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Less stringent requirements in the European Union result in faster medical device approval times.
The way in which devices are regulated in the EU is very different from the way they are regulated in the United States, especially in terms of the clinical data required for premarket approval. This has introduced significant differences in time-to-market approval for the United States versus the EU, particularly in the case of high-risk Class III and Class IIb implantable devices.
As a result, some U.S. physicians have experienced one- to three-year delays in access to certain important technical innovations such as drug eluting stents compared to their European colleagues.1 This article will explain why these timelines can differ so extensively by examining the clinical data requirements for market approval in the two systems.
Medical devices are regulated in the European Union by three EC Directives.2 The main directive, which covers the vast majority of medical devices from surgical gloves to life sustaining implantable devices such as heart valves, is the Medical Devices Directive (MDD). The MDD is supplemented by an older directive on active implantable medical devices and a newer directive on in vitro medical devices. These three EC directives have been enacted ("transposed") into the national laws of each EU Member State, resulting in a legislative framework comprised of literally dozens of medical device laws.
The medical device directives are known as "New Approach" directives. This means that medical devices bearing a CE marking can circulate freely throughout the EU without any barriers. Examples of other products regulated by "New Approach" directives include pressure vessels, toys, and personal protective equipment.
The underlying principle of the "New Approach" is as follows. Each of the medical device directives contains a legislative list of "Essential Requirements" that must be met by any product falling within its scope. In the MDD, the list of Essential Requirements can be broken down into two groups: 1) a set of general requirements for safety and performance that applies to all devices, and 2) a list of specific technical requirements with regard to design and manufacturing that may or may not apply depending on the nature of the device. For example, the technical requirement for electrical safety would not apply to a urinary catheter.
Compliance with the technical requirements is generally demonstrated by using the relevant European Harmonized technical standard. The need for clinical data in the CE marking process arises from the general requirements for demonstrating safety and performance.
The Case for Trial Data on EU Devices
A key aspect of medical device regulation in the EU is that the responsibility for ensuring that devices meet the Essential Requirements lies with the manufacturer. For low risk devices (Class I) such as a tongue depressor or colostomy bag, the manufacturer is allowed to self declare conformity with the Essential Requirements. For medium- to high-risk devices (Class IIa, IIb, III), the manufacturer must call on a third party to assess conformity. To some degree, the manufacturer may choose among methods for "conformity assessment" of the device and/or manufacturing system. The end result is certificates of conformity that enable the manufacturer to apply a "CE marking" to the product.
Another major aspect of the CE marking process is that, unlike pharmaceutical products, the medical device "conformity assessment" is not conducted by a regulatory agency for drugs and devices (i.e., a Member State Competent Authority or a central authority such as the EMEA). The CE marking system relies heavily on "Notified Bodies" to implement regulatory control over medical devices.
The majority of Notified Bodies are independent commercial organizations that are designated, monitored, and audited by the relevant Member States via the national Competent Authorities. Currently, there are more than 50 active Notified Bodies within the EU. A company is free to choose any Notified Body to cover the particular class of device under review. After approval, postmarket surveillance functions are the responsibility of a member state via the Competent Authority.
What clinical data is required by the EU medical device regulations? How does this differ from U.S. FDA requirements? As previously mentioned, the need for clinical data in the CE marking process arises from the requirement to demonstrate that a device is safe, that it performs as intended by the manufacturer, and that any risks are acceptable when weighed against the benefits of the device. The term "clinical data" within the meaning of the EC Directives is a broad concept that includes everything from bench testing to clinical trials in human subjects. As stated in the MDD, the clinical data used for CE marking may be in one of two forms:
The first option, also referred to as the "literature route," is commonly used by manufacturers for the CE marking of low- to medium-risk devices (Class I, IIa and IIb) for which safety and performance can be adequately demonstrated by a combination of nonclinical data (i.e., bench testing and animal testing) and clinical data that already exists on the device (published or unpublished) or by analogy with published data generated on an equivalent device.
Even when it is clear that the "clinical data" should come from a prospective clinical investigation, specific guidance on the criteria to be used is limited. While some guidance specific to medical devices is available, in general it concerns good clinical practices and clinical trials methodology.4 Specific requirements for clinical evaluation of most devices are not available in the guidance. In the absence of such specific requirements, the manufacturer must decide which data are sufficient for CE marking (i.e., number of subjects, type of study design, primary and secondary endpoints, type and schedule of assessments, minimum patient follow-up period, etc.). The Notified Body may be consulted with prior to initiating the clinical trial to verify whether or not the protocol is designed to yield adequate data for CE marking.
