Full Text AI-95-014

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

NIH GUIDE, Volume 24, Number 29, August 11, 1995

RFA:  AI-95-014

P.T. 34

Keywords: 
  AIDS 
  Infectious Diseases/Agents 
  Microbiology 
  Drug Design 
  Biomedical Research, Multidiscipl 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  November 1, 1995
Application Receipt Date:  December 21, 1995

PURPOSE

The Opportunistic Infection Research Branch (OIRB) of the Treatment
Research Program in the Division of AIDS (DAIDS), National Institute
of Allergy and Infectious Diseases (NIAID), invites cooperative
agreement applications on the discovery and rational design of new
therapies with potential to treat and/or prevent infection caused by
opportunistic infections (OIs) in individuals infected with HIV.  The
opportunistic pathogens emphasized in this RFA are Mycobacterium
tuberculosis, Cryptosporidium parvum, and the Microsporidia (e.g.,
Enterocytozoon bieneusi, Septata intestinalis).  Responsive
applications will be directed toward discovery of selective drugs or
molecular strategies that are lethal for these pathogens with minimal
toxicity for the host.  Investigators pursuing similar drug discovery
for other AIDS-associated opportunistic infections (OIs) are strongly
encouraged to contact program staff listed under INQUIRIES to discuss
opportunities for support through other research support mechanisms.

Applications that include collaborations, research projects or core
components from the private sector (e.g., pharmaceutical, chemical,
or biotechnological companies) are strongly encouraged.  It is
anticipated that multidisciplinary approaches by scientists from a
combination of academic, non-profit research, and commercial
organizations, with the assistance of NIAID, will be necessary to
effectively accelerate discovery of new therapeutics.  The focus of
this RFA is on targeted drug discovery research; random or large
scale screening as well as clinical trials will not 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 RFA,
National Cooperative Drug Discovery Groups for the Treatment of
Opportunistic Infections in AIDS, 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 Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202/512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local government, and
eligible agencies of the Federal government.  Foreign organizations
are not eligible to apply as the primary institution, although
domestic applications may contain international components (projects
or cores).  Racial/ethnic minority individuals, women, and persons
with disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this
program will be the cooperative agreement (U01 or U19), an
"assistance" mechanism in which substantial NIH scientific and/or
programmatic involvement is anticipated.  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.
Cooperative agreements may include a combination of academic,
non-profit research, and commercial organizations; applications that
include collaborations, research projects, or core components from
industry are strongly encouraged.  Awards are made to the
institutions of each Principal Investigator, either as a U01 or U19
mechanism.  U01 awards may consist of one or two collaborative
projects.  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; and (3) common resources termed "cores," each of which must be
utilized by at least two research projects within the group program
(see also "APPLICATION PROCEDURES" in this RFA).  Details of the
responsibilities, relationships, and governance of a study funded
under a cooperative agreement are discussed in the RFA under the
section Terms and Conditions of Award.  At this time, the NIAID is
administratively limiting the duration of cooperative agreement
awards to four years.  The total project period proposed in
applications may not exceed four years.  The anticipated award date
is August-September 1996.  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 $2.4 million.  Because the nature and scope of the research
proposed in response to this RFA may vary, it is anticipated that the
size of a cooperative agreement award will vary also.  Individual
research projects, whether they are single (as for U01s) or part of a
multiple project proposal (two maximum for U01s, three or more for
U19s), should be approximately in the budget range of $ 175,000 to
225,000 total costs for the first year.  U01 applications with two
projects should not exceed $450,000 in first year total costs.  U19
applications received with budgets in excess of $800,000 first-year
total costs will be returned without review.  In Fiscal Year 1996,
the NIAID plans to make a total of three to six awards from new and
recompeting applications.  This includes approximately one group for
drug discovery against each of these high priority OIs:
Mycobacterium, Cryptosporidium, and the microsporidia (e.g.,
Enterocytozoon, Septata).  Although this program is provided for in
the financial plans of the NIAID, awards pursuant to this RFA are
contingent upon program priority and the availability of funds for
this purpose.

