Full Text AI-93-019

NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR THE TREATMENT OF
OPPORTUNISTIC INFECTIONS ASSOCIATED WITH ACQUIRED IMMUNODEFICIENCY
SYNDROME (NCDDG-OI): TUBERCULOSIS

NIH GUIDE, Volume 22, Number 32, September 3, 1993

RFA:  AI-93-019

P.T. 34

Keywords: 
  Pulmonary Diseases 
  Screening of Drugs/Agents 
  AIDS 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  November 15, 1993
Application Receipt Date:  January 21, 1994

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID)
invites applications for the establishment of National Cooperative Drug
Discovery Groups for the Treatment of Opportunistic Infections
Associated with Acquired Immunodeficiency Syndrome (NCDDG-OI) focusing
on tuberculosis.

It is the purpose of this Request for Applications (RFA) to invite
applications focused on the discovery of new, more effective,
selective, and diverse therapeutic agents to treat and prevent
infection caused by Mycobacterium tuberculosis.  Research in the
following areas is needed to provide the foundation for improvements in
therapeutics for tuberculosis (TB), particularly in the setting of HIV
infection:  unique metabolic activities for drug targeting;
biochemistry and molecular mechanisms of M. tuberculosis-host
interactions; inhibitors of enzymatic and regulatory functions and
biochemical pathways; mechanisms of overcoming drug resistance; and
identification of natural products or synthetic chemical compounds with
promise for development as TB therapies.  Research activities should be
directed toward discovery of selective drugs or molecular strategies
that are lethal for M. tuberculosis with minimal toxicity for the host.
It is anticipated that multidisciplinary approaches by scientists from
a combination of academic, non-profit research, and commercial
organizations, with the assistance of the NIAID, will be necessary to
effectively accelerate discovery of new therapeutics.

Applications that include research projects or core components from the
private sector (e.g., pharmaceutical, chemical, or biotechnological
companies) are encouraged.  M. tuberculosis is the single opportunistic
infection targeted in this RFA because of the compelling public health
emergency and the need for additional therapies to overcome multi-drug
resistant infections.  Investigators pursuing similar drug discovery
for other AIDS-associated opportunistic infections (OIs) are strongly
encouraged to apply through other research support mechanisms.

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 for-profit and non-profit
organizations, public and private organizations, such as universities,
colleges, hospitals, laboratories, units of State or 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 Cooperative
Agreement is an assistance mechanism, rather than an acquisition
mechanism, in which substantial NIAID programmatic involvement is
anticipated.  The NIAID will support and/or stimulate research activity
by collaborating and otherwise working jointly with the award recipient
in a partner role, but is not to assume direction, prime
responsibility, or a dominant role in the activity.  Details of the
responsibilities, relationships, and governance of studies funded under
a cooperative agreement are discussed later under SPECIAL REQUIREMENTS.

In applying for a cooperative agreement, the Principal Investigator
defines his/her objectives in accord with his/her interests and
perceptions of approaches to the discovery of new treatments against
tuberculosis.  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.
Respondents to this RFA may include new applications for a maximum
period of four years support and competitive supplements to currently
funded NCDDG-OI Groups for research focused on M. tuberculosis.

Because the varied talents and commitment required for effective drug
discovery will be from diverse disciplines and may be located at
geographically disparate locations, it is anticipated that Project
Leaders within a Group may be associated with different institutions.
Each application must include two projects from independent
laboratories. For the purpose of encouraging new collaborations under
this RFA, projects within a single private company will not be
considered independent.  Similarly, two projects within the same
academic department will not be considered independent.

The Group will be led by a Principal Investigator who will also lead a
scientific project.  The applicant institution of the Principal
Investigator will provide a Central Operations Office for the Group
(usually as part of the Principal Investigator's research project),
will be responsible for the performance of the entire Group, and will
be accountable for the funds awarded.

This RFA is a one-time solicitation.  Plans for continued support in
this area are indefinite at this time.  If by the end of the third year
of the award, the NIAID has not announced its intent to re-issue the
RFA, incumbents should contact NIAID program staff and consider
submitting investigator-initiated (R01) applications that will compete
with all investigator-initiated applications and be reviewed according
to the customary peer review procedures.

Under the Cooperative Agreement, a negotiated partner relationship
exists between the recipient of the award and the NIAID in which the
Group is responsive to the requirements and conditions set forth in
this RFA.  The interaction of academic and non-profit research
institutions with commercial organizations and the Government is
encouraged and is expected to favor expeditious discovery and
preclinical development of agents active against tuberculosis and to
facilitate their subsequent development for clinical trials.  All
policies and requirements that govern the grant program of the U.S.
Public Health Service and the National Institutes of Health (NIH)
apply.

