PHARMACOGENETIC RESEARCH NETWORK AND DATABASE

Release Date: December 22, 1998

RFA:  GM-99-004

P.T.

National Institute of General Medical Sciences
National Heart, Lung, and Blood Institute
National Human Genome Research Institute
National Institute of Environmental Health Sciences
National Institute of Mental Health
National Institute on Alcohol Abuse and Alcoholism

Public Briefing Date:  March 19, 1999
Letter of Intent Receipt Date:  April 30, 1999
Application Receipt Date:  July 27, 1999

PURPOSE

The purpose of this request for applications (RFA) is to stimulate formation of
a network of Research Groups of investigators and development of a public
Pharmacogenetic Database, which will become available to the scientific community
for use as a research tool.  The study of pharmacogenetics and pharmacogenomics
presents opportunities to researchers working at levels ranging from the most
molecular to the most clinical, in the fields of pharmacology, physiology,
genetics, genomics, medicine, epidemiology, statistics, bioinformatics, and
computational biology.  It would be desirable to bring investigators with these
backgrounds together in a research framework, so that functional variation in
proteins and genes that play essential roles in determining drug responses can
be studied, interpreted, and related to clinical research situations in a rapid
and efficient manner.

This initiative is designed to support the establishment of a series of
multidisciplinary, collaborative Research Groups composed of investigators
interested in studying how genetic variation contributes to interindividual
differences in drug responses, and in collecting comprehensive, integrative
information about specific proteins and genes.  A Database Group will also be
established and will become responsible for design and implementation of the
Pharmacogenetic Database.  The questions formulated and addressed by the Research
Groups should be constructed so as to yield information that can be stored and
used in a database format.  All groups will be expected to work cooperatively so
that the Pharmacogenetic Database will become an information resource that is of
maximum utility to the entire research community, and can stimulate future
hypothesis-driven research.

This is one of a pair of initiatives designed to address the acquisition of
fundamental knowledge required to predict interindividual differences in drug
responses.  This RFA supports formation of a coordinated Pharmacogenetic Research
Network and Database, and is suitable for research conducted by multiple
collaborative arrangements.  A companion program announcement (PA) entitled
"Mechanisms Underlying Individual Variations in Drug Responses" (PA-99-016, see
http://www.nih.gov/grants/guide/pa-files/PA-99-016.html) describes opportunities
for the support of investigations of critical candidate proteins and genes that
may contribute to pharmacogenetic/pharmacogenomic variation, via traditional
individual investigator-initiated research projects.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This RFA, Pharmacogenetic Research Network
and Database, is related to one or more of the priority areas.  Potential
applicants may obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, 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.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) cooperative agreement
(U01) award mechanism, an "assistance" mechanism, which is distinguished from a
regular research grant in that substantial programmatic involvement by NIH staff
with the awardees is anticipated.  The cooperative agreement is used when
participation by NIH staff is warranted to support and stimulate the recipients'
activities by involvement in and otherwise working jointly with the award
recipients in a partnership role; NIH staff will not assume direction, prime
responsibility, or a dominant role in the activity.  Details of the
responsibilities, relationships, and governance of studies funded under
cooperative agreements are discussed later in this document under the section
Terms and Conditions of Award.  Each component of the Pharmacogenetic Research
Network and Database will be awarded as a separate U01.

Institutions may propose formation of a multidisciplinary, collaborative Research
Group only, or both a Research Group and a Database Group, the latter component
being responsible for development of the Pharmacogenetic Database.  If an
applicant institution wants to propose both a Research Group and a Database
Group, the two components should be developed as separate applications, because
NIH wants to retain maximum flexibility in organizing the best overall program,
and may choose to award only one or the other, or both.  It is possible to submit
an application for support of a Database Group only.  However, it is important
for a potential Database Group to demonstrate that there are good connections in
place to at least one potential Research Group, or similar site, so that a
smoothly integrated two-way exchange of information will take place during the
crucial developmental stages for the database.

All applications will be assigned to NIGMS initially, for administrative reasons. 
After discussion with the other participating Institutes, applications may be
reassigned where they are programmatically most appropriate.  Because the scope
of research proposed in response to this RFA may encompass the interests of
several Institutes, applications may receive dual assignments based upon
established PHS referral guidelines.  The anticipated earliest award date is
April 1, 2000.

FUNDS AVAILABLE

The participating Institutes and Centers (ICs) intend to commit $17 to 22 million
in FY 2000 to fund applications in response to this RFA.  It is anticipated that
there will be approximately eight to twelve Research Groups funded, and likely
one (but possibly more) Database Group(s) funded, although the actual funding
plan will depend upon the scientific opportunities presented and the results of
the peer review process.  An applicant may request a project period of up to five
years for either a Research Group or a Database Group.  Because the nature and
scope of the proposed research will vary, it is anticipated that the sizes of the
awards will also vary.  The financial plans of the participating ICs provide
support for this program, although awards pursuant to this RFA are contingent
upon the availability of funds and receipt of a sufficient number of applications
of outstanding scientific and technical merit.  It is anticipated that new and
renewal applications in this area may be supported in future years, depending
upon the success and the needs of the Pharmacogenetic Research Network and
Database.

