AUTOIMMUNITY CENTERS OF EXCELLENCE

Release Date:  May 29, 1998

RFA:  AI-98-010

P.T.

National Institute of Allergy and Infectious Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Office of Research on Women's Health

Letter of Intent Receipt Date: December 8, 1998
Application Receipt Date: January 8, 1999

APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST BE
PREPARED USING SPECIFIC INSTRUCTIONS IN THE NIAID BROCHURE ENTITLED
"INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" (September 1997).

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National
Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the
Office of Research on Women's Health (ORWH) invite applications for
Autoimmunity Centers of Excellence.  The purpose of this cooperative research
program is to support integrated basic, pre-clinical and clinical research
centers to: conduct single site and multi-site cooperative clinical trials and
studies of mechanisms of action of tolerance induction and new immune
modulation interventions in multiple autoimmune diseases; accelerate early
translation of basic findings into clinical application; facilitate the
utilization of clinical materials for basic research studies; enhance the
exchange of information between basic scientists and clinicians and among
various specialists involved in treating autoimmune diseases; and establish a
collaborative approach to clinical and basic research among multiple
institutions in various geographic areas.  Each Center will include: 1) a
clinical component, incorporating multiple clinical specialists to conduct
trials and clinical studies of new immunotherapies for autoimmune diseases in
cooperation with other Center clinical components, and 2) two or more
multidisciplinary, interactive basic and/or pre-clinical research components,
focused on elucidation of the basic mechanisms of autoimmunity, self tolerance
and/or immune modulation.  The basic and clinical components of all Centers
will work cooperatively to select, design, and perform the clinical
trials/studies and the adjunct basic mechanistic studies.  All applicants must
comply with the stipulations outlined in the section of this RFA entitled
"SPECIAL REQUIREMENTS."

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, Autoimmunity Centers of
Excellence, is related to the priority area of diabetes and chronic disabling
conditions.  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

Research grant applications may be submitted by domestic for-profit and non-
profit organizations, public and private institutions, such as universities,
colleges, hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Foreign organizations are not
eligible to apply.  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 Multiproject Cooperative Agreement (U19), an "assistance"
mechanism, rather than an "acquisition" mechanism.  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.  Essential elements of the
multiproject cooperative agreement mechanism also include: (1) a minimum of
three interrelated individual 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 administratively responsible for
the group effort; (4) a single applicant institution that will be legally and
financially responsible for the use and disposition of funds awarded; and (5)
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.  Details of the responsibilities,
relationships and governance of a study funded under a cooperative agreement
are discussed later in this document under the section "Terms and Conditions
of Award."

The total project period for an application submitted in response to this RFA
may not exceed five years.  At present, the NIAID is administratively limiting
the duration of U19 cooperative agreements to four year; this administrative
limitation may change in the future.

FUNDS AVAILABLE

The estimated total funds (direct and indirect) available for the first year
of support for this RFA will be $2.9 million:  $2.25 million from NIAID,
$300,000 from the Office of Research on Women's Health, NIH, $250,000 from
NIDDK, and $100,000 from NIAMS.  In fiscal year 1999, the NIAID plans to make 
approximately three awards under this RFA.  Applicants requesting in excess of
$750,000 in total (direct and indirect) first-year costs must obtain approval
from the program contact, listed under INQUIRIES, prior to submission.  This
level of support is dependent on the receipt of a sufficient number of
applications of high scientific merit. NIAID will also fund by a separate
solicitation a Data and Operations Center to support the Autoimmunity Centers
of Excellence.

The usual PHS policies governing grants administration and management will
apply.  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.  Funding beyond the first and subsequent years of the
grant will be contingent upon satisfactory progress during the preceding years
and availability of funds.

At this time, the NIAID has not determined whether or how this solicitation
will be continued beyond the present RFA.

RESEARCH OBJECTIVES

Background

Autoimmune disease results from direction of an immune response towards the
body's own tissues.  The most common of these diseases include systemic lupus
erythematosus, multiple sclerosis, type 1 diabetes mellitus, and rheumatoid
arthritis.  However, the immune response toward self can affect any organ or
organ system, resulting in a wide variety of autoimmune diseases, including
autoimmune myositis, thyroid disease, oophoritis and orchitis, hepatitis,
hemolytic anemia, pemphigus, inflammatory bowel disease, and alopecia.  Many
of these autoimmune diseases by themselves are considered orphan diseases, but
in toto autoimmune diseases disproportionately afflict millions of women in
this country.  The costs of these diseases are enormous, including
hospitalizations, outpatient visits, lost productivity, and decreased quality 
of life for patients and their families.

