PHARMACOGENETICS RESEARCH NETWORK AND KNOWLEDGE BASE Release Date: April 7, 2000 RFA: GM-00-003 National Institute of General Medical Sciences (http://www.nigms.nih.gov/) National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/) National Human Genome Research Institute (http://www.nhgri.nih.gov/) National Institute of Environmental Health Sciences (http://www.niehs.nih.gov/) National Library of Medicine (http://www.nlm.nih.gov/) National Institute of Mental Health (http://www.nimh.nih.gov/) National Institute on Alcohol Abuse and Alcoholism (http://www.niaaa.nih.gov/) Letter of Intent Receipt Date: June 9, 2000 Application Receipt Date: August 9, 2000 PURPOSE This announcement presents the opportunity to compete to join the recently established Pharmacogenetics Research Network and Knowledge Base. The original initiative (RFA GM-99-004, see http://grants.nih.gov/grants/guide/rfa-files/RFA-GM-99-004.html) was designed to stimulate the creation of a network of multidisciplinary, collaborative research groups of investigators that support the development of a public Pharmacogenetics Knowledge Base. The intention of this RFA is to expand the scope of the network by adding more groups interested in studying how genetic variation contributes to interindividual differences in drug responses by collecting comprehensive, integrative information about specific proteins and genes. The focus of research for a group will again not be specified, although variations in the effects of drugs as mediated by target receptors (or pharmacodynamics) are of particular interest. No further applications will be sought for a group that provides a comprehensive production databank or repository. However, applications will be accepted that offer a component or tool that complements the existing Pharmacogenetics Knowledge Base. All groups will be expected to work cooperatively towards the goal of making the Pharmacogenetics Knowledge Base an information resource of maximum utility to the entire research community, that can stimulate future hypothesis-driven research. This is one of a pair of initiatives designed to address the collection of fundamental knowledge required to predict interindividual differences in drug responses. This RFA is suitable for research conducted by multiple collaborative arrangements. A companion program announcement (PA) entitled Mechanisms Underlying Individual Variations in Drug Responses (PA-99-016, see http://grants.nih.gov/grants/guide/pa-files/PA-99-016.html) describes opportunities for support via traditional individual investigator-initiated research projects. 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, PHARMACOGENETICS RESEARCH NETWORK AND KNOWLEDGE BASE, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) cooperative agreement (U01) award mechanism, an "assistance" mechanism, which is distinguished from a regular research grant in that substantial programmatic involvement by NIH staff with the awardees is anticipated. The cooperative agreement is used when participation by NIH staff is warranted to support and stimulate the recipients activities by involvement in and otherwise working jointly with the award recipients in a partnership role; NIH staff will not assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of studies funded under cooperative agreements are discussed later in this document under the section Terms and Conditions of Award. Each component of the Pharmacogenetics Research Network and Knowledge Base will be awarded as a separate U01. All applications will be assigned to NIGMS initially for administrative reasons. After discussion with the other participating Institutes, applications may be reassigned where they are programmatically most appropriate. Because the scope of research proposed in response to this RFA may encompass the interests of several Institutes, applications may receive dual assignments based upon established PHS referral guidelines. The anticipated earliest award date is April 1, 2001. FUNDS AVAILABLE NIH intends to commit approximately $5 to $10 million in FY 2001 to fund applications in response to this RFA. It is anticipated that there will be two to four additional groups funded, although the actual funding plan will depend upon the scientific opportunities presented and the results of the peer review process. An applicant may request a project period of up to four years and a budget for direct costs of up to $2 million per year, with 3% inflationary increases allowed in the future years. Because the nature and scope of the proposed research will vary, it is anticipated that the sizes of the awards will also vary. Although the financial plans of the Institutes provide support for this program, the awards pursuant to this RFA are contingent upon the availability of funds and receipt of a sufficient number of applications of outstanding scientific and technical merit. New and renewal applications in this area may be supported in future years, depending upon the success and the needs of the Pharmacogenetics Research Network and Knowledge Base. RESEARCH OBJECTIVES Background: Genetic variants can be identified in individuals, families, and populations for proteins and genes involved in determining drug responses. Much more biological and clinical research is needed beyond accumulating sequences and identifying polymorphisms (variants that occur with a frequency of 1% or greater) to correctly interpret the functional consequences of genetic variation. In order to understand which sequence variations are functional and how they actually contribute to individual differences in drug responses, the genetic variation (genotype) must be related to biochemical changes in proteins, to cell and organ functions, to systemic effects, and to the range of possible clinical expressions (phenotype). Once comprehensive biological information for a particular protein or gene and its corresponding variants has been assembled, it can be catalogued in a manner that is accessible and interpretable to a wide range of scientists. The Pharmacogenetics Knowledge Base