MECHANISMS UNDERLYING INDIVIDUAL VARIATIONS IN DRUG RESPONSES

Release Date:  November 18, 1998

PA NUMBER:  PA-99-016

P.T.

National Institute of General Medical Sciences
National Cancer Institute
National Heart, Lung, and Blood Institute
National Institute of Child Health and Human Development
National Institute of Environmental Health Sciences
National Institute of Mental Health
National Institute on Aging
National Institute on Alcohol Abuse and Alcoholism

PURPOSE

The purpose of this program announcement (PA) is to stimulate research into
identifying the critical candidate proteins and/or genes that play essential
roles in determining individual variations in drug responses.  The study of
pharmacogenetic/pharmacogenomic variation presents opportunities to a wide range
of researchers, working at levels ranging from the most molecular to the most
clinical, in the fields of pharmacology, genetics, genomics, medicine,
epidemiology, statistics, and computer science.

This announcement is anticipated to be one of a pair of National Institute of
General Medical Sciences (NIGMS)-led initiatives designed to address the
collection of fundamental knowledge required to predict interindividual
differences in drug responses.  NIGMS expects to announce a companion
solicitation to create a common, public pharmacogenetic database.  Awardees from
this PA should plan to deposit sequence, function, and phenotype information into
the pharmacogenetic database as it is developed.

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 PA, Mechanisms Underlying Individual
Variations in Drug Responses, 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 PA will use the National Institutes of Health (NIH) research project grant
(R01) award mechanism.  Responsibility for the planning, direction, and execution
of the proposed project will be solely that of the applicant.  The total project
period for an application submitted in response to this PA may not exceed five
years.  Competitive supplement applications to existing will also be accepted,
if there will be at least one year remaining in the project period at the time
of supplement funding.

Program project (P01) and pilot project/feasibility study (R21) mechanisms are
not part of this announcement.  However, individual Institutes may be interested
in supporting research in this field using the P01 and R21 mechanisms. 
Investigators who want to apply for P01 or R21 grants should contact staff at the
appropriate Institutes (see INQUIRIES below) to learn the current guidelines for
those programs.  Foreign institutions are not eligible for P01 grants.

Investigators may also apply for the Small Business Innovation Research (SBIR;
R43, R44) and Small Business Technology Transfer Research (STTR; R41, R42) award
mechanisms.  For details of the SBIR and STTR application and review procedures,
consult the Omnibus Solicitation of the NIH, CDC, and FDA for SBIR grant
applications (PHS 98-2) and the Omnibus Solicitation of the NIH for STTR grant
applications (PHS 98-3).  These documents are available at
http://www.nih.gov/grants/funding/sbir.htm.  Foreign institutions are not
eligible for SBIR/STTR grants.

RESEARCH OBJECTIVES

Background:

Pharmacogenetics can be defined as the effect of inheritance on individual
variations in responses to drugs and xenobiotics.  These variations may involve
individual differences in therapeutic efficacy or adverse drug reactions. 
Pharmacogenomics can be defined as the comprehensive compilation of information
about genomic sequences and sequence variants, and the application of this
information to understanding individual variations in drug responses. 
Polymorphisms (common genetic variants that occur with a frequency of 1% or
greater) that are functionally significant have been identified for several
proteins that determine drug responses.  Functional polymorphisms of enzymes that
catalyze drug biotransformations were first identified following clinical
observations of an unusual phenotype, such as "fast" or "slow" metabolism, in
response to a drug therapy (e.g., N-acetyltransferase 2 with isoniazid,
cytochrome P450 2D6 with debrisoquine).  Functionally significant polymorphic
variants for several target receptors and proteins have also been identified, and
often their involvement is suspected both in the etiology of disease and in drug
therapy (e.g., apolipoprotein E4 in Alzheimer's disease, beta2-adrenergic
receptor variants in asthma).  The techniques of molecular biology, genetics, and
genomics taken together will likely spur discovery of more variants that are
logical targets for therapeutic intervention.

