Full Text AI-92-16

NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR THE TREATMENT OF HUMAN
IMMUNODEFICIENCY VIRUS INFECTION

NIH GUIDE, Volume 21, Number 38, October 23, 1992

RFA:  AI-92-16

P.T. 34

Keywords: 
  AIDS 
  Drug Design 
  Pharmaceuticals 
  Pharmacology 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January 15, 1993
Application Receipt Date:  March 17, 1993

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID)
invites applications for the establishment of National Cooperative
Drug Discovery Groups for the Treatment of Human Immunodeficiency
Virus Infection (NCDDG-HIV).  The NIAID announces availability of an
RFA for funding of the National Cooperative Drug Discovery Groups for
the Treatment of HIV Infection (NCDDG-HIV).  The prime objective of
this RFA is to support innovative research of sound scientific
rationale, which requires intra-Group interactions and that is likely
to result in the discovery of more effective therapeutic strategies
against HIV.  This RFA will support original and/or under-exploited
studies that are at the cutting edge of biomedical research.  Such
studies may have a greater risk-to-benefit quotient than is currently
considered under the more traditional investigator initiated (R01)
mechanism, but may also have a greater potential for effective,
long-term therapeutic returns.  Applications that include research
projects or core components from the private sector (e.g.,
pharmaceutical, chemical, or biotechnological companies) are strongly
encouraged.

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 RFA,
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 "Healthy People
2000" (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

Applications may be submitted by domestic and foreign for-profit and
non-profit organization, private and public, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

Awards will be made as Cooperative Agreements (U01s).  The NIAID, in
awarding a Cooperative Agreement, anticipates substantial
programmatic staff involvement during performance of the award.  The
nature of NIAID staff participation is described in SPECIAL
REQUIREMENTS - Terms of Award.  There is no intent, real or implied,
for NIAID to direct Group activities or to limit the freedom of
investigators.  It is the Principal Investigator who defines his/her
objectives in accord with his/her interests and perceptions of novel,
promising strategies for the treatment of HIV infection.

The applicant institution and the Principal Investigator will be
responsible for the Group's application.  Awards will be made to the
applicant institution on behalf of the group as a whole and not to
individual research projects within the Group.  The applicant
institution will provide a Central Operations Office for the Group,
will be responsible for the performance of the entire Group, and will
be accountable for the funds awarded.  The participation of the
Government through the NIAID extramural staff is intended to
facilitate a concerted effort by members of the Group by (1)
providing appropriate scientific input; (2) making available
biological materials for testing; (3) accessing appropriate data
bases; and (4) providing ancillary testing and other resources
available under existing contracts.  The interaction of academic,
non-profit research institutions, commercial (including industrial)
organizations, and Government under this Cooperative Agreement is
expected to promote and expedite discoveries of new entities and
strategies for the treatment of HIV infections and facilitate their
subsequent development to clinical trial.

Under the Cooperative Agreement, a partner relationship between the
recipient of the award and NIAID exists in which the Group is
responsive to the requirements and conditions set forth in this RFA.
Specifically, the Principal Investigator defines the details for the
project within the guidelines of the RFA, retains primary
responsibility for the performance of the scientific activity, and
agrees to accept close assistance in coordination, cooperation, and
participation of NIAID staff in all aspects of scientific and
technical management of the project in accordance with the terms
formally and mutually agreed upon prior to the award.  It is
presently envisioned that the NIAID will be actively engaged in
assisting the awardee in the coordination of scientific-programmatic
components consisting of:

o  Cooperative participation in data analysis and reporting.

o  Prior approval of changes of key personnel including the Principal
Investigator or Project Leaders

o  Retention of the option to withhold support if the Principal
Investigator or a Project Leader withdraws from the Group and a
suitable replacement of key personnel is not obtained.

All policies and requirements that govern the grant program of the
U.S. Public Health Service and the National Institutes of Health
(NIH) apply.

FUNDS AVAILABLE

The NIAID has set aside $3.0 million for the initial year's funding
of this RFA.  The amount spent is dependent on the continuing
availability of funds for this purpose and the quality and diversity
of approved applications.  Funding of three to four awards is
anticipated.  New awards are subject to a first year limit of
$800,000 in total costs (direct plus indirect costs), unless a
written request for waiver is submitted, and a written approval of
the request is obtained from the NIAID prior to submission of the
application.  The Principal Investigator is urged to contact Dr. Nava
Sarver (301-496-8197) prior to submitting a written request for
waiver to discuss the extenuating circumstances or needs that may
justify waiving the $800,000 total budget limit.  Applications in
excess of $800,000 total (direct and indirect) costs, and without a
written waiver from the NIAID, will be returned without review.
Funding in subsequent years will be at a level no greater than year
one plus four percent.  Funding duration will be four years for
competitive renewals and three years for new awards.  The anticipated
starting dates for the initial annual period are December 1993.

When the applicant institution is outside the United States, awards
will be limited to three years.  When the applicant institution is
within the United States and the application contains laboratory
projects in a foreign country, the request for funding may be up to
four years.

Previously funded NCDDG-HIVs may compete for renewal or for
supplemental support under this RFA.  The NIAID plans to continue its
support of the National Cooperative Drug Discovery Group program
through RFA-initiated new awards and competitive renewals.
Reissuance of this initiative in future years is anticipated but not
certain.

RESEARCH OBJECTIVES

Research Goals and Objectives of the NCDDG-HIV Program

The goals of the NCDDG-HIV program are:

o  The conceptualization, discovery and preclinical development of
drugs and strategies designed to effectively treat individuals
infected with HIV.

o  The recommendation of therapies, entities or strategies for
development to clinical trial.

o  The conduct of biological, biochemical, and pharmacological
studies that will permit design of predictive clinical evaluation
supported by sophisticated technology, and which may provide
information leading to the future discovery of more effective
treatments.

Applications for an NCDDG-HIV should stress creative approaches to
the discovery of effective anti-HIV therapies and should emphasize
the following:

o  Specific objectives of the proposed NCDDG-HIV.

o  Research approaches to the realization of objectives and the
provision of comprehensive information (including citations) in
support of the rationale(s) for the proposed approaches.

o  The scientific and technical areas of expertise (Principal
Investigators and Project Leaders) required to attain Group
objectives and the leadership ability of the Principal Investigator.

The Group's objectives and goals should be relevant and compatible
with NIAID Program's missions and directions as stated in this RFA.

Background and Summary

Acquired Immune Deficiency Syndrome (AIDS) is a disease that destroys
the body's capacity to overcome a variety of infections.  As of June
30, 1992, 230,179 cases of AIDS had been reported in the United
States by the Centers for Disease Control (CDC) and more than 152,153
of these patients (66.1 percent) had died.  Recent projections
indicate that between 1,000,000 to 1,200,000 persons in the United
States may already be infected with HIV, the infectious virus
associated with AIDS.  Three drugs, zidovudine (AZT, 3'-
azidothymidine), dideoxyinosine (ddI), and dideoxycytidine (ddC) are
currently licensed for the treatment of HIV-1 infection.   Of these,
ddC has only recently been conditionally approved by the FDA for
combination treatment with AZT.  All three drugs are nucleoside
analogues and all interfere with HIV reverse transcriptase (RT)
functions.  A serious shortcoming with these nucleoside analogues,
however, are toxic side effects which preclude their use, or require
discontinuation of treatment in certain patients. Another serious
deficiency with these inhibitors is the emergence of HIV drug
resistant variants, generally within six to twelve months of
treatment.  Rapid emergence of HIV drug resistant variants also
occurs with most non-nucleoside RT (NNRT) inhibitors (see below), at
times as early as four weeks after initiation of treatment.  Defined
sequence mutations associated with resistance to AZT, ddI, ddC, other
nucleoside analogues, or NNRT inhibitors have now been mapped to the
RT coding region.  Given the precedence of resistance to both
nucleoside analogue and NNRT inhibitors in clinical isolates, it is
expected that resistance to inhibitors directed against other viral
targets is likely to occur.  Indeed, at the recent VIII International
Conference on AIDS (July 19-24, Amsterdam, The Netherlands),
resistance (6-8 fold) to two protease inhibitors was shown to develop
in vitro.  The search for improved and diverse therapies to treat
HIV-1 infection and AIDS is thus among the highest priorities of the
Department of Health and Human Services.

