Navigating a Regulatory Path to Market Through EU MDR Article 117

The regulatory framework outlined in EU Medical Device Regulation (EU MDR) Article 117 to bring drug-device combination products to market remains subject to interpretation. Key stakeholders including manufacturers, notified bodies, and regulators continue using their own perspectives to interpret the framework and how it can be used to bring combination products to market in a timely and effective manner.

[Related: Learn more about the EU MDR by downloading the recent Redica Systems virtual panel discussion featuring author Mark Agostino and medical device expert Alison Sathe as panelists.]

Questions persist, however. Which products fall under Article 117 requirements? Should a CE certification be obtained for the device constituent? How does the Notified Body Opinion (NBO) integrate with the EMA review of a dossier? What is the best regulatory strategy for a device technology that can deliver multiple medicinal products?

At the RAPS Euro Convergence Conference, held virtually from May 10-12, 2021, four speakers discussed Article 117 in light of the then-upcoming date of application for EU MDR on May 26. The speakers on the topic were:

• Ypsomed AG Regulatory and Quality Intelligence Manager Stephen Affolter (medical device component manufacturer)
• MSD BV Medical Device Regulatory Affairs Liaison Veronica Gonzales (combination product manufacturer)
• TUV SUD Japan Ltd Medical and Health Service Director Julia Frese (notified body)
• European Commission Policy Officer Nada Alkhayat (regulator)

This range of speakers provided a holistic perspective with insights from industry, a notified body, and the regulators on their experience in dealing with Article 117.

European Commission Perspective

Alkhayat presented on how to correctly interpret EU MDR as it relates to Article 117. Article 117 provides a reference to Article 1(8) and Article 1(9) to determine if a product clearly falls under the requirements of Article 117. She explained that key stakeholders of an Article 117 task force composed of participants from industry, notified bodies, EMA, and European Commission regulators met regularly. This group struggled to clearly interpret the regulations as they relate to Article 117. She mentioned that their first task was to “break it down and see where there are differences in interpretation for certain words in Article 1(8), Article 1(9), and Article 117.” 

Figure 1 presents two pathways interpreting Article 1(8) and Article 1(9) in order to determine if a product falls under Article 117. She described a method of a “process of elimination.” By this, she would follow the language in Article 1(9) to decide which combination products are “intended to administer a medicinal product” and follow Article 1(8) to determine “which actions are principal or ancillary.”

A key point emphasized in the presentation is the distinction between an “integral product” and “single integral product” and when they are “put on the market” versus “put into service.” As she pointed out, there is “minimal difference” between “integral product” as opposed to a “single integral product.” But what about co-packaged products? For these products, the point at which the device and the medicinal product are combined matters for determining if the product falls under Article 117. A co-packaged product that is combined as it is “put into service” would not constitute as falling under Article 117.

Notified Body Perspective

Frese presented the perspective of a notified body in giving assessments when dealing with Article 117. TUV SUD has been providing the assessments since February 2020. Some of the benefits of their work have helped EMA gauge the risk of a device through device classification, including a summary of the risk assessment as well as providing the EU MDR Annex I General Safety and Performance Requirements (GSPR) in a tabular format in support of their decision. 

In her experience, she sees manufacturers “struggling” with providing the appropriate justification of the applicability of GSPR. For each GSPR that is considered applicable, the manufacturer must “present the data” that supports meeting the requirement.

A co-packaged product that is combined as it is ‘put into service’ would not constitute as falling under Article 117

Other discussions she has had with manufacturers have centered on assessing key features of device design toward identifying the relevant GSPR. Lastly, another topic of debate with manufacturers is shelf life. She concluded that this has introduced problems because the notified body’s assessment has not been “foreseen by the manufacturer.”

Supplier Perspective

Affolter provided the perspective of a medical device part supplier for a drug-device combination product. Figure 2 shows the regulatory pathway to approval for a drug-device combination product according to Article 117. This has become more detailed in comparison to the process laid out under the previous Medical Device Directive.

