Full Text AI-94-014

NATIONAL COOPERATIVE DRUG DISCOVERY GROUPS FOR THE TREATMENT OF
OPPORTUNISTIC INFECTIONS ASSOCIATED WITH TUBERCULOSIS IN AIDS

NIH GUIDE, Volume 23, Number 12, March 25, 1994

RFA:  AI-94-014

P.T.


Keywords: 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  July 15, 1994
Application Receipt Date:  August 11, 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
and Tuberculosis Associated with Acquired Immunodeficiency Syndrome
(NCDDG-OI).

The Developmental Therapeutics Branch (DTB) of the Division of AIDS
(DAIDS), NIAID, invites applications focused on the discovery and
rational design of new therapies with potential to treat and/or
prevent specific opportunistic infections (OIs) in individuals
infected with HIV.  Opportunistic pathogens targeted in this RFA are
human cytomegalovirus (HCMV), Mycobacterium tuberculosis,
Mycobacterium avium, Pneumocystis carinii, Cryptosporidium parvum,
Toxoplasma gondii, the microsporidia (e.g., Enterocytozoon bieneusi,
Septata intestinalis), and Cryptococcus neoformans.  Research
activities should be directed toward discovery of selective drugs or
molecular strategies that are lethal to the pathogen with minimal
toxicity for the host.  Multidisciplinary approaches by scientists
from consortia of academic, non-profit research, and commercial
organizations, with the assistance of the NIAID, will be necessary to
effectively accelerate discovery of new therapeutics for OIs
associated with AIDS.  Applications that include research projects or
core components from the private sector (e.g., pharmaceutical,
chemical or biotechnological companies) are encouraged.

No clinical trials will be supported under this RFA.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), National Cooperative Drug Discovery Groups
for the Treatment of Opportunistic Infections Associated with AIDS
(NCDDG-OI) Including Tuberculosis, 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
government, and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this
program will be the Cooperative Agreement (U19), an "assistance"
mechanism (rather than an "acquisition" mechanism), in which
substantial NIH scientific and/or programmatic involvement with the
awardee is anticipated during the performance of the activity.
Essential elements of the U19 mechanism include:  (1) a minimum of
three inter-related research projects organized around a central
theme; (2) collaborative efforts and interaction among independent
projects and their investigators to achieve a common goal; (3) a
single Principal Investigator who will be scientifically and
financially responsible for the use and disposition of funds awarded;
and (4) support provided, as necessary, for "Core" resources or
facilities, each of which is expected to  be utilized by at least two
research projects in order to facilitate the research effort.  Under
the cooperative agreement, the NIH purpose is to support and/or
stimulate the recipient's activity by involvement in and otherwise
working jointly with the award recipient in a partner role, but it is
not to assume direction, prime responsibility, or a dominant role in
the activity.  Details of the responsibilities, relationships, and
governance of a study funded under cooperative agreement(s) are
discussed later in this document under the section "Terms and
Conditions of Award."

The total project period for applications submitted in response to
the present RFA may not exceed four years.  The anticipated award
date is April/May 1995.  At this time, the NIAID has not determined
whether or how this solicitation will be continued beyond the present
RFA.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for
the first year of support for awards under this RFA reissuance will
be $5.6 million; estimated total project costs (direct and indirect)
over the four-year period will be $23.8  million.  Applications
received with budgets in excess of $700,000 first-year total costs
will be returned without review.  In Fiscal Year 1995, the NIAID
plans to fund approximately 7 to 9 applications, anticipating at
least one group each for drug discovery against these high priority
OIs: HCMV, Mycobacterium tuberculosis, Mycobacterium avium,
Pneumocystis carinii, Cryptosporidium parvum, Toxoplasma gondii, the
microsporidia (e.g., Enterocytozoon bieneusi, Septata intestinalis),
and Cryptococcus neoformans.  It is anticipated that ten existing
NCDDG-OI Groups targeting antimycobacterial, antifungal,
anti-toxoplasma, and anti-HCMV drugs will be eligible to recompete.
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.

The usual PHS policies governing grant administration and management
will apply.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Funding
beyond the first and subsequent years of the grant will be contingent
upon satisfactory progress during the preceding years and
availability of funds.