The NIAID and the PHS Centers for Disease Control are currently
supporting comprehensive extramural and intramural projects for (1)
the study of the etiology, natural history, and demographics of AIDS;
(2) determining means of diminishing the risk of infection; (3)
screening of high risk individuals;  (4) developing prophylactic
vaccines; (5) developing of therapies to treat those with
AIDS-related complex developing (ARC); and (6) developing of
therapies that may be useful chemopreventive or prophylactic agents.
Notwithstanding these efforts, the rapidity of the increase in
diagnosed cases of AIDS and the morbidity of the disease require
mobilization of the most creative scientific talents, regardless of
their scientific discipline or organizational affiliations, into
groups whose objective is to pursue aggressively a concerted research
effort to discover entities and strategies for treating this disease.

The NIAID realized that many single institutions may not have either
the critical mass or all the talents and ancillary resources needed
to translate discoveries of potential therapeutics from basic studies
into new entities and strategies for HIV/AIDS treatment.  A
cooperative arrangement that permits close interactions of the
highest quality research experts from diverse institutions with the
facilitating resources of the NIAID was, therefore, established.
Units in which these research talents and resources are combined are
referred to as "National Cooperative Drug Discovery Groups" (NCDDG).
NCDDG-HIVs are envisioned as having the capacity to generate new
approaches and strategies for the treatment of HIV infection and to
rapidly translate their concepts into anticipated effective
treatments.  Results from the research proposed under this RFA should
be used to identify and develop information for long-term planning of
potential therapeutic approaches or to recommend new potential
treatments worthy of further consideration in a clinical trial
setting.

The recognition of HIV as the etiological agent associated with AIDS,
the isolation and characterization of the virus, the ability to grow
HIV on a large scale, and the amassed knowledge of the molecular
biology of HIV have made it possible to screen for potentially
effective antiviral compounds, and to target specific antivirals to
unique steps in HIV infectious cycle.  The possibility of discovering
an effective treatment for HIV infection based on compounds targeted
against selected steps in the viral replication cycle has been
demonstrate in vitro with several analogues of natural substrates
(3'-azidothymidine, dideoxyinosine, dideoxycytidine), or
non-nucleoside allosteric compounds (e.g., nevirapine) as reverse
transcriptase inhibitors; peptide isosteres (e.g., A77003, A80987,
other C2 symmetric analogues) as HIV-1 protease inhibitors; a
benzodiazipine (Ro24-7429) as a Tat inhibitor; and fatty acid
analogues as inhibitors of N-myristoyltransferase and thus of HIV
assembly.  Most of the effort to date has been made with nucleoside
analogues designed to interfere with HIV-1 reverse transcriptase.
Considerable effort has also been directed toward development of
soluble CD4 and its congeners to block attachment of HIV to
uninfected cells, or CD4-toxin conjugates to kill cells expressing
HIV gp120 on their surface.  Despite the encouraging data with sCD4
obtained in cell culture studies, results from clinical trials to
date have been disappointing.

X-ray crystallography studies have yielded the structure of HIV-1
encoded enzymes (protease and RNaseH), both critical in the viral
life cycle.  In the case of HIV protease, the crystal structure has
already proven valuable in the design of potent inhibitors of HIV
replication.  Several groups are also working toward establishing the
crystal structures of reverse transcriptase and of HIV capsid protein
(p24), and the crystal structure at 3.5 Angstrom resolution of RT
complexed with nevirapine has recently been reported (LA Kohlstaedt
et. al., Science 256:1783, 1992).  But protease, RNaseH, and RT
represent only three of the more than 15 HIV processed proteins
identified to date, and additional structural work for other
structural and regulatory proteins is imperative for structure-driven
computational drug design.

Current efforts to block other viral specific targets, or the use of
substrate analogues to interfere with a cellular pathway obligatory
for virus maturation (e.g., myristoylation) are insufficient.  In
part, this is due to the fact that the function(s) and role(s) of
each HIV encoded protein in the infectious cycle, and their effect -
direct or indirect - on host immune system, are yet to be charted.
The involvement of cellular factors and biochemical processes in the
induction of HIV gene from a non-replicative state, or the
enhancement of HIV gene expression, must be addressed.  Conversely,
HIV-induced impairment(s) in cellular biochemical pathways need be
explored as another approach to counteract the consequences of
infection.   Complicating many of the proposed antiviral modalities
to date is the emergence of drug resistant HIV strains which imposes
a constant and relentless demand for alternative and combination
therapies.

As of August 1, 1992, 18 Groups will be funded under the NCDDG-HIV
program.  Eight of these Groups are eligible for competitive renewals
in 1993 in response to this RFA.  Current research pursuits within
the NCDDG-HIV program include:

Chemistry, delineation of HIV functions, and inhibition assays:

o  Synthesis, inhibition, and functional studies of RT
o  Pharmacology of nucleoside analogues and non-nucleoside RT
inhibitors
o  Structure-function studies of RNaseH
o  Design and synthesis of HIV protease inhibitors
o  Assays and inhibitors of Tat activity
o  Inhibitors of N-myristoyltransferase for blocking HIV assembly
o  Interference with RNA/Gag interaction
o  Integration process and assays for integrase inhibitors
o  Ribosomal frame shifting and potential interference
o  Natural products from plant and marine sources, metabolism,
pharmacology and toxicology

Regulation, intracellular suppression, and gene delivery:

o  Tat and Rev and their cognate cis-acting elements, TAR and RRE

o  Cellular transcription factors associated with HIV-LTR

o  Dominant repressors of viral functions (Tat, Rev, Gag, integrase)

o  Catalytic RNA (ribozyme)-mediated inhibition of HIV gene
expression

o  Mouse, mouse/human chimera, and simian models for gene therapy in
HIV/AIDS

o  Retroviral mediated transduction of antiviral genes into
hematopoietic CD34 progenitor cells and pluripotent stem cells

Structure-based drug design:

o  Structure-based drug design of HIV protease, RNaseH, Rev, p24/FAb
complex and gp120/CD4 complex
o  Non-peptide blockers of HIV binding to CD4
o  RNA specific organic repressors

Immunology, immune therapy, and animal models of AIDS:

o  CTL and monoclonal antibodies as potential therapeutics in HIV
infection
o  Universal CTLs for adoptive immunotherapy
o  CD4/gp120 interaction and mapping of functional gp120 and CD4
domains
o  Dendritic cells and their contribution to HIV spread
o  HIV interaction with neural cells
o  Molecular mechanisms of drug resistance, cross resistance, and
correlation with HIV sequence variation
o  FIV as a potential model of AIDS, and for evaluation antiviral
therapies
o  SIV/rhesus model for evaluating post exposure chemoprophylaxis,
and single/multiple agent therapies

The NCDDG-HIV program provides assistance to talented scientists to
interact as a unit to carry out the preclinical research essential
for the realization of project objectives.  An NCDDG-HIV could be
composed of scientists from any combination of academic, non-profit
research, and commercial organizations.

