PHARMACOGENETICS RESEARCH NETWORK AND KNOWLEDGE BASE RELEASE DATE: January 30, 2004 RFA Number: RFA-GM-04-002 Update: The following update relating to this announcement has been issued: March 5, 2009 - This RFA has been reissued as (RFA-GM-10-002) for (R24). January 30, 2009 - This RFA has been reissued as (RFA-GM-10-001) for (U01/U19). (see corrections and updates NOT-GM-04-108) Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of General Medical Sciences (NIGMS) (http://www.nigms.nih.gov) National Cancer Institute (NCI) (http://www.nci.nih.gov) National Heart, Lung and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) National Human Genome Research Institute (NHGRI) (http://www.nhgri.nih.gov) National Institute on Drug Abuse (NIDA) (http://www.nida.nih.gov) National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov) National Library of Medicine (NLM) (http://www.nlm.nih.gov) Office of Research on Women’s Health (ORWH) (http://www4.od.nih.gov/orwh) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.859, 93.395, 93.837, 93.838, 93.172, 93.279, 93.113, 93.879 LETTER OF INTENT RECEIPT DATE: July 19, 2004 APPLICATION RECEIPT DATE: August 19, 2004 PUBLIC INFORMATIONAL SESSION: March 7, 2004 (see WHERE TO SEND INQUIRIES) THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism 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 Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this RFA is to solicit applications for an open re- competition of the Pharmacogenetics Research Network and Knowledge Base (http://www.nigms.nih.gov/pharmacogenetics). This is a network of multidisciplinary, collaborative groups of investigators that contribute their data to the publicly available knowledge base PharmGKB, which is an open research tool accessible to all scientists. The research groups in the network have interests across a range of biological processes: drug metabolism, small molecule transport, target receptors, and biological pathways involved in the drug treatment of cardiovascular diseases, asthma, cancer, and depression; other areas are welcome consistent with the interests of the funding institutes. The groups are collecting comprehensive, integrative information about specific proteins and gene families important to the field of pharmacogenetics. Some groups are using a genotype-to- phenotype approach starting with the detection of all possible variants, while other groups are employing a phenotype-to-genotype approach beginning with well-characterized clinical samples. All investigations are converging on the association of single nucleotide polymorphisms (SNPs) and haplotypes with drug responses. The results are confirmed by studies of the mechanistic and clinical consequences of the molecular changes. The database groups in the network are working towards the goal of creating a centralized public knowledge base. PharmGKB (http://www.pharmgkb.org) is designed to categorize four types of phenotype information -- functional assays, pharmacokinetics, pharmacodynamics, and clinical outcomes -- correlated with genotype information. The knowledge base uses standardized drug, disease, and genetic vocabularies and is linked to existing databases. The plans are to continue funding this network as a series of cooperative groups conducting studies to address a wide variety of common research problems in pharmacogenetics. This initiative will further emphasize development of the PharmGKB knowledge base; it is envisioned as an information resource that will be useful to the entire pharmacogenetics research community to enable future hypothesis-driven research. This competition is open to both new and renewal research and database groups. RESEARCH OBJECTIVES Background Pharmacogenetics can be defined as the influence of human genetic variation on drug responses. It has long been known from family studies that variations found in enzymes of drug clearance have profound effects on the efficacy and duration of drug action, sometimes with significant adverse consequences. Genetic variations in drug metabolizing enzymes can lead to the excessive build-up of a drug with a narrow therapeutic index (e.g., thiopurine methyl-transferase and 6- mercaptopurine), or the lack of a therapeutic effect where metabolic activation is required (e.g., cytochrome P450 2D6 and codeine). Likewise, studies have shown that variations in target receptors can lead to a lack of beneficial effects of a drug, for example by increased desensitization (e.g., beta-2 adrenoreceptor and albuterol). Another mechanism impacting drug efficacy is altered binding kinetics (e.g., serotonin 1B receptors and fluoxetine). Recent studies have shown that genetic variants can be linked to the susceptibility and progression of disease as well as to a response to a drug treatment (e.g., cholesterol ester transfer protein, atherosclerosis, and statins; or apolipoprotein E, Alzheimer’s disease, and tacrine). There are multiple genetic mechanisms, including alterations in transcript stability, splice sites, or promotor binding regions, all of which can alter expression levels. The impact of these changes on functional protein levels such as reduced amounts or stability, or compromised enzymatic function, requires further study. Furthermore, how this fits into protein-protein interactions (e.g., coupling to second messengers) and biological pathways (e.g., redundant, competing, or complementary routes of clearance or signaling) needs to be understood in order to predict clinical consequences. With advances in genomic technology, large-scale accumulation of information on drug pathways (sometimes called pharmacogenomics) is possible. These profiling studies can be DNA-based, transcript-based, or protein-based. Both pharmacogenetics and pharmacogenomics studies are of interest under this solicitation. It is essential to completely understand the significance of genetic variation at the molecular level, and the implications of the diverse genetic contexts present in different human populations. The