MATERIAL MATTERS COLUMN
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Much has been written during the past few years about the precarious nature of developments in tissue engineering products and processes. In spite of massive industrial and intellectual investment, there have been few commercial and clinical successes in this area. There are many reasons for this, as I have discussed in several recent publications.1,2,3 ranging from regulatory and reimbursement issues to difficulties with basic science and logistics of bioprocessing. However, there are signs that progress is now being made, as witnessed, for example, by the recent publication of the outcomes of bladder regeneration using tissue engineering techniques in the United States.4 It is becoming clear that tissue engineering products and processes are starting to reach patients in a serious manner. It is important to bear in mind that tissue engineering is concerned with the facilitation of tissue regeneration rather than the replacement of compromised tissues by the synthetic manufactured products of conventional medical technology. A vital point is now being reached in the transition of tissue engineering from laboratory to clinic. This point reflects the question of how clinical trials should be undertaken and how clinical experiences should be reported and documented. The evolution of the pharmaceutical industry over the past 50 years has led to a well-defined, internationally agreed, set of procedures for the clinical trials of drugs. These are aimed at establishing safety and efficacy and are generally successful, notwithstanding the occasional difficulty.5 Although not standardised in the same way, the performance of implantable medical devices is evaluated by a series of clinical trials and postmarket-surveillance procedures with generally good outcomes. The products and processes of tissue engineering are different from those of either of these sectors, as reflected by the regulatory procedures that are still evolving. The question is arising, therefore, as to how these early clinical experiences with tissue engineering (and regenerative medicine more broadly) should be conducted. The chances are that the introduction of clinical trials will be ad hoc and uncoordinated and unlikely to yield any common approach to the complex issues that are involved.
This situation has been recognised by the newly formed Tissue Engineering and Regenerative Medicine International Society (TERMIS),6 and an international initiative is now under development to explore how these issues can be addressed at this early stage. Specifically, over the next six months, a framework for the introduction of a registry of clinical trials for tissue engineering products will be drawn up by an international group headed by Dr Jay Vacanti, regarded by many as the originator of tissue engineering, and myself.
Registries in implantable medical devices
This group has noted that, as far as it is aware, there is as yet no multicentred registry in tissue engineering and regenerative medicine, but there is considerable experience in other sectors of medical technology and therapies. Both orthopaedics and cardiology have substantial experience. We should bear in mind that there were two over-riding and separate factors that led to registries or databases with medical devices. The first was the need to have an efficient system for contacting patients or their families in the event that a product, usually a critical implantable medical device such as a heart valve or a pacemaker, is found to be suffering a systematic failure mode, which means that patients’ lives are at risk. These registries are run by the companies, they are obviously patient specific, but with little data stored other than contact details, and no analysis of these databases could be placed in the public domain. The second factor was the need to enhance the power of clinical trials, or more importantly, postmarket surveillance procedures, to detect poorer than expected performance of a device or treatment at a much earlier date than would be possible with small numbers of patients, and to identify trends of performance characteristics. It is this second reason that is most relevant to tissue engineering products.
Total joint replacements (particularly hips and knees) have been the focus of the most important registries. These were first established in Scandinavia, initially in separate countries and more recently combined, and they have played a profound role in identifying devices and materials that have performance problems at an early stage. This practice has spread across Europe, with increasing sophistication in the technology used by the registries. For example, the Institute for Evaluative Research in Orthopaedic Surgery at the University of Bern, Switzerland, has published the details of its Clinical Documentation Technology System; this is a web-based system that can be used on a regional, national or supranational basis.7,8
The United Kingdom has a national heart valves registry,9 which is more modest as far as technology is concerned and uses un-networked standalone computers to record confidential patient data. It has details of more than 100000 patients fitted with heart valves since the mid-1980s. It is funded by the Department of Health and managed by an academic department in a major teaching hospital, which produces a detailed annual report.
Some international registries are organised on behalf of, or funded by, the commercial sector, including the International Intraocular Lens and Implant Registry.10 Others are operated by societies, usually with a more limited set of objectives. The Society of Thoracic Surgeons has a port access international registry11 and the International Society for Heart and Lung Transplantation is running a database on the performance of mechanical circulatory support devices.12 In both cases, details and information about the database are published in the Society’s journal.
