31 Clinical Trials: Holy Grail or Poisoned Chalice?
Clinical trials for surgical devices are often the bane of an orthopedic surgeon’s life. This is not for want of enthusiasm about research; rather, it can largely be attributed to the burdensome and often bureaucratic process involved in obtaining (and maintaining!) authorization for a trial. In a regulatory environment that is rightly placing an increasing emphasis on patient safety, and with an increasingly litigious patient population, the need for a thorough vetting process of the medical devices used in clinical care is more pressing than ever.
Unfortunately, the regulatory requirements for placing a medical device on the market are rather unsatisfactory. Although drugs may be approved by a single body (the European Medicines Agency) after proof of safety and efficacy in controlled trials, there is no such centralized body in relation to medical devices. Instead, the Notified Body 1 in each European country must approve the CE (European Conformity) mark before the device may be marketed throughout Europe. Despite the aim of European legislation to harmonize regulation in this area, the lack of a central body to approve medical devices introduces a level of uncertainty to the process, and it inevitably increases the time and cost required to introduce a new medical device to the European market. Furthermore, unlike the position with regard to drugs, there is no need for proof of clinical efficacy of a medical device before its general use is allowed in Europe. Indeed, the regulatory body in the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA), has highlighted the poor evidence base for most medical devices. 1 , 2
Under The Medical Devices Regulations 2002, 3 there are four main risk-based categories for medical devices: I, IIa, IIb, and III. The level of risk to the patient increases from class I to class III. Device classification depends on the intended use of the device and the indications for use. The lowest-risk devices, such as stethoscopes, are in class I. Dental fillings are a class IIa device. Medical implants are always classified as IIb or III. Orthopedic devices are class III because they “support or sustain human life, are of substantial importance in preventing impairment of human health, or [prevent] a potential, unreasonable risk of illness or injury.” 4
In the United States, class III medical devices are regulated by the U.S. Food and Drug Administration (FDA) and are available for general use after going through one of two possible routes to authorization: either premarket authorization or submission of a 510(k) Premarket Notification Form to demonstrate that the device is at least as safe and effective as a legally marketed device that is not subject to premarket approval. The former route involves proof that the device is both safe and effective for its intended use (obtained through clinical trials). The latter involves demonstration that the medical device is substantially equivalent to an existing product on the market, known as the Predicate Device. Ninety percent of medical devices on the North American market have been approved through the 510(k) route.
The fundamental difference between the European 5 and American systems is the reliance on postmarketing surveillance by the European system, as opposed to premarket testing by the U.S. system. However, the FDA also cites postmarketing surveillance as a condition of approval, 6 whereas in Europe, manufacturers are guided by a medical device vigilance system. 2 In the United Kingdom, this vigilance is regulated by the MHRA.
Each system has its advantages and disadvantages. The U.S. system requires a device not only to be safe but also to demonstrate that it alters the outcome of the condition it is intended to treat. While this arguably limits adverse events, one could also argue that this premarket stringency stifles innovation. The European system, on the other hand, encourages innovation because the medical device is more readily accessible for patient benefit provided it is monitored post marketing. It is the nature of this vigilance that has caused concern. Firstly, postmarketing surveillance in Europe is obligatory, but there is no punishment if the surveillance is not performed, and secondly, such vigilance is usually carried out informally through feedback from users. I am of the belief that postmarketing surveillance should be performed in a strictly regulated environment, such as that provided by a clinical trial. This would allow surgeons to evaluate the risks and benefits of a device and would also enhance both surgeon and patient decision making in regard to treatment.
The Oxford Spine Unit recently set up a postmarketing surveillance study to evaluate a new device used in the treatment of early onset scoliosis, and I wish to share our trials and tribulations with the reader. This chapter may inspire the reader to immerse himself or herself in the intricate complexities and nuances of clinical research to complement an illustrious career as a spinal surgeon. On the other hand, the thought of unheard-of acronyms, mountains of forms to be filled out and letters to be written, and numerous meetings with bureaucrats may consign the idea of undertaking a surgical clinical trial to the darkest corners of the memory forever. I will leave the reader to judge.
