progress Reviews/Milestones and Evaluations
The progress of the MLSCN centers will be reviewed annually by the NIH Program
Officer(s), the External Scientific Panel, and the NIH Project Team to assure that
satisfactory progress is being made in achieving the project objectives. During
the first year of funding, and during subsequent years if deemed necessary by the
Program Officer(s) and the NIH Project Team, reviews may be more frequent. The
adherence of the MLSCN centers to the approved data sharing plan and intellectual
property plans, which will be part of the Terms and Consitions of award, will also
be reviewed annually. Should problems arise in the conduct of the study, the NIH
Program Officer(s) may require that the center awardee submit quarterly reports on
progress and fiscal matters.
The progress report will have two components. The first will be the standard NIH
progress report (Form 2590). The second will be a more specialized report that
will be developed by the MLSCN Steering Group in collaboration with the NIH Project
Team. This specialized report should be included as an attachment to the standard
progress report and will go to the NIH Program Officer(s) and the NIH Project Team.
The contents or the report may be changed according to programmatic needs, based on
discussion between NIH Program Officers, the center PI, and the MLSCN Steering
Group.
The center awardees' yearly milestones will be provided to the Science Officers(s),
the NIH Project Team, the MLSCN Steering Group, the MLIIG, and the External
Scientific Panel. It is expected that the milestones will be adjusted annually at
the award anniversary dates, both to incorporate the group's scientific
accomplishments and progress, as well as to reflect any recommendations of the NIH
Project Team and the External Scientific Panel. Following the review of
milestones, the NIH Project Team may recommend reducing or withholding funds for
any center/center project that substantially fails to meet its milestones or, if
the situation warrants, augmenting any center/center project. However, simply
meeting milestones may not be considered sufficient accomplishment for maintaining
funding at the initially committed level. Failure to remain at state-of-the-art
will also be considered grounds for reduction in funding levels.
11. Arbitration Process
Any disagreements that may arise in scientific or programmatic matters within the
scope of the award between recipients and the NIH may be brought to arbitration.
This special arbitration procedure in no way affects the center awardee's right to
appeal an adverse action in accordance with PHS regulations 42 CFR Part 50, Subpart
D and HHS regulation at 45 CFR Part 16. An Arbitration Panel will help resolve
both scientific and programmatic issues that develop during the course of work that
restrict progress. The Arbitration Panel will be composed of three members: a
designee of the MLSCN chosen without the NIH staff voting, one designee of the NIH
Project Team, and a third designee with expertise in the relevant area who is
chosen by the other two (in the case of an individual disagreement, the first
member will be chosen by the individual awardee rather than by MLSCN).
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and welcome the opportunity to answer
questions from potential applicants. Inquiries may fall into three areas:
scientific/research, peer review, and financial or grants management issues:
o Direct your questions about scientific/research issues to:
Linda Brady, Ph.D.
Project Team Leader, MLSCN
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7185, MSC 9641
Bethesda, MD 20892-9641
Rockville, MD 20852-9641 (for express/courier service)
Telephone: (301) 443-5288
FAX: (301) 402-4740
Email: lbrady@mail.nih.gov
o Direct your questions about peer review issues to:
Michael Kozak, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6138, MSC 9608
Bethesda, MD 20892-9608
Rockville, MD 20852-9608 (for express/courier service)
Telephone: (301) 443-1340
FAX: (301) 443-4720
Email: kozakm@mail.nih.gov
Rudy Pozzatti, Ph.D.
Office of Scientific Review
National Human Genome Research Institute
Building 31, Room B2B37, MSC 2032
Bethesda, MD 20982-2032
Telephone: (301) 402-0838
FAX: (301) 435-1580
Email: Rudy_Pozzatti@nih.gov
o Direct your questions about financial or grants management matters to:
Rebecca Claycamp
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6122, MSC 9605
Bethesda, MD 20892-9604
Telephone: (301) 443-3858
FAX: (301) 443-6885
Email: rclaycam@mail.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes the
following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does not enter
into the review of a subsequent application, the information that it contains
allows IC staff to estimate the potential review workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning of this
document. The letter of intent should be sent to:
Linda Brady, Ph.D.