RESEARCH OBJECTIVES

Background:

Pharmacogenetics and pharmacogenomics are related fields involving the study of
interindividual differences in drug responses based upon genetic approaches and
genomic information, respectively.  Polymorphisms (genetic variants that occur
with a frequency of 1% or greater) can be identified in individuals, families,
and populations for proteins and genes involved in determining drug responses. 
Yet much more biological and clinical research is needed beyond accumulating
sequences and identifying polymorphisms, in order to correctly interpret the
functional consequences of genetic variation.  This initiative proposes support
for development of a network of multidisciplinary Research Groups to study and
interpret functional variation in proteins and genes that determine drug
responses, and for creation of a Pharmacogenetic Database in which to store,
access, and analyze the information for future applications.

Establishment of a Pharmacogenetic Research Network and Database is the most
comprehensive yet efficient approach to systematically collecting and
interpreting pharmacogenetic/pharmacogenomic information.  In order to understand
which sequence variants are functional and how they actually contribute to
individual differences in drug responses, the genetic variation (genotype) must
be related to biochemical changes in proteins, to cell and organ functions, to
systemic effects, and to the range of possible clinical expressions (phenotype). 
For this reason, it is envisioned that several investigators trained in different
areas working as a collaborative team will be required to achieve insights into
the contribution of genetic variation to determining individual drug responses. 
Once a mosaic of comprehensive biological information for a particular protein
or gene and its corresponding variants has been assembled, it should be
catalogued in a manner that is accessible and interpretable to a wide range of
scientists, in order to have maximum utility as a research tool.  Thus, at the
same time that thought is being given to how to collect and express information,
a Pharmacogenetic Database will be designed to receive the information.  Such a
database will link genes and their sequence variants to their encoded proteins,
their functional changes, and consequent drug response phenotypes (and sometimes
disease phenotypes).  Representation of sequences and variation information
(including but not limited to single nucleotide polymorphisms, SNPs) is rather
straightforward.  Data representing protein function could include:  substrates,
inhibitors, reaction constants (Km, Ki, and conditions under which measured),
structural information, regulatory proteins, co-substrates or factors, tissue
distribution and levels, etc.  Sometimes an array of information such as
multiple, different mRNA levels will be the most appropriate, where there is a
concerted response.  There could be several measurable phenotypes associated with
a genotype.  Rigorous studies, both basic and clinical, are needed to correlate
phenotype with genotype.  Phenotype information should be standardized to the
extent possible.  For example, this could be catalogued as patient responses to
probe drugs used in a uniform manner, or by methods that stage disease
progression, or by an array of information.

In this RFA, NIH does not plan to specify which candidate proteins or genes
should be first to be studied in the Pharmacogenetic Research Network and
Database; a Research Group will specify where it wants to concentrate its
activities.  Both variation in drug biotransformation/elimination (effects on the
time course of drug action, or pharmacokinetics) and variation in the effects of
drugs on cells and tissues (as mediated by target receptors, or pharmacodynamics)
are of interest.  Initially, the NIH focus will be on examining a variety of
pharmacologically important proteins and genes, and this will be accomplished by
funding a series of Research Groups that are studying a range of different
proteins and genes.  The Pharmacogenetic Database will contain genotype and
phenotype information, as well as protein function, structure, and pathway
information where it can be correlated for relationships being studied. 
Polygenic traits will be particularly challenging to study, and may require
development of the appropriate methodology and techniques (see also PA-98-078,
http://www.nih.gov/grants/guide/pa-files/PA-98-078.html).  As the database grows,
it can be used to uncover unexpected relationships, interactions, or multigenic
processes that determine individual variations in drug responses.

Scope and Objectives:

The aim is to support development of a Pharmacogenetic Research Network and
Database, comprised of a series of Research Groups and a Database Group.  The
Pharmacogenetic Research Network and Database overall should have the capacity
to collect genetic sequence information, detect polymorphic variants, identify
the functional consequences of genetic variation, and rigorously correlate this
information with clinical drug responses.  A Database Group will be responsible
for designing, establishing, and maintaining the Pharmacogenetic Database.  A
Steering Committee with appropriate representation will be established and will
coordinate the activities and exchange of information.  The Pharmacogenetic
Research Network and Database should improve access to information resources,
ideas, expertise, and technology beyond the scope of any single group, and should
impact the entire community of researchers in this field.

Research Group Description and Tasks
A Research Group is a group of multidisciplinary, collaborating biological
scientists (at one or several sites) employing a state-of-the-art, comprehensive
approach to examining functional variation in their proteins or genes of interest
involved in drug responses.  Each should be formed by self-assembly of a group
of investigators into a cross-disciplinary team, and each will have a unique
blend and breadth of complementary research expertises.  A Research Group will
conceive, develop, and conduct research focused on proteins or genes or a disease
of interest to that group, where genetic variation is suspected to play a role
in determining interindividual differences in drug responses.  Each Research
Group must be interested in studying the consequences of genetic variation in
drug responses with a comprehensive strategy.  Taken as a whole, the
Pharmacogenetic Research Network and Database will encompass experiments to
examine fundamental relationships ranging from genetic/genomic examination,
through the molecular and biochemical levels, through a functional
physiological/pharmacological context, and clinical studies, and each group
should address several of these aspects.  The objective is to rigorously consider
how to relate drug response phenotype to genotype.

The comprehensive collection of sequence information (e.g., for mRNA, cDNA,
genomic DNA, or ESTs) is at times the starting point for initiating a study of
functionally significant sequence variation.  For example, a Research Group might
obtain reference DNA sequences for the exons, regulatory sequences, and introns
(where feasible) for the candidate gene(s) of interest, where that information
is not already available.  The next stage may be determining DNA sequence
variation (polymorphisms) in order to catalogue the most common genetic variants. 
A resource to search initially for possible variants is the NHGRI Human DNA
Polymorphism Discovery Resource, which is a publicly available, diversity-rich,
anonymous sample set stored at the NIGMS Human Genetic Mutant Cell Repository at
the Coriell Institute for Medical Research (see
http://www.nhgri.nih.gov/Grant_info/Funding/discover_polymorphisms.html). 
Investigators are specifically encouraged to use this resource to add to the
current body of SNP information, and to deposit the information in the companion
SNPs database (dbSNP).