31.1 The MAGEC Clinical Trial
The Spine Unit of the Oxford University Hospitals (OUH) recently introduced a new medical device for the treatment of early onset scoliosis: the MAGEC (magnetic expansion control) Remote Control Spinal Deformity System (Ellipse Technologies, Irvine, California). This product makes it possible to lengthen a growing rod noninvasively with a remotely controlled device. The decision to use this device was based on the fact that the need for repeated surgeries is eliminated, with a corresponding reduction in patient morbidity, in addition to psychosocial benefits to the patient and family. The potential cost savings were also a significant factor.
31.2 Basics of Setting Up a Clinical Trial
31.2.1 Approval from the Children’s Directorate
The first stage involved obtaining approval and support from the Women’s and Children’s Directorate of the OUH. Following preliminary discussions with the Clinical Director of the Women’s and Children’s Directorate, it was apparent that an application for approval to the OUH Technology Advisory Group would be first required. This group, which is part of the Clinical Governance Support Unit, was established to inform the OUH about new clinical technologic developments that might be beneficial to patients. Each application to the Technology Advisory Group is assessed according to three criteria: clinical effectiveness (benefit vs. risk), technical suitability (safety standards), and competency (training and competency evaluation). It consists of several submissions: background paper, competency and training, evidence on cost-effectiveness, ethical and consent processes, and presentation.
Background Paper
The background paper provides information about the device and discusses whether it is used in current practice, and if so the indications for its use. The paper then goes on to describe how the device will be used in the trial and considers whether there will be any effects on provision of service, including potential implications for other services. The level of risk to the patient both with and without the device, and alternative treatments, are also discussed.
Competency and Training
Research data with the relevant references are provided. Questions regarding proven benefits, the size of the benefit, improvement in quality of life, whether certain patients benefit more than others, and any evidence of risk are all assessed and addressed.
Evidence on Cost-effectiveness
Evidence of cost-effectiveness is made available, and comparisons with similar treatments are made.
Ethical and Consent Processes
Patient choice and view are central to the introduction of any new device, and therefore consideration is given to the ethical and consent processes.
Presentation
A presentation to a panel is undertaken and questions are asked. The Technology Advisory Group panel consists of up to 10 members. A final decision is made within 2 weeks of the session.
Once formal approval was given by the Technology Advisory Group, a submission was then made to the Women’s and Children’s Directorate Planning and Budgetary Office for further discussion with the health commissioners. An Options Appraisal Template was used to advance the case for the trial.
31.2.2 Quality Assurance Model
Once we had approval from the hospital management team and had agreed on funding streams with the health commissioners, the next stage of the process involved setting up a quality assurance model in line with Technology Advisory Group guidance. Initial consensus was that an ethics committee application would not be necessary because the device was being used for its intended purpose and had a track record in other centers in the United Kingdom. However, in order to optimize the evaluation of the safety and performance of the device, we felt that the trial had to be done in a regulated environment, as would be the case with a formal study. Because of the paucity of cases of early onset scoliosis in general, it was felt that a multicenter study would be the best option.
Our first port of call in deciding on a quality assurance model was the National Institute for Health Research (NIHR) via the Clinical Research Network. The NIHR was set up in 2006 by the U.K. government to create a high-quality health system within the National Health Service (NHS), and the Clinical Research Network is part of this organization. The NIHR model revolves around the principle of the Portfolio, which is a collection of high-quality clinical studies that benefit from the infrastructure provided by the Clinical Research Network. The first step in using the NIHR model involves applying to the Coordinated System for Gaining NHS Permission (CSP). In past multicenter studies, investigators had to make a separate application to each participating hospital. The CSP is intended to avoid bureaucracy by allowing study details to be entered only once. The CSP then coordinates further review across all participating hospitals. Despite these noble intentions, there is still a considerable amount of time spent filling out forms.
A lead Comprehensive Local Research Network (CLRN) is then assigned to the study, which provides a single point of contact for up-to-date developments in the study. There are 25 CLRNs making up the Comprehensive Clinical Research Network (CCRN). Together, they facilitate and coordinate clinical research across England. Advice on Research Management and Governance is also provided by the CCRN.
There is a cost burden to the health service for running clinical studies consisting of three categories: research, service support, and treatment costs. Studies in the Portfolio receive coordinated NHS support not only in the form of research nurse / allied health professional time but also of liaison with other recruiting centers to ensure adequate and appropriate research support. There is also help available for problem solving.
An initial meeting takes place to discuss this support and to agree on goals and escalation policies. Contact points are decided and future meetings are planned. It was at this meeting that I was introduced to the acronym-laden world of clinical research. The path to glory was strewn with CIs, PIs, GCPs, ISFs, SAEs, SARs, and SADEs. TMFs and SOPs were also thrown in for good measure.