Project Team Leader, MLSCN
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7185, MSC 9641
Bethesda, MD 20892-9641
Rockville, MD 20852-9641 (for express/courier service)
Phone: (301) 443-5288
FAX: (301) 402-4740
Email: lbrady@mail.nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). 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 DUNS number can be
obtained by calling (866) 705-5711 or through the web site at
http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of
the face page of the PHS 398 form. The PHS 398 document is available at
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format.
For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email:
GrantsInfo@nih.gov.
Applicants are strongly encouraged to call the NIH Roadmap Project Team Leader
listed under INQUIRIES with any questions regarding the responsiveness of their
proposed project to the goals of this RFA. Applications for the U54 cooperative
agreement are to be prepared in a manner consistent with the information presented
in this RFA.
SPECIFIC INSTRUCTIONS FOR PREPARING AN APPLICATION
Applications are to be submitted on Form PHS 398
(http://grants.nih.gov/grants/funding/phs398/phs398.html). All instructions and
guidelines accompanying the PHS 398 are to be followed, with the exception of the
sections modified by the specific instructions described below.
It is recognized that the applications in response to this RFA will be longer and
more complex than many other NIH applications. In order to ensure effective
review, the application should be well organized. In particular, the five
functions identified earlier in the RFA (Assay Optimization, HTS Implementation,
Synthetic Chemistry and Probe Development, Informatics, and Administration and
Management) must be clearly addressed. For example, if the applicant has chosen to
organize the proposed center into Cores corresponding to these functions, the
Research Plan section may be divided into five corresponding sections. An
applicant who has decided to organize the proposed center differently should,
nevertheless, organize the application so that these functions are clearly
identified.
Form Page 3: In lieu of the preprinted Table of Contents outline on Form Page 3 of
PHS 398, a Table of Contents should be prepared listing the information described
below.
ORGANIZATION OF THE APPLICATION:
The application should be organized as follows:
Face Page; Description, Performance Sites, and Personnel; Detailed Budget for
Entire Proposed Period of Support; Introductory Overview; First Functional Unit
Detailed Budget for Initial Budget Period, Budget Justification, Biographical
Sketch Principal Investigators/Program Director, Other Biographical Sketches,
Resources, Research Plan, and Appendix; Additional Functional Units (e.g., Cores 2,
3, 4, and 5) - information should be organized sequentially for each Core as
indicated for the First Functional Unit.
Form Pages 4-5: The budget should be completed as described in the instruction
sheet for Application for a Public Health Service Grant (Form PHS 398). Form page
4 (the detailed budget page) should be provided for each of the five functional
units, and for any subcontractual or consortium agreements. A separate overall
budget for the three-year project period should also be prepared using form page 4.
The budget justification beginning on PHS Form Page 5 should include a detailed
justification for key personnel. As part of the justification, the percent effort
that all staff are spending on each functional unit should be specified. A
detailed budget justification should also be provided for any subcontractual or
consortium agreements.
A detailed justification should also be supplied for equipment over $25,000
requested for the center. Equipment costs are allowable up to $500,000 in year
one. Existing equipment should also be described. No limit is placed on the
allowable costs for equipment in the second and third years, but equipment costs
should be well justified.
INTRODUCTORY OVERVIEW (5 pages):
Provide an overview of the proposed center describing the central theme or concept
and goals. Describe how the overall center can contribute to the MLSCN Research
Network to achieve the overall goals of the Molecular Libraries and Imaging
Initiative. Explain the proposed contribution of each of the functional units in
achieving the objectives of the center.
NOTE:
Applicants to this RFA will not be expected to already have all of the necessary
capabilities in place. The purpose of this RFA is to provide support for their
development, so that by the end of the three-year pilot phase, centers will be
fully operational and capable of providing HTS capacity to the academic scientific
community.
FUNCTIONAL UNITS:
Identify each proposed functional unit by title and present the information as
follows: Detailed Budget for Initial Budget Period; Budget Justification;
Biographical Sketch Principal Investigators/Program Director; Other Biographical
Sketches; Resources; Research Plan; and Appendix.
RESEARCH PLAN (50 pages overall, excluding the Introduction):
Introduction:
Provide a brief overview of the functional unit, its activities, and how the key
personnel will interact and coordinate with the other functional units.
