PHARMACOGENOMICS OF MOOD AND ANXIETY DISORDERS

RELEASE DATE:  September 4, 2003

RFA Number:  RFA-MH-04-001

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATIONS

National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATIONS

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

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:  93.242, 93.859

LETTER OF INTENT RECEIPT DATE:  January 12, 2004
APPLICATION RECEIPT DATE:  February 12, 2004

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o  Purpose of this RFA
o  Research Objectives
o  Mechanism(s) of Support
o  Funds Available
o  Eligible Institutions
o  Individuals Eligible to Become Principal Investigators
o  Special Requirements
o  Where to Send Inquiries
o  Letter of Intent
o  Submitting an Application
o  Peer Review Process
o  Review Criteria
o  Receipt and Review Schedule
o  Award Criteria
o  Required Federal Citations

PURPOSE OF THIS RFA

The goal of this Request for Applications (RFA) is to solicit applications to 
perform high-quality research studies that correlate responses to drugs used to 
treat mood or anxiety disorders with genetic variation, and create a valuable 
knowledge base populated with reliable information that links drug response 
phenotypes to genotypes.  Novel approaches, including the use of biomarkers and 
other phenotypes correlated with the clinical disorder as intermediate 
endpoints, are also encouraged.  This RFA focuses on studies that examine 
genetic influences on inter-individual differences in response to therapeutic 
drugs used to treat mood or anxiety disorders.  Data and biomaterials collected 
and produced in projects supported under this RFA will be included in the NIMH 
Human Genetics Initiative and distributed to the wider scientific community.

RESEARCH OBJECTIVES

The effect of heredity on the responses of individuals to drugs is a topic of 
exceptional scientific interest.  In the post-genomic era, researchers and 
clinicians will use human DNA sequence, genomic structures, human genetic 
variation, and changes in gene and protein expression to more precisely define 
disease and develop new therapeutic interventions.  Variations in genome 
sequence underlie differences in our vulnerability to disease and in the way our 
bodies respond to treatment.  A catalog of millions of single-base differences 
in our DNA sequence (primarily single nucleotide polymorphisms (SNPs)) is 
available, and those that alter protein sequence or structure may be of the 
highest relevance to disease.

The availability of such new genetic resources and technologies are setting the 
stage for an exciting new era of molecular psychiatry.  This initiative seeks to 
identify genomic, genetic, and proteomic data and to develop associations 
between these data and response patterns for drugs used to treat mood or 
anxiety disorders.  Clinical phenotypes observed prior to initiation of drug 
treatment are not sufficient to predict an individual's response to therapy.  
Assessment of sequence variation in participants exhibiting a wide range of 
responses to drugs used to treat mood or anxiety disorders, including enhanced 
response, lack of response, or adverse reactions, will allow the functional 
consequences of genetic variation to be examined.  Variation in drug 
biotransformation and elimination pathways (pharmacokinetics), variation in the 
direct effects of drugs on cells and tissues (pharmacodynamics), and variation 
at the drug target site (e.g., enzymes, second messengers) are of interest.  
Genetically-based circadian variations in the pharmacokinetics and 
pharmacodynamics of drugs are also of interest.

The underlying theme of this RFA will be to search across the genome for 
pharmacogenetically important sequence variations by correlating genotype with 
treatment response.  Such studies may help elucidate basic mechanisms of drug 
effects and adverse reactions and may facilitate optimal selection of therapy in 
individual patients, as well as mitigating serious adverse response or lack of 
response to therapy.

This initiative aims to fund projects that target the whole genome to identify 
the genetic basis of therapeutic response to one of several compounds (e.g., 
anti-depressants, anti-psychotics (specifically used in the treatment of 
patients with a psychotic mood disorder), anti-manics and anxiolytics).  For 
example, in recent studies combinations of multiple SNPs were predictive of 
bronchodilator response to a beta agonist (albuterol) in asthmatics, and 
association studies of multiple candidate genes have been used to study a 
combination of polymorphisms and therapeutic response to clozapine in 
schizophrenic patients.  This initiative will support research on patients with 
mood or anxiety disorders, and also will support studies of other patient groups 
where these compounds are used to treat co-morbid mood or anxiety disorders 
(e.g., anxiety disorder diagnosed in autistic or Fragile X patients).

