This section covers the borderline between products that may fall under the MDR, or possibly under Directive 2001/83/EC relating to medicinal products for human use.
What are borderline products?
Borderline cases are those for which it is not clear from the beginning whether a given product is a medical device, or an in vitro diagnostic medical device (IVD), or not. The correct qualification and classification is crucial to assess if it falls within MDR IVDR or other regulations.
What are medical devices with medicinal substances?
Medical device with medicinal substance can contain a substance having an action ancillary to that of the device, which, if used separately, would be considered as a medicinal product (drug).
What is an ancillary action to the medical device?
The ancillary action is when the main mode of action is due to the device and a medicine is incorporated within a medical device with a supporting function. Medicinal product is any substance or combination of substances intended to treat or prevent disease in human beings. Any substance or combination of substances that may be administered to humans for the purpose of making a therapeutic diagnosis or restoring, correcting or modifying physiological functions in humans shall be treated as a medicinal product. The action of the medicinal substance must be ancillary to the principal action of the device, not based on it.
In addition, the intention of the manufacturer regarding the effect of the substance on the device or organism is not relevant for deciding whether the substance will be considered a medicinal product, as intentionality is not mentioned in the MDR legislation in question. Therefore, the manufacturer’s intentions regarding the effect of a substance on an article or organism are irrelevant in deciding whether a substance will be considered a medicinal product. What matters is the actual mode of action of the substance on the body, based on general scientific knowledge. If it is the mode of action through a pharmacological or immunological or metabolic pathway, the substance will be considered a medicinal product.
The action of substances ancillary to the action of a device is to be understood as occurring in or on the human body or its components (e.g. blood, organs, in vivo or ex vivo, gametes, wound exudate) and assisting the device in achieving its specific medical use. We can only speak of the ancillary action of a medicinal substance in a medical device if the removal of the medicinal substance from the device does not alter the essential intended action and use of the medical device. If a device devoid of a medicinal substance will not have the same indication, use, action, it cannot be said to be ancillary to the medicinal substance, but the main action. Consequently, the product will not meet the definition of a medical device, but the definition of a medicinal product (drug).
What are regulations for medical devices with medicinal substance?
Medical devices containing as an integral part a substance with an action ancillary to that of the device, which, if used alone, would be considered a medicinal product are subject to the requirements of Regulation MDR 2017/745 (Article 1(8)). The requirements for a medicinal substance which, if used separately, would be considered a medicinal product within the meaning of Article 1(2) of Directive 2001/83/EC are set out in Annex I to that Directive.
What are examples of medical devices with medicinal substance?
- Irrigation solutions for mechanical flushing (e.g. bladder irrigation solution, eye irrigation solution)
- Bone cement with antibiotics
- Condoms with spermicide
- Catheters coated with anticoagulants (e.g. heparin)
- Endodontic materials with antibiotics
- Dressings containing an antimicrobial agent where the substance has an ancillary effect on the wound
- Drug-eluting stents (e.g. coronary, pulmonary)
- Implants coated with human fibrinogen
- Blood bags containing heparin or other substances as anticoagulants which, if used alone, may be considered a medicinal product
- Gels containing analgesics or anaesthetics, e.g. lidocaine.
Qualification and classification of medical devices with medicinal substance
The first and most important step in the qualification of products containing a substance, with an action ancillary to that of the device is to determine whether the product under consideration meets the definition of a medical device as set out in Article 2 of MDR 2017/745, including a determination supported by evidence that the action of the contained medicinal substance is indeed ancillary to, rather than based on, the main intended action of the device (see above). The classification of medical devices is set out in Annex VIII of MDR 2017/745, which contains 22 classification rules. For devices with a medicinal substance, Rule 14 applies.
Requirements for medical devices with medicinal substance
The requirements for medical devices containing, as an integral part, a substance which, if used separately, may be considered to be a medicinal product cover three areas:
- general requirements for all medical devices, which are set out in MDR
- additional requirements for Class III devices, which include devices with a medicinal substance
- additional requirements due to the presence of a medicinal substance, which are set out in Directive 2001/83/EC.
Challenges for manufacturers to introduce medical device with medicinal substance
The challenges for manufacturers of medical devices containing, as an integral part, a substance that, when used alone, may be considered a medicinal product are based on considerations:
- classification of this type of device to Class III, i.e. the highest risk, and the presence of a medicinal substance in the composition of the device. Their coexistence means that the number of challenges and requirements faced by manufacturers of devices with a medicinal substance is greater and more difficult than for lower-risk devices.
- verification and evaluation of the quality, safety and usability of the medicinal substance by the manufacturer and then by the notified body
- preparation of additional documentation;
- increased post-market surveillance of the product;
- a longer and more difficult certification process;
- higher costs.
What is the clinical evaluation of devices with medicinal substance?
The general requirements for the clinical evaluation of medical devices of all classes are set out in Article 61 of MDR. Additional requirements are set out for them.
In practice, this means that for devices with a medicinal substance, as Class III devices the manufacturer is obliged to:
- conduct a clinical trial although the regulation allows for the possibility of waiving clinical trials in the cases described in Article 61.
- explain how it intends to assess the benefits and risks posed by the presence of the medicinal substance as part of the overall clinical evaluation of the device.
- indicate in the Clinical Evaluation Plan how benefit/risk ratio issues will be addressed for the use of the medicinal substance
- produce a summary of safety and clinical effectiveness (SSCP for short). The draft SSCP is part of the dossier to be submitted to and approved by the notified body
- update the Post-Marketing Clinical Follow-Up.
What does the certification process of medical devices with medicinal substance look like?
Certification of a medical device is the procedure for obtaining a certificate of conformity with the MDR 2017/745 regulation, which is issued by the Notified Body carrying out the conformity assessment. Certification of products containing a medicinal substance is longer, more difficult and certainly much more expensive than products of lower classes. This follows directly from the provisions of MDR.
What changes has Regulation MDR brought for devices with a medicinal substance?
Regulation MDR introduced a number of key changes for medical devices containing a medicinal substance to get CE marking. The main aim of which is to increase the safety of users and patients using devices with a medicinal substance:
- all devices containing as an integral part a substance, and whose action is ancillary to that of the devices, have been classified as Class III devices and therefore those whose use presents the greatest risk to the user/patient;
- a requirement has been introduced to present data on the quality and safety of a medicinal substance in the technical documentation in the same way as for medicines;
- an obligation is placed on manufacturers to prove the ancillary effect of a medicinal substance in relation to a device, based solely on scientific data, to the exclusion of intentionality on the part of the manufacturer;
- more stringent conformity assessment and post-market surveillance procedures have been introduced,
- a requirement to prove the clinical safety of devices with a therapeutic substance has been introduced (in principle by conducting clinical trials);
- an obligation to produce and update (at least annually) a summary of safety and clinical effectiveness, the so-called SSCP, has been introduced.