The 50-page limit for this section of the application is the total of sections A
through D (specific aims, background and significance, preliminary/feasibility
studies, and experimental design and methods) for all of the functional units
together.
In the Research Plan section of the application, the applicant should clearly
describe existing capabilities, plans for acquiring additional needed capabilities,
and a clear plan for scaling up those capabilities so that by the end of the three-
year pilot phase, the center will have the capacity to screen, at minimum, 100,000
compounds in 20 assays, optimized by the center for HTS, per year.
Form Page 8, Resources: Complete the resources section for each of the functional
units. Describe the features of the institutional environment that are or would be
relevant to the effective implementation of the proposed MLSCN program. As
appropriate, describe available resources, such as equipment, cell culture
facilities, laboratory facilities, participating and affiliated units, geographical
distribution of space and personnel, and consultative resources. Include a letter
documenting institutional commitment to the MLSCN program, including provision of
funding, space, faculty positions, and/or commitments for construction or
renovation. Use continuation pages as needed.
Appendix: Appendix materials are limited to a total of 10 publications directly
relevant to the MLSCN program and original glossy photographs or color images
provided that a photocopy is included in the Research Plan.
Supplemental Materials: Supplemental materials submitted between the application
due date and the time of review are limited to a total of 2 pages per application.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001)
application form 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.
SENDING AN APPLICATION TO THE NIH: 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
Bethesda, MD 20817 (for express/courier service)
At the time of submission, 2 additional copies of the application, including all
appendix material, must be sent to:
Jean G. Noronha, Ph.D.
Molecular Libraries and Imaging Roadmap
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6154, MSC 9609
Bethesda, MD 20892-9609
Rockville, MD 20852 (for courier/express service)
Telephone: (301) 443-3367
FAX: (301) 443-4720
Email: jnoronha@mail.nih.gov
APPLICATION PROCESSING: Applications must be received on or before the application
receipt date listed in the heading of this RFA. If an application is received
after that date, it will be returned to the applicant without review.
Although there is no immediate acknowledgement of the receipt of an application,
applicants are generally notified of the review and funding assignment within 8
weeks.
The Center for Scientific Review (CSR) will not accept any application in response
to this RFA 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 an RFA, it is to be prepared as a
NEW application. That is, the application for the RFA 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.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIH Project Team. Incomplete and/or non-responsive
applications will be returned to the applicant without further consideration.
Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened jointly
by the Center for Scientific Review, the National Institute of Mental Health, and
the National Human Genome Research Institute in accordance with the review criteria
stated below. As part of the initial merit review, all applications will:
o Undergo a process in which only those applications deemed to have the highest
scientific merit, generally the top half of the applications under review, will be
discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Mental Health Advisory Council.
In addition, because of the trans-NIH nature of the Roadmap Program, all
applications submitted in response to Roadmap Initiatives will be provided for
informational purposes to the National Advisory Councils of all NIH Institutes and
Centers.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of biological
systems, improve the control of disease, and enhance health. In the written
comments, reviewers will be asked to evaluate the application in order to judge the
likelihood that the proposed research will have a substantial impact on the pursuit
of these goals. The scientific review group will address and consider each of the
following criteria in assigning the application’s overall score, weighting them as
appropriate for each application.
o Significance
o Approach
o Innovation
o Investigator
o Environment
The 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 or methods that drive this field?
APPROACH: Are the conceptual framework, design, methods, and analyses adequately
developed, well integrated, and appropriate to the aims of the project? Does the
applicant acknowledge potential problem areas and consider alternative tactics?
INNOVATION: Does the project employ novel concepts, approaches or methods? Are the
aims original and innovative? Does the project challenge existing paradigms or
develop new methodologies or technologies?
INVESTIGATOR: Is the investigator 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 (if any)?
ENVIRONMENT: Does the scientific environment in which the work will be done
contribute to the probability of success? Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements? Is there evidence of institutional support?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items
will be considered in the determination of scientific merit and the priority score:
A. Center as a Whole
1) The potential for impact
2) Degree of synergy, i.e., does the center as a whole serve a purpose greater than
the sum of the individual components?