will link genes and their sequence variants to their encoded proteins, their functional changes, and consequent drug response phenotypes (and sometimes disease phenotypes). Scope and Objectives: The Pharmacogenetics Research Network and Knowledge Base will have the capacity to collect genetic sequence information, detect polymorphic variants, identify the functional consequences of genetic variation, and rigorously correlate this information with clinical drug responses. This announcement seeks to expand the scope of the network. Investigators trained in different areas working as collaborative teams are needed to achieve insights into the contribution of genetic variation to determining individual drug responses. Rigorous studies, both basic and clinical, are needed to correlate phenotype with genotype. Researchers working at levels ranging from the most molecular to the most clinical, in the fields of pharmacology, physiology, genetics, genomics, medicine, medicinal chemistry, epidemiology, statistics, bioinformatics, and computational biology must demonstrate that they can work together, so that functional variation in proteins and genes that may play essential roles in determining drug responses can be studied, interpreted, and related to clinical research situations in a rapid and efficient manner. In this RFA, NIH does not plan to specify in advance which additional proteins, genes, or diseases are to be studied in the Pharmacogenetics Research Network and Knowledge Base; investigators will propose where they want to concentrate their activities. Both variation in drug biotransformation and elimination pathways (pharmacokinetics) and variation in the direct effects of drugs on cells and tissues (pharmacodynamics) are of interest overall. However, variation in the effects of drugs as mediated by their target proteins in cells and tissues are now of particular interest to add to the network. The receptors and enzymes that are involved in the etiology of many major common diseases, for example asthma, cancer, cardiovascular diseases, neuropsychiatric disorders, diabetes, and inflammation are potential drug targets. The underlying theme should be a search for pharmacogenetically important sequence variation. In some instances, a search based upon a candidate gene approach may be appropriate; in other situations, a gene discovery program may be a better strategy. Preference will be given to groups that add to the breadth of the entire Pharmacogenetics Research Network’s efforts. The Pharmacogenetics Research Network and Knowledge Base should ultimately encompass a variety of pharmacologically important proteins and genes. This will be accomplished by funding a balanced series of Research Groups and Knowledge Base Groups that are studying a range of different proteins or genes and systematically organizing this information. For a description of the existing funded groups and subject areas that comprise the Pharmacogenetics Research Network and Knowledge Base, see http://www.nigms.nih.gov/funding/pharmacogenetics.html after April 1, 2000 (this date is approximate, depending upon when the awards are actually made). Research Group Description and Tasks A Research Group is a group of multidisciplinary, collaborating scientists (at one or several sites) employing state-of-the-art, comprehensive approaches to examining functional variation in the proteins or genes of interest involved in drug responses. Each should be formed by self-assembly of a highly integrated group of investigators into a cross-disciplinary team, and each will have a unique blend and breadth of complementary research expertise. A Research Group will conceive, develop, and conduct research focused on proteins or genes or a disease of interest to that group, where genetic variation is suspected to play a role in determining interindividual differences in drug responses. In some cases, there may be selected individuals, families, populations, or patients already phenotyped for a drug response or for disease progression, that can be used to relate a characteristic drug response to a genetic variant. Clinical or epidemiological studies for linkage or association may be used to identify genes of interest, and functional studies can be designed to examine proteins that may contribute to drug response variations. Corresponding sequences from appropriate reference animals may also be examined, or mutant, transgenic, or knock-out organism studies may be included, as long as the goal is to identify human genetic drug response targets or variants. 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). Further human studies may be necessary to learn allele frequencies, characterize patterns of inheritance, or establish prevalence of a genotype (or haplotype) in selected populations, in order to make future predictions of drug responses. Additionally, the population significance can be addressed with statistical associations made between genotype and phenotype. In many circumstances, there may be modifying factors (e.g., environment, diet, age, gender) in addition to genetic variation, and these contributions should be examined where possible. A resource to search for possible variants is the NHGRI Human DNA Polymorphism Discovery Resource (see http://www.nhgri.nih.gov/Grant_info/Funding/discover_polymorphisms.html), which is a diversity-rich, anonymous sample set stored at the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research (see http://locus.umdnj.edu/nigms/). Investigators are specifically encouraged to use this resource to add to the current body of SNP information, and to deposit the information in the SNP database (dbSNP). It is expected that members of a Research Group will typically have research experience with the proteins or genes of interest. Members of the group should represent many of the areas of expertise required to address the research problem in a comprehensive manner through collaborations either on- or off-site. Equipment, staffing, or resources may be needed, such as acquisition of current technologies for SNP