March 9, 2021
The life-sciences industry has been working hard to meet the deadline for compliance with the European Union’s Medical Device Regulation (EU MDR, 2017/745) (1). Doing so has been a challenging journey for many companies. Therefore, the full-year postponement of the final application date has been a welcome development, particularly in view of the new and extraordinary challenges stemming from the COVID-19 global health crisis. The extension has instigated other important changes, so it is critical that life-science businesses familiarize themselves with their implications.
Key Takeaways for the Medical-Device Industry
In a 17 April 2020 amendment to the original regulation (2), the European Parliament approved by an overwhelming margin the new deadline of 26 May 2021. That delay applies to the EU MDR only, with no corresponding changes to the In Vitro Diagnostic Regulation (IVDR, 2017/746) (3). Likewise, regulatory requirements remain the same for medical-device manufacturers, notified bodies, authorized representatives, importers, and distributors.
An important takeaway for the medical-device industry is that transition dates have not changed. Conformité Européenne (CE) Mark certificates that were issued under the previous Medical Device Directive (MDD) still will expire no later than 26 May 2024 (4). But Article 120 of the EU MDR amendment now clarifies that transition dates also apply to class 1 devices for which compliance assessments require a notified body.
Another important detail is that the EU MDR amendment introduces staggered implementation dates for reusable devices that bear Unique Device Identification (UDI) carriers on the devices themselves. Given that implementation of UDI requirements influences regulatory documents and product labeling, the medical-device industry welcomed that development. For implantable and class 3 devices, the earliest UDI compliance date now is 26 May 2023; the deadline for class 2a and 2b devices is 26 May 2025; and class 1 devices must be compliant by 26 May 2027. This clarification in UDI timelines enables robust planning and implementation.
EU MDR Article 59 also has undergone some updates. The code pertains to exceptions to rules for conformity assessments, specifically to allow implementation of non–CE-marked products that are deemed to have a “humanitarian use.” The amendment explicitly references corresponding articles in the MDD (Article 11.13) and Active Implantable Medical Devices Directive (Article 9.9) (5). By referencing those directives, exceptions adopted under them may apply or be extended using implementing acts once the new EU MDR application deadline is reached. In the context of a pandemic, that clarification will be important in supporting efforts to advance products quickly and safely to market.
Having additional time will benefit many businesses struggling to become fully compliant by the deadline — if that time is used wisely. Manufacturers should take this opportunity to review their clinical-evaluations and technical-file documentation, assess postmarket surveillance documentation, and evaluate economic operator (EO) relationships and agreements.
Who Counts As an Economic Operator?
Requirements for EOs have not changed under the amendment; however, with many businesses still struggling to identify EOs and their requirements, the deadline delay will help manufacturers to ensure that their EOs are EU MDR-ready. Under the regulation, the responsibility of ensuring that medical devices meet all compliance requirements is a shared enterprise. No longer the sole responsibility for the legal manufacturer, verifying device compliance now extends to importers, distributors, and authorized representatives. By sharing compliance duties across the supply chain, each EO entity serves as a control on others, with each device receiving several checks throughout its advancement to market. Compliance issues emerging from any one EO entity can have direct legal implications on the other EOs in the supply chain.
After the deadline, all EO entities (excepting distributors who are not listed as liable) will need to have arranged financial coverage because they will be made jointly and severally liable for devices. Manufacturers would do well to use the additional time provided by the amendment to identify and help their EOs reach conformity, especially considering that a number of EOs are likely to be unaccustomed to such a high level of verification responsibility. On their side, manufacturers must equip themselves with the requisite personnel to manage EOs within supplier quality and audit teams, and they must have legal support for contract management.
What About Combination Products?
EU MDR developments involve not only medical-device manufacturers, but also pharmaceutical and biopharmaceutical companies. Pharmaceutical companies that produce combination products or companion diagnostics, for instance, also will find their products undergoing greater clinical scrutiny than before as laid out in the new regulations. Combination products are composed of any combination of an ancillary drug, device, and biologically active product. Examples include drug-eluting stents and medicated dressings, both in which a medicinal component contained within the device coating has an ancillary purpose to that of the device. Other types of combination products are insulin injector pens and metered-dose inhalers, which function as prefilled drug-delivery systems.