FUNDS AVAILABLE

At the present time, it is estimated that no more than one to two new
Groups will be funded for drug discovery against M. tuberculosis as a
result of this RFA.  Approximately $3.4 million (including direct and
indirect costs) will be available over the four year period, including
approximately $0.8 million (direct and indirect) during the first year.
Any application received with a budget in excess of $0.8 million total
costs (direct and indirect) for the first year will be returned without
review.  Awards and level of support are dependent on the receipt of a
sufficient number of applications of high scientific merit.  Because
the nature and scope of the research proposed in response to this RFA
may vary, it is anticipated that the size of awards will vary also.
Budget requests must be adequately justified and commensurate with the
complexity of the project.  Although this program is provided for in
the financial plans of the NIAID, awards pursuant to this RFA are
contingent upon the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Acquired Immunodeficiency Syndrome (AIDS) is a disease that destroys
host immunological defenses against a variety of infections.  As of
December 31, 1992, 253,448 cases of AIDS had been reported to the
Centers for Disease Control and Prevention (CDC) and more than 171,890
(67.8%) 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 people with AIDS and are
the principal reasons for hospitalization.

Individuals infected with HIV are susceptible to a range of protozoal,
fungal, viral, and bacterial infections. Pneumocystis carinii pneumonia
(PCP) remains the most common opportunistic infection reported to the
CDC for new cases of AIDS (approximately 50% of cases in 1990).
Because of a strong epidemiological association between HIV infection
and the development of TB, the CDC has recently included pulmonary TB
in the 1993 expanded surveillance case definition for AIDS.  Persons
co-infected with HIV and TB have an increased risk of developing active
and rapidly fatal pulmonary TB compared with persons without HIV
infection.  In addition, there is an association between lowered CD4+
T-lymphocyte counts in HIV-infected individuals and localized
extrapulmonary TB or disseminated or miliary TB.

Available drugs to treat opportunistic infections including TB lack the
potency to completely eradicate infecting microorganisms without
assistance from immune mechanisms.  Prolonged HIV-mediated
immunosuppression requires prolonged treatment schedules, and
prophylaxis regimens against recurrences must often be maintained
throughout the remaining lifetime of people with AIDS.

Combined infection with HIV and M. tuberculosis has contributed to a
public health crisis in many areas of the United States, particularly
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.

The NCDDG-OI program was launched in 1990 for the purpose of
stimulating discovery research in order to lay the foundation for
development and commercialization of therapeutic agents targeted
against the AIDS-associated OIs.

Within the currently funded NCDDG-OI program, the following approaches
are presently being pursued for OIs other than TB, and therefore serve
as examples of research approaches:  molecular modelling of chemical
structures to inhibit vital metabolic enzymes; macrolide transport and
activity; immunotherapy; gene cloning, expression, and
structure-activity relationships of candidate drugs; inhibitors of
protein N-myristoylation, cell wall biosynthesis, topoisomerases;
synthesis and assay of drug analogs, unique chemical classes,
heterocyclics; development of improved animal models for in vivo drug
evaluations.

M. tuberculosis is included as an opportunistic pathogen associated
with AIDS by the CDC and within the NCDDG-OI program.  Previous RFA
issuances have focused on: Pneumocystis carinii, Toxoplasma gondii,
Cryptosporidium parvum, Mycobacterium avium, Cryptococcus neoformans,
Candida albicans, and cytomegalovirus.  Similarities that exist between
drug targets in M. avium and M. tuberculosis will provide a framework
for information exchange between investigators supported as a result of
this RFA and those already funded as Groups within the NCDDG-OI
program.  As part of the cooperative nature of this program, compounds
identified as active against any of the OIs may be shared and evaluated
by all Groups.

Because of the compelling public health need for new, more effective
therapies to overcome the threat of multi-drug resistant TB, only
research focused on M. tuberculosis will be supported under this
re-issuance of the NCDDG-OI program RFA.

Research Goals and Objectives of the NCDDG-OI Program

The goals of the NCDDG-OI program relative to this RFA are:  to foster
innovative, multi-disciplinary research, conceptualization and targeted
discovery of drugs and strategies to treat and prevent tuberculosis
(TB); to support efficacy and pharmacological evaluations leading to
selection of candidate therapies through collaboration among
investigators and with the NIAID; and to assist in the preclinical
development of therapies for evaluation in clinical trials supported by
other mechanisms.

Scientific Scope, Restrictions, and Exclusions

Applications for this NCDDG-OI RFA should stress creative approaches to
the discovery of effective therapies to treat TB through a
comprehensive team effort.  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 defense mechanisms against infectious agents.
Applications should emphasize the following:  specific scientific
objectives focusing on targeted drug discovery; integration and
coordination of research aims from different scientific disciplines;
and research rationales, plans, and approaches designed to identify
candidate therapeutics within the support period requested.  The
Group's objectives and goals must be relevant and compatible with the
NCDDG-OI program's missions and directions as stated in this RFA.

