CENTERS OF EXCELLENCE IN CHEMICAL METHODOLOGIES AND LIBRARY DEVELOPMENT
 
RELEASE DATE:  December 17, 2002 
 
RFA:  GM-03-004 (Reissued as RFA-GM-08-007)

 
National Institute of General Medical Sciences (NIGMS)
 (http://www.nigms.nih.gov)

LETTER OF INTENT RECEIPT DATE:  January 24, 2003

APPLICATION RECEIPT DATE:  February 20, 2003
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism 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 Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The purpose of this RFA is to reannounce and to update the National 
Institute of General Medical Sciences (NIGMS) program of "Centers of 
Excellence in Chemical Methodologies and Library Development" (CMLD 
Centers), last issued as RFA-GM-01-006 in June 2001.

The goal of this program is to stimulate the establishment of multi-
investigator research centers whose mission will be to develop 
efficient, general, state-of-the-art methodologies for the design, 
synthesis, analysis, and handling of chemical diversity libraries.  The 
CMLD Centers will feature collaborations and team approaches that 
otherwise would not be established, including individuals from various 
subdisciplines within the field of chemistry and/or from cognate 
fields, that will develop novel enabling methodologies.

Each Center will establish a library synthesis core facility that will 
serve two purposes.  First, the library synthesis core will validate 
newly-developed methodologies for application to diversity-oriented 
synthesis (also known as combinatorial chemistry).  Second, the library 
synthesis core will apply newly-developed chemical methodologies and 
strategies to the generation of chemical diversity libraries for high-
throughput biological screening.  This will provide "real world" tests 
of the utility of new methodologies and will also facilitate the study 
of complex biological phenomena.  Each Center must develop a plan for 
outreach to the biology research community.

The essential goals of the CMLD Centers program are to discover and to 
implement fundamental new chemistry that will facilitate access to 
high-quality libraries of expanded diversity.
 
RESEARCH OBJECTIVES
 
Background

Consistent with the stated mission of NIGMS, which is to support "basic 
biomedical research that is not targeted to specific diseases, but that 
increases understanding of life processes...," the rationale behind 
this RFA is that advances in fundamental, enabling methodologies for 
chemical diversity libraries will produce lasting benefits for all of 
biomedical science, including biology and medicine.

Until recently, the predominant approach to drug discovery has involved 
in vivo and/or in vitro testing of individual, purified compounds, both 
natural and synthetic, for physiological properties such as 
cytotoxicity or antibiotic activity.  These screens have tended to be 
labor-intensive, slow, and expensive.  However, the last decade has 
witnessed major breakthroughs in the identification of genes, gene 
products, metabolic pathways, and signaling pathways, as well as 
progress in miniaturization and automation technologies.  These 
advances have led to the development of highly specific, mechanism-
based biological assays that are rapid, inexpensive, and compatible 
with automation.  The new assays have, in turn, revolutionized the 
discovery of small molecules with powerful physiological effects.  Not 
surprisingly, the ability to screen massive numbers of compounds 
quickly using these new technologies has stimulated the demand for 
collections of structurally diverse molecules.  

Historically, most drug leads have been either isolated from natural 
sources (e.g., plants, marine organisms, or microorganisms), 
synthesized individually from inexpensive starting materials, or 
obtained by chemical modification of natural products.  Molecules 
obtained from natural sources exhibit tremendous structural diversity 
as well as a great variety of bioactivities.  However, the collection 
of source materials and the isolation, separation, and purification of 
the constituent bioactive principles are relatively labor-intensive and 
time-consuming.  De novo synthesis of individual natural product (or 
natural product-derived) molecules is similarly demanding.

Concurrent with the aforementioned developments in bioactivity 
screening, pioneering advances have been made in strategies and 
techniques for diversity-oriented synthesis.  Diversity-oriented 
synthesis (also referred to as combinatorial chemical synthesis) is a 
process by which multiple compounds (chemical libraries) are generated 
simultaneously, in a predictable fashion, by using techniques that 
involve parallel chemical transformations.  Diversity-oriented 
synthesis may use solid- or solution-phase reaction and product 
isolation techniques.  A library may be small (e.g., a few compounds) 
or large (e.g., thousands or even millions of compounds), and it may 
focus on a narrow or wide range of "diversity space."  When subjected 
to high-throughput biological screening, chemical diversity libraries 
offer unprecedented opportunities for the rapid identification of small 
molecules with significant physiological effects.

