COOPERATIVE CLINICAL TRIAL:  PEDIATRIC RENAL TRANSPLANTATION

Release Date:  May 21, 1998

RFA:  AI-98-012

P.T.

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  July 21, 1998
Application Receipt Date:  December 29, 1998

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), National
Institutes of Health (NIH), invites applications from consortia of
institutions to participate in a multi-center, cooperative clinical trial
program to improve graft acceptance and patient/graft survival in pediatric
kidney transplant recipients up to 21 years of age. The goals of this research
program are to:  (1) evaluate the safety and efficacy of new and innovative
therapeutic approaches; (2) evaluate the safety and efficacy of modifications
in standard therapeutic approaches both to improve outcome and reduce
deleterious side effects of current immunosuppressive regimens; (3) assess the
underlying mechanisms of action of the therapeutic approaches under
investigation; and (4) develop and validate immune and/or surrogate markers of
graft acceptance and survival.  All applicants must comply with the
requirements outlined in the section below titled "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 Request for Applications (RFA),
Cooperative Clinical Trial in Pediatric Transplantation, 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

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 mechanism to be used to undertake this program
will be the Cooperative Agreement (U01), 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.  Details of the responsibilities, relationships, and governance of a
study funded under cooperative agreement(s) are discussed later in this
document under the section Terms and Conditions of Award.

The total project period for an application submitted in response to this RFA
may not exceed five years.  At present, the NIAID is administratively limiting
the duration of U01 cooperative agreements to four years; this administrative
limitation may change in the future.  At this time, the NIAID has not
determined whether and how this solicitation will be continued beyond the
present RFA.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for the first
year of support for all awards made under this RFA will be $2,050,000.  In
Fiscal Year 1999, the NIAID plans to fund at least two awards for consortia of
institutions.  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 and the receipt of a sufficient number
of applications of high scientific merit.  Funding beyond the first and
subsequent years of the grant will be contingent upon satisfactory progress
during the preceding years and availability of funds.

RESEARCH OBJECTIVES

Background

Kidney transplantation remains the therapy of choice for children with end-
stage renal failure. Although dialysis offers an alternative treatment, the
morbidity and side effects of this treatment remain significant.  While the
differences in one-year and five-year graft survival between children and
adults are not as pronounced as when the first Cooperative Clinical Trial in
Pediatric Transplantation (CCTPT) was established in 1994, children still are
not achieving the long-term graft survival rates of adults who receive
cadaveric renal transplants. This disparity in long-term graft survival is
very problematic for young children; retransplantation requires going back on
the waiting list and dialysis with its attendant morbidity and side effects.
Therefore, young children are unlikely to achieve a normal life span, or an
acceptable quality-of-life, as they are likely to receive a second, and even a
third or fourth transplant in their lifetime. Although many factors have been
implicated, the most important appears to be the pediatric immune system.  In
contrast to adults, children exhibit an "enhanced" immune state and require
higher doses of immunosuppressive therapy to prevent rejection. This
difference is reflected by measures of the immune system, such as increased
total T lymphocyte counts vs. adults and their heightened response to mitogen
stimulation.  These findings are associated with more frequent and more
episodes of vigorous graft rejection that are not as responsive to therapy as
in adults, resulting in a higher frequency of graft loss due to irreversible
rejection.  For example, cyclosporine A (CsA) needs to be administered in
higher doses to achieve effective blood levels because the shorter intestinal
length of children results in reduced absorption. In addition, children must
also receive CsA more frequently as they metabolize it faster.  Further, these
increased doses of CsA induce hyperlipidemia, which increases the risk of
atherosclerotic cardiovascular disease.  A well-documented side effect of the
corticosteroids that are part of the standard immunosuppressive regimen is
growth retardation, a serious problem unique to the pediatric population.
Growth retardation can lead to psychological problems and the inability to
lead a normal life. It is most problematic for the very young children who
receive a transplant, as they will never achieve normal stature.

Therefore, changes in standard immunosuppression or use of new treatment
regimens that reduce or completely abolish the need for global
immunosuppression hold promise of improving graft survival while reducing
adverse side effects.  This includes the use of new, less toxic induction
therapies, such as anti-IL-2 receptor antibodies to replace cyclosporine, or
the use of less toxic replacements for steroids. The CCTPT provides the
infrastructure to conduct these clinical trials, perform studies of underlying
mechanisms and develop immune and surrogate markers of graft acceptance,
rejection and function.

