The MDR recently celebrated its first birthday and still a lot is unknown. This is especially true for manufacturers of those combined products that are regulated as medicinal products (e.g. needle-based injection systems such as certain auto-injectors, patch-injectors etc.) but now are required to obtain an “opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to the MDR issued by a notified body designated for the type of device in question.

In May and June 2018, TOPRA ( published two highly interesting articles written by Mark Chipperfield and Tim Chesworth that list a number of concerns and open questions that require clarification. However, time is running out and I strongly suggest that marketing authorization applicants act pro-actively in order to not lose valuable time. Don’t wait for the questions to be answered! There are many stakeholders involved which let me doubt that clear requirements will be defined in a timely manner. My opinion is also based on the fact that the CAMD (Competent Authorities for Medical Devices) assigned the priority “low” to a guidance regarding combination products and companion diagnostics in their roadmap (see Not really encouraging but I also hope that time will prove me wrong!

Because of our vast experience and proven track record, confinis is currently consulting several Notified Bodies with regard to the interpretation of Article 117 and to develop respective documented procedures and templates. While I share most concerns of the authors of the TOPRA articles and would be happy to see answers to the questions raised, I take the risk and look into the crystal ball in this and some follow-up articles to come over the next days and maybe weeks. Please note that I’m providing my personal opinion on the interpretation based on my 20+ years of experience concerning combination products, because of my expertise as a technical documentation reviewer for a Notified Body and as somebody who is helping Notified Bodies to interpret Article 117. Having insight to some developments behind the scenery definitely helps. For example: in a meeting between the EU Commission and Notified Bodies a few months ago, the Commission clearly stated that Notified Bodies should not interpret the MDR but apply it as it is written. This definitely helps in addressing some of the open questions.

Please find below the respective text form the TOPRA articles (italic) and my interpretation:

Degree of applicability of the MDR to a medicinal product device. As with the MDD, the overarching principle is that the medicinal product device is not to be treated fully as a CE-medical device and will be assessed as part of the medicinal product, while the MDR Annex 1 requirements must be met. However, the extent of applicability of the MDR to the medicinal product device when operating under Article 117 would benefit from further clarification.

Since Article 117 amends the medicinal product directive 2001/83/EC (MPD), the applicability of the MDR (again, in my opinion) is limited to Annex I (General Safety and Performance Requirements; GSPR). This is also what the text in Article 117 says, nothing else.

Quality system. Subject to the risk classification of a CE-medical device there is a requirement to have in place an appropriate quality system, typically as per ISO 13485. This quality system is subject to third party audit to demonstrate the existence of robust processes behind design, development, manufacture and/or quality assurance; and therefore, enables further judgement on ability to comply with the Safety and Performance Requirements. In the case of the Medicinal Product device, the requirements for Quality System are unclear. It is assumed that the need to have an ISO 13485 compliant quality system would not apply. Clarification to confirm this would be welcome.

While I agree that an appropriate quality system is key to meet the GSPR, nothing in Article 117 says that a) a quality system needs to meet EN ISO 13485 and b) that said quality system needs to be certified. Based on the wording, the Notified Body shall provide an opinion on the device part at a specific point of time. Nothing stipulates that a quality system according to a specific standard needs to be established and certified. EN ISO 13485 is a harmonized standard under the MDD and may also be harmonized under the MDR but a standard is not a law. Other state of the art methods may be adequate as well!

Relevant scenarios where an NB opinion is not needed.It is inferred by Article 117 that an opinion needs to be incorporated into the marketing authorisation application for the medicinal product. The authors would propose that an NB opinion of this nature would not be required in the following scenarios:
• Prior to performance of a medicinal product human use clinical investigation.
• Prior to performance of a simulated-use, human factors design validation, summative study.
• Prior to performance of a device clinical investigation.
It is recommended that further clarification be issued to confirm the above, and any other common scenarios that industry may raise.

Again, by reading the article word by word it says that an opinion is required for the marketing authorization dossier which I interpret in the same way as the authors: it’s not required in other cases like those listed above.

Timing for seeking NB opinion. The working assumption is that the intent behind the text is that the outcome of the NB opinion is incorporated into the marketing authorisation dossier at the time of submission. It could be feasible for instance, to perform NB opinion assessment in parallel with dossier review. Confirmation is required of the assumption that the NB opinion assessment is performed prior to the submission of the marketing authorisation dossier.

This is one of the topics where I don’t have an opinion because it’s difficult to guess what is acceptable for the authorities and clarification would really be highly appreciated. On the other hand, the requirement to meet Annex I (GSPR) was already in the MDD (ER instead of GSPR) and sponsors always had to provide evidence regarding compliance. In all submissions where we were involved we provided this evidence as part of the initial submission and obviously doing so in the future is on the safe side. Therefore, plan for it! The “only” difference now is that it is mandatory to involve a 3rd party to provide an opinion.

More to follow in Part 2… Keep your eyes open!

I strongly encourage other professionals involved in this field to provide their opinion and start a lively conversation on this platform – the whole industry can only benefit from this!

by Beat U. Steffen, Founder & CEO of confinis ag