Several approaches are promising.  There may be selected study participants 
already phenotyped for a drug response or for disease progression, who can be 
used to relate a characteristic drug response to a genetic variant.  Sequence 
variation in key genes involved in drug metabolism and response, such as the 
cytochrome P450 superfamily and the ATP binding cassette (ABC) family, can be 
examined in relation to measured phenotypic responses to determine which 
variants are functional and how they contribute to individual differences in 
drug response.  This can be conducted efficiently by utilizing samples from 
well-characterized and carefully monitored study participants.  The biochemical 
significance of genetic sequence variation in coding and non-coding regions 
should be examined.  There may be a functional role for genetic variation in 
altered transcription, structure, splicing, or stability of mRNA, as well as 
changes in the structure, function, regulation, modification, or degradation of 
the encoded protein(s).

Projects funded under this RFA may also focus on "off target" screening to 
identify effects of therapeutic compounds that are not expected, e.g., adverse 
reactions, allergic responses, cellular apoptosis and cytochrome P450 
metabolism.  Successful projects will employ high-throughput genotyping and a 
sophisticated, state-of-the-art bioinformatics platform to interpret differences 
in genetic variation.  It is expected that the genes identified in these 
projects that predict therapeutic response may not be related to the drug target 
itself.  For example, a recent evaluation of the clinical response to statins 
(lipid-lowering agents with a well-known target of HMG-CoA reductase) has led 
to identification of combinations of SNPs for genes that predict treatment 
response, and none of the SNPs were related to the drug target.

One particular focus of this effort will be the construction of haplotypes, a 
pattern of nearby SNPs on the same chromosome inherited as a block, which in 
turn will facilitate pharmacogenetic prediction.  DNA database mining and de 
novo sequencing efforts will be directed toward identifying sets of alleles 
forming common haplotypes at important candidate loci.  This should 
substantially increase pharmacogenetic predictive power, because multiple SNPs 
that occur together in most individuals may have an additive effect on the 
phenotype.

Another major objective will be to support state-of-the-art pharmacogenomics 
research to identify novel drug targets for mood or anxiety disorders and to 
assess differential treatment response.  The products of genes identified in 
this initiative are expected to represent validated targets for future drug 
discovery.  This initiative will facilitate discovery of new drugable targets 
that can be successfully approached with conventional small-molecule or protein 
interventions.  Molecular characterization of therapeutic drug response will 
ultimately lead to therapies targeting individual patients, culminating in an 
era of "genomic medicine" to treat mental disorders.  Genetic information 
identified in research funded under this RFA will be made widely available to 
the scientific community, and is expected to greatly accelerate the development 
of new therapeutic compounds for the treatment of mood and anxiety disorders.

Research topics of interest include, but are not limited to, the following:

o Construction and analysis of SNP haplotypes that predict therapeutic response 
or adverse reactions to anti-depressants, anti-psychotics (specifically used in 
the treatment of patients with a psychotic mood disorder), anti-manics or 
anxiolytics in a large-scale clinical trial.

o Correlation of response profiles of anti-depressants, anti-psychotics 
(specifically used in the treatment of patients with a psychotic mood disorder), 
anti-manics or anxiolytics with intermediate phenotypes (e.g., brain imaging, 
neurophysiology, learning and memory, sustained attention).

o Identification of biomarkers (changes in gene or protein expression in 
relevant tissues or biofluids, as determined from laboratory- and non-laboratory 
based approaches, e.g., brain imaging, biochemical assays) to resolve clinical 
heterogeneity and heterogeneity of therapeutic drug response.

o Application of high-throughput approaches to screen for drug candidates 
metabolized by or inhibitors of polymorphic drug-metabolizing enzymes, e.g., 
CYP2D6.

o Studies of genetically determined functional changes in nuclear and cell 
surface receptors to explain the ineffectiveness of therapeutic agents and 
adverse or paradoxical drug responses.

o Studies of allelic variation occurring in individual transporter genes that 
are associated with a functional consequence.

Investigators trained in different areas and working as collaborative teams are 
needed to achieve insights into the contribution of genetic variation on 
individual drug responses.  Rigorous studies are needed to correlate such 
phenotypes with underlying genotypes.  Researchers working at the most molecular 
to the most clinical levels in the fields of pharmacology, physiology, genetics, 
genomics, medicine, epidemiology, statistics, bioinformatics, and computational 
biology should combine talents to interpret functional protein and gene 
variations having essential roles in determining drug response, and to translate 
these findings to improved therapeutic outcomes.  Projects that propose to 
conduct high-throughput genotyping are expected to utilize a single laboratory.