incidence of SNPs (singly and in combinations of haplotypes) and gene duplication or deletion events must be interpreted correctly to associate genetic variation with the prediction of drug effects, and this may require development of new analytical tools. Population-based studies that examine the interactions between genetic predisposition for disease and the genetic factors determining medication responses are also of interest for this initiative. Ultimately, both a mechanistic understanding and robust statistical validation of putative pharmacogenetics effects are sought, and the translation to clinical impact is highly desirable. The goal of the field is to be able to predict the effects of a medication in an individual based upon his/her genome, but much research must be performed before that is possible in a comprehensive manner. Accurate descriptions of drug response phenotypes are challenging and difficult, and further research is required to define these phenotypes. The Pharmacogenetics Research Network is intended to address this need to acquire basic research results and store the information in a knowledge base, which will lead to a more complete understanding of drug actions, clinical translation of the information, and future drug development. Objectives and Organization The Pharmacogenetics Research Network will continue to be comprised of a series of multidisciplinary research and database groups, each of which is performing state-of-the-art studies in pharmacogenetics, either independently or in conjunction with other network groups. While pursuing the highest quality research studies, each network group must agree to meet the following expectations: 1) to further develop the knowledge base, PharmGKB, which is a database with accurate and detailed definitions of pharmacogenetic phenotypes linked to genotypes; 2) to advance the research field, by defining common goals and needs, and contributing to solving problems of the field through discussions and workshops; 3) to produce and share resources, such as biological reagents, and experimental and computational tools, to be disseminated rapidly and with minimal restrictions; and 4) to communicate with scientists both within and outside the network, and to foster translation and application of this knowledge. These requirements are further detailed below, and are included in the specific review criteria. A research group should be organized around a unifying theme, for example, a family of proteins with which drugs interact, a set of drug pathways leading to the site of action, or drug treatments for a particular disease. The group should be comprised of a multidisciplinary team of investigators, minimally including personnel with backgrounds in cellular/molecular pharmacology, genetics/genomics, and clinical expertise. Individuals from the fields of pharmacology, pharmaceutics, physiology, genetics, genomics, clinical medicine, medicinal chemistry, epidemiology, statistics, bioinformatics, and computational biology may be incorporated and must demonstrate that they can work together. This research team should propose current, cutting-edge pharmacogenetics studies. They should be driven by the science to produce the highest quality research results for deposition into PharmGKB and for publication. The research groups will be responsible for serving as interactive resources for the developers of PharmGKB in their self-described areas. Applications should not simply be proposed as a series of projects from all investigators working in pharmacogenetics at an institution. Careful thought should be given to the definition of a research group’s goals, and the steps to be taken to accomplish those goals. The best core or project teams to accomplish the research goals should be assembled; applications that cross multiple institutions are acceptable. An application should discuss how existing databases were used to design and approach the solution of a pharmacogenetic problem, and how PharmGKB can better serve its users in the future. The assembled group must justify their choice of a research area as the most appropriate, demonstrate their study design and power, and employ state-of-the-art technical approaches, including statistics and analyses. The selected research problem in pharmacogenetics could be conceived starting with the identification of all possible variants (a genotype-to-phenotype approach) or beginning with well-characterized patient materials (a phenotype-to-genotype approach). The applicant group should state the advantages and disadvantages of the approach chosen, and where convergence is expected with other studies ongoing in the field. Correct and complete descriptions of phenotypes and association with genotypes form the core organizing principle underlying the Pharmacogenetics Research Network. The research groups being funded are required to produce meaningful data sets suitable to populate PharmGKB. Scientifically valid research questions should be constructed to yield data that contribute to advancing the understanding in the field, and that are appropriate for deposition into the knowledge base. The types of data deposits that are expected should be described in detail, along with the time frame for their submission. Both human and animal data, as well as non-mammalian systems, will be accepted. Where animals or cell lines or model organisms are being examined, they should be justified as the appropriate reference models, consistent with the goal of identifying and interpreting human genetic drug response variants. Research groups should address how the pharmacogenetic researchers outside of the network can be positively impacted. Useful sample sets should be offered to established repositories (e.g., the NIGMS Human Genetic Cell Repository at the Coriell Institute, http://locus.umdnj.edu/nigms/) for immortalization and distribution. Useful reagents (e.g., antibodies, primers) should be made easily available. Software tools should be shared freely whenever