The early success of this new strategy has led quickly to its 
widespread adoption, particularly in the pharmaceutical industry, where 
it has become a major approach for drug lead identification.  Now, 
however, limitations are becoming apparent.  At this relatively early 
stage in the development of diversity-oriented synthesis, the tools for 
planning, synthesizing, encoding, and chemically analyzing libraries 
are proving to be limited in both number and sophistication.  
Significantly, many synthetic reactions that work well under more 
standard conditions are not effective under the conditions that are 
used for diversity-oriented synthesis, particularly if the library 
components (or the reagents) are attached to a solid support.  As a 
simple example, catalytic hydrogenation using palladium on charcoal is 
a common, high-yielding method for reducing olefins; however, catalytic 
hydrogenation does not work well if the olefin is attached to a solid 
support.  Also, owing to the substantial, unique challenges that attend 
separation and purification procedures in diversity-oriented synthesis, 
only reactions that proceed cleanly, give high yields, and are 
extremely tolerant of structural variations in the substrates are truly 
useful.  This severely limits the number of reactions that may be 
employed reliably.  Even for reactions that do work for library 
synthesis, extensive time and effort must be invested in process 
development and optimization prior to synthesis of the actual library.  

Significantly, although screening of chemical diversity libraries is 
firmly established for the identification of drug leads in the 
pharmaceutical industry, relatively few novel library-related 
methodologies are being published by industrial chemists.  While this 
may be due, in part, to intellectual property concerns, the 
pharmaceutical industry's focus on discovering and developing 
commercial drug products limits the resources that are available for 
more basic types of research.  Thus, the emphasis in industry is on the 
screening of both existing libraries and libraries that can be 
synthesized rapidly by a limited number of currently available 
methodologies.  

Another factor that limits library diversity is that practitioners tend 
to reuse the small number of core scaffolds that have been used 
successfully in the past.  This is because (a) the derivatization 
chemistry is well understood and (b) these scaffolds are known to have 
acceptable biological properties.  Furthermore, the vast majority of 
the libraries that have been synthesized include molecules based upon a 
single core structure per library, with the structural variations 
confined to peripheral substituents.  There are very few strategies and 
synthetic methods that will lead in a predictable fashion to multiple 
scaffold structures in a given library.  

In contrast to the well-established use of retrosynthetic analysis for 
designing "target-oriented" syntheses of individual molecules, the 
strategies for planning diversity-oriented syntheses are not well 
developed.  Through retrosynthetic analysis, a synthesis is planned in 
reverse, beginning with the final product.  The investigator identifies 
a reaction that could afford a particular product and then deduces the 
structure of the required starting material.  This process is repeated 
until a set of easily-procured starting materials is identified that 
can be converted, by using an appropriate sequence of reactions, to a 
complex target structure.  Since diversity-oriented synthesis produces 
multiple products, it is not possible to use retrosynthetic analysis, 
at least in its current form. 

While the development of novel methodologies is a major goal of 
academic chemists, the academic chemistry community has not generally 
embraced the development of methods that are specifically applicable to 
diversity-oriented synthesis.  Similarly, few academic chemistry labs 
routinely synthesize libraries for screening by biology collaborators.  
The reasons for the limited involvement of academic chemists may 
include the burdensome nature of process development, the high cost of 
equipment for making large libraries, and the unfamiliarity of 
strategies for diversity-oriented versus traditional target-oriented 
organic synthesis. 

The limitations of current methodologies clearly restrict the degree of 
structural complexity, the diversity, and the quality of libraries.  It 
has been suggested that the theoretically accessible "chemical 
diversity space" is defined by approximately 10(E60) "small" molecular 
structures (i.e., molecular weights of 500 or lower).  Even today's 
largest libraries sample only a tiny fraction of this potential 
chemical diversity space.  Leaders in the pharmaceutical industry 
(where diversity-oriented synthesis is used extensively) view the 
limitations of current methodology as a problem of considerable urgency 
and a significant impediment to the identification of drug candidates 
in new classes and with new mechanisms of action.  Clearly, the same 
concerns would apply to the use of libraries by academic biologists who 
seek to discover new, specific, mechanism-based small molecule probes 
of fundamental biological processes.  Thus, it is evident that reliance 
on current techniques for producing and evaluating chemical libraries 
will limit the ability to capitalize on the plethora of new targets 
that will be uncovered through research in proteomics and functional 
genomics.  The goal of the CMLD initiative is to address these 
limitations by attracting the best academic chemists to the development 
of a wide range of versatile, dependable library-related methodologies.

