Subject: NIH GUIDE - RFA AI-91-13 - V20(41) 11/01/91
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Mon, 04 Nov 91 15:44 EST

Hi Paul,
   Hopefully this is the last one for today to be posted to the
NIH Listserver.  Please post as:
     RFAAI-91-13.911101
                                     Dottie
 ---------------------------- Text of forwarded message -----------------------
 
$$XID RFA AI9113 AI-91-13 P1O1 *****************************************
 
REQUEST FOR APPLICATIONS
 
RFA:  AI-91-13
 
NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR THE TREATMENT OF HUMAN
IMMUNODEFICIENCY VIRUS INFECTION
 
P.T. 34; K.W. 0715008, 0740020, 0755025
 
National Institute of Allergy and Infectious Diseases
 
Letter of Intent Receipt Date:  November 28, 1991
Application Receipt Date:  January  16, 1992
 
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 plans to continue its support
of the National Cooperative Drug Discovery Group program.  Reissuance
of this initiative in future years is anticipated but not certain.
 
Reissuance of RFA AI-90-09 dated September 7, 1990
 
I.  SUMMARY AND BACKGROUND
 
Acquired Immune Deficiency Syndrome (AIDS) is a disease that destroys
the body's capacity to overcome a variety of infections.  As of
August 30, 1991, 191,601 cases of AIDS had been reported in the
United States by the Centers for Disease Control (CDC) and more than
122,905 of these patients (64.1 percent) had died.  Recent
projections indicate that between 800,000 to 1,200,000 persons in the
United States may already be infected with HIV, the infectious virus
associated with AIDS.  The only drug currently licensed for the
treatment of HIV-1 infection is zidovudine (AZT, 3'- azidothymidine).
The search for improved therapies to treat HIV-1 infection and AIDS
is among the highest priorities of the Department of Health and Human
Services.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), National Cooperative Drug Discovery Groups
for the Treatment of HIV Infections, 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).
 
The NIAID and the PHS Centers for Disease Control are currently
supporting comprehensive extramural and intramural projects for the
study of the etiology, natural history, and demographics of AIDS;
screening of high-risk individuals; determining means of diminishing
the risk of infection; development of prophylactic vaccines;
development of therapies to treat those with AIDS-related complex
(ARC); and development 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 treatment of this disease.
 
The NIAID realized that many single institutions may not have either
the critical mass of all the talents or the ancillary resources
needed to translate leads from basic studies into new entities and
strategies for AIDS treatment.  A cooperative arrangement that
permits the combination of the highest quality research expertise
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).  They 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 treatment.  (A separate program, NCDDG for
the Treatment of Opportunistic Infectious (NCDDG-OI), focuses on the
opportunistic infections associated with AIDS and is mentioned at the
end of this RFA).  Results from the research proposed 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 emerging knowledge of the molecular biology
of HIV have made it possible to screen for potentially effective
antiviral compounds.  The possibility of discovering an effective
treatment of the infection based on compounds targeted against
selected steps in the viral replication cycle has been shown in vitro
with several drugs (3'-azidothymidine, dideoxycytidine,
dideoxyinosine, and non-nucleoside compounds as reverse transcriptase
inhibitors; peptide isosteres and A77003 as HIV-1 protease
inhibitors; a benzodiazipine - as Tat inhibitor; fatty acid analogues
as inhibitors of N-myristoyltransferase, and thereby of HIV assembly)
and other viral functions (soluble CD4).  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
entry of HIV into uninfected cells or CD4-toxin conjugates to kill
cells expressing HIV gp120 on their surface.  Despite the encouraging
data with sCD4 obtained in tissue culture studies, results from
clinical trials to date have been disappointing.
 
