NON-HUMAN PRIMATE IMMUNE TOLERANCE COOPERATIVE STUDY GROUP
Release Date: January 25, 2001
RFA: RFA-AI-01-006 (This RFA has been reissued, see RFA-AI-06-018)
National Institute of Allergy and Infectious Diseases
(http://www.niaid.nih.gov)
National Institute of Diabetes and Digestive and Kidney Diseases
(http://www.niddk.nih.gov)
Letter of Intent Receipt Date: June 11, 2001
Application Receipt Date: July 17, 2001
PURPOSE
The Division of Allergy, Immunology, and Transplantation (DAIT) of the National
Institute of Allergy and Infectious Diseases (NIAID) and the Division of
Diabetes, Endocrinology, and Metabolic Diseases (DDEMD) of the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite
applications from single institutions and consortia of institutions to
participate in the Non-Human Primate Immune Tolerance Cooperative Study Group
(NHPCSG). The NHPCSG is a multi-center, cooperative research program focused on
the study of immune tolerance in non-human primate models of kidney and islet
allograft rejection, asthma and allergic diseases and autoimmune diseases. The
goals of this research program are to: evaluate the safety and efficacy of novel
tolerance induction regimens; elucidate the mechanisms of the induction,
maintenance and loss of tolerance; and develop and validate biomarkers for
induction, maintenance, and loss of tolerance in these immune-mediated
disorders. For purposes of this Request for Applications (RFA), immune
tolerance is defined as a lack of a pathogenic immune response to allogeneic,
environmental, or self-antigens in the absence of ongoing immunosuppressive
therapy. Tolerance may be induced by a variety of approaches, including: clonal
deletion, clonal anergy, immune deviation, or suppression. Projects should be
designed to meet these goals in established and new non-human primate models of
kidney and islet transplantation, asthma and allergic diseases, and autoimmune
diseases. Because the ultimate purpose of this RFA is to develop candidate
tolerogenic approaches for the treatment of immune-mediated diseases in humans,
the sponsors expect that there will be reciprocal communication between the
NHPCSG and the Immune Tolerance Network and Type 1 Diabetes TrialNet.
HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2010," a PHS led national
activity for setting priority areas. This RFA, Non-Human Primate Immune
Tolerance Cooperative Study Group, is related to Diabetes and Chronic Disabling
Conditions. Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople.
ELIGIBILITY REQUIREMENTS
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 institutions 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 mechanisms to be used to undertake this program
will be the Cooperative Agreement (U01) and the Multi-project Cooperative
Agreement (U19), "assistance" mechanisms, rather than "acquisition" mechanisms.
Under the cooperative agreement, the National Institutes of Health (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 NIH Coordinators.
Essential elements of the multi-project cooperative agreement mechanism (U19)
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. Where necessary, support for "Core" resources or facilities, each of which
shall 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 applications submitted in response to this RFA may
not exceed five years.
FUNDS AVAILABLE
The estimated total funds (direct and facilities and administrative (F&A))
available for the first year of support for this RFA will be between $4,000,000
and $6,000,000. In fiscal year 2002, the NIH plans to make six to seven awards
related to this RFA. This level of support is dependent on (1) the receipt of a
sufficient number of applications of high scientific merit, (2) the relative
proportions of U01 and U19 applications, and (3) the availability of funds.
Applications for U01 awards may not request budgets in excess of $500,000 total
(direct and F&A) first-year costs. Applications for U19 awards may not request
budgets in excess of $1,000,000 total first-year costs. The NIH Grants Policy
governing grants administration and management will apply. Although this
program is provided for in the financial plans of the sponsoring institutes,
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.
RESEARCH OBJECTIVES
Background
The cosponsors of this RFA support research focused on immune tolerance, immune-
mediated diseases, diabetes, and kidney diseases, including the development of
improved therapies to prevent these diseases and treat their complications.
Supported research also focuses on the use of non-human primate models for
studies that elucidate human health problems and disease processes.
The NIAID and NIDDK have made research on immune tolerance a high scientific
priority and. In the fall of 1997, NIAID initiated a scientific planning
process designed to accelerate research in this area. The broad-based, long-
range NIAID Plan for Research on Immune Tolerance is available at:
http://www.niaid.nih.gov/publications/immune/bookcover.htm
The NIAID Expert Panel for Research on Immune Tolerance enthusiastically
endorsed the conceptual framework, scope and timeliness of the plan and
encouraged the NIAID to take a leadership role in designing and directing major
research programs focused on immune tolerance, particularly with respect to the
treatment of human disease. Two subsequent expert panels, the NIAID Expert
Panel on Ethical Issues in Clinical Trials of Transplant Tolerance and the
Expert Review Panel for NIAID's Extramural Transplantation Research Program,
identified non-human primate tolerance research as an essential step to provide
"...critical data on safety, toxicity and potential efficacy that can not be
obtained ethically in human clinical trials." In 1998, NIAID established a
program in non-human primate models of kidney and islet transplantation using
the NIH Director’s 1% Transfer Authority Funds. In 1999, this effort was
expanded though an RFA, co-sponsored by NIAID, NIDDK, and the National Center
for Research Resources (NCRR). The current, RFA seeks to expand support for
immune tolerance research in kidney and islet transplantation and initiate
support for immune tolerance research in non-human primate models of other
immune mediated diseases.