The underlying immune mechanisms of these multiple diseases may be
overlapping.  Specifically, self-reactive T cells play an important role in
the immune responses leading to many of these clinically divergent diseases. 
The presence, number, activity, and specificity of these self-reactive cells
are regulated by complex processes involving multiple molecules and
mechanisms.  These include the binding and presentation of antigen by the
molecules of the major histocompatibility complex (MHC), the number and
affinity of specific T cell receptors for these complexes, the presence of co-
stimulatory molecules, including the B-7 and CD40 families, the activity of
regulatory T cells, both T helper and T cytotoxic cells, the presence and
pattern of extracellular mediators including cytokines, lymphokines, and
chemokines, and the intracellular pathways leading to apoptosis or cell death. 
Strategies to interrupt the immune response at any of these sites could
prevent or down regulate the self-reactive response leading to autoimmune
disease.  In fact, agents which block co-stimulatory signals (anti-CD40L,
CTLA4-Ig) or cytokines (anti-TNF-alpha, TNFR:Fc, IL-1Ra), interrupt or alter
binding of antigen to MHC (antigen peptides, MHC peptides, peptide oligomers),
or modulate the appearance and activity of regulatory cells (various cytokines
and anti-cytokines) are now being evaluated for treatment of multiple
autoimmune diseases.  Other approaches are likely to be discovered in the next
few years.  Clinical evaluation of new immune interventions in various
diseases has often been performed without basic mechanistic studies to define
the actions of the experimental agents.  Closer interaction between clinicians
and basic scientists should accelerate clinical testing of new approaches to
tolerance induction and immune modulation and enhance understanding of their
underlying mechanisms of action.

Since the affected organ systems vary in different diseases, autoimmune
diseases are treated by multiple clinical specialists.  Thus, multiple
sclerosis is treated by neurologists, type 1 diabetes, Graves' disease, and
Hashimoto's thyroiditis by endocrinologists, systemic lupus erythematosus,
rheumatoid arthritis, and scleroderma by rheumatologists, idiopathic
thrombocytopenia purpura by hematologists, and inflammatory bowel disease by
gastroenterologists; many diseases are treated by multiple specialists. 
Because all these diseases will be increasingly approached with immunologic
interventions, a cooperative group with the capability to evaluate a new agent
in any of a number of diseases offers considerable advantages.  Increased
interaction of clinical specialists in planning, performance, and evaluation
of trials/studies should lead to a more coordinated approach to development of
new immune-based therapies for all autoimmune diseases.

Research Objectives and Scope

The major goal of this program is to support an integrated basic and clinical
research program focused on tolerance induction and immune modulation to
prevent or treat autoimmune disease.  The close interaction between basic
researchers and clinicians will accelerate the translation of basic advances
to the clinic and the utilization of patient materials for basic research. 
NIAID is seeking multidisciplinary centers that emphasize new ideas, novel
approaches, and state of the art technology to increase our understanding of
the basic mechanisms of autoimmunity and self tolerance and the translation of
that knowledge to design and evaluate clinical interventions to prevent or
treat autoimmune diseases.  The clinical components of the Autoimmunity
Centers of Excellence will perform pilot or exploratory clinical trials or
clinical studies, hereafter designated clinical trials/studies, in patients
with autoimmune disease(s) to test, evaluate, develop, or determine mechanism
of action of agents or interventions to prevent or treat autoimmune disease by
induction of tolerance or immune modulation.  While industry has supported
some translational activities, industry-supported trials have generally not
focused on questions about the basic mechanisms of action of these agents. 
Collaboration of the Autoimmunity Centers of Excellence with industry in
performance of clinical trials/studies and adjunct basic mechanistic studies
is encouraged.

Specific areas of interest include, but are not limited to:

o  clinical trials of tolerogenic and immunomodulatory approaches and agents
to treat and prevent autoimmune disease, including co-stimulatory blockade,
such as anti-CD40 ligand antibody and CTLA4-Ig; cytokines and anti-cytokine
molecules, such as anti-TNF, IL-4, and IL-12; and peptide ligands, such as MHC
peptides, antigen-specific peptides, or peptide oligomers;

o  stem cell and bone marrow transplantation for treatment of autoimmune
disease; determination of course of development of tolerance and/or immunity,
the cells that are necessary for tolerance induction, and the role of
chimerism;

o  relationship of response to therapy and various parameters:  stage of
disease, subsets of disease (i.e., relapsing vs. chronic progressive multiple
sclerosis), patient characteristics including race, ethnic background, and
genetic background, route of administration of agents;

o  development of new clinically useful agents to modulate the immune response
and modification of currently available agents to enhance agonist or
antagonist activity, to enhance efficacious activity, and/or eliminate adverse
effects;

o  determination of the mechanism of action of agents utilized:  the role of
cytokines, regulatory T cells, accessory cells (including macrophages, NK
cells, dendritic cells, and B cells), shifts in T cell subset response, T cell
anergy, T cell deletion, or induction of cell death pathways;

o  mechanisms responsible for tolerance initiation, maintenance, or loss; and

o  basic hypothesis driven research into mechanisms of self tolerance, the
pathogenesis of human autoimmune disease and/or its modulation.

