Understanding the Regulatory Hurdles for EU Premarket Submissions

The European Union’s Medical Device Regulation (MDR) took effect last May after the global pandemic delayed its implementation by a year. The MDR replaced the Medical Device Directive (MDD) to modernize Europe’s legal framework for manufacturing medical devices and align the continent’s regulatory environment with evolving global standards. The regulation also introduced new responsibilities for the European Medicines Agency (EMA) and each member state’s “competent authority,” or national agency that enforces medical device regulations. Put simply, the MDR aims to remove ambiguity in medical device manufacturing, alleviate subjectivity in regulatory approval, and prioritize patient safety.

But almost a year after implementation, the regulatory path to market a new medical device in Europe is still somewhat difficult to navigate.

The MDR’s new chemical characterization focus adds a level of risk management not seen in the EU before the MDR. Confusion exists about the roles played by competent authorities, notified bodies, and authorized representatives. Challenges abound for manufacturers whose devices are stuck in the certification cycle from MDD to MDR. And, the number of organizations certified to conduct reviews and approve devices (notified bodies) dwindled from around 125 under the MDD to approximately 25 today. Add the EMA’s new/revised oversight responsibilities for specific medical devices to the list, and companies may want to reconsider entering the European market. But the number of hurdles only underscores the importance of strong partnerships with experienced consultants and precise time management throughout the regulatory journey.

Robust Risk Management Requirements
Medical devices submitted in the EU must address “Physical and/or Chemical Information” as outlined by ISO 10993-1:2018. This is often achieved with chemical characterization data that complies with the revised ISO 10993-18:2020. The EU has not harmonized ISO 10993-18:2020 across all member states but regulators see it as “stat-of-the-art,” or the most recent published version of an accepted standard, and hold manufacturers to it.

The key contributor to the strictness of ISO 10993-18:2020 is the analytical evaluation threshold (AET). The AET is a concentration threshold for chemicals that requires chemists to identify and quantify any compounds at or above the threshold so toxicologists can evaluate whether each compound presents patient risk. ISO 10993-18:2020 also emphasizes exaggerated and exhaustive extractions, or intense analytical chemistry that helps determine potential hazards. These intense extraction methods combined with a low AET can create thousands of compounds for assessment. Any unidentified compounds, or those identified at a level of toxicological concern, are problems for manufacturers. There are risk mitigation strategies to address problematic findings but they divert precious time and resources from a device’s regulatory plan even if they are successful.

Who Does What?
The number of local, national, and continental organizations and individuals manufacturers must navigate to attain regulatory approval for their devices can be confusing. Manufacturers may not have to deal directly with all of them, but understanding the regulatory hierarchy may help answer important questions and set expectations.

• European Authorized Representative: Medical device manufacturers without a registered place of business in an EU member state must appoint an “EU Rep” to liaise between themselves and the Competent Authority. EU Reps must include all contact details on the device’s labeling, outer packaging, or instructions for use.
• Harmonised Standard Consultant: HAS consultants assess how European standards comply with EU legislation. They help manufacturers clarify the legal definition of their devices and determine the best risk category for them.
• Notified Body: Before attaining market approval, each medical device must be reviewed and approved by a notified body. NBs are independent organizations that ensure devices adhere to MDR regulations for as long as they remain on the market. Medical devices approved for use within the EU receive a “CE” mark that includes the NB’s unique four-digit code. Competent Authorities supervise notified bodies.
• Competent Authority: Generally a government agency within an EU member state, competent authorities monitor medical device safety after the products go to market. They also ensure European regulations become national legislation. Competent Authorities for Medical Devices (CAMD) is a pan-European network of all EU competent authorities tasked with improving collaboration, enforcing regulations, post-market surveillance, and supporting patient safety. The European Commission oversees competent authorities.
• European Medicines Agency: The EMA evaluates the quality, safety, and efficacy of human and veterinary medicine through protocols known as “centralised procedure.” Competent Authorities usually regulate medical devices, but the EMA gets involved if the device falls into certain categories (e.g., combination products) or if state regulators require scientific support.

Notified Bodies May Need Second Opinions
Manufacturers selling medical devices in the EU must conduct a conformity assessment or audit of its quality system and a technical documentation review to ensure their products’ safety and performance. Notified bodies conduct conformity assessments but the MDR introduced new responsibilities for the EMA that make it a more prominent player in the process. It is not uncommon for an NB to seek a scientific opinion from the EMA or a Competent Authority, depending on device type and function.

Combination products—The MDR divides combination products into integral devices and co-packaged products. Integral devices are those in which medicine and a product combine to form a single device. Co-packaged products are those in which the medicine and device are separate items but contained in the same package.

The EMA issued extensive guidance in July 2021 about the documentation required to market combination products. The agency requires manufacturers to understand everything in the document and how it pertains to their device. Notified bodies issue CE marks for these devices, but the EMA finalizes all applications for marketing approval.

Devices containing ancillary medicinal substances—These devices contain medicine and a device, but the device is responsible for the primary mode of action. NBs must seek the EMA’s opinion on the quality and safety of the ancillary substance if it comes from human blood or plasma. CE certification cannot be issued without taking this step. For other ancillary substances, NBs may seek competent authority approval.