RESEARCH OBJECTIVES

Background

The principal causes of morbidity and mortality in AIDS are
opportunistic infections (OIs).  Although HIV causes AIDS and is
responsible for the progressive immunological deterioration seen in
this disease, the OIs account for the vast majority of all
AIDS-related deaths as well as diminishing quality of life.  OIs are
also the principal reasons for hospitalization.  Individuals infected
with HIV are susceptible to a range of viral, bacterial, protozoal,
and fungal infections and the pathological consequences are retinitis
(HCMV), tuberculosis (Mycobacterium tuberculosis), disseminated
nontuberculosis mycobacterial disease (Mycobacterium avium),
pulmonary disease (Pneumocystis carinii), encephalitis (Toxoplasma
gondii), diarrhea (Cryptosporidium parvum, microsporidia), and
meningitis (Cryptococcus neoformans).

Available drugs to treat opportunistic infections (including
tuberculosis) do not exhibit adequate potency to completely eradicate
infecting organisms, and prolonged HIV-mediated immunosuppression
requires prolonged treatment schedules and prophylaxis regimens
against recurrence of infections. Overall, the management of OIs in
AIDS patients is difficult and complicated due to:  (1) simultaneous
infections with other OIs; (2) toxicity and adverse side effects of
therapeutic agents; (3) long-term drug use leading to patient
intolerance or pathogen drug resistance; (4) occurrence of relapses
after discontinuation of therapy; and (5) lack of effective therapies
for newly emerging OIs.

The NCDDG-OI program was launched in 1990 for the purpose of
stimulating research for development and commercialization of
therapeutic agents targeted against AIDS-associated OIs.  The goals
of the NCDDG-OI are:  (1) the conceptualization, discovery and
preclinical development of therapies designed to effectively treat
OIs in individuals infected with HIV; (2) the conduct of biological,
biochemical, and pharmacological studies leading to selection of
potential therapies; and (3) the recommendation of therapies,
entities or strategies for development in clinical trials.

Objectives and Scope

The purpose of this RFA is to foster multi-disciplinary research
projects aimed at the discovery and rational design of new therapies
against the OIs associated with AIDS.  The objective is to stimulate
drug discovery through original and innovative research focused on
the microbiology, molecular biology, chemistry, computer-assisted
drug design, drug delivery vehicles, and animal models that will lead
to the identification of new drug targets.  Additionally, this RFA
will foster the development of improved in vitro assays for drug
screening, predicting drug efficacy through animal models, and
development of surrogate markers of efficacy to circumvent slow
culture of organisms.  Ultimately, this research should lead to the
development of safe, well-tolerated, and effective new drug therapies
for treatment and prophylaxis against the high priority OIs. Research
objectives in this RFA reissuance include, but are not necessarily
limited to:

o  the discovery and development of effective therapies to treat high
priority opportunistic infections associated with AIDS;

o  identification and characterization of new molecular targets for
exploitation toward selective virucidal, mycobactericidal,
parasiticidal, and fungicidal therapeutic agents;

o  establishment and utilization of in vitro assays for selected
molecular targets to identify active compounds and biologicals, and
to guide synthesis of new compounds or analogs;

o  refinement of novel and innovative animal models to evaluate the
therapeutic potential of new compounds and to compare efficacy in
normal and immunocompromised models;

o  development of improved methodologies or surrogate markers for
assessing therapeutic efficacy in animal models; and

o  elucidation of mechanisms of drug resistance and study of
strategies to overcome such resistance.

SPECIAL REQUIREMENTS

A.  Minimum Requirements for NCDDG-OI Application

All applications must consist of at least three interrelated projects
focusing on a unifying central theme conducted by at least three
independent laboratories.  For the purpose of encouraging new
collaborations under this RFA, two (or more) projects within a single
company will not be considered independent.  Similarly, two (or more)
projects within the same academic department will not be considered
independent.  This limitation on the number of independent projects
from the same academic or private sector organization is intended to
increase the diversity and multi-disciplinary expertise available to
the Group from other than the parent institution or organization.
Random or large scale screening as well as clinical trials will not
be supported under this RFA.  A minimum 10 percent (time) effort by
the Principal Investigator and each Project Leader should be devoted
to the study, unless there are compelling arguments to the contrary.

