Medical device manufacturers are no doubt aware of the seismic impact the EU Medical Device Regulation (MDR) and the EU In Vitro Device Regulation (IVDR) will have on the medical device regulatory environment. On the other hand, pharmaceutical companies producing combination products or companion diagnostics may not have a clear idea of the effect of these new regulations on their products. However, under the new regulations, no medical device will escape regulatory scrutiny, regardless of whether its function is central or ancillary to the product.

The lack of any clear regulatory requirements for these device elements in the past means that many pharmaceutical companies are likely to be unfamiliar with the process of achieving medical device compliance and might have to liaise with a notified body for the first time. It is therefore vital that pharmaceutical companies read up about the implications of this regulatory upheaval now in order to meet the upcoming deadline for EU MDR and EU IVDR compliance in May 2020 and May 2022, respectively. Failure to achieve compliance on time will potentially provoke an immediate removal of noncompliant products from the market, causing an avalanche of negative repercussions on any affected business. With these high stakes in mind, this article covers the most essential points and challenges around the regulations for combination product and companion diagnostic manufacturers and provides guidance on the first steps pharmaceutical manufacturers can take toward a timely compliance.

Weathering The EU MDR Storm

Combination products may be composed of any combination of an ancillary drug, a device, or a biologically active product. Particularly affected by the EU MDR are products in which the drug component is principal to the function of the combination, which are currently regulated as medicinal products under the EU Medicinal Product Directive 2001/83/EC (MPD). Some examples of products where the device serves as the applicator of the integral drug component are insulin injector pens and metered dose inhalers. With medical devices becoming increasingly complex, it stands to reason that these devices would be more strictly regulated. For instance, sensors within “digital pills” that track the delivery of the drug throughout its ingestion by the patient require total safety regulation for clear health and safety reasons. Going forward, pharmaceutical companies will therefore be subject to regulatory oversight for both the device and medicinal parts of their combination products, rather than solely having to liaise with national Competent Authorities (CAs) for authorization.

Under the EU MDR, all medical devices need a CE mark to stay on the market. Given that manufacturers of these types of products did not previously require such strict proof of compliance for the ancillary device component, it is probable that they will lack the data required to submit an updated clinical evaluation report and will therefore need to carry out fresh clinical testing. With such evaluations taking time and money, it is strongly encouraged that manufacturers start assessing early on what data they already have and what they are missing. Manufacturers have until May 26, 2020 to gather the relevant data for submission and achieve compliance. Pharmaceutical companies are therefore urged to invest resources into this process, particularly the first time around, in order to guarantee a successful submission and facilitate the task of keeping clinical data up to date and easily accessible for the future. It is worth noting that drug device combination products already holding a CE mark under the current Medical Device Directive 93/42/EEC (MDD) can benefit from an extended deadline, until May 26, 2024; however, no changes can be made to these Class III devices unless they are recertified under the EU MDR.  This only applies if the manufacturer holds a valid EC Certificate under the MDD.

Similarly, liaising with a notified body will be a new experience for manufacturers of combination products regulated as medicinal products. Currently, only five notified bodies have been designated under the EU MDR. Manufacturers must be aware that these organizations are under severe pressure and will be submerged in pending documentation reviews. Considering these constraints, it is worth manufacturers getting a head start on their journey toward compliance before the few available notified bodies find themselves at full capacity and unable to review documentation in time for the upcoming deadline.

The specific part of the regulation requiring this regulatory inspection of the device component of combination products is Article 117 of the EU MDR. Providing an amendment to Annex I of the EU MPD, Article 117 requires pharmaceutical companies producing products currently regulated as medicinal products to include proof of conformity of the device component within their submitted marketing authorization dossier. This documentation can take two forms: manufacturers can either (1) present the results of the conformity assessment of the device part in accordance with the requirements of Annex I of the MDR or (2) submit the certificate issued by a notified body, allowing them to affix a CE mark.

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IVDR On The Regulatory Horizon

Companion diagnostics will also be subject to new kinds of regulatory inspection, as stipulated in the In Vitro Diagnostic Regulation (IVDR) about such products. The IVDR introduces a new risk-based classification system for in vitro devices. Devices can fall into one of four categories, where Class A represents the lowest risk and Class D, the highest. Under the EU IVDR, companion diagnostics will fall under Class C and will therefore undergo a high level of scrutiny from notified bodies as well as tighter clinical requirements, particularly for pharmaceutical companies developing their own companion diagnostics. Companion diagnostics are IVD devices that serve to strengthen the safety and efficacy of the medicinal product, by determining which patients would most benefit from a corresponding medicinal product or which patients are likely to be at risk of serious adverse effects. Given the co-development of the IVD device with its associated medicinal product, the IVD notified body will also need to liaise with a medicinal CA.

Presently, there is not a single notified body designated under the EU IVDR, and fewer organizations are awaiting designation than for the EU MDR. It is crucial that manufacturers begin to research which notified bodies are awaiting designation to certify their specific type of device. Pharmaceutical companies are therefore not only waiting to receive certification from a notified body, but also for these notified bodies to be designated for companion diagnostic conformity assessments under the IVDR. As with the EU MDR, both collecting the necessary documentation and data required for submissions and liaising with a notified body represent uncharted territory for pharmaceutical companies. Companies manufacturing companion diagnostics should therefore get started with their regulatory obligations, particularly given the current shortage of notified bodies.

While most medical device companies will have investigated and initiated their necessary compliance routes with the EU MDR deadline in sight, pharmaceutical companies are less likely to have given such attention to these new regulations and the impact on the ancillary device/IVD components of their products. Given the EU MDR and the EU IVDR’s impact on combination products and companion diagnostics, pharmaceutical companies will be just as affected as medical device companies and will have to build their clinical documentation from the ground up in many cases. Pharmaceutical businesses should act now or be prepared to face the negative consequences of noncompliance on their product as a whole, namely the loss of market access and devastating reputational losses for the company.

About The Author:

Elizma Parry is director of the Global Clinical Practice at Maetrics. She brings over 25 years of experience, providing clients with expert counsel in the clinical practice environment. Parry has a strong track record of clinical safety, regulatory, and quality management experience. Before joining Maetrics, she was in a shared acting role as the head of a Europe-based notified body, while also managing a multinational clinical team within the notified body that was responsible for the clinical safety, performance, and clinical benefit conformity assessments of medical device manufacturers’ clinical evidence, as well as the clinical lead for liaising with the MHRA.

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