TREATMENT OF HIV AND ASSOCIATED COMPLICATIONS IN HEMOPHILIACS

Release Date:  April 4, 2000

RFA:  AI-00-011

National Institute of Allergy and Infectious Diseases
http://www.niaid.nih.gov/
National Heart, Lung, and Blood Institute
http://www.nhlbi.nih.gov/
National Institute of Child Health and Human Development
http://www.nichd.nih.gov/

Letter of Intent Receipt Date:  May 26, 2000
Application Receipt Date:       June 27, 2000

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 initiative will provide funding for investigator-initiated 
research focusing on the unique effects of HIV and its complications on 
the hemophilic population. It seeks to support clinical research 
applications to test and improve pathogenesis or therapeutic concepts. 
The need for this solicitation is based upon the outcomes of a workshop 
designed to identify research areas targeting the clinical issues 
unique to the HIV-infected hemophilic population. Research areas 
include: short and long-term outcomes of antiretroviral therapy; 
protective resistance to HIV-infection; non-progression to AIDS; and 
co-infection with Hepatitis C.

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 Request for 
Applications (RFA), Treatment of HIV and Associated Complications in 
Hemophiliacs, is related to Priority Area #18: HIV Infection Potential 
applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit 
organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and 
eligible agencies of the Federal government. Foreign institutions are 
ineligible. Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research 
project grant (R01) award mechanism. Responsibility for the planning, 
direction, and execution of the proposed project will be solely that of 
the applicant. The total project period for an application submitted in 
response to this RFA may not exceed four years. At this time, it is not 
known if this RFA will be reissued. The anticipated award date is March 
1, 2001.

Specific application instructions have been modified to reflect 
"MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined 
by the NIH. Complete and detailed instructions and information on 
Modular Grant applications can be found at 
<http://grants.nih.gov/grants/funding/modular/modular.htm>

FUNDS AVAILABLE

The National Institute of Allergy and Infectious Diseases (NIAID) the 
National Heart, Lung, and Blood Institute (NHLBI), and the National 
Institute of Child Health and Human Development (NICHD) intend to 
commit approximately $3 million in FY 2001 to fund three to twelve new 
grants in response to this RFA. Because the nature and scope of the 
research proposed may vary, it is anticipated that the size of each 
award will also vary. Although the financial plans of the NIAID, NHLBI, 
and NICHD provide support for this solicitation, awards pursuant to 
this RFA are contingent upon the availability of funds and the receipt 
of a sufficient number of applications of outstanding scientific and 
technical merit. At this time, it is not known if this RFA will be 
reissued.

RESEARCH OBJECTIVES

Background
Research on the HIV-infected hemophilic population was initiated more 
than 10 years ago. An RFP issued in FY 1988 resulted in an award to 
establish and maintain a system for recruiting HIV-infected 
hemophiliacs and their partners into AIDS Clinical Trials Group (ACTG) 
studies. This contract was renewed in FY 1993; however during the 
latter years of this contract, as treatments became more widely 
available, enrollment of this special population into ACTG studies 
decreased progressively, making it impractical to renew the contract. 
Although the treatment and management of HIV in hemophiliacs broadly 
follows established standards of care, it has been recognized that HIV 
and its associated complications have unique effects on hemophiliacs 
that requires the joint endeavors of specialists in many disciplines, 
namely infectious disease, hepatology, immunology, hematology, and 
epidemiology. 

The Division of AIDS (DAIDS), NIAID, NIH convened a workshop, 
“Strategies for Treatment of HIV & Associated Complications in the 
Hemophilia Population”, on October 1, 1999 to assess the status of NIH-
funded research relating to the treatment of HIV and associated 
complications in hemophiliacs. Workshop participants defined a number 
of key issues requiring further study that are the basis for the 
objectives of this new RFA. Through this solicitation, research in the 
HIV-infected hemophilic population will now focus specifically on the 
defined scientific needs within this special disease population.