Research Objectives and Scope

The purpose of this RFA is to support a program of prospective, multi-site
cooperative clinical trials in pediatric kidney transplantation, including the
components outlined below.  All participating clinical sites will utilize
uniform controlled study designs and standardized data collection procedures.
Pediatric patients up to 21 years of age may be studied, with the specific age
groups to be determined by the design of the common protocols. Specifically,
applications must propose:

o  Clinical trials to evaluate the safety and efficacy of new and innovative
therapeutic approaches to improve graft and patient survival, including: pre-,
peri-, and post-transplant tolerogenic and immunomodulatory interventions to
induce donor-specific tolerance with and without temporary or permanent
withdrawal of, or new combinations of, standard immunosuppression; new less
toxic immunosuppressive agents to prevent rejection; and new approaches to
reduce the number of immunosuppressive agents required to prevent rejection;

o  Clinical trials of the safety and efficacy of modifications in standard
therapeutic approaches both to improve short- and long-term graft/patient
survival and to reduce the deleterious side effects of current
immunosuppressive regimens, including withdrawal of one or more standard
therapies, reduction in dosage, and modifications in timing and administration
or new combinations of immunosuppressive agents;

o  Adjunct studies of the underlying mechanisms of action of the therapeutic
approaches being evaluated, including changes in immune response and function,
measures of donor-specific tolerance and loss of tolerance; and

o  Adjunct studies to develop, evaluate and validate sensitive immune and/or
surrogate markers of short- and long-term graft survival and rejection, with
particular emphasis on defining clinically relevant predictors of acute and
chronic rejection. The use of non-invasive approaches is highly encouraged.

SPECIAL REQUIREMENTS

A.  Study Organization

1.  Steering Committee

A Steering Committee will be established to serve as the main governing body
of the cooperative research program.  At a minimum, the Steering Committee
will be composed of the NIAID Pediatric Transplantation Research Coordinator
(PTRC), the Principal Investigators, and one additional Senior Investigator
from each consortium as a permanent member, or on a rotating basis, if
appropriate, as determined by the protocols under development or implemented. 
A Senior Investigator is the person responsible for on-site scientific
direction and implementation of the consensus protocols at a participating
Pediatric Transplant Institution (PTI).  Senior Investigators must be
physicians with substantial experience in pediatric kidney transplantation and
in the design, implementation and evaluation of clinical trials.

The Steering Committee shall appoint an Adjunct Studies Subcommittee to
design, implement and evaluate (1) studies of underlying mechanisms of action
of the therapeutic approaches under investigation and (2) studies to develop,
evaluate and validate immune and/or surrogate markers of graft survival and
rejection. The members of the Adjunct Studies Subcommittee shall be selected
by the Principal Investigators, with each Principal Investigator having two
representatives on this Subcommittee, and shall include the PTRC as a voting
member.  The Chair of the Adjunct Studies Subcommittee shall be elected by its
members, not including the PTRC, and shall serve as a voting member of the
Steering Committee.  The Subcommittee will meet annually in conjunction with
Steering Committee meetings and its members will be expected to participate in
all meetings and in other Subcommittee activities, e.g., conference calls.

All major scientific decisions will be determined by the Steering Committee,
with each Principal Investigator, Senior Investigator, Chair of the Adjunct
Studies Subcommittee, and the NIAID PTRC having one vote.  The Chairperson
will be selected by the Steering Committee from among the non-Federal members
during the first meeting of the Committee, to be convened by the NIAID PTRC. 
The Committee will meet at least twice during the first 12 months of the study
and annually thereafter.  This Committee will have primary responsibility for
developing the common clinical protocols, approving the design and
implementation of all adjunct studies, facilitating the conduct and monitoring
of all clinical trials and adjunct studies, analyzing and interpreting study
data, and reporting study results.  Clinical trials and adjunct studies will
proceed into the implementation stage only with the concurrence of both the
Steering Committee and the NIAID PTRC. Each Steering Committee member will be
expected to participate in all other Steering Committee activities, e.g.,
conference calls, special subcommittees as may be necessary, etc.

Other subcommittees of the Steering Committee may be established as necessary.

2.  Data and Safety Monitoring Board

An independent Data and Safety Monitoring Board, to be appointed by the NIAID,
will review progress at least annually and report to the NIAID PTRC.  Clinical
protocols and adjunct studies will be subject to review by the Data and Safety
Monitoring Board in an advisory capacity prior to implementation.

