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:
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).
“Substance-based medical devices are medical devices that are composed of substances or of combinations of substances. Although they are similar to medicinal products in their presentation and pharmaceutical form, they achieve their principal intended effect via a physicochemical and/or physical mechanism of action. Medicinal products, in contrast, have a pharmacological, immunological or metabolic mechanism of action.”
Source: MEDDEV 2.1/3 rev3
Substance-based medical devices include:
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.
The MDR has introduced a new classification rule for substance-based medical devices, namely Rule 21 in Annex VIII:
“Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body via a body orifice or applied to the skin and that are absorbed by or locally dispersed in the human body are classified as:
– class III if they, or their products of metabolism, are systemically absorbed by the human body in order to achieve the intended purpose;
– class III if they achieve their intended purpose in the stomach or lower gastrointestinal tract and they, or their products of metabolism, are systemically absorbed by the human body;
– class IIa if they are applied to the skin or if they are applied in the nasal or oral cavity as far as the pharynx, and achieve their intended purpose on those cavities; and
– class IIb in all other cases.”
MDR, Annex VIII, Rule 21
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.
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.
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:
The device is:
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.
Note that for some attributes the medical device and the equivalent device have to be identical while for others they can be merely “similar”.
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.
“It shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in order to justify their claims of equivalence.”
MDR, Annex XIV
For implantable and class III devices, the following applies:
“the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis”
The MDCG 2020-5 guideline states that for all other devices, a corresponding contract is not required.
“For devices other than implantable devices and class III devices there is no MDR requirement of a contract between the manufacturers for regulating the access to the technical documentation.”
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.
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:
“The manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements. That level of clinical evidence shall be appropriate in view of the characteristics of the device and its intended purpose.”
The article on clinical data describes what clinical data are and how they can be collected.
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.
“Devices that are composed of substances or of combinations of substances that are intended to be introduced into the human body, and that are absorbed by or locally dispersed in the human body shall comply, where applicable and in a manner limited to the aspects not covered by this Regulation, with the relevant requirements laid down in Annex I to Directive 2001/83/EC for the evaluation of absorption, distribution, metabolism, excretion, local tolerance, toxicity, interaction with other devices, medicinal products or other substances and potential for adverse reactions, as required by the applicable conformity assessment procedure under this Regulation.”
MDR, Annex I, 12.2
Therefore, you should make sure that the pharmacokinetics of the substances are documented in your biocompatibility evaluation.
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:
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.
While some substances have a clearly identifiable mechanism of action, the type of processing can play an important role in the resulting mechanism, for example, in the case of mixes of herbal substances. For other ingredients, there is a threshold value for the pharmacological effect that you should take into account in your formulation. Feel free to contact us if you need help determining the mechanism of action or differentiating your medical device from a medicinal product.
Review the available (clinical) data from the following sources:
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.
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.
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:
“In some cases, it may be necessary for the manufacturer to undertake PMCF to generate new data for these legacy devices prior to CE marking under the MDR, whereas in other cases (…) it may be possible to demonstrate conformity with the relevant GSPRs with a more limited clinical data set.”
If clinical data are required to fill existing gaps, you should initiate a PMCF study now and do so whenever
If you want to be able to continue to market your existing substance-based device under the MDR after the end of the transitional periods, we advise you to act now in order to be able to meet the regulatory requirements.
Use the time you have and generate the missing (clinical) data. The budget and time outlay should be based on the risk class while at the same time conserving resources, i.e., as little as possible and as much as necessary to ensure patient safety. The various options for generating data for your existing substance-based medical devices according to the risk class are summarized in Fig. 2:
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:
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.