Pharamcogenomic studies supported under this initiative that are conducted 
within the context of ongoing clinical trials must not interfere with or 
overburden participants in the parent study.  In order to be responsive to this 
RFA, the applicant must provide adequate documentation that patients, samples, 
data, and/or materials are available from the parent clinical trial.

Information regarding NIMH-supported large-scale clinical trials that include 
patients with mood or anxiety disorder are available at http://www.stepbd.org/ 
(bipolar disorder), https://trialweb.dcri.duke.edu/tads/index.html 
(adolescent depression) and http://www.edc.gsph.pitt.edu/stard/ancillary.html 
(treatment-resistant depression).  Immortalized cell lines and DNA samples are 
available, in accordance with existing procedures for conducting ancillary 
genetic studies in these trials (see 
http://grants.nih.gov/grants/guide/notice-files/not-mh-01-005.html).  
Other clinical studies of relevance are supported by NIMH's Division of 
Services and Intervention Research (http://www.nimh.nih.gov/dsir/index.cfm).  
Regularly updated information about federally and privately supported clinical 
trials that include patients with mood or anxiety disorders is available at 
http://clinicaltrials.gov/.  Focused studies on 
patients in smaller trials and other studies are encouraged.  Appropriate power 
calculations must be provided, and ancillary study policies from the parent 
study followed.  Additional phenotyping may be necessary for these studies, and 
funds must be included within the proposed budget.

The NIMH Center for Collaborative Genetic Studies on Mental Disorders 
(http://zork.wustl.edu/nimh/) (see below under 
SPECIAL REQUIREMENTS) is available for the long-term storage and distribution 
of DNA, cell lines and data to the scientific community.  Access to the Center 
is granted by NIMH when an applicant agrees to follow existing access procedures 
and policies utilized in the NIMH Human Genetics Initiative 
(http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html).  
Further information is available from the staff contact for scientific/research 
issues listed below.  The Center will also establish high-quality lymphoblastoid 
cell lines and extract DNA.  There is no cost to the investigator for the 
storage and distribution of data and biomaterials, shipping of blood samples or 
for cell line immortalization and DNA extraction.  The Center will also provide 
the investigator at no cost high-quality cell lines and DNA for use in the 
proposed project.

MECHANISM(S) OF SUPPORT

This RFA will use the National Institutes of Health (NIH) Research Project Grant 
(R01) and the Collaborative R01 for Clinical and Services Studies of Mental 
Disorders and AIDS (http://grants.nih.gov/grants/guide/pa-files/PA-01-123.html) 
mechanisms.  Under this RFA, you may request a project period of up to five 
years.  As an applicant you will be solely responsible for planning, directing, 
and executing the proposed project.  This RFA is a one-time solicitation.  
Future unsolicited, competing-continuation applications based on this project 
will compete with all investigator-initiated applications and will be reviewed 
according to the customary peer review procedures.  The anticipated award date 
is September 30, 2004.  Applications that are not funded in the competition 
described in this RFA may be resubmitted as NEW investigator-initiated 
applications as described at NOT-OD-03-019 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-019.html) 
using the standard receipt dates for NEW applications 
(http://grants.nih.gov/grants/funding/submissionschedule.htm).

This RFA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular budget format.  Otherwise, follow the 
instructions for non-modular budget research grant applications.  This program 
does not require cost sharing as defined in the current NIH Grants Policy 
Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.

FUNDS AVAILABLE

The participating ICs intend to commit $3 million in FY 2004 to fund 3 to 5 new 
and/or competitive continuation grants in response to this RFA.  An applicant 
may request a project period of up to 5 years.  Because the nature and scope of 
the proposed research will vary from application to application, it is 
anticipated that the size and duration of each award will also vary.  Although 
the financial plans of NIH provide support for this program, awards pursuant to 
this RFA are contingent upon the availability of funds and the receipt of a 
sufficient number of meritorious applications.
 
ELIGIBLE INSTITUTIONS

You may submit (an) application(s) if your institution has any of the following 
characteristics:

o  For-profit or non-profit organizations 
o  Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o  Units of State and local governments
o  Eligible agencies of the Federal government  
o  Domestic or foreign institutions/organizations

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to carry out 
the proposed research is invited to work with their institution to develop an 
application for support.  Individuals from underrepresented racial and ethnic 
groups as well as individuals with disabilities are always encouraged to apply 
for NIH programs.