3.  Data Coordination and Management

The NIAID will be responsible for ensuring the provision of centralized data
collection, management and quality assurance.  Under the direction of the
Steering Committee, the NIAID will provide technical assistance and data
management services to the PTIs with respect to quality control, uniformity of
data collection, management of the collective data base, and data analysis. 
PTIs will submit data to the NIAID or its designate; specific data analyses to
be carried out will be determined by the Steering Committee and the results of
those analyses will be delivered to the Steering Committee as the group
responsible for determining which further analyses should be performed, how
the results are interpreted, whether the results should influence ongoing data
collection, and how the findings should be disseminated.  Although the PTIs
will be closely involved with these centralized data collection and management
services, applicants should include in their budget requests only support for
on-site data collection and transmittal.

B.  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 two (2) proposed protocols for clinical trials
that meets the objectives and scope of this RFA, as well as a discussion of
the rationale for the patient population, the statistical calculations and
considerations in determining sample size, the study design and the
therapeutic approach(es) selected for study, and an assessment of how
anticipated study results can be expected to contribute to improvements in
patient/graft survival.  One protocol must be using new or innovative
approaches and one must be modification of standard therapeutic approaches.
Award of the Cooperative Agreement does not imply that any of the proposed
protocols will be implemented.  Since the actual protocols will be selected by
the Steering Committee, the final clinical trials may not reflect any single
protocol submitted in response to this RFA.

2. The application must include at least two (2) proposed hypothesis-driven
adjunct studies of underlying mechanisms of action to be carried out as part
of each of the proposed protocols, including: the rationale for the adjunct
studies proposed in terms of feasibility, validity, and
sensitivity/specificity; the specific aspects of immune response and function
to be measured; a description of the patient samples required, including time
and frequency of collection, number and quantity of samples required and
methodologies to be used to analyze patient samples, including new and non-
invasive techniques for collection and analysis; and a discussion of how the
results of the adjunct studies will contribute to further understanding of the
clinical effects of the therapeutic approaches under investigation. As in the
case of the proposed clinical protocols, award of the Cooperative Agreement
does not imply that any proposed adjunct studies will be implemented. Actual
studies to be performed will be selected or designed by the Adjunct Studies
Subcommittee, and approved by the Steering Committee

3. The application must include at least one proposed adjunct study to
develop, evaluate and validate sensitive immune and/or surrogate markers of
short- and long-term graft survival and/or rejection.  One of the overall
goals of these adjunct studies is to develop predictors of rejection prior to
organ damage.  Descriptions of proposed adjunct studies are to include:
identification of and rationale for the immune and/or surrogate markers
selected, including published data from animal and/or human studies;
description of the source, quantity and number of patient samples required;
methodologies proposed to collect and analyze samples; and a discussion of how
the results of the proposed adjunct studies will contribute to improvements in
the capacity to utilize immune and surrogate markers to predict graft
acceptance, changes in graft function, rejection and patient survival.  It is
not a requirement that these adjunct studies be associated with the clinical
protocols proposed in the application. However, studies may use patient
samples from the proposed protocols or from other sources.  Applications must
identify the source of patient materials required for the adjunct studies, and
provide documentation of the availability of the appropriate number and type
of patient materials and the willingness of the source to make such samples
available to the investigators. As in the case of the proposed clinical
protocol, award of the Cooperative Agreement does not imply that any proposed
adjunct studies will be implemented. Actual studies to be performed will be
selected or designed by the Adjunct Studies Subcommittee, and approved by the
Steering Committee.

4. The applicant institution and each institution participating in the
consortium must document: their experience and capacity to recruit and retain
pediatric study participants up to 21 years of age, including sufficient
numbers of patients for Phase III efficacy trials; provide a description of
the population currently available for the proposed protocol; and describe
proposed mechanisms for monitoring accrual performance and criteria for
continued participation by each participating institution.

5. 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 PTIs and other
institutions participating in the consortium, and show availability of
personnel and facilities capable of performing and supporting the
administrative functions necessary.

