The Act on the Implementation of EU Regulations Concerning Medical Devices (Medizinprodukterecht-Durchführungsgesetz – MPDG) has formally entered into force on May 26, 2021, and has replaced the former Medical Devices Act (Medizinproduktegesetz MPG) – at least for medical devices that are not in vitro diagnostics. But how will the national innovations play out in practice? And what do manufacturers need to bear in mind to avoid unpleasant surprises?

The new law presents itself as a complex piece of work, with direct reference to European legislation and a new overall structure. It is not only the merging of the content with other former regulations such as the Regulation on Clinical Trials of Medical Devices (MPKPV) that has increased the scope. The restructuring and the larger scope have already been discussed in previous articles.

Not only the name is longer: from MPG to MPDG
A steady hand and calm considerations: MDR and national legislation
The medical device manufacturer, as the central addressee of the law, is confronted with a number of changes. He must evaluate their effects in detail for his company, his products, their further development and his comprehensive innovation policy. For many a highly innovative start-up, this can also become a question of principle. To make matters worse, some effects will probably only reveal themselves in the concrete implementation details. A close look and good planning are therefore advisable.

The focus of all regulatory and legislative efforts at the European and national levels will be on the safety and performance of products in their clinical use. Appropriate clinical data for the medical device in question are required for proof. Unfortunately, the inclusion of data from “similar” products is becoming less and less successful due to the narrower equivalence approach in the MDR. This means that own clinical data must be generated for the own medical device. In addition, clinical data must continue to be collected for the post-marketing period.

Clinical data is the magic word. And that’s why clinical trials that deliver precisely this required clinical data as efficiently as possible will increasingly become the focus of manufacturers. We already reported on the handling of clinical trials in the last article. The MDR requires clinical trials for class III products almost without exception. But for all other medical devices, too, it will often only be possible to generate suitable data in a study. Increasingly, manufacturers will also enter the ring again for product developments and then have to contend with the regulations that apply to products with CE marking when studies are conducted. All in all, patient-relevant data sets are at the center of attention.

Manufacturers should therefore address the issue of clinical data and trials sooner rather than later – especially for existing products.

It is therefore not surprising that a considerable part of the MDR and now also of the MPDG concerns the topic of “clinical trials”. We would like to try to shed some light on this and in one of the next blog posts we will focus on the changes of the MPDG with regard to clinical trials. In doing so, we will highlight a few aspects that we think need our attention, as they could impact the type or duration of procedure and thus cost the manufacturer valuable time to approval.

The changes we would like to address concern, on the one hand, the area of classification of various clinical trials (keyword “Other Clinical Trials”) and, on the other hand, the area of approval procedures.

Let us first address the application procedures for clinical trials according to MDR Art. 62:

The most obvious change in the application procedure for a clinical trial is the newly introduced sequential processing by the responsible institutions: First, the application is processed by the ethics committee and then by the BfArM.

The MDR only regulates the requirements at the beginning of a clinical trial:

MDR Art. 62 (4) a) Approval by national authority
MDR Art. 62 (4) b) positive vote of the ethics committee.
A sequence is not specified nor required, parallel processing is possible. It is even explicitly left to the discretion of the member states which procedure they choose (MDR Annex XV Chap. II No. 4.2).

In the MPDG, Section 38 (1) Sentence 2 stipulates that the vote of the ethics committee should be part of the application to the BfArM – and thus the entire procedure is stretched forward.

How is this sequential procedure regulated in detail by the MPDG on the basis of the MDR?
regulated in detail?

Regarding the application procedure and the processing of the application, the MDR provides a time window of 10 days for the BfArM to check the competence and completeness of the submitted application (MDR Art. 70 [1] Sentence 1). If documents are to be submitted subsequently, the manufacturer/sponsor is given a maximum of 10 days to provide them (according to MDR Art. 70 [3]). After that, the BfArM has another 5 days to again determine completeness. Since only one subsequent request is possible, this results in a maximum duration of 25 days until the start of the substantive review of the application – if all regular deadlines are exhausted.

The MDR further provides that at the national level, an extension of the deadline for subsequent submission of documents from 10 to up to 30 days is possible. Furthermore, the MDR offers a further extension of all deadlines mentioned so far (MDR Art. 70 [4]) by up to 5 days each. The latter seems to us not to be formulated precisely, because a reference to this 5-day extension would only make sense for the examination deadlines of the BfArM, because the subsequent submission deadline has already been taken into account with the 20-day extension.

If the competence and completeness are determined by the BfArM, the applicant will be informed – or not. According to MDR Art. 70 (5), the so-called validation date is set at the latest with the expiry of the above-mentioned deadlines, even in the absence of a response from BfArM.

The deadline for the next phase of the approval process – the actual substantive review of the application – begins with the said validation. MDR Art. 70 (7) b) specifies 45 days for this deadline, which can be extended by 20 days at national level if external experts are still consulted on the part of BfArM. However, this only applies to certain higher risk classes. Clinical trials for products of lower risk classes can already be started immediately after validation (MDR Art. 70 (7) a) (assuming a positive vote of the ethics committee). More on this later.

