In Europe, the commercialization of healthcare products is highly regulated. While medical devices are marketed according to EU Regulation 2017/745 (known as the Medical Device Regulation, MDR), medicinal products for human use are marketed following Directive 2001/83/EC (known as the Medicinal Product Directive, MPD). Deciding whether a product meets the definition of medical device or medicinal product is usually a straightforward decision. However, in some instances, this decision can be challenging (this is what we will refer to as “borderline products”). This article summarizes the guidance document released by the Medical Device Coordinating Group (MDCG 2022-5) to support manufacturers in qualifying borderline products.
The qualification of a product into a medical device (MD) or medicinal product (MP) is done following the definitions provided in the MDR and MPD, respectively. Once the product is qualified, the manufacturer must follow the conformity assessment procedure (MD) or the marketing authorization procedure (MP) that applies to the product type. Generally, only one regulation is followed, the MDR and the MPD do not apply cumulatively. However, in some instances (such as in the case of combination products), there might be some cross references.
What is a medical device?
The definition of medical device is provided in MDR Article 2(1):
“‘Medical device’ means any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific medical purposes:
— diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease,
— diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury or disability,
— investigation, replacement or modification of the anatomy or of a physiological or pathological process or state,
— providing information by means of in vitro examination of specimens derived from the human body, including organ, blood and tissue donations,
and which does not achieve its principal intended action by pharmacological, immunological or metabolic means, in or on the human body, but which may be assisted in its function by such means.”
Thus, a medical device is a product with a medical purpose and does not have a pharmacological, immunological, or metabolic principal mode of action in or on the human body.
What is a medicinal product?
The definition of medicinal product is provided in MPD Article 1(2):
(a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or
(b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.”
This definition is broad, particularly considering section (a) since many MDs could fulfill this part of the definition. Therefore, we should focus on paragraph (b) when qualifying borderline products.
Principal mode of action
Looking at the different definitions, the critical demarcation aspect in borderline products is the principal mode of action.
The principal mode of action is how a product achieves its principal intended action as described in the labeling and claims of the manufacturer.
MDs shall achieve their principal mode of action by means other than pharmacological, immunological, or metabolic. In general, MDs achieve their principal mode of action by physical means, hydration, dehydration, and pH modification. The justification of the mode of action should always be based on state-of-the-art scientific data.
What do we understand by pharmacological, immunological, or metabolic action? Here are some definitions and examples:
- Pharmacological means: interaction between a substance and a constituent of the human body, which results in a physiological/pathological change. An example would be the interaction between a ligand and a receptor.
- Immunological means: action initiated by a substance on the human body and mediated by cells or molecules of the immune system. An example would be the replacement of immune cells.
- Metabolic means: the action of a substance that involves an alteration of a biochemical process participating in a function of the human body. An example would be the inhibition of endogenous enzymes.
In this context, a substance is understood as any substance, irrespective of its origin.
Products used for diagnostic purposes
Products used for diagnosis can either fit the MD or MP definition. Here, the key differentiator is not the mode of action but the product type (substances vs other products). Hence, diagnostic substances are MPs. Other products used for diagnosis can be regarded as medical devices, accessories of medical devices (governed by EU Regulation 2017/745), or even in vitro diagnostic medical devices (governed by EU Regulation 2017/746).
Substances with ancillary action
The MDR specifies that devices incorporating a substance that, if used separately, might be considered an MP and that have an action ancillary to that of the device should be assessed and authorized as MDs.
When thinking about MDs containing an MP, it is essential to consider the following:
- If the substance is available to the human body:
- If the answer is NO, the substance has no ancillary action.
- If the answer is YES, then the manufacturer should check if the substance supports the device in achieving its medical purpose by:
- Assessing if it is available in sufficient quantity to trigger an ancillary action.
- Backed-up by state-of-the-art scientifically objective data.
If an MP is found to have no ancillary action, then the manufacturer cannot claim benefits related to that MP in the IFU, labeling, or other commercial documentation.
According to the MPD, herbal MPs are defined as MPs exclusively containing herbal substances or herbal preparations as active ingredients. Traditional herbal MPs are those which, among others, have plausible pharmacological effects or efficacy due to longstanding use and experience.
When the herbal substance is responsible for the principal intended action or the mode of action is unknown (and it is pharmacological, immunological, or metabolic), the product will be considered an MP.
If the manufacturer demonstrates that the product’s mode of action is not pharmacological, immunological, or metabolic, the product can qualify as MD. Similarly to other substances, if there is a device that contains an herbal substance with an ancillary action, only specific provisions of the MDR will apply.
Substance-based medical devices
Substance-based medical devices are MDs composed of substances permitted in MDs and that do not achieve their principal intended action by pharmacological, metabolic, or immunological means. Such devices can be similar in formulation and might be used similarly to MPs.
Substance-based devices are mentioned explicitly in two of the MDR Annex VIII rules:
- Rule 3, related to substances used in vitro with human cells, such as IVF media.
- Rule 21, related to substances introduced into the human body via a body orifice or skin that are absorbed or locally dispersed in the body, such as eye or ear drops.
Substance-based devices are classified according to general rules if they do not meet these two rules.
The MDR contemplates different scenarios for devices intended to be used with MPs. These scenarios depend on the following:
- If the device is an integral product, a product that contains at least two parts (MP + MD) combined in a way that they form a single entity when placed in the market. This also includes devices intended to administer an MP, when the MD and MP are not intended to be separated before administration, can only be used in this combination, and are not reusable.
- The principal mode of action of the device.
Drug-device combinations regulated as MPs
Drug-device combinates are regulated as MPs in the case of:
- Devices intended to administer a medicinal product forming a single integral product that can only be used in the given combination and is not reusable.
- Devices that incorporate as an integral part an MP responsible for the principal mode of action of the device.
These devices need to comply with the MPD. Moreover, the device features must comply with the General Safety and Performance Requirements on the MDR Annex I.
Examples of drug-device combinations include syringes prefilled with a drug, patches for transdermal drug delivery, and progestogens-releasing IUDs.
No-combination devices for the administration of medicinal products, regulated as MDs
Devices intended to administer MPs, where the device and the MP are not integral, are governed by the MDR. These devices include drug delivery pumps, implantable infusion pumps, or syringes.
Devices incorporating, as an integral part, an ancillary MP, regulated as MDs
Devices incorporating, as an integral part, an ancillary MP are governed by the MDR. These devices include IUDs containing copper, drug-eluting coronary stents, or soft tissue fillers containing local anesthetics.
How can AKRN support you?
AKRN’s team has thorough expertise working with borderline medical device – medicinal products. Our team specializes in the following:
- Qualification of products and commercialization strategy
- Regulatory consulting and Notified Body interaction
- Preparation of Technical Documentation
- Preparation of Clinical Evaluation Documentation
- Designing and conducting pre- and post-market clinical investigations across Europe
- Package preparation and regulatory submissions to Ethics Committee and competent authorities
- Designing and managing of CRFs and EDC platforms
- Clinical project management
- Site selection and qualification and contact with key opinion leaders
- Clinical Investigation monitoring
- Data management
- Biostatistics and data analysis
Subject Matter Experts
Ariadna Navarro, Ph.D. Associate Director Quality & Regulatory Affairs LinkedIn
Beatriz Rodríguez, Ph.D. Regulatory Affairs Manager