SPECIAL REQUIREMENTS

1.  Clinical Component

Each Autoimmunity Center of Excellence must include a clinical research
component, which encompasses participation by multiple clinical specialists,
who have access to patient populations in which to conduct clinical
trials/studies in autoimmune diseases.  This component must include a minimum
of three clinical specialties and demonstrate the ability to perform clinical
trials/studies in at least three different autoimmune diseases.  The clinical
component may represent a single institution or a consortium of institutions. 
Diseases amenable to clinical intervention and of interest to the NIAID
include, but are not limited to:  systemic lupus erythematosus, multiple
sclerosis, rheumatoid arthritis, type 1 diabetes mellitus, idiopathic
thrombocytopenia purpura, inflammatory bowel disease, and scleroderma. 
Specialists that could participate in the clinical component include, but are
not limited to:  endocrinologists, neurologists, rheumatologists,
gastroenterologists, and hematologists.  The multiple specialists in the
clinical component must be willing and able to work collaboratively and
cooperatively, both within their Center and with clinical and basic components
of other Centers to facilitate clinical and adjunct basic studies.  The
application should include written letters of commitment to this principal. 
Applications proposing clinical components that do not meet the above criteria
concerning the number of clinical specialties represented and available
disease populations will be judged non-responsive and returned to the
applicant without review.

The application for the clinical component should describe the populations of
patients available for utilization in clinical trials/studies, and demonstrate
the ability to perform clinical trials/studies, including the ability to
recruit and retain subjects for at least three different autoimmune diseases. 
The application should include two proposed clinical trial/study protocols for
immune interventions for autoimmune diseases. These protocols should include
the rationale for the agent(s) and disease(s) selected, patient population,
study design, and primary and secondary outcome measures.  These two protocols
may utilize the same or different agents, but must intervene on different
autoimmune diseases.  Award of a Center does not imply that the proposed
protocols will be implemented.  Since the clinical trials/studies that are
ultimately undertaken by the Centers will be selected by the Steering
Committee (see below), the trials/studies selected for implementation may not
be identical to any single protocol submitted in response to this RFA. 
Funding for clinical components will be contingent upon participation in
approved clinical studies or trials.

In addition to the two proposed clinical trials/studies submitted with the
application, proposals for adjunct basic studies related to these clinical
trials/studies should be included in the application.  The submitting Center's
basic components do not necessarily need to include the expertise to perform
these studies, however, the studies must be feasible, i.e., the techniques
must be established.

2.  Basic Components

Each Autoimmunity Center of Excellence must include two or more basic research
components.  The basic components must be multi-disciplinary, interactive
basic or pre-clinical research projects focused on elucidation of the basic
mechanisms and pathogenesis of autoimmunity, self tolerance, and/or immune
modulation.  In addition to the proposed basic research project, each basic
component must demonstrate interest and capability for carrying out adjunct
basic studies related to clinical trials/studies in the context of an overall
Centers' program; work cooperatively with basic and clinical components from
their and other Centers; work with clinicians in development of clinical
trials/studies; and attend biannual Centers' meetings.  These basic components
may utilize animal models for their studies, but must also incorporate basic
research in humans.

