Many thanks to all of you who provided their feedback to Part 1, 2 and 3 of this series of articles – highly appreciated and overall a lot of great information for all stakeholders!

Flaschback: 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. As in part 1 and 2, please find below the respective text form the TOPRA articles (italic) and my interpretation / suggestion:

Labelling. The current situation is that medicinal product devices carry labelling and markings that satisfy the medicinal product legislation only. It is anticipated that this would not change.
Clarification is required on the expectation for the labelling and use of symbols on medicinal product devices.

Since the combination product is regulated as a medicinal product according to the MPD, labeling requirements of the MPD should indeed take precedence over those listed in GSPR 23. However, I disagree that the labeling should satisfy medicinal product legislation only. While this may be acceptable for very simple products it may not appropriate for very complex devices (e.g. those containing electronics and software). Respective standards (such as but not limited to e.g. EN 60601-1 concerning electrical safety as well as EN ISO 11608-1 concerning needle-based injection systems) have specific clauses regarding labeling / instructions for use which are important regarding the safe use of the device. The same is valid for residual risks that are an outcome of the risk management process according to EN ISO 14971.
Applying only the medicinal product legislation would result in a situation where drug/device combination products regulated as medicinal products are labelled very differently (with regard to the device part) from those regulated as medical devices. This doesn’t make sense and can’t be in the interest of safe products for patients and other users.
I strongly suggest that it should be made clear which of the sub-clauses of GSPR 23 don’t apply and UDI is definitely not among them!

Notified body expertise.It is recognised that for many pharma companies without CE-medical devices in their portfolio, the Article 117 requirement will introduce new commercial arrangements and a need to interact with an NB as a service provider.
Similarly, device developers are typically used to either following CE-medical device approval routes or having their pharma company customer make the submission under their own assessment of satisfying Annex 1 requirements. They will now potentially need to form a slightly different relationship with an NB; or perhaps even select a different service provider to address this specific area.
In evaluating and selecting a suitably-qualified NB, an applicant should be seeking relevant capabilities specifically in reviewing medicinal product devices (as opposed to CE-medical devices), and in understanding medicinal products, drug delivery and drug-device interaction.
Currently, the November 2017 Notified Body Operations Group (NBOG) Best Practice Guide: “Applied-for scope of designation and notification of a Conformity Assessment Body” (NBOG_F_2017_3_ MDR) does not appear to identify a specific designation code for expertise associated with review of “Single integral medicinal products which are intended exclusively for use in the given combination and which are not reusable”.
It is strongly recommended that NBOG considers the need for specific designation code(s) for those bodies that have built valuable experience in the review of integrated drug-device products.

Given the vast number of different (medical) devices which is growing day by day, a categorization can’t be avoided; otherwise a designation process for NBs would hardly be possible. There are drug-delivery devices which are CE marked (e.g. insulin pumps, pen-injector with replaceable cartridges) and there are scopes for these products. If a NB is designated for said scopes, he also needs to have the required expertise. I was part of joint assessments under the MDD and the requirements for product experts defined by the authorities are high (several years of practical experience in the respective scope).
It is also important to understand that several scopes may apply for one product. For a (hypothetical) electronic on-body injector, the following may apply (depending on the specific embodiment):
– MDA 0306: Active non-implantable devices for extra-corporal circulation, administration or removal of substances and haemapheresis
– MDS 1005 Devices in sterile condition
– MDS 1009 Devices incorporating software / utilizing software / controlled by software, including devices intended for controlling, monitoring or directly influencing the performance of active or active implantable devices
– MDT 2002 Devices manufactured using plastic processing
– MDT 2007 Devices which require knowledge regarding the production of pharmaceuticals
– MDT 2008 Devices manufactured in clean rooms and associated controlled environments
– MDT 2011 Devices which require packaging, including labeling
A NB needs to be designated for all the above scopes to provide an opinion for said on-body injector.

