Full Text DC-96-002

CLINICAL TRIALS COOPERATIVE GROUPS

NIH GUIDE, Volume 24, Number 34, September 29, 1995

RFA:  DC-96-002

P.T. 34

Keywords: 
  Communicative Disorders, Hearing 
  Communicative Disorders, Speech 
  Clinical Trial 


National Institute on Deafness and Other Communication Disorders

Letter of Intent Receipt Date:  November 1, 1995
Application Receipt Date:  April 11, 1996

PURPOSE

The National Institute on Deafness and Other Communication Disorders
(NIDCD) invites applications from organizations, institutions, or
groups of institutions that have the capability and resources to
organize multicenter cooperative clinical trials of the efficacy of
treatment for diseases and disorders of human communication.  These
consortia, referred to as Cooperative Groups, will plan, implement,
conduct, analyze, and disseminate results of clinical studies on the
treatment or management of diseases and disorders of hearing,
balance, smell, taste, voice, speech or language, or any combination
thereof.  The goal of these studies will be to evaluate:  (1)
innovative therapeutic approaches; (2) established but controversial
therapeutic approaches; or (3) modifications in existing therapeutic
approaches to diseases and disorders affecting the processes involved
in human communication.

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), Clinical Trials Cooperative Groups, 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
202-512-1800).

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 and 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 support 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 "SPECIAL
REQUIREMENTS:  B.  Terms and Conditions of Award."

The total project period for an application submitted in response to
this RFA may not exceed five years.  The anticipated award date is
December 1, 1996.  Because the nature and scope of the research
studies proposed in response to this RFA may vary, it is anticipated
that the sizes of awards will vary also.  Awards and level of support
will depend on receipt of a sufficient number of applications of high
scientific merit.  At this time, the NIDCD has not determined whether
and how support for the Cooperative Groups will be continued beyond
the period specified in 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
$2,000,000.  In Fiscal Year 1997, the NIDCD plans to award up to two
Clinical Trials Cooperative Groups.  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.  Although this program is provided for in the financial
plans of the NIDCD, awards pursuant to the RFA are contingent upon
the availability of funds for this purpose.  Funding in the second
and subsequent years of the grant will also be contingent upon
satisfactory progress during the preceding years and availability of
funds.

RESEARCH OBJECTIVES

The objective of this RFA is to provide support for clinical trials
collaborative groups proposing to access the appropriate populations
and to provide the expertise to construct and conduct controlled
clinical trials addressing issues in the treatment of diseases and
disorders affecting hearing, balance, smell, taste, voice, speech, or
language.  The primary goal is to evaluate existing and new
therapeutic strategies and interventions, based upon emerging
knowledge of the biological and other factors influencing disease
development and progression and treatment outcome.  This initiative
is specifically designed to strengthen the coordination of the NIDCD
clinical research agenda with progress in basic research, and to
emphasize the rapid integration of these discoveries into
multidisciplinary clinical research.

The primary objectives of the studies include the design and
execution of common protocols to determine the efficacy of treatment
in a controlled manner for established but controversial therapeutic
approaches to the treatment and/or alleviation of diseases and
disorders affecting human communication; and innovative therapeutic
approaches, including modifications in existing therapeutic
approaches.

Study Design

The Cooperative Group must be able to transform a new research
concept into an active protocol; conduct the study within a specified
time period; analyze and publish the results in peer-reviewed
publications for the benefit of the entire scientific community;
integrate findings with current research; and develop subsequent
research concepts.  The Cooperative Group will identify key questions
substantiating the need for specific clinical trials in human
communication, and formulate scientific agendas prioritized according
to public health need for approval by the NIDCD.  The Cooperative
Group will secure support for patient care and related costs to
enable the proposed trials to run to completion, providing
administrative, data management, and statistical support for the
planning, implementation, execution, analysis and dissemination of
the results of the clinical trials.  It will also provide quality
assurance monitoring.  A separate Data and Safety Monitoring
Committee will be established for each clinical trial, responsible
for assuring, to the extent possible, the safety of the study
participants and to ensure the integrity of the study.

In order to ensure a subject population of adequate size for the
study, a collaborative effort will be required by participating
Clinical Facilities.  In this collaborative effort, the Clinical
Facilities will follow a uniform study protocol, standardized
treatment regimens, and predetermined data collection procedures.  It
is anticipated that although most studies will be carried out
consecutively, some concomitant studies are possible since additional
protocols may be developed and implemented throughout the award
period.

SPECIAL REQUIREMENTS

A.  Study Organization

1.  Executive Policy Board

An Executive Policy Board, responsible for establishing policy and
procedures and for representation of each participating institution
and the awardee organization, will be established to serve as the
main governing body of the study.  This committee will be responsible
for overseeing all scientific and operational activities of the
Cooperative Group including, but not limited to, scientific
directions; policies and bylaws; standards of performance; study
oversight; evaluation of collaborating institutions; and criteria and
review procedures for the distribution of funds.  The Executive
Policy Board will also develop research hypotheses and ensure that
individual protocols are prioritized among existing protocols.

