* Regulatory Approval Process (European Union)
Though there are many similarities in the regulatory process in the United States and countries within the European Union, there are important differences that impact the time and cost associated with the introduction of a new medical device. We have identified 3 illustrative examples: Use of notified bodies, criteria for approval, and local site (IRB/site negotiation).
The European Union system relies heavily on notified bodies (NBs), which are independent commercial organizations to implement regulatory control over medical devices. NBs have the ability to issue the CE mark, the official marking required for certain medical devices. NBs are designated, monitored, and audited by the relevant member states via the national competent authorities. Many functions performed by the FDA/CDRH within the United States are performed by NBs, including medical device certification, device type designation, assessment and verification of quality systems, and review of design dossiers for high-risk devices.11,12 Currently, there are more than 50 active NBs within Europe. A company is free to choose any notified body designated to cover the particular class of device under review. After approval, post-market surveillance functions are the responsibility of the member state via the competent authority. NBs typically function in a closed manner, providing little visibility on criteria required for approval. This dynamic allows for a high degree of variation as well as competition among NBs. As a result, NBs are perceived by industry to be less bureaucratic organizations that can respond more quickly and efficiently than the FDA. These potential benefits may be offset by a system that is intrinsically more fragmented and highly variable and has resulted in the approval and continued marketing of devices, eg, abdominal aorta stent grafts, in Europe that failed efficacy trials in the United States.
Criteria for approval of high-risk devices are different in the European Union. To receive approval to market a class III high-risk (and some class II) device in the United States, the manufacturer must demonstrate the device to be reasonably safe and effective, which typically requires a prospective, randomized controlled clinical trial. To receive approval to market a device in the European Union, the manufacturer must demonstrate that the device is safe and that it performs in a manner consistent with the manufacturer’s intended use.12 This difference has a profound impact on the size and scope of the clinical studies for regulatory approval. This significant difference is illustrated by examining the introduction of distal protection systems. The GuardWire developed by PercuSurge, Inc (later acquired by Medtronic) is a specialized coronary guidewire with an elastomeric balloon mounted at the tip. During an angioplasty/stent procedure, the operator crosses the lesion with the GuardWire and inflates the balloon. Stent placement is then performed, after which a specialized catheter is used to evacuate any arterial debris that may have become dislodged during the procedure. The GuardWire balloon is then deflated. Demonstration of safety and performance, ie, ability to aspirate material during the stenting procedure, was demonstrated in a 22-patient single-arm study.13 In contrast, in the United States, this device was designated class II (requiring 501[k] clearance and clinical data). To satisfy US criteria for clearance, the standard of safety and effectiveness required in this case was defined as the ability to reduce complications associated with stenting of saphenous vein grafts. To meet this criterion, an 800-patient multicenter trial randomized trial comparing distal protection to usual care (no protection) was performed. At 30 days, a 42% relative reduction in major adverse cardiac events (primarily myocardial infarction) was observed.14 A trial of this type is estimated to cost US$10 to $12 million and may take 24 months to perform.
* Conclusion
As this review highlights, the demonstration of safety and efficacy for a new medical device is a long, arduous, and expensive developmental path from early concept to introduction into clinical practice. Only by understanding this path and its complexity may we hope to make the most efficient use of this critical process and allow the timely introduction of important new devices into our therapeutic armamentarium. The above review outlines this process and highlights some of the differences in the clinical and regulatory environments in the United States and Europe. Understanding these differences, moreover, helps explain why much early device testing takes place outside of the United States, and why the introduction of new devices into clinical practice is usually significantly delayed in the United States when compared with Europe. Both phenomena are direct results of inherent differences in the criteria for approval and the process required to obtain approval. In particular, the European CE Mark process requires demonstration of safety only (and not efficacy) and relies heavily on non-governmental notified bodies to regulate the approval and post-approval process. In contrast, the approval of a new high-risk device in the United States requires demonstration of both safety and efficacy and is more highly regulated by a central governmental agency (CDRH/FDA). Even when the FDA has authorized early US clinical trials, clinical testing must pass significant additional hurdles at each clinical site in terms of IRB and contract approvals. This process has become significantly more arduous in the wake of recent misadventures in drug and gene therapy testing.
Taken together, these factors account for the 1- to 3-year delays in the introduction of new device technologies into general clinical practice within the United States as compared with Europe. Each system has strengths and weaknesses that must be evaluated within the context of different health delivery systems. Through better understanding of these systems, will we be able to recommend modifications and improvements toward improving speed and efficiency (shorter delay to US versus European testing and ultimate clinical approval), without compromising the basic demonstration of safety and efficacy that remains the US regulatory mandate.
