RFA-HL-98-012: CARDIOVASCULAR COMPLICATIONS FROM COCAINE ABUSE IN HIV INFECTION

Department of Health
and Human Services (HHS)

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CARDIOVASCULAR COMPLICATIONS FROM COCAINE ABUSE IN HIV INFECTION Release Date: May 15, 1998 RFA: HL-98-012 P.T. National Heart, Lung, and Blood Institute National Institute on Drug Abuse Letter of Intent Receipt Date: July 15, 1998 Application Receipt Date: October 14, 1998 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE This solicitation invites research grants focusing on the pathology and pathophysiology of cardiovascular complications associated with cocaine abuse in the setting of HIV infection. Studies focusing on pathology, cellular and molecular mechanisms, autonomic effects, and genetic susceptibility are encouraged. Ultimately, the goal of this solicitation is to provide a rational basis for prevention, optimal diagnosis, and/or therapy for the cardiovascular complications of patients with HIV infection and cocaine abuse. HIV infection, cocaine physiology, cardiovascular pathology, biochemistry, genetics, cellular biology, and molecular biology are among the disciplines and expertise that may be appropriate for this research program. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2000, a PHS-led national activity for setting priority areas. This Request for Application (RFA), Cardiovascular Complications From Cocaine Abuse in Hiv Infection, is related to the priority area, alcohol and other drugs, maternal and infant health, heart disease and stroke, HIV Infection, and sexually transmitted diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research project grant (R01) mechanism of support. However, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. For this RFA, funds must be requested in $25,000 direct cost modules with a maximum of 10 modules ($250,000 direct costs) per R01 per year may be requested. A feature of the modular grant concept is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. Instructions for completing the Biographical Sketch have also been modified. In addition, Other Support information and the application Checklist page are not required as part of the initial application. If there is a possibility for an award, necessary budget, Other Support and Checklist information will be requested by NHLBI or NIDA staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. It is anticipated that support for this program will begin in April 1999. Administrative adjustments in project period and/or amount may be required at the time of the award. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE It is anticipated that for fiscal year 1999, approximately $3 millions total costs will be available for the first year of support for this initiative. Award of grants pursuant to this RFA is contingent upon receipt of such funds for this purpose. It is anticipated that up to twelve new grants will be awarded under this program. Applicants may request up to five years of support. The specific number to be funded will depend on the merit and scope of the applications received and on the availability of funds. Direct costs will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. Facilities and Administrative costs will be awarded based on the negotiated rates. RESEARCH OBJECTIVES Background Since the 1980s, cocaine use has increased dramatically, causing significant social, economic, and medical complications. According to the 1996 National Household Drug Survey, about 1.7 million Americans (12 years and older) were (at least once per month) cocaine users, about 668,000 of these used crack. The rate of cocaine use was 2% among 18-25 year olds, significantly higher than 1.3% in 1995. The 1996 survey, however, does not provide estimates for the route of administration such as snorting or injecting cocaine. Furthermore, based on the 1997 DAWN report, cocaine-related episodes comprised 30% (144,200) of all emergency department drug-related episodes (487,600) in 1996. Chest pain was the most common cocaine related medical complaint, leading to the evaluation of over 64,000 patients in the emergency room annually for possible acute myocardial ischemia, with 57% of these patients being hospitalized at an estimated cost of more than $83 million per year. The cardiovascular complications of cocaine abuse include chest pain, myocardial ischemia and infarction, myocarditis, dilated cardiomyopathy, congestive heart failure, cardiac arrhythmias, and sudden death, as well as coronary spasm, aortic dissection, atherosclerosis, and pathologic alterations in the blood vessels. The etiology of these cardiovascular complications associated with cocaine abuse remains undefined. Since 1993, HIV infection has been the leading cause of death in 25-45 years old in the United States. Following the report, in 1986, of the first case of rapidly fatal dilated cardiomyopathy in AIDS patients, echocardiographic studies have indicated an alarmingly high incidence of symptomatic cardiac disease in HIV-infected individuals. The cardiovascular complications that have been described in patients infected with HIV include myocardial (most commonly dilated cardiomyopathy, and