At a minimum, the Executive Policy Board will be composed of the
Cooperative Group Principal Investigator (CGPI) who has scientific
responsibility for the project as a whole, including all Cooperative
Group-related research activities performed under it; a
representative from the Cooperative Group Coordinating Center (see
A.5. below); an epidemiologist; the NIDCD Project Scientist; and the
Principal Investigator of each Clinical Facility (see A.8. below),
whether a single institution or a consortium of institutions.  Senior
Investigators, responsible for on-site scientific direction and
implementation of the protocol at institutions participating in a
consortium arrangement, will not be considered as members of the
Executive Policy Board.  The CGPI must have substantial experience in
both the treatment of diseases and disorders affecting human
communication, and the design, implementation, and evaluation of
clinical trials.  Principal Investigators must have knowledge of the
diseases and disorders affecting human communication, and experience
in the design, implementation, and evaluation of clinical studies or
clinical trials.  All major scientific and operational decisions will
be determined by the Executive Policy Board, with each member having
one vote.  The Chairperson will be selected by the Executive Policy
Board from among the CGPI and Principal Investigators during the
first meeting of the Board.  The Executive Policy Board will be
responsible for organizing and conducting Cooperative Group meetings.

Three subcommittees of the Executive Policy Board must be
established:  (1) a Protocol Writing Subcommittee; (2) a Quality
Assurance Subcommittee; and (3) a Publication Subcommittee, described
in sections A.2., A.3., and A.4. below, respectively.  Additional
subcommittees may be established as necessary.

2.  Protocol Writing Subcommittee of the Executive Policy Board

The Executive Policy Board will establish a Protocol Writing
Subcommittee with primary responsibility for developing research
designs and protocols.  Topics for the protocols will be proposed by
the Executive Policy Board.  Following NIDCD concept concurrence of
protocol hypotheses for public health needs, the protocols will be
written by the Protocol Writing Subcommittee, whose membership may be
broadened beyond the membership of the Executive Policy Board.
Proposed protocols will then proceed forward to the NIDCD for peer
review for scientific merit (see A.6 below).  Each protocol should
include a controlled clinical trial designed to determine the
efficacy of innovative therapeutic approaches, established but
controversial therapeutic approaches, or modifications in existing
therapeutic approaches for diseases and disorders affecting the
processes involved in human communication.  Each protocol must
address randomization of treatment groups and complete and unbiased
outcome ascertainment.  It is anticipated that additional research
hypotheses with subsequent protocol development, in addition to the
detailed protocol submitted with this application (see "SPECIAL
REQUIREMENTS:  C. Minimum Requirements for Application"), may be
proposed during the award period.

3.  Quality Assurance Subcommittee of the Executive Policy Board

The Executive Policy Board will establish a Quality Assurance
Subcommittee.  For the purposes of this RFA, a quality assurance
program is defined as the philosophy, procedures, and methods for
generating, collecting, processing, and analyzing data aimed at
guaranteeing its reliability and validity.  The Quality Assurance
Subcommittee will have primary responsibility for monitoring the
quality of diagnostic and therapeutic performance of the Clinical
Facilities.  The monitoring of the Clinical Facilities will include
both remote (information questionnaire) and on-site activities.
Issues to be considered in monitoring Clinical Facilities include,
but are not limited to, status of facilities and equipment;
calibration of equipment; patient/study records; proper surgical,
laboratory and patient care techniques; adherence to protocol; and
forms of therapy.  Reports prepared by the Quality Assurance
Subcommittee will be provided to the Executive Policy Board and the
NIDCD, with copies provided to the Clinical Facility under
examination.  The Executive Policy Board is responsible for
responding to reports of the Quality Assurance Subcommittee and for
determining appropriate follow-up actions to recommendations of the
Quality Assurance Subcommittee.  Responses and actions should be
recorded and the report forwarded to the Executive Policy Board, the
NIDCD, and the Clinical Facility.  Copies will also be provided to
the Data and Safety Monitoring Committee upon request, forwarded
through the Executive Policy Board (see A.7. below).  The membership
of the Quality Assurance Subcommittee may be broadened beyond the
membership of the Executive Policy Board.

4.  Publication Subcommittee of the Executive Policy Board

The Publication Subcommittee will have primary responsibility for the
establishment of all policies and bylaws regarding Cooperative Group
publications, and for writing scientific publications resulting from
the Cooperative Group.  The Executive Policy Board will approve all
policies, bylaws, and products of the Publication Subcommittee, and
resolve issues related to scientific content, authorship, and journal
selection.  All manuscripts must be reviewed and approved by the
Executive Policy Board, the Publication Subcommittee, and submitted
to the NIDCD Project Scientist.

