MDR Article 117 – a look into the Crystal Ball (Part 1)
The MDR recently celebrated its first birthday and still a lot is unknown. This is especially true for manufacturers of those combination 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 (www.topra.org) 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 level “low” to a guidance regarding combination products and companion diagnostics in their roadmap (see https://bit.ly/2JoAaWc). 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!
#MDR #Article117 #CombinationProducts #TOPRA
Quality Product Steward @ Bayer | Expertise in combination products, medical devices and pharmaceutical packaging
6 年Beat, I like your article. I also had a couple of discussions about that matter in the past months. In summary, we could conclude that from today's perspective there are no significant new requirements when it comes to development and documentation of such a product. In the past, as you mentioned, the need to have evidence that the relevant essential requirements are fulfilled was already in place. Therefore this documentation should already be in place. Also in the past, there could have been a review of this documentation, e.g., as part of a quality inspection or during the review of the dossiers. And my understanding is that for some products (injection pens) this has been done from time to time. However, I also understood that at least some competent authorities were not that experienced and comfortable with such kind of documentation. The main difference is now that an NB would review the documentation. This leads to timeline risks as in future the NB involvement would probably be done before submission of the drug and with start of this process, the NBs might be pretty busy with other activities. This is from my perspective the main issue. Of course, if the compliance with the MDD for specific products was already insufficient, then now there is even a more significant issue. And to some extent, the article 117 can be interpreted in a way that it could also be applied retrospectively. Otherwise, it would not make sense that the article 117 differentiate between "the marketing authorisation dossier shall include" and "If the dossier does not include".
Serving the medical technology industry in Europe
6 年Also bear in mind that Notified Bodies need to be designated under the MDR before they can undertake (or even start) this work. There are severel dozen Notified Bodies designated under the MDD but that gives them no automatic legal status as Notified Bodies under the MDR. Several organizations have applied to become Notified Bodies under the MDR, but none are designated yet, and the process takes several months. Drug-device combination product manufacturers need to navigate this uncertainty as May 2020 approaches, just like manufacturers of "normal" medical devices.
European Editor at International Pharmaceutical Quality
6 年Perfect timing Beat! Please do contact Serge Mathonet, who is leading the European Biopharmaceutical Enterprises initiative on DDCs and Article 117. A proposal for a workable procedure for incorporating an NB opinion in an MAA is in final stages now. EBE are also reaching out to other industry groups to join in aligned communication with regulators - working together will really help things move forward efficiently. Very glad to say Mark Chipperfield is already actively involved! Some more great news is that the EMA QWP/BWP group working on EMA guidance are proactively participating in dialogue with industry now - in preparation for the stated goal of publication of draft guidance in Q4 2018. The EMA BWP (Biologics Working Party) have an Interested Parties meeting at EMA June 18 and the DIA CMC Workshop in Basel June 20-21 also have two sessions on DDCs, well supported by EMA on the planning committee and with Nick Lee from the QWP (Quality Working Party) DDC group participating. He is speaking and will be available over both days to listen to stakeholders. Bassil Akra will also be speaking, so anyone interested in this topic - please make the most of these and other opportunities to engage in discussions over the next few months!
Founder, Chairman and Principal Consultant
6 年Thanks! I tried not to take anybody's position here but encourage pharma and biotech companies to be pro-active and get prepared rather than wait for input that may come late. The only thing they can directly influence is what is on their plate which is basically get their technical documentation ready and initiate discussions with their NB. I simply don’t see how the industry and notified bodies will obtain a clear feedback from the authorities about their expectations in the near future. If it happens I’m the first one to applaud! As you know, evidence regarding compliance with Annex I was already required under the MDD but to be frankly honest our clients rarely got questions regarding this part of the submission. Now the medicine competent authorities will get at least an independent opinion which (again in my opinion) is a step in the right direction. Regarding a possible format and Content of such an opinion, I will provide input in one of the upcoming posts. There are existing processes at NBs that can be leveraged but may require adaption. Again, the overall intention was to provide some insight concerning ongoing discussions and interpretations from various stakeholders, not to influence it. Many pharma and biotech companies are not familiar with conformity assessments / CE marking and my hope was that they benefit from this input.
Dealing with prostate cancer and keeping busy doing nothing.
6 年I think you indirectly expose one fundamental point throughout your opinions here - and that is the pharma consideration for an appropriate process is being almost totally disregarded. The nature of an integrated Medicinal Product makes it an interacting system, and any NB review of the delivery device constituent must suitably integrate with review of the medicine. This is of course is not unlike the handling of a medical device with ancillary substance where two bodies review two parts. Yes, the Notified Bodies who will pursue this area of business will need processes to support the granting of an opinion - however the pharma customer of that fee-for-service offering needs an appropriate output that is ultimately acceptable to the medicine Competent Authority, reviewer or rapporteur. This is the basis of many of the questions from industry, who are reluctant to ‘be pro-active’ and mis-judge this important deliverable. Delayed product approval is not just painful, but costly, public and can affect investor relations. Therefore clarity is sought to minimize that likelihood. This discussion is not all about how NBs should address the requirement. This is now a Pharma requirement via the MPD amendment created in Article 117.?