CENTERS OF EXCELLENCE IN CHEMICAL METHODOLOGIES AND LIBRARY DEVELOPMENT

Release Date:  June 18, 2001 (see RFA-GM-03-004)

RFA:  RFA-GM-01-006

National Institute of General Medical Sciences

Letter of Intent Receipt Date:  January 8, 2002
Application Receipt Date:       February 19, 2002

PURPOSE 

The National Institute of General Medical Sciences (NIGMS) solicits 
applications for 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 Chemical Methodologies and Library Development (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 contribute toward the development of novel enabling 
methodologies.

Each Center will establish a diversity-oriented synthesis core facility 
that will serve two purposes.  First, the synthesis core will validate 
newly-developed methodologies for application to diversity-oriented 
synthesis.  Second, the 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 generate and to 
reduce to practice fundamental new chemistry, enabling the generation 
of high-quality libraries of expanded diversity.

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, 
“Centers of Excellence in Chemical Methodologies and Library 
Development,” 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.

ELIGIBILITY REQUIREMENTS 

Applications may be submitted by domestic for-profit and non-profit 
organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of state and local governments, and 
eligible agencies of the Federal government.  Racial/ethnic minority 
individuals, women, and persons with disabilities are encouraged to 
apply as Principal Investigators.  Foreign institutions are not 
eligible to apply for research center grants.  However, subcontracts to 
foreign institutions are allowable, with sufficient justification. 

MECHANISM OF SUPPORT

Support of this program will be through the NIH Specialized Center 
Grant (P50) mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  

A P50 Center grant application may request up to five years of support. 
The actual length of award will be determined through the peer review 
and Council advisory processes.  Diversity-oriented synthesis is a 
rapidly developing field, and it is anticipated that most projects that 
can be initiated now are likely to have a limited lifetime during which 
support from the NIGMS will be appropriate, either because the project 
goals will have been accomplished or the Center will have developed to 
the point that support from other sources will be more appropriate.  
Therefore, the total length of support for any P50 Center under this 
program will be no more than ten years.  

P50 grants may support projects that are performed at multiple sites 
but coordinated by a single Principal Investigator (PI) at the grantee 
institution.  An award will be made only to the PI's institution.  
Awards will be made on or before September 30, 2002.

FUNDS AVAILABLE

NIGMS anticipates funding three to four CMLD research Centers in Fiscal 
Year 2002, with a maximum direct cost (not counting capital equipment 
and F&A costs for subcontracts) of $1.1 million in the first 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 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).  

Only applications of high scientific merit that are responsive to this 
announcement will be considered for funding. Not all of the funds will 
be spent if there are not enough highly meritorious applications.  
Support in future years is subject to the availability of funds.

SCIENTIFIC RATIONALE

This RFA announces a special funding initiative to establish research 
Centers that will pursue the development of chemical methodologies 
pertinent to chemical diversity libraries.  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 diversity-oriented synthesis 
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 various 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 (commonly 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 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 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 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 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 
favorable 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 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 with 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 see this as 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 
molecular 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 become evident 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 recent 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 biological 
research.  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.

SCIENTIFIC COMPONENTS OF A CMLD CENTER

a. Fundamental methodologies

A minimum of three faculty-level (or the equivalent) participants 
(which may include the PI), each proposing one or more projects that 
are focused on chemistry methodology, are required for each CMLD 
Center. Many specific topics warrant intensive research effort.  
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 permit or even require 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 for 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 
important to justify the proposed Center in terms of the “value added” 
beyond what would be expected from a set of independent R01 grants.

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 library development.  Second, it will apply newly-
developed 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 synthesis 
core, including the approaches to be used for optimizing and validating 
new methodologies as well as the design strategies and methods that 
will be used for the synthesis of actual libraries.  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 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.  
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. 

POST-AWARD MANAGEMENT

During the grant period, experimental technologies will improve, and 
the rate of progress and 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 research Center's progress and recommendations to modify funding 
may be made annually to the National Advisory General Medical Sciences 
Council.

LETTER OF INTENT

Prospective applicants are asked to submit by January 8, 2002 a letter 
of intent that includes a descriptive title of the proposed grant 
application, the name, address, telephone number, and e-mail address of 
the PI, names of other key personnel and participating institutions, 
and the 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 
subsequent applications, the information that it contains will allow 
NIGMS staff to estimate the potential review workload and to avoid 
possible conflicts of interest in the review.  