possible. Current papers representative of the research field being studied should be deposited by the research groups into the community submissions project in PharmGKB. Evidence of these steps taken will attest to the desire of the research group to serve in a scientific network and to share their findings with the scientific community, and should be presented in the application. A database group applying to continue PharmGKB should present a plan to further develop the knowledge base as a research resource that will store, organize, present, and integrate pharmacogenetic knowledge. PharmGKB must display a variety of data types: genetic variants, haplotypes, population frequencies, summary statistics, oligonucleotide and cDNA microarray data, molecular and functional screening assays, pharmacokinetic data, pharmacodynamic data, and, where appropriate, clinical data demonstrating the consequences of genetic variation. It should have in place user-friendly methods to accept these data deposits of diverse forms and sizes. In all cases, the data should be described using the standard nomenclature of the respective fields. The knowledge base should have reciprocal links to other established databases, such as GenBank, dbSNP, PDB, etc. The knowledge base should describe gene-protein-drug-disease relationships, with each object layer completely represented. Relationships between these different data types should be displayed visually, and reflect the opinions and agreement of researchers working in these fields. Raw data should be stored wherever possible, so that PharmGKB can be mined to learn of new correlations. This is intended to be a hypothesis-generating tool. Moreover, data should also be summarized and interpreted so that the information in the knowledge base is accessible to all scientist-users. Given the long history of the field of pharmacogenetics, there should be a current and complete literature archive linked to complete publications wherever possible. Existing high value data sets outside of the network research groups should be sought to populate PharmGKB, to ensure complete and even- handed representation across the field of pharmacogenetics. Methods to establish credit and provide practical scientific incentives for submitters should be proposed. Applications to continue the knowledge Base PharmGKB should reflect the current status of the project, and describe how the design aspects, implementation, and maintenance will be continued or improved upon. Careful attention should be paid to issues of curation, and delineating who has the responsibility to format, abstract, and check the different kinds of data sets for completeness and accuracy. Comparisons should be made to other successful ongoing database efforts. Future major design directions should be presented and discussed, with prototypes. Discussion of accomplishments, challenges, and obstacles should be provided, and/or external observations and alternative strategies on how to overcome problem areas. There should be evidence of the practical ability to work with the research groups in the network. If a new database group is funded, copies of the existing datasets and data tables will be provided at the time of award, according to the prior negotiated terms and conditions regarding future portability. All of the data in PharmGKB are currently available to authenticated users for downloading by standard formats. The name PharmGKB has been copyrighted by NIGMS. Taken together, the research and database groups of the Pharmacogenetics Research Network and Knowledge Base should encompass a range of ongoing studies and original data on pharmacologically important genes, proteins, and pathways. This will be accomplished by funding a balanced series of research groups that are studying different gene families, drug treatments, and diseases of significance to human health. The scope of the Pharmacogenetics Research Network will likely continue to include enzymes of drug metabolism, small molecule transporters, and target receptors and pathways involved in drug treatment of cardiovascular diseases, asthma, cancer, and depression, and may broaden somewhat in reflection of the participating NIH institutes interests. This network will be continued as a trans-NIH effort; the institutes specific interests are described below: NIGMS is interested in studies identifying robust, statistically valid correlations between pharmacogenetic responses (phenotypes) and genetic variation (genotypes, haplotypes) using state-of-the-art approaches and technologies, and in the deposition of this knowledge into a database designed to be accessible by the entire research community. NCI is interested in projects that can potentially lead to meaningful improvements in clinical and survival endpoints, and in studies of genetic variability in human populations that may influence risk of preneoplastic conditions or primary and secondary malignancies after exposure to medications, including cancer therapies. NHLBI is interested in studies of the role of genetic polymorphisms and their functional consequences in modulating treatment responses in heart, lung, blood, and sleep diseases. NHGRI supports research on how databases represent phenotypes, particularly related to genetic variation, and encourages the use and extension of standardized ontologies, as well as rapid data release. NIDA is interested in the influence of genetic variation on metabolic, homeostatic, neurocognitive, and physiological responses to abused drugs, as well as the safety and efficacy of drugs used for the treatment of addiction, dependence, and withdrawal, and in drug-drug interactions (e.g., antiretrovirals and drugs of abuse). NIEHS is interested in identifying the response genes that are important to understanding genetic susceptibility to environmental exposures (see the Environmental Genome Project at http://www.niehs.nih.gov/envgenom/home.htm). NLM is interested in knowledge representation and the design and management of databases with medical data. ORWH is interested in evaluating the importance of gender differences in genetic polymorphisms of proteins important in the pharmacokinetics and pharmacodynamics of drugs and drug reactions, and the role of hormones and other factors. MECHANISM OF SUPPORT This RFA will use the NIH U01 award mechanism. The applicant is solely responsible for planning, directing, and executing the proposed project. The RFA is a one-time solicitation. The anticipated award date is on or after July 1, 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. It uses the non-modular budgeting formats. Follow the instructions for non-modular budget research grant applications and submit the detailed categorical budget information on the PHS 398 form. 