A little closer to regenerative medicine, some societies are collecting data on autologous stem-cell transplantation. The European Group for Blood and Marrow Transplantation, in conjunction with the European League Against Rheumatism, has collected and analysed data from patients with severe systemic sclerosis who have been treated by haematopoietic stem-cell transplantation in one of the several European Phase I-II studies over a six-year period13 and the outcome was helpful in determining the nature of subsequent prospective randomised trials.
Identifying the parameters
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David Williams Clinical Engineering Department, Royal Liverpool University Hospital, Liverpool L69 3BX, UK, tel. +44 151 706 5606 fax +44 151 706 5803, e-mail: dfw.ce@liverpool.ac.uk |
Based on the experiences and precedents with implantable medical devices, the TERMIS group will be identifying the parameters that could be included in an international registry for tissue engineering clinical trials. The issues that must be addressed at an early stage are those that concern the definition of the precise scope and objectives of a TERMIS registry. Initially, a group of products and procedures that are amenable to being included in a registry will be identified together with what data should be included in it and the nature of the outcomes and end-points that would be addressed. The starting list should include examples of different formats of tissue engineering, including commercial autologous cell procedures, noncommercial autologous procedures, and in-situ tissue engineering and commercial allogeneic products. This initial exploratory study will also address information technology, ethical and confidentiality issues and financial aspects.
Perhaps the most important aspect here is whether the registry should be solely concerned with a database of clinical trials, with information about the broad metrics and generic details of these trials, or whether it should include actual data from the patients within the trials. It is likely that it would start in the former mode and develop into the latter in due course.
Your views are invited
It is important that the TERMIS group interacts with as many academic, clinical and commercial teams as possible over the next few months, and the leaders of these teams are invited to contact me (dfw@liv.ac.uk) to discuss this initiative.
1. D.F. Williams, “Tissue Engineering: The Multidisciplinary Epitome of Hope and Despair,” in Multidisciplinary Approaches to Theory in Medicine, Ed L. McNamara, Elsevier Science Ltd, Amsterdam, The Netherlands (2006).
2. D.F. Williams, “To Engineer is to Create,” Trends in Biotechnology, 24, pp. 4–8 (2006).
3. D.F. Williams, “Business Models for Tissue Engineering,” Clinica, Issue 1179, pp. 8–9 (28 October 2005).
4. A. Atala et al., “Tissue Engineered Autologous Bladder for Patients Needing Cystoplasty,” The Lancet, published online, 4 April 2006. www.thelancet.com
5. “MHRA, Clinical Trial Suspension,” Press release dated 5 April 2006, www.mhra.gov.uk
7. C. Roder et al., “A Centralised Total Joint Replacement Registry Using Web-Based Technologies,” J.Bone Jt.Surgery, 86A, pp. 2077–2080 (2004).
10. J.T. Holladay, “International Intraocular Lens and Implant Registry,” J. Cataract & Refractive Surgery, 29, pp. 176–197 (2003).
11. A.C. Galloway et al., “First Report of the Port Access International Registry,” Annals Thoracic Surgery, 67, pp. 51–56 (1999).
12. M.C. Deng et al., “Mechanical Circulatory Support Device Database of the International Society for Heart and Lung Transplantation — First Annual Report,” J. Heart Lung Transplantation, 22, pp. 653–662 (2003).
13. D. Farge et al., “Autologous Stem Cell Transplantation in the Treatment of Systemic Sclerosis: Report from the EBMT/EULAR Registry,” Annals Rheumatic Diseases, 63, pp. 974–981 (2004).
Professor David Williams DSc, FREng is Professor of Tissue Engineering at the University of Liverpool and Director of the UK Centre for Tissue Engineering located in the Universities of Liverpool and Manchester. He is Editor-in-Chief of Biomaterials, the leading journal in the biomaterials field. He is Scientific Director of STEPS, the European Commission Framework VI Programme on a Systems Approach to Tissue Engineering Products and Processes. Professor Williams is also a Managing Partner of Morgan & Masterson LLC, a consulting partnership that focusses on global health-care issues.