In some cases, there may be selected individuals, families, populations, or
patients already phenotyped for a drug response or for disease progression, that
can be used to relate a drug response to a genetic variant.  Clinical or
epidemiological studies for linkage or association can be used to identify genes
of interest, and functional studies can be designed to examine proteins that may
contribute to drug response variations.  Corresponding sequences from appropriate
reference animals can also be examined, or mutant, transgenic, or knock-out
organism studies can be included, as long as the goal is to identify human
genetic drug response targets or variants.  The biochemical significance of
genetic variation, such as altered transcription, structure, splicing, or
stability of mRNA, as well as the altered structure, function, regulation,
modification, or degradation of the encoded protein(s) can be examined.  Or there
may be a functional role for genetic variation in non-coding regions. 
Additionally, the population significance can be addressed, and statistical
associations should be made between genotype and phenotype.  Further human
studies may be necessary to learn allele frequencies, characterize patterns of
inheritance, or establish prevalence of a genotype (or haplotype) in selected
populations, in order to make future predictions of drug responses.  In many
circumstances, there may be modifying factors (e.g., environment, diet, age,
gender) in addition to genetic variation, and these should be examined where
possible in order to gain the most complete insight.

It is expected that members of a Research Group will typically have research
experience with their proteins or genes of interest.  Members of the group should
represent many of the areas of expertise required to address the research problem
in a comprehensive manner (e.g., molecular and cellular biology, genetics,
genomics, pharmacology, clinical pharmacology, pharmaceutics, epidemiology,
clinical medicine, computational biology, bioinformatics, or statistics) through
collaborations either on campus or off-site.  Applicants are expected to have
some facilities already available.  Other equipment, staffing, or resources may
be needed, such as acquisition of current technologies for SNP detection
(particularly as sequencing and variant detection become affordable and widely
available), or establishment of a transgenic animal colony to study disease
progression and variable responses to drug therapy.  New technologies may be
needed to detect genotype or measure phenotype.  New data analysis or
mathematical tools may be required at a Research Group site, and these can be
developed in order to aid in interpreting results, such as discerning causality
versus association of genetic variation.  These situations are only examples;
there are many possibilities.

Applicants should request the funds necessary to assemble a Research Group with
a state-of-the-art, cross-disciplinary, comprehensive approach to detecting and
studying pharmacogenetic/pharmacogenomic variation in their selected class of
proteins or genes.  Research Groups will also be expected to represent their
research areas, and a mechanism should be proposed to collect the views from
members of the specific research communities studying their proteins or genes of
interest.  These views will be presented and discussed at the Steering Committee
meetings (see below).

Database Group Description and Tasks
A Database Group is a group of bioinformatics scientists or computational
biologists responsible for the design, development, implementation, and
maintenance of the Pharmacogenetic Database.  The group should be united by the
aim of designing and developing a Pharmacogenetic Database that will contain and
link the information necessary to make pharmacological and possibly disease-
related interpretations based upon genetic variation.  The database may be
organized as component parts initially.  It should reflect relationships between
genes and gene products that will be complex.  It should integrate sequence,
function, structure, and distribution information, and reflect concepts where
possible (e.g., temporal or sequential responses).  The database must allow for
the possibility of multiple functions per gene, and for genes that interact with
non-genetic factors such as the environment, leading to complex predictors of a
drug response.  Ultimately, the Pharmacogenetic Database should be designed to
serve as a foundation for future hypothesis-driven experiments, and to uncover
previously unsuspected correlations, perhaps with genes not yet known to
contribute to individual variations in drug responses.

A Database Group must interact with the Research Groups to ensure that data
entered into the Pharmacogenetic Database are of high quality, complete,
accurate, and standardized.  The data must be deposited in a manner that is
timely yet validated, with properly annotation.  Standardized information should
be accessed from existing databases already supported by the scientific
community, such as Genbank, dbSNP, protein structure database, chemical
databases, etc.  There should be good interoperability through robust and
reciprocal links with these databases.  The Database Group may also propose to
develop the computational tools necessary to view and evaluate the data in
different ways, and to query the data to learn of new relationships, such as the
regulation of blocks of genes, or pleiotropic responses.  The goal will be to
manage complex, interconnected data, with some unknown patterns and
relationships, and to integrate the data while retaining its biological meaning.

The Pharmacogenetic Database should be well-organized, efficient, convenient,
powerful, and structured yet flexible.  While one Pharmacogenetic Database is the
ultimate goal, it may need to be designed as components or developed in stages,
thus proposals for significant components will be considered.  Specific issues
to be considered include:  proposing the optimal database design, identifying a
timetable for database development, determining the most appropriate nomenclature
where possible in advance, suggesting how to express conditions for the
collection of biological information, describing timing for the submission of
information, whether stages should exist in the database (raw vs. finished data,
validated vs. unvalidated data), documenting validation of the deposited
information, establishing a mechanism for correcting errors in the database,
coordinating comments from the scientific users, obtaining peer or editorial data
review, and identifying and installing the appropriate database links.  All
aspects of the Pharmacogenetic Database design should be considered and
discussed, and the approaches proposed should be clearly explained and justified. 
Examples should be given where possible.  Resources should be requested
commensurate with these goals and others as they are identified.

