Full Text AI-93-020

COOPERATIVE CLINICAL TRIAL IN PEDIATRIC TRANSPLANTATION

NIH GUIDE, Volume 22, Number 42, November 19, 1993

RFA:  AI-93-020

P.T. 34

Keywords: 
  Transplantation of Organs 
  Clinical Trial 
  Children (Patients) 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  December 1, 1993
Application Receipt Date:  March 15, 1994

PURPOSE

The Division of Allergy, Immunology and Transplantation, National
Institute of Allergy and Infectious Diseases (NIAID), invites
applications from single institutions or consortia of institutions
wishing to participate in a multi-center, cooperative clinical trial
to improve the outcome of kidney and/or liver transplants in
pediatric populations.  The goal of this study is to evaluate new and
innovative therapeutic approaches, including evaluation of
modifications in existing therapeutic approaches, for enhancing graft
acceptance and patient/graft survival among kidney and/or liver
transplant recipients up to 16 years of age.  Because of the
importance of the immune system in graft acceptance/survival, this
study also seeks to enhance basic knowledge about the pediatric
immune system and foster the application of such knowledge in the
clinical setting.

HEALTHY PEOPLE 2000

The Public Health Service 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 disabiling diseases.  Potential applicants may obtain a copy
of "Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local government, and
eligible agencies of the Federal government.  Foreign organizations
are not eligible to apply.  Domestic applications may not include
international components. Applications from minority individuals and
women are encouraged.

MECHANISM OF SUPPORT

The administrative and funding mechanism to be used to undertake this
program will be the Cooperative Agreement (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 applications 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 awards under this RFA will be
$1,000,000.  In Fiscal Year 1994, the NIAID plans to fund at least
two Pediatric Transplant Units (PTUs) either as individual projects
or as a consortium.  It is anticipated that the size of awards will
vary depending on the number of participating institutions and the
number of potential study participants.  The usual PHS policies
governing grants administration and management will apply.  This
level of support is dependent on the receipt of a sufficient number
of applications of high scientific merit.  Although this program is
provided for in the financial plans of the NIAID, awards pursuant to
this RFA are contingent upon the availability of funds for this
purpose.  Funding beyond the first and subsequent years of the grant
will be contingent upon satisfactory progress during the preceding
years and availability of funds.

RESEARCH OBJECTIVES

Background

Kidney and liver transplantation remains the therapy of choice for
children with end-stage renal or hepatic failure.  There are no
alternative therapies for hepatic failure and, although dialysis
offers an alternative treatment for children with renal failure, the
morbidity and side effects remain significant.  Unfortunately, the
improvements seen in renal allograft survival in adults which have
occurred during the last decade have not been seen in pediatric
patients.  Children have significantly poorer one-year graft survival
rates for both kidney and liver transplantation than adults.
Although many factors have been implicated, the most important
appears to be the pediatric immune system.  For example, in contrast
to adults, children apparently exhibit an "enhanced" immune state and
require higher doses of immunosupressive therapy.

Although it appears that end-stage organ disease produces a
generalized immunosuppression, children are less affected than
adults.  The concept of the pediatric patient being less
immunocompromised than adults is further supported by the results of
non-specific assays, such as total T lymphocyte counts and response
to mitogen stimulation.  This, in turn, is associated with more
frequent and more vigorous graft rejection episodes and a high
frequency of graft loss due to rejection.

Also problematic are the immunosuppressive drugs currently used, both
in the inability to readily determine optimal regimens and
exacerbation of side effects.  For example, cyclosporin A (CsA) needs
to be delivered in greater doses because the intestinal length of
children apparently results in reduced absorption, and more
frequently because children metabolize CsA faster.  Further,
increased doses of either CsA or corticosteroids increase
hyperlipidemia which, in turn, increases the risk of atherosclerotic
cardiovascular disease.  Other side effects of corticosteroids
include growth retardation.  However, attempts to reduce or eliminate
corticosteroids from the treatment regimen lead to rejection episodes
in 50 percent of pediatric patients.  Such episodes reduce glomerular
filtration rates in renal transplants and this diminishes the growth
improvement achieved by steroid removal.

