Full Text AI-92-15

NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR THE TREATMENT OF
OPPORTUNISTIC INFECTIONS ASSOCIATED WITH ACQUIRED IMMUNODEFICIENCY
SYNDROME

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

RFA:  AI-92-15

P.T. 34

Keywords: 
  AIDS 
  Inhibitors 
  Drug Design 
  Pharmaceuticals 
  Biotechnology 
  Drug Resistance+ 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January 15, 1993
Application Receipt Date:  March 10, 1993

PURPOSE

The NIAID invites applications for the establishment of National
Cooperative Drug Discovery Groups for the Treatment of Opportunistic
Infections Associated with Acquired Immunodeficiency Syndrome
(NCDDG-OI).

The purpose of this Request for Applications (RFA) is to invite
applications aimed at the discovery of new, more effective,
selective, and diverse therapeutic agents to treat AIDS-associated
opportunistic infections (OIs) caused by Mycobacterium tuberculosis,
Mycobacterium avium, Cryptosporidium parvum, Toxoplasma gondii,
Cryptococcus neoformans, Pneumocystis carinii, and Candida albicans.
Applications that include research projects or core components from
the private sector (e.g., pharmaceutical, chemical, or
biotechnological companies) are encouraged.  Organisms associated
with additional OIs have not been included in this RFA reissuance in
order to achieve programmatic balance among existing NCDDG-OI Groups.
Investigators pursuing similar studies of other OIs are encouraged to
apply through existing research support mechanisms.

Research in the following areas is needed to provide the foundation
for improvements in therapeutics for the OIs: selective drug
targeting; unique metabolic activities for drug targeting;
structure-function properties of microbial proteins; biochemistry and
molecular mechanisms of OI-host interactions; improved culture
methods for conducting metabolic studies on parasite-host
interactions; inhibitors of enzymatic and regulatory functions, and
of biochemical pathways; mechanisms of drug resistance; and discovery
and biochemical characterization of promising natural products or
synthetic chemical compounds.  It is anticipated that
multidisciplinary approaches by scientists from a combination of
academic, non-profit research, and commercial organizations, with the
assistance of NIAID, will be necessary to effectively accelerate drug
discovery for the OIs associated with AIDS.

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
Opportunistic Infections Associated With Acquired Immunodeficiency
Syndrome (NCDDG-OI), 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 organizations, public and private, 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.  However, it is the Principal
Investigator who defines his/her objectives in accord with his/her
interests and perceptions of approaches to the treatment of
AIDS-associated opportunistic infections.  There is no intent, real
or implied, for NIH staff to direct Group activities or to limit the
freedom of investigators.

The applicant institution and the Principal Investigator will be
responsible for the Group's application.  Awards will be made to the
Principal Investigator's 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 all members of
the Group by providing appropriate scientific input, by making
available to the Group biological materials for testing, by accessing
appropriate data bases, by providing ancillary testing and other
resources available under existing contracts.  The interaction of
academic and non-profit research institutions with commercial
organizations and Government is strongly encouraged and is expected
to favor expeditious discovery and preclinical development of agents
active against OIs in AIDS patients and to facilitate their
subsequent development for clinical trials.

Under the Cooperative Agreement, a negotiated 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
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
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
Public Health Service and the National Institutes of Health (NIH)
apply.

FUNDS AVAILABLE

The NIAID has set aside $3.5 million for the initial year's 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 five to seven awards is
anticipated.  It is anticipated that no more than one Group each will
be funded for drug discovery against M. tuberculosis, T. gondii, P.
carinii, C. parvum, M. avium, C. neoformans, and C. albicans as a
result of this RFA.  Applications focusing on C. albicans must study
novel drug targets; further study of triazoles or polyene antibiotics
will not be supported.  Awards are subject to a first year limit of
$650,000 in total costs (direct plus indirect costs).  Subsequent
years will be funded at a level no greater than the first year plus
four percent.  Applications with budgets in excess of $650,000 total
(direct and indirect) costs will be returned without review.  Funding
duration will be three years for new applications and up to four
years for competitive renewal applications. The anticipated starting
dates for the initial annual periods will be December 1993.

Previously funded NCDDG-OIs 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 competitive renewals and new awards.
Reissuance of this initiative in future years is anticipated but not
certain.  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.