In September 1997, the Director of National Institutes of Health (NIH) and the
Director of NIDDK sponsored - with the co-sponsorship of eight other Institutes
and Centers of NIH - a unique landmark symposium on "Diabetes Mellitus:
Challenges and Opportunities." This symposium brought together over 150
investigators to develop recommendations on how diabetes research should be
intensified to close research gaps, take advantage of new technologies, and
capitalize on highly promising research leads and advances. One recommendation
was the development of and access to larger animal models of diabetes.
Subsequently the Congress established the Diabetes Research Working Group to
develop a strategic research plan for NIH-funded diabetes research. This plan,
Conquering Diabetes: A Strategic Plan for the 21st Century, Report Summary and
Recommendations, can be found at
(http://www.niddk.nih.gov/federal/dwg/dwgsummary.htm). This panel identified
research on autoimmunity and the beta cell as one of five extraordinary
opportunities and recommended expanded research on islet transplantation and
immune intervention as well as support of centers using large animal models to
test new therapies for type 1 diabetes.
1. Transplantation
Transplantation is now routine therapy for end-stage renal disease, with one-
year graft survival approaching 90% using standard immunosuppressive therapy.
However, long-term graft survival has improved only slightly since the early
1980s, with about 62% of cadaveric kidneys surviving five years post-transplant.
For other organs (e.g., heart, liver, lung and pancreas), graft survival rates
are similar. While new immunosuppressive drugs have reduced acute rejection in
the first year post-transplant, it is clear that these therapeutic improvements
have only marginally altered long-term clinical outcomes.
Therefore, current attention has focused on the potential for donor-specific
immune tolerance to achieve long-term graft survival without non-specific, life-
long immunosuppressive therapies that have deleterious and often life-
threatening side effects. Although certain promising tolerogenic regimens have
been shown to induce donor-specific immune tolerance in animal models, and are
being tested in humans for the treatment of selected autoimmune diseases, these
approaches have not been rigorously evaluated in the transplant setting. Both
the Expert Panel on Immune Tolerance and the Expert Panel on Ethical Issues in
Clinical Trials of Transplant Tolerance recommended that NIAID pursue tolerance
research in non-human primate models of kidney and islet transplantation as a
prelude to human clinical trials. These recommendations were reinforced and
expanded by the extraordinary opportunities as presented in the Congressionally-
requested report "Conquering Diabetes: A Strategic Plan for the 21st Century."
2. Asthma and Allergic Diseases
Asthma and allergic diseases, including allergic rhinitis, atopic dermatitis,
urticaria and anaphylaxis, are among the major causes of illness and disability
in the United States. NIAID vigorously pursues research on asthma and allergic
diseases by fostering investigator-initiated projects and by supporting a
national network of research centers, cooperative clinical studies, and
demonstration and education research projects. The cause, pathogenesis,
diagnosis, treatment, and prevention of asthma and allergic diseases are major
areas of emphasis for the NIAID Division of Allergy, Immunology, and
Transplantation, and recent research advances have led to a better understanding
of the pathogenesis of these diseases. Nevertheless, translation of the basic
research findings into new approaches to treatment and prevention of asthma and
allergic diseases has been hampered by the lack of animal models that accurately
simulate the important features of human disease. This is particularly
important with respect to asthma, for which there is increasing epidemiological
and clinical evidence that early life changes in immune system function
contribute to the development of the disease. Because of the similarity in the
development of the non-human primate immune system to that of man, there is a
need for non-human primate models that will facilitate the investigation of the
early life origins of asthma and the tracking of changes in immune function that
occur as the disease progresses. The Expert Panel convened to review the NIAID
Extramural Asthma and Allergy research program underscored the limitations of
currently available animal models of asthma and suggested that the NIAID support
suitable non-human primate models. This can be best accomplished through the
coordinated, high quality infrastructure provided by expansion of the NHPCSG.