detection, or establishment of a transgenic animal colony to study disease progression and variable responses to drug therapy. New technologies may be needed to detect genotype or measure phenotype. New data analysis or mathematical tools may be required at a Research Group site, and these can be developed in order to aid in interpreting results, such as discerning causality versus association of genetic variation. These situations are only examples; there are many possibilities. Applicants should request the funds necessary to assemble a Research Group with a cross-disciplinary, comprehensive approach to detecting and studying pharmacogenetic variation in their selected class of proteins or genes or area of focus. Research Groups should be well-integrated and will be expected to represent their research areas. A mechanism should be proposed to collect views from other members of the specific research communities studying the proteins or genes of interest. These views will be presented and discussed at the Steering Committee meetings (see below). Knowledge Base Group Description and Tasks A Knowledge Base Group is a group of bioinformatics scientists contributing to the aim of designing and developing a public Pharmacogenetics Knowledge Base, which will become available to all researchers for study and analysis. This repository will contain and correlate the information necessary to make pharmacological, and possibly disease-related, interpretations based upon genetic variation. A central Pharmacogenetics Knowledge Base is currently under development. Therefore, no further applications will be sought for a comprehensive production databank or repository. However, a potential applicant may propose a component or tool that is complementary to and consistent with the existing Pharmacogenetics Knowledge Base. The Pharmacogenetics Knowledge Base (see a description of the funded Knowledge Base at http://www.nigms.nih.gov/funding/pharmacogenetics.html) will link genomic, molecular, cellular, and clinical data for systems where variation information is required to optimally predict therapeutic drug responses. A secure, stable, interactive central structure is being created that will link to other biological and clinical data resources. The primary Knowledge Base Group will cover the design, implementation, and maintenance of the repository. Modelling and analysis of the data, as well as the development of support strategies to fulfill both the submitters and the users requirements are planned. Ultimately, the Pharmacogenetics Knowledge Base should serve as a foundation for future hypothesis-driven experiments, and will be a useful resource to discover previously unsuspected correlations, perhaps with genes not yet known to contribute to individual variations in drug responses. The Pharmacogenetics Knowledge Base architecture should evolve to integrate all types of information regarding sequence, function, structure, and distribution, and reflect concepts where possible such as temporal or sequential responses. It must allow for the possibility of multiple functions per gene, and for genes that interact with non-genetic factors such as the environment, leading to complex predictors of a drug response. While one Pharmacogenetics Knowledge Base is the final goal, it may be necessary to develop it in stages, thus applications for significant components that complement the central Pharmacogenetics Knowledge Base will be considered. A new Knowledge Base Group may propose to develop computational tools to view and evaluate the data in different ways, and to query the data to identify new relationships, for example, the regulation of blocks of genes, or pleiotropic responses. The goal will be to explore complex, interconnected data, with as yet unknown patterns and relationships, and to integrate the data in order to enhance understanding of its biological significance. All aspects of the component design should be considered and discussed, and the approaches proposed should be clearly explained and justified. In the final form, these functions must be presented in a user-friendly manner. Examples should be given where possible. A willingness and practical ability to work with the central Pharmacogenetics Knowledge Base Group are required. Resources should be requested commensurate with these and other goals as they are identified. Steering Committee Description and Tasks A Steering Committee will be the main governing body for the Pharmacogenetics Research Network and Knowledge Base. The Steering Committee will include representation from each of the new Research Groups and Knowledge Base Groups (along with the existing awarded groups), up to two additional NIH Scientist/Administrators (beyond the six identified in the original RFA) of the appropriate scientific expertise (e.g., pharmacology, genetics, epidemiology), as well as selected scientists other than the awardees when additional expertise is required to provide committee breadth and balance. NIH representation on the Steering Committee will never make up a majority of the total number. The Steering Committee will discuss the overall progress made within the Pharmacogenetics Research Network and Knowledge Base at its meetings. The committee will make recommendations regarding how data should be obtained and expressed, in order to encourage data collection that is as uniform and yet as complete as possible and maximally valuable to all investigators. The committee will discuss and advise development of the Pharmacogenetics Knowledge Base, and it will seek to develop common guidelines and procedures for depositing the information. The committee will work to set standards for data format and nomenclature. The Steering Committee will also identify and discuss any issues that arise in connection with the scientific aspects of the Pharmacogenetics Research Network and Knowledge Base. It can create information-gathering subcommittees to follow up on particular issues or needs at any time. The Steering Committee will also listen to the views of the scientific research