The Medical Device Regulation and its impact on device development and research in Germany

In May 2021, the Medical Device Regulation (MDR; Regulation (EU) 2017/745) [1] entered into effect. Unlike its predecessors, the Medical Device Directive (MDD, 93/42/EEC) [2] and the Active Implantable Medical Device Directive (AIMDD, 93/385/EEC) [3], which had to be implemented into national law, the MDR as a regulation is immediately binding and should be directly applied in all EU member states. Nevertheless, the MDR does defer many details of implementation to national law and also opens the possibility for member states to require additional measures beyond those in the MDR itself. In Germany, it is thus necessary to consider the Medizinprodukterecht-Durchführungsgesetz (MPDG) [4] and other legislation to fully understand the treatment of medical device development and approval as well as the impact on the conductance of clinical investigations.

The MDR was conceived to improve the safety and quality of medical devices. Significant consideration was given to incidents involving medical devices under the predecessor legislation, including problems with metal-on-metal hip implants [5] and in particular the very public scandal involving breast implants [6], [7]. The MDR has thus significantly increased requirements for the collection of clinical data before approval as well as requirements for post-market follow-up studies to ensure continued device performance and safety. The MDR also establishes the framework for an EU-wide European Databank on Medical Devices (EUDAMED) to centrally collect data on all medical devices, with many similarities to the Manufacturer and User Facility Device Experience (MAUDE) database maintained by the U.S. FDA. EUDAMED should facilitate monitoring by national authorities and ensure efficient sharing of data between countries. However, the use of the EUDAMED database is not yet mandatory, and full functionality is not expected until 2026 [8].

A significant consideration for device manufacturers regarding the MDR is that there was no grandfathering of devices already on the market. It is thus necessary for all devices, whether existing or novel, to undergo the full clinical testing required by the new legislation. Due to inadequate capacity at the Notified Bodies responsible for device approval, delays have arisen. The EU has recognized the insufficient capacity of Notified Bodies and, thus, extended the timeframe within which manufacturers need to achieve reapproval for legacy devices. Originally, all re-certifications would have had to been completed by May 2024. The current timeline differentiates based on the risk class of the device. Regulation (EU) 2023/607 [9] was implemented in March 2023 and extends the transition period to the end of 2027 for high-risk devices and 2028 for lower-risk devices. There are, nevertheless, several prerequisites that manufacturers need to fulfill in order to take advantage of the extension. For instance, they must have implemented a quality management program according to the MDR and initiated an application for conformance assessment of the device with a Notified Body by May 2024.

Concerns have been raised that the additional data collection and monitoring requirements of the MDR may hamper innovation in the European medical device industry. The regulatory requirements imply that the cost and effort to introduce a new product to the market may lead to slower progress compared to other markets with lower regulatory burden [10]. In addition to the additional resources required for new devices, at least in the short term manufacturers will have to divert significant time and money to re-certify devices already on the market. These factors are of particular concern to niche devices with limited market demand, so-called orphan devices [11]. For example, pediatric subdisciplines such as cardiology and interventional radiology could be faced with devices being removed from the market and/or too few new devices entering [12]. In general, small and medium-sized companies appear to be have specific difficulties adapting to the new regulations [13], [14]. Nevertheless, it is still too early to determine whether the MDR will lead to a reduction in the introduction of new medical devices in the EU.

Aside from the impact of the MDR on commercial enterprises, it also has wide-ranging implications for the performance of clinical investigations at research institutions and universities in collaboration with commercial entities as well as the performance of research studies in humans involving self-developed hardware and software where there may be no intention to pursue CE certification. Under the predecessor law in Germany, the Medizinproduktegesetz (MPG) [15], it was clearly necessary to perform a clinical investigation according to MPG if the goal of the study was to assess conformity to regulatory requirements and achieve CE certification. In other cases, it was often possible to perform the study according to the Berufsordnung für Ärzte [Professional Code of Conduct for Physicians] (BO-Ä). Although each Landesärtzekammer [State Medical Association] issues its own BO-Ä, the relevant paragraph in the model BO-Ä issued by the Federal Medical Association is § 15, which specifies that advice of the competent ethics committee be sought and the research conducted according to the Declaration of Helsinki [16].