Several different strategies for research approaches are encouraged in order to
move the field of pharmacogenetics/pharmacogenomics forward.  In some instances,
the starting point will be the identification of a protein through molecular or
pharmacological studies, where genetic variation is suspected to lead to distinct
drug response phenotypes.  The candidate protein should be examined in normal and
altered form, its mechanism of action verified, perhaps in a cellular assay or
in appropriate model animals, and functional correlations should be made to
clinical responses in human and/or patient populations.  In other situations, a
normal human or patient population that exhibits significant variation in a drug
response phenotype will be an accessible resource for study, and genetic and/or
molecular epidemiologic studies will lead to the identification of a candidate
drug response gene.  The gene (or genes) can be located and cloned, and the
function/misfunction characterized and linked to expression.  Alternatively, non-
human model organisms may prove useful for genetic manipulation, and this will
lead to identification of a drug response mechanism.  Sometimes the starting
point will be a collection of sequence information for proteins and/or genetic
material (e.g., genomic DNA, cDNA, or RNA) known to be associated with drug
response variations.  These approaches and others are appropriate for this
program announcement.

Advances are occurring rapidly in our appreciation of the extent and the
significance of genetic variation, including but not limited to single nucleotide
polymorphisms (SNPs), both in humans and in experimental animals.  In some
instances variations in drug response traits result from polymorphisms of single
genes, usually leading to impaired or null function, although it is possible to
have enhanced function through different mechanisms.  There may even be modifying
factors, such as diet, age, gender, or environmental exposure.  Some of the same
proteins/genes that are responsible for variations in drug responses will also
be associated with the pathophysiology of certain diseases.  Furthermore, some
disorders appear to have multigenic determinants (e.g., atherosclerosis, certain
cancers, neurodegenerative disorders).  Understanding the etiology of a disease
is also essential to designing effective drug treatments (see also "Genetic
Architecture of Complex Phenotypes", PA-98-078,
http://www.nih.gov/grants/guide/pa-files/PA-98-078.html).  The proposed research
to be supported by this announcement should be aimed at identifying and
characterizing proteins and/or genes or gene families where genetic variation is
causative of drug response variations.  This may involve studies of susceptible
individuals, families, and/or high-risk populations.  It is important to address
how to relate a phenotype for a drug response to a genotype.  The ultimate goal
is to draw conclusions that contribute to the prediction of drug response
variations.

Scope and Objectives:

The aim is to identify the fundamental mechanisms that appear to play a role in
determining individual variations in drug responses, through biochemical,
pharmacological, genetic, and/or genomic studies, and to accelerate the pace of
discovery in pharmacogenetics.  "Drug" is defined to include both small organic
molecules and macromolecular drugs such as peptides and oligonucleotides. 
Possible examples of proteins and/or genes which could be studied are: 
cytochromes P450, N-acetyltransferases, sulfotransferases, UDP-
glucuronyltransferases, p-glycoprotein, organic anion/cation transporters,
multispecific drug resistance proteins, beta-adrenergic receptors, dopamine
receptors, serotonin receptors, lipoxygenases, phosphodiesterases, GTP-binding
proteins, and others.  These examples are not intended to limit the responses.

Investigator-initiated research grant applications are invited in the following
areas:

1.  Identification of candidate proteins and/or their genes and their gene
families, that play a role in determining individual variations in drug
responses, and may ultimately have functionally significant, common genetic
polymorphisms leading to different drug response phenotypes.  These would include
but not be limited to -

o  enzymes of biotransformation
o  transporter proteins controlling cellular influx/efflux
o  target receptors and enzymes
o  signal transducing complexes
o  control and regulation of these systems
o  interactions and pleiotropic responses