Thus, several important questions can be addressed in children that
are relevant to both renal and hepatic transplantation. These
include:  the causes of the poor patient and graft survival rates,
the effects of therapy on growth and development, and how best to
optimize treatment regimens.

Objectives and Scope

The purpose of this RFA is to provide support for a prospective,
multi-center, cooperative clinical trial in pediatric transplant
recipients.  The primary objectives of this study may include, but
are not limited to, the following:

o  design and implement a common protocol to evaluate, in a
controlled setting, therapeutic approaches for enhancing graft and
patient survival in pediatric kidney and/or liver transplant
recipients up to 16 years of age;

o  evaluate new and innovative therapeutic approaches, including
modifications in existing therapeutic approaches, as a means of
improving outcome; and

o  conduct appropriate correlative laboratory studies in support of
the common protocol.

A secondary objective of this study is to enhance basic understanding
of the pediatric immune system, i.e., differences between children
and adults that are essential to understanding graft rejection.
Specific questions to be addressed in this area may include, but are
not limited to, the following:

o  What qualitative and quantitative differences in immune response
to transplantation exist between pediatric and adult transplant
recipients?  To what extent are these differences the result of other
factors, e.g., the size and volume of the pediatric patient?

o  What is the nature of the apparent "enhanced" immune state of the
pediatric patient and to what extent does it account for/contribute
to differences in outcome relative to adults?

o  What are the major mediators of graft rejection?

o  What impact, if any, does the immune system have on growth and
development in pediatric transplant recipients?

o  What immunologic differences exist among various pediatric age
groups with respect to immune system function/activity?

Although it is recognized that many factors may play a role in
enhancing outcome, such as compliance, socioeconomic factors, and
other systems (e.g., the endocrine system), the limited funds
available for this RFA may preclude study of each and every such
factor.  Emphasis will be focused on the immune system.

Study Design

In order to accumulate sufficient sample size for the study, a
collaborative effort will be required by at least two PTUs, funded as
either individual projects or as a consortium.  In this collaborative
effort, the PTUs will follow a uniform study protocol with
standardized data collection procedures.

The protocol may focus on pediatric kidney transplant recipients
alone, pediatric liver transplant recipients alone, or both.
Combined kidney/liver transplantation is not within the scope of this
RFA.  Pediatric transplant recipients up to 16 years of age may be
studied.  The specific age groups to be studied will be determined by
the design of the consensus protocol.  The protocol should include a
controlled clinical trial designed to evaluate new and innovative
therapeutic approaches, including modifications in existing
therapeutic approaches, to enhance graft and patient survival.

SPECIAL REQUIREMENTS

A.  Study Organization

1.  Steering Committee

A Steering Committee will be established to serve as the main
governing body of the study.  At a minimum, the Steering Committee
will be composed of the NIAID Pediatric Transplantation Research
Coordinator (PTRC) and one representative from each participating
institution as follows:  the Principal Investigator of each PTU
whether a single institution or a consortium of institutions, and a
Senior Investigator from each additional institution participating in
a consortium arrangement.  The Senior Investigator is the person
responsible for on-site scientific direction and implementation of
the consensus protocol at institutions participating in a consortium
arrangement.  Senior Investigators must be physicians with
substantial experience in (1) pediatric kidney and/or liver
transplantation; (2) immunosuppression; and (3) the design,
implementation and evaluation of clinical trials.  All major
scientific decisions will be determined by the Steering Committee,
with each Principal Investigator, Senior Investigator, 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 three times during the first 12
months of the study and at least semi-annually thereafter.  This
Committee will have primary responsibility for developing the
consensus protocol, facilitating the conduct and monitoring of the
study, analyzing and interpreting study data, and reporting study
results.  The study will proceed into the implementation stage only
with the concurrence of both the awardees and the NIAID PTRC.  Topics
for the protocols will be proposed and prioritized by the Steering
Committee.  Each Principal Investigator and Senior Investigator (or
his/her designee) 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
Immunology Research Advisory Subcommittee to provide advice to the
Steering Committee with respect to research on the peditric immune
system, as described under the section "RESEARCH OBJECTIVES."  The
Immunology Research Advisory Subcommittee will be composed of one
representative selected by each member of the Steering Committee, as
well as the NIAID PTRC.  This Subcommittee will meet annually in
conjunction with one of the Steering Committee meetings.

