By Dr. Catarina Carrao
The European Medicines Agency (EMA) has seen an increase in the number of scientific advice requests and Marketing Authorisation Applications (MAAs) for devices where a medicinal product incorporates, either in an integral or non-integral manner, a medical device component1. Such devices have clear benefits for patients with regular long-term dosing requirements in outpatient settings, either by self-administration or with the support of a lay caregiver. This reduces not only the burden on patients, but also on healthcare systems.
Previously, there were no clear regulatory requirements for such types of medical devices. But, to ensure that such components do not escape regulatory scrutiny, Article 117 of the European Union (EU) Medical Device Regulation (MDR) has provided an amendment outlining specific requirements for drug device combination medical products.
Article 117 finds itself within Chapter X (10) of the Final Provisions of the new MDR. This article is of high impact to market authorisation holders who provide medicinal products integral with administration devices, known as Drug-Device Combination (DDC) products2.
Article 117 requires that the MAA for an integral DDC device should include a declaration of conformity, or relevant certificate, issued by a Notified Body (NB) 3. If the product dossier does not include the results of the assessment of conformity, then the manufacturer will be required to provide an opinion from a NB on the conformity of the device part, in relation to the relevant requirements of Annex I (MDR 2017/745) 3.
The NB is an entity designated by an EU Competent Authority to assess the conformity of medical devices before being placed on the market. Companies are free to choose the NB they engage with; the only criterion is that the NB must be designated to carry out the conformity assessment procedure for the particular medical device type(s) for which a certification is sought3. As such, applicants can check the NANDO website (New Approach Notified and Designated Organisations), by clicking on ‘Legislation’, and then select the relevant Directive/Regulation to search for a NB designated for the product types and technical competences needed4. The guideline even goes the extra-mile and contains a proposed template for the NB opinion on the conformity of the device in relation to the relevant safety and performance requirements of the new regulation5.
Article 117 only applies to medicinal products that form an integral product with a medical device - also known as integral DDC. These are devices necessary for the administration, dosing or use of a specific human medicine5; and, can fall into two categories: 1. Devices that incorporate a substance as an integral part; that, if used separately, would be considered a medicinal product (according to Article 1(8) MDR); 2. Devices intended to administer a medical product, envisioned exclusively in that given combination; and, which are not reusable (according to Article 1(9) MDR)1.
As such, if a medical device is used to administer a medicinal product, and it is placed on the market in such a way that the device and medicinal product form a single product, intended exclusively for use in the given combination and not reusable, then Article 117 applies3.
For example, pre-filled syringes, pre-filled pens, nebulizers pre-charged with a specific drug, patches for transdermal drug delivery and pre-filled inhalers are all integral products which are not reusable. On the other hand, an example of a combination product which is not an integral product, is a vial containing a drug solution with an (empty) co-packaged syringe.
As always, there is an exception to the rule, which falls in the case of combined Advanced Therapy Medicinal Products (ATMPs), where the guidelines are clear that Article 117 does not apply (Article 2(1)(d) of Regulation EC 1394/2007) 3.
According to the EMA, integral DDCs currently authorized for sale in the EU, or those whose applications which will be submitted prior to the MDR enforcement date (26th May 2021), will not be impacted by Article 117 requirements6. But, such products may become subject to those requirements if manufacturers make substantial modifications to the device components of their products (e.g., addition, full parts replacement or design changes) 3.
After the 26th of May 2021 all MAAs for integral DDCs must demonstrate that the device part meets the relevant requirements of the regulation. As such, if the device component has CE marking, then the manufacturer is expected to provide a Declaration of Conformity, or the NB certificate, allowing the manufacturer to affix CE marking to the device3.
In the case the product file does not include at least one of those documents, and the device component is a risk classification of sterile class I, measuring class I, class IIa, class IIb or class III medical device, then the applicant must provide an opinion from an NB on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I of MDR 2017/745.
In November 2019, the EMA released an update on the guidelines based on a stakeholder public consultation. It focusses on aspects relating to the implementation and applicability of the requirements of Regulation EU2017/745 to medicinal products with an integral medical device, and it is meant to be a living document. The questions and answers are being updated continuously, and will be marked by “NEW” or “Rev.” with the relevant date upon publication until the final date of enforcement of the new MDR7.
To smooth the procedures, there is a strong recommendation from the agencies for the EU certificate or declaration of conformity or NB opinion to be already included as part of the dossier of the initial MAA for the medicinal product. The absence of such documents could result in additional clock stops during the procedure, as these are fundamental for the adoption of a positive opinion by the Committee for Medicinal Products for Human Use (CMPHU) and market approval.
NBs will require Technical Documentation that provides evidence and scientific data to support the product claims; and, expectations of which Technical Documentation to include are detailed in Annex II of the MDR8. The information that is usually needed by NBs to support a conformity assessment for medical devices includes:
The submitted scientific data must demonstrate conformance to the appropriate General Safety and Performance Requirements (GSPRs), found in Annex I of the EU MDR (not all GSPR’s will be applicable to integral drug-device combination products)8. Based on the data provided, NBs will assemble a report that concludes whether the device meets, or does not meet, all the relevant requirements. If the NB concludes that requirements are not met, the manufacturer should work with the NB to obtain a positive opinion. NB reports will not include quality management certification8.
To meet the deadlines in time, and efficiently manage compliance timelines and expectations, planning is of the upmost importance. Manufacturers should take into account NB liaison and procedures, as well as the level of device risk and, therefore, the level of scrutiny required for market approval. To ensure patient safety, avoid any interruption to the market, and, by that a negative impact on the company’s reputation; maybe, seeking advice and practical support from a third-party specialist might be the way to go.
Most medical device developers already follow the design and development methodology ISO 13485, though pharma developers will now need to register their products under medical device regulations when they previously didn’t. The requirements listed in Annex I of the EU MDR and needed for compliance with article 117 will represent only a small proportion of the total number of physical and performance characteristics of the intended medical device.
Most developers have prepared and keep an up to date “checklist” listing each of the general safety and performance requirements, a short summary of how the requirements are fulfilled, or explanation for why the requirement is not applicable. So, on the most part, the information is already in the hands of the manufactures and just needs to be delivered to the NBs upon the MAA.
Dr Catarina Carrao gained a PhD in Biochemistry from Northeastern Ohio Medical and Pharmacy University and an M.Phil in Biochemistry at the University of Beira Interior. She has worked as a researcher at Max F. Perutz Laboratories, Yale Cardiovascular Center at Yale University School of Medicine, and the Center Cardiovascular Research (CCR) at Charité Medical University.
