We all know and love (ahem) the EU MDR (2017/745).
And although it is defined as the EU Medical Device Regulation, it applies to certain other devices as well.
The continued innovation of the medical device industry has created a limbo between medical devices and pharma and continues to push the boundaries of mixing the two.
Combination products, which integrate drugs, medical devices, and/or biologics, have emerged as powerful tools in both the pharmacological and medical space.
In the European Union, these products are partly governed by the EU MDR.
In this article, we delve into the world of combination products under the European MDR, exploring their definition, classification, regulatory requirements, and the impact of the new regulation (can we even keep calling the MDR new at this point?) on the market.
Defining Combination Products
A combination product is a unique type of medical device that combines two or more regulated components into a single integrated product.
For the purposes of this article, “combination product” will always refer to medical devices that implement a pharmacological or biologic component.
The goal is to address complex medical needs and deliver therapeutic benefits greater than those achieved with individual products.
Combination products come in various forms, including drug-eluting stents, drug-infused wound dressings, auto-injectors with integrated drugs, pre-filled syringes, and many more.
Combination products are typically produced to improve a patient’s life and independence.
Regulatory Framework for Combination Products in the European Union
The regulatory framework for combination products in the European Union is largely defined by the European Medical Device Regulation (MDR), which replaced the previous Medical Device Directive (MDD) in May 2021.
The MDR encompasses a wide range of medical devices, including combination products, to ensure patient safety and product efficacy.
For combination products, the MDR outlines specific guidelines and requirements that manufacturers must adhere to.
And while the MDR does not specifically mention combination products, it does set out requirements for which regulation manufacturers must use in articles 1(8) and 1(9):
“Any device which, when placed on the market or put into service, incorporates, as an integral part, a substance which, if used separately, would be considered to be a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the device, shall be assessed and authorised in accordance with this Regulation.
However, if the action of that substance is principal and not ancillary to that of the device, the integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004 of the European Parliament and of the Council, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part are concerned”.
“Any device which is intended to administer a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC shall be governed by this Regulation, without prejudice to the provisions of that Directive and of Regulation (EC) No 726/2004 with regard to the medicinal product.
However, if the device intended to administer a medicinal product and the medicinal product are placed on the market in such a way that they form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single integral product shall be governed by Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable. In that case, the relevant general safety and performance requirements set out in Annex I to this Regulation shall apply as far as the safety and performance of the device part of the single integral product are concerned.”
Types of Combination Products
Combination products are classified into one of four categories:
- Drug-Device Combinations (DDCs): These products consist of a medical device and a medicinal product, such as an auto-injector that administers a specific drug. DDCs are regulated under both the MDR and the Medicinal Products Regulation (MPR).
- Device-Drug Combinations (DDCs): In contrast to DDCs, these products primarily function as medical devices, with the drug component offering support, such as an intravenous catheter with an antimicrobial coating. DDCs are primarily regulated under the MDR.
- Device-Device Combinations (DDCs): These combinations involve two or more medical devices, with each device serving its intended purpose. An example is a combination of an insulin pump and a continuous glucose monitor. DDCs are regulated under the MDR.
- Borderline Products: These products blur the lines between medical devices, medicinal products, and other regulatory categories. Regulatory authorities evaluate such products on a case-by-case basis to determine their classification and applicable regulatory pathway.
The MDR emphasizes that the classification of combination products should consider their primary mode of action (PMOA).
This means that the medical device’s intended purpose and primary function are critical in determining its regulatory pathway. Most combination products under the EU MDR are Class III, according to rule 14.
Regulatory Requirements for Combination Products
To comply with the European MDR, manufacturers of combination products must meet specific requirements, which can vary depending on the classification of the product:
Manufacturers must conduct clinical evaluations of their combination products to establish their safety, performance, and clinical benefits.
This involves collecting and analyzing clinical data, including data on patient populations, endpoints, and follow-up periods.
Manufacturers must perform a risk assessment to identify and mitigate potential risks associated with their combination products.
This includes evaluating the risks related to both the device and the drug or biologic components.
Combination product manufacturers must engage a Notified Body to assess and certify their products for conformity with the MDR.
This process includes reviewing the technical documentation, risk management, and clinical evaluation.
Ongoing monitoring and reporting of the performance and safety of combination products are essential.
Manufacturers must maintain a robust post-market surveillance system to capture and respond to adverse events and other safety concerns.
Labeling and Instructions for Use
Combination product labeling must be clear, concise, and user-friendly.
Manufacturers must provide detailed instructions for use to ensure proper handling, administration, and disposal of the product.
Unique Device Identification (UDI)
Under the MDR, manufacturers must assign a UDI to their devices, allowing for traceability and post-market monitoring.
Impact of the MDR on Combination Product Manufacturers
The European MDR has introduced several significant changes that impact combination product manufacturers.
While pharmaceutical regulations have been strict for decades, it is only with the updates to the MDR that medical device manufacturers must up their regulatory compliance game to higher standards closer to that of their pharmaceutical cousins.
Stricter Regulatory Oversight
The MDR imposes more rigorous requirements for clinical evaluations, risk assessment, and post-market surveillance.
Manufacturers must invest in comprehensive safety and performance data to demonstrate compliance.
New Technical Documentation
Combination product manufacturers must create extensive technical documentation to support their conformity assessment.
This includes data on the device’s design, clinical performance, and risk management.
Notified Body Involvement
The MDR mandates that most combination products be certified by a Notified Body.
This change necessitates collaboration between manufacturers and these accredited organizations, increasing oversight.
Labeling and Instructions
Manufacturers must invest in improved labeling and user instructions to ensure that healthcare professionals and patients understand how to use their combination products safely and effectively.
Combination products play a crucial role in modern healthcare by offering innovative solutions to complex medical challenges.
The European Medical Device Regulation (MDR) has introduced a more robust regulatory framework to govern these products compared to previous regulations.
And although MDR compliance is old hat for some at this point, the MDR’s classification, requirements, and the role of Notified Bodies significantly impact combination product manufacturers and necessitate comprehensive clinical evaluation, risk assessment, and technical documentation.