In the context of the introduction of the MDR (Medical Device Regulation), the Medical Device Coordination Group (MDCG) regularly publishes recommendations which, based on the MEDDEV documents used to date, represent recommendations for action in dealing with the implementation of the requirements of the MDR.
In particular, the area of clinical investigations for medical devices places high demands on sponsors within the framework of the MDR Regulation. The recently published guidance document MDCG 2021-6″Regulation (EU) 2017/745 -Questions & Answers regarding clinical investigation” attempts to provide answers to the most urgent and important questions concerning the planning and performance of clinical investigations.
The objective of clinical investigation prior to obtaining CE certification is to prove the safety and, in particular, the performance of a medical device. In this context, it is important to clearly distinguish between the terms used in the MDR in order not to get into trouble when setting up the study design of a clinical investigation:
means the ability of a device to achieve its intended purpose as stated by the manufacturer.
means the ability of a device, resulting from any direct or indirect medical effects which stem from its technical or functional characteristics, including diagnostic characteristics, to achieve its intended purpose as claimed by the manufacturer, thereby leading to a clinical benefit for patients, when used as intended by the manufacturer.
means the positive impact of a device on the health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient management or public health.
Even more important than these terms is the distinction between certain types of clinical investigations, also with respect to the time at which they are carried out. In the context of generating clinical data by means of clinical trials for highly innovative products, a multi-stage procedure is appropriate, and this must also be recorded and described in the corresponding clinical development plan. A reference to the clinical development plan can then be found in the clinical evaluation plan, which forms the basis for the clinical evaluation report. At this point, therefore, the circle closes between the area of clinical testing and clinical evaluation prior to CE authorisation.
The multi-stage procedure can be as follows:
1. Start with an animal study/cadaver study/experimental study in order to elicit fundamental basic information on the planned application of the planned medical device and to clarify the scientific
2. Carrying out a pilot study; a distinction is typically made here between
1. “First in man” studies,
2. Early feasibility studies and
3. Traditional feasibility studies
The primary purpose of a pilot study is to test the planned study design for the subsequent pivotal study with a limited number of test subjects and to determine the initial clinical safety and performance of the medical device at an early stage of development. In this context, modifications in the design of the medical device occur or may occur. According to this, clinical data obtained from pilot studies are unsuitable for the purposes of CE authorisation.. However, they represent an important building block in this process and have gained further importance with the introduction of the MDR.
3. Conducting the pivotal study: After completion of the pilot study(s) and the final design freeze of the planned medical device, the pivotal study follows; here, the wise choice of the primary and secondary endpoints as well as the central study hypothesis is crucial. The clinical data gathered are the basis for the preparation of the clinical evaluation and the final proof of conformity with the Essential Safety and Performance Requirements under the MDR.
The responsibility for determining the applicable regulatory basis for conducting a clinical investigation (Article 62 MDR versus Article 82 MDR, for example) lies solely with the sponsor of the clinical trial. This should be taken into account in advance during planning. The MDR also stipulates in Article 15 that the manufacturer/sponsor must appoint a responsible person in the organisation who can deal with these issues and also provide the necessary evidence of qualification.
A primarily important aspect when conducting a clinical investigation with a medical device without CE authorisation is the handling of safety-relevant events during the conduct of the clinical trial. Article 80 of the MDR regulates the procedure for these cases. Again, the sponsor is responsible for reporting; he must maintain corresponding operating procedures withdeadlines to be observed, the responsible persons, the procedure in detail, from the occurrence of theadverse event until the close of the reporting incident . Further information and assistance on this topic is provided in MDCG document 2020-10/1 “Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745”.
The requirements for conducting clinical trials also apply to the area of “custom-made devices” as defined in Article 2(3) of the MDR, as well as to devices manufactured and used exclusively within healthcare facilities established in the European Union (Article 5). Accordingly, Articles 62 and 82 of the MDR then also apply here.
In connection with the actual conduct of the clinical investigation, questions may also arise in the course of the trial about modifications of the original trial setting. A distinction is made between substantial and non-substantial modifications. The first question on this complex of topics will be: As a sponsor, how do I know what is a substantial adjustment? Ultimately, any adjustment that can foreseeably have a substantial impact on the safety or health or rights of the test subject, or can affect the data quality or reliability of the clinical data collected by the clinical trial. Once agreed on this essential question, Article 75 of the MDR provides further information for documentation of the substantial modification and the corresponding approval process. It is recommended not to submit several applications for substantial modifications in parallel, but to wait until the processing of one application has been completed. As a rule, modifications to the test product itself always constitute a substantial modification. In some cases, this may then lead to a new clinical investigation application. The decision in this matter is made by the competent licensing authority on a case-by-case basis.