Centers Network Organization

Steering Committee

A Steering Committee will be established to serve as the main governing body
of the cooperative network.  At a minimum, the Steering Committee will be
composed of the NIAID Autoimmunity Research Coordinator and two
representatives from each of the Centers: one Clinical Research Representative
and one Basic Research Representative.  The Clinical Research Representative
is the person responsible for the overall management of the clinical research
component, including:  coordination of the participating Center specialists,
whether within a single institution or a consortium of institutions;  design
and submission of proposed protocols for clinical trials/studies; and
implementation, monitoring, and data submission and analysis of clinical
trials/studies.  This person must be a physician with substantial training and
experience in 1) clinical management of one or multiple autoimmune diseases,
2) clinical immunology, and 3) the design, implementation and evaluation of
clinical trials.  The Basic Research Representative is the person responsible
for coordination of the Center's basic research scientists, whether within a
single institution or a consortium of institutions, in: development of
proposed clinical trials/studies and adjunct basic studies in cooperation with
clinicians, conduct of the basic studies in conjunction with ongoing clinical
trials/studies; and collaboration and sharing of basic resources and reagents
within a Center and with other Centers.  The collaboration of clinicians
and/or basic scientists from different Centers is highly encouraged based on
shared interests and complementary talents.  Designation of the Clinical
Research Representative and the Basic Research Representative is the
responsibility of the Center Principal Investigator, who may serve as either
representative, but not both.  The Chairperson of the Steering Committee will
be selected by the Steering Committee from among the non-Federal members
during one of the early meetings of the Committee to be convened by the NIAID
Autoimmunity Research Coordinator.  All major scientific decisions will be
determined by the Steering Committee, with each Clinical Research
Representative, Basic Research Representative, and the NIAID Autoimmunity
Research Coordinator having one vote.  The Committee will meet at least three
times during the first 12 months of the program and at least semi-annually
thereafter.

The Steering Committee will have responsibility for facilitating the conduct
of clinical trials/studies and basic research related to these trials/studies,
promoting trans-Center collaboration among and between clinical and basic
components, analyzing and interpreting Center-wide study data, and
establishing procedures for reporting results of Center trials/studies. 
Proposed protocols for clinical trials/studies to be performed by a single
Center or groups of Centers will be submitted to the Steering Committee for
review and evaluation.  Protocols to be implemented will be selected by the
Steering Committee in accordance with criteria and procedures established by
the Steering Committee. Timely review and evaluation are expected.  After
approval, those clinical investigators participating in the trial/study in
collaboration with investigators from the basic components who will be
performing adjunct basic mechanistic studies will develop detailed protocols. 
As needed, the Steering Committee may establish subcommittees for special
purposes.  It is expected that most of the work of the Steering Committee will
be performed in these subcommittees.  Clinical trials/studies will proceed
into the implementation stage only with the concurrence of the Steering
Committee and the NIAID Autoimmunity Research Coordinator.  Each Basic and
Clinical Research Representative will be expected to actively participate in
all other Steering Committee activities.

b.  Data, Safety and Quality Monitoring Board

The NIAID will appoint an independent Data, Safety and Quality Monitoring
Board to review the endpoint and safety data for all trials/studies on an
ongoing basis, but at least twice a year, and report directly to the NIAID
Autoimmunity Research Coordinator.  Protocols and data collection and quality
assurance procedures will be reviewed by this Board in an advisory capacity.
This Board will be funded separately from the Centers.

c.  Biannual Centers Meetings

A meeting of the Principal Investigators of each Clinical and Basic research
project from all of the Centers (usually 3 investigators/Center) will be held
biannually at a site designated by the NIAID (usually Washington, DC).  Each
of the Principal Investigators will present significant findings and report on
progress, review the focus and plan of the Centers' program, and establish and
strengthen collaborations among the Centers.  It is expected that meetings of
the Steering Committee and other Centers committees will occur in conjunction
with this meeting.  Travel funds for these meetings should be included in the 
budget of the individual Centers.

Additional Application Requirements

To promote the development of an interactive integrated network, a minimum
number of issues need to be addressed in the applications, as outlined below.

a.  Intra- and Inter-Institutional Arrangements

Single institutions or consortia of institutions may submit applications.
However, the application must identify a single applicant organization that
will be legally and financially responsible and accountable for the use and
disposition of funds awarded to the other institutions.  The development of
Centers, which include multiple institutions and geographic areas, is
encouraged when such an institutional arrangement provides the most
appropriate mixture of clinical and basic science components.  Evidence that
the components can work together effectively must be provided in all
applications regardless of whether the applicant is a single institution or a
consortium of institutions.

b.  Cooperative and Collaborative Responsibilities

Each clinical and basic component of each Center must be willing to work
cooperatively and collaboratively both within their Center and with other
Centers. The application must indicate commitment/willingness to the
collaborative organization, steering committee, and participation of NIAID
staff as described in the "Terms and Conditions." The Steering Committee as
defined in section entitled "Steering Committee" will be the main governing
body of the Centers network and will have responsibility for establishing
procedures for the selection of clinical trials/studies and adjunct basic
studies to be performed; developing procedures for prioritization of use of
samples from patients for basic studies; implementing clear, inclusive, and
effective communication among the components of all Centers; establishing
procedures for the monitoring of performance and progress of the clinical
trials/studies, including accrual, timely submission and quality of data and
samples, and conscientious observance of protocol requirements; and
instituting procedures for data collection, management, quality control, and
reporting results of clinical trials/studies.

c. Budgets

All costs requested for the proposed studies must be included in the
application.  Requested budgets should include: 1) travel for three one-day
Steering Committee meetings during the first 12 months of the study and
semiannual Steering Committee meetings thereafter for the Clinical and Basic
Research Representatives of each Center; and 2) travel for the Principal
Investigator of the Center components to a two-day biannual meeting (usually
in Washington, DC area), beginning in the second year.