It is not a requirement of this RFA that a complete development plan
for new drugs or biological agents be proposed, 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 target
identification and drug development 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 proposed
therapies with potential for combatting multi-drug resistant
tuberculosis, improving prophylaxis approaches, practicality of
administration to HIV-infected people, and low toxicity.

Examples of research projects considered responsive to this RFA
include, but are not necessarily restricted to, the following:

o  Identification and development of drug evaluation assays for
molecular targets with selectivity for M. tuberculosis, such as
recombination repair mechanisms, elongation factors, cell wall
assembly, and others with potential for mycobactericidal consequences
of inhibition.

o  Development of drug evaluation assays for essential mycobacterial
gene products, particularly biochemical activities expressed in vivo
and associated with pathogenicity.

o  In vitro and in vivo evaluation of new chemical entities with
potential for mycobactericidal activity within a framework of logical
plans that examine structure-activity relationships and potential
toxicities.

o  Development, validation, and implementation of drug evaluation
systems capable of predicting bactericidal and sterilizing activity of
new agents, or combinations of agents against M. tuberculosis.

o  Studies on the effects of drugs on slow-growing M. tuberculosis,
such as those found in granulomatous tubercular lesions, identification
of drugs with extended lengths of biological activity, and development
of methods to assess post-antibiotic effect on M. tuberculosis.

o  Development, validation, and implementation of improved models for
in vivo drug evaluations, such as immunosuppressed animals, or animals
with disrupted interferon-gamma or other immune effector genes.

o  Development and evaluation of biological entities, such as
recombinant mycobacteriophage as drug or suicide gene delivery
vehicles, and evaluation of these for efficacy and safety.

o  Identification and development of systems to predict emergence of
resistance to established and newly identified antibiotics, and to
evaluate new therapies for their ability to prevent or overcome
resistance.

Discovery and evaluation of new potential therapeutics is the major
goal of this initiative.  It is anticipated that no more than one or
two Groups will be supported to pursue drug discovery research against
M. tuberculosis as a result of this RFA.  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 may be withheld until compounds generated by the Group are
available for animal efficacy studies.  It is strongly encouraged that
discovery of new mycobactericidal targets and associated therapies with
selectivity for these targets be the focus of all applications.

Exclusions:  Random or large scale screening of compounds will not be
supported.  Organisms other than M. tuberculosis causing infections
associated with AIDS have been excluded from this RFA.  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, R43
(Small Business Innovative Research Program), Interactive Research
Project Grants, or other existing funding mechanisms.  No clinical
trials will 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 certain developmental tasks supported by other mechanisms (NIAID
Staff Responsibilities:  Nature of NIAID Participation).

DEFINITIONS

ADMINISTRATIVE SUPPORT - Administrative efforts that provide support
for the overall management of the cooperative agreement and services
shared by the Group as a whole.  Administrative support for the Group's
activities should be included in that of the Principal Investigator's
project, and be administered by the Principal Investigator's
organization.

ARBITRATION PANEL - A panel that may be formed to review any scientific
or programmatic activity that is impeding progress within a Group.  It
will be 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 "Terms of Award".

AWARDEE INSTITUTION - The 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 in
accordance with PHS policies.

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

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

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
tuberculosis.

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.
Two 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 tuberculosis.  All applications must
consist of two independent Projects conducted by at least two
independent laboratories.  For the purpose of this RFA, two projects
within a single company or within a single academic department will not
be considered independent.  This limitation on the number of
independent projects from the same academic department or private
sector company is intended to increase the diversity and
multi-disciplinary expertise available to the Group.

An NCDDG-OI Group consists of the following:  (1) a Principal
Investigator, (2) two research projects, (3) a Scientific Advisors
Panel, and (4) an NIAID Scientific Coordinator (see below).

NIAID NCDDG-OI PROGRAM DIRECTOR - A Senior Scientist of the NIAID
extramural staff who coordinates NIAID's participation in the NCDDG-OI
program.

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
will be assigned to each Group by the NCDDG-OI program director.

PRINCIPAL INVESTIGATOR - The person who assembles the NCDDG-OI, who is
responsible for the performance of the Group as a whole and who submits
the single application in response to this RFA.  The Principal
Investigator will coordinate Group activities scientifically and
administratively and should be project leader of one of the Research
Projects of the Group.

PROJECT LEADER - The leader of one of the scientific research projects
of the NCDDG-OI who is directly responsible to the Principal
Investigator.  Project Leaders will not be supported by more than one
Cooperative Agreement awarded under this RFA unless the research is
clearly and separately delineated in each application.  Individuals
currently supported under an existing NCDDG-OI or other programs may be
funded under this RFA provided there is no scientific or budgetary
overlap in funded activities.

RESEARCH PROJECT - A discrete, specified project with a separate budget
that relates to the overall theme and objectives of the NCDDG-OI.  A
maximum of two research projects per Group is stipulated.

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 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.  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 the first year of funding.