Under the MDR and MPDG, the concept of an “other clinical investigation [sonstige klinische Prüfung]” is introduced, which expands the type of studies falling under the MDR and MPDG. In particular, § 3 Abs. 4 MPDG defines a “sonstige klinische Prüfung” to include studies that “serve to answer scientific or other questions” [4]. Since the introduction of the MDR, there has been a lack of clarity about which studies must be conducted according to MDR and which can continue to be conducted according to BO-Ä. A guidance document has recently been published under the patronage of Medtec Online [17], an initiative of the Bundesministerium für Bildung und Forschung [German Federal Ministry for Education and Research], that provides very useful decision trees to not only decide whether a study falls under the MDR (cf. Figure 1, Prüfschema zur regulatorischen Qualifizierung als klinische Prüfung [Decision tree for regulatory qualification as a clinical trial], [17]), but if so, as what type of study it should be classified under MDR (cf. Figure 2, Prüfschema zur regulatorischen Typisierung der klinischen Prüfung [Decision tree for regulatory classification of the clinical trial], [17]).

One important distinction made in the first decision tree is whether the object under test is even a medical device according to MDR. For this, the object must have an intended purpose that is specifically medical according to Art. 2 Nr. 1 MDR [1]. As an example given in [17], a study involving a new virtual reality headset that examines the effect of the headset on patient comfort does not fall under the MDR, as the intended purpose of the headset is not medical (diagnosis or therapy) according to MDR. Other examples are given that involve basic scientific research targeting gains in knowledge about the principle function of a device without specifically investigating its diagnostic or therapeutic performance or its safety in a medical context (cf. case examples 4.17 and 4.18, Wissenschaftliche Forschung mit einem Prüfgegenstand [Scientific research with a test item], [17]).

The manufacturer of a device is responsible for defining the intended purpose and thus whether it is to be classified as a medical device according to MDR. Under the predecessor legislation MDD, the European Court of Justice made it clear that in cases where the manufacturer did not conceive the product to be used for medical purposes, its certification as a medical device could not be required, i.e. not every device that potentially can be utilized as a medical device is a medical device [18]. Of course, as soon as a user does use the device for a medical purpose, the device becomes a medical device and must be treated according to MDR/MPDG.

The question of what constitutes a medical device in relation to device prototypes that are to be used in purely research contexts without any type of individual patient benefit in regards to diagnosis or therapy is discussed by Lempp and Gassner [19]. Especially for new devices, where the clinical usefulness is unclear and it is not yet foreseeable whether the development of a medical device will ultimately be pursued, the question arises whether the MDR should be applied. The UK health authority Medicines and Healthcare products Regulatory Agency (MHRA) issued a statement very early on that research tools that do not yet have a medical intended purpose with individual patient benefit do not fall under the MDR (this guidance was necessary due to the continued application of EU law in Northern Ireland) [20]: “Products used on humans for research purposes, where there is no intended medical purpose, are considered to be research tools and should not be CE marked or CE UKNI marked under MDR or IVDR. 'Research use' products are specifically excluded from the IVDR and although are not explicitly excluded from MDR, they do not have a medical purpose and are therefore considered as excluded from the MDR.”

Although the guidance document published by Medtec Online [17] is not as explicit as the statement by MHRA, the case examples they provide do seem to support that many research studies involving human subjects performed at universities and other research institutions do not fall under the MDR and should continue to be performed according to BO-Ä. Further helpful guidance can be found in an editorial issued by the Deutsche Röntgengesellschaft [German Roentgen Society] together with several other German medical scientific societies, which provides a checklist to help differentiate whether studies involving novel MRI pulse sequences should be conducted according to MDR/MPDG or to BO-Ä [21].

The new MDR that came into force in 2021 was introduced with the laudable goals of increasing device quality and patient safety as well as harmonizing medical device handling across the EU. Nevertheless, the MDR and the German-specific MPDG have generated concerns about device innovation and the burdens of new regulations on commercial enterprises, particularly smaller companies without the resources to maintain a large regulatory group. The laws have also raised many questions about their exact interpretation and their impact on the interactions between university clinics and device manufacturers, and it will take additional time before there is consensus on the part of individual ethics committees across Germany on how to treat specific studies. It is still too early to judge how successful the laws will be in achieving their goals. On the one hand, no quantifiable evidence yet exists that device safety has improved, but, on the other hand, no explicit evidence has yet been presented that manufacturers are deciding to first enter other markets with less stringent regulations or perform their clinical studies outside the EU. Future studies will have to assess the economic and patient care impact of the MDR, but if the increased standards for clinical and post-market data lead to fewer safety incidents and device recalls, it is likely that other regions around the world will consider emulating the EU regulations.