5.  Coordinating Center

The Coordinating Center is responsible for providing data management
and coordination assistance to the Cooperative Group.  The
Coordinating Center will have primary responsibility for supporting
the Cooperative Group activities and providing operational, data
management, analysis and statistical support, and technical services
addressing methodological issues.  Specifically, the Coordinating
Center will:  (1) determine patient eligibility and provide
subsequent registration; (2) provide randomization; (3) receive
consent and data forms and enter the data; and (4) analyze data.  The
Coordinating Center will be responsible for receiving and processing
proposed protocols; tracking ongoing protocol status; preparing and
transmitting status reports to the NIDCD; coordinating submission of
protocols, consent forms, site registration, local Institutional
Review Board approval documents and other information, as
appropriate; preparing a list of responsibilities delineating the
role of industry, the Cooperative Group, and the NIDCD in each of the
trials; and developing manuals of operations.  The Coordinating
Center will also provide the technical assistance and data management
services to the Clinical Facilities with respect to quality control,
uniformity of data collection, management of the collective database,
and data analysis.  The Coordinating Center will also develop
monitoring guidelines to ensure compliance with protocols; signing
and filing of consent forms; current information for contacting trial
participants; status of on-site medical records; local conditions or
situations; appropriate storage and dispensation of patient records;
agreement of reported data with other available records; observation
of standardized interviews; data handling techniques; and training of
new personnel.  The Coordinating Center maintains data on the
performance of the Clinical Facilities, including accrual and
delinquent consent and data forms, and regularly reports this
information to the Executive Policy Board.  Under certain
circumstances, it may be appropriate for the Coordinating Center to
conduct an on-site visit to a Clinical Facility.

Clinical Facilities will submit data to the Coordinating Center.
Specific data analyses to be carried out will initially be determined
by the Coordinating Center, and the results of those analyses will be
delivered to the Executive Policy Board as the group responsible for
determining which further analyses should be done, how the results
should be interpreted, whether the results should influence ongoing
data collection, and how the findings should be disseminated.

Monitoring of the Coordinating Center should include review of the
timeliness and quality of centralized data analysis and reporting,
assistance to the Clinical Facilities, and database errors in
treatment allocation, data entry and/or procedures.

6.  Protocol Review

Each protocol, whether proposed in the application submitted in
response to this RFA or proposed at a later date by the awardee, will
be subject to peer review for scientific merit by a scientific review
committee, to be established and administered by the Scientific
Review Branch, Division of Extramural Activities, NIDCD.

Hypotheses will be proposed and prioritized by the Executive Policy
Board.  The hypotheses will be forwarded to the NIDCD for concept
concurrence in the light of public health importance and need.  Those
hypotheses, for which the NIDCD has concurred are an important public
health need, will be assigned by the Executive Policy Board to the
Protocol Writing Subcommittee for protocol development.  Proposed
protocols will be forwarded to the NIDCD to be peer reviewed for
scientific merit.  Upon receipt of a meritorious and approbative
evaluation, the protocol may be implemented.  Upon receipt of a less
favorable evaluation for scientific merit, the protocol will be
returned to the CGPI with advice.  Protocols will also be subject to
review and acceptance by the Data and Safety Monitoring Committee in
an advisory capacity only.  In summary, protocols will proceed into
the implementation stage only following Executive Policy Board
prioritization; NIDCD concept concurrence; peer review for scientific
merit; advisory review and acceptance by the Data and Safety
Monitoring Committee; and NIDCD award of funding.

7.  Data and Safety Monitoring Committee

A separate Data and Safety Monitoring Committee will ordinarily be
established for each protocol. The primary function of the Data and
Safety Monitoring Committee is to assure, to the extent possible, the
safety of the study participants and to ensure the integrity of the
study.  The Data and Safety Monitoring Committee will be familiar
with the protocol and accept the study concept, propose appropriate
analyses, and periodically review data on outcome and safety.  It
will also review data on such aspects as participant accession,
appointments and procedures; forms completion; data quality; losses
to follow-up; and other measures of adherence to protocol.  The Data
and Safety Monitoring Committee will make independent recommendations
to NIDCD concerning the continuation, termination, or modification of
the trial based on ethical concerns or observed beneficial or adverse
effects of any of the interventions under study.  Proposed protocols
will be subject to review and acceptance by the Data and Safety
Monitoring Committee in an advisory capacity.