Funding for clinical components will be contingent upon participation in
approved clinical studies or trials/studies.

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.

These 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 part 74 and 92, and other HHS, PHS, and NIH Grant Administration
policy statements.  The administrative and funding instrument used for this
program is the multiproject 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.  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 awardees for
the project as a whole, although specific tasks and activities in carrying out
the research will be shared among the awardees and the NIAID Autoimmunity
Research Coordinator.

1.  Awardee Rights and Responsibilities

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

Steering Committee Membership and Meeting Attendance

Each Center Principal Investigator will designate a Clinical Research
Representative and a Basic Research Representative as defined under "Steering
Committee" to serve as voting members of the Steering Committee and
participate in all Committee decisions.  Each Clinical and Basic Research
Representative will be responsible for attending all Steering Committee
meetings, including not less than three during the first 12 months of the
program and two per year thereafter.  The Steering Committee shall be
responsible for determining the frequency of meetings and scheduling the time
and location. Each Clinical and Basic Research Representative will be expected
to participate in all other Steering Committee activities, including, but not
limited to, conference calls and special subcommittees as may be necessary. 
The Steering committee will establish the procedures for the function of the
Centers network, as outlined in section "Steering Committee."

Data Coordination and Management

The NIAID will be responsible for ensuring the provision of centralized data
management and coordination assistance, including analysis support.  This Data
Management service will be funded separately from the Centers. Under the
direction of the Steering Committee, the NIAID will provide technical
assistance and data management services to the Autoimmunity Centers of
Excellence with respect to quality control, uniformity of data collection,
management of the collective data base, and data analysis.

Each awardee will be responsible for providing the NIAID with all primary
study data for management, quality control and analysis, using procedures and
standards determined by the Steering Committee.  All data will be available to
all awardees.  Specific analysis to be performed by NIAID will be directed by
the Steering Committee or its designee.  The awardees will retain custody of
and have primary rights to all data developed under these awards, subject to
Government rights of access consistent with HHS and NIH policies.

Publication and Presentation of Study Findings

Early publication of major findings is encouraged.  Publications and oral
presentations of work performed under this agreement will require appropriate
acknowledgment of the Autoimmunity Centers of Excellence and NIAID support. 
Analyses to be performed using collective data from multiple centers will be
determined by the Steering Committee.  Centers wishing to perform analysis of
local data or of single site studies should inform the Steering Committee
prior to initiation to avoid duplication.  The Steering Committee will
establish the procedures and criteria for presentation and publication of data
developed within the Centers network.

Federally Mandated Regulatory Requirements

Each institution participating in the Clinical component of an Autoimmunity
Center of Excellence is required to meet DHHS regulations for the protection
of human subjects and FDA requirements for the conduct of research using
investigational agents.  At a minimum, these include:

o  methods for assuring that each institution at which Autoimmunity Centers of
Excellence investigators are conducting clinical studies has a current,
approved assurance on file with the Office of Protection from Research Risks
(OPRR); that study protocols are reviewed and approved by the responsible
Institutional Review Board (IRB) prior to patient entry; that active protocols
are reviewed at least annually by the IRB, and that amendments are approved by
the IRB.

o  methods for assuring or documenting that each patient, or patient's
parent/legal guardian, gives fully informed consent to participation in a
research protocol prior to the initiation of the experimental intervention.

2.  NIAID Staff Responsibilities

NIAID staff assistance will be provided by an NIAID Autoimmunity Research
Coordinator, who will have substantial scientific/programmatic involvement
during the conduct of this activity through technical assistance, advice and
coordination above and beyond normal program stewardship for grants, as
described below.

Steering Committee Membership and Meeting Attendance

The NIAID Autoimmunity Research Coordinator will serve as a voting member of
the Steering Committee, will attend all Steering Committee meetings, and will
participate in other Committee activities, including, but not limited to,
conference calls, subcommittees, and special committees.

Clinical Trials Protocol Development

As a member of the Steering Committee, the NIAID Autoimmunity Research
Coordinator will serve as a resource with respect to the design of protocols.

