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NHLBI
Clinical Research Network Program
On this page:
INTRODUCTION
The National Heart, Lung, and Blood Institute (NHLBI)
established Clinical Research Networks in 1993 to address
clinical topics of significant public health concern. The
Networks were designed for clinical research questions
requiring multiple centers to secure sufficient patients
and for circumstances where multiple clinical research
questions can be studied concurrently over a defined
funding period. The Networks provide a flexible,
collaborative framework that enables multiple therapeutic
studies and trials to be conducted with relative speed
and efficiency when well-trained clinical investigative
teams are prepared to work closely with the NHLBI in
a joint effort.
A Network is a group of Clinical Centers (CC) and a
data coordinating center (DCC) cooperating to undertake
collaborative clinical studies with the NHLBI. Currently,
NHLBI funds the following Networks:
Networks may be solicited through a grant (RFA) or contract
process (RFP) and undergo formal
peer review by the NHLBI. Networks are administered and
funded through either Cooperative Agreements (U01/U10),
or research contracts (N01), depending on funds available.
The decision to add Networks is made on the basis of
scientific need and budget considerations.
NETWORK STRUCTURE
There are various structural models for Networks at
NHLBI. The types of clinical questions, the disease
under study, budget and the experiences of the scientific
staff may dictate the configuration of a Network. The
main components of a Network are discussed below; however
each Network at NHLBI may be organized differently.
Steering Committee (SC)
The main governing body of a Network is the Steering
Committee, which includes the Principal Investigators
of the CCs and the DCC; one or more Chairpersons who
may be chosen by the NHLBI or the Steering Committee;
and a representative from the NHLBI Project Office.
The Steering Committee is responsible for prioritizing
clinical research topics, developing protocols, facilitating
and monitoring the conduct of the research, and reporting
study results in a timely manner. The Steering
Committee conducts its business through several annual
meetings and regularly scheduled conference calls. Other
Network investigators and study coordinators also participate
in these meetings. These meetings and other Network
activities are one of the ways in which Networks foster
the development of junior members of the clinical investigative
team.
Clinical Centers (CC)
Many Networks fund academic medical centers, hospitals
or physician practices and are commonly known as Clinical
Centers. Some Networks utilize a Regional Clinical
Center (RCC) concept in which institutions form partnerships
with multiple clinical centers to gain the required number
or type of potential participants and to access specific
specialties needed in the Network. Clinical Center
applicants are asked to propose one or more protocols
suitable for a Network environment, and are judged based
on the scientific merit of the proposed research, as
well as on their experience in conducting clinical studies. Most
Networks require a minimum time commitment from the principal
investigator, nurse coordinators, and other core personnel. To
make more efficient use of resources, Centers from institutions
that have a General Clinical Research Center (GCRC) funded
by the NIH National Center for Research Resources are
expected to use the GCRC as a resource for conducting
the proposed research.
Center investigators oversee local protocol implementation,
including IRB submissions, data collection and adherence
to quality assurance measures, adverse event reporting,
and preparation of study and overall budgets and annual
reports. Clinical Centers are periodically evaluated
through site visits and other quality control measures.
Data Coordinating Center (DCC)
Data Coordinating Centers are also selected through
a peer review process administered by NHLBI, and are
judged on the basis of experience in organizing, planning
and conducting multi-center clinical trials in the scientific
areas of the Network. The DCC organizes the central
research activities for the Network, including maintaining
a secure data entry system, preparing data collection
forms and manuals of operations for each study, participating
in the development of study protocols, monitoring recruitment
and adverse events, conducting statistical planning and
analyses, organizing meetings and conference calls, training
study coordinators, overseeing core laboratories for
central interpretation of study data, and managing randomization
schemes.
The DCC also develops procedures for quality control,
training and certification, and data management. The
DCC monitors the quality and quantity of data received
from the Clinical Centers and prepares specific statistical
analyses and other reports for the CCs, SC and DCC; prepares
protocols for submission to the PRC and DSMB; and assists
manuscript preparation through data analysis, statistical
consultation, editorial support, and meeting coordination. DCC
operations are evaluated once per funding cycle through
a site visit.
Subcommittees of
the Steering Committee
Subcommittees consisting of qualified individuals from
the clinical centers, the DCC, and the NHLBI staff, may
be established within the Network for specific tasks. Some
examples of NHLBI Network subcommittees include:
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Publication and Presentation Subcommittee: To
develop policies and processes for reviewing and
publishing results of studies from the CCs and DCC
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Quality Control Subcommittee: To
develop standards for specific laboratory tests and
other measures and monitor clinical center performance
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Equipment Subcommittee: To present
options for equipment needed in the Network, propose
pilot studies for testing equipment, and train and
certify staff
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Genetics Subcommittee: To establish
techniques for collecting, processing, and storing
of samples obtained for genetic studies, and to establish
genotyping standards and techniques.
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Core Lab Selection Subcommittee: To
establish selection criteria, develop RFPs, and review
proposals for Network Core Labs
The NHLBI and the Program Scientist
The NHLBI is responsible for organizing and providing
support for Networks. Because
the awards are made using the Cooperative Agreement mechanism, the
NHLBI is involved substantially with the awardees as
a "partner", through the designated program office and
Office of Biostatistics Research staff. The investigators
and the NHLBI program staff share in the collaborative
activities required such as protocol development, quality
control, interim data and safety monitoring, final data
analysis and interpretation, preparation of publications,
and performance monitoring. Program staff may include
physicians, nurse or data coordinators, budget specialists,
biostatisticians and others.