Steering Committee Description and Tasks
A Steering Committee will be the main governing body of the Pharmacogenetic
Research Network and Database.  The Steering Committee will include
representation from each of the Research Groups and the Database Group, up to six
NIH Scientist/Administrators of the appropriate scientific expertises (e.g.,
pharmacology, genetics, epidemiology), as well as selected scientists other than
the awardees where additional expertise is required (e.g., computational
biology), when necessary for committee breadth and balance.  NIH representation
on the Steering Committee will never make up a majority of the total number. 
This committee will be assembled very soon after the awards are made.

The Steering Committee will discuss the overall progress made within the
Pharmacogenetic Research Network and Database at its meetings.  The committee
will make recommendations regarding how data should be obtained and expressed,
and encourage data collection that is as uniform and yet as complete as possible,
in order to be maximally valuable to all investigators.  The committee will
discuss and advise development of the Pharmacogenetic Database, and it will seek
to develop common guidelines and procedures for depositing the information.  The
committee will work to set standards for data format and nomenclature.  The
Steering Committee will also identify and discuss any issues that arise in
connection with the scientific aspects of the Pharmacogenetic Research Network
and Database.  It can create information-gathering subcommittees to follow up on
particular issues or needs at any time.

The Steering Committee will also listen to the views of the scientific research
communities that the Research Groups represent in their respective fields, and
consider how the Pharmacogenetic Research Network and Database can have an impact
on the larger community.  For example, it is possible that as new candidate genes
are discovered, they may be nominated to, and evaluated by, the Steering
Committee.  If a determination is made that a candidate is of pressing importance
for pharmacogenetic/pharmacogenomic study, a recommendation could be made that
comprehensive variant detection is necessary.  In exchange for gaining the
equipment, staffing, resources, and infrastructure, the Research Groups must be
willing to consider addressing these future, related scientific needs when the
time comes, as discussed through the Steering Committee.  One Research Group
might consent to assume a particular task, subject to mutual agreement, and
funding being provided by NIH for a project.  In this manner, the Pharmacogenetic
Research Network and Database can serve as a resource for scientists conducting
investigations outside of the Research Groups.

The Steering Committee will in general participate in the process of developing
a cohesive Pharmacogenetic Research Network and Database, and will advise NIH on
scientific opportunities, emerging needs, or impediments.  There should be
continued dialogue and a bidirectional exchange of ideas and information between
the biological and the informatics dimensions of the overall Pharmacogenetic
Research Network and Database.  To facilitate this bidirectional exchange, each
Research Group will be asked to identify a key data liaison individual with the
appropriate experience to interact with the Database Group.  The National Center
for Biotechnology Information (NCBI) will advise coordination of the
Pharmacogenetic Database with other NIH databases it supports (e.g., Genbank,
dbSNP).

Applicants should request funds according to a plan to send the Principal
Investigator or his/her designate to attend the Steering Committee meetings in
Bethesda, MD at least twice per year.  Funds should also be requested to permit
the data liaison individual to meet with a representative of the Database Group
at least twice per year in Bethesda, MD (these meetings may be moved to the
Database Group site, if practical).

Other Institutes of the NIH will be participating in the Pharmacogenetic Research
Network and Database, based upon their interests in the following areas:

National Heart, Lung, and Blood Institute (NHLBI) - interested in proteins and
genes and their variants involved in the treatment and variable responses in
cardiovascular, pulmonary, hematological, and sleep disorders

National Human Genome Research Institute (NHGRI) - interested in large scale SNP
discovery and scoring, and development of tools for analyzing relationships
between genotype and phenotype

National Institute of Environmental Health Sciences (NIEHS) - interested in
proteins and genes affected by environmental exposure; NIEHS also supports the
Environmental Genome Project, http://www.niehs.nih.gov/envgenom/home.htm

National Institute of Mental Health (NIMH) - interested in proteins and genes
involved in the treatment of mental and cognitive disorders; NIMH also supports
the NIMH Human Genetics Initiative, http://zork.wustl.edu/nimh/
NIMH_initiative/NIMH_initiative_link.html

National Institute on Alcohol Abuse and Alcoholism (NIAAA) - interested in
proteins and genes that mediate the effects of alcohol and drugs to modify
alcohol's effects

SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS

I.  Definitions

AWARDEE:  The institution to which a cooperative agreement is awarded

COOPERATIVE AGREEMENT (U01):  An assistance mechanism in which there is
anticipated substantial programmatic involvement by NIH staff with the recipient
organizations during performance of the planned activities

PRINCIPAL INVESTIGATOR:  The person who assembles the project (for either a
Research Group or Database Group) and is responsible for submitting the
application in response to this RFA and for performance of the project

PHARMACOGENETIC RESEARCH NETWORK AND DATABASE:  A series of Research Groups and
a Database Group, each funded by a separate cooperative agreement, working
together to study pharmacogenetic/pharmacogenomic variation

RESEARCH GROUP:  A group of multidisciplinary, collaborating biological
scientists (at one or several sites) employing a state-of-the-art, comprehensive
approach to examining functional variation in their proteins or genes of interest
involved in drug responses

DATABASE GROUP:  A group of bioinformatics scientists or computational biologists
responsible for the design, development, implementation, and maintenance of the
Pharmacogenetic Database