Study Materials

The NIAID may negotiate with companies interested in participating in trials
or studies.  The NIAID may facilitate the appropriate approvals (when
necessary) from the Food and Drug Administration with respect to the use of
investigational drugs.

Monitoring Performance

The NIAID Autoimmunity Research Coordinator will provide assistance to the
Steering Committee in the development of procedures for monitoring the
performance of the clinical trials/studies.  This includes participation in
periodic on-site monitoring with respect to compliance with protocol
specifications, quality control and accuracy of data recording, and accrual.

Clinical Data Coordination and Management

The NIAID will be responsible for ensuring the provision of centralized data
management and coordination assistance, including analysis support.  Under the
direction of the Steering Committee, the NIAID will provide technical
assistance and data management services to the Autoimmunity Centers of
Excellence with respect to quality control, uniformity of data collection,
management of the collective data base, and data analysis.

The Government, via the NIAID Autoimmunity Research Coordinator, will have
access to data generated under this Cooperative Agreement and may periodically
review the data and progress reports.  Information obtained from the data may
be used by NIAID staff for the preparation of internal reports on the
activities of the clinical trials/studies.  However, awardees will retain
custody of and have primary rights to all data developed under these awards.

Publication and Presentation of Clinical Trials/Studies Findings

The NIAID Autoimmunity Research Coordinator may contribute, through review,
comment, analysis, and/or co-authorship, to reporting results of the clinical
studies and trials/studies to the investigator community and other interested
scientific and lay organizations.  Co-authorship by the NIAID Autoimmunity
Research Coordinator will be subject to approval in accordance with the NIH
policies regarding staff authorship of publications resulting from extramural
awards.

Organizational Changes

Certain organizational changes require the prior written approval of the NIAID
Autoimmunity Research Coordinator.  These changes include the
addition/substitution/removal of a principal investigator, clinical component,
basic component, or member of an affiliated clinical group associated with the
Centers network. A change in the designated principal investigator, or in any
key personnel identified in the application, must have the prior written
approval of the NIAID Grants Management Specialist in consultation with the
NIAID Autoimmunity Research Coordinator.

Program Review

The NIAID Autoimmunity Research Coordinator will review the progress of each
Autoimmunity Center through consideration of the annual reports, site visits,
patient logs, etc.  This review may include, but is not limited to,
participation in and compliance with clinical trials/studies protocols,
uniform data collection and timely reporting of data, and participation in
collaborative basic studies.

Collaborative Responsibilities

Each clinical and basic component of each Center must be willing to work
cooperatively and collaboratively both within their Center and with other
Centers. The application must indicate commitment/willingness to the
collaborative organization, steering committee, and participation of NIAID
staff as described in the "Terms and Conditions of Award:  NIAID Staff
Responsibilities."  The Steering Committee as defined below will be the main
governing body of the Centers network and will have responsibility for
establishing procedures for the selection of clinical trials/studies and
adjunct basic studies to be performed; developing procedures for
prioritization of use of samples from patients for basic studies; implementing
clear, inclusive, and effective communication among the components of all
Centers; establishing procedures for the monitoring of performance and
progress of the clinical trials/studies, including accrual, timely submission
and quality of data and samples, and conscientious observance of protocol
requirements; and instituting procedures for data collection, management,
quality control, and reporting results of clinical trials/studies.

a. Steering Committee

A Steering Committee will be established to serve as the main governing body
of the cooperative network.  At a minimum, the Steering Committee will be
composed of the NIAID Autoimmunity Research Coordinator and two
representatives from each of the Centers: one Clinical Research Representative
and one Basic Research Representative.  The Clinical Research Representative
is the person responsible for the overall management of the clinical research
component, including:  coordination of the participating Center specialists,
whether within a single institution or a consortium of institutions;  design
and submission of proposed protocols for clinical trials/studies; and
implementation, monitoring, and data submission and analysis of clinical
trials/studies.  This person must be a physician with substantial training and
experience in 1) clinical management of one or multiple autoimmune diseases,
2) clinical immunology, and 3) the design, implementation and evaluation of
clinical trials.  The Basic Research Representative is the person responsible
for coordination of the Center's basic research scientists, whether within a
single institution or a consortium of institutions, in: development of
proposed clinical trials/studies and adjunct basic studies in cooperation with
clinicians, conduct of the basic studies in conjunction with ongoing clinical
trials/studies; and collaboration and sharing of basic resources and reagents
within a Center and with other Centers.  The collaboration of clinicians
and/or basic scientists from different Centers is highly encouraged based on
shared interests and complementary talents.  Designation of the Clinical
Research Representative and the Basic Research Representative is the
responsibility of the Center Principal Investigator, who may serve as either
representative, but not both.  The Chairperson of the Steering Committee will
be selected by the Steering Committee from among the non-Federal members
during one of the early meetings of the Committee to be convened by the NIAID
Autoimmunity Research Coordinator.  All major scientific decisions will be
determined by the Steering Committee, with each Clinical Research
Representative, Basic Research Representative, and the NIAID Autoimmunity
Research Coordinator having one vote.  The Committee will meet at least three
times during the first 12 months of the program and at least semi-annually
thereafter.