The Panel will provide the Principal Investigator and the NIAID
Scientific Coordinator with a comprehensive written review of the
Group's activity during the second and third years of funding.  Reviews
will encompass timeliness of progress in individual projects relative
to original projections; progress relative to the Group's objectives
and needs; continued relevance of a given project to the Group's
function; continued coordination of the Group's objectives with the
objectives of the NCDDG-OI program; and recommendations for new
directions, as appropriate.  The Principal Investigator will invite the
Scientific Coordinator to all meetings of the Panel, which may be
combined with Group meetings.

SCIENTIFIC SUPPORT CORE COMPONENT - Facilities for equipment and
services which are shared by two projects of the NCDDG-OI may be
provided for within a Research Project.  Examples of Scientific Support
Core components are:  biochemical assays, in vitro or animal model
testing, production of monoclonal antibodies, scale-up synthesis of
drugs.  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 research plan of the projects
and in adequate detail to enable the evaluation of its scientific and
technical merit.

A CORE COMPONENT cannot be considered toward fulfilling the required
two research projects per Group. (See details for preparation of the
budgets under XI. APPLICATION PROCEDURES).

SPECIAL REQUIREMENTS

Terms and Conditions of Award

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

A.  Working Relationships Within a Cooperative Agreement

Under the Cooperative Agreement, a negotiated partner relationship
exists between the recipient of the award and NIAID in which the Group
is responsive to the requirements and conditions set forth in this RFA.
The participation of the Government through the NIAID extramural staff
is intended to facilitate a concerted effort by all members of the
network of Groups by providing appropriate scientific input, by
coordinating efforts among Groups, by making available to Groups
biological materials for testing, by accessing appropriate data bases,
and by providing ancillary testing and other resources, such as
reagents, samples or experimental animals, available under existing
Government contracts.  The interaction of academic and non-profit
research institutions with commercial organizations and Government is
strongly encouraged and is expected to favor expeditious preclinical
discovery and development of new drugs for the treatment of
tuberculosis.

B.  Patent coverage

Since the discovery of agents active against tuberculosis 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 the potential for involvement of multiple institutions,
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.

Attention is drawn to the reporting requirements of 35 U.S.C. Parts
200-212 and 37 CFR Part 401 or FAR 55.227-11. Instructions were also
published in the NIH GUIDE FOR GRANTS AND CONTRACTS, Vol. 19, No. 23,
June 22, 1990.  Note that non-profit organizations (including
universities) and small business firms retain the rights to any patent
resulting from Government contracts, grants or Cooperative Agreements.

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

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.

C.  Awardee Rights and Responsibilities and Nature of NIAID
Participation

It is the primary responsibility of the Principal Investigator to
clearly define 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.

Meetings

a.  Two mandatory Group meetings are required per year.  The Principal
Investigator and Project and Core Leaders will meet to review progress,
plan and design research activities, and establish priorities within
the Group.  The Principal Investigator will be responsible for
scheduling the time and place (generally at one of the performance
sites), for notifying the Scientific Coordinator at least thirty days
prior to the meeting date, and for preparing concise (2-3 pages)
minutes or summaries of the Group meetings which will be delivered to
the members of the Group including the Scientific Coordinator within
thirty days following the meeting.  NIAID Scientific Coordinator will
participate but not chair Group meetings.

b.  One mandatory meeting of the entire NCDDG-OI program will be held
each year at a site designated by NIAID (Bethesda, Maryland is
anticipated) during which all Principal Investigators and Project
Leaders will present significant findings in symposium format.  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.

c.  Group communications.  A critical determinant of Group success will
be the degree of communication among members.  Therefore, in addition
to the three meetings listed above, additional meetings for
coordination of Group activities may be necessary.  Regular telephone
and written communication will be important and are encouraged.

d.  Groups will designate a Scientific Advisors Panel within the first
year of funding.  The Principal Investigator will convene a meeting, or
meetings, of the Group with the Panel during the second and third years
which may be in conjunction with the required Group meetings (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 with a comprehensive written review (2 to 3
pages) of the Group's activity each year.  Members of the Panel will
not be affiliated with any of the institutions comprising the Group.

Publications

The Principal Investigator will be responsible for the timely
submission to the Scientific Coordinator 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 Leader 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.

Publications or oral presentations of work done under this Agreement
are the responsibility of the Principal Investigator and appropriate
Project Leader.

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 whole
(or in part) by the NCDDG-OI program, cooperative agreement number
U01-AI-12345, NIAID."

Progress Reports

An annual Progress Report will be submitted with the Application for
Continuation Grant which must include significant experimental data
obtained and 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.

The Progress Report must also include basic information as instructed
with PHS 2590 Noncompeting Continuation Application forms.

Rights to Data

Although the NIAID Scientific Coordinator has a right of access to the
data (see NIAID staff responsibilities below), the applicant will
retain custody of and rights to the data.  Information obtained from
the data may be used by the Scientific Coordinator for the preparation
of internal reports on the Group's activities.  Timely publication of
major findings is strongly encouraged.