B.  Definitions

1.  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.  Each group may consist of  a number of scientific
investigators from academic and/or non-profit research institutions
as well as scientists from commercial organizations, performing
research on interdependent projects.  The minimum requirement is
three independent laboratory research projects representing diverse
scientific disciplines and organizations, which join together under a
Principal Investigator and function as a unit with a common goal.  A
CORE COMPONENT cannot be used toward fulfillment of the three
research projects requirement.

2.  NIAID NCDDG-OI PROGRAM DIRECTOR:  A Senior Scientist of the NIAID
extramural staff who coordinates NIAID's participation in the
NCDDG-OI program, oversees the entire NCDDG-OI program, maintains the
overall scientific balance in the NCDDG-OI program commensurate with
new research and therapeutic findings and emerging research
opportunities, and who ensures that the NCDDG-OI program is
consistent with NIAID's missions and goals.

3.  NIAID SCIENTIFIC COORDINATOR:  A Senior Scientist of the NIAID
extramural staff who functions as a peer with the Principal
Investigator and Project Leaders and who facilitates the partnership
relationship between NIAID and each Group.  The Scientific
Coordinator is the immediate contact person to the Group and is
assigned by the NCDDG-OI program director.

4.  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.  A minimum 10 percent
(time) effort by the Principal Investigator should be devoted to the
study.  The Principal Investigator's institution establishes and
operates the Central Operations Office that funds Group members and
is legally and fiscally accountable for the disposition of funds
awarded.

5.  PROJECT LEADER:  The leader of one of the scientific research
projects of the NCDDG-OI who is directly responsible for the
scientific conduct of that project and also directly responsible to
the Principal Investigator.

6.  RESEARCH PROJECT:  A discrete, specified project with a separate
budget that relates to the unifying central theme and objectives of
the NCDDG-OI.

7.  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.  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; members of the Panel will not be
affiliated with any of the institutions comprising the Group.

8.  SCIENTIFIC SUPPORT CORE COMPONENT:  Facilities for equipment and
services which must be utilized by at least two research projects in
order to facilitate the research effort.  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 minimum
of three research projects per Group.

C.  Patent Coverage

Because the discovery of innovative, effective drug therapies for OIs
is the goal of this effort, and since active involvement by private
sector laboratories is facilitated by the existence of adequate
patent coverage, it is essential that applicants provide plans to
ensure such coverage.  With the potential for involvement of several
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.  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.

It is also noted that a Presidential memorandum of February 18, 1983
extended to all business concerns, regardless of size, the first
option to the ownership of rights to inventions as provided in P.L.
96-517.  As a result of this memorandum, the relationships among
industrial organizations and other participants are simplified, since
all Group members can now be full partners in the research and in any
inventions resulting therefrom.  The specific patenting arrangements
among 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 37 CFR 401 and HHS Inventions regulations
at 45 CFR Parts 6 and 8 require that NIH be informed of inventions
and licensing occurring under NIH funded research.  Invention and
licensing reports must be submitted to Extramural Invention Reports
Office, Office of Extramural Research, Building 31, Room 5B41, NIH,
9000 Rockville Pike, Bethesda, Maryland 20892.

D.  Terms and Conditions of Award

The following terms and conditions will be incorporated into the
award statement and provided to the Principal Investigator as well as
the institutional official at the time of award.

The following special terms of award are in addition to, and not in
lieu of, otherwise applicable OMB administrative guidelines, HHS
grant administration regulations at 45 CFR Parts 74 and 92 [Part 92
is applicable when State and local Governments are eligible to
apply], and other HHS, PHS, and NIH grant administration policies

The administrative and funding instrument used for this  program is
the Cooperative Agreement (U19), an "assistance" mechanism (rather
than an "acquisition" mechanism), in which substantial NIH scientific
and/or programmatic involvement with the awardee is anticipated
during the performance of the activity.  The U19 must contain a
minimum of three inter-related research projects organized around a
central theme.  A Core resource or facility must be utilized by at
least two research projects.  Under the Cooperative Agreement, the
NIH purpose is to support and/or stimulate the recipient's activity
by involvement in and otherwise working jointly with the award
recipient in a partner role, but it is not to assume direction, prime
responsibility, or a dominant role in the activity.  Consistent with
this concept, the dominant role and prime responsibility for the
activity resides with the awardee(s) for the project as a whole,
although specific tasks and activities in carrying out the study will
be shared among the awardees and the NIAID Scientific Coordinator.