A workshop sponsored by NIGMS focusing on the needs and opportunities 
in diversity-oriented synthesis affirmed the importance, timeliness, 
and feasibility of stimulating further research in this area.  There 
was agreement that improvements in chemical methodology for the 
development of chemical diversity libraries are necessary for this 
approach to realize its full potential to benefit biomedical science 
and human health.  A summary of the August 19, 2000 workshop at NIGMS 
may be found on the NIGMS web site at: 
http://www.nigms.nih.gov/news/reports/chemical_diversity.html.

Elements and Organization of a CMLD Center of Excellence

A CMLD Center must be an integrated, coordinated project, with 
interdependent subprojects that are described fully and justified in 
the grant application.  Collaborations and consortia are strongly 
encouraged, and the interactive nature of the proposed research is a 
key factor that will be evaluated in peer review.  The benefits to be 
achieved through the establishment of multidisciplinary teams and novel 
collaborations, as opposed to working independently, should be 
described fully.  The applicant should identify clearly in the 
abstract, and more fully in the research plan, the new capabilities 
that are proposed to be developed, or what specific questions are to be 
studied, as a result of the establishment of the Center.

The minimum requirements for a CMLD Center will be three research 
projects, three faculty-level participants (but not necessarily one per 
project), and a library synthesis core.  NIGMS is not specifying a 
maximum number of projects or participants; rather, the size of a CMLD 
Center should be a function of the science as well as the available 
funds (see below).  Additional cores (e.g., an administrative core) or 
shared resources may be proposed as appropriate to each Center.  The 
anticipated effectiveness of the proposed Center structure will be a 
criterion of the peer review evaluation prior to an award and will be 
monitored after an award is made.

a. Research projects on methodology development

Examples of topics that would be appropriate for investigation within a 
CMLD Center might include (but not be limited to) the following: 

o chemical reactions that will increase the diversity and/or quality of 
chemical libraries; 
o new core scaffolds; 
o methods for chemically derivatizing scaffolds; 
o solid supports and linkers; 
o new strategies for generating structural diversity; 
o fractionation, purification, and reagent scavenging techniques; 
o assessment of library purity and diversity; 
o strategies and/or instrumentation for automation of library 
synthesis;
o methods of sample preparation for biological screening of libraries; 
o encoding and identification of the structures of active compounds 
within libraries;
o storage and maintenance of libraries; or
o managing data on chemical diversity libraries.

It is clear that innovations in one aspect of library methodology 
research will stimulate complementary advances in others.  For 
instance, new polymeric supports may prompt developments in linker or 
sample purification technology; new core scaffolds may influence the 
development of linkers as well as derivatization chemistry; and new 
reaction methodologies may lead to changes in library design 
strategies.  Thus, for maximum impact, Centers should feature broadly-
diversified research teams.  While chemists from any subdiscipline may 
participate in a CMLD Center, collaborations that cross traditional 
subdisciplinary boundaries (e.g., organic, inorganic, analytical, 
physical, computational, and polymer chemistry) and that feature 
complementary (i.e., nonredundant) skills are particularly encouraged.  

Participants in a CMLD Center may come from the same or different 
departments of a single academic institution or from different 
institutions, and they may come from industry as well as academia.  
However, industry participants must be willing to abide by the CMLD 
guidelines, including data sharing and handling of intellectual 
property.