The Steering Committee will have responsibility for facilitating the conduct
of clinical trials/studies and basic research related to these trials/studies,
promoting trans-Center collaboration among and between clinical and basic
components, analyzing and interpreting Center-wide study data, and
establishing procedures for reporting results of Center trials/studies. 
Proposed protocols for clinical trials/studies to be performed by a single
Center or groups of Centers will be submitted to the Steering Committee for
review and evaluation.  Protocols to be implemented will be selected by the
Steering Committee in accordance with criteria and procedures established by
the Steering Committee. Timely review and evaluation are expected.  After
approval, those clinical investigators participating in the trial/study in
collaboration with investigators from the basic components who will be
performing adjunct basic mechanistic studies will develop detailed protocols. 
As needed, the Steering Committee may establish subcommittees for special
purposes.  It is expected that most of the work of the Steering Committee will
be performed in these subcommittees.  Clinical trials/studies will proceed
into the implementation stage only with the concurrence of the Steering
Committee and the NIAID Autoimmunity Research Coordinator.  Each Basic and
Clinical Research Representative will be expected to actively participate in
all other Steering Committee activities.

4.  Arbitration

Any disagreement that may arise on scientific or programmatic matters (within
the scope of the award) between award recipients and the NIAID may be brought
to arbitration.  An arbitration panel will be formed to review any scientific
or programmatic issue that is significantly restricting progress. This panel
will be composed of three members -- one selected by the Steering Committee or
by the individual awardee in the event of an individual disagreement, a second
member selected by the NIAID, and a third member with expertise in the
relevant area and selected by the two prior members.  While the decisions of
the Arbitration Panel are binding, these special arbitration procedures will
in no way affect the awardee's right to appeal an adverse action in accordance
with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45
CFR Part 16.

Cooperative agreements are subject to the administrative requirements outlined
in OMB circulars A-102 and A-110.  All pertinent HHS, PHS, and NIH grant
regulations, policies and procedures, with particular emphasis on PHS
regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74, are
applicable. These special terms and conditions pertaining to the scope and
nature of the interaction between the NIAID and the investigators will be
incorporated in the Notice of Grant Award.  However, these terms will be in
addition to, not in lieu of, the customary programmatic and financial
negotiations that occur in the administration of cooperative agreements.

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 are provided that inclusion is
inappropriate with respect to the health of the subjects of the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).  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
the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.  All investigators proposing research involving
human subjects should read the "NIH Policy and Guidelines on the Inclusion of
Children as Participants in Research Involving Human Subjects" that was
published in the NIH Guide for Grants and Contracts, March 6, 1998, and is
available at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by December 8, 1998, a letter of
intent that includes a descriptive title of the overall proposed research, the
name, address and telephone number of the Principal Investigator, and the
number and title of this RFA.  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. Kevin Callahan at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the standard research grant application
form PHS 398 (rev. 5/95).  Application kits are available at most
institutional offices of sponsored research and may be obtained from the
Division of Extramural Outreach and Information Resources, National Institutes
of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
(301) 435-0714, email: GrantsInfo@nih.gov

Applicants for U19 cooperative agreements must follow special application
guidelines in the NIAID Brochure entitled "Instructions for Applications for
Multi-Project Awards" (Sept 1997); this brochure is available via the WWW at: 
http://www.niaid.nih.gov/ncn/grants/multibron.htm.  This brochure presents
specific instructions for sections of the PHS 398 (rev. 5/95) application form
that must be completed differently than usual.

The RFA label available in the PHS 398 (rev. 5/95) kit 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 may not reach the
review committee in time for review.  In addition, the RFA title (AUTOIMMUNITY
CENTERS OF EXCELLENCE) and number (AI-98-010) must be typed on line 2 on 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-sided photocopies, in one package
to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional exact copies of the grant
application and all five sets of any appendix material must be sent to Dr.
Kevin Callahan at the address listed under INQUIRIES.