1.  Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the details
for the project within the guidelines of the RFA and for performing
the scientific activity, and agree to accept close coordination,
cooperation, and participation of NIAID staff in those aspects of
scientific and technical management of the project as described under
"NIAID Staff Responsibilities".  Specifically, awardees have primary
responsibilities as described below:

Meetings and Scientific Advisors Panel

Two 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.  The NIAID Scientific Coordinator
will participate but not chair Group meetings.

One mandatory meeting of the entire NCDDG-OI program will be held
each year at a site designated by NIAID during which all Principal
Investigators and Project Leaders will attend and 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.

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.
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 (2-3 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 and Presentation of Findings

Early publication of major findings is encouraged.  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 U19-AI-1234, 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 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 assays).  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

While the NIAID Scientific Coordinator has a right of access to the
data, 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.  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.

2.  NIAID Staff Responsibilities

The NIAID shall participate as a member of the Group and shall be
represented by a Scientific Coordinator or the NCDDG-OI program
director.  The Scientific 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.  The
NIAID Scientific Coordinator will have substantial
scientific/programmatic involvement during the conduct of this
activity through technical assistance, advice and coordination such
as 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.

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.

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.

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
pre-clinical 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.

3.  Arbitration Process

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between award recipients and the
NIAID may be brought to arbitration.  An arbitration panel will be
composed of three members -- one Group designee, one NIAID designee,
and a third designee with expertise in the relevant area and chosen
by the other two.  This special arbitration procedure in no way
affects the awardee's right to appeal an adverse action that is
otherwise appealable in accordance with PHS regulations 42 CFR Part
50, Subpart D and HHS regulation at 45 CFR Part 16.

STUDY POPULATIONS

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 9, 1994 (FR 59 11146-11151) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

(NOTE:  When the proposed study or studies in the RFA or PA involves
a gender specific study or a single or limited number of minority
population groups, this should also be stated to inform potential
applicants and reviewers.)

NOTE:   Peer review groups need adequate information about the
composition of proposed study populations in all applications
involving human subjects.  To  avoid delays in review of such
applications, the NIAID therefore requires that, as a minimum, the
application must contain demographic data about the clinic and/or
in-patient population from which the study subjects will be drawn:
average hospital admissions per year; percentage distribution of
black/hispanic/other minority/non-minority populations; gender; etc.
Studies using non-hospital populations, such as community-based
studies, should provide similar data about populations in the area or
region from which the study subjects will be drawn.  In the absence
of current data, historical demographic information and/or previous
recruitment data for similar studies from the proposed sites should
be provided.

LETTER OF INTENT

Prospective applicants are asked to submit, by July 15, 1994, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator, the number and title of this RFA, and a list
of the key investigators and their institution(s) and projects.
Although the letter of intent is not required, is not binding, does
not commit the sender to submit an application, and does not enter
into the review of subsequent applications, the information that it
contains allows NIAID staff to estimate the potential review workload
and to avoid 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

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 9/91).  For purposes of identification
and processing, item 2a on the face page of the application must be
marked "YES" and the RFA number and the words "NATIONAL COOPERATIVE
DRUG DISCOVERY GROUP FOR TREATMENT OF OPPORTUNISTIC INFECTIONS
(NCDDG-OI)" must be typed in.  Applications must be received by
August 11, 1994.

Applications from multi-component consortia must contain a single
face page. an overall budget page, and separate budget pages for each
institution involved.  Each consortium institution is allowed 25
pages for the research plan if different plans are proposed by the
different member institutions.  Because of the multi-institutional
nature of and the special requirements in this RFA, additional
instructions regarding format are contained in NIAID POLICY ON
MULTIPROJECT APPLICATIONS (PROGRAM PROJECT GRANTS AND MULTIPROJECT
COOPERATIVE AGREEMENTS), which is available from the program staff
listed under INQUIRIES.  If a conflict exists between instructions as
presented in the program policy guidelines and this RFA, this RFA
takes precedence.

The application forms may be obtained from the institution's office
of sponsored research or its equivalent, 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) 435-0714.

Applications must address the requirements below as outlined in the
section "SPECIAL REQUIREMENTS."

A.  Composition of First Section of the Application

1.  It is suggested that applications provide 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 that meets
the scope of this RFA.

2.  It is suggested that applications provide an organizational chart
of the NCDDG-OI showing the name, organization, and scientific
discipline of the investigators comprising the Group.