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 hospitalizations and deaths as well as diminishing
quality of life.  The intent of this project is to foster research in
mycobacterial and diarrheal disease arenas that have not been
adequately addressed by either the government or the private sector.
Mycobacterial infections have become an increasing cause of morbidity
among this population and has led to a public health imperative.
Epidemiologic evidence has shown that disease progression of TB is
much more rapid among individuals with AIDS compared to that in the
general population.  In addition, new TB cases are further
complicated by the lack of an effective treatment for drug-resistant
strains of M. tuberculosis.  New therapies for treating TB have not
emerged from the private sector.

Currently, no effective therapies exist for Cryptosporidium parvum or
the enteric Microsporida.  Progressive weight loss and debilitation
are often inevitable consequences of infection with these agents, and
malnutrition has been recognized as a major cause of morbidity in
this disease. Severe diarrhea and weight loss associated with
intestinal damage and malabsorption are life-threatening in the acute
phase; in the chronic state these agents are also responsible for
poor absorption of medications, and a particularly devastating
quality of life for the individuals affected.

Available treatments for mycobacteria and the infectious causes of
AIDS-related diarrhea do not have adequate potency to completely
eradicate the infections.  Further, HIV-mediated immunosuppression
requires prolonged treatment schedules and prophylaxis regimens
against recurrence of infections.  The management of these infections
is complicated by toxicity and adverse side effects of therapeutic
agents, development of drug resistance, the occurrence of relapses,
and simultaneous infections with other OIs.  Due to the absence of
support by the pharmaceutical industry, the high morbidity and
mortality associated with these diseases requires government
promotion of new drug discovery research.

The NCDDG-OI program was launched in 1990 for the purpose of
stimulating targeted drug discovery research, development and
commercialization of therapeutic agents directed against
AIDS-associated OIs.  The program has supported over 20 cooperative
agreements focusing on selected opportunistic pathogens, including
Pneumocystis carinii, Toxoplasma gondii, Cryptococcus neoformans,
Candida albicans, Histoplasma capsulatum, Cryptosporidium parvum,
Mycobacterium avium, and M. tuberculosis.  The goals of the NCDDG-OI
program 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 preclinical 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 solicit applications for research
projects aimed at the discovery, rational design, and preliminary
development of new therapies against the OIs associated with AIDS.
Applications should reflect a comprehensive, multidisciplinary
approach to the study of potential new therapies:  this can be
accomplished through collaborations in single project applications,
or through multiple-project applications for Group awards.  Original
and innovative research is encouraged in areas such as 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.  Random or large scale
screening as well as clinical trials will not be supported under this
RFA.

Examples of responsive studies to be supported by this RFA include,
but are not limited to:

1.  characterization and further development of molecular targets;

2.  exploitation of biochemical and metabolic differences between
pathogen and host to develop new therapeutics;

3.  design and use of new assay systems for identification of active
compounds;

4.  development of innovative animal models and culture systems to
test the therapeutic efficacy of compounds, particularly in an
immunocompromised setting;

5.  elucidation of mechanisms of drug resistance and strategies to
overcome such resistance.

All proposed studies should carefully consider issues of toxicity of
the candidate compounds, in view of the ultimate potential for
clinical application.

SPECIAL REQUIREMENTS

A.  Minimum Requirements for NCDDG-OI Applications

Applications may consist of a single project or two or more
interrelated projects focusing on a unifying central theme. A minimum
20 percent effort by the Principal Investigator and each Project
Leader should be devoted to the proposal, unless there are compelling
arguments to the contrary. Investigator responsibilities and group
organization is detailed in the following section.

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.  Award will be made to the
Principal Investigator's institution as a cooperative agreement,
either a U01 or U19 award mechanism.  U01 awards may consist of one
or two collaborative projects.  A U19 award is for three or more
independent laboratory research projects.  Each group is intended to
represent diverse scientific disciplines that join together under a
Principal Investigator and function as a unit with a common goal.