31.2.3 Good Clinical Practice
The first step of the journey toward inclusion in the Portfolio required training in Good Clinical Practice (GCP) 7 so that I could familiarize myself with the nuances of clinical research and gain acquaintance with the many acronyms one is expected to reel off with ease. It is a legal requirement in the United Kingdom to conduct all clinical trials according to the principles of GCP as defined by The Medicines for Human Use (Clinical Trials) Regulations 2004. 8
GCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. It is based on 14 principles of GCP set forth by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Compliance with GCP ensures first and foremost that study participants (patients) are protected, and secondly that the data produced are credible. The 14 principles are listed below:
The rights, safety, and well-being of the trial subjects shall prevail over the interests of science and society.
Each individual involved in conducting a trial shall be qualified by education, training, and experience to perform his tasks.
Clinical trials shall be scientifically sound and guided by ethical principles in all their aspects.
The necessary procedures to secure the quality of every aspect of the trial shall be complied with.
The available nonclinical and clinical information on an investigational medicinal product shall be adequate to support the proposed clinical trial.
Clinical trials shall be conducted in accordance with the principles of the Declaration of Helsinki.
The protocol shall provide for the definition of inclusion and exclusion of subjects participating in a clinical trial, monitoring, and publication policy.
The investigator and sponsor shall consider all relevant guidance with respect to commencing and conducting a clinical trial.
All clinical information shall be recorded, handled, and stored in such a way that it can be accurately reported, interpreted, and verified while the confidentiality of the records of the trial subjects remains protected.
Before the trial is initiated, foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients. A trial should be initiated and continued only if the anticipated benefits justify the risks.
The medical care given to, and medical decisions made on behalf of, subjects shall always be the responsibility of an appropriately qualified doctor or, when appropriate, of a qualified dentist.
A trial shall be initiated only if an ethics committee and the licensing authority come to the conclusion that the anticipated therapeutic and public health benefits justify the risks and may be continued only if compliance with this requirement is permanently monitored.
The rights of each subject to physical and mental integrity, to privacy, and to the protection of the data concerning him in accordance with the Data Protection Act 1998 are safeguarded.
Provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor which may arise in relation to the clinical trial.
For further guidance in this area, readers are referred to 10 Golden Rules for Pharmacists by David Hutchinson (Canary Publications, 1999).
31.2.4 Trial Protocol
Compliance with GCP begins with a GCP-compliant protocol. This is a document that describes the objective, design, methodology, statistical considerations, and organization of a trial.
The first part of the protocol contains the study outline, which summarizes the study in terms of design, inclusion and exclusion criteria, and end points. A detailed protocol is then written to ensure that the reader can easily understand what the study is about. It comprises the following sections:
Detailed Protocol
General Information
Background Information
Trial Purpose and Objectives
Trial Design
Selection and Withdrawal of Subjects
Treatment of Subjects
Assessment of Efficacy
Assessment of Safety
Statistics
Direct Access to Source Data / Documents
Quality Control and Assurance
Ethics
Data Handling and Record Keeping
Finance and Insurance
Publication Policy
Supplements
A Gantz chart (Table 31.1) provides a summary of the expected timeline for each phase of the study.
Research activities | N | D | J | F | M | A | M | J | J | A | S | O | N | D | J | F | M | A | M | J | J | A | S | O | N | D | J | ||
Steering committee meeting | |||||||||||||||||||||||||||||
Recruitment of sites | |||||||||||||||||||||||||||||
Recruitment of participants | |||||||||||||||||||||||||||||
Outcome measures | |||||||||||||||||||||||||||||
Imaging | |||||||||||||||||||||||||||||
Surgery | |||||||||||||||||||||||||||||
Physiotherapy | |||||||||||||||||||||||||||||
Follow-up in outpatient department | |||||||||||||||||||||||||||||
Data monitoring | |||||||||||||||||||||||||||||
Baseline data collection | |||||||||||||||||||||||||||||
Data collection periods | |||||||||||||||||||||||||||||
Data entry and cleaning | |||||||||||||||||||||||||||||
Data analysis | |||||||||||||||||||||||||||||
Writing and dissemination | |||||||||||||||||||||||||||||
Feedback |
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