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
may have supplied the compounds for testing through NIAID.

The applicant institution and the Principal Investigator will be
responsible for the Group's application.  The award will be made to the
applicant institution on behalf of the Group as a whole and not to
individual research projects within the Group.  The applicant
institution will provide a Central Operations Office for the Group,
will be responsible for the performance of the entire Group, and will
be accountable for the funds awarded.

D.  NIAID Staff Responsibilities:  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 awarding component
(NIAID) anticipates substantial programmatic involvement during
performance of the research program.  NIAID shall participate as a
member of the Group and shall be represented by a Scientific
Coordinator or the NCDDG-OI program director.  The Coordinator shall 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.

During performance of the award, the NIAID Scientific Coordinator, may
provide appropriate assistance, advice, and guidance by:  participating
in the design of Group activities; advising in the selection of sources
or resources; 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 will be reached by
consensus of the Group and that NIAID staff 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.

o  NIAID Participation in Design of Group Activities, Development of
Research Protocols and Evaluation of Results

a.  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, but not in the execution,
of experiments agreed to by the Group; and may participate in the
analysis of results.

b.  The NIAID Scientific Coordinator may assist the Group or other
individual members in research planning, particularly by:

o  providing needed resources and information that may not be otherwise
be available to the Group;

o  providing data from testing conducted in resource contract
laboratories;

o  providing information concerning work being conducted in other
NIAID-supported extramural projects, in order to reduce or prevent
duplication of efforts.

c.  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 NIAID has a contract
program for the preclinical development of compounds for the treatment
of AIDS-associated opportunistic infections, including animal models.
These resources are intended for initial studies and may not be
available on a continual basis.  Examples of potential assistance
include:  reference compounds for standardization of test systems,
facilitation of confirmatory testing at research sites including other
NCDDG-OI Groups, limited testing in appropriate animal model(s),
focused searches of NIAID's computer files of chemical structures and
biological activity, chemical re-synthesis, analysis, formulation, and
toxicology testing through existing pre-clinical development contracts
(contingent upon NIAID's recommendation and prioritization), and
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.

In addition, the NIAID supports Phase I, Phase II and Phase III
clinical trials through a variety of mechanisms.  These clinical
development resources are available to study promising therapies
brought forward from sources such as the NCDDG-OI program.  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.

NIAID Participation in 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.

a.  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 including tuberculosis.  Subsequent
developmental work through private resources is encouraged.
Alternatively, the Group may recommend that development be sponsored by
NIAID (see below).  In the latter case, it will be necessary for the
Principal Investigator, appropriate Project Leaders and NIAID
Scientific Coordinator to collaborate in the analysis, summarization,
preparation, and presentation of data to the appropriate NIAID staff
and its advisory committees.

b.  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.

E.  Arbitration Process

Inasmuch as certain activities under VIII. Special Requirements: Terms
and Conditions of Award 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, 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.

These special Terms and Conditions of Award 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.

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

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  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.  If so, 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 November 15, 1993, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address, telephone number, and institution
of the Principal Investigator, descriptive title, name of prospective
project leaders and other key investigators, and the institution for
each component research project, and the number and title of this 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.

The letter of intent is to be sent to Dr. Dianne Tingley at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

Special Instructions for Preparing Applications

These instructions for preparing the NCDDG-OI application supplement
the instructions found in form PHS 398 (rev. 9/91), which is available
as an application kit at most grantee institutions and from the
Division of Research Grants, Office of Grants Information, National
Institutes of Health 5333 Westbard Avenue, Room 449, Bethesda, MD
20892, telephone 301-710-0267.  Additional instructions are required
because the form PHS 398 is designed primarily for individual research
grant (R01) applications, whereas the Group application consists of
research projects interrelated by a common theme.  Items that require
modification for U01 applications, in addition to other information not
requested in form PHS 398, are detailed below:

A.  Introductory Section

Face Page of Form PHS 398

Complete items 1 through 18 as instructed.  Please note that this
should be Page 1 of the entire application; all succeeding pages should
be numbered consecutively.  To ensure 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-93-019" typed on item 2a of the face page
of the application form and the YES box must be marked.

o  Overall Description.  Use Page 2 of Form PHS 398

Provide a succinct but accurate description of the OVERALL goals of the
NCDDG-OI, addressing the major, common theme of the Group.  Do not
exceed space provided.