The Committee membership, which must be multidisciplinary and include
a biostatistician and a bioethicist, will be entirely independent of
the Cooperative Group personnel and funded separately by the NIDCD.
All of the voting members should be external to the investigative
group, assuring independent assessment and minimizing the chances of
biased data collection and ethical conflicts in cases where
accumulating data suggest trends.  With the exception of selected
NIDCD staff and the trial biostatisticians, only voting members of
the Data and Safety Monitoring Committee should be made aware of
accumulating trial data.  Exceptions may be made under circumstances
where there are serious adverse events.  Nominations for committee
membership will be provided by the Cooperative Group; however,
authority for membership selection resides solely with the NIDCD.
Conflict of interest statements, written and oral and updated over
time, will be obtained from all members of the committee.
Individuals who have a conflict of interest, as determined by the
NIDCD, will be excluded from service on the Data and Safety
Monitoring Committee.

While an Executive Policy Board member(s) may attend or be requested
to attend some parts of a Data and Safety Monitoring Committee
meeting, attendance will be denied in closed session when outcome
data are discussed.  The Data and Safety Monitoring Committee will
review progress at least every six months, more frequently if
determined necessary.  Recommendations and a summary report of the
Data and Safety Monitoring Committee's deliberations will be provided
to the NIDCD within one week of each review. The NIDCD is responsible
for the implementation of any recommendations.  The Data and Safety
Monitoring Committee will not have enforcement responsibilities.  A
summary report, which does not contain confidential data, will be
prepared by the Data and Safety Monitoring Committee Chair and
distributed to its members, the Executive Policy Board, and the
NIDCD.

8.  Clinical Facilities

Clinical Facilities with clinical research capabilities and
experience will be responsible for providing an adequate patient base
and clinical expertise for the conduct of diverse clinical trials in
human communication.  Participating Clinical Facilities may be
structured as either single institutions or consortia of
institutions.  Every Clinical Facility, whether a single institution
or a consortium of institutions, will designate a Principal
Investigator.  Additionally, Senior Investigators will be designated
from each institution participating in a consortium arrangement.

9.  Awardee organization

The awardee organization will be responsible for the development,
organization and conduct of the Cooperative Group and its required
entities, and also for the fiscal resources and operations.

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 and Conditions of Award are in addition to, and
not in lieu of, otherwise applicable OMB administrative guidelines,
DHHS Grant Administration Regulations at 45 CFR parts 74 and 92, and
other DHHS, 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 awardee for the
project as a whole, although specific tasks and activities in
carrying out the study will be shared between the awardee and the
NIDCD Project Scientist.

1.  Awardee Rights and Responsibilities

The awardee 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 NIDCD staff in those aspects of
scientific and technical management of the project as stated in these
terms and conditions. Specifically, the awardee has primary
responsibilities as described below:

Executive Policy Board Membership and Meeting Attendance

The Cooperative Group Principal Investigator (CGPI) and each
Principal Investigator will serve as a voting member of the Executive
Policy Board and will participate in all scientific decisions.  The
CGPI and each Principal Investigator (or his/her designee) will be
responsible for attending all Executive Policy Board meetings.  The
Executive Policy Board shall be responsible for determining the
frequency of meetings and scheduling the time and location.  There
must be no less than three meetings during the first 12 months of the
study and no less than two per year thereafter.  The CGPI and each
Principal Investigator (or his/her designee) will be expected to
participate in all other Executive Policy Board activities (e.g.,
conference calls, special subcommittees as needed).

Subcommittees of the Executive Policy Board may be established as
needed.  At a minimum, the Executive Policy Board will establish a
Protocol Writing Subcommittee, a Quality Assurance Subcommittee, and
a Publication Subcommittee.

Protocol Review and Conduct

Each protocol will undergo peer review for scientific merit.
Protocols will also be subject to review and acceptance by the Data
and Safety Monitoring Committee in an advisory capacity only.  Upon
implementation of a protocol, each Clinical Facility, whether a
single institution or a consortium of institutions, will follow the
procedures required by the protocol regarding study conduct and
monitoring, patient management, data collection and quality control.

Data Coordination and Management

Each awardee will be responsible, through a Coordinating Center, for
ensuring the provision of centralized data management and
coordination assistance.  The Coordinating Center is responsible for
providing all data coordination and management, including quality
control and analysis, using procedures and standards determined by
the Coordinating Center.  Specific analyses to be performed will
initially be determined by the Coordinating Center and the results of
these analyses will be provided to the Executive Policy Board as the
group responsible for determining which further analyses should be
done.  Additional analyses may be requested by the Executive Policy
Board on behalf of any of its Subcommittees or the Data Safety and
Monitoring Committee.  Under the direction of the Executive Policy
Board, the Coordinating Center will provide technical assistance and
data management services to the Clinical Facilities with respect to
quality control, uniformity of data collection, management of the
collective data base, and data analysis and publication. Any post-
award changes in the selection of the facility or organization
serving as the Coordinating Center will require NIDCD approval.