communities which the Research Groups represent in their respective fields, and consider how the Pharmacogenetics Research Network and Knowledge Base can have an impact on the larger community. In exchange for gaining the equipment, staffing, resources, and infrastructure, the Research Groups must be willing to consider addressing these future, related scientific needs when the time comes, as discussed through the Steering Committee. One Research Group might consent to assume a particular task, subject to mutual agreement, and funding being provided by NIH for a project. In this manner, the Pharmacogenetics Research Network can serve as a resource for scientists conducting investigations outside of the Research Groups. The Steering Committee will in general advise NIH on scientific opportunities, emerging needs, or impediments. There should be continued dialogue and a bidirectional exchange of ideas and information between the biological and the informatics dimensions of the overall Pharmacogenetics Research Network and Knowledge Base. To facilitate this bidirectional exchange, each Research Group will be asked to identify a key data liaison individual with the appropriate experience to interact with the central Pharmacogenetics Knowledge Base. Applicants should request funds incorporating to a plan to send the Principal Investigator or his/her designate to attend the Steering Committee meetings in Bethesda, MD at least twice per year. Funds should also be requested to permit the data liaison individual to meet with a representative of the Pharmacogenetics Knowledge Base at least twice per year in Bethesda, MD (these meetings may be held at alternate sites). SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS I. Definitions AWARDEE: The institution to which a cooperative agreement is awarded COOPERATIVE AGREEMENT (U01): An assistance mechanism in which there is anticipated substantial programmatic involvement by NIH staff with the recipient organizations during performance of the planned activities PRINCIPAL INVESTIGATOR: The person who assembles the project (for either a Research Group or Knowledge Base Group) and is responsible for submitting the application in response to this RFA and for performance of the project PHARMACOGENETICS RESEARCH NETWORK AND KNOWLEDGE BASE: A series of Research Groups and Knowledge Base Group(s), each funded by a separate cooperative agreement, working together to study pharmacogenetic variation RESEARCH GROUP: A group of multidisciplinary, collaborating biological scientists (at one or several sites) employing a state-of-the-art, comprehensive approach to examining functional variation in the proteins or genes of interest involved in drug responses KNOWLEDGE BASE GROUP: A group of bioinformatics scientists or computational biologists responsible for contributing to the design, development, implementation, or maintenance of the central Pharmacogenetics Knowledge Base PHARMACOGENETICS KNOWLEDGE BASE: A comprehensive central public repository, with computational tools, for the storage, integration, and use of pharmacogenetic/pharmacogenomic information NIH SCIENTIST/ADMINISTRATORS: Representative NIH extramural staff (up to eight) who serve on the Steering Committee, who have substantial coordinating scientific roles on the Steering Committee and can guide its recommendations based upon their knowledge of other, related NIH-supported research and resource activities NIGMS PROGRAM DIRECTOR: NIGMS extramural staff person who provides stewardship for the awards, and evaluates and implements the advice of the Steering Committee for allocating NIH support; the NIGMS Program Director also coordinates administrative management of the Pharmacogenetics Research Network and Knowledge Base STEERING COMMITTEE: A committee that is the main governing body of the Pharmacogenetics Research Network and Knowledge Base. Membership will include representation from each of the Research Groups and Knowledge Base Groups, NIH Scientist/Administrators of the appropriate scientific expertises, as well as selected scientists other than the awardees where additional expertise is required, when necessary for committee breadth and balance. NIH representation on the Steering Committee will never make up a majority of the total. ARBITRATION PANEL: A panel formed as needed to review scientific or programmatic disagreements (within the scope of the award) that may arise between the Pharmacogenetics Research Network and Knowledge Base and the NIH. It will be composed of three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of an individual disagreement, the first member may be chosen by the individual awardee. II. Terms and Conditions of Award The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies: The administrative and funding instrument used for this program will be the cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH through the Steering Committee. 1. Principal Investigator Rights and Responsibilities The Principal Investigator will coordinate project activities scientifically and administratively at the Institution. The Principal Investigator will have the primary responsibility for defining the details for projects within the guidelines of this RFA, and for performing the scientific activities. A Principal Investigator will agree to accept close coordination, cooperation, and participation of NIH staff in those aspects of management of the project as described under "NIH Scientist/Administrator Responsibilities". Awardees agree to accept and implement the guidelines of the Steering Committee regarding data release into the Pharmacogenetics Knowledge Base. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The Principal Investigator of a Research Group or Knowledge Base Group will: o Determine and coordinate the experimental approaches and procedures o Set project milestones for the Research Group or Knowledge Base Group o Accept and implement common guidelines approved by the Steering Committee o Submit data to the Pharmacogenetics Knowledge Base, according to policies agreed upon and established by the Steering Committee o Solicit representative views of other researchers for the proteins or genes of interest o Attend Steering Committee meetings, and participate in the cooperative nature of the group 2. NIH Scientist/Administrators Responsibilities The NIH Scientist/Administrators are representative NIH extramural staff (up to eight) who will serve on the Steering Committee based upon their areas of scientific expertise (e.g., pharmacology, genetics, epidemiology) and actively guide development of the Pharmacogenetics Research Network and Knowledge Base by providing overall advice and coordination. They should facilitate a partnership relationship between NIH and the Research Groups and Knowledge Base Groups, and ensure that the directions taken remain consistent with NIH’s missions and goals. They will make recommendations and provide specific guidance to aid in both accomplishing the existing goals and addressing emerging research opportunities. These tasks are in addition to the normal stewardship role of providing scientific oversight, as well as monitoring adherence to policies and procedures specific to the funding Institute. The role of NIH staff will be to facilitate and contribute, but not to direct activities. It is anticipated that decisions will be reached by consensus with the Principal Investigators through the Steering Committee. The NIH Scientist/Administrators will: o Actively share his/her relevant expertise and overall knowledge o Help to coordinate activities among the awardees, commensurate with their expertise o Be information resources about ongoing NIH-supported research and resource collections o Attend Steering Committee meetings, and participate in the cooperative nature of the group o Promote the Pharmacogenetics Knowledge Base to the scientific community at large o Assist in implementing recommendations for allocating NIH support among the awardees o Monitor adherence to policies and procedures of the funding Institute 3. Collaborative Responsibilities A Steering Committee will serve as the governing board of the Pharmacogenetics Research Network. Membership will include representation from each of the Research Groups and Knowledge Base Groups, up to eight NIH Scientist/Administrators of the appropriate scientific expertises (e.g., pharmacology, genetics, epidemiology), as well as selected scientists other than the awardees when additional expertise is required as necessary for committee breadth and balance. The rest of the Steering Committee will appoint these members by majority vote. NIH representation on the Steering Committee will not make up a majority of the total number. Each member will have one vote. The NIGMS Program Director is not a member of the Steering Committee, but will facilitate creation of the group and will attend all meetings. Awardee members of the Steering Committee will be required to accept and implement common guidelines and procedures approved by the Steering Committee. The NIGMS Program Director will schedule the meetings of the Steering Committee and actively assist the Chair in developing the meeting agendas. The Chair will run the Steering Committee meetings. Two meetings will be held each year, usually in Bethesda, MD. Around the time of the meetings, the data liaisons of the Research Groups and representatives of the Pharmacogenetics Knowledge Base will also meet, possibly in Bethesda, MD, or possibly at the central Pharmacogenetics Knowledge Base site. Subcommittees may be established by the Steering Committee as necessary. Additional members may be added by action of the Steering Committee, through discussion with the NIGMS Program Director. The NIGMS Program Director will ensure coordination of the Steering Committee’s activities and implementation of the group’s recommendations. The Steering Committee will: o Serve as the main governing board o Discuss progress within the Pharmacogenetics Research Network and Knowledge Base o Set standards and work to standardize data format and nomenclature o Develop common guidelines and procedures o Consider the representative views of other researchers o Participate in the process of developing a cohesive group o Advise NIH on scientific opportunities, emerging needs, or impediments o Ensure the timely release of data to the Pharmacogenetics Knowledge Base 4. Administrative Coordination Activities The NIGMS Program Director will assume responsibility for normal stewardship of the awards, and for coordination of the Pharmacogenetics Research Network and Knowledge Base. Logistical arrangements will be made for the Steering Committee meetings and other administrative duties related to the committee functions, such as conference calls, report mailings, publications tracking, etc. These activities may be accomplished by a variety of arrangements, such as by adding funds to the Research Groups or Knowledge Base Groups to support an administrative contractor. Data and intellectual property will not be handled centrally prior to its public release; the awardees are responsible for providing data tracking. If clinical studies are proposed, NIH may establish a Data and Safety Monitoring Board(s). 