Scientific Scope, Restrictions and Exclusion

The prime objective of this RFA is to stimulate original and
innovative research of sound scientific rationale that requires
intra-Group interactions and is likely to result in the discovery of
new agents and modalities effective against HIV.  In line with this
objective, the NCDDG-HIV program supports projects for innovative and
under-exploited studies that are at the cutting edge of biomedical
research.  Such studies may have a greater risk-to-benefit quotient
than is currently considered under the more traditional investigator
initiated (R01) mechanism, but may also have a greater potential for
effective, long-term therapeutic returns.  In addition to the
scientific criteria, these efforts are to be implemented through a
collaborative, concerted effort by components of the Group.
Applications where collaborations among components of the Group are
not required for the success of Group activities will not be funded
under the NCDDG mechanism.  In these instances, investigators are
encouraged to submit independent R01 (or equivalent) grant
applications.

Applications that include a research project(s) or a core
component(s) from the private sector (e.g., pharmaceutical, chemical,
or biotechnological companies) are strongly encouraged.  The private
sector generally has the infrastructure to continue development of a
promising antiviral lead and can mobilize additional resources
rapidly as needed.  Research directed toward drug discovery in the
following major areas will be considered responsive to this RFA:

o  Discovery, elucidation and application of modalities that inhibit
HIV gene expression via interference with HIV regulatory elements.

o  Inhibition of critical steps in HIV replication via intracellular
delivery and expression of antagonists using viral vectors or other
delivery strategies (gene therapy).

o  Intervention with cellular biochemical pathways required for
induction of HIV from a 'latent' or non-replicative state and/or for
enhancement of HIV replication.

o  Structure-based drug design encompassing novel chemistry,
synthesis and development of stable, small molecules that block HIV
infection or impair virus replication.

o  Innovative exploitation of the humoral and cellular arms of the
immune system for a targeted anti-HIV affront and immune system
reconstitution.

o  Studies of non-T cells compartment(s) that may serve in the
initial infection by HIV, and which may play an essential role in
free virus transport, cell-cell transmission, and general
dissemination of HIV in the body.

o  New and sound conceptual strategies which are not or minimally
pursued for the discovery of new entities (or combinations) with
potential for the treatment of HIV infection.  Examples include
triplex-forming oligonucleotides, agents which disrupt virus
structure, newly identified enzymatic activities as targets,
catalytic RNAs, transdominant suppressors, gene therapy for the
treatment of HIV, new inroads into deciphering and treating
HIV-induced immune dysfunction(s), and others.

Examples of proposed research in these major areas are:
structure-function of HIV encoded target proteins; early events in
viral replication suitable for drug targeting; biochemical pathways
and host interactions critical to virus replication and/or drug
action; drug metabolism; innovative drug delivery strategies;
emergence of resistance to drugs targeted to specific HIV enzymatic,
structural or regulatory function; and innovative ways to control,
counteract and/or prevent drug resistance.

Projects or cores with proposed animal model development and/or
efficacy testing in animal models must be integrated into and
required to attain the Group's objectives.  Animal model component(s)
may be requested by the NIAID to evaluate in vivo compounds other
than those generated by the Group.  Funds awarded for the evaluation
of new agents in animal models will be withheld until compounds
generated by the Group or provided by the NIAID are available for
animal efficacy studies.  Due to budgetary limitations, primate
animal models should not be requested in the original application.
Should the need for such models become evident during the course of
studies under this cooperative agreement, the Principal Investigator
may submit a competitive supplement request for the support of
primate animal models.  Funding of competitive supplement will be
from set aside funds allocated to future RFAs for this initiative,
and is not guaranteed.  Consideration for funding will also depend on
the competitive merit and justification of the competitive supplement
relative to all other competing applications submitted in response to
the RFA.  Projects utilizing non-random cell-based assays for
screening natural products, biologics and/or synthetic compounds must
not exceed 25 percent of the total level of effort of the Group.

The following research areas currently under intense investigation or
that have already been included in other NIH initiatives are
specifically excluded from this RFA:  (1) synthesis or development of
analogues or prodrugs of known anti-HIV nucleosides and
non-nucleoside inhibitors of RT; (2) reverse transcriptase screens;
(3) evaluation of recombinant human cytokines; (4) development of
exogenous, soluble CD4 or its conjugated peptidyl congeners; (5)
anti-protease screens and peptide-based protease inhibitors; (6)
mechanism of action studies unlinked to inhibitor identification;
(7) large scale random screening of compounds with potential activity
against HIV in cell culture-based systems; such a program is operated
by the National Cancer Institute (see below); (8) research on
opportunistic infections associated with AIDS.  A separate Request
for Applications (RFA) for the National Cooperative Drug Discovery
Groups for the Treatment of Opportunistic Infections Associated with
AIDS (NCDDG-OI) is re-issued in 1992 for the fourth consecutive year.
Scientists whose research does not lie within the areas defined as
responsive to this RFA are encouraged to apply for investigator-
initiated (R01) grants.

To permit rapid and thorough analysis of agents developed by the
NCDDG-HIV, applicants are strongly encouraged, but not required, to
include in their application a core for testing such agents in
screening systems.  When and where appropriate, cooperation among
funded Groups or with the National Cancer Institute may be arranged
through the Scientific Coordinator (see Terms of Award: Awardee
Rights and Responsibilities:  Nature of Participation of NIAID
Staff), these cooperations would serve to broaden the base of
screening efforts beyond those used by the NCDDG-HIV or to confirm
the biological findings of the NCDDG-HIV.

While it is recognized that testing of drugs against HIV in a
cell-based assay is an essential element in evaluating potential
anti-HIV agents, a random screening program is beyond the scope of
this RFA and will not be supported under this RFA.  A random
screening program is operated by the National Cancer Institute.  For
information contact:

Dr. Robert Schultz
Drug Synthesis and Chemistry Branch
National Cancer Institute
Executive Plaza North, Room 831
Bethesda, MD  20892
Telephone:  (301) 496-8795

Studies required for the IND-directed preclinical development
(formulation, toxicology) of identified potential treatments are
beyond the scope of this RFA, but development through private venture
capital is encouraged.  Alternatively, an NCDDG-HIV may request that
the NIH assist in these developmental tasks using contracts now in
place.  The NIH has a contract program for the preclinical
development of compounds for the treatment of HIV/AIDS.  The NIAID
has contracts for the evaluation of relevant therapies in appropriate
animal models.  In addition, the NIAID has awarded AIDS Clinical
Treatment Units (ACTUs) for Phase I, Phase II and Phase III clinical
trials at different geographical sites.  It is envisioned that these
ACTU cooperative agreements will be available for clinical studies of
treatments discovered under this initiative, upon the recommendation
of the NCDDG-HIV and concurrence of the AIDS Clinical Drug
Development Committee, ACTU investigators and the Division of AIDS.

DEFINITIONS

ADMINISTRATION CORE - An administrative facility that provides
support for the management of the grant and services shared by the
Group as a whole.  The Administrative Core will have in its budget
travel costs for (i) one required Group meeting; (ii) NCDDG-HIV
program meetings; (iii) travel expenses for the Scientific Advisor
Panel (see below).  The Administrative Core will be responsible for
allocating required travel expenses to appropriate members of the
Group.  These travel expenses will be restricted to travel listed
above. (For additional details of required travel see Special
Requirements - Terms of Award, PART A.1,2,3).

ARBITRATION PANEL - A group composed of one Group designee, one NIAID
designee not from the Developmental Therapeutics Branch, and a third
designee with expertise in the relevant research area and chosen by
the other two.  The interaction of this panel is detailed in Terms of
Award.