The awardee will retain custody of and have primary rights to all
data developed under these awards, subject to Government rights of
access consistent with DHHS, PHS, and NIH policies.

Data and Safety Monitoring Committee

A separate Data and Safety Monitoring Committee will ordinarily be
established for each protocol.  The Data and Safety Monitoring
Committee will make independent recommendations to NIDCD concerning
the continuation, termination or modification of the trial based on
ethical concerns or observed beneficial or adverse effects of any of
the interventions under study.  The Committee membership, which must
be multidisciplinary and include a biostatistician and a bioethicist,
will be entirely independent of the Cooperative Group personnel and
funded separately by the NIDCD.  Nominations for committee membership
will be provided by the Cooperative Group; however, authority for
membership selection resides solely with the NIDCD.  Conflict of
interest statements, both written and oral and updated over time,
will be obtained from all members of the committee.  Individuals who
have been determined by the NIDCD to have a conflict of interest will
be excluded from service on the Data and Safety Monitoring Committee.

Recommendations and summary reports of Data and Safety Monitoring
Committee deliberations will be forwarded to the NIDCD within one
week of each review.  A summary report, which does not contain
confidential data, will be prepared by the Data and Safety Monitoring
Committee Chair and distributed to its members, the Executive Policy
Board, and the NIDCD.  The NIDCD is responsible for the
implementation of any recommendations.  The Data and Safety
Monitoring Committee will not have enforcement responsibilities.

Study Materials

The Coordinating Center will be responsible for the acquisition and
distribution of those study materials involved in the protocol.  The
Coordinating Center 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 of investigational
drugs.

Publication and Presentation of Study Findings

Early publication of major findings is encouraged.  Review and
approval by the Executive Policy Board will be required for all
analyses prior to publication or presentation according to criteria
that will be developed by the Executive Policy Board.  Publications
and oral presentations of work performed under this agreement will
require appropriate acknowledgement of support by both the
Cooperative Group and NIH/NIDCD.  Analyses to be performed using the
data will be determined and directed by the Executive Policy Board in
conjunction with the Coordinating Center.  Clinical Facilities
wishing to perform analyses of local data must obtain consent of the
NIDCD Project Scientist for any such analyses prior to initiation.

Monitoring Study Progress

The Executive Policy Board, through a Quality Assurance Subcommittee,
will establish mechanisms for assessing and evaluating the quality of
the diagnostic and therapeutic performance of the Clinical
Facilities, whether individual institutions or institutions
participating in consortia arrangements.  All reports and
recommendations will be forwarded from the Quality Assurance
Subcommittee to the Executive Policy Board.

Organizational Changes

Each awardee is responsible for developing a plan for managing
organizational changes. These include the changes of the CGPI,
Principal or Senior Investigator, affiliate, component, or research
facility or organization that is associated with this study.  A
change in the CGPI, or in any key personnel identified on the Notice
of Award, as well as the facility serving as the Coordinating Center,
must have the prior written approval of the NIDCD Grants Management
Specialist in consultation with the NIDCD Project Scientist.

2.  NIDCD Staff Responsibilities

The NIDCD will have a staff representative known as the NIDCD Project
Scientist.  The NIDCD Project Scientist 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:

The NIDCD Project Scientist will serve as a voting member and attend
all Executive Policy Board meetings; will participate in other Board
activities (e.g., conference calls, special subcommittees); will
serve on Executive Policy Board Subcommittees; will  participate in
periodic on-site monitoring; will serve as a member of the Protocol
Writing Subcommittee and will assist the Subcommittee in protocol
development; will attend protocol peer reviews; will serve as a
resource in the development of operations manuals; and will serve as
a resource to the Quality Assurance Subcommittee of the Executive
Policy Board in the development of mechanisms and procedures for
monitoring quality of diagnostic and therapeutic performance of the
Clinical Facilities.

The Government, through the NIDCD Project Scientist, will have access
to data generated under this Cooperative Agreement at the end of each
clinical trial.  The awardee will retain custody of and have primary
rights to all data developed under these awards subject to
regulations regarding Government rights to access.

The NIDCD Project Scientist will review the progress of each
Cooperative Group and Clinical Facility 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 NIDCD reserves the right to terminate or curtail the study (or
any individual study component at any individual Clinical Facility)
in the event of:  (1) substantial shortfall in participant
recruitment, follow-up, data reporting, quality control, or other
major breach of the protocol; (2) substantive changes in the agreed-
upon protocol to which the NIDCD does not agree; (3) reaching a major
study endpoint substantially before schedule with persuasive
statistical significance; or (4) human subject ethical issues that
may dictate a termination.

