Clinical Data Requirements for EU Medical Devices: Upcoming Changes

On 26 September 2012, the European Commission (EC) adopted two proposals that, once adopted by the European Parliament and the Council, will replace the three existing medical devices directives with one regulation for medical devices (including active implantable medical devices) and another for in vitro diagnostic (IVD) medical devices. This revision of EU medical device legislation is rapidly approaching. Although the timeline for implementation of this new framework is not yet clear, we have recently seen the publication of two significant documents: Commission Recommendation of 24 September 2013 on unannounced audits¹ and Regulation 920/2013 on the designation and supervision of Notified Bodies.²

The first document stipulates the EC's expectations on the practice of on-site auditing of manufacturers and their critical suppliers. Until now, on-site inspections have not been a requirement for medical device manufacturers (other than their ISO 13485 certification). Inspection of manufacturers without forewarning represents a significant shift in atmosphere. The second document is critical because it comes in the form of a regulation and (unlike an EU directive) does not need to be transposed into national legislation. The regulation aims to create a level playing field for European Notified Bodies. As these organizations are notified by their respective Member States, there has been a lack of EU-wide, consistent criteria for conformity assessment. Some argue that this has undermined the perceived quality of the CE Mark.

The pressure of the new regulatory regime is expected to extend to Notified Bodies and, in turn, to the medical device manufacturers whose CE marking they oversee. Although the exact legislative text has been subject to much debate, it has become clear that the revision will entail a considerable increase in scrutiny of manufacturers. Anticipating these changes, Notified Bodies already are enforcing stricter requirements for CE marking of medical devices. It is important to note here that in the EU, the manufacturer is understood as the entity that places a device on the market under its own name. This means even if a manufacturer outsources all its activities to another company, the regulatory responsibilities nevertheless reside with the former entity.

The best tools to prepare for future requirements are the guidance documents published by the EC. These include "MEDDEV" guidance documents on various topics published on the EC website.³ There is also the Manual on Borderline and Classification in the Community Regulatory Framework for Medical Devices, which is continually updated to reflect the position of the EC as well as Member State representatives on borderline products.⁴ Although officially nonbinding, these guidance documents are understood to represent best practices. They also provide insight into real-world application of existing requirements and set expectations for current requirements and enforcement. To some extent, these expectations will be formalized once the regulations are put in place. Therefore, companies that have not been using these texts to facilitate compliance will need to consider doing so.

The Future Role of Clinical Data

Performance and safety information generally are anticipated to play a more central role in the new legislation. Most members of industry are aware compliance with the new requirements will involve increased efforts on their part, particularly where clinical data are concerned. Many manufacturers may feel overwhelmed at the thought of additional costs and more burdensome demands. Going forward, it is likely they will need to take more responsibility for their products and accept full accountability for device compliance when placing a product on the market. However, the need for clinical data is nothing new.

As most will recall, amending Directive 2007/47/EC made clinical evaluation mandatory for all medical devices (per Annexes X and 7 of the Medical Devices Directive (MDD), Directive 93/42/EEC and Active Implantable Medical Devices Directive (AIMDD), Directive 90/385/EEC, respectively). Since 2010, clinical evaluation has applied to medical devices of all risk classes, including Class I non-sterile and non-measuring medical devices to which the manufacturer self-affixes the CE Mark. Clinical evaluation is discussed in depth in the guidance document MEDDEV 2.7/1, Rev. 3, Clinical evaluation: A guide for manufacturers and notified bodies.⁵

The medical devices directives define "clinical data" as "the safety and/or performance information that is generated from the use of a device." These data can be obtained from any of the following sources:

• clinical investigation of a device
• clinical investigations or studies, reported in the literature, of a similar device for which equivalence to the device in question can be demonstrated
• published and/or unpublished reports on other clinical experience of either the device in question or a similar device for which equivalence to the device in question can be demonstrated^6,7

The revised legislation is not expected to alter these definitions, although clinical data to support the performance and safety of Class III and implantable devices should be sourced directly from clinical investigations (this essentially is required today, as well). Rather, emphasis will be placed on enforcement. Clinical data will be central to demonstrating a favorable benefit-risk ratio and specific claims. The data identified in the clinical evaluation are compiled into a report subsequently reviewed by a Notified Body in cases where CE marking is approved by a third party. This clinical evidence will be retained together with the manufacturer's technical documentation, as it has been under the medical devices directives.