SPECIAL REQUIREMENTS

Dissemination of Data, Biomaterials

This RFA is responsive to the NIH Grants Policy Statement requiring 
investigators to provide prompt and effective access to unique research 
resources generated by NIH funds 
(http://grants.nih.gov/grants/policy/nihgps_2001/part_iia_6.htm).  
As described below, applications must include a data sharing plan.  Data and 
biomaterials from subjects included in projects funded under this RFA will be 
made available and distributed to the broader scientific community, in 
accordance with existing procedures and protocols for the NIMH Human Genetics 
Initiative and for PharmGKB, an NIH-supported knowledge base for pharmacogenetic 
information (http://www.pharmgkb.org/) (see below).

The sharing of biomaterials, data, and software in a timely manner has been an 
essential element in the rapid progress that has been made in the genetic 
analysis of human diseases.  To address the joint interests of the government in 
the availability of, and access to, the results of publicly funded research and 
in the opportunity for economic development based on these results, NIH requires 
applicants who respond to this RFA to develop and propose detailed plans for 
sharing specific data and biomaterials generated through the grant.  It is 
expected that the information to be shared includes all pharmacogenomic, 
clinical and diagnostic information, in addition to cell lines and DNA.

For this purpose, it is the opinion of NIH that dissemination of such data and 
materials via individual laboratories and Web sites is not sufficient, as it 
would force interested investigators to have to search several different data 
collections to make use of the results of this initiative.  In addition, 
differences in protocols across projects for creating databases, establishing 
cell lines, and extracting DNA may make it impossible for researchers to combine 
information for integrated genetic analyses.  It is preferable that data and 
materials generated in grants funded under this RFA should be placed in common, 
public cell repositories and databases that are widely accessible by 
investigators in the scientific community.  An NIMH-supported data management 
facility and cell repository – the NIMH Center for Collaborative Genetic Studies 
on Mental Disorders (http://zork.wustl.edu/nimh/) - is such a community 
resource.  Access to the Center is granted by NIMH when an applicant agrees to 
follow existing access procedures and policies utilized in the NIMH Human 
Genetics Initiative 
(http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html).  
Further information is available from the staff contact for scientific/research 
issues listed below.

It is expected that the investigator's data sharing plan will specify the 
following elements:  (1) the creation of comprehensive and verified databases 
that contain all clinical, diagnostic, and genetic information collected and 
produced in the project; (2) the establishment of high-quality cell lines, from 
which DNA will be extracted and stored, for all subjects studied from whom blood 
samples have been obtained; (3) mechanisms by which all databases and 
biomaterials (DNA samples, cell lines) are widely distributed to qualified 
investigators in the scientific community; (4) a protocol for wide dissemination 
of these data and biomaterials; (5) a timetable for distribution; and 
(6) an assurance that data and biomaterials are disseminated in a manner 
comparable to pre-existing protocols and procedures for distributing such data 
and biomaterials in the NIMH Human Genetics Initiative 
(see http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html).

The Initial Review Group will comment on the proposed plan for sharing and data 
access.  The plan will be considered part of the methodology for carrying out 
the research and, as such, the adequacy of the plan will be considered by NIH 
staff in determining whether the grant shall be awarded.  The sharing plan as 
approved, after negotiation with the applicant when necessary, will be a 
condition of the award.  Evaluation of renewal applications will include 
assessment of the effectiveness of data and biomaterial release.

After extensive discussion with mental health and human genetics researchers and 
advocacy members, the Genetics Workgroup of the National Advisory Mental Health 
Council (NAMHC) recommended that NIMH should draft a policy that provides for 
the sharing of genetic materials after a 12- to 18-month proprietary period (see 
http://www.nimh.nih.gov/research/genetics.htm).  Adherence with the time 
frame recommended by the NAMHC's Genetics Workgroup is highly desirable.  This 
is expected to result in all data being released to the scientific community by 
the end of the award period, even if a competing renewal application is 
submitted.  More rapid sharing is encouraged.  Requests for exemptions or 
extensions will require compelling justification and will be fully evaluated 
through peer review and by program staff.