RESEARCH OBJECTIVES

Research Goals and Objectives of the NCDDG-OI Program

The goals of the National Cooperative Drug Discovery Groups for the
Treatment of Opportunistic Infections are:

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

o  The conduct of biological, biochemical, and pharmacological
studies leading to selection of potential therapies.

o  The recommendation of therapies, entities or strategies for
development in clinical trials.

Applications for an NCDDG-OI should stress creative approaches to the
discovery of effective therapies to treat opportunistic infections
and should emphasize the following:

o  Specific objectives of the proposed NCDDG-OI.

o  Research rationale and approaches to the realization of objectives
for proposed studies.

o  The scientific and technical expertise of the Principal
Investigator and Project Leaders 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 Immunodeficiency Syndrome (AIDS) is a disease that destroys
host immunological defenses against a variety of infections. As of
June 30, 1992, 230,179 cases of AIDS had been reported to the Centers
for Disease Control (CDC) and more than 152,153 (66.1 percent) of
these patients have died. Recent projections indicate that between
800,000 to 1,200,000 persons in the United States may be infected
with human immunodeficiency virus (HIV), the infectious virus
associated with AIDS.  Opportunistic infections (OIs) are the most
frequent causes of morbidity and mortality in AIDS patients and are
the principal reasons for hospitalization.

Individuals infected with HIV are susceptible to a range of
protozoal, fungal, viral, and bacterial infections.  The actual
incidence of these OIs over the lifetime of HIV-infected individuals
far exceeds AIDS-defining statistics collected by the CDC, although
medical history information on specific infections is not known with
precision.  Pneumocystis carinii pneumonia (PCP) is the most common
opportunistic infection reported to the CDC for new cases of AIDS
(approximately 50 percent of cases in 1990).  Relapses of PCP and
other opportunistic infections frequently occur later in the course
of HIV infection concomitant with profound depletion of CD4+
T-lymphocytes.  It is estimated that more than 50 percent of AIDS
patients will have become massively infected with Mycobacterium avium
at the time of death.

Available drugs to treat these opportunistic infections have limited
value because toxicity and other adverse reactions frequently occur
in people with AIDS.  Prolonged immunosuppression requires prolonged
treatment and prophylaxis regimens which are often costly.  There are
no therapies proven effective for C. parvum and M. avium infections,
and limited treatment options are available for infections caused by
T. gondii, M. tuberculosis, P. carinii, C. neoformans, and C.
albicans.  Combined infection with HIV and M. tuberculosis have
contributed to a public health crisis in many areas of the United
States where health care delivery systems are inadequate.  Recent
outbreaks of multidrug-resistant tuberculosis and the emergence of
certain strains resistant to all approved anti-tuberculous therapies
poignantly illustrate the critical requirement to identify more
effective therapeutic approaches.  The need exists for more potent
and selective therapeutic agents with activity against the OIs, and
particularly multi-drug resistant forms of M. tuberculosis.

Seven NCDDG-OIs were awarded in 1990, four were awarded in 1991, and
four more are anticipated to be awarded in 1992.  Five Groups are
eligible for re-competition under this RFA.  Within the currently
funded NCDDG-OI program, the following approaches are presently being
pursued for each organism:

Pneumocystis carinii - cloning and expression of folate pathway
genes, synthesis of anti-folate compounds, molecular modelling of
chemical structures to inhibit enzymes of folate metabolism, lipid
uptake and metabolism, and development of in vitro culture systems.

Toxoplasma gondii - molecular biology, glycolytic enzymes, arprinocid
analogs, purine salvage enzymes, macrolide transport and activity,
animal models.

Cryptosporidium - immunotherapy with monoclonal antibodies,
interactions with host cells.

Mycobacterium avium - cell wall biosynthesis enzymes, gene cloning,
animal models, structure-activity relationships of candidate drugs.

Candida albicans - inhibitors of protein N-myristoylation, cell wall
biosynthesis, topoisomerases.

Cryptococcus neoformans - cloning and expression of folate pathway
genes, cationic peptides (defensins), interactions with human cells,
immunotherapy, pheromones, mannitol metabolism, liposomes.

Cytomegalovirus - synthesis and assay of nucleoside analogs, unique
chemical classes, heterocyclics, cloning and expressing the UL97 gene
product and DNA polymerase.

Scientific Scope, Restrictions and Exclusions

It is the intention of this RFA to encourage investigators to
collaborate in new approaches to drug discovery against the OIs
associated with AIDS and to complement and balance the efforts
presently being pursued by existing NCDDG-OIs.  It is recognized that
the ultimate objective of selective therapy against microbial
infection requires a solid knowledge base of the biology,
composition, physiology, molecular biology, and host interactions of
infectious agents.  The 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 OIs associated with AIDS.

