and Human Services (HHS)
EXPIRED
HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) CARDIOVASCULAR TOXICITIES RELEASE DATE: March 7, 2002 RFA: HL-02-028 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov) LETTER OF INTENT RECEIPT DATES: April 1, 2002 and January 20, 2003 APPLICATION RECEIPT DATES: April 29, 2002 and February 19, 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 objective of this RFA is to support basic research to elucidate how nucleoside reverse transciptase inhibitors (NRTI), non-nucleoside reverse transciptase inhibitors (NNRTI), and/or protease inhibitors (PI) affect the development of cardiovascular disease. Ultimately, better understanding of HAART-induced cardiac dysfunction will permit development of effective strategies for prevention and treatment. Successful applications should address the basic cellular mechanism(s) underlying the development of these pathologies. Studies may include any or all of the following: interdisciplinary and collaborative research focused on pediatric or adult clinical cardiac complications; basic studies using animal models (e.g., rodent, nonhuman primate); in vitro mammalian cell; and human tissue studies. RESEARCH OBJECTIVES HAART regimens have improved the course of HIV disease. Patients live longer and have a better quality of life. However, new clinical complications have emerged as a result of the therapy, including peripheral and coronary arterial diseases, and metabolic disturbances seen typically in diabetes. Throughout the world, patients with HIV infection represent one of the most rapidly growing groups of individuals with cardiovascular disease. Significant cardiac morbidity from HIV disease is estimated at 6-7% and mortality between 1-6% based on US and European data. Cardiac abnormalities in patients with HIV-infection range from asymptomatic mild dysfunction, which is evident only on echocardiographic evaluation, to severe dysfunction with development of congestive heart failure (CHF) and dilated cardiomyopathy (DCM). Pediatric and adult echocardiographic examination reveal that 15-20% of patients having left ventricle dysfunction on echocardiography. Of these patients, 3-5% are symptomatic with CHF or DCM, requiring medical treatment to improve cardiac function. Antiretroviral drug regimens are strongly suspected as one factor responsible for adult and pediatric cardiac dysfunction. These drugs are associated with increases in the incidence of unstable angina, myocardial infarction, pulmonary hypertension, right ventricular dysfunction, and stroke in HIV-infected adults. HAART may also be associated with development of myocardial dysfunction during fetal development, in young children, and teenagers. Studies in non-infected non-human primates with NRTIs demonstrate fetal cardiac morphological, biochemical, and genetic abnormalities. However, clinical pediatric studies are still inconclusive; some reports support NRTI-induced cardiotoxicity while others show no association between NRTIs and cardiac dysfunction. Furthermore, basic research studies have focused on the NRTI, zidovudine and not combination therapies. Thus, the contribution of NRTIs and/or combination therapies to the cellular mechanisms involved in these pathologies have not been well defined. The goal of this program is to encourage research likely to produce a better understanding of the mechanisms and/or clinical approaches to HAART cardiovascular toxicities. Suggested clinical research topics include, but are not limited to: o Evaluation of cellular functional, metabolic, and structural alterations with NRTIs, NNRTIs, and/or PI combinations. This could include evaluating intracellular parameters and correlations with clinical presentation in HIV-infected adults and/or children. o Understanding of the cellular vascular pathology, including endocardial involvement of treatment regimens in patients at high risk for or with peripheral and coronary arterial diseases. o Clinical studies using imaging techniques to correlate vascular reactivity, endothelial cell function, cellular energetics to clinical presentation of ischemic heart disease. o Determination of the mechanisms and effects of NRTIs, NNRTIs, and/or PI combinations in pericardial effusion, endocardial involvement, and cardiac arrythmias. o Evaluation of the mechanisms and impact of specific treatment strategies on cardiovascular function in HIV-infected patients. o Studies in high-risk patients (hyperlipidemic, hypertension, dysmetabolic) dealing with the mechanisms of cardiovascular function, coagulation, and inflammatation. o Studies to evaluate the mechanisms and effects of in utero exposure to antiretroviral drugs on the heart, including but not exclusively limited to cardiac development, dysfunction, and/or mitochondrial abnormalities. Proposed studies should differentiate between the effects of HIV and other co-infections where possible. Populations chosen should be carefully defined and characterized as to environmental (e.g. smoking, etc.) and other risk factors or diseases. Basic research studies should be translatable to human studies. Thus, in animal and mammalian cell experiments, the drug combinations and amounts should be pharmacologically relevant and animal models chosen should exhibit similar systemic pharmacokinetics and pharmacodynamics as humans. Appropriate basic research topics to respond to this RFA include but are not limited to: o Studies to examine the