NETWORK OVERSIGHT COMMITTEES
Protocol Review Committee (PRC)
Although the protocols proposed by Clinical Center applicants
undergo peer review during the selection process for
the Network, the protocols that are ultimately developed
by the Network Steering Committee once the Network is
established may be modified or completely different. Therefore,
PRCs are established for each Network to assess the scientific
merit and design of each proposed protocol. The
PRC Chair and members are appointed by the NHLBI to provide
independent peer review for Network protocols. PRC
members have expertise in basic and clinical research,
clinical trial design, biostatistics, ethics and outcome
measures. The PRC is a standing committee and
ad hoc consultants are added, as needed.
Data Safety and Monitoring Board (DSMB)
DSMBs are established for all large multi-center clinical
trials funded by the NHLBI and should be independent
of the PRC. As with the PRC, the DSMB Chair and
members are appointed by the NHLBI, and include similar
expertise. Some DSMBs also have members who are
experts in ethical considerations in human subject research,
and lay members who are advocates for the disease(s)
under study. The DSMB advises the NHLBI on the
conduct and progress of studies, the quality of data
generated, and issues regarding the safety of study participants.
The DSMB meets regularly to monitor data quality, protocol
adherence, and to identify any emerging operational issues. In
addition, the Chair of the DSMB and other DSMB members
may review serious adverse events as they occur. If
there are severe unanticipated problems with any aspect
of the study including concerns for patient welfare or
scientific integrity, the DSMB may recommend to the Director,
NHLBI, that the protocols be modified, or that the study
be suspended or even terminated. NHLBI staff work
with the SC to assure that appropriate steps are taken
to implement the recommendations of the DSMB.
PROTOCOL DEVELOPMENT AND IMPLEMENTATION
Preliminary concepts for clinical trials are formulated
by individual CCs (although they can come from any source)
and presented to the SC. Concepts approved by the
full SC become the responsibility of the lead center
which then develops a detailed preliminary protocol. The
preliminary protocol includes a rationale for the study
as well as estimates of the numbers of patients needed
with rationale based on expected effect size and statistical
power, the required recruitment rates, the expected project
length, the proposed end points, the required staff time,
and other needed resources. The SC may request
PRC review of a concept protocol, especially if there
are particularly difficult issues to consider.
Once a preliminary protocol is approved by the full
SC, and the PRC if applicable, the lead center works
with the DCC and a subcommittee of investigators from
other centers to prepare a detailed draft protocol, which
is subject to revision and approval by the SC. The
final protocol is reviewed by the PRC, which may recommend
approval, modification and re-review, or disapproval,
of the protocol.
Once a protocol is approved, the DCC completes the study
forms, sets up the data entry system for that protocol,
and generates generic IRB materials and a manual of operations. A
training session is held for study coordinators and the
DCC certifies that the participating Clinical Centers
meet all requirements for beginning the study. Individual
CCs can begin recruiting when these and any other NHLBI
requirements are met, and they have local IRB approval.
BUDGETS AND RELATED ISSUES
The NHLBI program and budget or contracts staff is responsible
for fiscal management of Networks. Funds are provided
separately for the CCs and the DCC and cover administrative
(core) and patient care (protocol) costs.
Each CC is provided a Core budget to maintain the infrastructure
required for performing multiple clinical trials and
sustaining the organizational aspects of the Network. The
core budget covers a minimum effort for the combined
physician leadership (Principal Investigator and any
Co-investigators) and other key personnel (e.g., clinical
coordinator, data entry clerk), travel costs for SC meetings
and other travel related to Network operations, supplies
and equipment. The total costs for the core budget
are stipulated at the time of grant application or contract
proposal.
The DCC budget is also set in the solicitation, and
covers all central administrative aspects of the Network
as outlined above. The DCC also assumes costs for
core labs, DSMB and PRC meetings, and site visits to
each CC over the study period. A substantial minimum
time commitment is expected from the Principal Investigator
of the DCC; the specific effort expected may vary by
Network.
Funds for patient care may be provided to the CCs or
directly to the DCC. The capitated patient care
budget for each protocol is developed during the final
protocol stages, after consideration of the elements
that are required to screen, recruit, and study patients.
As protocols are approved, funds are released from the
Patient Care category and authorized for the specific
protocol. Payments are continued or adjusted based
on recruitment. The NHLBI Carryover Approval
Process applies to Networks funded by grant mechanisms.
DISSEMINATION OF FINDINGS
NHLBI policies for the dissemination of findings applies
to all funded research, but are particularly important
for Networks. A dissemination plan provides information
about:
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How the study investigators will distribute study
results (e.g., journal articles, presentations) as
well as study intervention materials, if relevant
(e.g., patient educational materials, physician guidelines).
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Who will receive the information or how materials
would be distributed
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The process and timing for the distribution
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Educational and informational sessions for the public,
patients, and providers, as is appropriate for the
purpose of the research.
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