The letter of intent is to 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
TEL: (301) 594-5560
FAX: (301) 480-2802
Email:  schwabj@nigms.nih.gov

Potential applicants are encouraged to contact the staff listed under 
INQUIRIES for guidance in the preparation of the application. 

GUIDANCE FOR APPLICANTS FOR P50 CENTER GRANTS

The research Center should be an integrated, coordinated project, with 
interdependent subprojects as described above.  It must be fully 
described 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 synergies achieved through the establishment of 
multidisciplinary teams and novel collaborations 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, 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 above).  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 evaluation 
prior to an award and will be monitored after an award is made.

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 goals.  

Core facilities and shared resources should be described, as should 
their management and service to the research projects.  The applicant 
should explain how different components of the organization, including 
key personnel, will interact; why they are essential to accomplishing 
the research; and how the combined resources create capabilities that 
are more than the sum of the parts.  "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 (i.e., different departments or 
institutions), the proposal should address how interactions will be 
facilitated.  Since the team may include 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 in 
order to achieve and maintain successful leadership and implementation 
of the Center.  Thus, the PI will be required to devote sufficient 
effort to ensure adequate 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.  

SPECIAL REQUIREMENTS

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

Intellectual property. The NIH has an interest in ensuring that the 
information about new methods, technologies, strategies, and computer 
software that are developed through this program becomes readily 
available to the research community for further research and 
development, with the expectation that this will eventually lead to 
information and products that improve the health of the public.  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.  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.

External scientific advisory committee.  Each CMLD Center should have 
an external advisory committee of research scientists 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.

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. 

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups 
and their sub-populations must be included in all NIH-supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of the research. This policy results 
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 
103-43).

All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: 
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age 
of 21) must be included in all human subjects research, conducted or 
supported by the NIH, unless there are scientific and ethical reasons 
not to include them. This policy applies to all initial (Type 1) 
applications submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines" on the Inclusion of Children as 
Participants in Research Involving Human Subjects that was published in 
the NIH Guide for Grants and Contracts, March 6, 1998, and is available 
at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators also may obtain copies of these policies from the program 
staff listed under INQUIRIES. Program staff may also provide additional 
relevant information concerning the policy.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All 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.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.

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 (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.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 
(revised 4/98) and will be accepted only on or before the application 
deadline indicated on the first page of this RFA.  Application kits are 
available at most institutional offices of sponsored research and also 
may be obtained from:

Division of Extramural Outreach and Information Resources
National Institutes of Health
6701 Rockledge Drive, MSC 7910
Bethesda, MD 20892-7910
TEL: (301) 435-0714
Email: GrantsInfo@nih.gov

The RFA label available in the PHS 398 (rev. 4/98) application form 
must be affixed to the bottom of the face page of the application.  
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 title and number of the RFA must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked.  The sample RFA label available at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change.  Please note that this file is in 
pdf format.

The application should include: (a) a single face page for the entire 
application; (b) abstract; (c) key personnel listing; (d) table of 
contents; (e) consolidated budget; (f) individual project and core 
budgets; (g) biographical sketches for 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/
p1_preparing_application.htm - others); (i) resources and 
facilities (including major instruments and special program resources);
 (j) institutional support; (k) project overview (including an 
description of the overall scope and objectives; a discussion 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); (l) plans for 
administrative management; (m) plans for project management; (n) plans 
for handling intellectual property issues; (o) project descriptions; 
(p) description(s) of core(s); (q) 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).  

For each research project, the research plan (including specific aims, 
background and significance, preliminary studies, and research design 
and methods) should be organized as specified in the PHS 398 
application form, and the usual 25 page limit will apply.  An abstract 
(one page maximum) also should be included for each project, 
immediately preceding the project description.  The special benefits 
associated with being part of the Center must also be addressed. Each 
core facility should be described in no more than 20 pages.  Separate 
sections describing and justifying the core resource(s) should be 
included.  Sections (j) through (n) of the application (see above) 
should be presented in no more than 30 pages.  In addition to a 
consolidated budget, a separate budget should be provided for each 
component of the Center, including the individual projects and core 
facilities.  