PHARMACOGENETIC DATABASE:  A comprehensive database, with computational tools,
for the storage, integration, and use of pharmacogenetic/pharmacogenomic
information

NIH SCIENTIST/ADMINISTRATORS:  Representative NIH extramural staff (up to six)
who serve on the Steering Committee, who have substantial coordinating scientific
roles on the Steering Committee and can guide its recommendations based upon
their knowledge of other, related NIH-supported research and resource activities

NIGMS PROGRAM DIRECTOR:  NIGMS extramural staff person who provides stewardship
for the awards, and evaluates and implements the advice of the Steering Committee
for allocating NIH support; the NIGMS Program Director also coordinates
administrative management of the Pharmacogenetic Research Network and Database

STEERING COMMITTEE:  A committee that is the main governing body of the
Pharmacogenetic Research Network and Database.  Membership will include
representation from each of the Research Groups and the Database Group, NIH
Scientist/Administrators of the appropriate scientific expertises, as well as
selected scientists other than the awardees where additional expertise is
required, when necessary for committee breadth and balance.  NIH representation
on the Steering Committee will never make up a majority of the total.

ARBITRATION PANEL:  A panel formed as needed to review scientific or programmatic
disagreements (within the scope of the award) that may arise between the
Pharmacogenetic Research Network and Database and the NIH.  It will be composed
of three members:  a designee of the Steering Committee chosen without NIH staff
voting, one NIH designee, and a third designee with expertise in the relevant
area who is chosen by the other two; in the case of an individual disagreement,
the first member may be chosen by the individual awardee.

II.  Terms and Conditions of Award

The following Terms and Conditions will be incorporated into the award statement
and will be provided to the Principal Investigator as well as to the appropriate
institutional official, at the time of award.  The following special terms of
award are in addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, HHS grant administration regulations at 45 CFR Parts
74 and 92 (Part 92 is applicable when State and local Governments are eligible
to apply), and other HHS, PHS, and NIH grant administration policies:

The administrative and funding instrument used for this program will be the
cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH programmatic involvement with
the awardees is anticipated during performance of the activities.  Under the
cooperative agreement, the NIH purpose is to support and stimulate the
recipients' activities by involvement in and otherwise working jointly with the
award recipients in a partnership role; it is not to assume direction, prime
responsibility, or a dominant role in the activities.  Consistent with this
concept, the dominant role and prime responsibility resides with the awardees for
the project as a whole, although specific tasks and activities may be shared
among the awardees and the NIH through the Steering Committee.

Principal Investigator Rights and Responsibilities

The Principal Investigator will coordinate project activities scientifically and
administratively at the Institution.  The Principal Investigator will have the
primary responsibility for defining the details for the projects within the
guidelines of this RFA, and for performing the scientific activities.  A
Principal Investigator will agree to accept close coordination, cooperation, and
participation of NIH staff in those aspects of management of the project as
described under "NIH Scientist/Administrator Responsibilities".  Awardees agree
to accept and implement the guidelines of the Steering Committee regarding data
release into the Pharmacogenetic Database.  Awardees will retain custody of and
have primary rights to the data developed under these awards, subject to
Government rights of access consistent with current HHS, PHS, and NIH policies. 
Awardees should comply with their institutional property policies and practices
as approved in the award.

The Principal Investigator of a Research Group or Database Group will:

o  Determine and coordinate the experimental approaches and procedures o  Set
project milestones for the Research Group or Database Group o  Accept and
implement common guidelines approved by the Steering Committee o  Submit data to
the Pharmacogenetic Database, according to policies established by the Steering
Committee
o  Solicit representative views of other researchers for the proteins or genes
of interest
o  Attend Steering Committee meetings, and participate in the cooperative nature
of the group

NIH Scientist/Administrators Responsibilities:

The NIH Scientist/Administrators are representative NIH extramural staff (up to
six) who will serve on the Steering Committee based upon their areas of
scientific expertise (e.g., pharmacology, genetics, epidemiology) and guide
development of the Pharmacogenetic Research Network and Database by providing
overall advice and coordination.  They should facilitate a partnership
relationship between NIH and the Research Groups and Database Group, and ensure
that the directions taken remain consistent with NIH's missions and goals.  They
will make recommendations regarding support to help maintain scientific balance
between directly accomplishing goals and addressing emerging research
opportunities.  The role of NIH staff will be to facilitate and not to direct
activities.  It is anticipated that decisions will be reached by consensus with
the Principal Investigators through the Steering Committee.

The NIH Scientist/Administrators will:

o  Share his/her relevant expertise and overall knowledge
o  Help to coordinate activities among the awardees, commensurate with their
expertises
o  Be information resources about ongoing NIH-supported research and resource
collections
o  Attend Steering Committee meetings, and participate in the cooperative nature
of the group
o  Promote the Pharmacogenetic Database to the scientific community at large o 
Assist in implementing recommendations for allocating NIH support among the
awardees

Collaborative Responsibilities

A Steering Committee will serve as the governing board of the Pharmacogenetic
Research Network.  Membership will include representation from each of the
Research Groups and the Database Group, up to six NIH Scientist/Administrators
of the appropriate scientific expertises (e.g., pharmacology, genetics,
epidemiology), as well as selected scientists other than the awardees where
additional expertise is required, when necessary for committee breadth and
balance (e.g., computational biology).  The rest of the Steering Committee will
appoint these members by majority vote.  NIH representation on the Steering
Committee will not make up a majority of the total number.  Each member will have
one vote.  The NIGMS Program Director is not a member of the Steering Committee,
but will facilitate creation of the group and will attend all meetings.  Awardee
members of the Steering Committee will be required to accept and implement common
guidelines and procedures approved by the Steering Committee.