Under "Key Personnel Engaged on Project," list the Principal
Investigator of the overall NCDDG-OI, followed by the Project Leaders
of the component research projects and cores and then the other key
personnel.

o  Table of Contents.  Use Page 3 of Form PHS 398

The NCDDG-OI application should be assembled and paginated as one
complete application.   Bearing in mind that the application will be
scientifically reviewed project by project, prepare a detailed table of
contents that will enable reviewers to readily locate specific
information pertinent to the overall U01 application as well as to each
component research project and core.  A page reference should be
included for each summary budget (overall) as well as the budget for
each project.  Further, each project should be identified by number,
title and responsible Project Leader.  Page locations of summary tables
following suggested formats shown in Tables I-IV of this document
(APPENDIX) should be indicated in the Table of Contents.

o  Composite Budget

To aid in peer review, applicants are requested to prepare a Composite
Budget for the first twelve month budget period using a format such as
that shown in Table I of this RFA.  Do not use page 4 of form PHS 398
for this purpose.  Detailed justification for budget elements should
not be presented here, but in the individual budget of the projects and
cores.

Summary budgets should be prepared for the total Group application.
The maximum dollar request permitted under this RFA is $0.8 million
total costs (direct and indirect) during the first year, and $3.4
million over the four year period.

o  Summary Budget by Category.  Use page 5 from the Form PHS 398

Prepare a Summary Budget by category for ALL YEARS of the requested
support.

o  Personnel Listing and Distribution of Effort for "Other Support"

Applicants are requested to list all professional and non-professional
participants in the Group, including those with no salary requested,
for the first year of requested support using a format such as that
shown in Table II.  Using a format such as Table III, a similiar
distribution of professional effort (%) for other support would be
helpful for peer review.

o  Research Plan

a.  Program Introduction - Statement of Group Objectives

The NCDDG-OI should be viewed as a program of interrelated research
projects -- each capable of standing on its own scientific merit, but
complementary to one another.  It is very important to establish the
programmatic theme in the first few sentences describing the
collaboration.  The introduction is an important section, for it
provides the investigator an opportunity to give conceptual wholeness
to the overall program by giving a statement of the general problem
area and by laying out a broad strategy for attacking the problems.

The introductory section should briefly state the rationale of the
research proposed in each project describing how it relates to drug
discovery and the anticipated approach to achieve the work proposed.
It is essential to 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; i.e., it is
important to show that the total personnel of the Group are sufficient
in quality, number, and committed time and effort to assure successful
conduct of the proposed research.

Therefore, the first section of the NCDDG-OI application should
contain:

o  A clear, concise plan in narrative and diagrammatic form that
depicts the interrelationships among the members of the NCDDG-OI and
the contribution of each to fulfillment of Group objectives.

o  An organizational chart of the NCDDG-OI showing the name,
organization, and scientific discipline of the investigators comprising
the Group.

o  A plan to ensure maintenance of close collaboration and effective
communication among members of the Group in accord with Section VIII,
Special Requirements. The application should include plans for
scheduling Group meetings, notifying Group members, including the NIAID
Scientific Coordinator, and documenting and disseminating Group meeting
proceedings.

o  Letters of commitment to the overall plan and acceptance of the
participation of the NIAID Scientific Coordinator.

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

o  The anticipated unique advantages to be expected from the Group
operating within the proposed collaborative efforts; how the projects
are mutually reinforcing; and how collectively they will further the
stated goals of the proposed research.

b.  Organizational and Administrative Structure of the NCDDG-OI

Describe in detail and by diagram the chain of responsibility for
decision-making and administration beginning at the level of Principal
Investigator and including the different research Project Leaders and
other investigators. Indicate where in the chain of responsibility
advisory groups will be used. Describe their role in establishing
quality control of the research efforts.

c.  Consortium Arrangements

An application that includes research activity involving institutions
other than the sponsoring organization is considered a consortium
effort.  It is imperative that care be taken in preparing any
consortium application so that the programmatic, fiscal, and
administrative considerations are fully explained.  The policy
governing consortia is described in the NIH GUIDE FOR GRANTS AND
CONTRACTS (Vol. 14, No. 7, June 21, 1985), which should be available at
the sponsoring institution's business office, or in the Office of
Grants Inquiries' publication entitled, "Guidelines for Establishing
and Operating Consortium Grants," January 1989, which may be obtained
by calling 301-710-0267.  These guidelines should be read carefully
before an application is developed.  If clarification of the guidelines
is needed, the applicant is encouraged to contact grants management
staff, Ms. Jane Unsworth, at 301-496-7075.

d.  Patent Coverage

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 this U01.

NOTE:  A formal statement of Patent Agreement among all
Group members and their institutions as well as a detailed
description of procedures to be followed for the resolution
of legal problems which 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 in advance of the
application receipt date (for Dr. Laughon's complete address
see INQUIRIES, below.)

Should the Group wish to place all inventions and
discoveries resulting from these studies within the public
domain, a letter to that effect must be submitted to Dr.
Laughon in lieu of the patent agreement prior to submission
of the application.  The letter must be co-signed by the
Principal Investigator, Project Leaders, and each of the
business officials representing the respective institutions.

B.  Individual Research Projects

The strength of the application will be judged mainly on the basis of
the quality of each research project. Therefore, the reviewers will
expect each project to be described in the same detail as for a regular
research grant application, to enable them to judge the scientific
merit solely on the basis of the written applications.

