Substance-Based Medical Devices: What You Have to Do to Be Able to Continue Marketing Your Existing Devices Under The MDR

Anyone who produces substance-based medical devices, e.g., saline nasal sprays, cough syrups that soothe the mucous membranes or osmotic laxatives, will face several challenges all at once when Regulation (EU) 2017/745 (MDR) becomes fully applicable:

• The new Rule 21 will lead to a higher classification of class I substance-based medical devices. This will make it necessary to involve a notified body for the first time.
• The MDR establishes higher requirements for the clinical data. These also affect the demonstration of equivalence.

This article explains what you can do to overcome these regulatory hurdles and ensure that you are still able to place your substance-based medical devices on the market even after the transition periods. This is important to ensure that patients continue to receive safe and proven healthcare.

The article will also give you some tips on what you should do in the case of new features or significant modifications to substance-based medical devices (e.g., modifying the formulation or intended purpose) when full compliance with the MDR is demanded (from May 26, 2021).

1. Introduction

a) Definition of “substance-based medical devices”

a) Obligation to provide evidence based on clinical data

In contrast to a lot of other medical devices, substance-based medical devices generally have clinical functions and achieve their effect in direct contact with the human body. Therefore, the safety and performance of these devices cannot or cannot fully be demonstrated using pre-clinical data or performance data. Instead, clinical data is required to provide this evidence.

While clinical investigations are generally mandatory for class III devices and newly developed devices, for existing devices that have been on the market for a long time and that have a low risk profile according to Directive 93/42/EC (MDD), specific clinical investigations are usually not performed.

However, clinical investigations are associated with considerable time and resource costs and represent a major challenge for small and medium-sized companies in particular.

b) Higher classification of substance-based medical devices and involvement of notified bodies

The MDR has introduced a new classification rule for substance-based medical devices, namely Rule 21 in Annex VIII:

This means that all substance-based medical devices that were previously in class I under the MDD now have a higher classification under the MDR. Therefore, if these devices are to be marketed after the transitional periods, the involvement of a notified body is required for the first time.

c) Obligation to conduct clinical investigations for certain substance-based medical devices

The key to distinguishing medicinal products from substance-based medical devices is the correct interpretation of the mechanism of action used to achieve its principal intended action. While medicinal products have a pharmacological, immunological or metabolic mode of action, substance-based medical devices are defined by their chemical and/or physical mechanism through which they achieve their principal action. This is also reflected in their intended purpose.

If substance-based medical devices contain medicinally active substances that support the principal intended action, they are classified as class III devices. For these devices, as with all other class III substance-based medical devices, clinical investigations are mandatory.

d) Higher requirements for the proof of equivalence

According to the MDR, a clinical evaluation based solely on literature is only permitted if there is sufficient equivalence to a reference device. The requirements for the proof of equivalence have been significantly tightened in MEDDEV 2/7.1 rev. 4 and now also in the MDR compared to the requirements of the MDD.

According to ANNEX XIV Part A of the MDR, the following technical, biological and clinical characteristics are used to demonstrate equivalence:

Clinical equivalence

The device is:

• used for the same clinical condition or purpose, including similar severity and stage of disease
• used at the same site in the body
• used in a similar patient population
• has the same kind of user and
• has similar relevant critical performance in view of the expected clinical effect for a specific intended purpose

Technical equivalence

The device:

• is of a similar design
• is used under similar conditions of use
• has similar specifications and properties
• uses similar deployment methods and
• has similar principles of operation and critical performance requirements

Biological equivalence

The device:

• uses the same materials or substances in contact with the same human tissues or body fluids
• has a similar kind and duration of contact
• has similar release characteristics of substances

The MDR also states that the materials must be similar to the extent that there is no clinically significant difference in the safety and clinical performance of the device. Furthermore, the evaluation of equivalence must be based on proper scientific justification.

d) Difficulties in accessing data on equivalent devices

The MDR requires manufacturers to clearly demonstrate that they have sufficient levels of access to the data relating to the equivalent devices to be able to prove equivalence.