pathological effects of NRTIs, NNRTIs, and/or PI combinations in adult or pediatric (including in utero) animal models for either heart, peripheral vascular, and/or coronary arterial diseases. o Studies in vitro with NRTIs, NNRTIs, and/or PI combinations and mammalian cells or tissues associated with the cardiovascular system that could contribute to the etiology of these diseases, such as vascular endothelial, myocardial, and/or adipocyte cells. o Studies to evaluate the mechanisms and effects of NRTIs, NNRTIs, and/or PI combinations in any of the following animal or in vitro models: interferences with ion pumps or exchange mechanisms, mitochondrial damage and enzymatic dysfunction, premature truncation of genes, oxidative stress, apoptosis, nucleoside imbalances, phosphorylation, and post-transcriptional changes in glycosylation, and how these genetic, biochemical, and/or morphological changes contribute to the etiology of cardiovascular diseases. MECHANISM OF SUPPORT This RFA will use the NIH R01 award mechanism. The applicant will be solely responsible for planning, directing, and executing the proposed project. There will be two receipt dates: April 29, 2002 and February 19, 2003. Applicants who submit to the first receipt date and are not funded may revise and submit an amended application for the second receipt date. 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 dates are September 30, 2002 and 2003, respectively. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. FUNDS AVAILABLE NHLBI intends to commit approximately $5.0 million in FY 2002 and another $2.0 million in FY 2003 to fund 10 to 20 new and/or competitive continuation grants in response to this RFA. NICHD intends to commit $500,000 to fund 2 new applications relevant to studies in children in 2003. 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. An applicant may request a project period of up to five years. Although the financial plans of the IC(s) 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 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 The Principal Investigators of grants funded under this RFA will be expected to participate in yearly grantee meetings to present findings of the research supported and suggest future research directions. Funds for travel to such meetings must be incorporated in the development of the budget. Applications focused on the development of metabolic complications (hypercholesterolemia, hyperinsulinemia, lipoatrophy) will not be considered responsive to this RFA. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research 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: gerschem@nhlbi.nih.gov Lynne M. Mofenson, M.D. Pediatric, Adolescent and Maternal AIDS Branch Center for Research for Mothers and Children National Institute of Child Health and Human Development National Institutes of Health 6100 Executive Boulevard, Room 4B11 Rockville, MD 20852 Telephone: 301-435-6870 Fax: 301-496-8678 Email: LM65D@nih.gov 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 7178 (MSC 7924) Bethesda, MD 20892-7924 (20817 for Courier) Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: ClarkA@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Kevin Keating Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive Suite 7159, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0185 FAX: (301) 480-3310 Email: KeatingK@nhlbi.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows 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: Anne Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr., Room 7178 (MSC 7924) Bethesda, MD 20892-7924 (20817 for Courier) Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: ClarkA@nhlbi.nih.gov 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 http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR 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 http://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application as well as six collated sets of appendix material must be sent to: Anne Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr., Room 7178 (MSC 7924) Bethesda, MD 20892-7924 (20817 for Courier) Telephone: (301) 435-0270 FAX: (301) 480-3541 Email: ClarkA@nhlbi.nih.gov 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. 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 (IC) 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 and the National Child Health and Human Development 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? 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, animals, 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 Dates: April 1, 2002 and January 20, 2003 Application Receipt Dates: April 29, 2002 and February 19, 2003 Peer Review Dates: July, 2002 and June, 2003 Council Reviews: September 5, 2002 and September 4, 2003 Earliest Anticipated Start Dates: September 30, 2002 and 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: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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 (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_20 01.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA 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 http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.837 and 98.865 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 http://grants.nih.gov/grants/policy/policy.htm 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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