The portion of the application for each component research project
should be prepared in the same manner as an R01 application, following
carefully the instructions found in the grant application kit form PHS
398 (rev. 9/91).  A few modifications are pointed out below for
selected items, to address the interactive, collaborative contributions
of the individual project.

Face Page of Form PHS 398.  Complete a Face Page of form PHS 398 for
each project.

Page 2 of form PHS 398.  Provide an abstract of the research proposed
in the project.  Prepare the abstract according to the instructions
provided on page 2 of form PHS 398.  In addition, the abstract should
contain a brief description of how the research project will contribute
towards attainment of the Group's objectives.

Under "Personnel Engaged on Project", follow instructions on page 2 of
PHS 398, listing all individuals participating in the project,
beginning with the Project Leader.

Page 3 of Form PHS 398.  Prepare a Table of Contents for the research
project using page 3 of form PHS 398.

Pages 4 and 5 of Form PHS 398.  Detailed first year budget and budget
for entire project period: follow instructions on pages 16-19 of the
form PHS 398 instructions.  The budget pages should have the project
number and the project leader's name in the upper left hand of each
budget page.  Funds for attending the Group meetings and the annual
NCDDG-OI program meeting (section VIII.C.1) should be included in the
budget.  Funds to cover operating costs of the NCDDG-OI program annual
meeting may be contributed by one or more Groups.  NIAID will provide
administrative supplements for this purpose, as needed.  Funds to cover
expenses incurred by the Scientific Advisors Panel should be included
in the Principal Investigator's component of the application.

Pages 6 - 7 of Form PHS 398.  Provide the biographical sketches and
information on "Other Support" of all participating investigators in
the Project.  FOLLOW INSTRUCTIONS CAREFULLY.  If a similar R01 or R29
is submitted concurrently or is pending, it should be so stated in this
section.  Incomplete, inaccurate or ambiguous information about OTHER
SUPPORT, whether active or pending, may lead to delays in the review of
the application.

Research Plan:  Follow the instructions indicated in IV. C., pages 19
through 22 of the form PHS 398 Instructions, completing items 1 through
4 in detail.  In addition, attention should be given to integration of
the component project into the overall Group project.  As with a
regular research grant application, the overall research plan for each
project should not exceed 25 pages (from Specific Aims through Research
Design and Methods).  The following points should be addressed in the
appropriate sections.

Item 1 - Specific Aims:  In addition to listing the specific objectives
for the total period of requested support for the component, state the
overall objective or long-term goal of the research and its
relationship to the goals of the NCDDG-OI and how it relates to other
projects or cores in the Group.

Item 2 - Significance:  In addition to the overall biological
significance of the proposed research, this section should indicate the
relevance of the project to the drug discovery efforts of the Group.

Item 7 - Collaborative Arrangements:  This item should include a brief
statement of the collaborative contribution that this project will make
towards the achievement of the Group's objectives, and with which
component projects it will actively interact.  Collaborative
arrangements anticipated, either internal or external to the Group
should be described and documents with letters from collaborating
investigators.

C.  Scientific Core Support

Scientific core support units, if required, must be included as
subprojects within the budgets of one of the Projects.  Core support
may be provided as consortia if performed at institutions different
from that of the Principal Investigator (see Consortium Arrangements,
above.)

Describe the role and importance of the core as a resource to the
NCDDG-OI as a whole. Indicate the specific service(s) such core support
will provide and the projects it will serve, e.g., production of
monoclonal antibodies and distribution to research projects 1 and 2.
This section should present a clear description of the facilities,
techniques, and professional skills that the core will provide.  The
role of the core leader and each of the key participants should be
described.  The portion of the application describing each scientific
core should be prepared with the same level of detail as an R01
application in order for the technical merit and appropriateness of
each core to be evaluated.

A summary table following the format suggested in Table IV (Appendix)
should be submitted listing any cores and showing the apportionment of
core resources between the research projects.

In the event that any core support subproject is located at an
institution other than that of the project it supports, the following
form PHS 398 pages should be used and the instructions for preparing a
consortium budget should be followed:

Face Page Form PHS 398.  Complete the form and enter a descriptive name
of the requested core (e.g., Administrative Core, Monoclonal Antibody
Production Core) in item 1, Title of Project.

Pages 4 and 5 of Form PHS 398:  Complete the budget pages providing
justifications with the same detail as in research projects.  The
budget for core units should be presented according to the instructions
indicated on pages 16-19 of the form PHS 398 Instructions. A detailed
budget is required for the first year (form PHS 398, page 4) and a
budget summary for all additional years (form PHS 398, page 5).
Explicit detailed budget justifications for all years should be
included.