NIMH, in consultation with NIH's Office of the General Counsel, the National 
Human Genome Research Institute's Ethical, Legal, and Social Implications 
Research Program and the Department of Health and Human Services' Office for 
Human Research Protections, has developed a model consent form for use in human 
genetic research at 
http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html.  
This may then serve as a template that is subject to modification and/or 
approval by local institutional review boards.  It is expected that the 
applicant's approved consent form address the following:  (1) disclosure that 
biomaterials (DNA and cell lines) and clinical data will be stored at a central 
data management/laboratory facility as part of a national resource of data and 
biomaterials distributed for the genetic analysis of the disease under 
investigation; (2) assurance that such data will be provided to a central 
facility without personal identifiers; (3) disclosure that analyses of these 
data will be conducted by other scientists currently not included within the 
current research team; and (4) disclosure that there is no plan to provide 
subjects with any financial benefits from commercial products derived from the 
data.  The consent form should also include explicit disclosure that 
de-identified data will be posted to PharmGKB, a knowledge base for 
pharmacogenetic information (see below under Data Submission to PharmGKB).  
NIH will review consent forms and IRB approvals for all projects prior to 
funding under this RFA.

Data Submission to PharmGKB 

Principal investigators of awards funded through this RFA will be required to 
deposit their data into PharmGKB (http://www.pharmgkb.org), a knowledge base 
for pharmacogenetics information maintained by Stanford University.  Data 
sharing should adhere to the practices of the NIH and the Pharmacogenetics 
Research Network, for example, all bulk variant sequence data should be 
deposited within 90 days of discovery, and more complex data sets should be 
deposited concurrent with acceptance of a publication; unpublished data sets 
with unique value will also be accepted into PharmGKB 
(http://www.pharmgkb.org/do/serve?id=network.policies.2).  
All data generated in response to this RFA should also be provided to the NIMH 
Center for Collaborative Genetic Studies on Mental Disorders 
(http://zork.wustl.edu/nimh/) for distribution to 
the scientific community, and where feasible, PharmGKB will make such deposits 
automatically, similar to the arrangement it has made with dbSNP 
(http://www.ncbi.nlm.nih.gov/SNP/index.html).

PharmGKB is organized around the principle that pharmacogenetics information 
can be indexed by genes, drugs, and categories of evidence that drug response 
differences result from genetic variation.  PharmGKB includes genotypic and 
phenotypic information collected in research studies conducted by the NIH 
Pharmacogenetics Research Network (http://www.nigms.nih.gov/pharmacogenetics), 
as well as information gathered from external sources relevant to 
pharmacogenetics studies.  Access to subject-specific genotype and phenotype 
data in PharmGKB is granted to researchers who have requested the data for 
appropriate scientific purposes, who have been authenticated and received 
passwords, and who promise to respect the confidentiality of subjects.  No data 
are directly identifiable, and PharmGKB requires authentication and password 
protection in order to abide by HIPAA regulations covering the research use of 
potentially identifying research data.

PharmGKB entries consist of (1) genotypic data, submitted using an XML standard 
format (http://www.pharmgkb.org/do/serve?id=submit.xml), and 
(2) linked phenotypic information, without personal identifiers, submitted using 
an EXCEL template (http://www.pharmgkb.org/do/serve?id=submit.phenotype).  
In cases where individual phenotypic information are judged to be too sensitive 
to release, the investigators may contact PharmGKB staff to learn of the best 
ways to summarize data.  Community annotations of existing gene-drug-disease 
relationships are also accepted into PharmGKB 
(http://www.pharmgkb.org/do/serve?id=submit.relationship).  The 
PharmGKB team will work with investigators to define the XML-based and 
spreadsheet-based submission of data; however, it is the responsibility of the 
investigators funded under this RFA to have access to and request funding for 
the support of informatics staff with sufficient skills to understand and 
create XML files and appropriately submit phenotype files.

