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Without careful consideration and understanding, new regulations for medical devices could lead to the withdrawal of combination products from the market.
Editor’s Note: This article was published in Pharmaceutical Technology Europe’s January 2020 print issue.
In May 2017, new regulations covering medical devices were formally published by the European Union (1)-the EU Medical Device Regulation (MDR) and the In-Vitro Diagnostic Medical Device Regulation (IVDR). These new regulations must be implemented by medical device manufacturers by May 2020 and May 2022, respectively; however, as the new regulations address some of the ‘oversights’ of previous ones, some pharma companies may be unaware of the criteria now required of them, which could hypothetically lead to cases of non-compliance.
To discuss the intricacies and potential impacts of the new regulations in more detail, Pharmaceutical Technology Europe spoke with Volke Watzke, EU Medical Devices Sector manager, Domino Printing Sciences, and Elizma Parry, director, Global Clinical Practice at Maetrics.
PTE: Could you briefly run through some of the main aspects of EU MDR and IVDR?
Watzke (Domino Printing Sciences): The key aspect of the EU MDR and IVDR requirements is focused on patient safety. The regulations will improve patient safety by requiring manufacturers to register every medical device (MD) and in-vitro diagnostic medical device (IVD MD) in the European database, EUDAMED. Each device will also be categorized in different risk classes depending on its risk to the patient. Class III is identified as critical risk, Class IIa/b is medium-to-high risk, and Class I is low risk. EUDAMED will link different platforms together and will cover registration information, certificates, vigilance, market surveillance, clinical investigation, and unique device identification (UDI).
The deadlines for the implementation of the EU MDR begin in May 2020. By this time every medical device sold in Europe will need to be registered in EUDAMED. EUDAMED has been postponed by two years due to technical difficulties linking the databases together but this postponement does not impact the legislative requirement to register each product UDI. The next deadline is the coding of Class III medical devices in May 2021. The deadline for coding on the packaging of Class II medical devices follows and then direct parts marking (DPM) if required of Class III medical devices. By May 2025, coding on the packaging of Class I medical devices will be required and DPM marking if required of Class II medical devices. Lastly, in May 2027, coding DPM if required of Class III medical devices.
With regards to IVD, the categorization of IVD MD is also divided into different risk classes. Class D is critical risk, Class C high risk, Class B medium risk, and Class A low risk. The initial deadline for complying with the regulation is May 2022 for registering every IVD MD in the database. The database will include information on the use of the device, the dimensions, the brand name, the product name, and the manufacturing company. A unique device–device identifier (UD–DI) will be required, which includes the Global Trade Item Number, as well as a unique device–production identifier (UD–PI), which includes an expiry date, batch number, and, if required, a serial number.
Parry (Maetrics): Drug–device combination products are either regulated as devices or medicinal products, depending on which component has the main intended use. When the drug element is the main intended use of the product, pharmaceutical companies are responsible for ensuring regulatory compliance. However, in the past, their main focus was the medicinal part of the product. In fact, in some cases, pharmaceutical manufacturers may have been unaware that they were affected by the Medical Device Directive (MDD). For instance, where the device component is considered as packaging, the need to ensure compliance may not have been apparent to pharmaceutical companies unfamiliar with device regulation.
This oversight in relation to device components has now been addressed with the arrival of the EU MDR; a lack of awareness of these new requirements could result in combination products being withdrawn from the market, as pharmaceutical manufacturers are now responsible for ensuring compliance of both the medicinal and device components of their combination products. A three-year transition period for the regulation began in May 2017, allowing manufacturers until May 2020 to review and implement the changes.
PTE: How will these new regulatory requirements impact the industry?
Parry (Maetrics): For drug–device combination products, the key reference point of the EU MDR is Article 117. Article 117 is an amendment to Annex I of the Medicinal Product Directive and specifies that pharmaceutical companies must provide proof of conformity for the device part of combination products (if available) within the marketing authorization dossier.
What does proof of conformity consist of? There are three options. The first is to provide the results of a conformity assessment of the device part, showing compliance with the relevant general safety and performance requirements of Annex I of the EU MDR. This conformity assessment should be supported with the manufacturer’s European Commission declaration of conformity. The second option is to provide a certificate issued by a notified body, which allows the manufacturer to affix a European Conformity (CE) mark to the medical device. If there is no conformity assessment, and the involvement of a Notified Body is required, there is a third option. The applicant must be able to provide an opinion issued by a Notified Body, which shows that the device component complies with Annex I of the EU MDR. However, the Notified Body must be designated under the EU MDR for the type of device in question.
For its part, the EU IVDR affects companion diagnostics, which were not specifically mentioned in the preceding directive. The term ‘companion diagnostic’ refers to devices that help to determine patients who are most likely to benefit from a medicinal product, or patients who may be at risk of serious adverse reactions if they are treated with a certain medicinal product. Manufacturers have until 26 May 2022 to comply, but it is important for them to start the compliance process as soon as possible as they are reliant on two separate organizations, with different timelines for review: a notified body for the medical device component and a national competent authority for the associated medicinal product (or the European Medicines Agency). Companion diagnostics are categorized as Class C devices (Class D devices present the highest risk), so pharmaceutical companies must expect closer regulatory scrutiny from Notified Bodies and more stringent requirements.