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.  The program director 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
application, 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 20 percent
effort by the Principal Investigator should be devoted within the
overall Group effort.  The Principal Investigator's institution may
establish and operate a 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.  A project leader is expected to commit a
minimum of 20 percent effort to the project.

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:  U19 awards, i.e., groups consisting
of three or more interrelated research projects, will have 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.  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.  The Principal Investigators
budget should include travel funds for the Panel to attend one group
meeting a year, starting from the second year.

8.  SCIENTIFIC SUPPORT CORE COMPONENT:  One or more cores may be
proposed to provide facilities for equipment and/or 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 that 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.

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.  Since several institutions may be involved,
complex patent situations may arise.  Each applicant Group must,
therefore, provide a detailed description of the approach to be used
for obtaining patent coverage and for licensing where appropriate, in
particular where the invention may involve investigators from more
than one institution.  Each Group must provide a detailed description
of the procedures to be followed for the resolution of legal problems
that may develop (see "Application Procedures, Part D" in this RFA).
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, National Institutes of Health,
Building 31, Room 5B62, 9000 Rockville Pike, Bethesda, MD 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 (U01 or 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.  A U01 award consists of 1 or
2 collaborative projects.  The U19 contains 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 Scientific Advisors Panels 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.
Funds to support Panel member travel should be included in the
Principal Investigator's budget.  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 should 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-or 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 that 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.  Copies of
publications or reprints should be appended.  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
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: provision of 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.  The Government provides
its consulting and testing services in the interest of expeditious
pre-clinical and clinical development of experimental anti-infective
agents.

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 1.

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 sub-populations 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 28, 1994 (FR 59 14508-14513) and printed in
the NIH Guide for Grants and Contracts, Volume 23, Number 11, March
18, 1994.

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

LETTER OF INTENT

Prospective applicants are asked to submit, by November 1, 1995, 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 identities of other key personnel and
participating institutions, 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 a subsequent application, the information that it
contains allows NIAID staff to estimate the potential review workload
and 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 research grant application
form PHS 398 (rev. 5/95).  The application form 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, Room 3032, 6701 Rockledge Drive, MSC
7762, Bethesda, MD 20892-7762, telephone (301) 710-0267 (e-mail:
GIRG@DRGPO.DRG.NIH.GOV).

The RFA label available in the PHS 398 (rev.5/95) application form
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, for purposes of identification and
processing, item 2 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 IN AIDS
(NCDDG-OI)" must be typed in.  Applications must be received by
December 21, 1995.

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 APPLICATION
GUIDELINES FOR MULTIPROJECT RESEARCH AWARDS, 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.

Applications must address the requirements below as outlined in the
section "SPECIAL REQUIREMENTS"; see also NIAID APPLICATION GUIDELINES
FOR MULTIPROJECT RESEARCH AWARDS.

A.  Composition of the Program Overview 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
that may be derived 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.

7.  Applications that are recompeting should describe accomplishments
and progress made toward the scientific aims in the previous award. A
rationale for new specific aims in the current applications should be
provided that is based on knowledge gained in the course of the
previous award.

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 office of sponsored research, or in
the Office of Grants Information's publication entitled "Guidelines
for Establishing and Operating Consortium Grants", January 1989,
which may be obtained by calling (301) 710-0267.

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 or U01.
"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

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.  Research projects that are re-competing should describe progress
made toward previous scientific aims and a rationale for proposed
changes in aims or scope.

3.  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. 5/95), and as modified in NIAID APPLICATION
GUIDELINES FOR MULTIPROJECT RESEARCH AWARDS, SPECIFIC INSTRUCTIONS:
INDIVIDUAL RESEARCH PROJECTS.