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. The NIH U01 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator as described under the section "Cooperative Agreement Terms and Conditions of Award . NIH makes no commitment to continue the cooperative agreement programs beyond the initially awarded period of performance. FUNDS AVAILABLE The participating ICs intend to commit up to $25 million in FY 2005 to fund approximately 10 to 12 new and/or continuation grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs up to $2 million per year. Facilities and administrative costs for subcontracts may be excluded from this direct costs limit. 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 the ICs 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 Foreign institutions are not eligible to apply Foreign institutions are not eligible to apply, but foreign components may be included as subcontractors, where unique opportunities are offered. These circumstances should be described and justified in the application. 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 o Attendance at two Steering Committee meetings per year is required. These will likely rotate between the East and West coasts and central US. Travel funds should be requested for this purpose for the Principal Investigator and for one to two other Observers. o A plan for depositing data into PharmGKB is required. See the current submission methods at http://www.pharmgkb.org/submit/index.jsp. This satisfies the NIH requirement for sharing research data for applications greater than $500,000 direct costs in any year of the proposed research. Funds should be requested to support individuals capable to submitting data to PharmGKB. o A letter should be included in the application, stating that the applicant research group members have read all of the existing policies of the Pharmacogenetics Research Network (http://pharmgkb.org/home/policies/index.jsp). The letter should indicate that the group members will adhere to each of the policies and will contribute to the development of future policies that will guide the network’s actions. SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS Cooperative Agreement 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 and cores 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 below. Awardees agree to accept and implement the guidelines of the Steering Committee regarding data release into PharmGKB. Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. The Principal Investigator of a research or database group will: o Coordinate the experimental approaches and procedures o Set annual project milestones for the research or database group o Report annually on progress towards the set milestones o Accept and implement polices approved by the Steering Committee o Submit data to PharmGKB, according to guidelines agreed upon and established by the Steering Committee o Attend Steering Committee meetings, and participate in the cooperative nature of the group o Represent the views of other researchers in their research area 2. NIH Scientist Administrators Responsibilities NIH Scientist Administrators from the participating ICs will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. They are representative NIH extramural staff who will serve on the Steering Committee based upon their areas of scientific expertise (e.g., pharmacology, genetics) and actively guide development of the Pharmacogenetics Research Network by providing overall advice and coordination. They should facilitate a partnership relationship between NIH and the research and database 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. Additionally, an IC program director will be assigned to each award and is responsible for the normal stewardship role of providing scientific oversight, as well as monitoring adherence to policies and procedures specific to the funding institutes; the assigned program director may also serve as an NIH Scientist Administrator. The NIH Scientist Administrators will: o Actively share their 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 PharmGKB to the scientific community at large o Assist in implementing recommendations for allocating NIH support among the awardees o Work with the program director(s) to monitor adherence to policies and procedures of the funding ICs 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 database groups, and NIH Scientist Administrators of the appropriate scientific expertise representing the funding ICs. It may include 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 be roughly proportional to the IC investment, and there may be rotating positions. Each full member will have one vote; however, NIH voting representation on the Steering Committee will not exceed one-third of the allowed number of votes. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee. The Steering Committee will: o Meet regularly and serve as the main governing board o Be run by the Chair of the Pharmacogenetics Research Network o Develop common policies, guidelines, and procedures o Facilitate the process of developing and maintaining a cohesive group o Authorize administrative and scientific subcommittees to follow through on its business o Identify scientific opportunities, emerging needs, or impediments o Interact productively with the External Scientific Panel 4. NIH Network Program Director and Administrative Coordination Activities The NIH Network Program Director will assume responsibility for overall stewardship of the network, and for coordination of the Pharmacogenetics Research Network and Knowledge Base. 