Defining the differences when regulating medical devices, medicinal and combination products

Clinical trial and healthcare regulations are notoriously complex. The complexity increases with each additional stakeholder and geographic region involved. Added to this are the blurred boundaries between the medicinal products and medical devices. As technology has advanced in recent years, classifications of these products have become ever more complicated.

This article outlines some of the regulatory requirements for medical devices and combination products. It provides a basic outline of some of the expectations of those regulations. While mostly focused on EU regulations, it contrasts some of the EU requirements with those in the US where relevant.

Medical device vs combination product

The multipurpose use of medical devices across a wide array of diagnostic and medical treatment settings blurs their definitions depending on the applicable regulations. Medical devices can range from a simple adhesive patch to a complex iris prosthesis. There is no standardised global medical device definition and there are key differences between EU and US regulations.

Article 2 of the EU Medical Device Regulations (MDR) limits the use of medical devices exclusively to human application and includes software designed for medical use. In comparison, the US regulations (Federal Food, Drug, and Cosmetic Act (FD&C Act), Sec. 201(h)) extends the medical device definition to veterinary use, but excludes software.

Further complexity is added when defining drug device combination products (DDCs). In July 2021, EMA published the Guideline on Quality Documentation of Medicinal Products when Used with a Medical Device. It defines three types of combination products as medicinal products:

Integral DDCs:
the medical device and/or device part and the medicinal product form an integral product that is not reusable and where the action of the medicinal product is principal. Example: a single-use dry powder inhaler preassembled with the medicinal product. It is ready for use but cannot be refilled when all doses are exhausted.
Co-packed DDCs:
the medical device is packed (or packaged) together with the medicinal product. Example: Reusable dry powder inhaler packed with dry powder capsules.
Referenced DDCs:
the product information refers to a specific medical device to be used with the medicinal product, and the medical device is obtained separately by the user of the medicinal product. Example: Reusable dry powder inhaler and dry powder capsules packed separately but the patient information leaflet indicates that the capsules can only be used with a specific inhaler.

Integral DDCs are considered as medicinal products if the action of the drug is principal relative to that of the device. For example, patches for transdermal drug delivery or prefilled syringes are integral DDCs classified as medicinal products. If the action of the drug is ancillary to that of the device, then the integral DDC is considered to be a medical device. An example of this is a drug eluting coronary stent or a bone cement which contains antibiotics.

DDC conformity

Article 117 of the MDR introduced additional requirements for the manufacturers of integral DDCs. It requires a notified body to provide an opinion on the conformity of the device aspects against MDR Annex I GSPRs. For devices already CE marked there is no need for an opinion on conformity.

In both co-packaged and referenced DCC configurations, the medical device should comply with the requirements of the applicable medical device legal framework and undergo full conformity assessment for CE marking.

Risk class is another key factor in determining the appropriate conformity assessment procedure and the amount of clinical data needed to demonstrate device safety and performance. The criteria and responsibility for risk classification of medical devices depend on country or regional regulations. In the US, the FDA assumes this task, while in the EU the manufacturer is responsible and must adhere to the guidelines outlined in MDR Annex VIII.

Clinical investigations

The definition of clinical evaluation as per Art. 2(45) of the MDR emphasizes the assessment of clinical benefit alongside safety and performance verification. Manufacturers need to define their device’s direct or indirect clinical benefits and establish specific and measurable objectives for each benefit. The device’s benefit-risk profile should be evaluated against similar devices and alternative options available on the market. MDR made clinical investigations mandatory for class III and implantable devices (Art. 61(4)) allowing only several exceptions.

Clinical investigations should be conducted in line with the provisions of Chapter VI and Annex XV of the MDR, and with global standards, like ISO 14155:2011. Additionally, manufacturers must establish and maintain a post-market surveillance system to monitor the device’s performance, enabling prompt corrective actions when necessary.

Clinical investigations that assess the medical device’s safety and performance fall within the scope of the MDR and progress through the various clinical development stages outlined below.