Annex II of MDCG Guidance 2021-6 provides a non-exhaustive overview of modifications that can in principle be considered substantial to better understand the topic.
With regard to time limits in the clinical investigation environment, the start and end of the actual clinical trial are important aspects that go hand in hand with certain reporting obligations. While a declaration or notification at the start of a trial is not explicitly required by the MDR (national regulations may provide for different rules here), Article 77(3) of the MDR regulates that the sponsor shall notify the end of the clinical trial no later than fifteen days after its completion. This applies to each individual member state in which the clinical trial is conducted. If there are different times in the different Member States where the clinical trial is conducted, this must be done in each individual Member State. Article 77(2) of the MDR regulates by definition when a clinical trial is considered “terminated”: “The end of a clinical trial is considered to be the last visit of the last subject, unless another time is specified in the clinical trial protocol. “
Furthermore, the MDR obliges the sponsor to provide a clinical trial report at the latest after or within one year after the defined end of the clinical trial. Again, this requirement applies to each Member State in which the clinical trial was conducted. The applicable regulations can be found in Section 2.8, Chapter I and Section 7, Chapter III of Annex XV of the MDR. In the case of a prematurely terminated clinical trial, the above-mentioned period is reduced to three months.
What does such a report look like, what basic requirements does the MDR place on the content, or does the MDR place any requirements at all on the content? This can be answered with a clear “yes”; the current edition of ISO 14155:2020-7 “Clinical investigation of medical devices for human subjects – Good clinical practice” also provides guidance here in Annex D on what should ideally be documented in a report. At this point, we will limit ourselves to the requirements of the MDR: Chapter 3, point 7 of Annex XV of the MDR specifies the minimum requirements for the content, which would be:
- Cover page/introductory page(s) indicating the title of the trial, the investigational product, the single identification number, the clinical trial protocol number, and details of the coordinating investigator(s) and principal investigator(s) of each trial site with signatures.
- Detailsof the author and date of the report
- A summary of the investigation covering the title, purpose of the investigation, description of the investigation, investigational design and methods used, the results of the investigation and conclusion of the investigation. The completion date of the investigation, and in particular details of early termination, temporary halts or suspensions of investigations.Investigational device description, in particular clearly defined intended purpose.
- A summary of the investigation covering the title, purpose of the investigation, description of the investigation, investigational design and methods used, the results of the investigation and conclusion of the investigation. The completion date of the investigation, and in particular details of early termination, temporary halts or suspensions of investigations.
- Results of the clinical investigation covering, with rationale and justification, subject demographics, analysis of results related to chosen endpoints, details of subgroup analysis, as well as compliance with the CIP, and covering follow-up of missing data and of patients withdrawing from the clinical investigation, or lost to follow-up.
- Overview of serious adverse events, adverse effects of the product and product deficiencies and any relevant corrective actions.
- Discussion and overall conclusions covering safety and performance results, assessment of risks and clinical benefits, discussion of clinical relevance in accordance with clinical state of the art, any specific precautions for specific patient populations, implications for the investigational device, limitations of the investigation.
In principle, the MDR requires a notification of a clinical trial via EUDAMED, but the module for clinical trials is still not available. So how can a clinical trial be properly notified?
For the application, all necessary documents should be sent to the national competent authorities, i.e. in the case of Germany to the Federal Institute for Drugs and Medical Devices (BfArM ). Other transitional regulations may apply in other member states, which may need to be taken into account when submitting the application. The EU Commission has compiled an overview of all national competent authorities, which can be downloaded from the following link:
Finally, a sentence on the handling of clinical trials that were started before the MDR came into force under the MDD (93/42/EC) and are currently still ongoing: These can of course be continued and completed. However, the deadlines and procedures for reporting serious incidents must be observed in accordance with Article 80 of the MDR. In order to facilitate the transition period for the sponsor to adapt its Clinical Investigation Plan (CIP) as well as its procedures for handling serious incident reporting, it may continue to report to its national competent authority until the above mentioned EUDAMED module is available.
Please note that all details and listings do not claim to be complete, are without guarantee and are for information purposes only.