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 institutes. The NIH Network Program Director will facilitate creation of the Steering Committee and will attend all meetings. 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 one of the research or database groups to support an administrative position. The NIH Network Program Director will appoint a Steering Committee Chair to serve on a year-to-year mutually renewable basis, will aid in outlining responsibilities on a regular basis, and will arrange resources necessary to accomplish the targeted administrative goals. The NIH Network Program Director will actively assist the Chair in developing the meeting agendas. Two to three meetings will be held each year, and the Chair will run the Steering Committee meetings. Subcommittees will be established by the Steering Committee as necessary. The NIH Network Program Director will ensure coordination of the Steering Committee’s activities and implementation of the group’s recommendations. The NIH Network Program Director will also assist the External Scientific Panel, which is advisory to the Pharmacogenetics Research Network. The Steering Committee Chair will take the lead on interactions representing the network with the External Scientific Panel. These groups will meet jointly approximately twice per year. Institutes will not handle data prior to its public release in PharmGKB; the awardees are responsible for providing data tracking. If clinical studies are proposed, data and safety monitoring plans should be described. The policies of the funding ICs must be followed (consult with the appropriate institute). 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 have 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 45 CFR Part 16. 6. External Advisory Groups A standing External Scientific Panel (see membership at http://www.nigms.nih.gov/pharmacogenetics/esp.html) has been appointed to guide the Pharmacogenetics Research Network and Knowledge Base, following consultation with the network awardees and the funding ICs. Additional members may be added to this panel, through discussion with the NIH Network Program Director. In its charter, the group agreed to twice a year meetings with the network, with written reports sharing evaluative advice consisting of suggestions and recommendations. It will be the responsibility of the Chair of the Pharmacogenetics Research Network to prepare written responses to the External Scientific Panel, and to share copies of the report and the reply with the funding NIH institutes in a timely manner. The Director, NIGMS, retains the right to call any additional meetings of advisors, most likely members of the National Advisory General Medical Sciences Council or their designees, 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 Pharmacogenetics Research Network as part of its fact-finding mission. Any information or reports will be shared with the other ICs participating in this initiative. 7. 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 may 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 and the External Scientific Panel. 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 does not remain state-of-the-art. WHERE TO SEND INQUIRIES The next public meeting of the Pharmacogenetics Research Network will take place on March 8, 2004, in Los Angeles; see http://www.pharmgkb.org/meetings/2004 for more information and to register. If there is sufficient interest, an informational session will take place late afternoon on March 7 at the meeting hotel. Contact staff in advance to discuss this possibility. Frequently asked questions (FAQs) will be developed from this session and shared with all potential applicants. 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 grants management/financial issues: o Direct your questions about scientific/research issues to the relevant IC representative: Rochelle M. Long, Ph.D. Pharmacology, Physiology, and Biological Chemistry Division NIGMS, NIH Building 45, Room 2AS.49G, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-1926 FAX: (301) 480-2802 Email: email@example.com Richard A. Anderson, M.D., Ph.D. Genetics and Developmental Biology Division NIGMS, NIH Building 45, Room 2AS.25B, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-0943 FAX: (301) 480-2228 Email: firstname.lastname@example.org Ken Kobayashi, M.D. Cancer Therapy Evaluation Program NCI, NIH 6130 Executive Blvd. Suite 7131, MSC 7426 Rockville, MD 20852 Telephone: (301) 496-1196 Fax: (301) 402-0428 Email: email@example.com J. Fernando Arena, M.D., Ph.D. Division of Cancer Control and Population Sciences NCI, NIH 6130 Executive Blvd., Executive Plaza North MSC 7395, Rm. 5104 Rockville, MD 20852 Telephone: (301) 594-5868 Fax: (301) 402-4279 E-mail: firstname.lastname@example.org Susan-Banks Schlegel, Ph.D. Division of Lung Diseases NHLBI, NIH Rockledge Two, Rm. 10220 6701 Rockledge Drive, MSC 7952 Bethesda, MD 20817 Telephone: (301) 435-0202 Fax: (301) 480-3557 Email: email@example.com Dina Paltoo, Ph.D., M.P.H. Division of Heart and Vascular Diseases NHLBI, NIH Rockledge Two, Rm. 9180 6701 Rockledge Drive, MSC 7940 Bethesda, MD 20817 Telephone: (301) 435-1802 Fax: (301) 480-1336 Email: firstname.lastname@example.org Lisa D. Brooks, Ph.D. Genetic Variation Program NHGRI, NIH 31 Center Dr., Rm. B2B07 Bethesda, MD 20892-2033 Telephone: (301) 435-5544 Fax: (301) 480-2770 Email: email@example.com Joni L. Rutter, Ph.D. Division of Neuroscience and Behavioral Research NIDA, NIH 6001 Executive Blvd., Rm. 5227, MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 435-0298 Fax: (301) 594-6043 Email: firstname.lastname@example.org Kimberly