Respondents to this RFA may include:  new applications for a maximum
period of three years support, competitive renewal applications from
existing Groups for up to four years of support, and competitive
supplements to currently funded NCDDG-OIs.

No clinical trials will be supported under this RFA.  Research
efforts should be directed towards the discovery and preclinical
evaluation of new entities with potential to control infections
caused by the following pathogens: M. tuberculosis, T. gondii, C.
parvum, P. carinii, M. avium, C. neoformans, and C. albicans (see
restrictions below).  It is not a requirement of this RFA that a
complete development plan for new drugs be included, although
applications which include research projects or core components from
the private sector (e.g., pharmaceutical, chemical, or
biotechnological companies) are encouraged.  Projects focusing on the
early phases of new drug target identification are appropriate.
However, each application must clearly state in an introductory
section how information from the proposed projects will directly
accelerate new drug discovery and what therapeutic approaches are
likely to ultimately derive from these studies.  Priority will be
given to therapies with potential for prophylaxis, practical
administration to AIDS patients, and low toxicity.

Applications focusing on the biochemical and metabolic activities of
these microorganisms as drug targets are strongly encouraged.
However, research focusing on anti-folates or sulfonamides for
Pneumocystis or Toxoplasma infections or on triazoles or polyene
antibiotics for C. albicans will not be supported under this RFA
because of advances currently being pursued in this area.  Other
organisms causing infections which may be associated with AIDS have
been excluded from this RFA due to competing priorities and in order
to achieve programmatic balance within the NCDDG-OI program.
Scientists studying opportunistic infections whose research does not
lie within the areas defined as responsive to this RFA are strongly
encouraged to apply for investigator-initiated grants through the
R01, R29, and R43 (Small Business Innovative Research Program)
mechanisms.

Research considered responsive to this RFA may include, but is not
necessarily restricted to, the following:

o  Studies designed to discover therapeutic agents capable of
producing selectively lethal effects on opportunistic infectious
pathogens.

o  Studies to identify and characterize molecular and metabolic
targets with potential for design of new therapeutic candidates and
for development of practical prophylaxis agents.

o  Design of selective inhibitors using molecular modelling.

o  Identification of selected molecular functions which may be used
to establish in vitro assay systems for discovery of active agents.

o  Improvements in in vitro culture or animal model systems with
potential for acceleration of drug discovery, particularly for M.
tuberculosis, Cryptosporidium, Toxoplasma bradyzoites, and
Pneumocystis.

It is anticipated that no more than one Group each will be supported
to pursue drug discovery against M. tuberculosis, T. gondii, P.
carinii, C. parvum, M. avium, C. neoformans, and C. albicans as a
result of this RFA.  Applications focusing on C. albicans must study
novel drug targets.  Projects or cores that include proposed animal
model development must be integrated within the major goal of
targeted drug discovery and required to attain the Group's
objectives.  Funds for evaluation of new agents in animal models will
be withheld until compounds generated by the Group are available for
animal efficacy studies.  Testing of natural products, biologics
and/or synthetic compounds must not exceed 25 percent of the total
level-of-effort of the Group.  Random or large scale screening of
compounds will not be supported under this RFA.

Although studies required for the clinical development of identified
potential treatments are beyond the scope of this RFA, development
through private venture capital is encouraged.  Alternatively, an
NCDDG may request that the NIAID assist in these developmental tasks.
The NIH has a contract program for the preclinical development of
compounds for the treatment of AIDS-associated opportunistic
infections, including animal models.  In addition, the NIAID supports
AIDS Clinical Treatment Units (ACTUs) for Phase I, Phase II and Phase
III clinical trials.  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 and concurrence of the AIDS Clinical Drug Development
Committee, the Division of AIDS, and the ACTU investigators.

DEFINITIONS

ADMINISTRATIVE CORE - An administrative facility that provides
support for the overall management of the cooperative agreement and
services shared by the Group as a whole.  The Administrative core
will have in its budget travel costs for (1) one required annual
Group meeting; (2) the NCDDG-OI annual meeting; and (3) 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.)

ARBITRATION PANEL - A group composed of one Group designee, one NIAID
designee, and a third designee with expertise in the relevant area
and chosen by the other two.  The interaction of this panel is
detailed in VIII, "Terms of Award".