X-ray crystallography has yielded the structure of two HIV-1 enzymes
(protease and RNaseH), both critical in the viral life cycle.  In the
case of protease, the crystal structure has already proven valuable
in the design of potent inhibitors of HIV replication.  But these two
proteins represent only 11-12 percent of the 15-17 HIV-1 proteins
identified to date and additional structural work is imperative.
Although efforts are underway to design therapies that block other
viral specific targets (e.g., inhibitor of HIV regulatory functions,
Tat and Rev) or use of substrate analogues to interfere with enzymes
or pathways obligatory for virus replication (e.g. inhibitors of
myristoylation), these efforts are insufficient.  To date, not all
HIV-1 genes are fully characterized and the function of some is still
elusive (e.g., Nef, Vif); further, new gene products have been
identified in the last one to two years raising the possibility that
other HIV genes are yet to be discovered.  HIV-induced defects in
biochemical pathways need be explored as another approach to
counteract the consequences of infection; the involvement of cellular
factors and biochemical processes in the induction of "latent"
provirus and enhancement of HIV growth cycle must be addressed; and
the emergence of drug resistant HIV strains imposes a constant demand
for alternative therapies.
 
As of November 30, 1991, 22 Groups will have been funded under the
NCDDG-HIV program.  Eight of these Groups are eligible for
competitive renewals in fiscal year 1991.  Current research pursuits
within the NCDDG-HIV program include:
 
o Inhibition and biochemistry of reverse transcription:
 
synthesis, evaluation and pharmacology of nucleoside analogues and
non-nucleoside inhibitors of HIV replication;
 
natural products from plant and marine sources;
 
metabolism, pharmacology and toxicity of natural and synthetic
compounds.
 
o Delineation of HIV functions and establishment of biochemical
assays:
 
functional delineation of RT and RNaseH activities;
 
studies and inhibition of HIV RNaseH;
 
design and synthesis of HIV protease inhibitors (small symmetrical
molecules, peptidyl and non-peptidyl inhibitors);
 
assays for inhibitors of Tat activity;
 
screening and inhibition of glycosylation;
 
assays for inhibition of N-myristoyltransferase for blocking HIV
assembly;
 
interference with RNA/GAG interaction;
 
integration process and assays for integrase inhibitors;
 
ribosomal frame shifting;
 
CD4 peptides as blockers of HIV binding;
 
RNA specific organic repressors.
 
o Immunology, immune therapy and virus/cell interaction:
 
humoral and cellular aspects of immune dysfunction;
 
CTL, monoclonal antibodies, CD4-toxins and immunotoxins as potential
therapeutics in HIV infection;
 
CD4/MHCII interaction;
 
dendritic cells and contribution to HIV spread;
 
HIV interaction with neural cells;
 
abortive reverse transcription;
 
gp120/CD4 interaction and mapping of functional gp120 and CD4
domains;
 
molecular mechanisms of drug resistance, cross resistance and
correlation with sequence variation.
 
o Animal model studies:
 
FeLV as potential targets for rational drug design;
 
post exposure chemoprophylaxis using single agent and combination
evaluation in simian models;
 
evaluation of anti-viral and immunomodulators in the LP-BM5 murine
model.
 
o Regulatory genes and factors:
 
interaction of Tat and Rev with their cognate cis elements TAR and
REV;
 
role of Nef in HIV replication and cytopathicity;
 
function analysis of ancillary regulatory gene products (Vif, Vpu,
Vpr);
 
transcriptional factors associated with HIV-LTR.
 
o Intracellular suppression and gene delivery:
 
CD4-mediated intracellular suppression of HIV entry;
 
retroviral mediated transduction into human hematopoietic cells;
 
dominant repressors of viral functions (Tat, Rev, GAG);
 
catalytic RNA mediated inhibition of HIV gene expression;
 
mouse and mouse/human chimera as models for gene therapy in AIDS.
 
o Rational drug design:
 
X-ray crystallography of HIV protease, Rev, p24/FAb complex and
gp120/CD4 complex.
 
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 may be
composed of scientists from any combination of academic, non-profit
research, and commercial organizations.
 
II.  SCIENTIFIC SCOPE, RESTRICTIONS AND EXCLUSIONS
 
The prime objective of this RFA is to stimulate original and
innovative research of sound scientific rationale, requiring
comprehensive team effort that is likely to result in the discovery
of agents effective against HIV.  In line with this objective, the
NCDDG-HIV program supports and implements 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 acceptable 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 in which collaboration among components of the Group are
not required for the success of Group activities will not be funded
and are encouraged to submit an R01 (or equivalent) grant
application.
 