Watzke (Domino Printing Sciences): For medical device manufacturers, the regulations will make a big impact. There is a lot of work to be done to ensure every product is registered in the EUDAMED database, a database that didn’t exist before. From what we understand, there are at least two million products in the market, and so complying with these new regulations is a big task. Some medical device manufacturers have very limited employees but sell up to 6000 products in a range of different product groups. The concept of basic UDI for registering each product group will be very helpful once implemented.
There are examples of medical device companies where around a third of the employees are working on fulfilling the requirements of the EU MDR. The regulation also has a large impact on the developers, due to notified bodies having to be notified by the EU authorities if new companies are founded or new products developed. Due to the complexity of the regulation, a small number (at the time of writing) of the 57 former existing notified bodies for MDD and AIMDD have been notified and around an additional 40 have applied to be notified (2). Nevertheless, the regulation will be a step forward in terms of patient safety, as only registered products will be allowed to be sold in Europe and all databases will be linked.
PTE: How will the new regulatory submission information requirements for companies differ from those required under the previous regulation(s)?
Parry (Maetrics): The criteria for clinical data are stricter under the EU MDR, so it is critical that manufacturers get up to speed with what is needed. They must submit clinical evaluation reports (CER) that demonstrate clinical safety, performance, and clinical benefit. CERs must provide objective evidence to meet the specific related general safety and performance requirements in Annex I of the EU MDR.
As historical market clearance does not apply, every medical device must receive new CE marking under the EU MDR (no ‘Grandfathering’ allowed). It may be necessary to perform additional clinical investigations to obtain the necessary data. Manufacturers cannot rely on data from equivalent devices as they may have been able to do previously, unless they have contracted agreed direct access to the original data supporting clinical safety, performance, and clinical benefit of the medical device component. They must factor in enough time to perform clinical investigations as needed, and then to critically evaluate the results, as well as relevant scientific literature. Notified bodies can also be expected to look for evidence of post-market surveillance, assessing how the device holds up once placed on the market and whether any complications occur in relationship to the device component. Ideally, standardized processes should be put into place so that this type of data is readily available and up to date.
PTE: How should companies proceed if they already have a CE marked drug-device combination product? Any advice concerning the extension deadline?
Watzke (Domino Printing Sciences): Every manufacturer producing combination products should be focusing on the normal deadlines, only in cases of uncertainty, should they resort to using the extension deadline. To ensure manufacturers are future proofing and to be seen as innovative, they should be meeting the deadlines outlined by the regulation. If they fail to do this, they ultimately may not be able to sell their product and they may not be a first-choice supplier for hospitals.
Parry (Maetrics): There is no grandfathering under the EU MDR, so all devices must have a new CE mark under the new regulation. Drug–device combination product manufacturers have until 26 May 2020 to make the transition and procure new CE marking. Products that currently hold a certificate under the current MDD 93/42/EEC can benefit from a variable extension period until their certificate expiry date, but this can be no later than 26 May 2024. However, it is important to note that no changes can be made to products during this extension unless they are re-certified under the EU MDR. Achieving compliance can be complex, so delaying the process of understanding and meeting the requirements is not advisable, especially taking into account factors such as the availability of resources and expertise, as well as the stretched capacity of Notified Bodies as a result of the new regulations.
PTE: Are there any best practices you could share with pharma companies in terms of complying with these new regulations?
Parry (Maetrics): If they haven’t already, they should engage with Notified Bodies, where needed, right away to determine which organizations are designated or awaiting designation for the type of devices they will need to subject to conformity assessment under the EU MDR. It is important to secure a place in the queue, as so far, only nine Notified Bodies have been designated under MDR and only three under IVDR, and these will be under severe pressure for some time to come. Secondly, it is essential for pharma companies to familiarize themselves with medical device regulation, as they will be in new territory. It is essential to build up internal expertise or procure external support to make the process of understanding requirements and achieving compliance as efficient as possible. As the medical device industry moves towards greater harmonization and tighter scrutiny, the value of investing the necessary resources in compliance now cannot be stressed enough.
Watzke (Domino Printing Sciences): With the deadline for ensuring compliance with the EU MDR fast approaching, the time to act is now. Apart from the regulatory implementation and preparing the documents to share with EUDAMED and the notified bodies, coding of product packaging or on the product itself should be considered during the first steps of the overall project planning. The coding required to comply with the regulation could end up having a huge impact on the packaging design, the substrate that is used for packaging, and the size of the product. Therefore, it is important to consider at the beginning how the newly required coding will fit into the production process.
1. European Commission, “New EU Rules to Ensure Safety of Medical Devices,” Press Release, ec.europa.eu, 5 April 2017.
2. European Commission, “Internal Market, Industry, Entrepreneurship, and SMEs,” Tools and Databases, ec.europa.eu [accessed 20 Jan. 2020].
Pharmaceutical Technology Europe
Vol. 32, No. 1
When referring to this article, please cite it as F. Thomas, “Devices Under Scrutiny,” Pharmaceutical Technology Europe 32 (1) 2020.