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

CORE COMPONENT - Facilities for equipment and services which are
shared by two or more projects of the NCDDG-OI.  Examples of core
components are:  biochemical studies, in vitro testing, animal model
evaluations, toxicology studies, pharmacology studies, scale-up
synthesis of drugs (10 grams or less).  The core can be defined as a
component with established techniques and assays which perform a
service function resulting in an economy of effort and savings in the
overall costs of the NCDDG-OI.  The core unit is to be described in
the same detail as research projects to enable the evaluation of its
scientific and technical merit.

DISCOVERY - The term "discovery" is used explicitly to limit
activities of the NCDDG-OI to preclinical identification, design and
development of new entities.

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
Opportunistic Infections (NCDDG-OI) - In this RFA the terms NATIONAL
COOPERATIVE DRUG DISCOVERY GROUP, NCDDG-OI, and "Group" are
synonymous.  A minimum of two laboratory research projects
representing diverse scientific disciplines and organizations that
join together under a single Principal Investigator and that function
as a unit with a common goal:  the conceptualization, invention, and
evaluation of new entities and strategies for the treatment of OIs.
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 or
academic department will not be considered independent.  A CORE
COMPONENT cannot be used toward fulfillment of the two Projects
requirement.

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

NIAID NCDDG-OI PROGRAM DIRECTOR - A Senior Scientist of the NIAID
extramural staff who coordinates NIAID's participation in the
NCDDG-OI program.  This responsibility includes:  (1) overseeing the
entire NCDDG-OI program; (2) assuring that Groups' objectives are
consistent with NIAID's 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-OI program; (5)
networking and facilitating collaboration between Groups and industry
to expedite development of promising anti-OI agents; (6) keeping the
NCDDG-OI 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 the
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-OI program director, and is the immediate contact
person for the Group.

PRINCIPAL INVESTIGATOR - The person who assembles the NCDDG-OI,
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-OI.

SCIENTIFIC ADVISORS PANEL - A panel, comprised of two to three peers
from the scientific community, whose mission is to provide the
Principal Investigator with comprehensive review 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, 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 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 function; continued coordination of Group's objectives with
the objectives of the NCDDG-OI program; and recommendations for new
directions, as appropriate.

SPECIAL REQUIREMENTS

Composition of an NCDDG-OI

The NCDDG-OI will consist of the following:

o  A Principal Investigator.

o  Project Leaders, each heading an independent research project.
The research projects will utilize diverse scientific disciplines or
alternative disciplines that are appropriate to the realization of
Group objectives (e.g., microbiology, structural biology, biophysics,
biochemistry, medicinal chemistry, organic chemistry, pharmacology,
toxicology, drug delivery).  Interdisciplinary projects are
encouraged.

o  A Scientific Coordinator designated from the NIAID extramural
staff.

o  An Administrative Core component that must provide for required
travel and may also include support for the costs of administration,
purchasing and secretarial services.

o  A Scientific Advisors Panel to be designated within six months of
funding (see Definitions: Scientific Advirose Panel).  This Panel
will meet with the Group, evaluate and advise on the 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  OPTIONAL - Core components that provide laboratory facilities,
equipment and services to be shared by two or more projects.  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.

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-OI should
be the mobilization of maximum intellectual talent and the ability to
carry out the proposed research.

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-OI applications.  Individuals
currently supported under an existing NCDDG-OI or other NCDDG
programs (e.g., NCDDG-HIV) 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-OI 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 cannot be considered toward fulfilling the required
two research projects per Group.

In forming Groups, Principal Investigators should remain cognizant of
the need for communication, including regular meetings of the
members.  While it is not a requirement of this RFA, the formation of
Groups 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 is encouraged to include 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-OI therapies.

Patent coverage

Since the discovery of agents active against OIs in AIDS patients 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 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 that
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
are encouraged to develop 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:

Dr. Barbara Laughon
Developmental Therapeutics Branch
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building Room 2C10
Bethesda, MD  20892

For express mail or courier services, the address is 6003 Executive
Boulevard, Rockville, MD 20852.

Federal regulation clause 37 CFR 401 and HHS Inventions regulations
at 45 CFR Parts 6 and 8 require that the 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, NIH,
Building 31, Room 5B41, Bethesda, MD 20892, with a copy to Dr.
Barbara Laughon at the address listed above.

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

Assistance via a 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-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 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-OI program
director.  The Coordinator will be selected from the Developmental
Therapeutics Branch of the Division of Acquired Immunodeficiency
Syndrome, or from the Division of Microbiology and Infectious
Diseases, which are extramural programs of the NIAID.