Applicants should describe their plans for data deposits, identify specific 
staff who will be responsible and plan for their financial support, and indicate 
that they will obtain adequate informed consent for posting de-identified data 
to PharmGKB.  Samples of model informed consent language used by the 
Pharmacogenetics Research Network can be found at 
http://www.pharmgkb.org/do/serve?id=network.policies.3, and 
should be considered in conjunction with NIMH recommendations regarding 
informed consent, detailed above.  Protection of participant confidentiality 
and plans for materials and data sharing will be subject to peer review.  
Arrangements for data sharing will be specified in the terms and conditions of 
these awards, and will be updated and finalized in the first year of the 
studies.  At that time, current needs for the assistance of programmers and 
curators at PharmGKB will be considered at NIMH for awards made under this RFA.  
The award of annual non-competing continuation applications will also be 
contingent on the satisfactory completion of this requirement.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to answer 
questions from potential applicants.  Inquiries may fall into three areas:  
scientific/research, peer review, and financial/grants management issues:

o  Direct your questions about scientific/research issues to:

Steven O. Moldin, Ph.D.
Office of Human Genetics and Genomic Resources
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7189, MSC 9643
Bethesda, MD  20892-9643
Telephone:  (301) 443-2037
FAX:  (301) 443-9890
Email:  smoldin@mail.nih.gov

o  Direct your questions about PharmGKB or the Pharmacogenetics Research Network 
to:

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

o  Direct your questions about peer review issues to:

Michael Kozak, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6138, MSC 9609
Bethesda, MD  20892-9608
Telephone:  (301) 443-1340
FAX:  (301) 443-4720
Email:  kozakm@mail.nih.gov

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

Carol J. Robinson
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6118, MSC 9605
Bethesda, MD 20892-9605
Telephone:  (301) 443-3858
FAX:  (301) 443-6885
Email:  crobinso@mail.nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes the 
following information:

o  Descriptive title of the proposed research
o  Name, address, and telephone number of the Principal Investigator
o  Names of other key personnel
o  Participating institutions
o  Number and title of this RFA

Although a letter of intent is not required, is not binding, and does not enter 
into the review of a subsequent application, the information that it contains 
allows NIH staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the letter of receipt date listed at the 
beginning of this document to:

Steven O. Moldin, Ph.D.
Office of Human Genetics and Genomic Resources
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Boulevard, Room 7189, MSC 9643
Bethesda, MD  20892-9643
Rockville, MD 20852 (for courier/express mail service)
Telephone:  (301) 443-2037
FAX:  (301) 443-9890
Email:  smoldin@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  Applications must have a DUN and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal 
Identifier when applying for Federal grants or cooperative agreements.  The DUNS 
number can be obtained by calling (866) 705-5711 or through the web site at 
http://www.dunandbradstreet.com.  The DUNS number should be entered on line 11 
of the face page of the PHS 398 form.  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an 
interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email:  GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular budget grant format.  The modular budget grant format simplifies the 
preparation of the budget in these applications by limiting the level of 
budgetary detail.  Applicants request direct costs in $25,000 modules.  Section 
C of the research grant application instructions for the PHS 398 (rev. 5/2001) 
at http://grants.nih.gov/grants/funding/phs398/phs398.html 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL:  The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label could 
result in delayed processing of the application such that it may not reach the 
review committee in time for review.  In addition, the RFA title and number must 
be typed on line 2 of the face page of the application form and the YES box must 
be marked.  The RFA label is also available at:  
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of the 
application, including the Checklist, and three signed, photocopies, in one 
package to:

Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be 
sent to:

Jean G. Noronha, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Boulevard, Room 6154, MSC 9609
Bethesda, MD  20892-9663
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 443-3367
FAX:  (303) 443-4720
Email:  jnoronha@mail.nih.gov

APPLICATION PROCESSING:  Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an application 
is received after that date, it will be returned to the applicant without 
review.

Although there is no immediate acknowledgement of the receipt of an application, 
applicants are generally notified of the review and funding assignment within 8 
weeks.

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes from the previous 
unfunded version of the application.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by the participating ICs.  Incomplete applications will not be 
reviewed.  If the application is not responsive to the RFA, NIH staff may 
contact the applicant to determine whether to return the application to the 
applicant or submit it for review in competition with unsolicited applications 
at the next appropriate NIH review cycle.  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 the participating ICs in accordance 
with the review criteria stated below.  As part of the initial merit review, 
all applications will:

o  Undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, will 
be discussed and assigned a priority score
o  Receive a written critique
o  Receive a second level review by the National Advisory Mental Health Council 
and the National Advisory General Medical Sciences Council

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In the 
written comments, reviewers will be asked to evaluate the application in order 
to judge the likelihood that the proposed research will have a substantial 
impact on the pursuit of these goals.  The scientific review group will address 
and consider each of these criteria in assigning the application's overall 
score, weighting them as appropriate for each application.

o  Significance
o  Approach
o  Innovation
o  Investigator
o  Environment

The application does not need to be strong in all categories to be judged 
likely to have major scientific impact and thus deserve a high priority score.  
For example, an investigator may propose to carry out important work that by 
its nature is not innovative but is essential to move a field forward.

