Full Text PAR-95-047

NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR THE TREATMENT OF HIV INFECTION (NCDDG-HIV)

NIH GUIDE, Volume 24, Number 14, April 14, 1995

PA-95-047

P.T.


Keywords: 


National Institute of Allergy and Infectious Diseases
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke

Application Receipt Date:  July 1, 1995
Application Receipt Date:  June 1, 1996
Application Receipt Date:  June 1, 1997

PURPOSE

The Division of AIDS (DAIDS), National Institute of Allergy and
Infectious Diseases (NIAID), solicits applications on the discovery,
preclinical efficacy evaluation, and development of novel agents and
strategies that suppress HIV replication, interfere with disease
progression, and ameliorate the consequences of infection.
Responsive applications will involve creative and original research
that emphasizes under- exploited facets of HIV infection.  The
National Institute of Mental Health (NIMH) solicits grant
applications directed toward identifying the mechanisms underlying
the cognitive and behavioral changes associated with HIV infection.
The National Institute of Neurological Disorders and Stroke (NINDS)
solicits grant applications directed toward studies on the
neurological complications of HIV infection.  Both institutes seek
grant applications investigating potential CNS-targeted drug
therapies that prevent or alleviate CNS dysfunction.  Under this PA,
applications in the following areas are not being solicited:  (1)
anti-viral agents and therapeutic strategies currently under intense
investigation, (2) clinical studies, (3) studies of AIDS- related
malignancies, and (4) studies of AIDS-associated opportunistic
pathogens.  Support under this PA will be provided to inter-related
research consortia that include the private sector as one of its
Group components.  Applications funded in response to this PA will
become part of the NCDDG-HIV.

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 program
announcement (PA), National Cooperative Drug Discovery Groups for the
Treatment of HIV Infection (NCDDG-HIV), is related to the priority
area of HIV infection.  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 202-783-3238).

ELIGIBILITY REQUIREMENTS

Research grant applications may be submitted by domestic for-profit
and non-profit organizations, public and private institutions, such
as universities, colleges, hospitals, laboratories, units of State
and local governments, and eligible agencies of the Federal
government.  Foreign organizations are not eligible to apply.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The mechanism of support will be the program project (P01) grant.  In
previous years, the NCDDG-HIV program was supported under cooperative
agreements solicited by Request for Applications (RFAs).  Because of
the continuing need for a drug discovery program and the maturity of
the field, a program announcement for program projects is now being
used.  The program project mechanism supports multi- disciplinary
research programs that have a well-defined research focus or
objective.  The program project grant consists of a minimum of three
interrelated individual research projects that contribute to the
program objective.  An important feature of the program project is
that the interrelationships of the individual scientifically
meritorious projects will result in a greater contribution to the
overall program goals than if each project were pursued individually.
Consortia that include the private sector are of particular interest
because of the unique capability of this sector to rapidly develop
and advance promising therapeutic strategies to clinical studies.
The program project grant can provide support for common resources
termed cores.  Each core should be utilized by two or more projects
within the program project.  Responsibility for the planning,
direction, and execution of the proposed project will be that of the
applicant.  The total project period may not exceed four years.  The
earliest anticipated award date is January 1996.

FUNDS AVAILABLE

In fiscal year 1996, the NIAID plans to fund two to three new or
competing renewal program projects related to this PA.  The NIMH and
NINDS each plan to support up to three additional program projects
that focus on CNS-HIV related issues as described.  This level of
support is dependent upon the receipt of a sufficient number of
applications of high scientific merit and programmatic relevance.
NIH is limiting inflationary increases to no more than four percent
per year.  The current goal is to maintain an NCDDG-HIV program size
of 8 to 12 groups.  Funding in future years will depend on program
size, quality of applications submitted, and availability of funds.
PHS policies governing grants administration and management will
apply.  Awards pursuant to this PA are contingent upon the
availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Notwithstanding intense, multi-national efforts to halt the HIV
epidemic, effective, long-term therapies are lacking, and the number
of HIV-infected individuals and AIDS cases is increasing.  As of June
1994, 401,749 cases of AIDS had been reported in the U.S. by the
Centers for Disease Control (CDC) and more than 243,423 of these
patients had died.  Recent estimates indicate that 1,000,000
individuals in the U.S. are infected with HIV.  The World Health
Organization projection of worldwide HIV infection is placed at 30 to
40 million individuals by the year 2000.