Gray, Ph.D. Division of Extramural Research and Training NIEHS, NIH 111 TW Alexander Drive P.O. Box 12233, MD EC-21 Research Triangle Park, NC 27709 Telephone: (919) 541-0293 Fax: (919)316-4606 Email: email@example.com Milton Corn, M.D. Extramural Programs NLM, NIH 6705 Rockledge Drive Building 1, Suite 301 Bethesda, MD 20892 Telephone: (301)496-4621 Fax: (301) 402-2952 Email: firstname.lastname@example.org Lisa Begg, Dr.P.H., R.N. Research Programs ORWH, OD, NIH 1 Center Dr., Rm. 201, MSC 0161 Bethesda, MD 20892 Telephone: (301) 496-7853 Fax: (301) 402-1798 Email: email@example.com o Direct your questions about peer review issues to: Richard Panniers, Ph.D. CSR, NIH Rockledge Two, Rm. 5148 6701 Rockledge Dr., MSC 7842 Bethesda, MD 20817 Telephone: (301) 435-1741 Fax: (301) 480-1988 Email: firstname.lastname@example.org o Direct your questions about grants management/financial matters to the relevant IC representative (new applicants, or renewal applicants funded by NIGMS should contact that institute; renewal applicants funded by NHLBI should contact that institute): John Matala PPBC/MORE Grants Management NIGMS, NIH Building 45, Rm. 2AS.55K, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-3928 FAX: (301) 480-2554 Email: email@example.com Holly Atherton Grants Operations Branch NHLBI, NIH Rockledge II MSC 7926 Rockledge Two, Rm. 7152 Bethesda, MD 20817 Telephone: (301) 435-0166 Fax: (301) 480-3310 Email: firstname.lastname@example.org 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Rochelle M. Long, Ph.D. Pharmacology, Physiology, and Biological Chemistry Division NIGMS, NIH Building 45, Room 2AS.49G, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-1926 FAX: (301) 480-2802 Email: email@example.com 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 document 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. SUPPLEMENTARY INSTRUCTIONS: Applicants should use the following guidance, in addition to the instructions accompanying the PHS 398 form. The application process should be followed for regular research grant applications (http://grants.nih.gov/grants/funding/phs398/instructions2/p1_general _instructions.htm#Page_Limitations), with the exception that the page limit for the Research Plan is raised to 50. Additionally, the specific instructions below must be addressed. All other instructions (e.g., font size, limit on appendix materials) remain the same. Abstract, Research Sites, Key Personnel (page 2): Briefly describe the proposed plans and identify whether this is a research or database group, and a new or continuing group in the Pharmacogenetics Research Network. If this group was part of a previous award in the network, explain the relationship. List all key personnel significantly involved in the project. Table of Contents (page 3): Prepare a detailed Table of Contents that includes all elements of the application. Use numeric pagination only. Organizational components should be presented in the order in which they appear in the application, and identified with an institutional location. New components of groups previously in the Pharmacogenetics Research Network should be identified. Budgets: These must be prepared as overall composites as well as according to individual components with details (see below). Composite budget - initial budget period (page 4) and entire proposed period (page 5): Use "DETAILED BUDGET FOR INITIAL BUDGET PERIOD" of Form PHS 398 to present the total budget for all requested support for the first year. For each category such as Personnel, Equipment, etc., give the total amounts requested for each component core or project. Use "BUDGET FOR ENTIRE PROPOSED PROJECT PERIOD" of Form PHS 398 to prepare a budget which provides totals for each year of requested support. Requests beyond the IC standard inflationary increases (3%) for any increases in succeeding years must be noted and well-justified in the individual component core and project budgets. Individual scientific component budgets - initial budget period (page 4) and entire proposed period (page 5). Detailed, itemized individual budgets for each scientific core and project should be prepared and placed immediately prior to the description of the relevant individual component in the Research Plan section. This is where justifications and explanations should be provided. Note: Where there are multiple participating subcontracting organizations, each entity will additionally need submit a separate composite budget for both the initial budget period and the entire proposed project period. Follow instructions for collaborations and included signed institutional letters. Biographical sketches and letters of commitment: Biographical sketches must be included for all key personnel and consultants, clearly indicating their backgrounds and expertise. Research Environment: Complete the Resources page of PHS 398 for the overall program, including both the host institution and any other participating institutions. Briefly describe the features of the institutional environment(s) that are relevant. Research Plan: There is an overall page limit of 50 pages for this section. A recommended organization (Progress Report/Preliminary Data, Future Plans, Data Deposits, Other) is below. Progress Report: A Progress Report (or Preliminary Data section, if this is a new application) section must have an over-arching summary that includes discussion of major contributions to the research area, as well as to the overall goals of the Pharmacogenetics Research Network. Specific references to successful data deposits should be made; these deposits must be explained well enough for the reviewers to understand completely. Critical assessment of genotypes/haplotypes generated, and association with functional and clinical phenotypes, should be provided. Tools, resources, and reagents previously offered for sharing should be included here, as well as a description of whether or how they have been utilized by others. Future Plans: Past experience has shown that a series of cores