6. 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.  The PI must be a physician with
substantial experience in pediatric kidney transplantation, and in the design,
implementation and evaluation of clinical trials.  In addition, applications
must name a single Senior Investigator for each PTI in the consortium who will
be responsible for on-site clinical and scientific implementation, direction
and management of the clinical protocols, as well as the coordination of
requirements for adjunct studies of underlying mechanisms and immune/surrogate
markers.  The P.I. would be the Senior Investigator from his or her
Institution. Senior Investigators must also be physicians with substantial
experience in pediatric kidney transplantation and in the design,
implementation and evaluation of clinical trials.

7. Applications must demonstrate the scientific expertise required to design,
conduct and analyze all adjunct studies.  Such expertise may be provided by a
single scientist serving the entire consortium or more than one such scientist
depending upon the proposed clinical protocols and adjunct studies.

8. The application must name a Project Coordinator who is an individual with
substantial technical/administrative experience in managing patient
enrollment, patient follow-up, and multi-source data collection for clinical
studies.  Each participating institution associated with an applicant
consortium must also name such a Project Coordinator.

9. The application must provide: a clear, concise plan, in narrative and
diagrammatic form, that depicts the interrelationships among the members of
the consortium, 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.

10. The application 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.

11. The application should discuss the capability of the applicant
organization and each institution in an applicant consortium to participate
and interact effectively in cooperative, multi-center clinical trials.

12. The application must include a written commitment to accept the
participation and assistance of NIAID staff in accordance with the guidelines
outlined under "Terms and Conditions of Award: NIAID Staff Responsibilities." 
The application must also include a written commitment to the cooperative
organization and willingness to serve on the Steering Committee and adhere to
the decisions reached by that Committee, including following the consensus
protocols and adjunct studies. Also, PTIs will be required to affirm that
their commitment of patients to the CCTPT for specific protocols will take
precedence over subsequent non-CCTPT clinical trials started after the CCTPT
protocols are implemented.

13. All costs required for the proposed protocols and adjunct studies must be
included in the application and must be fully justified.  These include the
additional costs of clinical research associated with the proposed protocols,
costs for patient recruitment and follow-up, adjunct studies, data collection,
and participation in on-site quality assurance audits.  Requested budgets
should also include: (1) travel to the Chicago, Illinois area for two 1-day
Steering Committee meetings during the first 12 months, and annually
thereafter for the Principal Investigator and one Senior Investigator for the
consortium, and (2) travel to the Chicago, Illinois area for annual one-day
meetings of the Adjunct Studies Subcommittee for the two representatives from
each consortium.

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
cooperative agreement (U01), 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 PTRC.

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 activity. Specifically, awardees
have primary responsibility as described below.

Steering Committee Membership and Meeting Attendance

Each Principal Investigator and Senior Investigator from a consortium will
serve as a voting member of the Steering Committee and will participate in all
scientific decisions.  Each Principal Investigator and Senior Investigator (or
his/her designee) from a consortium will be responsible for attending all
Steering Committee meetings, including not less than two meetings during the
first 12 months of the study and annually thereafter.  The Steering Committee
shall be responsible for determining the frequency of meetings and scheduling
the time and location.  Each Principal Investigator and Senior Investigator
(or his/her designee) from a consortium will be expected to participate in all
other Steering Committee activities, e.g., conference calls, special
subcommittees as may be necessary, etc.

Subcommittees of the Steering Committee may be established as necessary.  At a
minimum, the Steering Committee will establish an Adjunct Studies Subcommittee
to provide advice to the Steering Committee with respect to research on the
pediatric immune system, as described under the section "RESEARCH OBJECTIVES." 
The Adjunct Studies Subcommittee will be composed of two representatives
selected by each consortium Principal Investigator, as well as the NIAID PTRC. 
This Subcommittee will meet annually in conjunction with the Steering
Committee meetings.

Protocol Development and Conduct

The Steering Committee will define protocol objectives and approaches and
design the consensus protocol or establish a Protocol Design Subcommittee to
perform this function.  Each PTI will follow the procedures required by the
consensus protocol generated by the Steering Committee regarding study conduct
and monitoring, patient management, data collection and quality control.

Data Coordination and Management

Each PTI 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 analyses to be performed by NIAID will be directed by
the Steering Committee.  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.

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 PTIs and NIAID support.  Analyses to be performed
using the collective data from all PTIs will be determined and directed by the
Steering Committee.  PTIs 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
will be required for all analyses prior to publication or presentation
according to criteria that will be developed by the Steering Committee. The
Steering Committee may establish a Publications Subcommittee to serve this
function.