Research advances in recent years have yielded a wealth of
information on HIV molecular biology, the pathogenic aspects of the
infection, and the impact of disease progression on immune
parameters.  Concomitantly, seminal technological breakthroughs have
been realized.  However, development of effective HIV therapies has
not been commensurate with this expansion: almost all antiretroviral
therapies to date target either the viral reverse transcriptase (RT)
or protease.  Other viral genes identified to be critical for HIV
replication remain largely under-exploited as therapeutic targets.
In part, this is attributable to the fact that many single
institutions do not have the critical mass, diverse scientific
talents, and/or ancillary resources to translate basic discoveries to
applied treatment entities.  Research on HIV infection of the brain
and potential CNS-targeted drug therapies are also not sufficiently
addressed.

The NCDDG-HIV program is an integral component of NIAID support of
novel therapeutic opportunities and complements existing NIAID
programs for treatment research in HIV disease.  One of the principal
goals of the NCDDG-HIV program is to fund research for the discovery
of novel therapeutic strategies and their rapid translation to
effective treatments suitable for clinical studies.  This is
accomplished by supporting multi- component research groups -
comprising the academic and commercial sectors - with the needed
scientific talents and development capabilities.  This framework of
multi-component research linked to the private sector will be used
for this PA to fund groups that work in cooperative manner to
discover and develop novel therapeutic modalities for HIV disease.
Scope of Research

The principal objective of this PA is the discovery and preclinical
development of new and effective therapies for HIV disease.  In line
with this objective, this PA will support creative therapeutic
strategies of sound scientific rationale that are not pursued or
extensively studied.  Such therapeutic approaches may have a greater
risk-to-benefit quotient than currently funded research supported
under the individual investigator initiated (R01) mechanism, but may
also have a greater potential for effective, long-term therapeutic
returns.  As stated above, these efforts will be conducted in
collaboration with the private sector, which has the infrastructure
and resources required for the development of antiviral leads and
strategies.  Moreover, the private sector has the capabilities to
mobilize additional resources rapidly as needed.

Examples of responsive studies to be supported by this PA include,
but are not limited to:

o  targeting new and/or under-explored viral functions;
o  interfering with viral functions required for replication (e.g.
Nef, VPU, VPR, Vif) and cellular   factors associated with their
activity;
o  targeting cellular factors required for HIV function (e.g. NFkB;
IkB) and effectors that modulate viral   activity;
o  interfering with HIV/cell interaction (entry, subcellular
transport, assembly, release);
o  creative strategies unlikely to be affected by emergence of escape
mutants or drug resistant variants;                strategies that
target non-T cell compartments (e.g. dendritic cells, follicular
dendritic cells,                     monocyte/macrophage, epithelial)
involved in pathogenesis and virus dissemination;
o  cell and tissue based approaches to modulate organ damage;
o  mediators, factors, and neural receptors involved in
HIV-penetration of the blood brain barrier and the   resulting neural
injury or neurological complications (unique to either pediatric or
adult patients).

Studies involving anti-viral agents (such as nucleoside analogue
inhibitors of reverse transcriptase) and therapeutic strategies
currently under intense investigation in the private or academic
sector are excluded.

A program project application as a whole, which must consist of three
or more projects and include the private sector, must address the
development of a specific strategy in a cohesive, concerted manner.
Thus, responsive applications would be those in which each project
provides information necessary to determine the utility of the single
intervention strategy chosen as the overall program objective and/or
develop the strategy.  Each application must provide an experimental
plan that details methods to evaluate the usefulness of the
therapeutic approach, and must include a schedule or time table to be
followed.  Examples of confirmatory evaluation include:  inhibition
of infection or documented correlates of pathology in in vitro or in
vivo model systems; design and validation of novel and predictive
models amenable to efficacy testing; design and validation of assay
systems amenable to large scale testing by the private sector
component (excluding random screening, see below).