COOPERATIVE AGREEMENT - An assistance mechanism in which substantial
NIAID programmatic involvement is anticipated with the recipient
organization during the performance of the planned activity.

CORE COMPONENT - Laboratory facilities for equipment and services
which are shared by two or more projects of the NCDDG-HIV.  Examples
of core components are:  screening studies, biochemical assays,
cell-based assays, animal model evaluation, toxicology studies,
pharmacology studies, scale- up synthesis of drugs (10 grams or
less).  The core can be defined as any project with established
techniques and assays which performs a service function resulting in
an economy of effort and savings in the overall costs of the NCDDG.
The core unit must be described with the same detail as the research
projects to enable evaluation of its scientific merit.

DISCOVERY - The term 'discovery' is used explicitly to limit
activities of the NCDDG-HIV to preclinical identification, design and
development of new entities.  The NIAID encourages the investigator
to determine if the drug or biologic proposed can be used in the
treatment of HIV-infected individuals.

INVENTION - A new drug or innovative treatment that is or may be
patentable under Title 35 of the United States Code.

NATIONAL COOPERATIVE DRUG DISCOVERY GROUP for the Treatment of HIV
Infection (NCDDG-HIV) - In this RFA the terms National Cooperative
Drug Discovery Group, NCDDG-HIV, and "Group" are synonymous.  A Group
comprises a number of laboratory research projects representing
diverse scientific disciplines and organizations which join together
under a single Principal Investigator and which function as a unit
with a common goal, namely the conceptualization, invention, and
evaluation of new entities and strategies for the treatment of HIV
infection.  All applications must consist of at least two independent
projects conducted by at least two independent laboratories.  More
than one Project Leader may be enlisted from a single institution but
at least two Projects Leaders must be from independent laboratories.
For the purpose of this RFA, two (or more) projects within a single
company or academic department will not be considered independent.  A
CORE COMPONENT can not be used toward fulfillment of the two research
projects requirement.

NEW DRUG - In the context of the NCDDG-HIV program, the term "drug"
is used broadly to encompass new synthetic agents, natural and
biological products, or novel therapeutic strategies designed to
effectively treat HIV infection.

NIAID NCDDG-HIV PROGRAM DIRECTOR - A Senior Scientist of the NIAID
extramural staff who coordinates NIAID's participation in the
NCDDG-HIV program.  This responsibility includes (1) overseeing the
entire NCDDG-HIV program; (2) assuring that Groups' objectives are
consistent with the Division of AIDS preclinical program and NIAID
mission and goals; (3) assigning Scientific Coordinators to
appropriate Groups based on scientific expertise and compatibility
with the Group research interests; (4) assuring overall scientific
balance among Groups in the NCDDG-HIV program; (5) networking and
facilitating collaboration among Groups and industry to expedite
development of promising anti-HIV agents; (6) keeping the NCDDG-HIV
program current with regard to scientific developments and
breakthroughs; and (7) identifying research gaps not adequately
pursued.

NIAID SCIENTIFIC COORDINATOR - A Senior or Associate Scientist of
NIAID extramural staff who functions as a peer with the Principal
Investigator and Project Leaders and facilitates the partnership
relationship between NIAID and the Group.  The Scientific
Coordinator, based on his/hers scientific expertise, interests and
compatibility with the Group's areas of research, is assigned to the
Group by the NCDDG-HIV program director, and is the immediate contact
person for the Group.

PRINCIPAL INVESTIGATOR - The person who assembles the NCDDG-HIV,
assembles a single application with the information provided by the
Project Leaders and submits the application in response to this RFA,
and who is responsible for the performance of the Group as a whole
and each of the Project Leaders.  The Principal Investigator is
strongly encouraged to lead one of the research projects of the Group
and is expected to coordinate Group activities scientifically and
administratively.  The Principal Investigator's (awardee) institution
establishes and operates the Central Operations Office that funds
Group members and is legally and fiscally accountable for the
disposition of funds awarded.

PROJECT LEADER - The leader of one of the scientific research
projects of the NCDDG-HIV.

SCIENTIFIC ADVISORS PANEL - A panel, comprised of two to three peers
from the scientific community, whose mission is to provide the
Principal Investigator with a comprehensive review of the Group's
activities and progress, consult on future goals and strategies, and
recommend alternative directions, as appropriate.   Selection and
appointment of the Panel is the responsibility of the Principal
Investigator.  The Scientific Coordinator will participate in all
meetings of the Panel, which may be combined with Group meetings.
Members of the Panel will not be affiliated with any of the
institutions comprising the Group.  A Scientific Advisors Panel is
required of all Groups.  The composition of the designated Panel will
be provided to the NIAID within six months of funding.  The Panel
will provide the Principal Investigator and the NIAID Scientific
Coordinator with a comprehensive written review of the Group's
activity in years one, two, three (and four, if applicable) of
funding.  These reviews will encompass timeliness of progress in
individual projects relative to original projections; progress
relative to Group's objectives and needs; continued relevance of a
given project to Group's goals; continued coordination of Group's
objectives with the objectives of the NCDDG-HIV program; and
recommendations for new directions, as appropriate.

SPECIAL REQUIREMENTS

Composition of an NCDDG-HIV

The NCDDG-HIV will consist of the following:

o  Principal Investigator.

o  Project Leaders, each heading an independent research project (see
also item "E" below, this section).  The research projects will
utilize diverse scientific disciplines or alternative disciplines
that are appropriate to the realization of Group objectives (e.g.,
virology, humoral immunology, cellular immunology, structural
biology, biophysics, biochemistry, medicinal chemistry, organic
chemistry, pharmacology, toxicology, drug delivery, etc.).
Interdisciplinary projects are encouraged.

o  A Scientific Coordinator designated from the NIAID extramural
staff by the NIAID NCDDG-HIV program director.

o  A Scientific Advisors Panel to be designated within six months of
funding (see Section VII:  DEFINITIONS: SCIENTIFIC ADVISORS PANEL).
The Panel will meet with the Group, evaluate and advise on Group's
progress, future goals, strategies and new directions, as
appropriate.  Panel members will not be affiliated with any of the
institutions comprising the Group.

o  Administrative core that disburses travel expenses to required
meetings specified in the RFA (see Terms of Award: Awardee Rights and
Responsibilities, Part A.1, 2, 3, for details of required meetings).
The travel budget in the Administrative Core will be restricted for
the sole purpose of attending required meetings.  The Administrative
Core may also include support for the costs of administration,
purchasing and secretarial services.  Items described above that are
included in the institution's indirect cost rate are subject to
negotiations, based on their applicability as direct or indirect
charges.

OPTIONAL - core components which provide laboratory facilities,
equipment and services to be shared by two or more projects.

The Principal Investigator, in addition to providing scientific and
administrative leadership, is strongly encouraged to have a research
project.  Project Leaders will be directly responsible to the
Principal Investigator.  The formation of the Group, the application
in response to this RFA, the overall management of the Group, and the
allocation of funds to the various laboratory projects will be the
responsibility of the Principal Investigator and the Principal
Investigator's institution in accordance with PHS policies.

The composition of the Group and its research projects should depend
on the talents required to accomplish its scientific and technical
objectives as perceived by the Principal Investigator and Project
Leaders.  The major consideration in structuring an NCDDG-HIV should
be the mobilization of maximum intellectual talent and the ability to
carry out the proposed research in an integrated and synergistic
manner.