3.  Applications are to provide a plan to ensure maintenance of close
collaboration and effective communication among members of the Group.
The application should include plans for scheduling Group meetings,
notifying Group members including the NIAID Scientific Coordinator,
and documenting and disseminating Group meeting proceedings.

4.  Applications must include letters of commitment to the overall
plan and acceptance of the participation of the NIAID Scientific
Coordinator.

5.  Applications are to provide a rationale for the drug discovery
approach(es) proposed and discussion of the therapeutic approaches
which may derive from the research projects.

6.  Applications should present 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

The application should describe in detail and by diagram the chain of
responsibility for decision-making and administration beginning at
the level of the Principal Investigator and including the different
research Project Leaders and other investigators.  Where in the chain
of responsibility advisory groups will be used should be indicated
and their role in establishing quality control of the research
efforts should be described.

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) 435-0714.

D.  Patent Coverage Agreement

1.  The application should provide a description of the Group's plan
for assuring adequate patent coverage of new inventions that may
arise as a result of Government funding of this U19. "Invention" is
defined as a new drug or innovative treatment that is or may be
patentable under Title 35 of the United States Code.  A copy of the
proposed patent plan among the institutions comprising the Group must
be submitted with the application.  This patent agreement, signed and
dated by the organizational officials authorized to enter into patent
arrangements for each Group member and member institution, must be
delivered two weeks prior to submission of the application to Dr.
Barbara Laughon at the address listed under INQUIRIES.

2.  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.

E.  Individual Research Projects

1.  The strength of the complete application package will be judged
mainly on the basis of the quality of each research project.
Reviewers will expect each project to be described in the same detail
as for a regular research grant application to enable the reviewers
to judge the technical and scientific merit solely on the basis of
the written applications.

2.   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
form PHS 398 (rev. 9/91).

F.  Scientific Core Support

1.  The application should describe the role and importance of the
core as a resource to the NCDDG-OI as a  whole and the specific
service(s) such core support will provide and the projects it will
serve.  The facilities, techniques, and professional skills that the
core will provide should be described.  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.

2.  Core support may be provided as consortia if performed at
institutions different from that of the Principal Investigator.

3.  The budget for each scientific core should be presented according
to the instructions of the form PHS 398 (rev. 9/91); see also NIAID
POLICY ON MULTIPROJECT APPLICATIONS (PROGRAM PROJECT GRANTS AND
MULTIPROJECT COOPERATIVE AGREEMENTS).

All components, subparts and sections of the application must be
collated into the application, and the packages sent to the Division
of Research Grants (DRG) and to the NIAID must each be complete in
themselves.  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 nonresponsive and will be returned to the applicant.

The RFA label in the application form PHS 398 must be affixed to the
bottom of the face page of the application.  Failure to use this
label could result in delayed processing of the application such that
it may not reach the review committee in time for review.  In
addition, the RFA title and number must be typed on line 2a of the
face page of the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including
the checklist; and three signed, exact, single-spaced photocopies in
one package to:

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

At the time of submission, also submit two additional exact copies of
the application, and five sets of the appendix and reprints directly
to Dr. Dianne Tingley at the address listed under INQUIRIES.

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 should be included
with the application.

Applications must be received by August 11, 1994.  If an application
is received after that date, it  will be returned to the applicant
without review.  The DRG will not accept any application in response
to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending
application.  The DRG will not accept any application that is
essentially the same as one already reviewed.  This does not preclude
the submission of a substantial revision of an application already
reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

General Considerations

All applications will be judged on the basis of the scientific and
technical merit of the proposed projects and the documented ability
of the investigators to meet the RESEARCH OBJECTIVES of the RFA.
Applications with first year total costs (direct and indirect) in
excess of $700,000 will be returned without review.

Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants and for responsiveness by NIAID
staff.  Incomplete applications will be returned to the applicant
without further consideration.  If the application is not responsive
to the RFA, it will be returned without further consideration.

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

Those applications judged by the reviewers to be competitive for
award will undergo further scientific merit review by an appropriate
peer review group convened by the Division of Extramural Activities,
NIAID.  The second level of review will be provided by the National
Advisory Allergy and Infectious Diseases Council.