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.  Protocols will be subject to review by the Data and
Safety Monitoring Board in an advisory capacity.

3.  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 PTUs with respect to
quality control, uniformity of data collection, management of the
collective data base, and data analysis.  PTUs will submit data to
the NIAID; 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 done,
how the results are interpreted, whether the results should influence
ongoing data collection, and how the findings should be disseminated.
Although the PTUs will be closely involved with these centralized
data collection and management services, applicants should not
include in their budget requests support for any of these functions.

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 should include a proposed protocol that meets the
objectives and scope of this RFA, as well as a discussion of the
rationale for the patient population, 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.  Award of the Cooperative
Agreement does not imply that the proposed protocol will be
implemented.  Since the actual study will be designed by the Steering
Committee, the final study may not reflect any single protocol
submitted in response to this RFA.

2.  The applicant institution and each participating institution
associated with an applicant consortium must document their
experience and capacity to recruit and retain pediatric study
participants, 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.

3.  The application must identify the single applicant
organization that will be legally and financially
respnsible and accountable for the use and disposition
of funds awarded on the basis of this RFA to other
institutions and/or individual components of the PTU,
and show availability of personnel and facilities
capable of performing and supporting the
administrative functions of the PTU.

4.  The application must name a single Principal Investigator (PI)
who will have scientific responsibility for the application as a
whole including all PTU-related research activities included under
it.  The PI must be a physician with substantial experience in (1)
pediatric kidney and/or liver transplantation; (2) immunosuppression;
and (3) the design, implementation and evaluation of clinical trials.
In addition, applications from consortia of institutions must name a
single Senior Investigator for each participating institution (other
than the applicant institution) who will be responsible for on-site
scientific direction and implementation of the consensus protocol.
Senior Investigators must also be physicians with substantial
experience in (1) pediatric kidney and/or liver transplantation; (2)
immunosuppression; and (3) the design, implementation and evaluation
of clinical trials.

5.  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 much also name such a Project
Coordinator.

6.  The application must provide:  a clear, concise plan in narrative
and diagrammatic form that depicts the interrelationships among the
members of the PTU, their relevant experience/expertise, and the
contribution of each to fulfillment of the objectives of this RFA; an
organizational chart of the PTU 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.

7.  The application must provide a plan to assure the maintenance of
close cooperation and effective communication among members of the
PTU, whether a single institution or a consortium of institutions,
including letters of commitment to this plan from all participating
institutions.

8.  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.

9.  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 protocol.

10.  All costs required for the proposed protocol must be included in
the application and must be fully justified.  These include the
additional costs of clinical research associated with the proposed
protocol, costs for patient recruitment and follow-up, laboratory
studies, data collection, and participation in on-site quality
assurance audits.  Requested budgets should also include: (1) travel
to the Chicago, Illinois area for three two-day Steering Committee
meetings during the first 12 months of the study and semi-annual
Steering Committee meetings thereafter for the Principal Investigator
and Senior Investigator(s) of each institution participating in an
applicant consortium, and (2) travel to the Chicago, Illinois area
for annual one-day meetings of the Immunology Research Advisory
Subcommittee for one representative from each PTU and each
institution participating in a consortium arrangement.

C.  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 study will be shared among the awardees and the
NIAID PTRC.

1.  Awardee Rights and Responsibilities

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

Steering Committee Membership and Meeting Attendance

Each Principal Investigator and Senior Investigator 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) will be responsible for attending
all Steering Committee meetings, including not less than three
meetings during the first 12 months of the study and two per year
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) 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
Immunology Research Advisory Subcommittee to provide advice to the
Steering Committee with respect to research on the peditric immune
system, as described under the section "RESEARCH OBJECTIVES."  The
Immunology Research Advisory Subcommittee will be composed of one
representative selected by each member of the Steering Committee, as
well as the NIAID PTRC.  This Subcommittee will meet annually in
conjunction with one of the Steering Committee meetings.