myocarditis), pericardial, endocardial, rhythm, and vascular abnormalities. In the United States, the cardiovascular mortality rate associated with HIV infection is estimated to be 1% to 6% of infected individuals. The requirement for specialized cardiac care for these patients has a marked impact on health resource utilization. The combination of cocaine abuse and HIV infection represents a unique challenge to both researchers and health practioners. Illicit drug use, particularly by injection, has been associated closely with the HIV epidemic. In 1994, 27% of the 80,691 newly reported AIDS cases in the United States occurred in persons with a history of drug use. The possibility that HIV infection increases the risk of infective endocarditis among intravenous drug abusers seems likely, but this relation has not yet been clearly established. Both HIV infection and cocaine abuse can cause cardiovascular complications possibly resulting from separate mechanisms. However, in HIV-infected individuals who also abuse cocaine these etiologies converge and overlap to expose these individuals to increased risks of cardiomyopathy and myocarditis. With longer survival, an increasing number of AIDS victims show evidence of heart disease: e.g. myocarditis, myocardial necrosis, cardiomyopathy, pericardial disease, and endocarditis. Left ventricular dysfunction without dilatation is common with or without infective endocarditis. Cardiovascular involvement can occur at any stage of HIV infection and may involve all cardiovascular tissues. A high prevalence of echocardiographically detected myocardial and pericardial abnormalities has been reported among acutely ill HIV-infected individuals in Zimbabwe without concomitant intravenous drug use nor antiretroviral therapy with zidovudine or any other reported cardiotoxic drugs (e.g., pentamidine or ganciclovir). Anecdotal reports of severe coronary atherosclerosis in HIV- infected young adults and reports of coronary arteriopathy associated with HIV infection in children have also been described. Dramatic coronary vascular lesions have been seen in juvenile SIV-infected rhesus monkeys. The association between HIV infection and an accelerated form of atherosclerosis has an appealing theoretical basis: i.e., exposure to vasculotropic viruses such as cytomegalovirus or activated macrophages triggered via enhanced production of interferon-gamma by activated T cells may form the immunologic substrate for the development of premature atherosclerosis. However, this relationship has yet to be demonstrated. Current hypotheses regarding the etiology of HIV-related cardiomyopathy include myocardial infection with HIV, co-infection with other cardiotropic viruses and other opportunistic infections, postviral cardiac autoimmunity, cardiotoxicity resulting from concurrent use of illicit drugs such as cocaine, and cardiac hypersensitivity or toxicity from iatrogenic pharmacologic agents (e.g. nucleoside analogues and pentamidine). Other factors may include selenium deficiency and tumor necrosis factor. The etiology of myocardial dysfunction in HIV infection is thus probably complex and multifactorial. Viral myocarditis, as well as infection of cardiac tissue with other opportunistic infections, may result in the loss of immune function, especially TH1 responses, that is characteristic of AIDS. Several observations in rhesus monkeys chronically infected with simian immunodeficiency virus (SIV) and with cardiac involvement suggest that some degree of immunocompetence is necessary for a development of cardiomyopathy. Cocaine addiction is a staggering health problem in the United States with cardiovascular problems among the most common ailments seen with cocaine abuse. Cocaine affects many systems. Myocardial ischemia, infarction, and sudden death are most likely to occur in chronic cocaine users, but, they have been reported in first-time users as well, following any route and with large or small amounts of drug. The specific causes responsible for the cardiac abnormalities are unknown. In pigs, acute cocaine administration causes regional myocardial ischemia and left ventricular dysfunction as well as patchy necrosis with a 50-70% coronary artery stenosis. Experimentally, a high intracoronary dose of cocaine causes a modest decline in left ventricular systolic and diastolic performance in humans. It is known that cocaine produces central and peripheral adrenergic stimulation by blocking presynaptic reuptake of norepinephrine and dopamine, thereby increasing their postsynaptic concentrations and neurotransmitters in the central and peripheral nervous system. Activation of the sympathetic nervous system can produce vasoconstriction, an abrupt increase in arterial blood pressure, and tachycardia. Cocaine can cause coronary thrombosis by activating platelets, increasing potential for platelet aggregation, and potentiating platelet thromboxane production. Cocaine abuse may accelerate atherosclerosis through a combination of pathogenic processes. Catecholamine toxicity causes increases in LDL uptake in the arterial wall and may lead to left ventricular hypertrophy. Catecholamines also activate cardiac mast cells which are present