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

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

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

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

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

ADDITIONAL REVIEW CRITERIA:  In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK:  The involvement of human 
subjects and protections from research risk relating to their participation in 
the proposed research will be assessed. (See criteria included in the section 
on Federal Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH:  The adequacy of plans 
to include subjects from both genders, all racial and ethnic groups (and 
subgroups), and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria in the sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH:  If vertebrate animals are to be 
used in the project, the five items described under Section f of the PHS 398 
research grant application instructions (rev. 5/2001) will be assessed.

ADDITIONAL REVIEW CONSIDERATIONS

SHARING RESEARCH DATA:  Applicants requesting more than $500,000 in direct costs 
in any year of the proposed research must include a data sharing plan in their 
application.  The reasonableness of the data sharing plan or the rationale for 
not sharing research data will be assessed by the reviewers.  However, reviewers 
will not factor the proposed data sharing plan into the determination of 
scientific merit or priority score.

The adequacy of the proposed plan to share data, in accordance with the 
procedures and mechanisms employed in the NIMH Human Genetics Initiative 
(http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html) 
will be assessed.  The adequacy of the proposed plan by which data will be 
deposited into PharmGKB will be assessed.

BUDGET:  The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    January 12, 2004
Application Receipt Date:         February 12, 2004
Peer Review Date:                 June 2004
Council Review:                   September 2004
Earliest Anticipated Start Date:  September 30, 2004

AWARD CRITERIA

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

o  Scientific merit (as determined by peer review)
o  Availability of funds
o  Adequacy of plans to make data and biomaterials widely accessible in a 
timely manner to the research community
o  Adequacy of plans to integrate data and biomaterials with comparable 
resources in the NIMH Human Genetics Initiative
o  Programmatic priorities
 
REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against these 
risks, the potential benefits of the research to the subjects and others, and 
the importance of the knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

DATA AND SAFETY MONITORING PLAN:  Data and safety monitoring is required for all 
types of clinical trials, including physiologic, toxicity, and dose-finding 
studies (phase I); efficacy studies (phase II); efficacy, effectiveness and 
comparative trials (phase III).  The establishment of data and safety monitoring 
boards (DSMBs) is required for multi-site clinical trials involving 
interventions that entail potential risk to the participants.  (NIH Policy for 
Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
Investigators submitting an NIH application seeking more than $500,000 or more 
in direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible 
(http://grants.nih.gov/grants/policy/data_sharing).  
Investigators should seek guidance from their institutions, on issues related to 
institutional policies, local IRB rules, as well as local, state and Federal 
laws and regulations, including the Privacy Rule.  Reviewers will consider the 
data sharing plan but will not factor the plan into the determination of the 
scientific merit or the priority score.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  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 clinical research projects unless a clear and 
compelling justification is 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 clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts on 
October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates:  the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that:  
a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, 
as appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
The NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH policy 
requires education on the protection of human subject participants for all 
investigators submitting NIH proposals for research involving human subjects.  
You will find this policy announcement in the NIH Guide for Grants and Contracts 
Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to the 
"Standards for Privacy of Individually Identifiable Health Information", the 
"Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal regulation 
under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 
that governs the protection of individually identifiable health information, and 
is administered and enforced by the DHHS Office for Civil Rights (OCR).  Those 
who must comply with the Privacy Rule (classified under the Rule as "covered 
entities") must do so by April 14, 2003  (with the exception of small health 
plans which have an extra year to comply).

Decisions about applicability and implementation of the Privacy Rule reside with 
the researcher and his/her institution.  The OCR website 
(http://www.hhs.gov/ocr/) provides 
information on the Privacy Rule, including a complete Regulation Text and a set 
of decision tools on "Am I a covered entity?"  Information on the impact of the 
HIPAA Privacy Rule on NIH processes involving the review, funding, and progress 
monitoring of grants, cooperative agreements, and research contracts can be 
found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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

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

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of Federal 
Domestic Assistance at http://www.cfda.gov/ and is not 
subject to the intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under the authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 
and 284 and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm.

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


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