By approximately one month after award of the cooperative agreements, the NIH
Scientist/Administrators and the Principal Investigators will meet (perhaps by
telephone conference) to select the outside committee members and to elect a
Chair.  NIH staff may not serve as the committee Chair.  The NIGMS Program
Director will schedule the first meeting of the Steering Committee.  The Chair
will be responsible for developing meeting agendas and chairing meetings.  A
meeting schedule will be prepared at the first meeting.  Two meetings will be
held each year, usually in Bethesda, MD.  Around the time of the meetings, the
data liaisons of the Research Groups and a representative of the Database Group
will also meet, possibly in Bethesda, MD, or possibly at the Pharmacogenetic
Database site.  Subcommittees may be established by the Steering Committee as
necessary.  Additional members may be added by action of the Steering Committee,
through discussion with the NIGMS Program Director.

The Steering Committee will:

o  Serve as the main governing board
o  Discuss progress within the Pharmacogenetic Research Network and Database o 
Set standards and work to standardize data format and nomenclature o  Develop
common guidelines and procedures
o  Consider the representative views of other researchers
o  Participate in the process of developing a cohesive group o  Advise NIH on
scientific opportunities, emerging needs, or impediments

Administrative Coordination Activities

The NIGMS Program Director will assume responsibility for normal stewardship of
the awards, and for coordination of the Pharmacogenetic Research Network and
Database.  Logistical arrangements will be made for the Steering Committee
meetings and other administrative duties related to the committee functions, such
as conference calls, report mailings, publications tracking, etc.  These
activities may be accomplished by a variety of arrangements, such as by adding
funds to the Research Groups and Database Group to support an administrative
contractor.  Data and intellectual property will not be handled centrally prior
to its public release; the awardees are responsible for providing data tracking. 
If clinical studies are proposed, NIH may establish a Data Safety and Monitoring
Board.

Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within
the scope of the award) between award recipients and the NIH may be brought to
arbitration.  An Arbitration Panel composed of three members will be convened. 
It will be composed of three members:  a designee of the Steering Committee
chosen without NIH staff voting, one NIH designee, and a third designee with
expertise in the relevant area who is chosen by the other two; in the case of an
individual disagreement, the first member may be chosen by the individual
awardee.  This special arbitration procedure in no way affects the awardee's
right to appeal an adverse action that is otherwise appealable in accordance with
PHS regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16.

Milestones and Evaluations

Applicants should define yearly milestones in their applications, and the
selected awardees will have the opportunity to modify these milestones at the
time of their awards.  The awardees' milestones will be provided to the Steering
Committee.  It is expected that the milestones should be adjusted annually at the
award anniversary dates, both to incorporate a group's scientific accomplishments
and progress in the field in general, as well as to reflect the recommendations
of the Steering Committee.  In accordance with the procedure described above, the
NIH Scientist/Administrators may recommend augmenting any project, as discussed
through the Steering Committee, or reducing or withholding funds for any project
that substantially fails to meet its milestones or to remain state-of-the-art.

The Director, NIGMS, retains the right to call a meeting of advisors, most likely
members of the National Advisory General Medical Sciences Council or their
designee(s), at any time to provide advice on the scientific progress of the
Pharmacogenetic Research Network and Database.  It is anticipated that such a
group of advisors may want to attend a meeting of the Steering Committee as part
of its fact-finding mission.  Any information or reports will be shared with the
other Institutes/Centers of the NIH participating in this initiative and the
Director, NIH.

ISSUES IN RESEARCH INVOLVING HUMAN SUBJECTS

The nature of the research proposed in response to this initiative will likely
include applications to conduct studies on the genetic basis of variation in drug
responses among different racial, ethnic, and sociocultural populations, or in
individuals and families affected by particular diseases.  Sensitivity to issues
involving the protection of human subjects will be required in approaching this
research.  Every effort should be made to consider the potential impact of the
proposed research on the particular group proposed for study.  Careful
consideration should be given to the potential risks of stigmatization and
discrimination as well as the benefits of the knowledge to be gained.  Thorough,
current, and clear informed consent of the appropriate scope must be obtained
from all participants.  Subjects must be informed about the potential for
information generated from their samples being deposited into the Pharmacogenetic
Database.

The value of the information gained through studies of human genetics will be
diminished if that information is misinterpreted or misused to stigmatize or
discriminate against defined populations.  Thought must be given to these issues
in human subjects research prior to responding to this RFA with a proposal. 
Clear plans for recruitment, informed consent, and the protection of privacy and
confidentiality of human subjects should be addressed in the application and will
be considered during the review process.  Potential applicants are referred to
the NIH Office of Protection from Research Risks
(http://www.nih.gov/grants/oprr/oprr.htm) for discussion of the NIH application
requirements, and also to the OPRR Institutional Review Board Guidebook Chapter
5 - Human Genetics Research (http://www.hhs.gov/ohrp/irb/irb_chapter5.htm)
and other applicable sections, as well as to the Ethical, Legal, and Social
Issues Program (ELSI) of NHGRI (http://www.nhgri.nih.gov/ELSI/) for discussion
of human subjects protections related to human genetic research.  NIH Program
Staff (listed below) may also be contacted and can provide guidance on current
NIH policies and practices in this area.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided 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 "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," which was published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994, and is available at: 
http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html.