1. Pilot stage evaluation

Preliminary safety and performance information is gathered from a small number of participants to plan the medical device’s further development. Those investigations typically have an exploratory or confirmatory design. They are often defined as first in human (FIH) clinical investigations or feasibility clinical investigations. The data collected informs design improvements and ensures adequate planning for one or more pivotal clinical investigations.

2. Pivotal stage evaluation

Confirmatory clinical investigations are conducted to evaluate the clinical performance, effectiveness and safety of the device for its specified intended use. These investigations enrol large cohorts of human subjects to ensure statistically robust results.

3. Postmarket stage

Additional confirmatory and observational investigations are conducted in this stage. The goal is to establish the medical device’s effectiveness and/or clinical performance in a broader population. Observational investigations provide an opportunity to observe device safety, including adverse events and long-term safety aspects.

Clinical research at the crossroad of CTR, MDR and IVDR

There are numerous cases when a medical device is used with an investigational medicinal product in a clinical trial. The assessment of the safety or performance of the devices is not in scope, but the device is necessary to conduct the study. According to MDCG Q&A Regarding Clinical Investigations, any medical device used for medical purposes in a research study involving people needs to comply with the applicable MDR requirements, as per in Article 2(1) of the MDR. This means that any device used in a clinical trial must be either:

CE-marked
An in-house device meeting Article 5.5 requirements
A custom-made device compliant with Article 52(8)
An investigational device per Article 2(46)

For devices lacking CE-marking, submitting a clinical investigation application in parallel with the application for the clinical trial is recommended. For this purpose, endpoints related to the device’s performance and/or safety could be added as secondary objectives to the clinical trial protocol.

Alternatively, a standalone clinical investigation plan (CIP) should be developed.

Combination DDCs

The path for clinical development of combination DDCs depends on the configuration type, as well as on the primary mechanism of action. In the co-packaged and referenced DDC configurations, the medical device and the medicinal product are governed by two different frameworks (MDR for the device and either Directive 2001/83/EC, orCTR for the medicinal product). Therefore, the device’s safety and performance will be assessed independently following the three stages already mentioned, while the medicinal product will undergo the standard phase 1-4 development path.

Integral DDCs

For integral DDCs, the development route is dictated by the primary mechanism of action. If the action of the medicinal product is principal relative to that of the device, the study will be submitted as a clinical trial under CTR requirements. If the action of the medicinal product is ancillary, the study will be submitted as a clinical investigation under the MDR framework.

Co-packaged DDCs with no CE marking

An even more complex scenario occurs when a co-packaged DDC with a non-CE-marked device is used in a clinical trial together with a companion diagnostic (CD). In this case three different regulations need to be fulfilled for one study. Clinical investigations of medical devices are regulated by the MDR, clinical trials of medicinal products are by the CTR and clinical performance studies of in-vitro diagnostic medical devices are regulated by the IVDR (Regulation (EU) 2017/746 In Vitro Diagnostic Medical Devices).

The COMBINE Project

The COMBINE Project was launched by the European Commission to assess the interface between CTR, MDR and IVDR in clinical studies. There is no dedicated procedure for combined studies foreseen in the regulations. The analysis report of the COMBINE Project identified over a hundred issues related to these types of studies. You can read more about the COMBINE project in our article on performance studies of in-vitro diagnostics. The findings of the next phase are expected to be published later in 2024.

Conclusion

The borders between medicinal products and medical devices are constantly evolving. Deciding the right development path is fraught with challenges. One of the biggest challenges is navigating the intricate web of regulations governing clinical research in the European Union for trials that combine multiple healthcare products. To successfully traverse these complexities, companies need in-country intelligence and the expertise of clinical trials regulatory professionals. Developing a comprehensive clinical trial submission strategy supported by regulatory experts ensures compliance with all applicable regulations and prevents trials from stalling.

Learn more about how we can support your trial’s global regulatory needs.