Studies Reported in the Literature

To fulfill clinical evaluation requirements, many manufacturers use published data to support device performance and safety, known as using the literature route. The literature route is an appealing option, as large-scale clinical trials may not be feasible for small and medium-size device companies. Some critics have argued that manufacturers historically have overused this option, which is a mechanism likely conceived as an exception to the rule for performing clinical studies. Certainly, many manufacturers presume published data generated by their competitors will be available and therefore take a complacent approach to clinical evaluation. But despite the fact that another company operates in the same space, only the manufacturer ultimately bears responsibility for its own products.

Medical devices based on longstanding technology with a well-documented mode of operation benefit greatly from existing data identified via methodologically sound literature searches. But information may not be transferred as easily to sophisticated devices that use an advanced device design. If a device has truly novel features (or if there is insufficient data in the literature), the manufacturer is expected to generate data by performing clinical studies.

Further, a manufacturer must consider state of the art. Although vague, this concept can be understood as the sum of an objective assessment concerning the product's benefit-risk ratio and should take into account the constant evolution of research. In other words, a device that was considered the preferred treatment modality when it was first CE marked 10 years previously may have been superseded by more advanced technology. In this situation, it is the manufacturer's obligation to demonstrate that the anticipated clinical benefits of device use continue to outweigh its risks (even though the market may offer more sophisticated alternatives). Some clinical applications may no longer be state of the art, but are still widely employed by clinicians. The application of recognized standards published in the Official Journal of the EU also plays a part in the wider notion of "state of the art." As per Article 5 of the MDD, compliance with such standards further presumes compliance with the relevant Essential Requirements.

Clinical Evaluation--Best Practices

Although widely used, there seem to be some prevalent misinterpretations surrounding the literature route. Understanding how to approach published data effectively likely will become even more important under the future regulatory framework.

As mentioned previously, if there is no clinical experience from a device in human use, the manufacturer may use data from a device "for which equivalence…can be demonstrated." The bottom line is the data in the clinical evaluation report need to be relevant to the device in question. This relevance must be supported by a thorough comparison of clinical, technical and biological device characteristics. The manufacturer is expected to include a thorough demonstration of equivalence, which may even involve comparative bench testing to elucidate similarities or differences in device specifications. These characteristics are discussed briefly in the current guidance document, MEDDEV 2.7/1, Rev. 3, but were addressed in detail in the first version published in 2003 (see excerpt in Figure 1).

Figure 1. Specific Characteristics and Features of the Device Under Consideration

Notified Bodies have suggested they will be less flexible about allowing datasets from multiple devices to support the clinical evaluation. In the past, it may have been possible to combine data derived from several similar devices to arrive at a general conclusion regarding safety and performance of a device in question. Moving forward, any discrepancies must be evaluated carefully to determine whether data generated by one device are applicable to another. A manufacturer must be confident study results can be attributed to characteristics shared by the device in question. This may not be possible when a device's mode of operation is based on slightly different characteristics or combines a set of features for the first time.

Another commonly occurring, and perhaps more significant, misconception concerns the link between equivalence and data availability. It is important to recognize Notified Bodies are not concerned with equivalence per se. The only reason for discussing an equivalent device in a clinical evaluation is because it has generated data readily available in the public domain, such as results from published studies or postmarket surveillance data. This use of data illustrates a significant difference between the US and EU regulatory systems. While the US regulatory system is based on substantial equivalence to a marketed product, the existence of a "predicate" device is irrelevant in Europe. Manufacturers must rid themselves of the notion that because a competitor's device has CE marking, the clinical evaluation requirement will be satisfied easily. If a competitive product-even a predicate device used in a 510(k) submission-has not generated any available data, it most likely will be of limited use in clinical evaluation.

Know Your Data-and How to Use Them

A wise strategy for manufacturers is to familiarize themselves with existing clinical data and identify relevant datasets well in advance of the Notified Body review. Ideally, a manufacturer will strive to identify both favorable and unfavorable datasets to further understand their device, its risks and how it relates to technological advancement. Only by obtaining this knowledge will a manufacturer be able to translate the relevance of these results to its own device and define the state of the art. Similarly, even if the manufacturer concludes published study data are not sufficient to support device performance and safety, thorough knowledge about existing data will be useful in identifying the appropriate research objectives and narrowing down a study scope.