Protocol Development and Conduct

The Steering Committee will define protocol objectives and approaches
and design the consensus protocol.  Each awardee 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 awardee will be responsible for providing the NIAID with all
primary study data for management, quality control and analysis,
using procedures and standards determined by the Steering Committee.
All data will be available to all awardees.  Specific 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 acknowledgement of both the PTUs and NIAID
support.  Analyses to be performed using the collective data from all
PTUs will be determined and directed by the Steering Committee.  PTUs
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 Committee.

Monitoring Study Progress

The Steering Committee will establish mechanisms for assessing
performance of the PTUs, 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 PTU, and each institution 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:

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

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

2.  NIAID Staff Responsibilities

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
Immunology Research Advisory 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 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) and the Bureau of Biologics (BOB) with respect
to the use investigational drugs.

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 PTUs 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.  Information obtained from the
data may be used by NIAID Staff 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/deletion 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 PTU 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, Senior
Investigators of institutions participating in a 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 Immunology Research
Advisory Subcommittee to provide advice with respect to research on
the pediatric immune system as described under the section "RESEARCH
OBJECTIVES."  The Immunology Research Advisory Subcommittee will be
composed of one representative selected by each member of the
Steering Committee, as well as the NIAID PTRC.  This Subcommittee
will meet annually in conjunction with one of the Steering Committee
meetings.

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.  The protocol will be subject to review by this Board in
an advisory capacity.

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

4.  Arbitration

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award) between award recipients and the
NIAID may be brought to arbitration.  An arbitration panel will be
composed of three members -- one 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 selected by the two prior members.
This special arbitration procedure in no way affects the awardee's
rights to appeal an adverse action that is otherwise appealable in
accordance with the PHS regulations at 42 CFR part 50, subpart D and
HHS regulation at 45 CFR part 16.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them. This policy is intended to
apply to males and females of all ages. If women or minorities are
excluded or inadequately represented in clinical research,
particularly proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in
Section 5, Human Subjects.  Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans [including American Indians or Alaskan
Natives], Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including, but not limited to,
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded. However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

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

LETTER OF INTENT

Prospective applicants are asked to submit, by December 1, 1993, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator, the number and title of this RFA, and a list
of the key investigators and their institution(s).  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. Mark Rohrbaugh at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 9/91).  For purposes of identification
and processing, item 2 on the face page of the application must be
marked "YES" and the RFA number and the words "COOPERATIVE CLINICAL
TRIAL IN PEDIATRIC TRANSPLANTATION" must be typed in.

Applications from multi-component consortia must contain a single
face page and additional face pages for each institution involved, an
overall budget page, and separate budget pages for each institution
involved.  Each consortium institution is allowed 25 pages for the
research plan if different plans are proposed by the different member
institutions.  For additional information, refer to page 8 of the PHS
398 application form.

These application forms may be obtained from the institution's office
of sponsored research or its equivalent and from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
(301) 710-0267.

Applications must address the requirements below as outlined in the
section "SPECIAL REQUIREMENTS:  Minimum Requirements for
Application."

1.  Applications should include a proposed protocol that meets the
objectives and scope of this RFA, as well as a discussion of the
rationale for the patient population, the study design and the
therapeutic approach selected for study, and an assessment of how
anticipated study results can be expected to contribute to
improvements in patient/graft survival.

2.  The applicant institution and each participating institution
associated with an applicant consortium must document their
experience and capacity to recruit and retain pediatric study
participants, 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.

3.  Applications must name a single Principal Investigator (PI) who
will have scientific responsibility for the application as a whole
including all PTU-related research activities included under it.  The
PI must be a physician with substantial experience in (1) pediatric
kidney and/or liver transplantation; (2) immunosuppression; and (3)
the design, implementation and evaluation of clinical trials.  In
addition, applications from consortia of institutions must name a
single Senior Investigator for each participating institution (other
than the applicant institution) who will be responsible for on-site
scientific direction and implementation of the consensus protocol.
Senior Investigators must also be physicians with substantial
experience in (1) pediatric kidney and/or liver transplantation; (2)
immunosuppression; and (3) the design, implementation and evaluation
of clinical trials.

