Oversight and management of a cell therapy clinical trial network: Experience and lessons learned
Introduction
Clinical trial networks are uniquely positioned to conduct simultaneous research studies at multiple locations on a variety of related health topics. The central development of these trials allows them to be executed in ways that maximize the scientific knowledge gained while utilizing standardized methods of protocol development, scientific and safety review, and safety reporting [1]. Networks also provide the opportunity for sequential development of new therapies which represent logical extensions of previous work conducted by those with demonstrated leadership in the field. The structure and support provided by a network can be used to facilitate clear communication of results and provide consistency in new emerging fields for which there is both great promise and apprehension.
This article describes the ethical and political research environment into which the Cardiovascular Cell Therapy Research Network (CCTRN) was founded, the resultant challenges of critical review by numerous oversight committees, and the management and educational strategies utilized to successfully establish and maintain working relationships with these oversight groups.
Section snippets
Research environment
The 1990s opened to the great promises of gene therapy; however the Jesse Gelsinger case at the University of Pennsylvania highlighted the potential for serious lapses in reporting prior research experience, safety monitoring, and conflicts of interest [1]. Simultaneously, a sharp rise in the number of adverse event reports to the FDA occurred, and the number of drugs withdrawn from the market increased. The removal of twelve drugs from US formularies in the four year period from 1997 to 2000
The Network
Earlier this decade, intriguing small animal studies demonstrated that delivery of bone marrow-derived mononuclear cells (BMMNCs) enabled improved ventricular function following induced myocardial infarction [5], [6], [7]. In response to the pervasive morbidity and mortality resulting from coronary artery disease in the US, the CCTRN was established by the National Heart, Lung, and Blood Institute (NHLBI) to develop, coordinate, and conduct multiple collaborative protocols testing the effects
Scientific review
The Principal Investigators devoted themselves to writing protocols that would test the ability of cell therapy to improve LV function in the AMI and heart failure setting. To facilitate this work and distribute the labor, internal subcommittees were established. Each committee was charged with creating a protocol sufficiently organized and detailed to be reviewed by the NHLBI established protocol review committee.
Data and Safety Monitoring Board (DSMB)
The Network's DSMB members were appointed in accordance with established NHLBI policies governing the use of advisors who were experts not directly involved in the study. In the case of CCTRN, the NHLBI did not appoint a new board, but extended the purview of an existing DSMB whose standing responsibilities included review of gene therapy research.
Initial review of the protocols by the DSMB yielded concerns about 1) study recruitment plans, 2) standardization of the bone marrow aspiration
Institutional Review Boards (IRBs)
IRBs have been charged with a wide spectrum of research oversight responsibilities. In contemporary management these boards are responsible for the simultaneous monitoring of 1) multi-center pharmaceutical and device trials, 2) single investigator initiated trials in hospital and academic settings, 3) basic science studies, 4) social science initiatives, and 5) animal investigations. The composition of such panels often includes physicians, surgeons, pharmacists, nurses, clergy, and laypersons
Discussion
The Network and oversight committees faced a daunting challenge-ensuring the safe delivery of autologous cell therapy when the field faced substantial criticism from both lay and scientific groups. CCTRN was conceived into a polarized field and the Network leadership was understandably frustrated at times. The group believed that in order to investigate interventions that would reduce the public health crises of heart disease, it would require a flexible infrastructure that could rapidly
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2013, Expert Review of Cardiovascular Therapy
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For the Cardiovascular Cell Therapy Research Network (CCTRN).