2.  Development and characterization of the appropriate in vivo and in vitro
models (including human, animal, and non-mammalian species) and computer-based
models, to identify human genetic polymorphisms and to study their functional
effects, both mono- and polygenic, in determining individual variations in drug
responses.  These would include but not be limited to:

o  transgenic, knock-in and knock-out animal models
o  other model organisms amenable to genetic manipulation
o  cultured cell and microbial models
o  computer-based models for analyzing functional effects
o  identification of probe drugs for use in phenotyping

3.  Genetic and molecular epidemiologic studies to identify candidate genes
associated with variations in drug responses, involving families, patients,
and/or human populations.  Genetic determinants could be assessed in other
organisms, as appropriate.  This would include the study of variations among
individuals that are multigenic in origin that contribute to determining drug
responses.  Approaches might include but are not limited to:

o  pedigree-based linkage analysis
o  sib-pair studies
o  allelic association studies
o  genome-wide association studies
o  population-based epidemiologic studies

Supplemental applications to existing research grants are invited in the
following areas:

1.  Supplemental support to individual investigators for the creation and
maintenance of shared patient sample repositories (e.g., DNA, tissue, and blood
samples), to be used to link clinically significant phenotypes to functionally
important genetic polymorphisms for variations in drug responses.  This might
include -

o  samples from patients well-characterized for drug response phenotype and
history
o  additional parental/family sample materials, where feasible

2.  Supplemental support to research laboratories to implement the most recent
technologies for rapid detection of DNA sequence variants, in order to correlate
genotypes with clinically significant drug response phenotypes.  This might
include:

o  collaborations between academic research programs and technology developers
o  implementation of high-throughput screening methodologies to test hypotheses

Other supplemental applications will be considered where specific and well-
justified requests are made that expand the scope of an investigator's existing
support and are consistent with the goals of this initiative.

This is a trans-NIH initiative and is intended to encourage examination of a
variety of basic mechanisms that determine individual variations in drug
responses.  Although NIGMS is leading the initiative, a number of other
Institutes of the NIH are participating, and they are particularly interested in
studies in the following areas:
NCI - drug response proteins and/or genes involved in cancer, genetic/molecular
epidemiologic studies of polymorphisms associated with cancer, and studies of
nicotine susceptibility;
NHLBI - drug response proteins and/or genes involved in cardiovascular,
pulmonary, and hematologic systems;
NICHD - development of drug response proteins and/or genes in children;
NIEHS - drug response proteins and/or genes affected by environmental exposure,
NIEHS also supports the Environmental Genome Project,
http://www.niehs.nih.gov/envgenom/home.htm;
NIMH - drug response proteins and/or genes involved in the treatment of mental
disorders and cognitive disorders;
NIA - drug response proteins and/or genes involved in susceptibility to adverse
drug reactions and drug-drug interactions in older persons;
NIAAA - drug response proteins and/or genes that mediate the effects of alcohol
and/or drugs that modify alcohol's effects.

Inquiries should be directed to the appropriate program staff, listed below in
the announcement.

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 or 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/notice-files/not94-105.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.  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" 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.

Investigators may obtain copies of these policies from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning these policies.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted at the standard application deadlines as indicated in
the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained 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, Email: 
[email protected].

Applicants planning to submit an investigator-initiated new (type 1), competing
continuation (type 2), competing supplement (type 3), or any amended/revised
version of the preceding grant application types requesting $500,000 or more in
direct costs for any year are advised that he or she must contact the Institute
program staff before submitting the application, as plans for the study are being
developed.  Furthermore, the applicant must obtain agreement from staff that the
Institute will accept the application for consideration for award.  Finally, the
applicant must identify, in a cover letter sent with the application, the staff
member (and Institute) who agreed to accept assignment of the application.  This
policy requires an applicant to obtain agreement for acceptance of both any such
application and any such subsequent amendment.  Refer to the NIH Guide for Grants
and Contracts, March 20, 1998, at
http://www.nih.gov/grants/guide/notice-files/not98-030.html.

The title and number of the program announcement must be typed on line 2 of the
face page of the application form and the YES box must be marked.