3. Autoimmune Diseases
Autoimmune diseases, which are caused by immune reactions against self-antigens,
affect more than five (5) percent of the U. S. population and disproportionately
affect women. These diseases are a significant cause of chronic morbidity,
costing billions of dollars annually in health care expenses and lost
productivity. NIAID supports a program of basic and clinical research in
autoimmunity. NIDDK supports basic and clinical research on type 1 diabetes,
inflammatory bowel disease and liver and kidney diseases resulting from
autoimmune mechanisms. Basic research focuses on: understanding the genetics of
autoimmunity, elucidating the mechanisms that underlie self-tolerance, inducing
self-tolerance, and characterizing the pathways of immune-mediated tissue
destruction. Knowledge gained from basic studies provides the rationale for:
developing clinical tests to diagnose autoimmune diseases; therapies to prevent
autoimmune diseases; and novel treatments for ongoing disease. Efforts to
induce tolerance in autoimmunity have focused primarily on the oral
administration of antigens. Oral tolerance can be induced in animal models and
is now being evaluated in human diseases, including type 1 diabetes. However,
the encouraging responses in animal studies have not been duplicated in recent
clinical trials of rheumatoid arthritis and multiple sclerosis. There are a
number of promising tolerogenic approaches other than oral tolerance that can be
pursued, including: costimulatory blockade, anti-cytokine monoclonal antibodies,
hematopoietic stem cell and bone marrow transplantation, and gene transfer-based
therapies for cytokine modulation. Expansion of the NHPCSG will follow the
recommendation in The Report of the NIH Autoimmune Diseases Coordinating
Committee and the Diabetes Research Working Group, which encourage the
exploration of therapeutic approaches to autoimmunity in animal models that more
faithfully mimic human autoimmune diseases. In addition, the Expert Panel on
Immune Tolerance and the Congressional-established Diabetes Research Working
Group highlighted the need to evaluate the safety and efficacy of various
tolerance induction regimens and agents in non-human primate models of
autoimmune diseases.
4. Non-Human Primates
Studies of existing and new tolerogenic treatment regimens in non-human primate
models of kidney and islet transplantation, asthma and allergic diseases, and
autoimmune diseases are critical to the design of scientifically sound and
ethically acceptable clinical trials. In addition, non-human primates are
especially useful as they closely approximate the human immune system and
physiology. Non-human primates also allow collection of important biological
samples necessary to validate new non-invasive or minimally invasive diagnostic
tests for tolerance, graft function, survival, and rejection, asthma and
allergic diseases, and autoimmune diseases.
Research Objectives and Scope
The purpose of this RFA is to support a multi-site cooperative research program
to develop tolerance induction protocols in non-human primate models of immune-
mediated diseases. For purposes of this RFA, immune tolerance is defined as a
lack of a pathogenic immune response to allogeneic, environmental, or self-
antigens in the absence of ongoing immunosuppressive therapy. Tolerance may be
induced by a variety of approaches as described below.
All participating sites will use uniform controlled study designs and
standardized data collection procedures. Specifically, the cooperative research
program will design and conduct:
1. Studies on the safety and efficacy of tolerance induction therapies alone,
in combination with immunosuppressive therapies, and in combination with
immunosuppressive therapy withdrawal. Approaches to immune tolerance may
include, but are not limited to, the following:
o Co-stimulatory blockade
o Cytokine modulation
o Clonal deletion
o DNA vaccination
o Oral administration of antigen
o Bone marrow transplantation or donor-specific transfusion
o Other approaches such as leukocyte migration blockade, allergen- or
autoantigen-specific immunotherapy, and the use of molecularly engineered cells
and tissues for deletion or inactivation of pathogenic lymphocytes.
2. Studies of the underlying mechanisms of action of the therapeutic approaches
being evaluated, including changes in immune response and function and measures
of the induction, maintenance, and loss of donor-specific tolerance. Possible
approaches to mechanistic studies include, but are not limited to, the
following:
o Quantitation of alloreactive, autoreactive, or allergen-specific T
lymphocytes
o Analysis of alloreactive, autoreactive, or allergen-specific T cells for gene
expression that correlates with functions such as inflammation or homing
o Comparison of samples from peripheral blood and urine with those from sites
of rejection (for transplantation studies), autoimmune tissue destruction, or
pulmonary function.
3. Studies to develop, evaluate, and validate biomarkers of immune tolerance.
This includes establishing appropriate measures (e.g., cytokines and/or their
receptors, lymphocyte subsets, etc.), selecting appropriate samples (e.g.,
blood, urine, biopsies, etc.), and selecting appropriate techniques (e.g.,
quantitative PCR, DNA microarrays, imaging, cellular immune assays, etc.) for
routine use. Possible markers include: changes in gene or protein expression in
blood, urine or biopsy materials; antibody or cytokine levels in blood, urine or
biopsies; or in vitro and in vivo immune responsiveness to antigens as
determined by T-cell proliferation, cytotoxic T-cell activity, antibody
production, cytokine secretion, and immediate or delayed-type hypersensitivity.
This RFA will not provide support for:
o Studies in animal models other than non-human primates;
o Studies to improve the viability or supply of organs, tissues, or cells for
transplantation;
o Preliminary development of immune-mediated disease models in non-human
primates; or
o Xenotransplantation into non-human primates.
However, this RFA will provide support for costs associated with the procurement
of allogeneic non-human primate islets and kidneys.
SPECIAL REQUIREMENTS
A. Study Organization
1. Steering Committee
A Steering Committee, composed of principal investigators, additional
investigators where appropriate, and NIH staff will serve as the main governing
body of the NHPCSG. Specific details on the composition of the Steering
Committee, its responsibilities, and the establishment of subcommittees are
listed under Terms and Conditions of Award, Collaborative Responsibilities.