An individual scientist may be proposed as a Project Leader by more
than NCDDG-HIV as part of a CORE COMPONENT.  Project Leaders who do
not have a core function will not be supported by more than one
Cooperative Agreement awarded under this RFA unless the research is
clearly delineated in separate NCDDG-HIV applications.  Individuals
currently supported under an existing NCDDG-HIV or other NCDDG (e.g.,
NCDDG-OI) may be funded under this RFA provided there is no
scientific or budgetary overlap in funded activities.

More than one Project Leader of an NCDDG-HIV may be enlisted from a
single institution but at least two Projects Leaders must be from
independent laboratories.  However, the varied talents and commitment
required for effective drug discovery are not usually present in most
single institutions and it is anticipated that the Project Leaders
within a Group will be "enlisted" from, or associated with several
institutions.  For the purpose of this RFA, two (or more) projects
within a single company or academic department will not be considered
independent.

A minimum of two but no maximum number of research projects per Group
is stipulated.  However, the Principal Investigator could experience
difficulty in providing the desirable level of guidance, and Project
Leaders might communicate and collaborate less efficiently if the
Group were to contain more than five or six research projects.  A
CORE COMPONENT can not be considered as a research project in
fulfilling the requirement of two research projects per Group.

In forming an NCDDG-HIV, the Principal Investigator should remain
cognizant of the need for communication, including regular meetings
of the members.  Although it is not a requirement of this RFA, the
formation on a geographically regional basis may be advantageous.
This is a particularly important factor to be considered by
applicants from outside the United States or if the applicant
proposes laboratory projects in foreign countries.

An NCDDG-HIV is encouraged to consist of scientists from academia,
non-profit institutions, and/or commercial organizations.  The active
participation of industry is encouraged because it allows this sector
of the scientific community to contribute its intellectual and
material resources.  The private sector is also efficient in
mobilizing additional manpower and other resources as needed for the
expeditious development of promising anti-HIV lead therapies.

Patent Coverage

Since the discovery of active anti-HIV entities and strategies is the
objective of this effort, and since active involvement by private
sector laboratories is facilitated by the existence of adequate
patent coverage, it is essential that applicants provide plans to
assure such coverage.  With multiple institutions involved, complex
patent situation may arise.  Each applicant Group must, therefore,
provide a detailed description of 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.

In addition each Group must provide a detailed description of the
procedures to be followed for the resolution of legal problems which
potentially may develop.  All Group members can 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 and exclusive licensing arrangements.
Applicants should implement an arrangement that is most suitable for
their own particular circumstances.  The NIAID will not be a partner
in any patents or royalties ensuing from the Group's research.

The patent agreement, signed and dated by the organizational
officials authorized to enter into patent arrangements for each Group
member and member institution, must be sent before the application
deadline to Dr. Nava Sarver, Targeted Drug Discovery Section,
Developmental Therapeutics Branch, Basic Research and Development
Program, Division of AIDS, 6003 Executive Boulevard, National
Institutes of Health, Bethesda, MD  20892.

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 the Extramural Invention
Reports Office, Office of Extramural Research, Building 31, Room
5B41, NIH, with a copy to Dr. Nava Sarver, Chief, Targeted Drug
Discovery Section, Developmental Therapeutics Branch, Basic Research
and Development Program, Division of AIDS, 6003 Executive Boulevard,
NIH, Bethesda, MD 20892.

Terms of Award:  Awardee Rights and Responsibilities and Nature of
NIAID Participation

Assistance via Cooperative Agreement differs from the traditional
research grant in that in addition to the normal programmatic and
administrative stewardship responsibilities, the component awarding
the Cooperative Agreement anticipates substantial programmatic
involvement during performance of the project.  However, the applying
Group must define its objectives and approaches in accord with its
own interests and perceptions of novel and exploitable approaches to
the discovery of effective anti- HIV treatment and must develop the
details of the research design following the guidance given in this
RFA.  It is the primary responsibility of the Principal Investigator
to clearly state the objectives and approaches of the Group, to plan
and conduct the research stipulated in the proposal, and to ensure
that the results obtained are analyzed and published in a timely
manner.  The data obtained will be the property of the awardee.

The NIAID will participate as a member of the Group and will be
represented by a Scientific Coordinator or the NCDDG-HIV program
director.  The Scientific Coordinator will be selected by the NIAID
NCDDG-HIV program director from the Developmental Therapeutics Branch
of the Division of AIDS, which is an extramural program of the NIAID.

The specific Terms of Award are detailed below.  The Terms of Award
will be presented in the Notice of Award.  Failure to abide by these
Terms of Award may result in withholding of funds by the NIAID.

Awardee Rights and Responsibilities

o  The Principal Investigator, Project Leaders, and the NIAID
Scientific Coordinator will meet periodically to review progress,
plan and design research activities, and establish priorities.  The
frequency of meetings (not less than two per year) will be determined
by the Principal Investigator who will be responsible for scheduling
the time and place (generally at one of the performance sites),
notifying the Scientific Coordinator at least thirty days prior to
the meeting date.  The NIAID Scientific Coordinator will participate
but not chair Group meetings.  The Principal Investigator will
prepare concise (2-3 pages) minutes or summary of Group meetings
which will be delivered to Group members, including the Scientific
Coordinator, within thirty days following the meeting.

Travel funds for attending one of the required Group meetings should
be included in the Administrative Core budget for Project and Core
Leaders, and will be restricted solely for this purpose.  The
application should also include plans for scheduling Group meetings,
notifying Group members including the NIAID Scientific Coordinator,
and documenting and disseminating Group meeting proceedings.

o  In addition to these meetings, one meeting every 12-18 months will
be held at a site designated by NIAID during which all Principal
Investigators and Project Leaders will present significant findings
in symposium format.  The NCDDG-HIV program meeting is one of the
central points for information flow among the Principal
Investigators, Project Leaders, NCDDG-HIV program director NIAID
Scientific Coordinator, the private sector, other drug development
concerns, and NIAID.  The NIAID NCDDG-HIV program director consults
with the Groups' key personnel in formulating the overall agenda,
selecting session Chairs and in identifying key topics for
discussion.  Session Chairs select the workshop participants who
constitute the bulk of invited speakers.  This forum is central for
cross fertilization of ideas, inter-Group collaborations, integration
of unique anti-HIV strategies, and a critical source for updating
NIAID and keeping it abreast of scientific and technological
innovation toward the discovery of new anti-HIV modalities.  Data
presented at this meeting are selected by the individual presenters
in consultation with their Principal Investigator thus affording
appropriate protection of proprietary or commercially sensitive
information.

It is expected that selected NIH staff, members of established
committees and advisory boards, and others active in the process of
discovery and development of therapies for HIV/AIDS will be invited
to this meeting.  The Principal Investigator will have control over
the data and results presented by his/her Group.

In addition to the Group meetings discussed above, funds for
attending the NCDDG-HIV program meeting should be included in the
Administrative Core budget for the Principal Investigator, and
Project and Core Leaders.  Historically, the NCDDG-HIV program
meeting has been held every 18 months.  For budgetary purposes,
anticipated dates for future NCDDG-HIV program meetings are November
1994 and May 1996.  Travel budget to the NCDDG-HIV program meetings
should, therefore, allow for two program meetings during the duration
of the grant.  These travel funds will be solely restricted for this
purpose.  Invited NCDDG-HIV speakers will be expected to utilize
budgeted travel funds to cover expenses incurred while attending the
program meeting.  Funds to cover operating costs of the NCDDG-HIV
meeting will be contributed by one or more Groups.  The NIAID will
provide administrative supplements for this purpose, as needed.

o  Groups will designate a Scientific Advisors Panel within six
months of funding.  The Principal Investigator will convene a
meeting, or meetings, of the Group with the Panel in years 01, 02,
03, and 04 (if applicable) of funding.  Meeting with the Panel may be
in conjunction with the Group's own meeting (see item 1, above).  The
Panel will meet with the Group, and advise the Principal Investigator
on Group's progress, future goals, strategies and new directions, as
appropriate.  The Panel will provide the Principal Investigator and
the NIAID Scientific Coordinator a comprehensive written review of
the Group's activity in years one, two, three and four (if
applicable) of funding, as specified under Definitions:  NIAID
Advirors Panel.