The specific Terms of Award are detailed below and 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) 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 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 summaries of the Group
meetings that will be delivered to the members of the Group including
the Scientific Coordinator within thirty days following the meeting.

Funds for attending the one required Group meeting must 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 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-OI annual meeting is one of the
central points for information flow among the Principal
Investigators, Project Leaders, NCDDG-OI program director, the
private sector, other drug development concerns, and the 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-OI strategies, and a critical source for updating
NIAID and keeping it abreast of scientific and technological
innovation toward the discovery of new anti-infective 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, funds for
attending the NCDDG-OI annual meeting must be included in the
Administrative Core budget for the Principal Investigator, and
Project and Core Leaders.  These travel funds will be restricted for
use to attend the annual NCDDG-OI meeting.  Invited NCDDG-OI speakers
will be expected to utilize budgeted travel funds to cover expenses
incurred while attending the annual meeting.  Funds to cover
operating costs of the NCDDG-OI annual 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 each year which may
be in conjunction with the required Group meetings.  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 with a comprehensive written review
of the Group's activity each year.

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 the 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
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 an up-to-date
summary of program accomplishments can be maintained.

o  Each Progress Report should 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 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-OIs should be specified, where
applicable.  Interaction with the Scientific Coordinator and the
NIAID during the reporting period should be described.

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

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

NIAID Assistance in Implementation and Management of Research
Activities

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

o  The Scientific Coordinator may serve as a resource for
information, laboratory 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 is a list of some resources that may be available from the
NIAID.  These resources are intended for initial studies and may not
be available on a continual basis:

(a) reference compounds for standardization of test systems, as
analytical standards and for related purposes;

(b) materials for biological testing;

(c) 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-OI sites.  The Groups are
expected to provide sufficient test material for requested testing;

(d) 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;

(e) 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-OI will be restricted by the standard confidentiality
agreements between the Government and suppliers of test materials to
the Government;

(f) computer processing and statistical evaluations if costs and time
are not excessive;

(g) chemical re-synthesis, analysis, formulation, and toxicology
testing through existing pre-clinical development contracts
(contingent upon NIAID's recommendation and prioritization);

(h) networking with other NIH staff, NCDDGs, other collaborators and
other Government and non-Government researchers who may provide
guidance, expertise or resources to facilitate development of
therapies identified by the Group.

It is understood that the Government provides its consulting and
testing services in the interest of promoting experimental
anti-infective agents through preclinical and clinical testing and
development in the most expeditious fashion, and that newly marketed
agents that have utilized this service will be offered to the public
at a reasonable cost.

o  The NIAID Scientific Coordinator may assist the Groups by
providing them with compounds for voluntary initial and 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 the
NIAID.

o  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 the NIAID will be to facilitate
rather than 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.

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 awardees of traditional NIH research project grants.

o  The principal end product of NCDDG-OI activities will be the
discovery of new entities and strategies for development to clinical
trials for AIDS-associated OIs.  Subsequent developmental work
through private resources is encouraged.  Alternatively, the Group
may recommend that development be sponsored by the NIAID.  In the
latter 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 the appropriate NIAID 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 the 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 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 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, redistribution of biological materials received
through the Scientific Coordinator and dissemination of research
findings resulting from the use of these materials), the NIAID will
establish an arbitration process to resolve any differences of
opinion with regard to scientific- programmatic matters.  An
arbitration panel, composed of one Group designee, one NIAID
designee, 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.  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 RFA may result in the 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 Opportunistic Infections must meet the
following requirements.

The application must be from a Group and must:

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.

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-OI.

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 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 to Dr. Barbara Laughon,
Developmental Therapeutics Branch, Division of AIDS, NIAID, Solar
Building, Bethesda Maryland, 20892 in advance of the application
receipt date (see Patent Coverage above).

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.

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
participation of the NIAID Scientific Coordinator, defined under
Terms of Awards.

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).

Demonstrate that each component research 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.

Demonstrate that each component laboratory project, core facilities,
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 OIs and other pathogens and pathogen-producing
cell lines as outlined in The Federal Register, Volume 49, Number
201, Tuesday, October 16, 1984, p. 40556; include a description of
the Institutional Safety Guidelines and 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 group 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 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 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 t it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations, i.e., native
Americans [including American Indians or Alaskan Natives],
Asian/Pacific Islanders, Blacks, Hispanics.

