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) 710-0267, 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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