Release Date:  May 15, 1998

RFA:  HL-98-012


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 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.


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).


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.


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.


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.



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

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

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

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.


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.


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.


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
þNIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjectsþ that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:


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


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:; and on the internet at

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.


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:

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.

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.

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.


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.


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.


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

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.


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:

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.


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.


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


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 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

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

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

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


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

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