3.  Collaborative Responsibilities

An Executive Policy Board, responsible for establishing policy and
procedures and for representation of each participating institution
and the awardee organization, will be established to serve as the
main governing body of the study.  This committee will have primary
responsibility for overseeing all scientific and operational
activities of the Cooperative Group.

At a minimum, the Executive Policy Board will be composed of the CGPI
who has scientific responsibility for the project as a whole,
including all Cooperative Group-related research activities included
under it; a representative from the Cooperative Group Coordinating
Center; an epidemiologist; the NIDCD Project Scientist; and the
Principal Investigator of each Clinical Facility, whether a single
institution or a consortium of institutions.  All major scientific
and operational decisions will be determined by the Executive Policy
Board, with each member having one vote.

The Executive Policy Board will establish three subcommittees.  The
Protocol Writing Subcommittee will have primary responsibility for
the development of research designs and protocols. Hypotheses for the
protocols will be proposed by the Executive Policy Board and
forwarded to the NIDCD for public health concept concurrence.
Following NIDCD concurrence, the protocol will be written by the
Protocol Writing Subcommittee.  Proposed protocols will then proceed
forward to peer review for scientific merit.  Upon receipt of peer
review approval of the protocol, the protocol may be implemented.
Protocols will proceed into the implementation stage only following
hypothesis prioritization by the Executive Policy Board; NIDCD
concept concurrence; peer review; advisory comment by the Data and
Safety Monitoring Committee; and NIDCD award of funding.

A Quality Assurance Subcommittee and a Publication Subcommittee will
also be established.  The Quality Assurance Subcommittee will have
primary responsibility for the monitoring of quality of diagnostic
and therapeutic performance of the Clinical Facilities. Reports
prepared by the Quality Assurance Subcommittee will be available to
the Data and Safety Monitoring Committee upon request, forwarded
through the Executive Policy Board. The Publication Subcommittee will
have primary responsibility for the establishment of all policies and
bylaws regarding Cooperative Group publications, and for the writing
of scientific publications resulting from the Cooperative Group.  The
Executive Policy Board will approve all policies, bylaws, and
products of the Publication Subcommittee.

The Data and Safety Monitoring Committee will have primary
responsibility for assuring, to the extent possible, the safety of
the study participants and to ensure the integrity of the study.  The
Data and Safety Monitoring Committee will make independent
recommendations to NIDCD concerning the continuation, termination or
modification of the trial based on ethical concerns or observed
beneficial or adverse effects of any of the interventions under
study.  The Committee membership, which must be multidisciplinary and
include a biostatistician and a bioethicist, will be entirely
independent of the Cooperative Group personnel and funded separately
by the NIDCD.  Reports from the Quality Assurance Subcommittee of the
Executive Policy Board will be available to the Data and Safety
Monitoring Committee upon request.

Once a protocol is initiated, Clinical Facilities, whether individual
institutions or consortia of institutions, will be required to accept
and implement the protocol and procedures delineated within,
including study conduct and monitoring, patient management, data
collection and quality control.

4.  Arbitration

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award) between award recipients and the
NIDCD may be brought to arbitration.  An arbitration panel will be
composed of three members:  one selected by the Executive Policy
Board [with the NIDCD Project Scientist not voting] or by the
individual awardee in the event of an individual disagreement; a
second member selected by the NIDCD; and a 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 DHHS 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 have 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  the program staff listed under
INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by November 1, 1995, a
letter of intent that includes a descriptive title of the overall
proposed research; the name, address and telephone number of the
Cooperative Group 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 NIDCD staff to estimate the
potential review work load and to avoid conflicts of interest in the
review process.  The letter of intent is to be sent to Acting Chief,
Scientific Review Branch, at the address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the research grant application
form PHS 398 (rev. 5/95).  These application forms may be obtained
from the applicant institution's office of sponsored research or its
equivalent and from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 6701 Rockledge Drive,
Room 3034, MSC 7762, Bethesda, MD 20892-7762, telephone (301)
435-0714, email: girg@drgpo.drg.nih.gov.

Applications from multicomponent consortia must contain a single face
page, an overall budget page, and separate budget pages for each
institution involved.  Each application in response to this RFA is
allowed 35 pages for the overall administrative plan, 4 pages for
each of up to five hypotheses for which clinical trials could be
designed, and 200 pages for the one protocol proposed in detail.
Each application must contain a Detailed Budget for the First 12-
Month Period and a Budget for the Entire Proposed Project Period for
Direct Costs, including all expected costs for both the Cooperative
Group structure and administration and the one research protocol
proposed in detail.  Biographical sketches are limited to 2 pages
each.  For additional information, refer to page 14 of the PHS 398
application form.

Applications must address the requirements as outlined in the section
"SPECIAL REQUIREMENTS:  C.  Minimum Requirements for Application."
It is highly recommended that the applicant organization or the
proposed CGPI contact the Acting Chief, Hearing and
Balance/Vestibular Sciences Branch of the Division of Human
Communication, in the early stages of preparing the application.
(See program contact in INQUIRIES below.)