Pages 6 - 8 of form PHS 398.  Provide the biographical sketches and
information on "Other Support" of all participating investigators in
the Core.  FOLLOW INSTRUCTIONS CAREFULLY.   Incomplete, inaccurate or
ambiguous information about OTHER SUPPORT, whether active or pending,
may lead to delays in the review of the application.  Include
information required to describe Resources and Environment available to
the Core as well as appropriate sections pertaining to vertebrate
animals.

D.  General Instructions

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 institutional offices of sponsored research, and from the Office
of Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone (301) 710-0267.

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.

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) applications kit will be judged
non-responsive and will be returned to the applicant.

The applicant may include additional detailed information in an
appendix, but this should be limited only to information essential to
the application.  Item D of form PHS 398:  "Specific Instructions,
Appendix" should be carefully followed in preparing appendix material.
Applicants are advised to place data or information crucial to the
research plan within the application itself and not in the appendix;
failure to abide by this requirement may result in an inadequate
review.  All appended material must be clearly labelled and
cross-referenced to indicate the specific project to which it applies.
Prepare five sets of the appendix, including only relevant reprints,
making sure that the reprints are cross-referenced to specific projects
as well.

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

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

At the same time as the submission to DRG, send two additional exact
copies of the application with the five sets of appendices, in a
separate package, directly to:

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

Applications must be received by January 21, 1994.  Applications
received after that date will be returned without review.  The Division
of Research Grants (DRG) will not accept an application in response to
this RFA which is essentially the same as one pending initial review,
unless the applicant withdraws the pending application.  DRG will not
accept an application which is essentially the same as one already
reviewed.  Simultaneous submission of identical applications will not
be allowed, nor will essentially identical applications to be reviewed
by different review committees.  This restriction is superseded by an
NIH policy permitting concurrent submission of a duplicate R01 and a
component of a multi-project application.  The NIH policy however,
further stipulates that should both the R01 and the multi-project
application be considered for funding, the R01 will be relinquished in
favor of the multi-project application.

REVIEW CONSIDERATIONS

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 $800,000 total (direct and
indirect) first year costs will be returned without review.

Those applications that are complete and responsive may be subjected to
triage by an NIAID peer review group before or during the scientific
review, 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 that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by an appropriate review committee convened by the NIAID.  In the
event of multiple, highly qualified applications, final funding
recommendations will be based on highest Program priorities.  The
second level of review will be provided by the National Advisory
Allergy and Infectious Diseases Council.

Review Criteria

The application must be directed towards the attainment of the stated
programmatic goals (see Research Objectives).  The following factors
are the criteria used by peer review groups in the scientific and
technical review of applications for drug discovery:

o  The scientific and technical merit of the program as a whole, as
well as that of each individual research project and core components,
for realization of drug discovery objectives; the scientific and
technical significance of the overall program goals; the development of
a well-defined central research focus; and originality and uniqueness
of proposed research.  Each project must be supportable on its own
merit.

o  Relevance of the Group's objectives to the discovery of new entities
and strategies for the treatment of tuberculosis and the likelihood
that new potential therapies will be identified during the course of
the proposed study.  Priority will be given to proposed therapies with
potential for combatting multidrug resistant tuberculosis, improving
prophylaxis approaches, practicality of administration to HIV-infected
people, and low toxicity.

o  Specific competencies of the Principal Investigator and Project
Leaders to conduct the proposed work: documented research experience,
commitment, and time availability of Principal Investigator, Project
Leaders, and other key personnel.  While there is no mandatory 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 effort by the Principal Investigator and each
Project Leader may be important to the success of the Group.

o  Documented research experience and accomplishments of investigators
in the research areas outlined in the RFA; accomplishments of the Group
to date (for competitive supplement applications).

o  Technical merit of proposed methods for producing and evaluating
test materials, and technical sufficiency of methods for evaluation of
new discoveries, test systems, models, etc.

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

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.

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 review each project and core within the
application individually, followed by scoring of the application as a
whole.

AWARD CRITERIA

The primary criterion for award is the scientific and technical merit
of the application as judged by peer reviewers and reflected in the
priority score.  Additional award criteria are the availability of
funds, receipt of a sufficient number of scientifically meritorious
applications that are responsive to this RFA, and overall programmatic
relevance and priority.

INQUIRIES

The opportunity to clarify issues or questions about the RFA
from potential applicants is welcome.  Direct inquiries
regarding the RFA and programmatic issues should be sent to:

Barbara Laughon, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2C35
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 402-2304
FAX:  (301) 402-3211

Inquiries pertaining to review of applications may be directed to:

Dianne Tingley, Ph.D.
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
FAX:  (301) 402-2638

Inquiries regarding fiscal matters may be directed to:

Ms. Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B22
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7075
FAX:  (301) 480-3780

Schedule

Letter of Intent Receipt Date:  November 15, 1993
Application Receipt Date:       January 21, 1994
Scientific Review Date:         March 1994
Advisory Council Date:          June 1994
Award Date:                     July/August 1994

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 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 grant 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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