5. Arbitration Process Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will be composed of three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of an individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 6. Milestones and Evaluations Applicants should define yearly milestones in their applications (as well as in their progress reports), and the selected awardees will have the opportunity to modify these milestones at the time of their awards. The awardees milestones will be provided to the Steering Committee. It is expected that the milestones should be adjusted annually at the award anniversary dates, both to incorporate a group’s scientific accomplishments and progress in the field in general, as well as to reflect the recommendations of the Steering Committee. In accordance with the procedure described above, the NIH Scientist/Administrators may recommend augmenting any project, as discussed through the Steering Committee, or reducing or withholding funds for any project that substantially fails to meet its milestones or to remain state-of-the-art. The Director, NIGMS, retains the right to call a meeting of advisors, most likely members of the National Advisory General Medical Sciences Council or their designee(s), at any time to provide advice on the scientific progress of the Pharmacogenetics Research Network and Knowledge Base. It is anticipated that such a group of advisors may want to attend a meeting of the Steering Committee as part of its fact-finding mission. Any information or reports will be shared with the other Institutes/Centers of the NIH participating in this initiative and the Director, NIH. ISSUES IN RESEARCH INVOLVING HUMAN SUBJECTS The nature of the research proposed in response to this initiative will likely include applications to conduct studies on the genetic basis of variation in drug responses among different racial, ethnic, and sociocultural populations, or in individuals and families affected by particular diseases. Sensitivity to issues involving the protection of human subjects will be required in approaching this research. Every effort should be made to consider the potential impact of the proposed research on the particular group proposed for study. Careful consideration should be given to the potential risks of stigmatization and discrimination as well as the benefits of the knowledge to be gained. Thorough, current, and clear informed consent of the appropriate scope must be obtained from all participants. Subjects must be informed about the potential for information generated from their samples being deposited into the Pharmacogenetics Knowledge Base. The value of the information gained through studies of human genetics will be diminished if that information is misinterpreted or misused to stigmatize or discriminate against defined populations. Thought must be given to these issues in human subjects research prior to responding to this RFA with a application. Clear plans for recruitment, informed consent, and the protection of privacy and confidentiality of human subjects should be addressed in the application and will be considered during the review process. Potential applicants are referred to the NIH Office of Protection from Research Risks (OPRR, http://grants.nih.gov/grants/oprr/oprr_t.htm) for discussion of the NIH application requirements, and also to the OPRR Institutional Review Board Guidebook Chapter 5 - Human Genetics Research (http://www.hhs.gov/ohrp/irb/irb_chapter5.htm) and other applicable sections, as well as to the Ethical, Legal, and Social Issues Program (ELSI) of NHGRI (http://www.nhgri.nih.gov/ELSI/) for discussion of human subjects protections related to human genetic research. Applicants are particularly directed to review the advice received from the NIGMS Populations Advisory Group found at http://www.nigms.nih.gov/funding/pharmacogenetics.html. NIH Program Staff (listed below) may also be contacted and can provide guidance on current NIH policies and practices in this area. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, and is available at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects, which was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications 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 for the review, because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone and facsimile numbers of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information it contains allows I/C staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by June 9, 2000 to: Rochelle M. Long, Ph.D. Pharmacology, Physiology, and Biological Chemistry Division NIGMS, NIH Building 45, Room 2AS.49G, MSC 6200 45 Center Dr. (for express/courier service) Bethesda, MD 20892-6200 Telephone: (301) 594-1826 Fax: (301) 480-2802 E-mail: rochelle_long@nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, E-mail: GrantsInfo@nih.gov, URL: http://grants.nih.gov/grants/forms.htm. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 should be sent to: Rochelle M. Long, Ph.D. Pharmacology, Physiology, and Biological Chemistry Division NIGMS, NIH Building 45, Room 2AS.49, MSC 6200 45 Center Dr. (for express/courier service) Bethesda, MD 20892-6200 Telephone: (301) 594-1826 Fax: (301) 480-2802 E-mail: rochelle_long@nih.gov Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Special application requirements: An integrated application should be prepared for either a Research Group or a Knowledge Base Group. The aim is to present a comprehensive and cross- disciplinary team approach to the problem being studied. Some components may exist as cores or resources that are integral to the entire group. The components are expected to be much more interdependent than typically found in other large grant applications (such as program project grant applications). Each entire application should have a face page, abstract, consolidated budget, key personnel listing, biographical sketches, other support, existing resources and facilities, letters of collaboration, etc. The page limit for the research plan (including specific aims, background and significance, preliminary studies, and research design and methods) is increased to 60 pages total. See also the specific instructions for a Research Group or Knowledge Base Group application below. For a Research Group, an overview section should be prepared that includes an overall description which defines the scope and objectives, and provides the rationale for selection of the area of scientific concentration. Usually, for a Research Group, this would be the choice of proteins or genes, or perhaps a disease/model of interest, where genetic variation contributes to differences in drug responses. The application should have sections that are highly integrated, in order to provide a multidisciplinary approach to studying the proteins or genes of interest. All parts of the application must be described in sufficient detail to be completely understood, with the appropriate goals and timetable. These additional criteria should now be specifically addressed in all new or revised Research Group applications - 1. Explain the impact of understanding the pharmacogenetics of the proteins, genes, or disease(s) being studied, and how adding this area to the Network will advance the field overall. 