Applications must be received by April 11, 1996.  All components,
subparts and sections of the application must be collated into the
application, and the packages sent to the DRG and to the NIDCD must
each be complete in themselves.  Applications that do not conform to
the instructions contained in the PHS 398 (rev. 5/95) application
kit, will be judged nonresponsive 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.  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 "CLINICAL TRIALS
COOPERATIVE GROUP" must be typed in.

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, 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 appendix material must also be sent
to Acting Chief, Scientific Review Branch, 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 conduct of
the proposed research.  If so, a letter of agreement from either the
GCRC program director or Principal Investigator should 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.

C.  Minimum Requirements for Application

To ensure the development of collaboration among the participants of
the Cooperative Group, a minimum number of issues must be addressed
in the application, as outlined below:

1.  The application must contain up to five hypotheses for which
clinical trial protocols could be designed to answer high-priority
questions in the areas of human communication. A brief scholarly
discussion, describing the problem, current knowledge in the problem
area, and the experimental approach for its study, should be provided
for each of these hypotheses.  One of these hypotheses should be
further developed and submitted as a protocol prepared in sufficient
detail to undergo peer review for scientific merit.  The protocol
proposed in detail should meet the objectives and scope of this RFA,
as well as include a discussion of the rationale for the patient
population; the study design, including randomization and
ascertainment of outcome; the therapeutic approach(es) selected for
study; and an assessment of how anticipated study results can be
expected to contribute to improvements in treatment of diseases or
disorders affecting hearing, balance, smell, taste, voice, speech, or
language, or any combination thereof.  The submitted protocol will
involve as few or as many of the Clinical Facilities as may be
necessary for the recruitment of research subjects to reach
significant statistical power.  The submitted protocol will undergo
peer review for scientific merit as part of the application (see A.6.
above) submitted in response to this RFA.

2.  The application should include a detailed description of an
organizational and administrative structure, which includes the
following components:  Awardee organization; Executive Policy Board
and its Protocol Writing, Quality Assurance, and Publication
Subcommittees; Coordinating Center; and the Data and Safety
Monitoring Committee.  The Clinical Facilities in the Cooperative
Group should be briefly discussed, including the reason for their
selection.

3.  The applicant organization and each participating institution or
institution associated with a consortium must document its experience
and capacity to recruit and retain pediatric and adult study
participants and provide a description of the population currently
available for the proposed protocols.

4.  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
other institutions, consortia, and/or individual components of the
Cooperative Group, and demonstrate availability of personnel and
facilities capable of performing and supporting the administrative
functions of the Cooperative Group.

5.  The application must name a single CGPI who will have scientific
responsibility for the project as a whole, including all Cooperative
Group-related research activities included under it.  The CGPI must
have substantial knowledge of:  (1) diseases and disorders affecting
human communication; and (2) the design, implementation and
evaluation of clinical trials.  In addition, applications from
institutions or consortia of institutions must name a single
Principal Investigator or Senior Investigator for each participating
institution (other than the applicant organization) who will be
responsible for on-site scientific direction and implementation of
the protocol.  Principal Investigators and Senior Investigators must
have knowledge of:  (1) diseases and disorders affecting human
communication; and (2) the design, implementation and evaluation of
clinical trials or clinical studies.

6.  The application must name a lead Project Coordinator who has
substantial technical/administrative experience in managing patient
enrollment, patient follow-up, and multisource data collection for
clinical studies.  Each participating institution or institution
associated with an applicant consortium must also name such a Project
Coordinator.

7.  The application must provide a clear, concise plan in narrative
and diagrammatic form that depicts the interrelationships among the
members of the Cooperative Group, its relevant experience/expertise,
and the contribution of each to fulfillment of the objectives of this
RFA; an organizational chart of the Cooperative Group showing the
name, organization, and scientific discipline of the CGPI, Principal
Investigators, Senior Investigators and of all key scientific,
technical and administrative personnel; and a mechanism for selecting
and replacing key professional or technical personnel.

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

9.  The application must discuss the capability of the applicant
organization and each institution or institution in an applicant
consortium to participate and interact effectively in cooperative,
multicenter clinical trials.

10.  The application must demonstrate that consent is viewed as an
ongoing process of communication with the trial participants and
provide a plan to assure that the consent form is understandable,
written in a language that the patient or family can understand, and
be descriptive enough that the protocol and possible side effects can
be easily comprehended.  For trials involving special populations,
such as minorities and children, steps should be taken to ensure that
consent is fully informed.