In describing some of the challenges, he points out that “the process works but is not always smooth,” and parallel review of the medical device and the medicinal product is not possible at this present time. He emphasized that there is no coordinated approach, thus, manufacturers will have to gain experience with each notified body. This can also present issues with different notified bodies providing different nuanced assessments of the same device technology. Affolter mentioned that the industry has debated whether the assessment of the notified body should be for the final product versus the device part. 

He offered one possible means to improve the review of the medical device part: consider using a CE mark versus an NBO. The logic being to address the medical device separately by obtaining the CE mark, and then proceed with subsequent CTD review of the drug aspect of the product.

Industry Perspective

Gonzales provided her experience as someone in the industry in dealing with 117. She also used a platform approach to streamline the approval process for drug-device combination products. In particular, she presented some points of improvement for managing the NBO process.

One issue that is commonly known in the medical device industry is the difficulty in contracting with a notified body and securing the necessary time for review and interaction with the notified body. With no standard established among the MDR-certified notified bodies in regard to Article 117, there is variation among the notified bodies for documentation review expectations and timelines.

In her experience, she sees manufacturers ‘struggling’ with providing the appropriate justification of the applicability of GSPR

This has led to frustration and a lack of clarity as manufacturers embark upon the process to secure an NBO. Lack of clarity issues involving the documentation includes what is reviewed by a notified compared to what is reviewed by EMA. In some instances, such as risk management and clinical evaluation documentation, the documentation is reviewed by both given their criticality in the approval of the drug-device combination product.

A Platform Approach

In addition to presenting the challenges to securing an NBO, Gonzalez described a platform approach for a single device with multiple medicinal products. A reference was made to a European Federation of Pharmaceutical Industries and Associations (EFPIA) reflection paper by Amgen’s Andrew Lennard, “EFPIA Reflection Paper on Integral Drug-Device Combination Product Platform Approach.” This article presents a thorough explanation of the possible platform approach options for integral drug-device combination products.

As described in the article, the primary benefits of the platform approach are:

• Reduced risk in prolonging submission timelines
• Streamlined duplicate reviews of documentation for the same device and drug-device interaction information
• Reduced likelihood of multiple requests for information on the same aspect of the medicinal product by the NB and competent authority 

The platform approach can be used in one of three forms as shown below in Figure 3. This could potentially benefit a manufacturer in navigating the challenges with Article 117.

For the options shown in Figure 3, option 1 and option 2 are closely related. Option 1 would be applicable for a general use medical device that has secured an NBO that could be used with different medicinal products. Option 2 would be for a specific integral drug-device combination product that an NBO has been obtained for and is used with different medicinal products.

To successfully execute either of these options, similarities in the characteristics of the medicinal products, the intended uses, and the applicable GSPRs would need to be justified to support these options.

The practical benefit can be quickly realized and the logic in the approach is easily understood. For a manufacturer that would like to use a certain device technology in conjunction with multiple medicinal products, this clarifies the roadmap for the development and regulatory submission process for integral drug-device combination products.

The logic in option 3 is for a new integral drug-device combination product to build upon an existing NBO secured integral drug-device combination product. In essence, the NBO for the new integral drug-device combination product would be an assessment of the delta between the new integral drug-device combination product and for an existing integral drug-device combination product of the applicable GSPR and drug-device interaction information. 

With the appropriate planning and regulatory strategy, the existing challenges in managing notified bodies can be mitigated through these options for manufacturers.

Conclusion

Industry, notified bodies, and regulators are working through the process of becoming more familiar with the requirements for Article 117. There will be continued improvement as notified bodies and regulators become more experienced and work toward standardizing the submission and review process for drug-device combination products. At the same time, there are innovative regulatory strategies in using a platform approach that would be beneficial to a manufacturer trying to bring multiple medicinal products to market using the same device technology.

[Related: Author Mark Agostino addressed EU MDR Article 117 requirements during the virtual panel discussion, “Changing Medical Device Regulations,” which can be downloaded here.]