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NHLBI Clinical Research Network Program

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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:

  • Publication and Presentation Subcommittee: To develop policies and processes for reviewing and publishing results of studies from the CCs and DCC

  • Quality Control Subcommittee: To develop standards for specific laboratory tests and other measures and monitor clinical center performance

  • Equipment Subcommittee: To present options for equipment needed in the Network, propose pilot studies for testing equipment, and train and certify staff

  • Genetics Subcommittee: To establish techniques for collecting, processing, and storing of samples obtained for genetic studies, and to establish genotyping standards and techniques.

  • 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:

  • 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).

  • Who will receive the information or how materials would be distributed

  • The process and timing for the distribution

  • Educational and informational sessions for the public, patients, and providers, as is appropriate for the purpose of the research.


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