Applicants should describe collaborative research projects as well as 
mechanisms for promoting scientific interactions among the 
participants.  Plans must be presented for effective team communication 
and coordination of effort that covers the development, implementation, 
and conduct of all aspects of the research program.  The degree of 
synergy among the participating research groups and the benefits that 
may be expected to result from these interactions will be major 
criteria in peer review and in NIGMS funding decisions.  It is 
essential to justify the proposed Center in terms of the "value added" 
beyond what would be expected from a set of independent R01-style 
projects.

b. Library synthesis core facility

Each Center must establish a core facility for the synthesis of high-
quality chemical libraries.  The purpose of this core will be two-fold.  
First, it will validate newly-developed methodologies in the context of 
chemical diversity libraries.  Second, it will apply these new chemical 
methodologies and strategies to the generation of actual libraries for 
high-throughput biological screening.  This will provide "real world" 
tests of the utility of new methodologies and will also promote new 
approaches for studying complex biological phenomena.  The staff of the 
core synthesis facility must have the administrative and technical 
skills to ensure smooth operation for the validation and optimization 
of new methodologies, as well as for the application of new 
methodologies to the synthesis of libraries for screening.  Applicants 
should describe the scientific function of the library synthesis core, 
including the approaches to be used for optimizing and validating new 
methodologies; the design strategies and methods that will be used for 
the synthesis, purification (as necessary), sample handling, and 
analysis of actual libraries; and protocols to be used for archiving 
and analyzing both the data and the compounds that are generated by the 
library synthesis core.  Funding for process validation studies and for 
most library syntheses will be included in the P50 Center budget.

As the focus of the CMLD Centers program is on chemical methodology 
rather than biology, biological screening will best be accomplished via 
interdisciplinary collaboration involving the library synthesis core.  
Such collaborations must merge innovative chemistry with innovative and 
significant biology.

Applicants should describe the management plan for the library 
synthesis core.  There must be representation by the biological 
research community in the administration and/or oversight of the core, 
and a strategy should be presented for outreach to the biological 
research community in order to develop collaborative projects.  The 
administrative plan should indicate how requests for libraries will be 
prioritized, in the event that the demand outstrips the capacity to 
produce libraries. 

c. Administration and management

Due to the inherent complexity of the Center structure, including both 
interdependent research projects as well as shared resources, a well 
thought-out and carefully described management plan that ensures that 
the interests of all CMLD participants are represented will be 
required.  Whether or not an administrative core is specified, plans 
must be presented for the proper administration of the Center.  The P50 
grant application should specify the administrative and organizational 
structure(s) that will be used to support the research, and the 
synergies enabled by those structures.  The PI will be responsible for 
ensuring that scientific goals are met, and for developing and managing 
a decision-making structure and process that will allow resources to be 
allocated in order to meet those scientific goals.

"Centers-without-walls" (i.e., Centers that involve participants from 
more than one physical site) are welcome under this solicitation.  If 
any of the components is physically separated from the others (e.g., 
different departments or institutions), the applicant should describe 
how interactions will be facilitated.  If the team includes 
investigators from more than one institution, a "letter of intent to 
collaborate with the applicant organization" signed by the appropriate 
institutional official from each participating organization must be 
included in the application.

Projects of the anticipated degree of complexity, both scientific and 
managerial, will require a substantial investment of the PI's effort.  
The PI will be required to devote sufficient effort to ensure 
successful leadership and implementation of the goals of the Center.  

A timeline for the project should be presented.  This timeline should 
outline how the project's goals can be met within the time frame of a 
CMLD grant.  The timeline will also assist the investigators, NIGMS, 
and its advisors in evaluating progress toward the project's goals.  

d. External scientific advisory committee

Each CMLD Center should have an external advisory committee of research 
scientists who are not involved in the Center, to provide independent 
assessment and advice to the PI and staff.  This committee should be 
appointed by the PI and confer at least twice each year.  In order to 
maximize the pool of possible reviewers, the potential members of the 
advisory committee should not be contacted or selected until after an 
award has been made.  Nevertheless, the applicant should describe the 
criteria to be used in selecting the members of the external advisory 
committee.

MECHANISM OF SUPPORT
 
This RFA, which is a one-time solicitation, will use the NIH P50 award 
mechanism.  Awards are expected to be made during September 2003 or 
early in FY 2004.  Diversity-oriented synthesis is a rapidly developing 
field, and it is anticipated that most projects that can be initiated 
now will have a limited lifetime during which support from NIGMS will 
be appropriate, either because the project goals will have been 
accomplished or the Center will have developed to the point that 
support can be derived from other sources.  Therefore, the total length 
of support for any P50 Center under this program will be no more than 
ten years (an initial five-year award followed by a single five-year 
renewal).  The applicant will be solely responsible for planning, 
directing, and executing the proposed project.  