Monitoring Study Progress

The Steering Committee will establish mechanisms for assessing performance of
the PTIs, including institutions participating in consortia arrangements, with
particular attention to accrual of adequate numbers of eligible patients,
timely submission and quality of required data and conscientious observance of
protocol requirements.

Federally Mandated Regulatory Requirements

Each PTI participating in a consortium arrangement is required to meet the
DHHS/PHS regulations for the protection of human subjects and FDA requirements
for the conduct of research using investigational agents.  At a minimum, these
include:

methods for assuring that each institution at which PTI 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 all protocol amendments are approved by the IRB.

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.
All informed consent documents must be available for review upon request by
the PTRC or Steering Committee, or FDA or Industry sponsor, if applicable.

2.  NIAID Staff Responsibilities

NIAID staff assistance will be provided by Dr. Stephen Rose, Ph.D., Chief,
Genetics and Transplantation Branch, Division of Allergy, Immunology and
Transplantation, NIAID who will serve as NIAID's Pediatric Transplant Research
Coordinator (PTRC).  The NIAID PTRC 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 PTRC will serve as a voting member of the Steering Committee, will
attend all Steering Committee meetings, and will participate in other
Committee activities, e.g., conference calls, special subcommittees.  The
NIAID PTRC will also serve on the Adjunct Studies Subcommittee.

Protocol Development

As a member of the Steering Committee, the NIAID PTRC will serve as a resource
with respect to the design of the protocol and will assist the Steering
Committee in protocol development.

Study Materials

The NIAID PTRC will be responsible for the acquisition and distribution of
those study materials involved in the protocol developed by the consensus of
the Steering Committee.  The NIAID will also arrange for the appropriate
approvals (when necessary) from the Food and Drug Administration (FDA) with
respect to the use investigational drugs. The PTRC may also be the responsible
person for any Investigational New Drug Applications (IND), as applicable
(e.g.- may "hold" the IND)

Monitoring Study Performance

The NIAID PTRC will provide assistance to the Steering Committee in the
development of mechanisms and procedures for monitoring study performance. 
This includes participation in periodic on-site monitoring with respect to
compliance with protocol specifications, quality control and accuracy of data
recording, and accrual.

Data Coordination and Management

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

The Government, via the NIAID PTRC, will have access to data generated under
this Cooperative Agreement and may periodically review the data and progress
reports.  NIAID 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 NIAID PTRC may contribute, through review, comment, analysis, and/or co-
authorship, to reporting results of the study to the investigator community
and other interested scientific and lay organizations.  Co-authorship by the
NIAID PTRC 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 NIAID
PTRC.  These changes include the addition or replacement of a physician,
scientific investigator, affiliate, component, or research base that is
associated with this study.  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 NIAID Grants Management Specialist in consultation with the
NIAID PTRC.

Program Review

The NIAID PTRC will review the progress of each PTI through consideration of
the annual reports, site visits, patient logs, etc.  This review may include,
but is not limited to, compliance with the study protocol, meeting patient
enrollment targets, adherence to uniform data collection procedures, and the
timeliness and quality of data reporting.

The NIAID reserves the right to terminate or curtail the study (or any
individual award) in the event of (a) substantial shortfall in participant
recruitment, follow-up, data reporting, quality control, or other major breech
of the protocol, (b) substantive changes in the agreed-upon protocol to which
the NIAID does not agree, (c) reaching a major study endpoint substantially
before schedule with persuasive statistical significance, or (d) human subject
ethical issues that may dictate a premature termination.

3.  Collaborative Responsibilities

A Steering Committee, composed of the Principal Investigators and Senior
Investigators from each consortium and the NIAID PTRC, will be the main
governing body of the study and will have primary responsibility for all
scientific decisions, including: defining protocol objectives and approaches;
designing and implementing the protocol; developing procedures for data
collection, management and quality control; establishing procedures for
assessing performance with respect to accrual, timely submission and quality
of data, and conscientious observance of protocol requirements; analyzing and
interpreting study data; and publishing/presenting study findings.  Each
member of the Steering Committee will have one vote.  The chairperson will be
selected by the Steering Committee from among the non-Federal members. 
Subcommittees will be established by the Steering Committee, as it deems
appropriate.  At a minimum, the Steering Committee will establish an Adjunct
Studies Subcommittee to provide advice with respect to the mechanistic
research and immune/surrogate marker studies as described under "RESEARCH
OBJECTIVES."  The Adjunct Studies Subcommittee will be composed of two
representatives from each consortium selected by the Steering Committee, as
well as the NIAID PTRC.  This Subcommittee will meet annually in conjunction
with the Steering Committee meeting.