Implementing (EU) 2017/745: Combination Products |
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Shortly after adoption of the EU Medical Device Regulation, the Human Medicines Evaluation Division of the European Medicines Agency (EMA) compiled a guide to help businesses determine whether a combination product would be evaluated as a medical device or medicinal product (6). Below are excerpts from the guide. “What regulatory framework does a product incorporating both a medicinal product and medical device fall under?“Where the action of the medicinal substance is ancillary, the product is regulated as a medical device and must be CE marked. [Because] the action of the medicinal product is considered ancillary, a scientific opinion must be provided from a medicines authority before a notified body can issue a certificate for the combined product. “Where the action of the medicinal substance is principal, the combination product is regulated under the medicinal products framework. In that case, the relevant general safety and performance requirements of the MDR apply to the device part. “If the administration device is marketed as a single integral product intended exclusively for use in the given combination and is not reusable, the combination product is regulated under the medicinal products framework. In that case, the relevant general safety and performance requirements of the MDR apply to the device part. “In all other cases, the administration device is regulated under the medical device framework. When the medical device is not physically combined with the medicinal product the device will need to be CE marked.” “When is a medicinal product considered to form an integral product with the administration device?“The second paragraph of Article 1(9) of the MDR sets out three cumulative conditions that need to be satisfied at the moment of the placing on the market: (1) The device and the medicinal product form a single integral product that (2) is intended exclusively for use in the given combination and (3) is not reusable.” |
Drug companies increasingly must stay informed about implications of the EU MDR and IVDR. In the European Union, combination products are regulated as either medicinal products or medical devices, depending on which component has the ancillary function. The EU MDR particularly affects combination products that currently are regulated as medicinal products. Such products are ancillary drugs or biologically active components that function as the principal therapeutic outcome of the device. An insulin pump is an example: The device’s intended purpose is the delivery mechanism for the integral drug or biologic component.
The EU MDR’s inclusion of combination products results from their increasing design and production complexities. The strategy also ensures that combination products and standalone devices undergo equivalent risk management and safety scrutiny. Ancillary-device components now will be examined with the same care as standard medical-device products.
Under the EU MDR, combination products are categorized as class 3 devices by the presence of a medicinal substance. That classification is significant regarding clinical data requirements, data collection for clinical evaluation reports (CERs), and methods of analysis. Manufacturers of the drug components of combination products will need to ensure that clinical data collection and analysis are aligned to demonstrate device compliance. The deadline extension, therefore, greatly benefits biopharmaceutical companies for which clinical investigations and data gathering protocols are geared toward traditional pharmaceutical development practices rather than the enhanced clinical requirements of EU MDR. Such companies will have more time to make essential preparations.
Another important matter for biopharmaceutical combination devices as a result of the MDR extension is the degree of substantial changes to product design, including the addition or replacement of components or medicinal substances that manufacturers should consider during the extension period. Biopharmaceutical combination products currently authorized for sale in the European Union should assess MDR requirements for any proposed or future device changes until the conclusion of the extension to ensure that changes do not jeopardize a device’s current market access status. Significant or substantial changes during the extension period could result in requiring regulatory review and approval before the new deadline.
To ensure that operations conform with the EU MDR, pharmaceutical companies must have compliant design controls, integrated risk-management procedures, and improved processes for complaint handling. Furthermore, companies will need to update their corrective action and preventive action (CAPA) systems and their regulatory annual product reporting (APR) procedures, incorporating documentation such as CERs and periodic safety-update reports (PSURs). Finally, companies must have closer oversight of their device and component manufacturers.
Overcoming Barriers to Compliance
Compared with their medical-device counterparts, pharmaceutical and biopharmaceutical companies could face significant hurdles that they might not be equipped to negotiate. Medical-device companies typically have invested time, resources, and energy into learning the art of interpreting device-specific regulations, applying that knowledge, and developing documentation to ensure regulatory compliance. Pharmaceutical companies must follow suit. Investing proper resources into that process will yield long-term benefits because having current, accessible clinical data will be crucial for maintenance of clinical records and postmarket surveillance activities.
Because compliance is an ongoing activity that lasts throughout a device’s product lifecycle, businesses are encouraged to incorporate device compliance processes into their operations as soon as possible. Given overdemand for notified bodies in the regulatory arena, an early start can make the difference between a product market freeze and full compliance for market access. Partnering with a regulatory consultancy with relevant industry insight and hands-on experience can be a critical strategic move to meet the new May 2021 deadline.
References
1 EU 2020/561. Amending Regulation EU 2017/745 on Medical Devices. Off. J. Eur. Union 130, 24 April 2020: 18–22; http://data.europa.eu/eli/reg/2020/561/oj.
2 EU 2017/745. Medical Devices. Off. J. Eur. Union 117, 5 May 2017: 1–175; http://data.europa.eu/eli/reg/2017/745/oj.
3 EU 2017/746. In Vitro Diagnostic Medical Devices. Off. J. Eur. Union 117, 5 May 2017: 176–332; http://data.europa.eu/eli/reg/2017/746/2017-05-05.
4 93/42/EEC. Medical Devices. Off. J. Eur. Econ. Community 169, 13 June 1993: 176–332; http://data.europa.eu/eli/dir/1993/42/oj.
5 90/385/EEC. Active Implantable Medical Devices. Off. J. Eur. Econ. Community 189, 20 June 1990: 17–36; http://data.europa.eu/eli/dir/1990/385/2007-10-11.
6 Questions & Answers on Implementation of the Medical Devices and In Vitro Diagnostic Medical Devices Regulations. European Medicines Agency: Amsterdam, The Netherlands, 2019; https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/questions-answers-implementation-medical-devices-vitro-diagnostic-medical-devices-regulations-eu/745-eu-2017/746_en.pdf.
Beth Crandall is managing director and global solutions delivery leader at RQM+, Global Headquarters, 2790 Mosside Boulevard #800, Monroeville, PA 15146; [email protected].
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