Members of the Panel will not be affiliated with any of the
institutions comprising the Group.  Funds to cover expenses incurred
by the Panel should be included in the Administrative Core component
of the application and will be restricted solely for this purpose.

o  A critical determinant of Group's success will be the degree of
communication among its members.  Therefore, additional informal
meetings among all participants as well as regular telephone and
written communication will be important.

o  The Principal Investigator will be responsible for the timely
submission of all abstracts, manuscripts and reviews (co)authored by
members of the Group and supported in part or in total under this
Cooperative Agreement.  The Principal Investigator and Project
Leaders are requested to submit manuscripts to the Scientific
Coordinator within three weeks of acceptance for publication so that
up-to-date summary of program accomplishments is maintained.

o  Each Progress Report should include a complete and cumulative list
of all publications (abstracts, manuscripts, reviews) (co)authored by
Groups members and supported in part or in total under this
Cooperative Agreement.

Each progress report should also include a brief section outlining
intra-Group interactions which have augmented activities, citing
specific occurrences (e.g., compound 'X' was synthesized under
Project 1 and transferred to Project 2 for bioassays).  Inter-Group
collaboration with other NCDDG- HIV should be specified, where
applicable.  Interaction with and facilitation of the Group effort by
the Scientific Coordinator and the NIAID during the reporting period
should be described.

o  Publications or oral presentations of work done under this
Cooperative Agreement is the responsibility of the Principal
Investigator and appropriate Project Leaders.

o  All published (abstracts, peer reviewed manuscripts, reviews) and
oral presentations of work supported in part or in total by the
NCDDG-HIV cooperative agreement must be acknowledged as part of the
presentation and must include the grant mechanism, grant number and
Institute; for example, "This work was supported in part by the NIAID
NCDDG-HIV program, grant number U01-AI-12345.

NIAID Assistance in Implementation and Management of Research
Activities

o  The NIAID Scientific Coordinator, like other Group members, may
suggest studies within the scope of the Group's objectives and
research activities; may present to the Group experimental findings
from published sources or from contract projects in support of these
suggestions; may participate in the design and execution of
experiments as agreed to by the Group; and may participate in the
analysis and publication of results.

o  The NIAID Scientific Coordinator may assist the Group or other
individual members in research planning, particularly with respect to
(1) reduction of duplication of efforts conducted in other extramural
projects; (2) provision of needed resources and information that
otherwise may not be available to the Group; and (3) provision of
data from testing conducted in resource contract laboratories.

o  The NIAID Scientific Coordinator may serve as a resource for
information, laboratory testing, animal model testing and biological
supplies when such resources are not a normal requirement of the
Group's day-to-day research activities but may be required on an
occasional basis.  The following are examples of resources available
from the NIAID; these resources are intended for initial studies and
will not be available on a continual basis:

(1) Reference compounds for standardization of test systems, as
analytical standards, and for related purposes.

(2) Materials for biological testing.

(3) Biochemical and cell based laboratory testing capacity.  Whenever
appropriate and possible, current contract-based
preclinical/therapy-related testing will be used.  On occasion, and
under mutual agreements, NIAID will arrange for limited preclinical
testing at other NCDDG-HIV sites. The Groups are expected to provide
sufficient test material for requested testing.

(4) Testing in appropriate animal model(s) when the occasional need
arises in Groups whose main research activities do not require these
resources on a regular basis.  Groups whose experimental approach
involves studies that require testing in animals on a regular basis
must budget for costs to be paid from award funding.  Requests for
testing in NIAID's animal model program are contingent upon NIAID's
recommendation and prioritization.

(5) Searches of NIAID's computer files of chemical structures and
biological activity, if requests for such searches are sufficiently
focused to avoid excessive costs and time.  Information given to an
NCDDG-HIV will be restricted by standard confidentiality agreements
between the Government and suppliers of test materials to the
Government.

(6) Computer processing and statistical evaluations if costs and time
are not excessive.

(7) Networking with other NIH Staff, NCDDG-HIVs, collaborators and
other Government and non-Government investigators who may provide
guidance, expertise or resources to facilitate development of
therapies identified by the Group.

NOTE:  It is understood that the Government provides its testing
services in the interest of promoting experimental anti-HIV agents
through preclinical and clinical testing and development in the most
expeditious fashion, and that newly marketed agents that have
utilized these services will be offered to the public at reasonable
costs.

o  The NIAID Scientific Coordinator may assist the Groups by
providing them with compounds for voluntary initial or confirmatory
testing.  In testing compounds supplied by the NIAID, the Groups
agree to abide by any confidentiality agreement between the NIAID and
a third party who has supplied the compounds for testing through
NIAID.

o  The role of NIAID is to facilitate and not direct the Group's
activities.  It is expected that decisions in all activities outlined
below will be reached by consensus of the Group, and that the NIAID
Scientific Coordinator will be given the asked to offer input to this
process.  The manner of reaching this consensus and the final
decision-making authority will rest with the Principal Investigator.

Collection and Analysis of Data, Procedures for Submission of Results
to NIAID, and Preparation of Group Findings for Presentation and
Publication

In addition to the special reports and stipulations described below,
reporting requirements will be identical to those currently in
existence for awardee of traditional NIH research project grants.

o  The principal end product of NCDDG-HIV activities will be the
discovery of new entities and strategies for development to clinical
trials against HIV infection.  Subsequent preclinical and clinical
development through private resources is encouraged.  Alternatively,
the Group may recommend that preclinical and/or clinical development
be sponsored by NIAID.  In this case, it will be necessary for the
Principal Investigator, appropriate Project Leaders and the NIAID
Scientific Coordinator to collaborate in the analysis, summary
preparation, and presentation of data to appropriate Division of AIDS
staff and its advisory committees, such as the Animal Model Operating
Committee or the AIDS Clinical Drug Development Committee.

o  The NIAID will retain the option to cross-file or independently
file an application for investigational clinical trial; e.g., an
Investigational New Drug (IND) application to the United States Food
and Drug Administration of any invention resulting from these
NIAID-supported Cooperative Agreements.  Reports of data generated by
the Group or any of its members required for inclusion in INDs and
Clinical Brochures and for cross-filing purposes will be submitted by
the Principal Investigator to the Scientific Coordinator upon
request.  Such reports will be in final draft form and include
background information, methods, results, and conclusions.  They will
be subject to approval and revision by NIAID and may be augmented
with test results from other Government sponsored projects prior to
submission to the appropriate regulatory agency.

o  The NIAID will have access to data generated under this
Cooperative Agreement and will review the data and progress reports.
Information obtained from the data may be used by the Scientific
Coordinator for the preparation of internal reports on the Group's
activities.  However, the applicant will retain custody of and rights
to the data, and timely publication of major findings is encouraged.