Notified body and medicine competent authority communication. A key question is whether there is any requirement for direct communication between the NB and the medicines CA, during the generation of an NB opinion.
In this specific scenario, the authors feel such communication is not seen as necessary and clarification to confirm this would be welcome.
According to the text of the MDR, the NB opinion is to be provided by the applicant. This is interpreted to mean simply the opinion, ie, a certificate or similar.
It is anticipated that detailed review reports would be retained by the applicant, for inspection by a medicines CA; and could be summarised or discussed during MAA review. This model is analogous to using a CE-medical device with a medicinal product and submitting the CE-certification. Confirmation of this interpretation would be extremely welcome.

Article 117 defines that the applicant needs to obtain an opinion and provide it to the medicines competent authority. As per the article, no direct communication is foreseen between the NB and the medicines competent authority. This would also ensure that the applicant is always informed in case one of the other two parties requests information.

“Negative” notified body opinion. Some thought needs to be given to how manufacturers should handle NB opinion assessments that result in a negative outcome. It is not clear how a negative outcome should be communicated. This could simply be verbal; refusal to issue a certificate; or it could be the issuance of a “negative statement” for the record.
Guidance regarding communication of negative outcome is needed to ensure consistency across NBs.

For products to be CE marked, NBs usually provide the applicant with a report summarizing the assessment and the outcome, regardless of whether this is favorable or not. In case the outcome is negative the report usually states the specific deficiency/ies. In the absence of specific guidance, this is what NBs will most probably do.

Visibility of outcome. There are several potential considerations for the obligation to make an NB opinion publicly “visible”.
Clarification of any expectations in relation to this would be welcomed in advance by industry.

The relationship between a NB and an applicant is purely business related and the NB is required to keep all information confidential. In the absence of specific regulatory requirements, NBs will not share any information regarding the opinion with third parties.

Leveraging of an NB opinion. For some applicants, there may be benefit in being able to leverage an opinion into subsequent products using the same technology.
For cases where the medicinal product device is identical or very similar to that reviewed in a prior submission, any prior opinion could be upheld to also apply to the new combination, while recognising and reviewing any changes.
The “platform” approach to medicinal product devices is common and supporting mechanisms for simplified subsequent NB opinions should be enabled.

Since the NB is a privately owned company/body, it’s at his discretion to develop specific internal procedures that will support such approaches. The NB is then responsible to defend the chosen approach during a re-designation process and/or joint assessments and provide objective evidence why the new opinion covers all relevant GSPRs for the new configuration (including but not limited to indication(s) and user population).
If the prior opinion was issued by another NB, I doubt this will be possible. For CE marked products, NBs are normally not encouraged by the local competent authorities to accept conformity assessments done by other NBs and I doubt this position will change with regard to Article 117.

Maintenance of status. There is a lack of definition of the requirements for maintenance of the “status” associated with an NB opinion.
Clarification would be beneficial in the context of post-approval change, post-market surveillance and facility inspection/quality systems audit.
A further point relates to the process needed to reconfirm an existing NB opinion. Our working assumption is that in taking full responsibility for the product approval based partly on the NB opinion, the CA would only question or review the opinion if informed of significant changes or issues related to the medicinal product device. It would then seem reasonable to have the NB conduct a further review if the relevant expertise did not reside within the medicines CA.
For such cases, confirmation would be welcomed that the CA would contact the applicant/licence holder and request an update of the NB opinion.

The opinion defined in Article 117 is something that needs to be obtained once and provided to the medicines competent authority as part of the marketing authorization dossier. According to my interpretation there is no need to “maintain” this in any way. However, this does not mean that the applicants should not improve their combination products based on post-market surveillance activities (e.g. complaints), on the contrary!
What is clearly not defined is how changes are handled. I personally consider this as one of the most important topics that requires clarification / guidance.

Remediation of marketed products. The approach for products that are currently approved and marketed appears unclear.
Clarity is needed that “remediation” of such products (ie, implementation of NB opinion where none exists) would not be required, since medicines CAs have already reviewed such products to grant approval(s).

According to my interpretation, no opinion is required for legacy products. If there is no new marketing authorization application, no opinion is required after the date of application. What remains unclear is how changes to such products are handled (see also previous topic).

More to follow in Part 5… Keep your eyes open!

Again, 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

#MDR #Article117 #CombinationProducts #TOPRA