Scope and Objectives

This initiative is intended to encourage innovative approaches to 
address aspects of pathogenesis, treatment, and management of HIV 
infection and its complications that are unique to the HIV-infected 
hemophilic population. This initiative is not intended to support the 
establishment of cohorts of HIV-infected hemophiliacs, but to 
facilitate collaborative research with on-going cohorts. Investigators 
with access to existing cohorts and large repositories of biologic 
samples from the relevant populations and appropriate controls are 
particularly encouraged to apply.  This initiative will support 
research to: 
(1) Delineate short and long-term outcomes of antiretroviral therapy; 
e.g., benefits, and adverse effects of HIV therapy 
(2) Investigate mechanisms defining resistance to HIV infection in HIV-
negative individuals exposed multiple times to potentially contaminated 
blood products 
(3) Investigate mechanisms responsible for delayed or non-progression 
of HIV disease; e.g. genetic, immunologic, and virologic factors 
(4) Evaluate the impact of Hepatitis C Virus (HCV) infection on HIV 
infection, and the impact of HIV infection on HCV infection by 
investigating the relationships between such factors as HCV viral load, 
HCV-induced liver disease, HCV genotype and quasi-species, HCV 
treatment and response to therapy, HCV host and immune factors; and, 
HIV viral load, HIV treatment and response to therapy, HIV disease 
status and progression
(5) Evaluate effects of HIV, HIV therapies, and HIV complications on 
hemostasis

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," that was published in the Federal 
Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for 
Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the 
web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. 

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.

Investigators also may obtain copies of these policies from the program 
staff listed under INQUIRIES. Program staff may also provide additional 
relevant information concerning the policy.

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.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that 
includes a descriptive title of the proposed research, the name, 
address, telephone number, and e-mail address 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 NIAID 
staff to estimate the potential review workload and to avoid conflicts 
of interest in the review.

The letter of intent is to be sent to Dr. Peter Jackson listed under 
INQUIRIES by the Letter of Intent Receipt Date listed in the heading of 
this RFA.

SPECIFIC APPLICATION PROCEDURES FOR MODULAR GRANTS

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. The research grant 
application form PHS 398 (rev. 4/98) is to be used in applying for 
these grants, with the modifications noted below.

Budget Instructions

Modular Grant applications will request direct costs in $25,000 
modules, up to a total direct cost request of $250,000 per year. 
(Applications that request more than $250,000 direct costs in any year 
must follow the traditional PHS 398 application 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:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct 
Costs (in $25,000 increments up to a maximum of $250,000) and Total 
Costs [Modular Total Direct plus Facilities and Administrative (F&A) 
costs] for the initial budget period. Items 8a and 8b should be 
completed indicating the Direct and Total Costs for the entire proposed 
period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form 
Page 4 of the PHS 398. It is not required and will not be accepted with 
the application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the 
categorical budget table on Form Page 5 of the PHS 398. It is not 
required and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget 
Narrative page. (See 
<http://grants.nih.gov/grants/funding/modular/modular.htm> for sample 
pages.) At the top of the page, enter the total direct costs requested 
for each year. This is not a Form page.

o Under Personnel: List key project personnel, including their names, 
percent of effort, and roles on the project. No individual salary 
information should be provided. However, the applicant should use the 
NIH appropriation language salary cap and the NIH policy for graduate 
student compensation in developing the budget request.

o For Consortium/Contractual costs: Provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each rounded 
to the nearest $1,000. List the individuals/organizations with whom 
consortium or contractual arrangements have been made, the percent 
effort of key personnel, and the role on the project. Indicate whether 
the collaborating institution is foreign or domestic. The total cost 
for a consortium/contractual arrangement is included in the overall 
requested modular direct cost amount. Include the Letter of Intent to 
establish a consortium.

Provide an additional narrative budget justification for any variation 
in the number of modules requested.

o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information 
used by reviewers in the assessment of each individual's qualifications 
for a specific role in the proposed project, as well as to evaluate the 
overall qualifications of the research team. A biographical sketch is 
required for all key personnel, following the instructions below. No 
more than three pages may be used for each person. A sample 
biographical sketch may be viewed at: 
<http://grants.nih.gov/grants/funding/modular/modular.htm>
- Complete the educational block at the top of the form page.
- List position(s) and any honors.
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations.