Inasmuch as certain activities under "Terms of Award: NIAID
Assistance in Implementation and Management of Research Activities"
require approval by NIAID staff during performance of this
Cooperative Agreement (specifically, reports intended for inclusion
in INDs and Clinical Brochures, change in Principal Investigator or
Project Leader(s), redistribution of biological materials received
through the Scientific Coordinator and dissemination of research
findings resulting from the use of these materials), NIAID will
establish an arbitration process to resolve any differences of
opinion with regard to these scientific programmatic matters.  An
arbitration panel, composed of one Group designee, one NIAID designee
not from the Developmental Therapeutics Branch, and a third designee
with expertise in the relevant area and chosen by the other two, will
be formed to review any disagreements regarding
scientific-programmatic issues that are restricting progress.  This
arbitration process in no way affects the right of an award recipient
to appeal selected post-award administrative decisions in accordance
with HHS, PHS, and NIH regulations and policies.  These special
arbitration procedures for scientific-programmatic matters in no way
affect the awardee's right to appeal an adverse action in accordance
with PHS regulations at 42 CFR Part 50, Subpart D, and HHS
regulations at 45 CFR, Part 16.

The special "Terms of Award: NIAID Assistance in Implementation and
Management of Research Activities" described in this section are in
addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines, HHS Grant Administration Regulations at 45
CFR Part 74, and other HHS, PHS, and NIH grant administration policy
statements.

NOTE:  Failure to abide by any of the "Terms of Award" stipulated in
this Section may result in withholding of funds by the NIAID until
compliance with the Terms is restored.

Minimum Requirements for Application

Applicants seeking funding as a NATIONAL COOPERATIVE DRUG DISCOVERY
GROUP FOR THE TREATMENT OF HIV Infection must meet the following
requirements:

The application must be from a Group and must:

o  Name a single Principal Investigator who is an employee of the
applicant institution and who will be responsible for the
application, for Group research activities, and for the support of
Group activities through a Central Operations Office.

o  Identify the single applicant organization (awardee institution)
that will provide the Central Operations Office and be legally and
financially responsible and be accountable for the use and
disposition of funds awarded on the basis of this RFA; show
availability of personnel and facilities capable of performing and
supporting the administrative functions of the NCDDG-HIV.

o  Provide a description of the Group's plan for assuring adequate
patent coverage of new inventions that may issue as a result of
Government funding of the proposed work.

NOTE:  A formal statement of Patent Agreement among all Group members
and their institutions as well as a detailed description of
procedures to be followed for the resolution of legal problems which
potentially may develop, signed and dated by the organizational
official authorized to enter into patent arrangements for each Group
member and member institution is to be submitted before the
application deadline to Dr. Nava Sarver, Chief, Targeted Drug
Discovery Section, Developmental Therapeutics Branch, Basic Research
and Development Program, Division of AIDS, 6003 Executive Boulevard,
Bethesda Maryland, 20892, in advance of the application receipt date
(see 'Patent coverage', above).

o  Provide a clear, concise plan in narrative and diagrammatic form
that depicts the interrelationships among the members of the Group
and the contribution of each to fulfillment of Group objectives;
provide an organizational chart of the Group showing the name,
organization, and scientific discipline of the Principal Investigator
and Project Leaders; provide an organizational chart for each
laboratory project within the Group showing relationships among the
key personnel.

o  Provide a plan to assure the maintenance of close collaboration
and effective communication among members of the Group which will
include letters of commitment to this plan and a letter accepting the
assistance of the Scientific Coordinator, defined under the TERMS OF
AWARD, this section.

o  Provide an introductory section that states the rationale of the
research proposed in each project describing how it relates to drug
discovery and the anticipated therapeutic approach which may result
(see APPLICATION PROCEDURES).

o  Demonstrate that each component laboratory project contributes to
the attainment of the Group's objectives and that each has available
the professional and technical personnel to permit efficient and
successful conduct of the proposed research; show that total
personnel of the Group are sufficient in quality and quantity to
assure successful conduct of the proposed research.

Other activities which are essential to maintaining or achieving the
objectives of the stated research projects (e.g., large scale
production of reagents, animal maintenance) should be included as
subcontracts under the budget for core resources.

o  Demonstrate that each component laboratory project and the Group
as a whole have available facilities required for conduct of the
proposed research; demonstrate that appropriate biohazard facilities
and safety procedures are in place for activities involving HIV,
related viruses and virus-producing cell lines as outlined in The
Federal Register, Volume 49, Number 201, Part II, Tuesday, October
16, 1984, p. 40556; include a description of the Institutional Safety
Guidelines and administrative approval procedures for each proposed
laboratory project.

NOTE:  The Principal Investigator will provide a narrative, supported
by diagrammatic presentation(s) as needed, addressing the points
raised above.  This description should clearly demonstrate the
interactive, cooperative, integrated and interdependent nature of
each proposed project and core to the Group activities as a whole.
The narrative is to be included under the Administrative Core; it
will serve as one of the criteria used by the peer review study
section to evaluate and rate the ability of the Principal
Investigator to assemble a comprehensive, interactive Group.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which apply to males and females of all ages.  If
women or minorities are excluded or inadequately represented in
clinical research, particularly in proposed population-based studies,
a clear compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study. This information should be included in the form PHS 398 in
Sections 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects.  Applicants are urged to assess carefully the feasibility
of including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States racial/ethnic minority population (i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
disease, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded from the
clinical research requirements.  However, every effort should be made
to include human tissues from women and racial/ethnic minorities when
it is important to apply the results of the study broadly, and this
should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies. If the representation of
women or minorities in a study design is inadequate to answer the
scientific questions(s) addressed and the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit by January 15, 1993, a
letter of intent (maximum of two pages) that includes:

o  A descriptive title of the overall proposed research.

o  The name, address, telephone number, and institution of the
Principal Investigator.

o  Names of prospective Project Leaders, other key investigators, and
their respective institutions.

o  The number and title of this RFA in response to which the
application is submitted.

Although the letter of intent is not required, is not binding, and is
not a factor in the peer review of the application, the information
it contains is helpful in planning for the review of applications.
It allows NIAID staff to estimate the potential review workload and
to avoid conflict of interest in the review process.

The letter of intent is to be sent to:

Nava Sarver, Ph.D., Chief, Targeted Drug Discovery Section
Developmental Therapeutics Branch
Basic Research and Developmental Program
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2C11
Bethesda, MD  20892
Telephone:  (301) 496-8197
FAX:  (301) 402-3211

Applicants who use express mail or courier services should use the
city and zip code of Rockville, MD 20852.

APPLICATION PROCEDURES

It is important to follow the instructions in this RFA for preparing
the application.  Failure to do so may result in an application with
insufficient information for appropriate scientific review.  The
prospective applicant is also urged to carefully read the sample
application which accompanies this RFA.

If additional information on how to prepare a multi-project
application is required, the applicant may request the NIAID
Information Brochure on Program Project and Center Grants, available
from:

Scientific Review Branch
Division of Extramural Affiars
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C19
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0123

Questions concerning review requirements of a complete application
may be directed to Dr. Dianne Tingley, (301) 496-0818.  Questions
regarding responsiveness to the RFA may be directed to Dr. Nava
Sarver, (301) 496-8197.

Receipt Date

The deadline for receipt of applications is March 17, 1993.
Applications received after this date will be considered not
responsive to this RFA and will be returned without review.