in excessive numbers in atherosclerotic lesions of cocaine users. Mast cells release granules containing histamine, bFGF, PAF, vasoactive eicosanoids, leukotrienes, IL5, and TNF-alpha that cause endothelial cell activation, smooth muscle proliferation, and the recruitment of T cells and macrophages to the atherosclerotic lesion resulting in myocardial ischemia. Cocaine has a number of other effects potentially important in the genesis of cardiovascular disease. Recent evidence suggests that nitric oxide may play a key role in the process of cocaine-associated vasospasm. Cocaine blocks fast inward sodium-ion channels in nerve and heart alike. Cocaine is also a blocker of the slow inward calcium-ion current and the delayed rectifier potassium-ion current. The latter has been implicated with clinical proarrhythmia and induction of torsade de pointes. Increased QT interval duration has been observed with cocaine toxicity in humans and in pigs given the drug. Cocaine-sensitive rats demonstrate decreased cardiac output and have a cocaine- induced burst in sympathetic nerve activity. Furthermore, these rats express a specific pattern of autonomic responses after exposure to psychoactive agents or stress that varies between individuals and involves both catecholamines (CNS and peripheral) and acetylcholine. This variable response is likely to be genetically determined. Data also suggest that low plasma levels of pseudo- cholinesterase, the enzyme that metabolizes cocaine, are associated with increased cocaine toxicity. Some individuals appear quite sensitive to cocaine even following low doses. These differences in cardiac output responses are related to race and gender and may also be genetically determined. There are several important differences in the treatment of chest pain due to potential ischemia chest pain secondary to cocaine ingestion compared to that in patients with myocardial ischemia unrelated to cocaine. While calcium antagonists have no proven benefit in acute myocardial infarction unrelated to cocaine, verapamil does reverse cocaine induced coronary vasospasm. Benzodiazepines attenuate the cardiac and central nervous system toxicity of cocaine. They are not part of the standard treatment algorithm for patients with potential myocardial ischemia, but can be beneficial when given early during cocaine related myocardial ischemia. On the other hand, beta adrenergic antagonists and thrombolytics, which are used to treat acute myocardial ischemia, should be avoided in patients with recent cocaine use. Beta adrenergic antagonists enhance cocaine induced coronary vasoconstriction, increase blood pressure, fail to control heart rate, enhance the likelihood of seizures, and worsen survival. Thrombolytics may result in increased bleeding complications. There have been no well designed randomized prospective clinical trials to compare different treatment regimens. In addition, the current treatment recommendations need to be rigorously evaluated. In summary, cardiovascular complications resulting from separate mechanisms are associated with HIV infection and with cocaine abuse. Therefore, cocaine induced hypersympathetic activity and exacerbation of cardiac dysfunction associated with chronic HIV infection needs to be explored. Future directions should include studies that focus on pathogenic mechanisms developing in the setting of cocaine- induced catecholamine toxicity and an HIV-induced immune deficient environment. Future studies should focus on pathogenic mechanisms that develop in the setting of cocaine toxicity and in an HIV-induced immune deficient environment. For example, infective endocarditis is more common among HIV-seropositive intravenous drug users than other HIV risk groups, but it is not exclusive to this HIV risk group. While it seems likely that HIV infection increases the risk of infective endocarditis among intravenous drug users, it has not yet been clearly shown. A limited amount of data suggests that long term complications in patients with cocaine associated chest pain may be related to underlying morbidity, especially concurrent HIV disease. Cocaine induced hypersympathetic activity and exacerbation of cardiac dysfunction associated with chronic HIV infection needs further exploration. The demographic and clinical characteristics of HIV- infected patients with cardiovascular complications and the involvement of cocaine abuse also require further research. Proposed Research This RFA invites research grant applications that examine the mechanisms responsible for development of cardiovascular complications in the setting of cocaine abuse combined with HIV infection. Studies focusing on pathophysiology, cellular and molecular mechanisms, genetic susceptibility, and pharmacologic intervention are encouraged. The following topics are suggested as examples only. Applicants should consider other topics within the scope of this RFA based on their own expertise and knowledge of the field. o Role of HIV infection in development of cardiomyopathy and vasculopathy, including frequency or extent of cardiovascular damage, early-onset coronary artery disease, and long term cardiovascular effects. o Role of cocaine in HIV-initiated