FUNDS AVAILABLE
 
NIGMS intends to commit approximately $6 million in FY 2003 to fund up 
to two new grants in response to this RFA.  Up to two additional grant 
awards, totaling approximately $6 million, may be made in early FY 
2004, if the funds are available.  An applicant may request a project 
period of up to five years and a budget for direct costs (not counting 
capital equipment and F&A costs for subcontracts) of up to $1.1 million 
per year per Center.  Inflationary increases in subsequent years (up to 
a total of five years) will be allowed at a rate of up to 3% per year.  
Because the library synthesis core may require significant capital 
equipment, a well-justified request for an additional allowance (up to 
$1.25 million) for the acquisition of capital equipment in the first 
year of the project will be considered.  The budget should be fully 
justified and should include funds for attending the annual meeting 
(see below).  Because the nature and scope of the proposed research 
will vary from application to application, it is anticipated that the 
size and duration of each award will also vary.  Although the financial 
plans of NIGMS 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 application 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

Foreign institutions are not eligible to apply for research center 
grants.  However, subcontracts to foreign institutions are allowable, 
with sufficient justification.
 
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 his or her 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups, as well as individuals with 
disabilities, are always encouraged to apply for NIH programs.  

SPECIAL REQUIREMENTS
 
NIGMS has adopted several policies that are applicable to the CMLD 
research centers.  Applicants must present plans for implementing these 
policies, where appropriate.

Intellectual property: The NIH has an interest in ensuring that the new 
inventions, including methods, technologies, strategies, and computer 
software, that are developed through this program become available to 
the research community conveniently and in a timely fashion.  It is 
expected that these inventions will be readily and broadly applicable 
to research and to the development of products and knowledge that will 
benefit public health.  For this reason, applicants should develop and 
propose specific plans for sharing the data, materials, and software 
generated through the grant, taking into consideration the recent 
Guidance issued by NIH (http://www.nih.gov/od/ott/RTguide_final.htm).  
The results of CMLD projects should be freely available for use by the 
entire research community, consistent with the terms of the Bayh-Dole 
Act (http://www.ucop.edu/ott/bayh.html).

The initial review group will comment on the proposed plan for data 
sharing and release, including publication of results and product 
licensing (where appropriate).  The adequacy of the plan will also be 
considered by NIH staff as one of the award criteria.  The proposed 
sharing plan, after negotiation with the applicant when necessary, will 
be made a condition of the award.  Evaluation of renewal applications 
will include assessment of the effectiveness of data, materials, and 
software release.

Applicants are also reminded that the grantee institution is required 
to disclose each subject invention to the Federal Agency providing 
research funds within two months after the inventor discloses it in 
writing to the grantee institution personnel who are responsible for 
patent matters.

Annual meeting:  Applicants should plan to attend an annual meeting of 
CMLD awardees, in order to present results and to discuss issues of 
common interest or concern.  For the purpose of preparing an 
appropriate budget, it should be presumed that two representatives of 
each Center will attend this annual meeting at the NIH campus in 
Bethesda, MD. 

Post-award management:  During the grant period, experimental 
technologies will improve, and the rate of progress and the focus of 
work supported by the grant may change.  It is expected that the PI 
will make any necessary adjustment in direction to accommodate a 
changing scientific environment, keeping the NIGMS staff informed if 
significant changes are made.  In order to ensure that each Center 
remains focused on appropriate goals, features truly integrated 
approaches to science, incorporates new technological advances, and 
makes sufficient progress, scientific and administrative visits to the 
grantee may be conducted by NIGMS staff.

NIGMS may include outside consultants in the annual progress review and 
may reduce or withhold funds in the case of limited progress toward the 
goals of the CMLD program.  A report by the NIGMS program director on 
each Center's progress and recommendations to modify funding may be 
made annually to the National Advisory General Medical Sciences 
Council.
 
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:

John M. Schwab, Ph.D.
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
National Institutes of Health
Building 45, Room 2AS.43A
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5560
FAX:  (301) 480-2802
Email:  schwabj@nigms.nih.gov

o Direct your questions about peer review issues to:

Helen R. Sunshine, Ph.D.
Chief, Office of Scientific Review
National Institute of General Medical Sciences
National Institutes of Health
Building 45, Room 3AN.12P
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-2881
FAX:  (301) 480-8506
Email: sunshinh@nigms.nih.gov

o Direct your questions about financial or grants management matters 
to:

Ms. Antoinette Holland
Grants Management Office
National Institute of General Medical Sciences
National Institutes of Health
Building 45, Room 2AN.50B
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5132
FAX:  (301) 480-2554
Email:  hollanda@nigms.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 NIGMS staff to estimate the potential review 
workload and plan the review.
 