Applications that include a research projects or a core component
from the private sector (e.g., pharmaceutical, chemical, or
biotechnological companies) are strongly encouraged.  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 or expression (gene therapy) of antagonists using viral
vectors or other delivery strategies;
 
o Intervention with cellular biochemical pathways required for
induction from latency and/or for enhancement of HIV growth cycle;
 
o Innovative approaches to exploit the humoral and cellular arms of
the immune system in a targeted anti-HIV affront;
 
o Other sound and new conceptual strategies, currently not being
pursued, for the discovery of new entities, or combinations, with
potential for treatment of HIV infection, such as inhibitors of viral
penetration, ribozymes, and agents that disrupt virus structure.
 
Examples of proposed research in these major areas are:  studies to
delineate structure-function of HIV encoded target proteins; evaluate
drug metabolism; devise and evaluate innovative drug delivery
strategies; appraise the emergence of resistance to drugs targeted to
specific HIV enzymatic, structural, or regulatory function; identify
early events in viral replication suitable for drug targeting; and
decipher biochemical pathways and host interactions critical to virus
replication and/or drug action.
 
Projects or cores with proposed animal model development 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
compounds 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.  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 integrated into other NIH initiatives are
specifically excluded from this RFA:  (i) synthesis or development of
analogues or prodrugs of known anti-HIV nucleosides and
non-nucleosides; (ii) reverse transcriptase screens; (iii) evaluation
of recombinant human cytokines; (iv) development of exogenous,
soluble CD4 or its conjugated congeners; (v) anti-protease screens
and peptide-based protease inhibitors; (vi) evaluation and synthesis
of myristoylation inhibitors; (vii) mechanism of action studies
unlinked to inhibitor identification; (viii) 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; (ix) research on the opportunistic infections
associated with AIDS; a separate RFA for the National Cooperative
Drug Discovery Groups for the Treatment of Opportunistic Infections
Associated with AIDS (NCDDG-OI) will be re-issued in 1991 for the
third 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.  Whenever appropriate, cooperation between funded
Groups or with the National Cancer Institute may be arranged through
the Scientific Coordinator (see Section VIII:  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 screening is necessary to evaluate
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, Maryland  20892.  Telephone:  (301) 496- 8795.
 
Studies required for the clinical development 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 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, the AIDS Clinical Trial Units (ACTU)
investigators and the Division of AIDS.
 
III.  DEFINITIONS
 
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 area and chosen by the other
two.  The interaction of this panel is detailed in Section VIII,
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
that shall be 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 may be defined as any project with established
techniques and assays that perform a service function or result 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 a research
project to allow 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.  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
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:  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.  For the purpose
of this RFA, two (or more) projects within a single company will not
be considered independent.  A CORE COMPONENT may not be used toward
fulfillment of the two 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, and novel therapeutic strategies or inventions
designed to effectively treat AIDS.
 
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 (i) overseeing the
entire NCDDG-HIV program; (ii) ensuring that Groups' objectives are
consistent with the Division of AIDS preclinical Program and NIAID
mission and goals; (iii) assigning Scientific Coordinators to
appropriate Groups based on scientific expertise and compatibility
with the Group research interests; (iv) ensuring overall scientific
balance among Groups in the NCDDG-HIV program; (v) networking and
facilitating collaboration between Groups and industry to expedite
development of promising anti-HIV agents; (vi) keeping the NCDDG-HIV
program current with regard to scientific developments and
breakthroughs; and (vii) identifying gaps not adequately pursued.
 
NIAID SCIENTIFIC COORDINATOR - A Senior or Associate Scientist of the
extramural staff of the NIAID 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.
 
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 2-3 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 Principal Investigator will invite the Scientific Coordinator to
all meetings of the Panel.  Members of the Panel will not be
affiliated with any of the institutions comprising the Group.  A
Scientific Advisors Panel is required only of Groups funded for more
than three years.  The composition of the designated Panel will be
provided to the NIAID in the Noncompetitive Continuation Application
at the completion of year one of funding.  The Panel will provide the
Principal Investigator and the NIAID Scientific Coordinator a
comprehensive written review of the Group's activity in years two,
three and four 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.
 