A broad range of scientific and technical expertise is required to carry out the
objectives of this RFA, including extensive experience in: immune-mediated
diseases; asthma and allergic diseases; autoimmune diseases; transplantation
immunobiology and genetics; solid organ, cell, and tissue transplantation; non-
human primate models of immune system disorders; molecular and cellular biology,
particularly as applied to the identification and evaluation of biomarkers and
assay development and validation; research design and statistics; and veterinary
care for non-human primates. Each participating member of the Cooperative Study
Group must possess scientific expertise in the appropriate areas under the
direction of a senior scientist as the Principal Investigator responsible for
the scientific, technical and administrative coordination and management of the
awardee institution(s).
NIH will facilitate collaboration and coordination between the Cooperative Study
Group and the Immune Tolerance Network (www.immunetolerance.org). Close
coordination among these two research programs will facilitate the development
of safety, toxicity, and potential efficacy data from non-human primate models
critical to the design and implementation of scientifically sound and ethically
acceptable human trials for both existing and new tolerogenic approaches. Close
coordination will also enable the application of findings from non-human
primates to the clinical setting with respect to important biomarkers and
reliable assays to measure tolerance.
2. Data Coordination and Management
Each Cooperative Study Group member institution will be responsible for
collecting, managing, interpreting, and assuring the quality of data collected
on site. Applicants should request support for all data collection and
analyses, including a Statistical Coordinator, in their budgets. For
collaborative studies and specific data analyses, the Steering Committee will
select a Statistical Coordinator from among the member institutions. Applicants
wishing to serve as a Data Coordinating Center for collaborative studies should
request appropriate levels of support in their budgets. The results of those
analyses will be delivered to the Steering Committee which will determine: if
and what further analyses should be performed; how the results are interpreted;
whether the results impact ongoing data collection, ongoing studies, or future
studies; and how the findings should be disseminated. 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, PHS, and NIH
policies.
B. Terms and Conditions of Award
The following terms and conditions will be incorporated into the Notice of Grant
Award and provided to the Principal Investigator as well as the institutional
official at the time of award. These special terms and conditions pertaining to
the scope and nature of the interaction between the NIH and the investigators
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. 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.
The administrative and funding mechanisms to be used to undertake this program
will be the Cooperative Agreement (U01) and the Multi-project Cooperative
Agreement (U19), "assistance" mechanisms, rather than "acquisition" mechanisms.
Under the cooperative agreement, the National Institutes of Health (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 NIH Coordinators
1. Awardee Rights and Responsibilities
Awardees will have primary responsibility for defining the research objectives,
approaches, and details of the projects within the guidelines of the RFA and for
performing the scientific activities. Specifically, awardees have primary
responsibility as described below.
Steering Committee Membership and Meeting Attendance
Each Principal Investigator and additional investigators where appropriate from
a consortium, will serve as a voting member of the Steering Committee and will
participate in all scientific decisions. Each Steering Committee member will be
responsible for attending all Steering Committee meetings and participating in
all other Steering Committee activities, e.g., conference calls, special
subcommittee meetings as may be necessary, etc. Applicants are instructed to
request funds for travel to Steering Committee meetings in their budgets.
Protocol Development and Conduct
All Cooperative Study Group institutions, upon acceptance of an award, agree to
participate in all studies, including those that involve collaborations with
biotechnology and pharmaceutical companies, as specified by the Steering
Committee. For all studies implemented by the Cooperative Study Group, the
Steering Committee will (1) define the objectives and approaches of treatment
protocols, mechanistic studies, and tolerance assay and biomarker development;
(2) design the consensus protocols and procedures for study conduct and
monitoring; and (3) determine the procedures for data collection and quality
control. Furthermore, the Steering Committee will decide which treatment
protocols will be conducted at multiple centers and which will be conducted at
individual institutions. Cooperative Study Group institutions will be required
to accept and implement the studies and data collection procedures approved by
the Steering Committee. Studies will proceed into the implementation stage only
with the concurrence of the Steering Committee.
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 both the Cooperative Study Group and NIH support. Analyses to
be performed using the collective data from the Cooperative Study Group
institutions will be determined and directed by the Steering Committee.
Cooperative Study Group institutions wishing to perform analyses of local data
will inform the Steering Committee of any such analyses prior to initiation in
order to avoid duplication. Review and approval by the Steering Committee, or a
Publications Subcommittee, will be required for all analyses prior to
publication or presentation according to criteria that will be developed by the
Steering Committee.
Monitoring Study Progress
The Steering Committee will establish mechanisms for assessing the performance
of the Cooperative Study Group institutions. This includes: quality, accuracy
and timeliness of data collection and management; conscientious observance of
study requirements; and presentation of study results at joint meetings with the
Executive Committee of the Immune Tolerance Network.