For implantable and class III devices, the following applies:

The MDCG 2020-5 guideline states that for all other devices, a corresponding contract is not required.

The requirements of the MDR for “sufficient levels of access” to the data on equivalent devices and for “sufficient clinical evidence” are the most open to interpretation. Even though and because it is not yet entirely clear how the notified bodies will interpret these requirements in practice, as the manufacturer, you are already required to explain and justify what you consider to be sufficient for your substance-based medical device.

e) Imprecise definition of the scope of clinical data

While the clinical performance, safety and clinical benefit of substance-based medical devices must be demonstrated with clinical data, the level of evidence that is considered sufficient depends on the characteristics of the device and its intended purpose:

f) New requirements for the documentation of substance pharmacokinetics

Another new requirement established by the MDR for substance-based medical devices that are absorbed by or locally dispersed in the human body is the requirement to document their pharmacokinetics, i.e., their absorption, distribution, metabolism and excretion, which is similar to the requirement for medicinal products for human use.

Therefore, you should make sure that the pharmacokinetics of the substances are documented in your biocompatibility evaluation.

3. Practical tips

In order to continue being able to market your existing device after the end of the transitional periods, we recommend taking the following steps now:

a) Review the mechanism of action of the substances in your substance-based medical device

Make sure that the formulation and intended purpose are aligned. Only if all the substances responsible for the intended purpose have a physicochemical and/or physical mechanism of action can you ensure a clear differentiation from medicinal effects and ensure that your substance-based medical device is not inadvertently classified in class III. For devices in this class, the MDR requires clinical investigations.

b) Review the available (clinical) data

Review the available (clinical) data from the following sources:

• Tests with your own device/studies with equivalent devices from the literature
  Check the equivalence when using literature data according to the requirements of the MDR and the MDCG 2020-5 document on the clinical evaluation and equivalence. Document that you have sufficient levels of access to the data relating to the equivalent devices and have enough data to be able to make an equivalence assessment.
• Post-market surveillance (PMS) data
  If you have been marketing the device for a sufficiently long time and have an established quality management system, these clinical data can help demonstrate the safety of your existing substance-based medical device.
• General PMCF activities
  The general PMCF activities listed in the PMCF plan and report that are required by the MDR for every device include, e.g., the gathering of clinical experience, collecting user feedback, and screening scientific literature and other sources. Analyzing these activities provides further clinical data for your device.

c) Identify missing data using a gap analysis

Work out which functions of your substance-based medical device can be demonstrated with clinical data and which can be demonstrated using performance data. Based on the device’s properties and its intended purpose, specify the amount of clinical data you consider sufficient for your existing substance-based medical device.

d) Generate the missing pre-clinical/in vitro data required to demonstrate the biocompatibility and/or non-clinical performance functions/claims

If pre-clinical or in vitro data can be used to fill existing gaps in the evidence proving the safety and performance of your substance-based medical device, you should generate them now.

e) If necessary, generate the missing clinical data for your substance-based medical device using a PMCF study

If, and in which cases, the conduct of PMCF studies for existing devices is necessary is subject to discretion according to the MDCG 2020-6 guideline on clinical evidence:

While the conduct of clinical investigations for class III devices and newly developed devices is mandatory, simpler, effective and more resource-efficient options for generating clinical data are available to you for all other existing substance-based medical devices. Make the most of the options open to you for these devices and start PMCF studies if the existing clinical data are not sufficient to demonstrate the safety and performance of the clinical functions.

The Johner Institute can help you overcome the regulatory hurdles and ensure that you can continue to market your substance-based medical devices. It can also answer your questions such as:

• Is your substance-based product actually a medical device? If yes, what class is it?
• Does your substance-based medical device contain substances that may be considered medicinal products?
• What clinical data do you need for the clinical evaluation of your substance-based medical device? What is the quickest way of collecting the missing data?
• Does your medical device meet the requirements of the MDR? Can you continue to market your existing product in compliance with the regulations?

Please contact us, for example via the web form or, for quick questions, use the Johner Institute’s free micro-consulting service.

Our experts will also be happy to write a clinical evaluation or biocompatibility evaluation for your substance-based medical devices.