IV.  COMPOSITION OF AN NCDDG-HIV
 
A.  The NCDDG-HIV will consist of the following:
 
1.  Principal Investigator;
 
2.  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, and drug delivery).
Interdisciplinary projects are encouraged;
 
3.  A Scientific Coordinator designated from the NIAID extramural
staff;
 
4. A Scientific Advisors Panel to be designated at the end of year
one of funding by Groups funded for more than three years (see
Section III:  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.  Members
in the Panel will not be affiliated with any of the institutions
comprising the Group;
 
5.  (OPTIONAL) core components that would provide for laboratory
facilities, equipment and services to be shared by two or more
projects.  It 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.
 
B.  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.
 
C.  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 strength and the
ability to carry out the proposed research.
 
D.  An individual scientist may be proposed as a Project Leader by
more than one applicant 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 as long as there
is no scientific or budgetary overlap in funded activities.
 
E.  More than one Project Leader of an NCDDG-HIV may be enlisted from
a single institution but at least two Project 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 will not be considered independent.
 
F.  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, including the Principal Investigator's project.  A
CORE COMPONENT can not be considered toward fulfilling the required
two research projects per Group.
 
G.  In forming NCDDG-HIVs, Principal Investigators 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.
 
H.  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 will
allow this sector of the scientific community to contribute its
intellectual and material resources and will favor expeditious
development of effective anti-HIV therapies.
 
V.  RESEARCH GOALS AND OBJECTIVES OF THE NCDDG-HIV PROGRAM
 
A.  The goals of the NATIONAL COOPERATIVE DRUG DISCOVERY GROUP FOR
THE TREATMENT OF HIV INFECTION are:
 
1.  The conceptualization, discovery and preclinical development of
drugs and strategies designed to effectively treat individuals
infected with the human immunodeficiency virus;
 
2.  The recommendation of therapies, entities or strategies for
development to clinical trial; and
 
3.  The conduct of biological, biochemical, and pharmacological
studies that will permit the most enlightened subsequent clinical
evaluation supported by the most sophisticated technology, and that
may provide information leading to the future discovery of more
effective treatments.
 
B.  Applications for an NCDDG-HIV should stress creative approaches
to the discovery of effective anti-HIV therapies and should emphasize
the following:
 
1.  Specific objectives of the proposed NCDDG-HIV;
 
2.  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; and
 
3.  The scientific and technical areas of expertise (Project Leaders)
required to attain Group objectives and the leadership ability of the
Principal Investigator.
 
C.  The Group's objectives and goals should be relevant and
compatible with NIAID Program's missions and directions as stated in
this RFA.
 
VI.  MECHANISM OF SUPPORT
 
A.  Awards will be made as COOPERATIVE AGREEMENTS (UO1).  The NIAID,
in awarding the Cooperative Agreement, anticipates substantial
programmatic staff involvement during performance of the award.  The
nature of NIAID staff assistance to the awardee is described in
Section VIII of this RFA under TERMS OF AWARD:  NATURE OF
PARTICIPATION OF NIAID STAFF.  There is no intent, real or implied,
for NIH staff to direct Group activities or to limit the freedom of
investigators.  The interaction of academic and non-profit research
institutions with commercial (including industrial) organizations and
Government is expected to promote and expedite discoveries of new
entities and strategies for the treatment of HIV infections and will
facilitate their subsequent development to clinical trial.
 
B.  NIAID has set aside $2.2 million for the initial year funding of
this RFA.  The amount spent will be dependent on the continuing
availability of funds for this purpose and the quality and diversity
of approved applications.  Funding of two to three awards is
anticipated.  New awards are subject to a first-year limit of
$1,000,000 in total costs (direct plus indirect costs), unless a
written approval by the NIAID waiving the limit is obtained prior to
submission of the application.  The Principal Investigator is urged
to contact Dr. Nava Sarver [(301) 496-8197] to discuss the need for a
waiver prior to submitting a written request.  Applications in excess
of $1,000,000 total (direct and indirect) costs, and without a
written waiver by the NIAID, will be returned without review.
Funding in subsequent years will be at a level no greater than year
one plus four percent (four percent). Funding duration will be four
years for competitive renewals and three years for new awards.  The
starting date for the initial annual period will be on or after June
15, 1992.
 
If the applicant institution is outside the United States, awards
will be limited to three years.  If 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.
 