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate 
the type of agreement and the date. All appropriate exclusions must be 
applied in the calculation of the F&A costs for the initial budget 
period and all future budget years.

o 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.

TRADITIONAL PHS 398 APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants. These forms are available at most 
institutional offices of sponsored research and from the Division of 
Extramural Outreach and Information Resources, National Institutes of 
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, 
telephone 301/435-0714, email: GrantsInfo@nih.gov.  In addition, the 
PHS 398 form and instructions can be found on the Internet at 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

The RFA label available in the PHS 398 (rev. 4/98) 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 and number must be typed on line 2 
of the face page of the application form and the YES box must be 
marked.

The sample RFA label is available at the following URL: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note that 
this is in a pdf format.

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 
must be sent to Dr. Peter Jackson listed under INQUIRES.

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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the CSR for completeness 
and by the NIAID for responsiveness. 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 NIAID in accordance with the review 
criteria stated below. As part of the initial merit review, a process 
will be used by the initial review group in which applications receive 
a written critique and undergo an evaluation in which only those 
applications deemed to have the highest scientific merit, generally the 
top half of the applications under review, will be discussed, assigned 
a priority score, and receive a second level review by the Advisory 
Council or Board of one of the co-sponsoring Institutes.

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 the application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals. Each of the criteria listed below will be 
addressed and considered in assigning the overall score, weighting them 
as appropriate for each application. Note that the application does not 
need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score. For example, 
an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

(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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research. Plans for the recruitment and retention of subjects will also 
be evaluated.

o The reasonableness of the proposed budget and duration in relation to 
the proposed research

o The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the 
project(s) proposed in the application

Additional scientific/technical merit criteria specific to the 
objectives of the RFA and the award mechanism must be included if they 
are to be used in the review.

SCHEDULE:
Letter of Intent Receipt Date:    May 26, 2000
Application Receipt Date:         June 27, 2000
Peer Review Date:                 October 15, 2000
Council Review:                   November, 2000
Earliest Anticipated Start Date:  November 27, 2000

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

INQUIRIES

Inquiries concerning this RFA are encouraged. The opportunity to 
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Margaret Matula, R.N., M.G.A.
Division of AIDS
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 5157, MSC 7624
Bethesda, MD 20892-7624
Bethesda, MD 20817 (for express/courier service)
Telephone: (301) 402-2302
FAX: (301) 480-4582
Email: mm154j@nih.gov

Rebecca P. Link, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10178, MSC 7950
Bethesda, MD 20892-7950
Bethesda, MD 20817 (for express/courier service)
Telephone: (301) 435-0070
FAX: (301) 480-1046
Email: linkr@nhlbi.nih.gov

Anne Willoughby, M.D., M.P.H.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Blvd, Suite 4B11J
Rockville, MD  20852
Telephone: (301) 402-0699 
FAX: (301) 496-8678
Email: aw55g@nih.gov

Direct inquires regarding review matters to:

Dr. Peter Jackson
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 2154, MSC 7616
Bethesda, MD 20892-7616
Bethesda, MD 20817 (for express/courier service)
Telephone: (301) 496-8426
FAX: (301) 402-2638
Email: pj8v@nih.gov

Direct inquiries regarding fiscal matters to:

Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 2128, MSC 7614
Bethesda, MD 20892-7614
Bethesda, MD 20817 (for express/courier service)
Telephone: (301) 402-6824
FAX: (301) 480-3780
Email: junsworth@niaid.nih.gov

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health 
Service Act, Sec. 301 (c) and 405 (42 USC 241 and 284).  The Catalogue 
of Federal Domestic Assistance Citations are Sec. 93.856, Microbiology 
and Infectious Diseases Research, and No. 93.855 - Immunology, Allergy, 
and Transplantation Research.  Awards will be administered under PHS 
grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 
74 and 94.  This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems review.

The PHS strongly encourages all grant 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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