or projects works well as a format for a systematic approach to a well- defined problem. The plans should be organized according to these cores or projects, keeping in mind that a major goal of the pharmacogenetics research network is to make scientific correlations linking phenotypes to genotypes and to deposit the information into PharmGKB. Again, references must be made to how the research program will fit into the Pharmacogenetics Research Network. There should be specific descriptions of future data deposits, with estimated timetables; these deposits should be explained well enough for the reviewers to understand completely. The applicant group’s views of important questions in the field, and areas that the network might address should be included. Potential tools, resources, and reagents should again be addressed if new ones will be disseminated. Describe the organizational relationships, the process for setting milestones, and the flow of materials and data through the cores or projects. Metrics for measuring progress as an individual research or database group, and for the network as a whole should be posed. Discuss meeting schedules and plans for any external advisory groups specific to the proposed core or project. Do name the relevant areas, but do not name the specific members of such groups if they are not yet constituted. Do name the members if they are already operating. The application should speculate regarding ways in which the Pharmacogenetics Research Network can improve the state of the field and enable new research by impacting all pharmacogenetics researchers. Applicants are strongly urged to read very carefully the Additional Criteria for Review section of this RFA (below). Data Deposits: Plans for making future data deposits into PharmGKB should be explicitly addressed. There is a Pharmacogenetics Research Network statement on the timing and tracking of data deposits (http://pharmgkb.org/home/policies/pgrn-timing.jsp). Sufficient funds must be requested for properly trained personnel to make timely data deposits and to maintain the representative area in the database though any proposed curation responsibilities. Participation in the Pharmacogenetics Research Network brings responsibility to represent a research area for development in the database. Research groups should be prepared to set standards for data deposits, to oversee these areas in PharmGKB, and to identify others in the research community where PharmGKB should reach out to accumulate data. Database groups should be prepared to seek valuable data sets, to oversee the deposit process, and to accurately estimate the demands of curation, maintenance, and future database development. Other: The next four requirements (intellectual property, human subjects, collaborations with clinical networks, and community consultation) must be addressed if relevant to the research being proposed in the application. Plans for handling intellectual property that may be generated should be addressed in the application. There is a Pharmacogenetics Research Network policy in this area (http://pharmgkb.org/home/policies/pgrn-property.jsp). The intention of the policy is to protect the rights of institutions, but also to encourage the rapid dissemination of results and open licensing of inventions for academic research purposes. A letter should be included in the application, stating that the applicant research group members have read the existing policies of the Pharmacogenetics Research Network and will adhere to its policies and/or contribute to the creation of future policies that will guide network actions. Plans to account for data derived from human subjects should be addressed in the application. A provisional letter should be provided, stating that that the recommended language for informed consents (http://pharmgkb.org/home/policies/pgrn-recommendation.jsp) has been viewed, and describing how it will be adapted for a research group’s use. This letter should specify the manner in which clinical data will be handled for deposit into PharmGKB, when individual research data will be permitted, and when summary data will be required, and how granular that summary may be. Plans to interact with existing clinical networks should be addressed in the application. There should be a letter(s) from any collaborators supplying materials for pharmacogenetics analysis, and this should grant permission and should also reconcile the restrictions (if any) and timing for deposit of the results into PharmGKB. Typically, letters indicating the approval of a Steering Committee and/or a Data Coordinating Committee of the clinical study or network are required. Plans to propose research studies collecting data for deposit into the public knowledge base PharmGKB must address in the application how the research group will consult with named communities involved in the research. This could include racial, ethnic, cultural, or religious communities, as well as patient or disease-defined groups. Funds may be requested for the purpose of fulfilling this goal. Please see the NIH Points to Consider document at http://www.nih.gov/sigs/bioethics/named_populations.html. It is important to involve representatives of populations to solicit their thoughts and learn of effective ways to share research results. See also the recommendations of the NIGMS Populations Advisory Group at http://www.nigms.nih.gov/pharmacogenetics/ethics_communities.html. 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/labels.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and five signed, photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) 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 the CSR and responsiveness by the participating ICs. Incomplete and/or non- responsive applications will not be reviewed. 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: 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 appropriate National Advisory Councils and Boards. 