C.  Awards will be made to successfully competing Groups rather than
to the individual scientists or institutions comprising the Group.
Support of all Group activities will be coordinated through a Central
Operations Office located within the applicant organization.  Each
award will be made only to the Principal Investigator's institution.
 
D.  Under the Cooperative Agreement, a partner relationship between
the recipient of the award and the NIAID exists in which the Group is
responsive to the requirements and conditions set forth in the 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 a Project Leader
withdraws from the Group and a suitable replacement of key personnel
is not obtained.
 
E.  All policies and requirements that govern the grant program of
the U.S. Public Health Service and the National Institutes of Health
(NIH) apply.
 
F.  Although this program is provided for in the financial plans of
NIAID, the award of Cooperative Agreements pursuant to this RFA is
also contingent upon the continuing availability of funds for this
purpose.
 
G.  There are presently no plans for extensions of U01 projects
beyond initial competition.  Reissuance of this initiative in future
years is anticipated but not certain.
 
VII.  PATENT COVERAGE
 
Since the discovery of active anti-HIV entities and strategies is the
objective of this effort, and since active involvement by industrial
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, the patent
situation could be complicated.  Each applicant Group must,
therefore, provide a detailed description of the approach to be used
for obtaining patent coverage and for licensing whenever appropriate,
in particular whenever 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 that may develop.  All Group members can
be full partners in the research and in any inventions resulting
there from. 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 this 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 Ms. Besita Wyche, Targeted Drug Discovery Section,
Developmental Therapeutics Branch, Division of AIDS, 6003 Executive
Boulevard, National Institutes of Health, Bethesda, MD  20892.
 
Federal regulation clause 37CFR401 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, Building 31, Room 5B41, NIH,
with a copy to Dr. Nava Sarver, Chief, Targeted Drug Discovery
Section, Developmental Therapeutics Branch, Division of AIDS, 6003
Executive Boulevard, NIH, Bethesda, MD 20892.
 
VIII.  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 usual 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-AIDS 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 application 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.
 
NIAID shall participate as a member of the Group and shall be
represented by a Scientific Coordinator.  The Coordinator shall be
selected from the Developmental Therapeutics Branch of the Division
of Acquired Immunodeficiency Syndrome, which is an extramural program
of the NIAID.
 
The TERMS OF AWARD are stated below.  Failure to abide by these TERMS
OF AWARD may result in withholding of funds by the NIAID.
 
A.  Awardee Rights and Responsibilities
 
1.  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) shall 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 45 days prior
to the meeting date, and preparing concise proceedings or minutes
that be delivered to the members of the Group,including the
Scientific Coordinator, within 30 days following the meeting.  The
NIAID Scientific Coordinator will participate in, but not chair,
Group meetings.
 
Funds for attending the two required Group meetings must be included
in the budget for each research project.  The application must also
include plans for scheduling Group meetings, notifying Group members
including the NIAID Scientific Coordinator, and documenting and
disseminating Group meeting proceedings.
 
2.  In addition to these two meetings, one meeting each year will be
held at a site designated by the NIAID during which all Principal
Investigators and Project Leaders will present significant findings
in symposium format.  The NCDDG-HIV annual meeting is one of the
central points for information flow among the Principal
Investigators, Project Leaders, NCDDG-HIV program Director, the
private sector, other drug development concerns, and NIAID.  The
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, 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-viral 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 AIDS will be invited to
this meeting.  The Principal Investigator will have control over the
data and results presented by the Group.
 
In addition to the two Group meetings discussed above under item 1,
funds for attending the NCDDG-HIV annual meeting must be included in
the budget for each research project.  Funds to cover operating costs
of the NCDDG-HIV annual meeting will be contributed by one or more
Groups;  NIAID will provide administrative supplements for this
purpose, as needed.
 
3.  Groups funded for more than three years will designate a
Scientific Advisors Panel by the end of year 01 of funding.  The
Principal Investigator will convene a meeting, or meetings, of the
Group with the Panel in years 02, 03, and 04.  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 the 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 02, 03, and 04 of
funding, as specified under Section III, DEFINITIONS:  NIAID ADVISORS
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 must be included in the Administrative Core component of
the application.
 
4.  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.
 
5.  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
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 the Scientific
Coordinator is alerted to results that are being made public and can
help coordinate activities with the NIAID Office of Communication, if
appropriate.
 