Federally Mandated Regulatory Requirements
The PHS Policy on Humane Care and Use of Laboratory Animals requires that
applicant organizations proposing to use vertebrate animals file a written
Animal Welfare Assurance with the Office of Laboratory Animal Welfare,
establishing appropriate policies and procedures for the humane care and use of
live vertebrate animals in research activities supported by the PHS. The PHS
policy stipulates that an applicant organization, whether domestic or foreign,
bears responsibility for the humane care and use of animals in PHS-supported
research activities.
All institutions are required to comply, as applicable, with the Animal Welfare
Act as amended (7 USC 2131 et sec.) and other Federal statutes and regulations
relating to animals. These documents are available from the Office of Laboratory
Animal Welfare, National Institutes of Health, Bethesda, MD 20892, (301) 496-
7163, http://grants.nih.gov/grants/olaw/olaw.htm
2. NIH Staff Responsibilities
The NIH Coordinators will be the Immunobiology Section Chief, Transplantation
Immunobiology Branch, DAIT, NIAID and the Senior Advisor for Diabetes, DDEMD,
NIDDK. The NIH Coordinators 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 NIH Coordinators will serve as voting members of the Steering Committee,
will attend all Steering Committee meetings, and will participate in other
Committee activities, e.g., conference calls, special subcommittees, etc.
Protocol Development
As members of the Steering Committee, the NIH Coordinators will serve as a
resource with respect to the design of treatment protocols and adjunct studies
and will assist the Steering Committee in study development.
Study Materials
The NIH Coordinators, in coordination with the DAIT Office of Clinical
Applications, will be responsible for coordinating the acquisition and
distribution of study materials to be used in the treatment protocol developed
by the consensus of the Steering Committee.
The NIH is not responsible for obtaining or distributing solid organs, tissues
or cells to be used by the Cooperative Study Group.
Monitoring Study Performance
The NIH Coordinators will provide assistance to the Steering Committee in the
development of mechanisms and procedures for monitoring study performance. This
includes: the accuracy, quality, and timeliness of data collection and
management; consistency in observing study requirements; and presentation of
study results at joint meetings with the Executive Committee of the Immune
Tolerance Network.
The Government, via the NIH Coordinators, will have access to data generated
under this Multi-Project Cooperative Agreement and may periodically review the
data and progress reports. NIH Staff may use information obtained from the data
for the preparation of internal reports on the activities of the study.
However, awardees will retain custody of and have primary rights to all data
developed under these awards.
Publication and Presentation of Study Findings
The NIH Coordinators and other NIH representatives may contribute, through
review, comment, analysis, and/or co-authorship, to reporting results of the
studies conducted by the Cooperative Study Group to the research community and
interested lay organizations. Co-authorship by the NIH staff will be subject to
approval in accordance with NIH policies regarding staff authorship of
publications resulting from extramural awards.
Organizational Changes
Certain organizational changes require the prior written approval of the NIH
Coordinators. These changes include the addition or replacement of a scientific
investigator, affiliate, component, or research base that is associated with
this research program. A change in the Principal Investigator, or in any key
personnel identified on the Notice of Award, must have the prior written
approval of the appropriate NIH Grants Management Specialist in consultation
with the NIH Coordinators and representatives of other sponsoring institutes.
Program Review
The NIH Coordinators will review the progress of the Cooperative Study Group
through consideration of annual progress reports, periodic reports on ongoing
progress, findings and future plans presented during meetings and conference
calls, publications, site visits, etc. This review may include, but is not
limited to, compliance with the study protocols, adherence to uniform data
collection procedures, and participation in Steering Committee and other
subcommittee meetings as necessary.
The NIH reserves the right to terminate or curtail the study (or any individual
award) in the event of (a) a major breech of any Cooperative Study Group
approved protocol, (b) substantive changes in the agreed-upon protocols to which
the NIH does not agree, (c) reaching a major study endpoint substantially ahead
of schedule with persuasive statistical significance, and (d) failure to meet
the collaborative responsibilities as determined by the Steering Committee.
3. Collaborative Responsibilities
A Steering Committee will serve as the main governing body of the NHPCSG. At a
minimum, the Steering Committee will be composed of the NIH Coordinators and the
Principal Investigators of each award. If the awardee is a consortium of
institutions, one additional investigator from the consortium will serve on the
Steering Committee, on an annual rotating basis, as determined by the protocols
under development or implemented. The Steering Committee will meet twice during
the first 12 months of the project and annually thereafter. The Steering
Committee will select a Chairperson from among the non-Federal members during
the first meeting of the Committee, to be convened by the NIH Coordinators.
The Steering Committee will be responsible for all major scientific decisions
and will have primary responsibility for developing the common treatment
protocols, approving the design and implementation of all collaborative studies,
facilitating the conduct and monitoring of all studies, analyzing and
interpreting collaborative study data, and reporting collaborative study
results. Studies will proceed to the implementation stage only with the
concurrence of the Steering Committee. The responsibilities of the Steering
Committee members are listed above under Terms and Conditions of Award.