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.  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, which was published in the NIH Guide for Grants and
Contracts, March 6, 1998, and is available at:
http://www.nih.gov/grants/guide/notice-files/not98-024.html.

PUBLIC BRIEFING

Prospective applicants are invited to attend a public briefing on the
Pharmacogenetic Research Network and Database on March 19, 1999 in Bethesda, MD. 
NIH staff will explain the purpose of this RFA, provide instructions regarding
the application process, and answer questions.  Potential applicant institutions
are urged to send a representative to this briefing, both to gather information
and to exchange ideas with other potential applicants.  Anyone who cannot attend
the pre-application meeting will be provided with any distributed materials and
a summary of the discussion.  For further information about this meeting, contact
the NIGMS Program Staff listed under INQUIRIES.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone and
facsimile numbers of the Principal Investigator, the identities of other key
personnel and participating institutions, and the number and title of this RFA. 
The letter should specify whether plans are to submit a Research Group proposal
or a Database Group proposal, or both.  Although a letter of intent is not
required and is not binding, it is highly encouraged.  The information it
contains will allows NIH staff to estimate the workload and also to avoid
potential conflicts of interest in the review.

The letter of intent is to be sent by April 30, 1999 to:

Rochelle M. Long, Ph.D.
Pharmacology, Physiology, and Biological Chemistry Division National Institute
of General Medical Sciences
45 Center Drive, Room 2AS.49H, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-1826
FAX:  (301) 480-2802
Email:  rochelle_long@nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/710-0267, E-mail:  GrantsInfo@nih.gov,
world wide web URL: http://www.nih.gov/grants/forms.htm.

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 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.  Applicant institutions proposing both a Research Group
and a Database Group must develop the components as separate applications.

Submit a signed, typewritten original of the application, including the
checklist, and five signed photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, SUITE 6095, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

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.  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(s).

Special application requirements:

An integrated application should be prepared for either a Research Group or a
Database Group.  The aim is to present a comprehensive and cross-disciplinary
team approach to the problem being studied.  The entire application should have
a face page, abstract, consolidated budget, key personnel listing, biographical
sketches, other support, existing resources and facilities, letters of
collaboration, etc.  The page limit for the research plan (including specific
aims, background and significance, preliminary studies, and research design and
methods) is increased to 60 pages total.

For a Research Group, an overview section should be prepared that includes an
overall description which defines the scope and objectives, and provides the
rationale for selection of the area of scientific concentration.  Usually, for
a Research Group, this would be the choice of proteins or genes, or perhaps a
disease/model of interest, where genetic variation contributes to differences in
drug responses.  The proposal may have sections that are highly integrated, in
order to provide a multidisciplinary approach to studying the proteins or genes
of interest.  Some components may exist as cores or resources that are integral
to the entire group.  All parts of the application must be described in
sufficient detail to be completely understood, with the appropriate goals and
timetable.

For a Database Group, an overview section should be prepared that includes an
overall description which defines the scope and objectives, and provides a
strategy for creating a common, public database.  For a Database group, the
overview section might describe the approaches taken to build a Pharmacogenetic
Database.  For example, the application may describe how the Pharmacogenetic
Database will be developed in stages or built around significant component parts. 
All parts of the application must be described in sufficient detail to be
completely understood, with the appropriate goals and timetable.

Additionally, the following areas should be addressed, where appropriate, in the
respective applications:

For a Research Group, describe the timing for release of data into the
Pharmacogenetic Database (this may be modified by recommendation of the Steering
Committee), or other databases

For a Research Group, describe plans for handling intellectual property resulting
from the studies, or for commercialization of any discoveries (and implications
for participating subjects)

For a Research Group, describe plans for human subjects, including definition(s)
of the population(s), plans for recruitment, informed consent forms (describing
anticipated risks and benefits, plans for subject confidentiality, deposition of
information into a database, follow-up with participants), plans for stored or
shared samples (and their prior informed consents), or use of any established
sample sets

For a Research Group, describe the phenotyping criteria (use NIH standards where
standardized criteria exist, e.g., information on clinical diagnostic tests used
for studies of the genetics of brain disorders such as schizophrenia, bipolar
disorder, and late-onset Alzheimer's disease can be found at 
http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html

For a Research Group, a data liaison person with the appropriate experience
should be identified, who will interact with the Database Group and the
Pharmacogenetic Database

For a Database Group, describe the timing and method desired for receipt of
information into the Pharmacogenetic Database (this may be modified by
recommendation of the Steering Committee)

For a Database Group, provide evidence of communication or links with a proposed
Research Group or similar site, assuring that the appropriate expertise is
available for interactions

For a Research Group or Database Group, identify any unique resources, services,
or facilities at the institution (even if support is not sought here, e.g., a
General Clinical Research Center, GCRC)

For a Research Group or Database Group, describe in detail any other support that
significantly impacts this application (even if funding is not sought here, e.g.,
where knowledge of ongoing research projects is essential to the evaluation of
this proposal)

For a Research Group or Database Group, describe plans for sharing any materials
with other researchers (e.g., samples, reagents, software)

For a Research Group or Database Group, specify the yearly milestones (these will
be provided to the Steering Committee, if the application is awarded)

For a Research Group or Database Group, describe the mechanism for administration
of the research activities within the Group (e.g. regular meetings, staffing,
data exchange, external evaluations, etc.)