The letter of intent is to be sent by the date listed at the beginning 
of this document.  The letter of intent should be sent to:

John M. Schwab, Ph.D. 
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
Bldg. 45, Room 2As.43A
45 Center Drive, MSC 6200
Bethesda, MD 20892-6200
Telephone: (301) 594-5560
FAX: (301) 480-2802
Email:  schwabj@nigms.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.
 
SUPPLEMENTAL INSTRUCTIONS: The application should include: (a) a single 
face page for the entire application; (b) abstract; (c) key personnel 
listing; (d) table of contents; (e) the consolidated budget for the 
entire CMLD grant [summarizing budgets for the component parts and 
core(s)]; (f) individual project and core budgets; (g) biographical 
sketches for all key personnel; (h) other sources of research support 
(both current and pending) for all key personnel (see
http://grants.nih.gov/grants/funding/phs398/instructions2/p3_other_support.htm);
(i) resources and facilities (including major instruments and 
special program resources); (j) institutional support; (k) project 
overview (including a description of the overall scope and objectives; 
(l) justification of the P50 Center mechanism, including a description 
of the synergy among the components of the Center and a discussion of 
how the scientific goals will be furthered via the P50 Center grant 
mechanism in ways that would not be readily attainable through 
individual research project grants; (m) plans for administrative 
management; (n) plans for project management; (o) plans for handling 
intellectual property issues; (p) project descriptions; (q) 
description(s) of core(s); (r) letters of collaboration; etc.  Section 
(h) must also detail the relationship of other support to the proposed 
Center and describe anticipated modifications to that support in the 
event of funding (e.g., folding in support for related, funded 
research).  

Each project description should include (in the following order) a cover 
page, an abstract, budget pages, and a detailed research plan.  The 
research plan should be organized as specified in the PHS 398 
application form; i.e., it should include specific aims, background and 
significance, preliminary studies, and research design and methods, and 
the usual 25 page limit will apply.  The special benefits (to the 
project) of being associated with the Center must also be addressed.  

Each core facility should be described in no more than 20 pages, in 
addition to the budget pages for that particular core.  Separate 
sections describing and justifying the core resource(s) should be 
included.  Sections (j) through (o) of the application (see above) 
should be presented in no more than 30 pages.  

Note that there is no requirement to submit the maximum number of 
pages; instead, concise, articulate applications are strongly 
encouraged.

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/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten or 
machine printed 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, two additional copies of the application, 
including all appendices, must be sent to:

Helen R. Sunshine, Ph.D.
Chief, Office of Scientific Review
National Institute of General Medical Sciences
Building 45, Room 3AN.12P
45 Center Drive, MSC 6200
National Institutes of Health
Bethesda, MD  20892-6200
 
APPLICATION PROCESSING: Applications must be received by 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.
 
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.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude 
the submission of substantial revisions of applications already 
reviewed, but such applications must include an Introduction addressing 
the previous critique.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by NIGMS.

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 by NIGMS in accordance with the review criteria 
stated below.  As part of the initial merit review, all applications 
will receive a written critique.  It is also possible that applications 
will 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.  Finally, all applications will receive a second level review by 
the National Advisory General Medical Sciences Council.

It is unlikely that site visits or applicant interviews will be 
performed as part of the initial review.  You should not assume that 
they will be conducted; therefore, you must present a complete and 
well-justified written proposal.  

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 order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals, the reviewers will be 
asked to discuss in their written comments the following aspects of 
your application: 

o Significance
o Approach
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Separate scores will not be 
assigned for each subproject; however the scientific merit of each 
subproject will be assessed, based on its merit as an independent 
effort and its potential importance/contribution to the success of the 
overall effort.  Core facilities and resources will be assessed for 
their quality, cost-effectiveness, and utility to the overall effort.