Consortium arrangements should follow the NIH Guide outline in
"Guidelines for Establishing and Operating Consortium Grants, January
1989."   These are available from the individuals listed under
INQUIRIES.

SPECIAL REQUIREMENTS

Patent Coverage

Because the implementation of innovative, effective clinical
therapies for HIV/AIDS is the principal goal of this PA and active
involvement by the private sector is facilitated by the existence of
adequate patent coverage, it is essential that applicants provide
plans to ensure such coverage.  Since several institutions may be
involved, complex patent situations may arise.  Each applicant Group
must therefore provide a detailed description of (1) the approach to
be used for obtaining patent coverage and for licensing where
appropriate, in particular where the invention may involve
investigators from more than one institution; and (2) the procedures
to be followed for the resolution of legal problems that potentially
may develop.  Attention is drawn to the reporting requirements of 35
U.S.C. Parts 200-212 and 37 CFR Part 401 or FAR 55.227-11.
Instructions were also published in the NIH GUIDE FOR GRANTS AND
CONTRACTS, Vol. 19, No. 23, June 22, 1990.  Note that non-profit
organizations (including universities) and small business firms
retain the rights to any patent resulting from Government contracts,
grants or Cooperative Agreements.

It is also noted that a Presidential memorandum of February 18, 1983
extended to all business concerns, regardless of size, the first
option to the ownership of rights to inventions as provided in P.L.
96-517.  As a result of this memorandum, the relationships among
industrial organizations and other participants are simplified, since
all Group members can now be full partners in the research and in any
inventions resulting therefrom.  The specific patenting arrangements
among the institutions may vary, and could include joint patent
ownership, exclusive licensing arrangements, etc.  Applicants are
encouraged to develop an arrangement that is most suitable for their
own particular circumstances.

The patent agreement among the institutions comprising the Group,
signed and dated by the organizational officials authorized to enter
into patent arrangements for each Group member and member
institution, must be submitted with the application.  If the Group
wishes to place all inventions and discoveries resulting from these
studies within the public domain, a letter to that effect must be
submitted to Dr. Sarver in lieu of the patent agreement two weeks
prior to submission of the application.  The letter must be co-signed
by the Principal Investigator, each of the Project Leaders, and each
of the business officials representing the respective institutions.

Federal regulation clause 37 CFR 401 and HHS Inventions regulations
at 45 CFR Parts 6 and 8 require that NIH be informed of inventions
and licensing occurring under NIH funded research.  Invention and
licensing reports must be submitted to Extramural Invention Reports
Office, Office of Extramural Research, NIH, Building 31, Room 5B41,
9000 Rockville Pike, Bethesda, MD 20892.

The application should budget appropriate funds to allow key
personnel to attend the annual meeting of the NCDDG-HIV, which is
generally held in Bethesda.

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 sub-populations 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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.

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 printed in
the NIH Guide for 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.

APPLICATION PROCEDURES

Potential applicants are strongly encouraged to discuss their
research concept with Dr. Nava Sarver (INQUIRIES below) before
preparing applications.  Applicants with a research focus on
neurological complications of HIV infection affecting cognitive
and/or motor function should discuss their proposed studies with Dr.
Dianne Rausch, and applicants with a research focus on the
neurological effects of HIV infection on the brain should discuss
their proposed studies with Dr. A. P. Kerza-Kwiatecki before
submitting an application (see INQUIRIES below).  Applications are to
be submitted on form PHS 398 (rev. 9/91), the standard application
form for research grants.  Application kits are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grants Information, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone 301/435-0714.  Applicants must adhere to the
format and requirements specified in the PHS 398 application kit.  In
addition, applicants are strongly advised to read the information
brochure "NIAID Program Project Grants and Multi-project Cooperative
Agreements", available from Dr. Nava Sarver at the address listed
under INQUIRIES.

For purposes of identification and processing, mark "YES" in item 2a
on the face page of the application and type in the PA number
PA-95-047 and the title "NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS
FOR THE TREATMENT OF HIV INFECTION (NCDDG- HIV)."  The signed,
typewritten original of the application, including the Checklist and
five exact single-sided copies must be sent to:

DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE  ROOM 1040  MSC 7710
BETHESDA  MD  20892-7710

BETHESDA  MD  20817 (for courier service)

The entire address should appear in UPPER CASE letters without
punctuation to allow optical scanners to read and sort mail.