General

o  The research grant application forms PHS-398 (rev. 9/91) is to be
used in applying for cooperative agreements.  These forms are
available at most institution sponsored research offices and from the
Office of Grants Inquiry, Division of Research Grants, National
Institutes of Health, ,Westwood Building Room 449, 5333 Westbard
Avenue, Bethesda, Maryland  20892, telephone (301) 496-7441.

o  Submit a signed, typewritten original of the application,
including the Checklist, and three signed, exact, single-sided
photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building Room 240
Bethesda, MD  20892**

The RFA label available in form PHS 398 (rev. 9/91) must be affixed
to the bottom of the face page of the original signed application.
Failure to use this label could result in delayed processing of the
application such that it may not reach the committee in time for
review.

o  To assure the identification of your application with this RFA
-the application form must have "NATIONAL COOPERATIVE DRUG DISCOVERY
GROUP FOR TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION
(NCDDG-HIV)" (RFA AI-92-16) typed on item 2a of the face page of the
application form.

o  Submit two exact copies of your application directly to:

Dianne Tingley, Ph.D.
Chief, AIDS Scientific Review Section
Scientific Review Branch
National Institutes Allergy and Infectious Diseases
Solar Building, Room 4C16
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0818

Applicants who use express mail or a courier service should use the
city and zip code of Rockville, MD 20852.

Organization of Application and Suggested Modifications of Form
PHS-398 (rev. 9/91)

This RFA requires the submission of a single application for the
proposed NATIONAL COOPERATIVE DRUG DISCOVERY GROUP HIV.  Because of
the multi-institutional nature of a NCDDG-HIV and the special
requirements in this RFA, additional instructions regarding format
are contained in the NIAID Information Brochure on Program Project
and Center Grants.

The special requirements of this RFA will also necessitate the
following modification.  The Introductory Section should apply to the
proposed NCDDG-HIV as a whole with respect to goals, objectives, and
overall research plan.

The Introductory Section, not to exceed two pages, should contain any
additional information about the proposed Principal Investigator or
his/her institution as evidence of capability to carry out the
scientific and administrative duties required in this RFA and the
functions of the Central Operations Office.

In addition, the Introductory Section must include the following
elements to be considered responsive to minimum requirements (See
SECTION VIII of this RFA):

o  The name of a single Principal Investigator in accordance with the
section on Minimum Requirements for Application.

o  The name of the single applicant organization that will provide
and operate the Central Operations Office in accordance with the
Section on Minimum Requirements for Applications.

o  A statement assuring adequate patent coverage of new inventions
that may issue as a result of Government funding in accordance with
Patent Coverage.

o  A statement of acceptance of the provisions of Terms of Awards:
Awardee Rights and Responsibilities and Nature of Participation of
NIAID Staff.

o  A description of the interrelationships among members of the Group
and organizational charts in accordance with Composition of an
NCDDG-HIV.

o  A plan to assure maintenance of close collaboration and effective
communication among members of the Group in accordance with Minimum
Requirements for Application.

o  A rationale for the drug discovery approach(es) proposed and
discussion of therapeutic approaches that may derive from the
research projects.

REVIEW CONSIDERATIONS

applications that are not received as a single package from the
Principal Investigator and that do not conform to the instructions
contained in the PHS 398 (rev. 9/91) application kit will be judged
non-responsive and will be returned to the applicant.

Applications will be reviewed by the Division of Research Grants for
completeness and by NIAID staff to determine administrative and
programmatic responsiveness to this RFA; those judged to be
non-responsive will be returned to the applicant without review.
Applications with first year total costs (direct and indirect) in
excess of $800,000 will be returned without review unless the
applicant has received a written waiver from the NIAID to exceed this
amount.

Those applications that are complete and responsive may be subjected
to a triage by an NIAID peer review group to determine their
competitiveness relative to the other applications received in
response to this RFA.  The NIAID will remove from further competition
those applications judged to be noncompetitive for award and will
notify the applicant (Principal Investigator) and responsible
institutional official.

Those applications judged to be competitive for award will be further
reviewed for scientific and technical merit by a Review Committee
convened by the Division of Extramural Activities, NIAID during June
1993.  Second level of review will be provided by the National
Advisory Allergy and Infectious Diseases Council.

Review Procedures and Criteria:

Applications will be reviewed in the AIDS Review Section, NIAID, by
an appropriate committee.  The application must be directed towards
the attainment of the stated programmatic goals (see Research Goals
and Objectives of the NCDDG-HIV.  The following factors will be
considered in the scientific and technical review of the application:

o  Relevance of applicant's (Group) objectives to the discovery of
new entities and strategies for the treatment of HIV infection.

o  Scientific and technical significance, originality and uniqueness
of proposed research.

o  Scientific merit of approaches to realization of objectives.

o  Likelihood that new potential therapy will be identified during
the course of the proposed study.

o  Specific competencies of the Principal Investigator and Project
Leaders to conduct the proposed work: research experience,
commitment, and time availability of the Principal Investigator,
Project Leaders, and other key personnel.  Although there is no
maximum percent effort set, it is anticipated that due to the
complexity and time required to maintain a well coordinated and
productive research effort a minimum 20 percent (time) effort by the
Principal Investigator and each Project Leader should be devoted to
the study, unless there is compelling evidence to the contrary.

o  Accomplishments of the Group to date (for renewal and supplemental
grant applications).

o  Technical merit of proposed methods for producing or obtaining
test materials and for their evaluation.

o  Technical sufficiency of methods for evaluation of new
discoveries, laboratory test systems, models, etc.

o  Administrative experience and competence of Principal Investigator
in the development, implementation, and management of comprehensive
research programs.

o  Plans for effective intra-Group communication and for assuring
Group cohesiveness.

o  Adequacy of existing physical facilities and resources available
to the Principal Investigator and Project Leaders including biohazard
containment facilities as stipulated in Section VIII - Minimum
Requirements for Application.

o  Documented commitment of institutions represented by Group
members; documented capability of Principal Investigator's
institution to serve as Central Operations Office for the Group.

o  Commitment to accept the assistance of NIAID staff in accordance
with the guidelines outlined under "Terms of Award: Awardee Rights
and Responsibilities and Nature of NIAID Participation."

o  Mechanism for selecting and replacing key professional or
technical personnel using the framework of the RFA.

o  Conformance to "Minimum Requirements for Application."

o  Reasonableness of cost.

INQUIRIES

Inquiries concerning the programmatic and scientific aspects of this
RFA may be addressed to:

Nava Sarver, Ph.D., Chief, Targeted Drug Discovery Section
Developmental Therapeutics Branch
Basic Research and Developmental Program
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2C11
Bethesda, MD  20892
Telephone:  (301) 496-8197
FAX:  (301) 402-3211

Inquiries regarding matters pertaining to the review of this
application may be addressed to:

Diane Tingley, Ph.D.
Chief, AIDS Scientific Review Section
Scientific Review Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C16
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0818

Inquiries regarding fiscal matters may be addressed to:

Ms. Jane Unsworth
Chief, AIDS Grants Management Section
Grants Management Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B22
Bethesda, MD  20892
Telephone:  (301) 496-7075
FAX:  (301) 480-3780

A separate request for Applications for the National Cooperative Drug
Discovery Groups for the Treatment of Opportunistic Infections
Associated with AIDS (RFA AI-92-15) has been issued.  To receive a
copy, please contact Dr. Barbara Laughon, Developmental Therapeutics
Branch, Basic Research and Development Program, Division of AIDS,
NIAID, 6003 Executive Boulevard, Bethesda, MD 20892, telephone:
(301) 402-2304.

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance Nos. 93.856, Microbiology and Infectious Diseases Research
and 93.855 - Immunology, Allergic and Immunological Diseases
Research.  Grants are awarded under the authority of the Public
Health Service Act, Section 301 (42 USC 241) and administered under
the PHS grants policies and Federal Regulations, most specifically at
42 CFR Part 52 and 45 CFR Part 74.  This program is not subject to
the intergovernmental review requirements of the Executive Order
12372 or Health Systems Agency Review.

.

Return to RFAs Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.