The rational for studies on single minority populations groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but limited to clinical
studies.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissue
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 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.

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.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  In such a case, a letter of agreement from
either the GCRC program director or principal investigator could be
included with the application.

LETTER OF INTENT

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

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 and other key investigators
and their respective responsibilities.

o  Title, project leader, and institution for each component research
project and brief descriptions of the proposed projects.

o  The number and title of the RFA in response to which the
application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of applications, the information that it
contains is helpful in planning for the review of applications.  It
allows NIAID staff to estimate the potential workload of the
reviewers and to avoid possible conflict of interest in the review
process.

The letter of intent is to be sent to:

Barbara Laughon, Ph.D.
Developmental Therapeutics Branch
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2C10
Bethesda, MD  20892
Telephone:  (301) 496-8197
FAX:  (301) 402-3211

Applicants who use express mail or courier services are advised to
follow the carrier's requirements for showing a street address.  The
address of the Solar Building is 6003 Executive Boulevard, 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 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:

Scientific Review Branch, DEA
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. Diane Tingley, (301) 496-0818.  Questions
regarding responsiveness to the RFA may be directed to Dr. Barbara
Laughon, (301) 496-8197.

Receipt Date

The deadline for receipt of applications is March 10, 1993.
Applications received after this date will be considered as not
responsive to this RFA and will be returned without review.

General

o  The research grant application form 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 Inquiries, Division of Research Grants, National
Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD
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 Opportunistic Infections (NCDDG-OI)" (RFA AI-
92-15) typed on item 2a of the face page of the application form.

o  Submit two exact copies of your application directly to:

Diane Tingley, Ph.D.
Chief, AIDS Scientific Review Section
Scientific Review Branch, Division of Extramural Activities
National Institute of 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 are to use the
city and the 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.  Because of the
multi-institutional nature of a NCDDG-OI 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-OI 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

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

o  The name of the single applicant organization that will provide
and operate the Central Operations Office in accordance with the
Minimum Requirements for Application in this RFA.

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

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

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

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

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 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 budgets in excess of $650,000 total (direct and
indirect) first year costs will be returned without review.

Those applications that are complete and responsive may be subjected
to a triage by an NIAID peer review group to determine their
scientific merit 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.  A second level of review will be provided by the National
Advisory Allergy and Infectious Diseases Council.  In the event of
multiple highly qualified proposals, final funding recommendations
will be based on highest Program priorities.

REVIEW PROCEDURES AND CRITERIA

Initial scientific review of applications will be conducted by the
Scientific Review Branch, DEA, NIAID, by an appropriate committee.
The application must be directed towards the attainment of the stated
programmatic goals (see Research Goals and Objectives).  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 OIs in AIDS
patients.

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

o  Scientific and technical merit of research projects and core
components for realization of drug discovery objectives.

o  Likelihood that new potential therapies 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 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 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 within each project and within the Group as a
whole.

o  Adequacy of existing physical facilities and resources of the
Principal Investigator and Project Leaders including biohazard
containment facilities as stipulated in 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: NIAID Assistance
in Implementation and Management of Research Activities.

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.

The initial review group may make recommendations regarding
appropriateness of applicants' specific aims to programmatic goals,
deletion of projects or cores not essential to drug discovery,
administrative oversight by program staff, and disaggregation of
outstanding projects for consideration as individual research grants.
The initial review group will score each project and core within the
application individually, followed by scoring of the application as a
whole.

INQUIRIES

It is essential that prospective applicants obtain a copy of the RFA
before preparing an application.  Written and telephone requests for
the RFA and the opportunity to clarify issues or questions from
potential applicants are welcome.  Direct requests for the RFA and
inquiries regarding programmatic or scientific issues to:

Dr. Barbara Laughon
Developmental Therapeutics Branch
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2C10
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
Division of Extramural Activities
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:

Jane Unsworth
Chief, AIDS Grants Management Section
Grants Management Branch
Division of Extramural Activities
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 Human Immunodeficiency Virus
Infection (RFA AI-92-16) has been issued.  To receive a copy, please
contact Dr. Nava Sarver, Targeted Drug Discovery Section,
Developmental Therapeutics Branch, Basic Research and Development
Program, Division of AIDS, NIAID, 6003 Executive Boulevard, Bethesda,
MD 20892, telephone:  (301) 496-8197.

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 Immunologic Diseases Research.
Awards are made under the authority of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158,
42 USC 241 and 285) and administered under PHS grants policies and
Federal Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program
is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review.

.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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