Cooperative Study Group institutions will be required to accept and implement
the studies and data collection procedures approved by the Steering Committee.
Studies will proceed into the implementation stage only with the concurrence of
the Steering Committee.
Subcommittees of the Steering Committee may be established as necessary to
provide guidance to the Steering Committee on: assays for tolerance and
biomarkers, data collection and analysis, collaboration with investigators
outside of the Cooperative Study Group, and reporting and publication of
collaborative studies.
4. Arbitration
Any disagreement that may arise on scientific or programmatic matters (within
the scope of the award) between award recipients and the NIH may be brought to
arbitration. An arbitration panel will be composed of three members - one
selected by the Steering Committee (with the NIH members not voting) or by the
individual awardee in the event of an individual disagreement, a second member
selected by the NIH, and the third member with expertise in the relevant area
and selected by the two prior members. The Arbitration Panel will review any
scientific or programmatic issue that is significantly restricting progress.
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.
LETTER OF INTENT
Prospective applicants are asked to submit, by June 11, 2001, 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 all
collaborators; 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 NIH staff to estimate the potential review
workload and to plan the review. The letter of intent is to be sent to Dr.
Priti Mehrotra at the address listed under INQUIRIES.
APPLICATION PROCEDURES
Applicants are strongly encouraged to call NIH program staff with any questions
regarding the responsiveness of their proposed project to the goals of this RFA.
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants. Application kits are available at most institutional
offices of sponsored research and from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email:
GrantsInfo@nih.gov. Applications are also available on the World Wide Web at
http://grants.nih.gov/grants/forms.htm.
Applications must be received by July 17, 2001.
For purposes of identification and processing, item 2a on the face page of the
application must be marked "YES" and the RFA number "AI-01-006" and the words
"Non-Human Primate Immune Tolerance Cooperative Study Group" must be entered on
the face page.
The RFA label and line 2 of the application should both indicate the RFA number.
The RFA label must be affixed to the bottom of the face page. 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.
The sample RFA label available at:
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to
allow for this change. Please note this is in pdf format.
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. Priti Mehrotra at
the address listed under INQUIRIES. DUE TO THE EXPEDITED NATURE OF THIS RFA,
IT IS VERY IMPORTANT TO SEND THESE ADDITIONAL COPIES IN ORDER TO FACILITATE THE
PEER REVIEW PROCESS.
Applicants from institutions that have a Regional Primate Research Center (RPRC)
funded by the NIH National Center for Research Resources may wish to identify
these centers as resources for conducting the proposed research. If so, a
letter of agreement from the RPRC program director or principal investigator
could be included with the application.
SPECIFIC INSTRUCTIONS FOR U01 COOPERATIVE AGREEMENT APPLICATIONS
If a U01 application submitted in response to this RFA is substantially similar
to a grant application already submitted to the NIH for review, but that has not
yet been reviewed, the applicant will be asked to withdraw either the pending
application or the new one. Simultaneous submission of identical applications
will not be allowed, nor will different review committees review essentially
identical applications. Therefore, an application that is essentially identical
to one that has already been reviewed cannot be submitted in response to this
RFA. This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
SPECIAL INSTRUCTIONS FOR U19 COOPERATIVE AGREEMENT APPLICATIONS IN RESPONSE TO
THIS RFA
Applicants for U19 cooperative agreements must follow special application
guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR
MULTI-PROJECT AWARDS (August 2000); this brochure is available via the web at:
http://www.niaid.nih.gov/ncn/grants/multibron.htm.
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. 4/98)
Application Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED
"INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" for U19 awards) will be
judged non-responsive and will be returned to the applicant.
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. However, concurrent submission of a component research
project of a multi-project U19 cooperative agreement application as an
individual U01 cooperative agreement application to this RFA is prohibited.
MINIMUM REQUIREMENTS FOR APPLICATION
To promote the development of a collaborative program among the award
recipients, a minimum number of issues need to be addressed in the applications,
as outlined below.
1. The application must include a broad-based research program designed to
evaluate the safety and efficacy of tolerogenic approaches in non-human primate
models of asthma and allergic diseases, autoimmune diseases, kidney
transplantation, or islet transplantation with the goal of inducing
immunosuppression free immune tolerance and delineating the mechanisms involved
in the induction, maintenance and loss of tolerance as an integral part of the
treatment protocols. U19 applications must contain more than one tolerogenic
approach. U01 applications may contain a single tolerogenic approach. The
research program shall include the following:
a) A discussion of the state-of-the-art of research focused on elucidating the
underlying mechanisms of immune tolerance and on evaluating tolerogenic
approaches in non-human primate studies and human clinical trials.
b) A description of gaps in knowledge and scientific opportunities relevant for
the application of tolerogenic approaches to non-human primate studies and human
clinical trials.
c) A plan to accelerate research on immune tolerance in non-human primate models
of immune-mediated diseases, including:
o A conceptual framework delineating approaches to tolerance induction and
their relevance to human immune-mediated diseases, priorities among the various
approaches and the rationale for such priorities, including potentially
promising reagents and molecules in development;
o A description of promising non-human primate treatment protocols, including
the rationale for the selection of tolerogenic approaches and overall study
design; and
o A description of promising mechanistic studies to be incorporated as an
integral part of the non-human primate treatment protocols, including the
rationale for the selection of the mechanistic studies, proposed techniques, and
the overall design of such studies.
o A plan detailing the acquisition and preparation, if applicable, of the solid
organs, tissues or cells to be used in the studies. All costs required for this
must be included in the application and fully justified.