3) Effectiveness of the proposed center in meeting the goals of the Molecular
Libraries and Imaging Initiative
B. Individual Functional Units
1) How effective is the overall organization of the proposed functional units in
relation to the center's goals?
2) Will each functional unit enhance collaborative and/or interdisciplinary
research within the center and the wider research community?
3) Would any proposed optional functional units duplicate existing resources or
services? If so, are the requested new resources justified?
4) The quality of the facilities or services provided by this functional unit
(including procedures, techniques, and quality control).
5) The qualifications, experience, and commitment of the personnel involved in the
functional unit.
C. Data Management
1) Are data management and support procedures developed sufficiently to allow
tracking of compounds, assays, and screening data? Are procedures in place for
quality control and quality assessment for assay and screening procedures?
D. Program Administration and Management
1) Does the PI have the scientific and organizational vision and experience to
serve effectively as the center Director?
2) Is there evidence of sufficient management capabilities for the center that
include fiscal administration, procurement, property and personnel management,
planning, and budgeting?
E. Facilities
1) Are facilities adequate for the overall functions of the center and to implement
the goals of the Molecular Libraries Screening Centers Program?
G. Institutional Commitment
1) Is there evidence for institutional commitment to the program, including
provision of funding, space, faculty positions, and/or commitments for construction
or renovation?
2) Are the research environment and resources, including equipment and facilities,
adequate? Is there potential for interaction with scientists from other
departments and components?
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects
and protections from research risk relating to their participation in the proposed
research will be assessed. (See criteria included in the section on Federal
Citations, below).
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to
include subjects from both genders, all racial and ethnic groups (and subgroups),
and children as appropriate for the scientific goals of the research. Plans for
the recruitment and retention of subjects will also be evaluated. (See Inclusion
Criteria in the sections on Federal Citations, below).
CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be
used in the project, the five items described under Section f of the PHS 398
research grant application instructions (rev. 5/2001) will be assessed.
ADDITIONAL REVIEW CONSIDERATIONS
BUDGET: The reasonableness of the proposed budget and the requested period of
support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: July 26, 2004 (see change NOT-RM-04-016)
Application Receipt Date: August 24, 2004 (see change NOT-RM-04-016)
Peer Review Date: November/December 2004
Council Review: January/February 2005
Earliest Anticipated Start Date: March 1, 2005
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities
o Programmatic balance: The purpose of the MLSCN program is to develop a network
of pilot centers with complementary capabilities that will allow the network to
address a wide range of biological opportunities. Therefore, decisions about
awards will consider the mix of capabilities offered by the proposed centers.
o Adequacy of proposed plans for sharing data, research resources, and for
exercising intellectual property rights: The goals of the MLSCN program are to
make screening data publically available through PubChem and to identify/generate a
diverse set of research tools (probes, assays) to explore biology and disease
mechanisms. Therefore, decisions about awards will consider the responsiveness of
the above-mentioned plans to the spirit of the Roadmap Initiative.
REQUIRED FEDERAL CITATIONS
ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities
involving live, vertebrate animals must comply with PHS Policy on Humane Care
and Use of Laboratory Animals
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as
mandated by the Health Research Extension Act of 1985
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA
Animal Welfare Regulations
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on
hESCs can be found at http://stemcells.nih.gov/index.asp and at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research
using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry
will be eligible for Federal funding (see http://escr.nih.gov). It is the
responsibility of the applicant to provide, in the project description and
elsewhere in the application as appropriate, the official NIH identifier(s) for the
hESC line(s)to be used in the proposed research. Applications that do not provide
this information will be returned without review.
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 applications 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.healthypeople.gov/.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal
Domestic Assistance at http://www.cfda.gov/ and is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health Systems
Agency review. Awards are made under the authorization of Sections 301 and 405 of
the Public Health Service Act as amended (42 USC 241 and 284) and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the
terms and conditions, cost principles, and other considerations described in the
NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at
http://grants.nih.gov/grants/policy/policy.htm
The PHS strongly encourages all grant recipients to provide a smoke-free workplace
and discourage the use of all tobacco products. In addition, Public Law 103-227,
the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some
cases, any portion of a facility) in which regular or routine education, library,
day care, health care, or early childhood development services are provided to
children. This is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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