6.  Each Progress Report must include a complete and cumulative list
of all publications (abstracts, manuscripts, reviews) (co)authored by
Group members and supported in part or in total under this
Cooperative Agreement.
 
Each progress report must also include a brief section outlining
intra-Group interactions that have augmented activities, citing
specific occurrences (i.e., compound X was synthesized under Project
1 and transferred to Project 2 for bioassays).  Inter-Group
collaboration with other NCDDG-HIVs must also be specified, whenever
applicable.  Interaction with the Scientific Coordinator and the
NIAID during the reporting period must also be described.
 
7.  Publications and oral presentations of work done under this
Cooperative Agreement are the responsibility of the Principal
Investigator and appropriate Project Leaders.
 
8.  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
NCDDG-HIV program, grant number U01-AI12345, NIAID."
 
B.  NIAID Assistance in Implementation and Management of Research
Activities
 
1.  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.
 
2.  The NIAID Scientific Coordinator may assist the Group or other
individual members in research planning, particularly with respect
to:
 
i.  reduction of duplication of efforts conducted in other extramural
projects;
 
ii.  provision of needed resources and information that otherwise may
not be available to the Group; and
 
iii.  provision of data from testing conducted in resource contract
laboratories.
 
3.  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 usual requirement of the
Group's day-to-day research activities but may be required on an
occasional basis.  The following is a list of some resources
available from the NIAID; these resources are intended for initial
studies and will not be available on a continual basis:
 
i.   reference compounds for standardization of test systems, as
analytical standards, and for related purposes;
 
ii.  materials for biological testing;
 
iii.  biochemical and cell-based laboratory testing capacity.
Whenever appropriate and possible, current contract-based
preclinical/therapy related testing program will be used.  On
occasions, 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;
 
iv.  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;
 
v.  searches of 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 any standard confidentiality agreements between
the Government and suppliers of test materials to the Government;
 
vi.  computer processing and statistical evaluations if costs and
time are not excessive; and
 
vii.  networking with other NIH Staff, NCDDG-HIVs, other
collaborators and other Government and non-Government employees 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-viral 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 a reasonable
cost.
 
4.  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.
 
5.  During performance of the award the NIAID Scientific Coordinator
will provide appropriate assistance by participating in the design of
Group activities; advising in the selection of sources or resources,
replacement of staff, etc.; coordinating or participating in
collection and/or analysis of data; advising in management and
technical performance; or participating in the preparation of
publications. However, the role of NIAID will be to facilitate and
not to direct the activities.  It is anticipated 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
opportunity to offer input to this process.  The manner of reaching
this consensus and the final decision making authority will rest with
the Principal Investigator.
 
C.  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.
 
1.  The principal end product of NCDDG-HIV activities will be the
discovery of new entities and strategies for development to clinical
trials against AIDS.  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, summarization,
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.
 
2.  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.
 
3.  The NIAID will have access to data generated under this
Cooperative Agreement and may periodically 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 awardee will retain custody of
and rights to the data, and timely publication of major findings is
encouraged.
 
D.  Inasmuch as certain activities under TERMS of AWARD:  NATURE OF
PARTICIPATION OF NIAID STAFF 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 scientific
programmatic issue that is significantly 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 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.
 
E.  The special "TERMS OF AWARD:  NATURE OF PARTICIPATION OF NIAID
STAFF" 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.
 
IX.  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:
 
A.  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;
 
B.  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;
 
C.  Identify the Group as having an approach that should be reviewed
as being comprehensive, immunological, biological, or synthetic in
its approach for the design of new treatments against HIV infection;
 
D.  Provide a description of the Group's plan for ensuring 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 that
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 Ms. Besita Wyche, Targeted Drug Discovery Section,
Developmental Therapeutics Branch, Division of AIDS, 6003 Executive
Boulevard, Bethesda, MD, 20892 (see Section VII).
 
E.  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;
 
F.  Provide a plan to ensure the maintenance of close collaboration
and effective communication among members of the Group that will
include letters of commitment to this plan and a letter accepting the
assistance of the Scientific Coordinator, defined under the TERMS OF
AWARD.
 