2. The application must also include a 1-2 page synopsis (to be included as
appendices) of the proposed treatment protocol(s) to assess safety and efficacy
and incorporating the proposed mechanistic studies. Since the actual study
protocols to be performed will be selected by the Steering Committee, the final
protocols implemented by the Cooperative Study Group may not reflect any
protocol submitted in response to this RFA. Budget requests should reflect and
fully justify all costs associated with the conduct of the above studies.
3. U19 applications must include at least two proposed specific aims focused on
the development, evaluation and validation of sensitive immune and/or surrogate
biomarkers of the induction, maintenance, or loss of tolerance. U01
applications may include a single specific aim on the above. Proposed tolerance
assay studies are to include: identification of and rationale for the immune
and/or surrogate markers selected, including published data from in vitro or in
vivo studies; description of and rationale for the proposed source, quantity and
number of samples required; methodologies proposed to collect and analyze
samples; and a discussion of how the results of the proposed studies will
contribute to improvements in the capacity to utilize immune and/or surrogate
biomarkers to predict the induction, maintenance or loss of tolerance. Use of
new technologies, including minimally and non-invasive approaches, is
encouraged. Since the actual tolerance and/or surrogate biomarker assays to be
performed will be selected by the Steering Committee, the final studies carried
out by the Cooperative Study Group may not reflect any single study submitted in
response to this RFA. All costs required for the proposed tolerance and
biomarker assays must be included in the application and must be fully
justified. These include the additional costs for data collection and analyses.
4. For a U19 multi-project cooperative agreement, the application must identify
the single applicant organization that will be legally and financially
responsible and accountable for the use and disposition of funds awarded on the
basis of this RFA to the applicant institution and other institutions
participating in the consortium, if applicable, and show availability of
personnel and facilities capable of performing and supporting the administrative
functions necessary. Essential elements of the multi-project cooperative
agreement mechanism (U19) 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) where necessary, support
for "Core" resources or facilities, each of which shall be utilized by at least
two research projects in order to facilitate the research effort.
5. The application must name a single Principal Investigator (PI) who will have
scientific responsibility for the application as a whole, including all
consortium-related research activities, if applicable. The PI must have
substantial experience related to the scope and objectives of the RFA. In
addition, applications from a consortium of institutions must designate a single
investigator for each participating institution who will be responsible for on-
site scientific implementation, direction and management of the studies, as well
as the coordination of requirements for adjunct studies of underlying mechanisms
and immune/surrogate markers.
6. The application must also demonstrate the scientific and technical expertise
required to design, conduct and analyze treatment protocols, mechanistic studies
and assay development and validation.
7. For a U19 multi-project cooperative agreement, the application must provide:
a clear, concise plan, in narrative and diagrammatic form, that depicts the
interrelationships among the research projects and the scientific and technical
staff, their relevant experience/expertise, and the contribution of each to
fulfillment of the objectives of this RFA; an organizational chart of the
consortium showing the name, organization, and scientific discipline of the PI
and of all key scientific, technical and administrative personnel; and a
mechanism for selecting and replacing key professional or technical personnel.
8. If the application is from a consortium of institutions, it must provide a
plan to assure the maintenance of close cooperation and effective communication
among members of the consortium, including letters of commitment to this plan
from all participating institutions.
9. The application must demonstrate the organization’s ability to participate
effectively in cooperative, multi-center studies. The application must also
include a written commitment to: participating in the cooperative study group;
serving on the Steering Committee and adhering to the decisions reached by that
Committee, including following the consensus treatment protocols and adjunct
studies; and accepting the participation and assistance of NIH staff in
accordance with the guidelines outlined under "Terms and Conditions of Award:
NIH Staff Responsibilities."
10. The application must include a written commitment to design and conduct
non-human primate research, in addition to the studies funded in the initial
application, under circumstances in which such additional research is of
significant importance to further the field of immune tolerance. Such
circumstances include the evaluation of safety and efficacy and studies of
underlying mechanisms for: existing tolerance induction treatment strategies in
non-human primate models to produce data of critical importance to the design
and conduct of scientifically sound and ethically acceptable human clinical
trials; newly discovered molecular targets for the induction of immune tolerance
identified through fundamental research in small animal models; and new non-
human primate models of kidney transplantation, islet transplantation for type 1
diabetes, autoimmune diseases, and asthma and allergic diseases. This written
commitment must also include the awardee’s willingness and agreement to: (1)
prepare scientific proposals for the design, conduct and analysis of such
additional studies and budget requests for all associated costs; (2) submit
proposals for scientific evaluation by NIH staff and, when appropriate, non-
Federal experts identified by the sponsors of this research program; and (3)
accept additional funding from NIH and non-Federal organizations to support such
additional investigations. The time frame within which such additional projects
can be initiated and completed will be negotiated and agreed upon jointly
between the awardees and the sponsors.