If BfArM requires additional information from the applicant when reviewing the application, the 45-day period is suspended until the information is received (MDR Art. 70 [6]) – and without any limit on the number or other restrictions. Here, only practice can show whether this opening clause leads to non-calculable approval procedures.

How are the requirements of the MDR implemented in the MPDG in the Federal Republic of Germany, how are the design options provided by the MDR exploited?

Here, MPDG § 31 is already surprising:

An additional 10-day “objection period” is introduced for clinical trials that may already be started after the validation date (§31 (1) 1.). It remains unclear what will be checked during this period on the part of the BfArM, which could then lead to an objection by the BfArM. This is because completeness has already been confirmed (=validation) and a substantive check is not provided for under MDR and under MPDG only for the correct application of the classification rule (MPDG §39 (3)). In the case of the latter, it can be discussed from our point of view whether this should not be checked beforehand. However, it is more problematic that currently it is not explained what happens after such a contradiction.
In addition, the division of the risk classes for which a substantive review is to take place is changed: While the MDR still leaves validation for class IIb (non-invasive), the MPDG requires a full approval process for clinical trials on such devices.
There are no procedural instructions for the review of the application by the ethics committee in the MDR, which deliberately leaves this to the member states. In the MPDG, this is extensively made up for.

After the sequential arrangement of the two application reviews has been established for the Federal Republic, the Ethics Committee must inevitably first review the completeness and regularity of the application. The MPDG (§34 [1]) does not specify a deadline for this. It merely states that if additional documents are requested, the applicant is granted a period of 10 days (§34 [2] sentence 1).

Unfortunately, the second sentence of § 34 [2] also states that the 10-day period for the Ethics Committee to notify completeness does not begin until after the last document received, resulting in compliance. In practice, there will probably always be subsequent requests. Regarding the total duration of the review by the Ethics Committee, this is another unknown.

A time limit for the actual review and consultation by the ethics committee is created by MPDG § 36 in interaction with § 35 (3): The regular period until the vote is 30 days. This period is suspended if the applicant requests additional documents. An individually defined deadline is set for this, but this can be a maximum of 45 days. A clear limit is set by the fact that the EC can only request documents once. The consultation of experts by the EC also has a lengthening effect, but here we are talking about a maximum of 15 days.

Since the MPDG itself does not provide any further details on the time frame for the application procedure at the BfArM, it can be assumed that the above sequence according to the MDR – including a renewed check for completeness – will be implemented in practice by the BfArM.

As an interim summary, it remains to be noted from our point of view that the deadlines for processing by the ethics committee of 60 days and by the BfArM of 30 days, which were previously regulated in the MPG, have in part been shortened in the MPDG – but now with sequential processing. Although the processing times have changed, it is possible that the processing time will be considerably longer than before, in particular due to the almost unlimited possibility of requesting additional documents or information. It remains to be seen to what extent ethics committees in the preliminary review or the BfArM in the main review will make use of the current right to make multiple subsequent requests for information. It remains to be hoped that, if possible, important components and aspects of the application will only be reviewed by one institution, which is indicated by § 39 (1), and therefore possibly no excessive loss of time will occur overall in the sequential execution. Similarly, it is hoped that not all deadlines will be exhausted.

Moving risk class IIb (non-invasive) products into full application review will likely trigger discussions about classification. Together with the possibility of objection by the BfArM in case of a different opinion regarding the risk classes chosen by the manufacturer with unclear legal consequences, resentment is pre-programmed.

A great deal of patience is demanded of the manufacturer of highly innovative medical devices anyway, since the complete technical file, including all test reports, must already be available before the application for the test is submitted, and after the clinical trial has been approved, it must also first be carried out. And this is followed by the processing time of the Notified Body, which is currently 6 to 12 months for certification. In this respect, it would (have been) desirable that no further stumbling blocks are placed in the way of a clinical trial during the approval process. A conscientious examination of the content of all aspects required in the MDR is undoubtedly a sensible measure and leads to confidence among patients and users. But hurdles of a more formal nature should not be erected.

Now, does the new federal German law fulfill its intended purpose of implementing the EU regulations for clinical trials at the national level? Have clarifications and interpretations been provided at the points required by the MDR that are prudent and conducive to innovation? Or have detailed regulations even created additional hurdles for medical device manufacturers and their products?

We definitely see some things in the practical implementation as critical. However, it remains to be seen how this will play out in actual regulatory life. After all, there is not yet much experience with the new regulations, not only among medical device manufacturers, but also among the higher federal authority and then subsequently the notified bodies. It also remains to be seen whether there will be any innovations or changes in practice at the level of the ethics committees.

Here at seleon, we are concerned with many other aspects of clinical data. We are observing the new regulations in daily, practical life and what trends can be identified. Therefore, you can already look forward to our follow-up article “Other Clinical Trials”, which will then be dedicated to specific issues, so that you know how the hare runs.

Please note that all details and listings do not claim to be complete, are without guarantee and are for information purposes only.