11.  The application must include a plan addressing data file
integrity.  This plan should address data backup, data security, data
validation, and the timeliness of data transfer from the Clinical
Facilities to the Coordinating Center.  The application must also
include management strategies to assure patient confidentiality such
that individual patients cannot be identified from study data and
information available to the public (e.g., birth or death records),
while maintaining the ability to track patients for future
notification.  The application should also specify the time window at
which all data and records from the clinical trial will be sealed.

12.  The application must include a written commitment to accept the
participation and assistance of NIDCD staff in accordance with the
guidelines outlined under "B. Terms and Conditions of Award:  2.
NIDCD Staff Responsibilities."  The application must also include
from each Clinical Facility a written commitment to the Cooperative
Group and a willingness to serve on the Executive Policy Board and
adhere to the decisions reached by that Board, including following
the protocol and publication guidelines.

13.  All costs required for the project must be included in the
application and must be fully justified.  Requested budgets should
also include travel for Executive Policy Board meetings and any
associated Subcommittees.  Costs for the Data and Safety Monitoring
Committee should not be included in the application.

14.  Costs for future protocols, which may be proposed at a later
date by the awardee, should be included as part of the future
protocol application and be fully justified.  Future protocol costs
will be paid subject to determination of actual expenses.

15.  The costs of patient care must not be included in the
application and will not be covered by this RFA.

REVIEW CONSIDERATIONS

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

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NIDCD in accordance with NIH peer review
procedures.  As part of the initial merit review, all applications
will receive a written critique and may undergo a process in which
only those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the National Deafness and Other Communication Disorders
Advisory Council.

Review Criteria

Each application will be evaluated for the administrative and
organizational structure, the expertise and capabilities of the
Coordinating Center, and the scientific merit of the protocol.

Applicants are expected to submit and describe their own methods and
procedures for meeting the goals of the RFA.  In addition, applicants
are expected to address the issues identified under "SPECIAL
REQUIREMENTS," as well as criteria specific to the objectives of this
RFA.

The initial review group will assess the technical and scientific
merit of the hypotheses, study protocol, and related factors,
including:

1.  The extent to which the application addresses the goals and
objectives of the RFA.

2.  The adequacy of the applicant's plans for addressing the special
scientific and technical requirements presented in the RFA.

3.  The scientific and technical significance, merit and originality
of the proposed protocols and their anticipated contributions to the
treatment of diseases and disorders affecting hearing, balance,
smell, taste, voice, speech, or language, or any combination thereof.

4.  Qualifications, experience, and availability of the Cooperative
Group in the content area of disorders and diseases of the processes
of human communication and clinical trial design, conduct and
analysis.

5.  Documentation of the availability of adequate patient
populations; experience and expertise of the key personnel, including
the availability of the necessary Clinical Facilities for the
recruitment, retention and follow-up of study participants; and
adequacy of ethical and human safety issues, including current IRB
approvals and informed consent/assent forms.

6.  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.

7.  Documentation of the sponsoring organization's or institution's
commitment to the Cooperative Group, including support for membership
of the proposed Cooperative Group Principal Investigator and
Principal Investigators on the Executive Policy Board; willingness to
abide by the scientific decisions made via consensus of Executive
Policy Board members; and willingness to accept the participation and
assistance of NIDCD staff.

8.  Adequacy of the proposed plan for coordination and communication
within the applicant organization, and with Clinical Facilities and
institutions participating in consortia-type arrangements,
particularly with respect to multicenter clinical trials.

9.  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.

10. The scientific and technical significance and originality of the
proposed protocols.

11.  Appropriateness of the proposed budget and requested period of
support.

AWARD CRITERIA

Recommendations of the initial review group will receive a second
level of review by the National Deafness and Other Communication
Disorders Advisory Council for consideration of programmatic needs
and priorities.  Funding decisions will be made on the basis of
scientific and technical merit, 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:

Amy M. Donahue, Ph.D.
Division of Human Communication
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Suite 400C
6120 Executive Boulevard MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-3458
FAX:  (301) 402-6251
Email:  Amy_Donahue@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:

Acting Chief, Scientific Review Branch
Division of Extramural Activities
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Suite 400C
6120 Executive Boulevard MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 496-8683
FAX:  (301) 402-6250

If the package for NIDCD is to be sent via overnight, express mail or
courier service, the zip code should be changed to 20852.

Direct inquiries regarding fiscal matters to:

Grants Management Officer
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Suite 400B
6120 Executive Boulevard MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-0909
FAX:  (301) 402-1758

Schedule

Letter of Intent Receipt Date:  November 1, 1995
Application Receipt Date:       April 11, 1996
Scientific Review Date:         July 1996
Advisory Council Date:          October 1996
Earliest Award Date:            December 1, 1996

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.173. Awards will be made under the authority of
the Public Health Service Act, Title III, Section 301 (Public Law
78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and
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 Agency 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.

.

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