An independent Data and Safety Monitoring Board, to be appointed by the NIAID,
will review progress at least annually and report to the NIAID PTRC.  All
proposed protocols and adjunct studies will be subject to review by this Board
in an advisory capacity.

PTIs will be required to accept and implement the common protocol and
procedures approved by the Steering Committee.  Studies will proceed into the
implementation stage only with the concurrence of the Steering Committee and
the NIAID PTRC.

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 composed of three members -- one
selected by the Steering Committee (with the NIAID member not voting) or by
the individual awardee in the event of an individual disagreement, a second
member selected by the NIAID, and the third member with expertise in the
relevant area and selected by the two prior members will be formed to 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.

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.

Investigators may obtain copies from these sources or from Dr. Stephen Rose
(listed in INQUIRIES below) who may also provide additional relevant
information concerning the policy.

INCLUSION OF CHILDREN 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:  https://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by July 21, 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. Madelon Halula at the address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant applications form PHS 398 (rev. 5/95) is to be used in
applying for these grants.  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) 710-0267, email: Grantsinfo@nih.gov.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES" and the RFA number "AI-98-012" and the words
"Cooperative Clinical Trials in Pediatric Renal Transplantation" must be
entered on the face page.

Applications must be received by December 29, 1998.  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 special instructions below, for the purposes of this
RFA), will be judged non-responsive and will be returned to the applicant. 
The RFA label available in the application form PHS 398 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.

If the 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.

It is highly recommended that the appropriate NIAID program contact be
consulted before submitting the letter of intent and during the early stages
of preparation of the application.  (See program contacts under INQUIRIES).

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.
Madelon Halula at the address listed under INQUIRIES.

Applicants from institutions that have a General Clinical Research Center
(GCRC) funded by the NIH National Center for Research Resources may wish to
identify the GCRC as a resource for conducting the proposed research.  If so,
a letter of agreement from either the GCRC Program Director or Principal
Investigator should be included with the application.

REVIEW CONSIDERATIONS

Review Considerations

Upon receipt, applications will be reviewed for completeness by the NIH Center
for Scientific Review (CSR) and for responsiveness by NIAID staff. 
Applications judged to be incomplete and/or non-responsive will be returned to
the applicant without review.  Applications that are complete and responsive
will be reviewed for scientific and technical merit by a review committee
convened by the Division of Extramural Activities, NIAID.

As part of the initial merit review, applications may be subjected to a
process by an NIAID peer review group to determine their scientific merit
relative to other applications received in response to this RFA.  The NIAID
will withdraw from competition those applications judged to be non-competitive
for award and will notify the applicant and institutional business officials. 
The National Advisory Allergy and Infectious Diseases Council will provide the
second level of review.

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.  Is 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 initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific goals of the
research and plans for the recruitment and retention of subjects; adequacy of
plans for including children as appropriate for the scientific goals of the
research; the provisions for the protection of human and animal subjects; and
the safety of the research environment.

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. 
The earliest anticipated date of award is September 1, 1999.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Stephen Rose, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A14
Bethesda, MD  20892-7640
Telephone:  (301) 496-5598
FAX:  (301) 402-2571
Email:  sr8j@nih.gov

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

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C16
Bethesda, MD  20892
Telephone:  (301) 402-2636
FAX:  (301) 402-2638
Email:  mh30x@nih.gov

Direct inquiries regarding fiscal matters to:

Celeste M. Kerner
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B32
Bethesda, MD  20892
Telephone:  (301) 402-6213
FAX:  (301) 480-3780
Email:  ck103k@nih.gov

Schedule

Letter of Intent Receipt Date:  July 21, 1998
Application Receipt Date:       December 29, 1998
Scientific Review Date:         March 1999
Advisory Council Date:          May 1999
Earliest Award Date:            September 1, 1999

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health Service
Act, Sec. 301 (c), Public Law 78-410, as amended.  The Catalogue of Federal
Domestic Assistance Citation is (Sec. 93.856, Microbiology and Infectious
Diseases Research, or No. 93.855 - Immunology, Allergy, and Transplantation
Research, or both, as appropriate).  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)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.