URLs in NIH Grant Applications or Appendices
All applications and proposals for NIH funding must be self-contained within
specified page limitations. Unless otherwise specified in an NIH solicitation,
Internet addresses (URLs) should not be used to provide information necessary to
the review because reviewers are under no obligation to view the Internet sites.
Reviewers are cautioned that their anonymity may be compromised when they
directly access an Internet site.
REVIEW CONSIDERATIONS
Review Procedures
Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and for responsiveness by NIH 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 NIH in accordance with the review criteria and minimum requirements stated
above. 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 National Council of the appropriate sponsoring institute.
Review Criteria
The criteria to be used in the evaluation of grant applications are listed
below. To put those criteria in context, the following information is contained
in instructions to the peer reviewers.
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals. Each of these
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application. Note that the
application does not need to be strong in all categories to be judged likely to
have a major scientific impact and thus deserve a high priority score. For
example, an investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward.
1. Significance. Does this study address an important problem? If the aims of
the application are achieved, how will scientific knowledge be advanced? What
will be the effect of these studies on the concepts or methods that drive this
field?
2. Approach. Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?
3. Innovation. Does the project employ novel concepts, approaches or method?
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?
4. Investigator. Is the investigator appropriately trained and well suited to
carry out this work? Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?
5. Environment. Does the scientific environment in which the work will be done
contribute to the probability of success? Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements? Is there evidence of institutional support?
The review criteria for U19 multi-project cooperative agreement applications are
presented in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR
MULTI-PROJECT AWARDS (August 2000); this brochure is available via the WWW at:
http://www.niaid.nih.gov/ncn/grants/multibron.htm. Applicants are instructed to
consult this website for details on the criteria for evaluating of each project
and core as well as the overall application. Five review criteria listed above
will be used to evaluate each project. Review criteria for scientific cores
consist of the following: justification and usefulness to the various research
projects, relationship to the central focus of the overall program, quality of
relevant services or facilities, qualifications of the personnel, and
appropriateness of the budget. In addition, the initial review group will
examine the appropriateness of proposed project budget and duration, the
provisions for the protection of animal subjects, and the safety of the research
environment.
Schedule
Letter of Intent Receipt Date: June 11, 2001
Application Receipt Date: July 17, 2001
Scientific Review Date: October-November 2001
Advisory Council Date: February 2002
Earliest Award Date: April 1, 2002
AWARD CRITERIA
Funding decisions will be made on the basis of scientific and technical merits
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 (research scope and
eligibility) issues, may be directed to:
Shiv A. Prasad, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr., Room 5255
Bethesda, MD 20892-7640 (20817 for express mail deliveries)
Telephone: (301) 496-5598
FAX: (301) 402-2571
Email: sprasad@nih.gov
Joan T. Harmon, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 697
Bethesda, MD 20892-5640 (20817 for express mail deliveries)
Telephone: 301-594-8813
FAX: 301-480-3503
Email: harmonj@ep.niddk.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:
Dr. Priti Mehrotra
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr., Room 2100
Bethesda, MD 20892-7616
Use Zip Code 20817 for overnight deliveries
Telephone: (301) 435-9369
FAX: (301) 402-2638
Email: pmehrotra@niaid.nih.gov
Direct inquiries regarding fiscal matters to:
Mollie Shea
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr., Room 2247
Bethesda, MD 20892-7614
Use Zip Code 20817 for overnight deliveries
Telephone: (301) 402-6576
FAX: (301) 480-3780
Email: ms256g@nih.gov
Florence Danshes
National Institute of Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, MSC 5456
6707 Democracy Blvd.
Bethesda, MD 20892-5456
For Courier service, use Zip Code 20817
Telephone: (301) 594-8861
FAX: (301) 480-3504
Email: DANSHESF@EXTRA.NIDDK.NIH.GOV
AUTHORITY AND REGULATIONS
This program is described in the Catalogue of Federal Domestic Assistance No.
93.855 Immunology, Allergy, and Transplantation Research, No. 93.847
Diabetes, Endocrinology and Metabolism Research, No 93.849 Kidney Diseases,
Urology and Hematology Research and No. 93.848 - Digestive Diseases and
Nutrition Research. Awards are made under authorization of Sections 301 and 405
of the Public Health Service Act as amended (42 USC 241 and 284) and
administered under NIH Grants policies and Federal Regulations 42 CFR 52 and 45
CFR Parts 74 and 92. This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency review.
The Public Health Service strongly encourages all grant 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.
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