progression of cardiovascular complications. o Identification of patients at greatest risk of cocaine cardiotoxicity due to genetic (e.g., pseudocholinesterase deficiency) vs. acquired predisposition for development and progression of cardiomyopathy and vasculopathy of patients with HIV infection and cocaine abuse. Studies of genetic determinants predisposing to cocaine cardiotoxicity, individual susceptibility, and relationship between genes encoding for cardiac structural proteins and cardiomyopathy. o Studies on cardiac function, coronary blood flow, evaluation of endothelial dysfunction, and metabolic assessment with state-of-the-art imaging methods of individuals with HIV infection and acute and chronic cocaine use. o Role of immune system activation with cocaine use and HIV infection to assess the role of immune mediated cardiac injury. o Role of central and peripheral neurotransmitters in cocaine cardiotoxicity and interaction between hypersympathetic activity and viral replication or immune function. o Development of chronic experimental animal models displaying the cardiovascular sequelae of chronic cocaine abuse and HIV cardiomyopathy. o Studies at the cellular, intracellular and subcellular levels to better understand the cardiovascular affects of cocaine abuse in the presence of HIV infection. o Clinical studies on cocaine cardiomyopathy and HIV infection to design effective treatment protocols. o Relationship between cocaine use, and HIV and other viral co-infections, and the development of atherosclerosis. These examples often overlap, and applicants may propose multidisciplinary approaches to address more than one of these areas. This initiative will not support grants that focus on large epidemiological studies or clinical trials. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI and NIDA will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. Applicants should include a statement in their applications indicating their willingness to participate in these meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide to Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html LETTER OF INTENT Prospective applicants are asked to submit, by July 15, 1998, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 NHLBI and NIDA staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be mailed, or faxed, to: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: James_Scheirer@NIH.GOV APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants, with the modifications noted below. These forms are available at most institutional offices of sponsored research, from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov, and on the internet at http://grants.nih.gov/grants/funding/phs398/phs398.html. The RFA label found in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. 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 (Cardiovascular Complications From Cocaine Abuse in HIV Infection) and number (HL-98-012) must be typed on line 2 of the face page of the application form and the YES box must be marked. BUDGET INSTRUCTIONS The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: FACE PAGE As a reminder, Items 7a and 8a should be completed to indicated Modular Direct Costs requested and Items 7b and 8b should reflect Total Costs (Modular Direct plus F&A costs). Item 7 should reflect costs for the Initial Budget Period and item 8 should reflect costs for the Total Budget Period. DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD Do not complete Form Page 4 of the PHS 398 (rev 5/95). It is not required nor will it be accepted at the time of application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT Do not complete the categorical budget tables on page 5 of the PHS 398 (rev. 5/95) Form. Only the requested total direct costs line for each year should be completed based on the number of $25,000 modules being requested. Applicants may not request a change in the amount of each module. A maximum of 10 modules ($250,000 direct cost) per year may be requested for each R01 application. Applicants may request for up to five years of support for this RFA. Direct cost budgets will remain constant throughout the life of the project (i.e., the same number of modules requested for all budget periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs for the Entire Proposed Project Period should be shown in the box provided. BUDGET JUSTIFICATION o Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. o List the names, role on the project and proposed percent effort for all project personnel (salaried or unsalaried)and provide a narrative justification for each person based on his/her role on the project. o Identify all consultants by name and organizational affiliation and describe the services to be performed. o Provide a general narrative justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one-time purchases, such as large equipment requests, must be accommodated within these limits. CONSORTIUM/CONTRACTUAL COSTS If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual TOTAL COSTS (direct and facilities and administrative costs) relative to the total DIRECT COSTS of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27% of overall