Medical Devices with Ancillary Medicinal Substances – EU MDR

The following is the sixth in the series of blogs related to some of the key challenges encountered due to the recent updates to EU MDR. Read our other posts about understanding:

• Medical Device Equivalence vs Demonstration of Equivalence
• Post-market Clinical Follow-up Requirements for EU MDR
• The New European Union MDR: Impact on Technical Files
• Low-risk Device Challenges
• Selecting and Working with your Notified Body.

In this post we’ll detail the changes the new EU MDR will have on medical devices with ancillary medicinal substances (combination products).

It can be challenging to determine the classification of your product under EU MDR 2017/745. To correctly understand if your product falls under the medicinal product directive or medical device regulation, you first need to evaluate the (PMOA) Primary Mode of Action.

A ‘medical device’ is 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.

A medicinal product example could be wound treatment product for delivery of an antimicrobial product whereby the PMOA is either (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.  For example, a wound dressing with an antimicrobial coating or a heparin-coated catheter are medical devices per the definition in Article 2 of the EU MDR 2017/745.

Devices which incorporate an ancillary medicinal substance or combination products, such as drug-eluting stents or metered-dose inhalers, contain a medical device component which acts as the delivery system of the integral drug element.  To be considered a device-drug and fall under the EU MDR, the PMOA should be achieved by the device part with the substance having an ancillary action. EU MDR Article 1 Subject Matter and Scope subpoint (8) states:

“Any device which, when placed on the market or put into service, incorporates, as an integral part, a substance which, if used separately, would be considered to be a medicinal product as defined in point 2 of Article 1 of Directive 2001/83/EC, including a medicinal product derived from human blood or human plasma as defined in point 10 of Article 1 of that Directive, and that has an action ancillary to that of the device, shall be assessed and authorised in accordance with this Regulation”.

Medical Devices:

• EU Medical Device Regulation (MDR) 2017/745
• EU In Vitro Diagnostics Regulation (IVDR) 2017/746
• MEDDEV guidelines

Medicinal Products Directive:

• Regulation 726/2004: Establishment of European Medicines Agency (EMA)Directive 2001/83/EC Medicinal products for human use
• Amended Directives 2002/98/EC; 2004/24/EC and 2004/27/EC.

For combination products, the documentation should be compiled in accordance with the relevant regulation either IVDR Annex II or MDR Annex II. For the drug section, requirements set out in Notice to Applicants Volume 2B are applicable. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-2/b/update_200805/ctd_05-2008_en.pdf eCTD format.

The European Medicines Agency (EMA), which oversees the European Union’s pharmaceutical market, published draft guidelines on Medical Devices Regulation (MDR) in 2019 for manufacturers of combination products with drug and medical device elements. The guidelines address Article 117 of the MDR, which will establish new compliance obligations for drug-device combination products.  It is expected that the final text will be issued ahead of the May 2020 MDR deadline. https://www.ema.europa.eu/en/quality-requirements-drug-device-combinations

Guidance from the EMA relating to the procedural aspects as well as format and data requirements to facilitate the consultation procedure to the European Medicines Agency (EMA) by notified bodies can be found here: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/ema-recommendation-procedural-aspects-dossier-requirements-consultation-ema-notified-body-ancillary_en.pdf (updated Jan 2020)

MEDDEV Borderline products, drug-delivery products and medical devices incorporating, as an integral part, an ancillary medicinal substance or an ancillary human blood derivative https://ec.europa.eu/docsroom/documents/10328/attachments/1/translations is a helpful document, but this will need to be updated to incorporate the MDR requirements, as this is currently written to address MDD93/42/EEC requirements.

The consultation process for devices which incorporate an ancillary medicinal substance has not changed dramatically under the new regulation. Depending on the type of ancillary medicinal substances, a consultation with either the European Medicinal Component Authority (CA) or with the European Medicines Agency (EMA) is required.

It usually is at the discretion of the notified body to choose who they feel is best suited to review based on previous experience and where the product will be sold. The consultation will include aspects of quality and safety of the drug substance alone, and also the usefulness of the drug into the device (clinical risk/benefit) of the ancillary medicinal substance. However, the notified body must consult the European Medicines Agency in the case of ancillary human blood derivative or medicinal products that fall within the scope of the Annex to Reg. (EC) No 726/2004.

The notified body will give due consideration to the opinion of the European Medicines Agency when making its decision. It will not deliver the certificate if the Agency’s scientific opinion is unfavourable. As part of this process, there will typically be a pre-submission meeting held, allowing the manufacturer and the notified body to meet with the CA or the EMA to have an opportunity to discuss the regulatory pathway. Scientific advice cannot be given during this meeting. Usually, the notified body should request this pre-submission meeting at least six months before the intended submission date.  Once the review has taken place, the CA/EMA will issue a decision to the notified body. The consultation process should take no longer than 210 days, from receipt of a completed/valid application. However, should the information be missing or inadequate, then the clock is stopped until the required data is provided.

The format for what needs to be provided as part of the consultation procedure is well documented in [1]Appendix 1, Data requirements and format of the application dossier and Appendix 2, Scientific explanation for qualification.

The recently published EMA document[2] discusses the requirements of Article 117 of the EU MDR 2017/745, and details requirements for Notified Body involvement of a medicinal product that incorporates a drug-device combination product. Article 117 of the has introduced amendments to Annex I section 3.2 (12) of (MPD) Medicinal Products Directive 2001/83/EC concerning the documents need to be submitted to the CA assessing Marketing Authorisation Applications (MAAs) for medicinal products incorporating a device as an integral part. These products are covered by the second subparagraph of Article 1(8) and the second subparagraph of Article 1(9) of the MDR.

The amended provisions of point 12 of Section 3.2 of Annex I to Directive 2001/83/EC, require applicants for Marketing Authorisation Applications (MAAs) of medicinal products incorporating as an integral part a device, to submit the results of the assessment of the device part with the relevant GSPRs set out in Annex I to the MDR. If the application dossier does not contain these results and where the conformity assessment of the device, if used separately, requires the involvement of a notified body, the applicant is required to provide an opinion on the conformity of the device with the relevant general safety and performance requirements (GSPRs) issued by a notified body. You should ensure that your notified body is appropriately accredited to render such opinions.

1. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/ema-recommendation-procedural-aspects-dossier-requirements-consultation-ema-notified-body-ancillary_en.pdf
2. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-requirements-drug-device-combinations_en.pdf

Obtaining marketing authorisation for devices which incorporate an ancillary medicinal substance is costly, time-consuming and can be challenging, especially if you are not familiar with the new requirements.

Most medical device companies are now familiar with the requirements of the new regulations; however, pharmaceutical regulatory teams may likely find themselves in uncharted waters.  The planning stage is crucial to meet the deadlines in time and efficiently manage compliance timelines and expectations. Therefore, partnering with a specialist that understands the requirements is essential to minimise the regulatory risk, and ensure speed to market.

Celegence can assist in navigating the medical device regulations and determining the way ahead for your device.  Get in touch, speak to our experts – we can offer a partnership approach while helping you gain the necessary regulatory approvals.