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

A signed original of the application (including the Checklist) and 
three signed photocopies should be submitted 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 1As.13
45 Center Drive, MSC 6200
National Institutes of Health
Bethesda, MD  20892-6200

Applications must be received by February 19, 2002.  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. This does not preclude the submission of 
substantial revisions of applications already reviewed, but such 
applications must include an introduction addressing the previous 
critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and 
for responsiveness to the RFA by NIGMS program staff.  Incomplete 
and/or nonresponsive applications will be returned to the applicant 
without further consideration.  Those applications that are complete 
and responsive will be evaluated in accordance with the criteria stated 
below for scientific/technical merit by an appropriate peer review 
group to be convened by NIGMS.  Site visits or applicant interviews may 
or may not be performed as part of the initial review.  Applicants 
should not assume they will occur and therefore must present a complete 
and well-justified written proposal.  As part of the initial merit 
review, all applications will receive a written critique and may 
undergo a process in which only those applications deemed to have the 
highest scientific merit will be discussed, assigned a priority score, 
and receive a second level review by the National Advisory General 
Medical Sciences Council.

Review Criteria 

The goals of NIH-supported research are to advance the understanding of 
biological systems, improve the control of disease, and enhance health.  
To ensure that applications for this CMLD program are evaluated 
appropriately, the standard NIH review criteria have been adapted to be 
more appropriate for proposals of the scope described in this RFA.  In 
the written comments reviewers will be asked to discuss the following 
aspects of the overall application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals.  Each of these criteria will be considered in 
assigning the overall score, weighted as appropriate for each 
application.  If the Center grant application includes distinct 
subprojects, the scientific merit of each project 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.

The five criteria to be used in the evaluation of grant applications 
are listed below. 

(1) Significance:  What is the importance of 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?  What will be the 
effect of these studies on the concepts or methods that drive the field 
of diversity-oriented synthesis?  What is the potential utility of any 
proposed methodologies, research tools, software, strategies, etc., for 
the facilitating the synthesis of high-quality, highly diverse chemical 
libraries and enhancing the availability of these libraries for high-
throughput biological screening?  How exportable are these strategies 
and technologies?  

(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?  Does the applicant acknowledge 
potential problem areas and consider alternative tactics?  How much 
interplay and synergy are there among the projects and the key 
personnel, and are the interactions among the key personnel critical to 
achieving the stated goals?  Is the proposed structure of the library 
synthesis core facility 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) Investigators:  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 synthesis core personnel qualified for 
their role in the Center?  Are the levels of effort of the key 
personnel adequate?

(5) Environment: Are the scientific environment and resources, 
including space, equipment, services, infrastructure, and facilities, 
adequate for the proposed research?  Does the proposed research Center 
take advantage of unique features of the scientific environment or 
employ useful collaborative arrangements?  Is there adequate 
institutional support, including any needed expansion of facilities, 
improvement of infrastructure, and relief from other academic duties, 
where necessary?

In addition to the above criteria, all applications will be reviewed 
with respect to the following:

o plans for outreach to the biomedical research community, 
including making chemical diversity libraries available for screening;

o appropriateness and quality of the management plan, including the 
effectiveness of the management structure; quality of the plan for 
deployment of equipment and human resources to attain the research aims 
and overall Center goals; organization and coordination of the 
personnel; quality of the plans for making critical decisions or 
choices about overall research direction during the project;

o plans for addressing intellectual property issues, including the 
dissemination of results and materials generated by this research;

o the appropriateness of the proposed budget and project duration 
in relation to the proposed research; and

o the adequacy of the proposed protection for humans, animals or 
the environment, to the extent they may be adversely affected by the 
project described in the application.

AWARD CRITERIA 

Applications will compete for available funds with all other approved 
applications assigned to the NIGMS.  Awards will be made on or before 
September 30, 2002.  The following factors will be considered in making 
funding decisions:

o responsiveness to the goals and objectives of the RFA; 

o quality of the proposed project as determined by peer review;

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

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

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

o availability of funds.

INQUIRIES 

Inquiries concerning this RFA are encouraged.  The opportunity to 
clarify any issues or questions from potential applicants is welcome. 

Direct inquiries regarding programmatic issues to: 

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

Direct inquiries regarding fiscal matters to:

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

AUTHORITY AND REGULATIONS 

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.821.  Awards are made under authorization of the Public Health 
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public 
Law 99-158, 42 USC 241 and 285) and administered under NIH Grants 
Policy Statement (March 1, 2001) and Federal Regulations 42 CFR 52 and 
45 CFR Part 74.  This program is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency 
review.

The PHS strongly encourages all grant and contract recipients to 
provide a smoke-free workplace and promote the non-use of all tobacco 
products.  In addition, Public Law 103-227, the Pro-Children Act of 
1994, prohibits smoking in certain facilities (or in some cases, any 
portion of a facility) in which regular or routine education, library, 
day care, health care or early childhood development services are 
provided to children.  This is consistent with the PHS mission to 
protect and advance the physical and mental health of the American 
people.

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	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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