2. Defend the effectiveness of the strategy chosen to approach the problem, and why it was chosen over the alternative approaches (e.g. a candidate gene vs. a gene discovery approach). 3. Justify how the subject area of the application complements the existing network of funded cooperative agreements (see the funded investigators and subject areas posted at http://www.nigms.nih.gov/funding/pharmacogenetics.html). For a Knowledge Base Group, an overview section should be prepared that includes an overall description which defines the scope and objectives, and presents a strategy for creating a central, public Pharmacogenetics Knowledge Base. All parts of the application must be described in sufficient detail to be completely understood, with the appropriate goals and timetable. These additional criteria should now be specifically addressed in all new or revised Knowledge Base Group applications 1. Defend how the component or computational tool complements the existing Pharmacogenetics Knowledge Base structure, and offers an additional dimension or feature not previously available, yet supports a single information repository. 2. Justify how the subject area of the application fits in with the existing network of funded cooperative agreements (see the funded investigators and subject areas posted at http://www.nigms.nih.gov/funding/pharmacogenetics.html). Additionally, the following areas should be addressed, where appropriate, in the respective applications: For a Research Group, describe the timing for release of data into the Pharmacogenetics Knowledge Base (this may be modified by recommendation of the Steering Committee), or other databases For a Research Group, describe plans for handling intellectual property resulting from the studies, or for commercialization of any discoveries (and implications for participating subjects) For a Research Group, describe plans for human subjects, including definition(s) of the population(s), plans for recruitment, informed consent forms (describing anticipated risks and benefits, plans for subject confidentiality, deposition of information into a database, follow-up with participants), plans for stored or shared samples (and the prior informed consents permitting this), or use of any established sample sets For a Research Group, describe the phenotyping criteria (use NIH standards where standardized criteria exist, e.g., information on clinical diagnostic tests used for studies of the genetics of brain disorders such as schizophrenia, bipolar disorder, and late-onset Alzheimer’s disease can be found at http://zork.wustl.edu/nimh/NIMH_initiative/ NIMH_initiative_link.html) For a Research Group, a data liaison person with the appropriate experience should be identified, who will interact with the Pharmacogenetics Knowledge Base For a Knowledge Base Group, describe the timing and method desired for receipt of information into the Pharmacogenetics Knowledge Base, as appropriate for the scope of the application (this may be modified by recommendation of the Steering Committee) For a Research Group or Knowledge Base Group, identify any unique resources, services, or facilities at the institution (even if support is not sought here, e.g., a General Clinical Research Center, GCRC) For a Research Group or Knowledge Base Group, describe in detail any other support that significantly impacts this application (even if funding is not sought here, e.g., where knowledge of the ongoing research projects is essential to the evaluation of this application) For a Research Group or Knowledge Base Group, describe plans for sharing any materials with other researchers (e.g., samples, reagents, software) For a Research Group or Knowledge Base Group, specify the yearly milestones (these will be provided to the Steering Committee, if the application is awarded) For a Research Group or Knowledge Base Group, describe the mechanism for administration of the research activities within the Group (e.g., regular meetings, staffing, data exchange, external evaluations, etc.) For a Research Group or Knowledge Base Group, state the mechanism for collecting other researchers views For a Research Group or Knowledge Base Group, funds should be requested for the Principal Investigator or his/her designate to attend two Steering Committee meetings annually in Bethesda, MD For a Research Group or Knowledge Base Group, funds should be requested for the data liaison person to meet with a representative of the Pharmacogenetics Knowledge Base two times annually in Bethesda, MD (these meetings may be moved to the central Pharmacogenetics Knowledge Base site, if practical) For a Research Group or Knowledge Base Group, funds should be requested to cover any data tracking and monitoring procedures, or data transfer activities associated with coordination of the Pharmacogenetics Research Network and Knowledge Base (e.g., reporting to a Data and Safety Monitoring Board for clinical studies, costs of depositing data into the Pharmacogenetic Knowledge Base, etc.) For a Research Group or Knowledge Base Group, the intellectual property policies of the applicant institution should be presented REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR) and for responsiveness by NIGMS. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by CSR, in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate National Advisory Council or Board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation: Does the program employ novel concepts, approaches or method? Are the aims original and innovative? Do the projects challenge existing paradigms or develop new methodologies or technologies? 