(1) SIGNIFICANCE:  How likely is it that any proposed methodologies, 
research tools, software, strategies, etc., will have a broad impact on 
the production of high-quality, highly diverse chemical libraries?  
Will these new methodologies substantially enhance the availability of 
chemical diversity libraries for high-throughput biological screening?  
Are the proposed strategies and technologies likely to be readily 
exportable?  How important are the proposed research areas and topics 
being explored, and how relevant are these research areas and topics to 
furthering the state of the art in developing high-quality chemical 
diversity libraries?  What is the likely effect of the proposed 
research on the field, and what is the likely impact on the larger 
scientific community?  If the aims of the application are achieved, how 
will scientific knowledge be advanced?  

(2) APPROACH:  How strong is the scientific research plan?  What is the 
likelihood that the proposed research plan will achieve the stated 
aims?  Are the conceptual framework, design, methods, analyses, 
techniques, and technologies adequately developed, well integrated, and 
appropriate to the aims of the project?  Are potential problem areas 
acknowledged and alternative tactics proposed?  How much interplay and 
synergy are there among the projects and among the key personnel?  Are 
the interactions among the key personnel critical to achieving the 
stated goals?  Is the proposed structure of the library synthesis core 
facility (including staffing, procedures, management, and equipment) 
appropriate for meeting the goals of the core--to validate new 
methodologies and to produce high-quality libraries for biological 
screening?  

(3) 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?

(4) INVESTIGATOR: Are the scientific training, background, and 
expertise of the Principal Investigator and key personnel appropriate 
to achieving the specific aims and overall goals of the proposed 
research?  Do the skills of the key personnel complement one another in 
a manner that is appropriate to an integrated, team-oriented project?  
Does the Principal Investigator have the appropriate management and 
administrative skills to lead and coordinate the activities, and to 
develop and implement the management plan, as required for the 
project's success?  Are the library synthesis core personnel qualified 
for their role in the Center?  Are the levels of effort of the key 
personnel adequate?

(5) ENVIRONMENT:  Does the scientific environment in which the work 
will be done, including space, equipment, services, infrastructure, and 
facilities, contribute to the probability of success?  Does the 
proposed research Center take advantage of unique features of the 
scientific environment or employ useful collaborative arrangements?  Is 
there evidence of institutional support, including any needed expansion 
of facilities, improvement of infrastructure, and relief from other 
academic duties, where necessary?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the 
application will also be reviewed with respect to the following:

o MANAGEMENT AND ADMINISTRATION: The suitability and quality of the 
management plan, including the management structure; the plan for 
deployment of equipment and human resources to attain the research aims 
and overall Center goals; the organization and coordination of the 
personnel; plans for making critical decisions or choices about overall 
research direction;

o OUTREACH: The plans for outreach to the biomedical research 
community, including solicitation of interest in using chemical 
diversity libraries; and making libraries available for screening;

o PROTECTIONS:  The adequacy of the proposed protection for humans, 
animals, or the environment, to the extent they may be adversely 
affected by the project proposed in the application;

o DATA SHARING:  The adequacy of the proposed plan to share data; the 
plan for addressing intellectual property issues, including the 
dissemination of intellectual and material products of this research, 
as well as mechanisms for the licensing of CMLD-supported inventions 
that are patented by a CMLD grantee;

o BUDGET:  The appropriateness 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:  January 24, 2003
Application Receipt Date:  February 20, 2003
Peer Review Date:  June/July 2003
Council Review:  September 2003
Earliest Anticipated Start Date:  September 15, 2003

AWARD CRITERIA

Applications will compete for available funds with all other approved 
applications assigned to NIGMS.  Awards will be made on or before 
September 30, 2003.  The following factors will be considered in making 
funding decisions:

o responsiveness to the goals and objectives of the RFA; 

o scientific merit, as determined by peer review;

o overall contribution of the project to the knowledge and experience 
required to advance the state of the art in the planning, generation, 
and/or analysis of chemical diversity libraries;

o program priority of research in this area and other areas of NIGMS 
interest;

o plans for rapid and effective dissemination of the results and 
information on technological developments; and

o availability of funds.

REQUIRED FEDERAL CITATIONS 

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 RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application.  In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures, given the potential for wider use of data collected under 
this award.

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

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas.  This RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.859, and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284) and administered under NIH grants policies described 
at http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

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.
http://grants.nih.gov/grants/guide/pa-files/PA-02-015.html.

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NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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