F.  Scientific Core Support

1.  The application should describe the role and importance of the
core as a resource to the Group 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.  Cores on recompeting applications should provide a description of
productivity and utilization by project investigators under the
previous award.

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

4.  The budget for each scientific core should be presented according
to the instructions of the form PHS 398 (rev. 5/95); see also NIAID
APPLICATION GUIDELINES FOR MULTIPROJECT RESEARCH AWARDS, SPECIFIC
INSTRUCTIONS: CORES.

Applications must be received by December 21, 1995.  All components,
subparts and sections of the application must be collated into the
application, and the packages sent to the DRG and to the NIAID must
each be complete in themselves.  Applications that do not conform to
the instructions contained in PHS 398 (rev. 5/95) application kit
will be judged non-responsive and will be returned to the applicant.

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
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/overnight services)

At the time of submission, two additional exact copies of the grant
application and all five sets of appendix material must also be sent
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 could be included
with the application.

Applications must be received by December 21, 1995.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (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

Review Method

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.  U19
applications with first year total costs (direct and indirect) in
excess of $800,000 will be returned without review.

Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants (DRG) and for responsiveness by NIAID
staff.  Incomplete and/or non-responsive applications will be
returned to the applicant without further consideration.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIAID in accordance with the review
criteria stated below.  As part of the initial merit review, all
applications will receive a written critique and undergo a process in
which only those applications deemed to have the highest scientific
merit, generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council or board.  For
applications found non-competitive, summary statements will be very
brief and will generally contain a one paragraph resume, based on
reviewers' comments, indicating the major reason(s) for the findings.

Those applications judged by the reviewers to be competitive for
award will be further reviewed for scientific and technical merit by
a review committee convened by the Division of Extramural Activities,
NIAID.  The second level of review will be provided by the National
Advisory Allergy and Infectious Diseases Council.

Review Criteria

The review criteria for this RFA are the same as those for
unsolicited research project grant applications.  In addition,
applicants are expected to address the issues identified under
special requirements as well as criteria specific to the objectives
of this RFA.  These criteria are:

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 and potentially practical
therapeutic strategies will be identified during the course of the
proposed project.

3.  For recompeting Groups, accomplishments and progress as defined
by the scientific aims of each project and core of the previous
award, including toxicity data supportive of eventual clinical
utility.

4.  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.

5.  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.

6.  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.

7.  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 20 percent effort by the Principal
Investigator (total Group effort) and each Project Leader should be
devoted to the study, unless there are compelling arguments to the
contrary.

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

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

10. Adequacy of plans to include both genders and minorities and
their subgroups as appropriate for the scientific goals of the
research.  Plans for the recruitment and retention of subjects will
also be evaluated.

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 and duration 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
also examine the provisions for the protection of human and animal
subjects and the safety of the research environment. 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 decisions 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 requests for the RFA and inquiries regarding
programmatic issues to:

Barbara Laughon, Ph.D.
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2C26
6003 Executive Boulevard
Bethesda, MD  20892-7620
Telephone:  (301) 402-2304
FAX:  (301) 402-3171
Email:  Barbara_Laughon@nih.gov

Direct inquiries regarding application preparation and review and
address the letter of intent to:

Dianne Tingley, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C07
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-2550
FAX:  (301) 402-2638
Email:  dianne_tingley@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Lesia Norwood
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B22
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  Lesia_Norwood@nih.gov

Schedule

Letter of Intent Receipt Date:  November 1, 1995
Application Receipt Date:       December 21, 1995
Scientific Review Date:         March 1996
Advisory Council Date:          June 1996
Anticipated Award Date:         August-September 1996

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.855 Immunology, Allergic and Immunological Diseases
Research and 93.856 Microbiology and Infectious Diseases Research.
Grants are awarded under the authority of the Public Health Service
Act, Section 301 (42 USC 241) and administered under PHS grants
policies and Federal Regulations, most specifically at 42 CFR Part 52
and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of the Executive Order 12372 or
Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.

.

Return to RFAs Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.