DEVICE REGULATIONS – The New Medical Device Regulation & the Applicability of Article 117 to Medicinal Products
“Those who expect moments of change to be comfortable and free of conflict have not learned their history.” For many involved in the medical and pharmaceutical industries within the past few years, this quote – attributed to American historian Joan Wallach Scott – has never been more true. From the impending switch to the Clinical Trials Regulation to the implementation of the Falsified Medicines Directive, and the evolution of the Medical Devices Regulation (MDR) or the current uncertainty around Brexit in Europe, change is everywhere. With so many new developments in progress, it is almost impossible to keep track of all the required updates to procedures – with a very real risk of missing something critical.
Article 117 of the new MDR, has the potential to be one such pitfall.1 Buried deep within the final chapter of the document, just before the annexes, is the somewhat innocuously titled Amendment to Directive 2001/83/EC. For many medical device manufacturers, this article is likely to be mostly disregarded, as Directive 2001/83/EC – also known as the Medicinal Product Directive (MPD) – has historically not been an essential part of placing a device on the market.2 For companies whose focus is primarily on the MPD – like many pharmaceutical and biotech companies – this update may pass completely unnoticed.
This article is primarily focused with the impact of Article 117 in Europe on the combination of a drug and a device, where the primary mode of action is performed by the drug and the two products are combined in a single, integral product that is exclusively for use in the given combination and not reusable. Some examples of products that would be categorized in this combination include a single-use, disposable auto-injector or a disposable pre-filled metered dose inhaler.
DIFFERENCES BETWEEN US & EUROPE
The US and EU have very different systems for determining assessment routes for drug (or biologic) and device combinations, as shown in Figure 1.
The US refers to these products as combination products and selects a lead division with primary jurisdiction based on the primary mode of action. The other division is also consulted for the relevant aspect of the product.
In Europe, the process is slightly different because the term combination product is not officially recognized – albeit more frequently used, even in the absence of an official “status.” Whilst products are still assessed based on the primary mode of action, this determines one of two primary assessment formats; either medicinal product or medical device.
THE EXISTING SYSTEM
The MPD requires evidence of CE marking when it is applicable but does not detail requirements for non-CE marked devices. Under Article 1 sub-part 3 of the Medical Device Directive (MDD), devices in which “the device and medicinal product form a single integral product which is intended exclusively for use in the given combination and which is not reusable” were governed by the MPD with the additional applicability of the essential requirements of Annex I to the MDD with regard to safety and performance-related device features.3
Devices that do not meet this clear definition were governed by the MDD, unless they were in vitro diagnostic devices or active implantable devices governed by Directive 98/79/EC and Directive 90/385/EEC respectively.4,5
Article 117 of the MDR legally amends Annex I, Section 3.2 point 12 of the MPD as follows:
“(12) Where, in accordance with the second subparagraph of Article 1 (8) or the second subparagraph of Article 1 (9) of Regulation (EU) 2017/745 of the European Parliament and of the Council (*), a product is governed by this Directive, the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer’s EU declaration of conformity or the relevant certificate issued by a Notified Body allowing the manufacturer to affix a CE marking to the medical device.
If the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a Notified Body is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation issued by a Notified Body designated in accordance with that Regulation for the type of device in question.”
For many medicinal products this amendment will not introduce an onerous change as a device that is non-integral to the medicinal product will still need a CE mark with the appropriate conformity contained within the declaration of conformity. The key element of this change applies to integrated, non-reusable products in which the drug element has the primary mode of action. In essence, the device element of a medicinal product – when integral, non-reusable, and intended exclusively for use in the given combination – needs to conform to the Annex I (MDR) general safety and performance requirements without the requirement to be regulated as a CE-medical device.
As part of demonstrating this, a Notified Body opinion must be incorporated into the marketing authorisation application for the medicinal product.
WHAT DOES IT MEAN?
With an increasing shift away from small molecule drugs toward biologics and an increased desire for patient self-administration to reduce the burden on healthcare systems, the option to combine a drug formulation with an integrated delivery device seems increasingly likely. There are some key implications of the Article 117 requirement that will require careful thought and implementation, not least that, as of the date of writing, no decision has been made as to how a Notified Body would issue an opinion on the device element of a medicinal product.
The overall implication of the MDR is that the device element of the medicinal product would not be treated as a fully CE-marked device but the Annex I requirements would still need to be met – as indeed was the case with the MDD. It should be noted however, that Annex I of the MDR has been expanded significantly and as such, it is likely that application for a medicinal product device element would not be dissimilar to that for application of the CE-mark; with the declaration of conformity being the significant omission. This also allows for continuing to handle the product development under the MPD and pharmaceutical practices.
It is assumed that a Notified Body would not issue a CE-mark certificate, and it is probable that a Notified Body would issue some form of report to the manufacturer, detailing an opinion of the conformity of the device. This report could be included either as part of the marketing authorization application or as a separate communication to the competent authority.