direct costs requested in the first year." A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Please indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility of an award, the applicant will be requested to identify actual direct and indirect costs for all years of the consortium. Please note that total subcontract costs need not be calculated in $25,000 modules. However, when subcontract funds are added to the parent grant budget, the total direct cost amount must be included in the number of $25,000 modules requested. BIOGRAPHICAL SKETCH A biographical sketch is required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. o Complete the educational block at the top of the form page, o List current position(s) and those previous positions directly relevant to the application, o List selected peer-reviewed publications directly relevant to the proposed project, with full citation, o The applicant has the option to provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other Support information will be requested by NHLBI or NIDA staff if there is a possibility for an award. CHECKLIST No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI or NIDA staff if there is a possibility for an award. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. Submit a signed, typewritten original of the application and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to Dr. C. James Scheirer, at the address listed under LETTER OF INTENT. Applications must be received by October 14, 1998. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NHLBI or NIDA. Incomplete and/or unresponsive applications will be returned to the applicant without further consideration. Remaining applications may be subjected to a streamlined review process by a Special Emphasis Panel convened by NHLBI Scientific Review Office to determine their scientific merit relative to other applications received in response to the RFA. The roster of reviewers for the RFA will be available on the NHLBI and NIDA home page approximately four weeks prior to the scheduled review date. Applications determined to be meritorious will be evaluated for scientific and technical merit by the review committee, be discussed and receive a priority score. All other applications will not be discussed or scored. Secondary review of the applications will be conducted by the National Heart, Lung, and Blood Advisory Council (NHLBAC) or National Institute on Drug Abuse Advisory Council (NIDAAC). Review Criteria Other review criteria and major factors to be considered in the evaluation of the applications will include: 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 review, comments on the following aspects of the application will be made in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in the assignment of the overall score. 1) Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2) Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3) Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4) Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5) Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? As part of the scientific and technical merit evaluation of the research plan, reviewers will be instructed to address the adequacy of plans for including both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research, or justification for exclusion. The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. AWARD CRITERIA Applicants should be aware that, in addition to scientific merit, program priorities and program balance, the total costs of the proposed project and the availability of funds will be considered by NHLBI/NIDA staff as well as NHLBAC/NIDAAC in making funding recommendations. In circumstances in which applications have similar scientific merit, but vary in cost competitiveness, NHLBI or NIDA is likely to select the more cost competitive application for funding. Schedule Letter of Intent Receipt Date: July 15, 1998 Application Receipt Date: October 14, 1998 Date of Initial Review: Dec 98/Jan 99 Review by NHLBI or NIDA Advisory Council: February 1999 Anticipated Award Date: April 01, 1999 INQUIRIES Inquiries concerning this RFA are encouraged. Potential applicants may request sample budget pages. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues and requests for sample budget pages to: Lan-Hsiang Wang, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 9148, MSC 7940 Bethesda, MD 20892-7940 Telephone: (301) 435-0510 FAX: (301) 480-1335 Email: LW72F@nih.gov Jag H. Khalsa, Ph.D. Division of Clinical and Services Research National Institute on Drug Abuse 5600 Fishers Lane, Room 10A-08 Rockville, MD 20857 Telephone: (301) 443-1801 FAX: (301) 594-6566 Email: JK98p@nih.gov Direct inquiries regarding fiscal matters to: Ms. Marie Willett Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7156 Bethesda, MD 20892-7128 Telephone: (301) 435-0144 FAX: (301) 480-3310 Email: Willettm@gwgate.nhlbi.nih.gov Gary Flemming, J.D. Grants Management Branch National Institute on Drug Abuse 5600 Fishers Lane, Room 8A-54 Rockville, MD 20857 Telephone: (301) 443-6710 FAX: (301) 594-6847 Email: GF6s@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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