Full Text AI-95-008

COOPERATIVE CLINICAL TRIAL IN ADULT TRANSPLANTATION

NIH GUIDE, Volume 24, Number 6, February 17, 1995

RFA:  AI-95-008

P.T. 34

Keywords: 
  Transplantation of Organs 
  Clinical Trial 
  Transplantation Immunology 
  Immune System 


National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  June 15, 1995
Application Receipt Date:  October 12, 1995

PURPOSE

The Division of Allergy, Immunology and Transplantation of the
National Institute of Allergy and Infectious Diseases (NIAID),
National Institutes of Health (NIH), 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 transplants in adult populations.  The goal of this study is
to evaluate new and innovative therapeutic approaches, including
modifications in existing therapeutic approaches, for enhancing graft
acceptance and patient/graft survival among kidney transplant
recipients.  Because of the importance of the immune system in graft
acceptance/survival, this study also seeks to enhance basic knowledge
about the immune system and foster the application of such knowledge
in the clinical setting.

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 Adult
Transplantation, is related to the priority area of diabetes and
chronic disabling diseases.  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 202-783-3238).

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.  Racial/ethnic minority individuals, women,
and persons with disability 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 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
$1,800,000.  In Fiscal Year 1996, the NIAID plans to fund at least 4
new and/or recompeting Adult Transplantation Units (ATUs) 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 NIH
is currently limiting annual inflationary increases to no more than
four percent for future years of awards.  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

Although kidney transplantation is the most effective therapeutic
regimen for the treatment of end-stage renal disease, several factors
continue to limit the success of this preferred therapy.  The major
remaining obstacles, other than the shortage of donor organs, relate
to rejection of the transplanted organ and to limitations of the
immunosuppressive therapies currently employed to prevent or control
rejection.  Although currently employed immunosuppressive therapies
have greatly improved the success rate of kidney transplants, their
side effects and the relatively poor long-term survival rate indicate
the need for new and more efficacious treatment approaches and
regimens.

In September 1991, the NIAID established the Cooperative Clinical
Trial in Transplantation (CCTT) to expedite the evaluation of new
treatment modalities to prevent kidney graft rejection.  The eight
centers participating in this cooperative research program have
explored multiple protocols focused on inducing tolerance in kidney
graft recipients and on new agents to reverse kidney graft rejection.
The CCTT has completed an evaluation of murine OKT4A induction, the
results of which have been presented and will be published shortly.
In addition, the following three protocols are currently open to
enrollment: (1) a living, donor specific blood transfusion protocol;
(2) a protocol using bone marrow infusion just after kidney
transplantation as a means of inducing donor specific
unresponsiveness; and (3) an evaluation of Rapamycin for acute
rejection.  Copies of all completed and ongoing protocols used by the
CCTT will be made available to applicants upon request to the program
contact listed under INQUIRES.

Research Objectives and Scope

The purpose of this RFA is to continue NIAID support for prospective,
multi- center, cooperative clinical trials in adult kidney transplant
recipients to evaluate many additional agents and therapeutic
modalities as they become available.  These include new drugs and
unique combinations of different drugs or antibodies, as well as
approaches for pretreating both the transplant recipient and the
donor organ.  In addition, efficacy and safety data being generated
from the current cooperative research program will be instrumental in
designing new protocols.

The primary objectives of this RFA include, but are not limited to,
the following:

o  design and implement common protocols, in a controlled setting,
evaluate therapeutic approaches for enhancing kidney graft survival
in adult transplant recipients;

o  evaluate new and innovative therapeutic approaches, including
modifications in existing therapeutic approaches, as a means of
improving outcome.  Specifically, approaches should be aimed at
inducing transplant tolerance; and

o  conduct appropriate laboratory studies in support of the common
protocols to elucidate the basic mechanisms involved.

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 four ATUs, funded
as either individual projects or as a consortium.  In this
collaborative effort, the ATUs will follow uniform study protocols
with standardized data collection procedures.

The protocol will focus on adult kidney transplant recipients and
will involve a controlled design to evaluate new and innovative
therapeutic approaches, including modifications in existing
therapeutic approaches, to enhance graft survival.  A key feature of
the strategy will be inducing tolerance to the donor kidney.

NOTE:  Although the actual protocols to be conducted will be designed
by the Steering Committee, applications must include a proposed
protocol that meets the objectives and scope of this RFA.

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 Adult Transplantation Research
Coordinator (ATRC) and one representative from each participating
institution as follows:  the Principal Investigator of each ATU
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) kidney 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 ATRC 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 ATRC.  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 common protocols, 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 ATRC.  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 immune system.
The Immunology Research Advisory Subcommittee will be composed of one
representative selected by each member of the Steering Committee, as
well as the NIAID ATRC.  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 ATRC. 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 through the
establishment of a Clinical Coordinating Center, to be funded
separately from this Cooperative Agreement.  The Clinical
Coordinating Center will have primary responsibility for quality
control and uniformity of data collection, as well as for managing
the collective data base.  Under the direction of the Steering
Committee, ATUs will submit data to the Clinical Coordinating Center;
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 ATUs 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.  However,
the budget should include appropriate support for personnel required
for data acquisition and entry (commonly referred to as a Data
Coordinator).  This function may be performed by the Study
Coordinator at the discretion of the applicant.

