ANCILLARY PHARMACOGENETICS STUDIES IN HEART, LUNG, BLOOD, AND SLEEP DISORDERS RELEASE DATE: August 22, 2002 RFA: HL-03-001 National Heart, Lung, and Blood Institute (NHLBI) ( LETTER OF INTENT RECEIPT DATE: December 17, 2002 APPLICATION RECEIPT DATE: January 14, 2003 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 Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA: The goal of this RFA is to conduct pharmacogenetic studies in ongoing or completed clinical trials/studies related to heart, lung, blood, and sleep disorders. Specifically, this RFA focuses on the collection and utilization of DNA from study participants to examine genetic influences on inter-individual differences in prescription drug response. Such studies may help elucidate basic mechanisms of drug effects and adverse reactions and may facilitate optimal selection of therapy in individual patients as well as mitigating serious adverse response or lack of response to therapy. RESEARCH OBJECTIVES Randomized controlled clinical trials and studies of pharmacologic agents typically involve large numbers of well-characterized participants followed for carefully defined, clinically important endpoints to produce statistically valid comparisons of drug effects. The effects of prescription drug therapy can also be assessed in carefully designed, non-randomized interventional studies and in observational cohort studies involving participants treated with various drugs. These studies constitute a substantial investment for the NHLBI and provide a unique potential resource for pharmacogenetic studies. According to a recent study, an estimated 2 million people were hospitalized in one year alone for reactions to properly prescribed medications and 100,000 of these people died, making unexpected adverse reactions to drugs a leading cause of death in the United States. There is growing recognition that individual drug responses are to a large degree modulated by proteins involved in drug absorption, transport, availability, activation, metabolism, and excretion, and that genetic variants in any of these pathways can lead to differences in response. Interaction of these genetic variants with non-genetic environmental determinants such as dietary factors, nicotine and alcohol use, pre-existing illness, sleep history, and other drugs can also influence individual response. Pharmacogenetic research focuses on identifying genetic influences on the biological response (or lack of response) to pharmacologic interventions. Understanding these genetic influences may permit better tailoring of medication choice and dosing in individual patients and help avoid serious adverse or lack of response to therapy. It may also aid in the development of drugs with narrower and more targeted therapeutic actions and with fewer side effects. Clinical phenotypes observed prior to initiation of drug treatment are often not sufficient to predict an individual"s response to therapy. Assessment of sequence variation in participants exhibiting a wide range of clinical drug responses, including enhanced response, lack of response, or adverse reactions, will allow the functional consequences of genetic variation to be examined. 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. Genetically-based circadian variations in the pharmacokinetics and pharmacodynamics of drugs are also of interest. The underlying theme of this RFA will be to search for pharmacogenetically important sequence variation by correlating genotype with treatment response. Thus, several approaches are promising. There may be selected study participants already phenotyped for a drug response or for disease progression, who can be used to relate a characteristic drug response to a genetic variant. Sequence variation in key genes involved in drug metabolism and response, such as the cytochrome P450 superfamily and the ATP binding cassette (ABC) family, can be examined in relation to measured phenotypic responses to determine which variants are functional and how they contribute to individual differences in drug response. This can be conducted efficiently by utilizing stored blood or tissue samples from well-characterized and carefully monitored study participants. The biochemical significance of genetic sequence variation in coding and non- coding regions should be examined. There may be a functional role for genetic variation in altered transcription, structure, splicing, or stability of mRNA, as well as changes in the structure, function, regulation, modification, or degradation of the encoded protein(s). These biochemical effects may be exhibited under specific pathophysiological conditions such as intermittent hypoxia and ischemia. Investigators trained in different areas and working as collaborative teams are needed to achieve insights into the contribution of genetic variation on individual drug responses. Rigorous studies, both basic and clinical, are needed to correlate phenotype with genotype. Researchers working at the most molecular to the most clinical levels in the fields of pharmacology, physiology, genetics, genomics, medicine, epidemiology, statistics, bioinformatics, and computational biology should combine talents to interpret functional protein and gene variations having essential roles in determining drug response and to translate these findings to improved therapeutic outcomes. These studies must not interfere with or overburden participants in the parent study. Information regarding potential NHLBI studies available for these studies can be found at the NHLBI Database to Facilitate Human Genetic Research web site: and the NHLBI Population Studies Database web site: Appropriate power calculations must be provided, acceptable informed consent ensured, and ancillary study policies from the parent study followed. Studies may utilize existing stored genetic material or collect samples from ongoing trial and/or studies. Investigators should consider whether an independent Observational Safety and Monitoring Board (OSMB) may be needed for their specific study, particularly in the case where there is re-recruitment or samples from a completed study are being used. If such a need is anticipated, funds for the OSMB (one meeting per year in Bethesda, MD with 5-7 members) should be included in the proposed budget. Additional phenotyping may be necessary for these studies and funds must be included within the proposed budget. For investigators who may require storage facilities at the end of the study, the NHLBI Biologic Specimen Repository ( is available for long term storage of blood, serum, plasma, tissue, DNA, etc. There is no cost to the investigator for storage. The investigator must arrange transportation of samples and access of the samples should be coordinated with the parent study. MECHANISM OF SUPPORT This RFA will use the NIH R01 award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2003. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. FUNDS AVAILABLE The NHLBI intends to commit approximately $6.0 million total costs in FY 2003 to fund 6-8 new grants in response to this RFA. An applicant may request a project period of up to four years. It is expected that applications will not exceed a budget of $600,000 in direct costs, excluding Facilities and Administrative costs on consortium arrangements, in the first year. Annual increases in non- competing years are not allowed. 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 NHLBI 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. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS To be responsive, the application must utilize clinical studies in progress or completed, and not develop new cohorts or trials. This award is limited to studying prescription drugs that are used to treat heart, lung, blood, and sleep disorders or which cause side effects resulting in heart, lung, blood, and sleep phenotypes. Studies evaluating solely alcohol and/or smoking will be considered non- responsive. Upon initiation of the program, the NHLBI will sponsor a yearly meeting to encourage exchange of information among investigators who participate in pharmacogenetic research. The NHLBI meeting will be in conjunction with the NIH Pharmacogenetics Research Network and Knowledge Base meeting ( Travel funds should be included for two people (the Principal Investigator and one-co-investigator from the grant) to attend a two-day meeting, once a year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their application indicating their willingness to participate in this meeting and to interact openly with other study participants. In order to be responsive to this RFA, the applicant must provide adequate documentation that patients, samples, data, and/or materials are available from the parent clinical trial. Principal investigators of awards funded through this RFA will be required to deposit their data into the PharmGKB, a knowledge base for pharmacogenetic information ( maintained by Stanford University. Data sharing should adhere to the Pharmacogenetics Network policy of that all data should be deposited within 90 days of discovery ( PharmGKB is organized around the principle that pharmacogenetic information can be indexed by genes, drugs, and levels of evidence that drug response differences are the phenotypic expression of genetic variation. PharmGKB includes genotypic and phenotypic information collected in research studies conducted by the Pharmacogenetics Research Network, as well as information gathered from external sources relevant to pharmacogenetic studies. Several institutes of the NIH, including NHLBI, support the Pharmacogenetics Research Network. The PharmGKB is different from traditional clinical trial data centers in that it does not store data for limited accessibility, all data must be submitted in a format suitable for public dissemination on the World Wide Web. PharmGKB entries consist of (1) genotypic data, suitably protected for confidentiality, (2) linked phenotypic information, appropriately de-identified, and (3) text summaries of study protocols. In cases where individual phenotypic information is judged to be too sensitive to release, summary data tables will be accepted. The PharmGKB team can work with investigators to define either spreadsheet-based submission of data or XML-based submission of data. Also, a computer specialist supported by NHLBI will be available to assist grantees in data retrieval, processing, storage, and presentation of data into PharmGKB at Stanford University, Palo Alto, CA. The specialist will assist network submitters and users seeking information and training. The specialist will be available to work with the grantee institution and at the annual meetings. Applicants should describe their plans for data deposits, and should indicate their plans for obtaining adequate informed consent for posting de-identified data to PharmGKB. Samples of model informed consent language used by the Pharmacogenetics Research Network can be found at Protection of participant confidentiality and arrangements for sample and data sharing will be subject to peer review. Arrangements for data sharing will be specified in the terms and conditions of award and finalized in the first year of the study. Award of non-competing continuations (type 5) will be contingent on satisfactory completion of this requirement. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Mariana Gerschenson, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Rockledge II, Room 9180 MSC 7940 6701 Rockledge Drive Bethesda, MD 20892-7940 Phone: 301-435-0515 FAX: 301-480-1336 Email: Susan Banks-Schlegel, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Rockledge II, Room 10018 MSC 7952 6701 Rockledge Drive Bethesda, MD 20892-7952 Phone: 301-435-0202 FAX: 301-480-3557 Email: Pankaj Qasba, Ph.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute Rockledge II, Room 10161 MSC 7950 6701 Rockledge Drive Bethesda, MD 20892-7950 Phone: 301-435-0050 FAX: 301-480-0868 Email: Ebony Bookman, Ph.D. Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute Rockledge II, Room 8166 MSC 7934 6701 Rockledge Drive Bethesda, MD 20892-7934 Telephone: 301-435-0446 FAX: 301-480-3667 Email: Carl E. Hunt, M.D. National Center on Sleep Disorders Research National Heart, Lung, and Blood Institute Rockledge II, Suite 10138 6701 Rockledge Drive Bethesda, MD 20892 Phone: (301) 443-0199 Fax: (301) 480-3557 E-mail: o Direct your questions about peer review issues to: Anne Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr., Room 7214 (MSC 7924) Bethesda, MD 20892-7924 (20817 for express/courier service) Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: Direct your questions about financial or grants management matters to: John Diggs Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive Suite 7172, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0177 FAX: (301) 480-3310 Email: 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 Dr. Anne Clark at the address listed under Where to Send Inquiries. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at 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: SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application as well as five collated sets of Appendix material must be sent to Dr. Anne Clark at the address listed under Where to Send Inquiries. Please note that applications delivered by individuals are no longer accepted, all applications must either come via courier delivery or the United States Postal Service APPLICATION PROCESSING: 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. Principal investigators should not send supplementary material without first contacting the Scientific Review Administrator (SRA). The SRA will be identified in the letter sent to you indicating your application has been received. If you have not received such a letter within three weeks after submitting the application, contact Dr. Anne Clark at the address listed under Where to Send Inquiries. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. 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 the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique 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 second level review by the National Heart, Lung, and Blood Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your 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, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? (6) COLLABORATIONS AND DATA SHARING: The adequacy of the proposed plan and time line to share data. The willingness to work and collaborate with the Pharmacogenetics Research Network and the PharmGKB database maintained at Stanford University. The willingness to provide data to a central data base and otherwise to disseminate resulting data and analytic tools. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: 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 included in the section on Federal Citations, below) o 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: December 17, 2002 Application Receipt Date: January 14, 2003 Peer Review Date: May/June, 2003 Council Review: September, 2003 Earliest Anticipated Start Date: September 30, 2003 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 REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: 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 AMENDMENT "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 (, a complete copy of the updated Guidelines are available at 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 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 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 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. 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 AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.837, 93.838, 93.839 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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