With Regulation (EU) 2017/745 (MDR) coming into force on 26 May 2021, the requirements for clinical evidence within the CE conformity assessment process of medical devices have further increased. The focus on clinical trials is already clear in the recitals of the MDR:
“To ensure a high level of safety and performance, demonstration of compliance with the general safety and performance requirements laid down in this Regulation [MDR] should be based on clinical data that, for class III devices and implantable devices should, as a general rule, be sourced from clinical investigations […]” (Recital 63). “The rules on clinical investigations should be in line with well-established international guidance in this field, such as the international standard ISO 14155:2011 on good clinical practice for clinical investigations of medical devices for human subjects […]” (Recital 64).
In addition, the source of clinical data that can be used to demonstrate the safety or performance of a device is explicitly intended to include post-market clinical follow-up of a medical device, so manufacturers must also consider post-market clinical trials of their devices.
Clinical trials at a glance:
1. Clinical trial in the context of conformity assessment for (extended) CE marking
Clinical trials, which constitute part of the clinical evaluation for conformity assessment purposes pursuant to Article 62 MDR, concern devices that do not yet have a CE marking. They are conducted in accordance with Article 62 MDR for one or more of the following purposes:
- “(a) to establish and verify that, under normal conditions of use,a device is designed, manufactured and packaged in such a way that it is suitable for one or more of the specific purposes listed in point (1) of Article 2, and achieves the performance intended as specified by its manufacturer;
- (b) to establish and verify the clinical benefit of a device as specified by its manufacturer;
- © to establish and verify the clinical safety of the device […]”
Appropriate clinical trials are subject to approval.
This approval requirement also applies to clinical trials of devices that are already CE marked but are to be used outside the intended purpose covered by the CE mark. Article 74 (2) MDR is relevant in these cases: “Where a clinical investigation is to be conducted to assess, outside the scope of its intended purpose, a device which already bears the CE marking in accordance with Article 20(1), Articles 62 to 81 shall apply.”
2. Post-market clinical trials with “additional burden” for subjects
If a clinical trial is intended to further the clinical evaluation of a medical device that is already CE-marked, within its intended purpose as defined by the CE-mark, Article 74(1) MDR must be observed “where the investigation would involve submitting subjects to procedures additional to those performed under the normal conditions of use of the device and those additional procedures are invasive or burdensome.”
Additional procedures that are burdensome may take a variety of forms and may include, for example, procedures that cause pain, discomfort, anxiety, potential risks, or complications/side effects. The presence of a “burden” is determined from the perspective of the subjects. Other invasive procedures include penetration of the body through the body surface as well as through the mucous membranes of the body orifices.
Corresponding clinical trials are not subject to approval, but are subject to notification.
3. Post-market clinical trials without “additional burden” for subjects
If a clinical trial is conducted with a device that is already CE-marked to evaluate its performance when used within the defined intended purpose without (having to) use additional burdensome or invasive procedures, the MDR rules for clinical trials are not relevant. Therefore, there is neither an approval nor a notification requirement in these cases.
4. Other clinical trials according to Article 82 MDR
Article 82 of the MDR also regulates clinical investigations of medical devices that are not initiated by the manufacturer or are not conducted in connection with a conformity assessment. Minimum requirements are also imposed on these other clinical trials. Thus, in particular, according to Article 62(2) and (3) MDR, these must also be “designed and conducted in such a way that the rights, safety, dignity and well-being of the subjects participating in a clinical investigation are protected and prevail over all other interests and the clinical data generated are scientifically valid, reliable and robust.” They, too, are “subject to scientific and ethical review.” The specific requirements for other clinical trials are defined in accordance with Article 82 (2) MDR in § 47 of the Medical Device Law Implementation Act (MPDG) (PDF only in German) applicable in Germany. There, too, a distinction is made between “other clinical trials” of products with and without CE marking, the use within or outside the intended purpose already covered by the CE marking, and the use of additionally invasive or stressful procedures.
Recommended action for sponsors
Clinical trials are time-consuming and costly, but essential to demonstrate the clinical benefit or added value of a medical device. In specific cases, especially in the case of tests with CE-marked products, questions may arise as to the scope of duties of the sponsor, and delimitation problems may arise. Therefore, before conducting corresponding studies, sponsors should carefully check the intention pursued and the given framework conditions in order to comply with their respective obligations and the requirements for the clinical trial in each case, thus avoiding liability risks.back