B.  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 Grants 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 those aspects of
scientific/programmatic management of the projectas stated below
under "NIAID staff responsibilities."

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 twelve 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 immune system.
The Immunology Research Advisory Subcommittee will be composed of one
representative selected by each member of the Steering Committee, as
well as the NIAID Adult Transplantation Research Coordinator (ATRC).
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 protocols.  Each awardee will follow the
procedures required by the consensus protocols 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 to the Clinical
Coordinating Center 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 the Clinical Coordinating Center
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 ATUs and NIAID
support.  Analyses to be performed using the collective data from all
ATUs will be determined and directed by the Steering Committee.  ATUs
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 ATUs, 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 ATU, 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 ATU
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 ATRC 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 ATRC 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 ATRC will also serve on the
Immunology Research Advisory Subcommittee.

Protocol Development

As a member of the Steering Committee, the NIAID ATRC 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 ATRC 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 establish a Clinical Coordinating Center, independent
of and supported separately from the ATUs, to provide technical
assistance and data management services to the ATUs with respect to
quality control, uniformity of data collection, management of the
collective data base, and data analysis.

The Government, via the NIAID ATRC, 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 ATRC 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 ATRC 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 ATRC.  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 ATRC.

Program Review

The NIAID ATRC will review the progress of each ATU 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 ATRC, 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 protocols; 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 immune system.  The Immunology Research Advisory Subcommittee
will be composed of one representative selected by each member of the
Steering Committee, as well as the NIAID ATRC.  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 ATRC.  The protocol will be subject to review by this Board in
an advisory capacity.

Awardees will be required to accept and implement the common
protocols 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 ATRC.

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.

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 is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which has been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 15, 1995, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address, and telephone number of the
Principal Investigator, the 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. Strickland at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 09/91).  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) 435-0714.  For
purposes of identification and processing, item 2a on the face page
of the application must be marked "YES" and the RFA number and the
words "COOPERATIVE CLINICAL TRIAL IN ADULT TRANSPLANTATION" must be
typed in.

The RFA label in the PHS 398 application form 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.

Applications from multi-component consortia must contain a single
face page, an overall budget page, and separate budget pages for each
institution involved.  Each consortium institution is allowed 25
pages for the research plan if different plans are proposed by the
different member institutions.

Applications must address the requirements below:

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 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 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 ATU-related research activities included under it.  The
PI must be a physician with substantial experience in (1) kidney
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) kidney 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 ATU, their relevant experience/expertise, and the
contribution of each to fulfillment of the objectives of this RFA; an
organizational chart of the ATU 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 ensure the maintenance of
close cooperation and effective communication among members of the
ATU, 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 Washington, DC 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 Washington, DC area for
annual one-day meetings of the Immunology Research Advisory
Subcommittee for one representative from each ATU and each
institution participating in a consortium arrangement.

It is highly recommended that the Chief of the 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 October 12, 1995.  Applications
received after the receipt date will be returned without review.
Applications 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 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.  This does not exclude the submission of substantial
revisions of an application already reviewed.  These applications
must, however, include an introduction addressing the previous
critique.

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

Division of Research Grants
National Institutes of Health
6701 Rockledge Drive, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (express mail)

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. Strickland 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.

REVIEW CONSIDERATIONS

Review Procedures

Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants (DRG) and for responsiveness by NIAID
staff. Incomplete and non-responsive applications will be returned to
the applicant without further consideration.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIAID in accordance with the review
criteria stated below.  As part of the initial merit review, a
process (triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the principal investigator and the official
signing for the applicant organization will be promptly notified.
The second level of review will be provided by the NIAID Advisory
Councils.  Review, Council and award dates are listed under Schedule.

Review Criteria

Applicants are expected to address the requirements identified under
APPLICATION PROCEDURES.  The review criteria for applications in
response to this RFA are:

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

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

The initial review group will also examine 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 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:

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

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:

Paula S. Strickland, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C02
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 402-0643
FAX:  (301) 402-2638
Email:  ps30f@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Carol Alderson
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C26
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  ca10h@nih.gov

Schedule

Letter of Intent Receipt Date:  June 15, 1995
Application Receipt Date:       October 12, 1995
Scientific Review Date:         March 1996
Advisory Council Date:          May 1996
Earliest Award Date:            July 1996

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.

The PHS strongly encourages all grant recipients to provide a smoke-
free work place and promote the nonuse of all tobacco products.  This
is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.

.

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