For a Research Group or Database Group, state the mechanism for collecting other
researchers' views

For a Research Group or Database Group, funds should be requested for the
Principal Investigator or his/her designate to attend two Steering Committee
meetings annually in Bethesda, MD

For a Research Group or Database Group, funds should be requested for the data
liaison person to meet with a representative of the Database Group two times
annually in Bethesda, MD (these meetings may be moved to the Database Group site,
if practical)

For a Research Group or Database Group, funds should be requested to cover any
data tracking and monitoring procedures, or data transfer activities associated
with coordination of the Pharmacogenetic Research Network and Database (e.g.,
reporting to a Data Safety and Monitoring Board for clinical studies, costs of
depositing data into the Pharmacogenetic Database, etc.)

For a Research Group or Database Group, applicant institutions should present
their intellectual property policies and practices

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and for 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 CSR in accordance with the review criteria stated below.  As part of
the initial review process a process may be used in which only those applications
deemed to have the highest scientific merit (generally the top half of the
applications under review) will be discussed, assigned a priority score, and
receive a second level review by the appropriate national advisory council or
board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written comments reviewers will be asked to discuss the following aspects of the
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 addressed and considered in assigning the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

Significance:  Does this study address an important problem?  If the aims of the
application are achieved, how will scientific knowledge be advanced?  What will
be the effect of these studies on the concepts or methods that drive this field?

Approach:  Are the conceptual framework, design, methods, and analyses adequately
developed, well-integrated, and appropriate to the aims of the project?  Does the
applicant acknowledge potential problem areas and consider alternative tactics?

Innovation:  Does the project employ novel concepts, approaches or method?  Are
the aims original and innovative?  Does the project challenge existing paradigms
or develop new methodologies or technologies?

Investigator:  Are the investigators appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

Applicants will be evaluated in the review process for their response to the
Research Objectives, described above, and for their ability to create an
infrastructure through complementary, synergistic connections.  In addition, the
scientific and technical criteria listed in the special application requirements
above will be considered and judged for appropriateness.  The initial review
group will also examine any special needs for the protection of human subjects
and the safety of the research environment.

In accordance with NIH policy, all applications will be reviewed with respect to
the following:

o  The adequacy of plans to include both genders, minorities and their subgroups,
and children as appropriate for the scientific goals of the research.  Plans for
the recruitment and retention of subjects will also be evaluated.

o  The reasonableness of the proposed budget and duration in relation to the
proposed research.

o  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.

Schedule:

Public Information Session at NIH:  March 19, 1999
Letter of Intent Receipt Date:      April 30, 1999
Application Receipt Date:           July 27, 1999
Peer Review Date:                   November 1999
Advisory Council Date:              January 2000
Earliest Anticipated Award Date:    April 1, 2000

AWARD CRITERIA

Award criteria that will be used to make funding decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  program priorities
o  program balance

The NIH retains the flexibility to select and assemble components of the
Pharmacogenetic Research Network and Database that optimally blend the research
areas, experience, creativity, and the applicants' collective knowledge and
combined expertises in the background sciences.

INQUIRIES

Inquiries concerning this RFA are encouraged.  NIH staff welcome the opportunity
to clarify any issues or questions from potential applicants.

Direct inquiries regarding programmatic issues to:

Rochelle M. Long, Ph.D.
Pharmacology, Physiology, and Biological Chemistry Division National Institute
of General Medical Sciences
45 Center Drive, Room 2AS.49H, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-1826
FAX:  (301) 480-2802
Email:  rochelle_long@nih.gov

Susan E. Old, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7940
Bethesda, MD  20892-7940
Telephone:  (301) 435-1802
FAX:  (301) 480-1336
Email:  so40y@nih.gov

Lisa D. Brooks, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
Building 38A,  Room 614
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  lisa_brooks@nih.gov

Jose Velazquez, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 542-4998
FAX:  (919) 541-4937
Email:  velazqu1@niehs.nih.gov

Hemin Chin, Ph.D.
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
Parklawn Building, Room 10C-26
Rockville, MD  20857
Telephone:  (301) 443-1706
FAX:  (301) 443-9890
Email:  hemin@nih.gov

Samir Zakhari, Ph.D.
Division of Basic Research
National Institute n Alcohol Abuse and Alcoholism
Willco Building, Suite 402
Bethesda, MD  20892-7003
Telephone:  (301) 443-0799
FAX:  (301) 594-0673
Email:  szakhari@willco.niaaa.nih.gov

Direct inquiries regarding fiscal matters to:

Antoinette Holland
Grants Administration Branch
National Institute of General Medical Sciences
45 Center Drive, Room 2AN.50B, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5132
FAX:  (301) 480-3423
Email:  hollanda@nigms.nih.gov

Jane R. Davis
Grants Operations Branch
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7174
Bethesda, MD  20892-7926
Telephone:  (301) 435-0166
FAX:  (301) 480-3310
Email:  davisj@gwgate

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  diana_trunnell@nih.gov

Linda Hilley
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 504
Bethesda, MD  20892-7003
Telephone:  (301) 443-4704
FAX:  (301) 443-3891
Email:  lhilley@willco.niaaa.nih.gov

Although the National Cancer Institute (NCI) is not a formal participant in this
RFA, NCI maintains an interest in genes and proteins involved in the activity or
metabolism of agents used in the prevention and treatment of cancer, or in the
cause and progression of cancer.

For more information at NCI contact:

Mary K. Wolpert, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 841
Bethesda, MD  20892-7456
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-8783
FAX:  (301) 402-5200
Email:  wolpertm@exchange.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.113, 93.172, 93.242, 93.273, 93.837, 93.859, 93.862.  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 (10/1/98) 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 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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