G.  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; and
 
NOTE:  Other activities that are essential to maintaining or
achieving the objectives of the stated research projects (e.g.,
large-scale production of reagents, animal maintenance) must be
included as subcontracts under the budget for core resources.
 
H.  Demonstrate that each component laboratory project and the Group
as a whole have available the 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.
 
X.  INCLUSIONS OF WOMEN AND MINORITIES IN BASIC RESEARCH STUDIES
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA 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 disproportionately affect
them.  This policy is intended to 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, together with a rationale
for its choice.  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 Section 2, A-D
of the Research Plan AND summarized in Section 2, E, Human Subjects.
 
NIH policy concerning inclusion of women and minorities in clinical
studies also applies to all research involving human subjects.  Where
the samples of human tissue are used in basic research, every effort
should be made to include tissues from women and racial/ethnic
minorities when it is important to apply the results of the study
broadly.  When the sex/race of the individuals are known, and if
samples from women and minorities are inadequately represented or
excluded, a clear and compelling rationale for exception to the
policy must be provided.  Use of human tissues that cannot be
identified or linked to individuals is permissible.  In this case,
the general makeup of the sample population should be defined where
possible.
 
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 review will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in the study design is inadequate to answer the
scientific question(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.  NIH
funding components will not award grants or cooperatives agreement
that do not comply with these policies.
 
XI.  REVIEW METHOD AND PEER REVIEW CRITERIA
 
APPLICATIONS THAT ARE NOT RECEIVED AS A SINGLE PACKAGE FROM THE
PRINCIPAL INVESTIGATOR AND THAT DO NOT CONFORM TO THE INSTRUCTIONS
CONTAINED IN PHS 398 (rev. 10/88, reprinted 9/89) APPLICATION KIT
WILL BE  RETURNED TO THE APPLICANT.
 
Applications will be reviewed 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 $1,000,000 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 institutional
business 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
March/April 1992.  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 Section V,
RESEARCH GOALS AND OBJECTIVES OF THE NCDDG-HIV.  The following
factors will be considered in the scientific and technical review of
the application:
 
A.  Relevance of applicant's (Group) objectives to the discovery of
new entities and strategies for the treatment of AIDS;
 
B.  Scientific and technical significance, originality, and
uniqueness of proposed research;
 
C.  Scientific merit of approaches to realization of objectives;
 
D.  Likelihood that new potential therapy will be identified during
the course of the proposed study;
 
E.  Specific competencies of the Principal Investigator and Project
Leaders to conduct the proposed work:  research experience,
commitment, and time availability of Principal Investigator, Project
Leaders, and other key personnel.  While 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 must be devoted to the study,
unless there is compelling evidence to the contrary.
 
F.  Technical merit of proposed methods for producing or obtaining
test materials and for their evaluation;
 
G.  Technical sufficiency of methods for evaluation of new
discoveries, laboratory test systems, and models;
 
H.  Administrative experience and competence of Principal
Investigator in the development, implementation, and management of
comprehensive research programs;
 
I.  Plans for effective intra-Group communication and for ensuring
Group cohesiveness;
 
J.  Adequacy of existing physical facilities and resources of the
Principal Investigator and Project Leaders including biohazard
containment facilities as stipulated in Section IX, MINIMUM
REQUIREMENTS FOR APPLICATION, Part H;
 
K.  Documented commitment of institutions represented by Group
members; documented capability of Principal Investigator's
institution to serve as Central Operations Office for the Group;
 
L.  Commitment to accept the assistance of NIAID staff in accordance
with the guidelines outlined under Section VIII, TERMS OF AWARD:
NATURE OF PARTICIPATION OF NIAID STAFF;
 
M.  Mechanism for selecting and replacing key professional or
technical personnel using the framework of the RFA;
 
N.  Conformance to MINIMUM REQUIREMENTS FOR APPLICATION (Section IX);
 
O.  Reasonableness of cost.
 
XII.  METHOD OF APPLYING
 
LETTER OF INTENT
 
Prospective applicants are asked to submit by November 28, 1991, a
letter of intent that includes a descriptive title of the overall
proposed research, the name and institution of the Principal
Investigator, a title for each component research project and brief
descriptions of the proposed projects.  Names of prospective Project
Leaders and other key investigators and their institutions should be
included (maximum of two pages).  The letter of intent is requested
in order to provide an indication of the number and scope of
applications to be reviewed and in order to allow early preparations
for review.  The letter of intent does not commit the sender to
submit an application, nor is it a requirement for submission of an
application, and does not enter into the review of an application
subsequently submitted.  The letter of intent is to be sent to:
 