The question then arises as to the format of any submission to a Notified Body and the information that would be assessed as part of that submission. For a CE mark applied to a medical device, this information would typically be presented as part of the summary technical documentation (STED) rather than in the appropriate section of the Marketing Authorization Application (MAA) as for the device element of a medicinal product. It is possible that section 3.2.R of the MAA, containing the device elements could be submitted to the Notified Body; however, it is likely that there will need to be some revision of this section to ensure it captures all of the required information. Alternatively, a new section could be created in the application to assess the Annex I requirements separately.
Clarification is also needed as to how a Notified Body would form an opinion on the device element of a medicinal product. Currently, medical devices are assessed on a risk-based principle, with the device classification determining assessment routes and additional requirements. Device elements of medicinal products are likely to automatically increase the risk classification due to the presence of the drug product. It should also be considered that even a device element that would be classed as a class I medical device – and thus subject to self-certification – would still need a Notified Body review and opinion.
Within the submission itself, it is worth considering that the system should not be simply split down the middle between the device element and drug. Whilst it is true that certain elements lend themselves to one route or the other – for example formulation versus material selection – many cannot be assessed in isolation. Certain attributes have relevance to both the drug and device elements. For example, the siliconization level in a pre-filled syringe may be impacted by the drug formulation, but is also key when considering the mechanical forces required to operate an auto-injector, especially over a claimed shelf-life. Therefore, it is important that assessment of any individual element also accounts for the interface and interaction of that element with other parts of the system. This is a critical element where the MAA and Notified Body evaluation may differ in their overall assessment of risk.
Post-market surveillance (PMS) is one of the most significant updates captured in the MDR. There is an increased requirement for manufacturers to take a more proactive approach to PMS and actively assess performance of medical devices once they are launched on the market, rather than purely relying on user feedback. Medicinal products are subject to their own PMS requirements, but it is likely that the device elements of medicinal products would have an increased requirement for PMS in line with the MDR.
Post-approval changes to a medicinal product with an integrated device element would likely need to be captured via the medicinal product variation procedures and would be assessed by the competent authority. It is not clear at which point a Notified Body assessment would be required, although it is likely that significant changes to the device element would require Notified Body involvement. The question arises as to when changes to one element of the product cease to impact on the other element(s) and thus when the requirement for Notified Body opinion would be triggered.
Existing marketed products pose an interesting question under Article 117. The MDR has been very clear that “grandfathering” of existing products is no longer permitted, and new certificates need to be issued for all medical devices in class 2 or higher. The case is not so clear cut for medicinal products and their integrated device elements, as such products fall under the medicinal products system. It is possible that implementation of the MDR would not apply to products previously assessed by a competent authority as part of a MAA. If this were not the case and Article 117 changes were applicable, significant remediation activities would be needed across industry. As with much of the regulatory situation at the moment, the position is currently unclear and may not become so until it is too late to change without significant resource and cost expenditure.
One of the obvious major impacts of the introduction of Article 117 is the need for pharmaceutical companies to involve a Notified Body. This has implications given the other changes in the medical device world in Europe. With the implementation of the MDR and the potential loss of UK notified bodies due to Brexit, notified bodies are currently limited on resource and may not be taking on new clients for the foreseeable future.
Selection of a suitable Notified Body also involves the capability of that Notified Body to assess a specific product type with an increased requirement for that Notified Body to demonstrate the relevant expertise in a product type. The additional complication is that currently, designation of notified bodies under the MDR has not been completed, so it is unclear as to which product codes notified bodies may assess against, which a Notified Body has chosen not to apply to assess, or which are relevant for medicinal products with integrated device elements.
In the regulatory arena, regulations and guidelines are always open to interpretation, and many regulatory professionals have been known to utter the words “it depends” when called upon to clarify. This seems unlikely to change with the implementation of the Medical Device Regulation, especially with regard to Article 117. What is clear however, is that with so much detail currently undefined and likely to remain so until the date of application in May 2020, impact assessments need to be performed, and companies need to have open discussions with notified bodies, if not already started, to ensure that appropriate support is available when needed. The time, effort, and skills required to implement the coming changes should not be underestimated and, as ever, the clock is ticking.
- Medical Device Regulation. Council Regulation (EU) 2017/745
- Medicinal Product Directive. Directive 2001/83/EC
- Medical Device Directive. Directive 93/42/EEC
- In Vitro Diagnostic Directive. Directive 98/79/EC
- Active Implantable Device Directive. Directive 90/385/EEC
To view this issue and all back issues online, please visit www.drug-dev.com.
Louise Place is Regulatory Lead at Cambridge Design Partnership, a full-service product development consultancy based in Cambridge, UK, and Palo Alto, TX. Originally training as a pharmaceutical scientist at Nottingham University, UK, she has more than 10 years of experience in medical device and combination product development with a particular focus on device technical management and regulatory strategy for FDA and EU submissions.
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