4. Investigator: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Applicants will be evaluated in the review process for their response to the Research Objectives, described above, and for their ability to create an infrastructure through complementary, synergistic connections. In addition, the scientific and technical criteria listed in the special application requirements above will be considered and judged for appropriateness. The initial review group will also examine any special needs for the protection of human subjects and the safety of the research environment. In accordance with NIH policy, all applications will be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. o The adequacy of the proposed plan to share data. o The additional scientific and technical merit criteria specific to the objectives of the RFA as described above, under Special Application Requirements. Schedule Letter of Intent Receipt Date: June 9, 2000 Application Receipt Date: August 9, 2000 Peer Review Date: Fall 2000 Advisory Council Date: January 2001 Earliest Anticipated Award Date: April 1, 2001 AWARD CRITERIA Award criteria that will be used to make funding decisions include: o scientific merit (as determined by peer review) o availability of funds o program priorities o programmatic balance The NIH retains the flexibility to select and assemble components of the Pharmacogenetics Research Network and Knowledge Base that optimally blend the research areas, experience, creativity, and the applicants collective knowledge and combined expertises in the background sciences. INQUIRIES Inquiries concerning this RFA are encouraged. NIH staff welcome the opportunity to clarify any issues or questions from potential applicants. Frequently asked questions will be posted at http://www.nigms.nih.gov/funding/pharmacogenetics.html and updated as necessary. Direct inquiries regarding programmatic issues to: Rochelle M. Long, Ph.D. Pharmacology, Physiology, and Biological Chemistry Division NIGMS, NIH Building 45, Room 2AS.49G, MSC 6200 (45 Center Drive for express/courier service) Bethesda, MD 20892-6200 Telephone: (301) 594-1826 Fax: (301) 480-2802 E-mail: rochelle_long@nih.gov Susan Banks-Schlegel, Ph.D. Division of Lung Diseases NHLBI, NIH 6701 Rockledge Drive, Room10018 Bethesda, Maryland 20892-7952 Telephone: (301) 435-0202 Fax: (301) 480-3557 E-mail: schleges@nih.gov Lisa D. Brooks, Ph.D. Division of Extramural Research NHGRI, NIH. Building 31, Room B2B07 Bethesda, MD 20892-2033 Telephone: (301) 435-5544 Fax: (301) 480-2770 E-mail: lisa_brooks@nih.gov Jose Velazquez, Ph.D. Division of Extramural Research and Training NIEHS, NIH P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 542-4998 Fax: (919) 541-4937 E-mail: velazqu1@niehs.nih.gov Hemin Chin, Ph.D. Division of Basic and Clinical Neuroscience Research NIMH, NIH Parklawn Building, Room 10C-26 Rockville, MD 20857 Telephone: (301) 443-1706 Fax: (301) 443-9890 E-mail: hemin@nih.gov Thomas Kresina, Ph.D. Division of Basic Research Willco Building, Suite 402 NIAAA, NIH Bethesda, MD 20892-7003 Telephone: (301) 443-6537 Fax: (301) 594-0673 E-mail: tk13v@nih.gov Peter Clepper Division of Extramural Programs One Rockledge Center, Room 301, MSC 6075 NLM, NIH Bethesda, MD 20892-6075 Telephone: (301) 594-4882 Fax: (301) 402-2952 E-mail: peter_clepper@nlm.nih.gov Direct inquiries regarding review issues to: Jeanne N. Ketley, Ph.D. Cardiovascular Sciences Integrated Review Group CSR, NIH Two Rockledge Center, Room 4130, MSC 7814 Bethesda, MD 20892-7814 (6701 Rockledge Drive and zip code 20817 for express/courier service) Telephone: (301) 435-1789 Fax: (301) 480-2644 E-mail: ketleyj@csr.nih.gov Direct inquiries regarding fiscal matters to: Antoinette Holland Grants Administration Branch NIGMS, NIH Building 45, Room 2AN.50B, MSC 6200 (45 Center Drive for express/courier service) Bethesda, MD 20892-6200 Telephone: (301) 594-5132 Fax: (301) 480-3423 E-mail: hollanda@nigms.nih.gov Jane R. Davis Grants Operations Branch NHLBI, NIH Two Rockledge Center, Room 7174 Bethesda, MD 20892-7926 Telephone: (301) 435-0166 Fax: (301) 480-3310 E-mail: davisj@gwgate.nhlbi.nih.gov Jean Cahill Grants Management Office NHGRI, NIH Building 38A, Room 613 Bethesda, MD 20892-6050 Telephone: (301) 402-0733 Fax: (301) 402-1951 E-mail: jean_cahill@nih.gov Dorothy Duke Division of Extramural Research and Training NIEHS, NIH P.O. Box 12233, MD EC-22 Research Triangle Park, NC 27709 Telephone: (919) 541-2749 Fax: (919) 541-2860 E-mail: dd185n@nih.gov Diana S. Trunnell Grants Management Branch NIMH, NIH Parklawn Building, Room 7C-08 Rockville, MD 20857 Telephone: (301) 443-2805 Fax: (301) 443-6885 E-mail: diana_trunnell@nih.gov Linda Hilley Grants Management Branch NIAAA, NIH Willco Building, Suite 504 Bethesda, MD 20892-7003 Telephone: (301) 443-4704 Fax: (301) 443-3891 E-mail: lhilley@willco.niaaa.nih.gov Dwight Mowery Division of Extramural Programs One Rockledge Center, Room 301, MSC 6075 NLM, NIH Bethesda, MD 20892-6075 Telephone: (301) 594-4221 Fax: (301) 402-2952 E-mail: dwight_mowery@nlm.nih.gov Although the National Cancer Institute (NCI) is not a formal participant in this RFA, NCI maintains an interest in genes and proteins involved in the activity or metabolism of agents used in the prevention and treatment of cancer, or in the cause and progression of cancer. For more information at NCI contact: Mary K. Wolpert, Ph.D., (301) 496-8783, wolpertm@exchange.nih.gov. Although the National Institute on Drug Abuse (NIDA) is not a formal participant in this RFA, NIDA is interested in the genetics of drug abuse vulnerability, and has a cell and data repository (The NIDA Center for Genetic Studies) that receives clinical and genetic data related to addiction. For more information at NIDA contact: Jonathan Pollock, Ph.D., (301) 443-6300, JP183r@nih.gov. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.113, 93.172, 93.242, 93.273, 93.837, 93.879, 93.859, 93.862 (NIEHS, NHGRI, NIMH, NIAAA, NHLBI, NLM, NIGMS [2]). Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended (42 USC 241 and 284) and administered under NIH Grants Policy Statement (10/1/98) and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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