Nava Sarver, Ph.D.
Chief
Targeted Drug Discovery Section
Developmental Therapeutics Branch
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 246P
Bethesda, MD   20892
Telephone:  (301) 496-8197
 
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 that 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:
 
Program and Project Review Branch
National Institute of Allergy and Infectious Diseases
Control Data Building
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0123
 
Questions concerning review requirements may be directed to Dr.
Hortencia Hornbeak, telephone (301) 496-0123.  Questions regarding
responsiveness to the RFA may be directed to Dr. Nava Sarver,
telephone (301) 496-8197.
 
A.  Receipt Date
 
The deadline for receipt of applications is January 16, 1992.
Applications received after this date will be returned without
review.
 
B.  General
 
1.  The research grant application form PHS 398 (rev. 10/88,
reprinted 9/89) are available at most institutional business offices.
If not available there, they may be obtained from:
 
Office of Grants Inquiries
Division of Research Grants
National Institutes of Health
Westwood Building, Room 449
5333 Westbard Avenue
Bethesda, MD  20892
 
2.  Submit a signed, typewritten original of the application,
including the Checklist, and six 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. 10/88, reprinted 9/89)
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.
 
3.  TO ASSURE THE IDENTIFICATION OF THE APPLICATION WITH THIS RFA
 
The application form must have "NATIONAL COOPERATIVE DRUG DISCOVERY
GROUP FOR TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION, RFA
AI-91-13) typed on item 2 of the face page of the application form;
and
 
4.  SUBMIT 17 EXACT COPIES OF THE APPLICATION DIRECTLY TO:
 
Hortencia Hornbeak, Ph.D.
Deputy Chief
Program and Project Review Branch, DEA
National Institute of Allergy and Infectious Diseases
Control Data Building
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0123
 
Organization of Application and Suggested Modifications of form PHS
398 (rev. 10/88, reprinted 9/89)
 
This RFA requires the submission of a single application for the
proposed NATIONAL COOPERATIVE DRUG DISCOVERY GROUP.  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 must  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, must 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 IX of this RFA):
 
1.  the name of a single Principal Investigator in accordance with
Section IX, Part A;
 
2.  the name of the single applicant organization that will provide
and operate the Central Operations Office in accordance with Section
IX, Part B;
 
3.  a statement assuring adequate patent coverage of new inventions
that may issue as a result of Government funding in accordance with
Section IX, Part D;
 
4.  a statement of acceptance of the provisions of Section VIII,
TERMS OF AWARD:  AWARDEE RIGHTS AND RESPONSIBILITIES; NATURE OF
PARTICIPATION OF NIAID STAFF;
 
5.  a description of the interrelationships among members of the
Group and organizational charts in accordance with Section IX, Part
E; and
 
6.  a plan to ensure maintenance of close collaboration and effective
communication among members of the Group in accordance with Section
IX, Part F.
 
XIII.  INQUIRIES
 
Inquiries of the program aspects of this RFA may be addressed to Dr.
Nava Sarver (see Letter of Intent).
 
Inquiries regarding matters pertaining to the review of this
application should be addressed to:
 
Hortencia Hornbeak, Ph.D.
Deputy Chief
Program and Project Review Branch, DEA
National Institute of Allergy and Infectious Diseases
Control Data Building
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0123
 
Inquiries regarding fiscal matters may be addressed to:
 
Mr. Gary Thompson
Chief, Grants Management Branch, DEA
National Institute of Allergy and Infectious Diseases
Control Data Building
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7231
 
XIV.  OTHER
 
A separate RFA for the National Cooperative Drug Discovery Groups for
the Treatment of Opportunistic Infections Associated with AIDS (RFA
AI-91-15) has been issued, NIH Guide for Grants and Contracts, Vol.
20, No. 39, October 18, 1991.  To receive a copy, contact Ms. Besita
Wyche (see Section XI, METHOD OF APPLYING).
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance, 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.