As a basic principle, the objective of a CE marking trial is to demonstrate safety and performance. Therefore, the majority of these trials are nonrandomized, single arm, feasibility studies involving less than 100 patients for which the primary objective is to demonstrate safety. In our experience, CE marking protocols rarely include a study hypothesis and a statistical calculation of sample size even though this is a requirement of the European Standard.5
Furthermore, Notified Bodies tend to function in a closed manner that provides little visibility on criteria required for approval, which allows for variations in clinical data requirements despite the fact that guidance documents have been mandated by the Commission to ensure a "level playing field."
The U.S. approval process for medical devices is very different, especially in terms of the scope and size of clinical trials required for high-risk devices. To receive approval to market a device in the EU, the manufacturer must demonstrate that the device is safe and that it performs in a manner consistent with the manufacturer's intended use. To receive approval to market a class III high-risk (and some class II) device in the United States, the manufacturer must demonstrate that the device is reasonably safe and effective. This typically requires a prospective, randomized controlled, adequately powered clinical trial involving hundreds of patients.
This significant difference is illustrated by the example of distal protection systems used in interventional cardiology. The first such system to be developed was a specialized coronary guide wire with an expandable balloon at its tip (GuardWire from Percusurge, Inc., which was later acquired by Medtronic). During a coronary angioplasty or stenting procedure, the device is inserted via femoral arterial access and the balloon is inflated distal to the lesion. After the balloon is expanded, the lesion is treated. The purpose of the device is to block any dislodged arterial debris from embolizing. After the lesion is treated, any debris is evacuated by aspiration and the GuardWire is removed.
In the EU, the GuardWire device was awarded CE marking by demonstrating safety and performance (i.e., the ability to aspirate material during the stenting procedure) in a 22-patient, single arm study.6 In the United States, this device was designated Class II. To demonstrate safety and effectiveness (defined as the ability to reduce complications associated with stenting of saphenous vein grafts) the FDA required an 800-patient, multicenter, randomized trial comparing distal protection to usual care (no protection).7
As a result, the GuardWire was available in the EU at least two years before U.S. physicians had access to the technology. On the other hand, one may argue that this early access must be weighed against the absence of proven efficacy.
Without careful trials evaluating efficacy, no legitimate medical judgement on the appropriate use of a medium- to highrisk medical device may be made. Unlike the United States, the EU approval process for medical devices does not incorporate such evaluations into its regulations.
What could already be perceived by some as a shortcoming in the EU regulatory requirements is further exacerbated by the fact that: 1) "real" clinical data in the form of results from prospective clinical investigation is not mandatory for medical devices in Class IIb, even though they are relatively "high risk"; and 2) Notified Bodies are not on a level playing field in terms of their criteria for approval.
There is a proposal currently to amend Annex X of the Medical Devices Directive to strengthen the language concerning clinical data requirements; however, the proposed changes will not fundamentally alter the spirit of the requirements, which remains the demonstration by the manufacturer of safety, performance, and acceptable risk/benefit ration. On the other hand, Notified Bodies will increasingly require effective postmarket surveillance in the form of postmarket clinical follow-up for certain types of devices.8
1. A.V. Kaplan, D.S. Baim, J.J. Smith, D.A. Feigal, M. Simons, D. Jefferys, T.J. Fogarty, R.E. Kuntz, M.B. Leon, "Medical Device Development: From Prototype to Regulatory Approval," Circulation, 109: 3068–3072 (2004).
2. Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical equipment (AIMDD); Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (MDD); Council Directive 98/79/EC of 27 October 1998 on in vitro diagnostic medical devices (IVDD).
3. NB-MED/2.7/Rec.1: Co-ordination of Notified Bodies Medical Devices. Recommendation—Guidance on Clinicals.
4. MEDDEV 2.7.1: European Commission—Guidelines on Medical Devices—Evaluation of Clinical Data: A Guide for Manufacturers and Notified Bodies.
5. EN ISO 14155-1&2: Clinical Investigations of Medical Devices for Human Subjects. Part 1: General Requirements, Part 2: Clinical Investigation Plans.
6. J.G. Webb, R.G. Carere, R. Virmani et al., "Retrieval and Analysis of Particulate Debris Following Saphenous Vein Graft Intervention," J Am Coll Cardiol, 34, 468–475 (1999).
7. D.S. Baim, D. Wahr, B. George et al., "Randomized Trial of a Distal Embolic Protection Device During Percutaneous Intervention of Saphenous Vein Aorto-coronary Bypass Grafts, Circulation, 105, 1285–1290 (2002).
8. MEDDEV 2.12.2: European Commission—Guidelines on Post Market Clinical Follow-up (PMCF).
Sarah Sorrel, MS, is founder and president of MedPass International SAS, 95bis Boulevard Péreire, 75017 Paris, France, +33 (0)1 4212 8330, fax +33 (0)1 4053 8111, email: firstname.lastname@example.org