Review Criteria

Scientific Considerations

1.  The scientific and technical merit of the application as a whole
as well as that of each individual research project and core
components, for the realization of drug discovery objectives.
Evaluations will be based on originality, novel and unique ideas, and
the incorporation of state-of-the-art approaches and methodologies of
the proposed project towards the attainment of the stated
programmatic goals.  Each project must be supportable on its own
merit;

2.  Relevance of the Group's objectives to the discovery of new
entities and strategies for the treatment of opportunistic infections
and the likelihood that innovative preclinical therapeutic strategies
will be identified during the course of the proposed project.  Groups
that are recompeting must demonstrate and document progress as
defined by the goals of the program;

3.  The cohesiveness, multi-disciplinary and multifaceted scope of
the application and the coordination and interdependence of the
individual projects and core(s) to the common theme;

4.  The justification for and the usefulness to the various research
projects of the core facilities.  The relationship of each core to
the central focus of the overall project.  Each core unit must
provide essential facilities or service for two or more individual
research projects;

5.  The leadership, scientific ability, and administrative competence
of the Principal Investigator for the development, implementation,
and management of the research program; and the Principal
Investigator's commitment to devote sufficient time and effort to the
program;

6.  The qualifications, experience, and commitment of the
investigators responsible for the individual research projects
(Project Leaders) or core(s) (Core Leaders) and their contribution to
the program, including their ability to devote adequate time and
effort to the Group.  It is anticipated that, due to the complexity
and time required to maintain a well-coordinated and productive
research effort, a minimum 10 percent (time) effort by the Principal
Investigator and each Project Leader should be devoted to the study,
unless there are compelling arguments to the contrary;

7.  Research training, experience and accomplishments of other
participating investigators and support personnel in the Group in the
research areas outlined in the RFA;

8.  Provisions for the protection of human subjects and the humane
care of animals; adequacy of biohazard containment facilities;

9.  Adequate representation of women and/or minorities in clinical
research populations.

Administrative Considerations

1.  Academic environment and resources in which the research will be
conducted, including the availability of space, equipment, human
subjects, animals, or other resources as required, and the potential
for interaction with scientists from other departments and/or
participating institutions;

2.  Documented commitment of Institutions represented by Group
members; documented capability of the Principal Investigator's
Institution to serve as the Central Operations Office for the Group;

3.  Soundness of the administrative and organizational structure that
facilitates attainment of the objective(s) of the program;

4.  Institutional strength, stability, and commitment to research and
to the program, including fiscal responsibility and management
capability to assist the Principal Investigator and staff in
following DHHS, PHS, and NIH policies;

5.  Administrative planning and leadership capability to provide for
internal quality control of on-going research, allocation of funds,
day-to-day management, internal communications and cooperation among
the investigators involved in the program, contractual agreements,
and replacement of the Principal Investigator, if required, on an
interim or permanent basis;

6.  Documented commitment of the sponsoring institution to the
cooperative agreement and willingness to accept the participation and
assistance of NIAID staff (Scientific Coordinator);

7.  Appropriateness of the budget in relation to the proposed
program.

The initial review group can make recommendations regarding
appropriateness of the applicant's 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,
in order to strengthen applications.  The initial review group will
review each project and core within the application individually,
followed by scoring of the application as a whole.

Council Review Stage

The second level review will be conducted by the National Advisory
Allergy and Infectious Diseases Council.  Factors that will be
considered in this review include:

1.  Results of the initial scientific and technical merit review;

2.  Significance to NIAID program goals in microbiology, infectious
diseases, allergy,  transplantation immunology, immunologic diseases,
or AIDS;

3.  National needs and NIAID program balance;

4.  Policy and budgetary considerations.

AWARD CRITERIA

Award criteria will be made on the basis of scientific and technical
merit as determined by peer review, program needs and balance, and
the availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues 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) 401-3211

Direct letters of intent, and inquiries regarding application
preparation and review 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

Direct inquiries regarding fiscal matters 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:  July 15, 1994
Application Receipt Date:       August 11, 1994
Scientific Review Date:         November 1994
Advisory Council Date:          February 1995
Anticipated Award Date:         April/May 1995

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.856 - Microbiology and Infectious Diseases
Research and No. 93.855 - Immunology, Allergic and Immunologic
Diseases Research.  Awards will be 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 Parts 52 and
45 CFR Part 74 [and Part 92 when applicable for State and Local
governments].  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency
review.

The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the american people.

.

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