In-vitro diagnostic devices (IVDs)—These devices have no patient contact and provide no therapeutic effect. However, they provide valuable information about patients and their suitability for specific treatments. NBs must seek a scientific opinion from the EMA to determine the IVD’s suitability with the medicinal substance. For substances not authorized under the centralised procedure, NBs may seek a second opinion from a competent authority. Notified bodies can also request a consultation with EMA officials to better understand procedural requirements.

Devices absorbed by the human body—These devices are introduced through a bodily orifice or applied to the skin. NBs must seek a scientific opinion from the EMA or competent authority on the safety and efficacy of the substance’s active ingredients. The EMA will direct the consultation procedure between NBs, competent authorities, and itself.

Additional Challenges
There are several other factors medical device manufacturers must weigh when considering entering the EU market.

First, manufacturers must ensure their products comply with EU health, safety, and environmental regulations. Manufacturers must work with NBs to perform conformity assessments, create technical files, write EU declarations of conformity when necessary, and ensure CE marks are affixed to products. It takes a team of consultants, regulators, biocompatibility and sterilization experts, and post-market surveillance monitors to bring a device to market in the EU but manufacturers are held accountable for the technical file’s accuracy and the device’s compliance with safety guidelines.

Second, the small number of NBs has become a critical issue. The 25 NBs operating in the EU are struggling to keep up with demand, creating massive backlogs for manufacturers who are ready but cannot find regulatory support. Many of these NBs operate with limited scope, fewer resources, and conflicting information about regulatory requirements. Many NBs have stopped accepting MDR applications for some device categories altogether for these reasons. Engaging an EU Rep’s help and advice can help manufacturers on tight timelines reassess their European plans’ viability.

Next, attaining MDR certification for devices previously approved under the MDD takes a long time, especially if manufacturers have not begun the process. It could take a year to attain MDR certification and potentially six additional months for the CE mark—and only if all documentation is correctly prepared and the safety data is acceptable. If chemistry and biocompatibility data is old, erroneous, or does not comply with current ISO standards, new data is likely necessary. NBs will inform manufacturers of these deficiencies, and their CE mark timeline may depend on how quickly these deficiencies can be remedied. For permanent or long-term medical devices, it could take six to 12 months from the start of testing to gain compliance.

Device manufacturers should treat MDR certification as though they are starting from scratch. It is also worth noting manufacturers may be asked to prove well-known or scientific principles about their devices and they must fully understand how MDR applies to the nuances of their product.

Finally, EU member states are not beholden to the current process. Brexit was a political maneuver that forced Europe and its economic partners to answer many interesting questions. No longer a part of the EU, the United Kingdom chose its regulatory requirements for medical devices. Rather than a CE mark, the U.K. uses a “CA” (conformity assessment) mark instead. CE marked products may go on the market in the U.K. until June 2023 as long as the manufacturer writes a declaration of uniformity.

As a part of the U.K., yet still sharing a land border with Ireland, Northern Ireland presents a unique case. NBs based in Northern Ireland can certify EU devices but the certificates they issue are only valid in Northern Ireland, not in the EU. Such medical devices must also indicate their certification with a “UK(NI)” mark next to its CE mark.

Swiss medical device manufacturers or those looking to sell devices in Switzerland may find themselves in a bind, too. Switzerland and the EU failed to reach a mutual recognition agreement before the MDR’s implementation in May 2021. Despite attempts to achieve a modified recognition agreement and create a transitional period, the two sides remained deadlocked. As a result, any existing Swiss certificates of conformity and certificates issued in the EU for Swiss devices are invalid.

A Final Word
The EU’s regulatory environment is challenging to navigate and will remain that way for the foreseeable future. However, Europe’s population continues to grow and its economy is strong. There are clear benefits for device manufacturers willing to endure the European market’s regulatory uncertainty but they must stay vigilant. NBs and like-minded Competent Authorities will not accept old/outdated data or technical documentation errors. To be successful in the EU, manufacturers must understand the inner workings of European regulations to ensure they do not run afoul of them. An experienced laboratory testing partner can play a critical role in helping manufacturers achieve their goals. 

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Mark Cabonce, M.S., DABT, is a principal toxicologist with a focus on medical devices and combination products. Before joining WuXi AppTec, he was a toxicologist managing regulated in vivo and in-vitro acute toxicology studies, assessing formulation dossiers for GHS classification and labeling, and preparing risk assessment in support of domestic and international product registrations. He earned a M.Sc. degree in biology from St. Louis University, and has been a diplomat of the American Board of Toxicology since 2005.

Dr. Kim Ehman, Ph.D., DABT, is a technical director of Regulatory Toxicology, with a focus on medical device and combination products. Prior to joining WuXi AppTec Medical Device Testing, she worked as a toxicologist for RTI International, Toxicology Regulatory Services, and Altria Client Services. In her current position, Dr. Ehman provides medical device manufacturers and suppliers with technical and regulatory support for biocompatibility test programs and conducts quantitative toxicological risk assessments to support product safety and risk management decisions. She earned a B.Sc. degree in biology from Seton Hill University.