Concurrent submission of an R01 and a Component Project of a
Multi-project Application

Current NIH policy permits a component research project of a
multi-project grant application to be concurrently submitted as a
traditional individual research project (R01) application.  If,
following review, both the multi-project application and the R01
application are found to be in the fundable range, the investigator
must relinquish the R0l and will not have the option to withdraw from
the multi-project grant.  This is an NIH policy intended to preserve
the scientific integrity of a multi-project grant, which may be
seriously compromised if a strong component project(s) is removed
from the program.  Investigators wishing to participate in a
multi-project grant must be aware of this policy before making a
commitment to the Principal Investigator and awarding institution.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG.
Incomplete applications will be returned to the applicant without
further consideration.  Applications will be assigned on the basis of
established PHS referral guidelines.  Applications will be evaluated
for scientific and technical merit by an appropriate peer review
group convened in accordance with the standard NIH peer review
procedures.  As part of the initial merit review, all applications
will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council or board.
Applications determined to be non- competitive will be withdrawn from
further considerations and the principal investigator and the
official signing for the applicant organization will be promptly
notified.

Review Criteria

Scientific Considerations

The review criteria for P01 grant applications are the same as for
large, multi-component, interdisciplinary program projects described
in NIAID brochure "NIAID Program Project Grants and Multi-project
Cooperative Agreements."  The program project grant application
should include a justification for using the P01 granting mechanism
for the proposed project.  In addition, the application must be
directed toward (1) attaining the programmatic goals as stated under
Research Objectives and Scope; and (2) as listed under AWARD
CRITERIA, below.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, the availability of
funds, and program balance, including relevance to the control of
public health problems.  In addition, for awards assigned to the
NIAID, the following considerations will be included in the award
criteria:

o  the novelty and appropriateness of the proposed research to the
discovery of new entities and/or strategies for   the treatment of
HIV infection;
o  the likelihood that a therapeutic strategy will be developed that
is suitable for clinical evaluation;
o  commitment of the PI and PLs to the program: a minimum of 20 per
cent effort by the PI and each PL is deemed   necessary for this
effort;
o  For competitive renewal by currently funded groups:  evidence of
past accomplishment under the NCDDG-HIV   program that fulfills the
programmatic goals (e.g. design, formulation, or development
therapeutic   strategies/agents for the treatment of HIV infection).

INQUIRIES

Written and telephone inquiries concerning this PA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.  Requests for the brochure "NIAID Program
Project Grants and Multi-project Cooperative Agreements," as well as
inquiries regarding programmatic issues may be directed to:

Nava Sarver, Ph.D.
Division of AIDS, NIAID
Solar Building, Room 2C01
6003 Executive Boulevard
Bethesda, MD  20892
(301) 496-8197
FAX:  (301) 402-3211
Email:  ns18p@nih.gov

For NIMH programmatic issues:

Dianne Rausch, Ph.D.
Office on AIDS
NIMH
Parklawn Building, Room 10-75
5600 Fishers lane
Rockville, MD 20857
(301) 443-6100
FAX:  (301) 443-9719
Email:  drausch@aoamh2.ssw.dhhs.gov

For NINDS programmatic issues:

Dr. A. P. Kerza-Kwiatecki
Division of Demyelinating, Atrophic, and Dementing Disorders, NINDS
Federal Building, Room 804
7550 Wisconsin Ave.
Bethesda, MD 20892
(301) 496-1431
FAX: (301) 402-2060
Email: ak64n@nih.gov

Direct inquiries regarding fiscal matters to:
Carol Alderson
Division of Extramural Activities, NIAID
Solar Building, Room 4C26
6003 Executive Boulevard
Bethesda, MD  20892
(301) 496-5937
FAX:  (301) 402-2638
Email:  carol_alderson@nih.gov

SCHEDULE

Application Receipt Date:     July 1, 1995
Scientific Review Date:       October/November 1995
Earliest Date of Award:       January 1996

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.856 - Microbiology and Infectious Diseases
Research.  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 work place 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 routing
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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