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 the following 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? 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 (criteria for research groups and database groups, as well as PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK, INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH, and CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH) will be considered in the determination of scientific merit and the priority score. Additional criteria for a new or renewal research group: o Is the choice of the research area of high significance to the field of pharmacogenetics, consistent with top level research opportunities, and relevant to human health? o Is the scope of the research area sufficiently broad to be a program in pharmacogenetics, and yet sufficiently cohesive as to have a distinct theme uniting the activities? o Is the overall strategic approach to the problem (phenotype-to- genotype or genotype-to-genotype) well-justified? o Are the specific experiments proposed consistent with a modern, comprehensive approach, including both adequate study design, statistical analyses, and technical methodologies? o Are the study populations well-described, and of sufficient sample size and power? o Is this a multidisciplinary group, with people of the appropriate expertise selected, participating at a reasonable level of effort? Is there evidence of their commitment to the project? o Is the organization (e.g., cores, projects) of the comprehensive research program and the team assignments practical and realistic? o Will this research effort produce data of sufficient quantity and in a realistic timeframe to significantly add to the database, PharmGKB? o If this is a new application, are meaningful data deposits planned in a timely manner? If this is a renewal application, what is the group’s track record in making meaningful data deposits into PharmGKB? o Has sufficient staffing of the appropriate backgrounds been assigned responsibility for database deposits for the group? o Is there interest expressed in the commitment to a research network? If this is a renewal application, what is the evidence of past involvement or service to the network? o Will the research program make contributions beyond a single laboratory, and will resources for the community be generated? Are there reasonable plans proposed to share the cell lines, reagents, specimens, software, etc? o Does this research program have a record of participating in collaborative studies, and do they have a plan to stimulate collegial communications with the pharmacogenetics research community? o How will research studies and their outcome eventually be shared with non-scientists, especially the study patient and volunteer populations (e.g., newsletter, website)? o How has the research group planned for issues related to data- gathering, including strategies to approach topics such as informed consents, identified populations, confidentiality, and intellectual property? Additional criteria for a new or renewal database group: o Has sufficient thought been given to the wide variety and depth and overall quantity of data that will be generated by the research groups? Will the knowledge base be optimized to maximize its scientific value? o Are there plans to solicit necessary pharmacogenetics information beyond that generated by the research groups, given knowledge of the field in general? o Does the knowledge base have the capacity for complex multi-factorial representations of pharmacogenetics phenotypes? o Are the data submission methods simple, intuitive, and realistic for genotype and phenotype information? o Has sufficient and skilled staffing been proposed to assist with data deposits from network (and non-network) scientists? o Has appropriate attention been paid to issues of curation and maintenance of datasets? o How has the database group planned for issues related to data- gathering, including strategies to approach topics such as informed consents, identified populations, confidentiality, and intellectual property? 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). Previous discussions with NIH and the Pharmacogenetics Research Network have led to the recommendation that people of varying racial and ethnic backgrounds be allowed to describe themselves freely and with cultural, geographic, and historical references (see http://www.nigms.nih.gov/pharmacogenetics/ethics_communities.html). These data will be captured into PharmGKB, along with traditional, required OMB categories used to describe the inclusion of women and minorities in clinical research. 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. For this RFA, because it is central to the core mission of the program to deposit data into PharmGKB, reviewers will factor the proposed data sharing plan into the determination of scientific merit or priority score. 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: July 19, 2004 Application Receipt Date: August 19, 2004 Peer Review Date: Winter 2004-2005 Council Review: May 2005 Earliest Anticipated Start Date: July 1, 2005 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 Programmatic priorities o Balance and continuity 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 and will factor the plan to deposit data into PharmGKB 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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. 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. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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.healthypeople.gov/. 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. NIAAA is not participating in this RFA, but is interested in studies to identify genetic variations contributing to increased susceptibility for alcohol dependence and alcoholism, and variations that modify efficacy, safety and toxicity of drugs for the treatment of alcohol dependence, alcoholism and alcohol-related disorders.
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