Another requirement receiving more attention these days is postmarketing clinical follow-up (PMCF), which is further described in MEDDEV 2.12/2, Rev. 2.⁸ PMCF studies, carried out after CE marking has been obtained, use information generated in the postmarketing phase. A PMCF study must follow a sound scientific design (as should any study) but need not be a clinical trial. Activities in this category may include efforts to confirm the Instructions for Use are fully understood by users and the device performs according to its intended function (e.g., summative testing, human factor studies), or a review of device registries, extended follow-up of patients enrolled in premarket investigation and so on.

Clinical experience is also a valuable tool for proactive manufacturers, as it involves real users (as opposed to study subjects in a controlled environment). Unfortunately, some companies seem preoccupied with the path of least resistance, even though PMCF has the potential to unlock valuable information throughout the device lifecycle. Other manufacturers appear reluctant to probe their complaint data for fear of raising unnecessary safety concerns. In actuality, data obtained in the postmarketing phase can be viewed as an opportunity to demonstrate appropriate actions are being taken to continually improve device design and reduce risks. More importantly, they may demonstrate to the Notified Body that the organization is unlikely to be caught off guard by an even greater safety issue.

Conclusion

The upcoming regulatory shift undoubtedly will bring about significant changes for manufacturers that place their medical device on the European market. The forthcoming medical device regulations are expected to be much more detailed. Regulatory compliance will have to be supported by well-documented processes and competency within an organization. EU regulators want manufacturers to assume full responsibility for their products and, therefore, medical device companies ought to pursue a sound understanding of the clinical framework in which they operate. This exercise includes a thorough understanding of device performance and safety as demonstrated by objective clinical data.

Where clinical evaluation is concerned, multiple concepts should be considered. First, the availability of data and their relation to the device in question must be discerned. Second, a manufacturer will want to continually assess the need for studies after the product is placed on the market-and throughout the postmarketing stages-to ensure it functions according to its intended use. Finally, the importance of state of the art should not be overlooked.

Clinical evaluation via the literature route may continue to be a viable alternative for many medical devices under the new regulations, but will be most useful when paired with a robust grasp of device performance and risk throughout the entire product lifecycle.

References

1. Commission Recommendation of 24 September 2013 on the audits and assessments performed by notified bodies in the field of medical devices. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2013:253:0027:0035:EN:PDF. Accessed 17 February 2014.
2. Commission Implementing Regulation (EU) 920/2013 on the designation and the supervision of notified bodies under Council Directive 90/385/EEC on active implantable medical devices and Council Directive 93/42/EEC on medical devices. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2013:253:0008:0019:EN:PDF. Accessed 17 February 2014.
3. Guidance MEDDEVs list. EC website. http://ec.europa.eu/health/medical-devices/documents/guidelines/index_en.htm. Accessed 17 February 2014.
4. Manual on Borderline and Classification in the Community: Regulatory Framework for Medical Devices. EC website. http://ec.europa.eu/health/medical-devices/files/wg_minutes_member_lists/borderline_manual_ol_en.pdf. Accessed 17 February 2014.
5. MEDDEV 2.7/1, Rev. 3 "Clinical evaluation: A guide for manufacturers and notified bodies" (December 2009). EC website. http://ec.europa.eu/health/medical-devices/files/meddev/2_7_1rev_3_en.pdf. Accessed 17 February 2014.
6. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (Article 1 (2) (k)). EUR-Lex website. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1993L0042:20071011:en:PDF. Accessed 17 February 2014.
7. Council Directive of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical (90/385/EEC) (Article 1 (2) (k)). EUR-Lex website. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1990L0385:20071011:en:PDF. Accessed 17 February 2014.
8. MEDDEV 2.12/2, Rev. 2 "Post Market Clinical Follow-up studies: A guide for manufacturers and notified bodies" (January 2012). EC website. http://ec.europa.eu/health/medical-devices/files/meddev/2_12_2_ol_en.pdf. Accessed 17 February 2014.

About the Author

Mary Couch, MA, RAC (EU) works as a global regulatory specialist at Emergo Group. She can be reached at [email protected].

Cite as: Couch M. "Clinical Data Requirements for EU Medical Devices: Upcoming Changes." Regulatory Focus. February 2014.Regulatory Affairs Professionals Society.