Applications must be received by January 8, 1999.  Applications that are not
received as a single package on the receipt date or that do not conform to the
instructions contained in PHS 398 (rev. 5/95) application kit (as modified in,
and superseded by, the NIAID brochure entitled, "Instructions for Applications
for Multi-Project Awards"), will be judged non-responsive and will be returned
to the applicant.  It is highly recommended that the appropriate Institute
program contact be consulted before submitting the letter of intent and during
the early stages of preparation of the application.  (See program contacts
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.

Concurrent submission of an R01 and a Component Project of a Multi-project
Application:  Current NIH policy permits a component research project of a
multi-project grant application to be concurrently submitted as a traditional
individual research project (R01) application.  If, following review, both the
multi-project application and the R01 application are found to be in the
fundable range, the investigator must relinquish the R01 and will not have the
option to withdraw from the multi-project grant.  This is an NIH policy
intended to preserve the scientific integrity of a multi-project grant, which
may be seriously compromised if a strong component project(s) is removed from
the program.

Investigators wishing to participate in a multi-project grant must be aware of
this policy before making a commitment to the Principal Investigator and
awarding institution.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) 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, a process may be used by
the initial review group in which applications will be determined to be
competitive or non-competitive based on their scientific merit relative to
other applications received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score.  Applications
determined to be non-competitive will be withdrawn from further consideration
and the Principal Investigator and the official signing for the applicant
organization will be notified.  The second level of review will be provided by
the National Advisory Allergy and Infectious Diseases Council and the National
Diabetes and Digestive and Kidney Diseases Advisory Council.

Review Criteria

The general criteria for U19 multiproject cooperative agreement applications
are presented in the NIAID BROCHURE.  In addition, applicants are expected to
address the requirements outlined in the section, "SPECIAL REQUIREMENTS." 
Additional review criteria specific to this RFA are:

o  the scientific and clinical expertise and experience of the Principal
Investigator, Project Leaders, and key project personnel;

o  a strong commitment to the clinical and basic study of multiple autoimmune
diseases by the investigators and their institutions;

o  willingness to work cooperatively and collaboratively both within the
proposed Center and with other Centers and to accept the participation and
assistance of the NIAID staff in accordance with the guidelines outlined under
"Terms and Conditions of Award:  NIAID Staff Responsibilities"

As part of the scientific and technical merit evaluation of the research plan,
reviewers will be instructed to address:

o  Adequacy of plans for including children as appropriate for the scientific
goals of the research, or justification for exclusion.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and technical merit
as determined by peer review, program 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.

Requests for the NIAID brochure "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-
PROJECT AWARDS" as well as inquiries regarding programmatic issues, may be
directed to:

Elaine Collier, M.D.
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A20
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571
Email:  ec5x@nih.gov

Joan T. Harmon, Ph.D.
Diabetes Research Section
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8808
FAX:  (301) 480-3503
Email:  JOAN_HARMON@NIH.GOV

Susana Serrate-Sztein, M.D.
Arthritis Branch
National Institute of Arthritis, Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS37G
Telephone:  (301) 594-5032
FAX:  (301) 480-4543
Email:  szteins@ep.niams.nih.gov

Direct inquiries regarding preparation of the application and review issues,
address the letter of intent to, and mail two copies of the application and
all five sets of appendices to:

Kevin M. Callahan, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C20
Bethesda, MD  20892-7610
Telephone:  (301) 496-8424
FAX:  (301) 402-2638
Email:  kc92t@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Lesia A. Norwood
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B28
Bethesda, MD  20892-7610
Telephone:  (301) 402-6581 or 496-7075
Email:  ln5t@nih.gov

Linda Stecklein
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6As-49J
Bethesda, MD  20892-6600
Telephone:  (301) 594-8847
FAX:  (301) 480-3504
Email:  steckleinl@ep.niddk.nih.gov

Ms. Carol Fitzpatrick
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS43K
Telephone:  (301) 594-3506
FAX:  (301) 480-4543
Email:  fitzpatric@ep.niams.nih.gov

Schedule

Letter of Intent Receipt Date:  December 8, 1998
Application Receipt Date:       January 8, 1999
Scientific Review Date:         May 1, 1999
Advisory Council Date:          May 24, 1999
Earliest Date of Award:         August 1999

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.855, 93.847, and 93.846.  Awards are made under authorization of the Public
Health Service Act, Sec. 301 (c), Public Law 78-410, as amended.  Awards will
be administered under PHS grants policies and Federal Regulations 42 CFR Part
52 and 45 CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems 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 Volume Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.