4.  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 much also name such a Project
Coordinator.

5.  The application must provide:  a clear, concise plan in narrative
and diagrammatic form that depicts the interrelationships among the
members of the PTU, their relevant experience/expertise, and the
contribution of each to fulfillment of the objectives of this RFA; an
organizational chart of the PTU 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.

6.  The application must provide a plan to assure the maintenance of
close cooperation and effective communication among members of the
PTU, whether a single institution or a consortium of institutions,
including letters of commitment to this plan from all participating
institutions.

7.  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.

8.  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 protocol.

9.  All costs required for the proposed protocol must be included in
the application and must be fully justified.  These include the
additional costs of clinical research associated with the proposed
protocol, costs for patient recruitment and follow-up, laboratory
studies, data collection, and participation in on-site quality
assurance audits.  Requested budgets should also include: (1) travel
to the Chicago, Illinois area for three 2-day Steering Committee
meetings during the first 12 months of the study and semi-annual
Steering Committee meetings thereafter for the Principal Investigator
and Senior Investigator(s) of each institution participating in an
applicant consortium, and (2) travel to the Chicago, Illinois area
for annual one-day meetings of the Immunology Research Advisory
Subcommittee for one representative from each PTU and each
institution participating in a consortium arrangement.

It is highly recommended that the Chief of the Transplantation
Section, Genetics and Transplantation Branch, NIAID Division of
Allergy, Immunology and Transplantation, be contacted in the early
stages of preparation of the application.  (See program contact in
"INQUIRIES" below.)

Applications must be received by March 15, 1994.

Applications that are not received by the receipt date or that do not
conform to the instructions contained in PHS 398 (rev. 9/91)
application kit, will be judged non-responsive and will be returned
to the applicant.

The RFA label in the application form PHS 398 must be affixed to the
bottom of the face page.  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.

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

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

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

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

The Division of Research Grants (DRG) will not accept any application
in response to this RFA that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application.  The DRG will not accept any application that is
essentially the same as one already reviewed.  This does not preclude
the submission of a substantial revision of an application already
reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Review Method

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

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

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

Review Criteria

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

1.  The scientific and technical significance, merit and originality
of the proposed protocol and its anticipated contributions to
improved graft/patient survival.

2.  The scientific expertise and experience of the Principal
Investigator, the Senior Investigators for an applicant consortium,
and key technical personnel in the fields of pediatric
transplantation, immunosuppression and clinical trial design, conduct
and analysis.

3.  Documentation of the availability of adequate pediatric patient
populations and experience and expertise of the applicant
institution(s) and key personnel in recruitment, retention and
follow-up of pediatric study participants.

4.  Documentation of the sponsoring institution's commitment to the
cooperative program, including support for membership of the proposed
Principal Investigator and Senior Investigator on the Steering
Committee; willingness to abide by the scientific decisions made via
consensus of Steering Committee members; and willingness to accept
the participation and assistance of NIAID staff.

5.  Adequacy of the proposed plan for coordination and communication
within the applicant institution and with institutions participating
in consortia-type arrangements, particularly with respect to
multi-center clinical trials.

6.  Adequacy of available laboratory and clinical facilities,
including information on the institution's present patient load and
access to and projections for patient involvement in clinical
investigations.

AWARD CRITERIA

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

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Andrea A. Zachary, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A13
Bethesda, MD  20892
Telephone:  (301) 496-5598
FAX:  (301) 402-2571

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

Mark Rohrbaugh, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C22
Bethesda, MD  20892
Telephone:  (301) 496-8424
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Jeffrey Carow
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B29
Bethesda, MD  20892
Telephone:  (301) 496-7075

Schedule

Letter of Intent Receipt Date:  December 1, 1993
Application Receipt Date:       March 15, 1994
Scientific Review Date:         June 1994
Advisory Council Date:          September 1994
Earliest Award Date:            September 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
Research.  Awards will be made under the authority of the Public
Health Service Act, Title III, Section 301 (Public Law 78-410, as
amended; 42 USC 241) and administered under PHS grants policies and
Federal Regulations 42 CFR Part 74.  This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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