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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications will be evaluated for scientific and technical merit
by an appropriate scientific review group convened in accordance with the
standard NIH peer review procedures.  As part of the initial merit review, all
applications will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit, generally the top
half of applications under review, will be discussed, assigned a priority score,
and receive a second level review by an 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.

1.  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?

2.  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?

3.  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?

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

5.  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?

In addition to the above criteria, in accordance with NIH policy, all
applications will also 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.

The initial review group will also examine the provisions for the protection of
human subjects and the safety of the research environment.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions: 
quality of the proposed project as determined by peer review, availability of
funds, and program priority.

INQUIRIES

Inquiries are encouraged.  We 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
Building 45, Room 2AS.49H
Bethesda, MD  20892-6200
Telephone:  (301) 594-1826
Fax:  (301) 480-2802
Email:  [email protected]

Kumiko Iwamoto, M.D., Dr.P.H.
Division of Cancer Control and Population Sciences
National Cancer Institute
Executive Plaza North, Room 535
Rockville, MD  20852
Telephone:  (301) 496-9600
Fax:  (301) 402-4279
Email:  [email protected]

Mary K. Wolpert, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
Executive Plaza North, Room 841
Rockville, MD  20852
Telephone:  (301) 496-8783
Fax:  (301) 402-5200
Email:  [email protected]

Peter J. Savage, M.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
Two Rockledge Centre, Room 8104
Bethesda, MD  20817-7938
Telephone:  (301) 435-0421
Fax:  (301) 480-1864
Email:  [email protected]

George Giacoia, M.D.
Endocrinology, Nutrition and Growth Branch
National Institute of Child Health and Human Development
Building 62, Room 4B11
Bethesda, MD  20892
Telephone:  (301) 496-5589
Fax:  (301) 480-9791
Email:  [email protected]

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:  [email protected]

Linda S. Brady, Ph.D.
Division of Basic and Clinical Science Research
National Institute of Mental Health
Parklawn Building, Room 11-97
Rockville, MD  20857
Telephone:  (301) 443-9875
Fax:  (301) 443-4822
Email:  [email protected]

Stanley L. Slater, M.D.
Geriatrics Program
National Institute on Aging
Gateway Building, Room 3E-327
Bethesda, MD  20892-9205
Telephone:  (301) 496-6761
Fax:  (301) 402-1784
Email:  [email protected]

Samir Zakhari, Ph.D.
Division of Basic Research
Willco Building, Suite 402
National Institute on Alcohol Abuse and Alcoholism
Bethesda, MD  20892-7003
Telephone:  (301) 443-0799
Fax:  (301) 594-0673
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Antoinette Holland
Grants Administration Branch
National Institute of General Medical Sciences
Building 45, Room 2AN.50B
Bethesda, MD  20892-6200
Telephone:  (301) 594-5132
Fax:  (301) 480-3423
Email:  [email protected]

William Wells
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext. 250
Fax:  (301) 496-8601
Email:  [email protected]

Marie A. Willett
Grants Operations Branch
National Heart, Lung, and Blood Institute
Two Rockledge Centre, Room 7156
Bethesda, MD  20817
Telephone:  (301) 435-0144
Fax:  (301) 480-3310
Email:  [email protected]

E. Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development
Building 61E, Room 8A07
Bethesda, MD  20814-9692
Telephone:  (301) 435-6999
Fax:  (301) 402-0915
Email:  [email protected]

David Mineo
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-22
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373
Fax:  (919) 541-2860
Email:  [email protected]

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
Parklawn Building, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-2805
Fax:  (301) 443-6885
Email:  [email protected]

Cynthia Riddick
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  20892
Telephone:  (301) 496-1472
Fax:  (301) 402-3672
Email:  [email protected]

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:  [email protected]

AUTHORITIES AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.113, 93.242, 93.273, 93.393, 93.395, 93.837, 93.859, 93.862, 93.865, and
93.866.  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 PHS grants policies 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, and 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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