The Medicinal Product Directive (MPD) mandates evidence of CE marking but does not detail the requirements for non-CE marked devices. According to Article 1 Subpart 3 of the MPD, devices in which ‘the device and medicinal product form a single integral product which is intended exclusively for use in the given combination and which is not reusable’ were governed by the MPD. Additionally, the essential requirements of Annex I in the MDD was applicable to establish safety and performance of the device.
The EMA, which oversees the European Union’s pharmaceutical market, has begun rolling out guidance and clarifications regarding Medical Devices Regulation (MDR) compliance issues for manufacturers of combination products with drug and medical device components. As per the EMA guideline, manufacturers of drug-device combination products will have to meet MDR Article 117 regulatory requirements. The EMA notes that Article 117 of the Regulation requires Notified Body (NB) involvement for European market authorization of a medicinal product that incorporates an integral medical device, or drug-device combination product.
Article 117 of the new EU MDR amends Annex I of the Medicinal Product Directive (MPD) 2001/83/EC, point 12 of Section 3.2. This states that:
“(12) Where, a product is governed by this Directive, the marketing authorization dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer’s EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device.
If the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation issued by a notified body designated in accordance with that Regulation for the type of device in question.”
The change mainly applies to integrated, non-reusable products where the drug element is the primary mode of action. Fundamentally, the device element of a medicinal product – when integral (classified either as Class I [i.e. sterile], Class IIa, Class IIb or Class III), non-reusable and intended exclusively for use in the given combination – needs to conform to the Annex I (MDR) GSPR and without the requirement to be regulated as a CE-medical device. Integral devices classified as Class I devices (i.e. non-sterile) are not subject to an NB opinion.
Although a short article, it introduces a new requirement for NB involvement in medicinal products with an integral medical device. Marketing such products as a ‘medicinal product’ would require manufacturers to seek a Notified Body Opinion (NBOp). The NB will access and confirm if the device is compliant with the relevant General Safety and Performance Requirements (GSPR) and issues an NBOp report to the manufacturer. The NBO report is expected to be submitted to the EMA in the Market Authorisation Application (MAA) by the manufacturer. This will be assessed by the Competent Authority and the final approval of the product will remain with the EMA.
With the changes implemented by the EU MDR, the MAA must include either a:
- CE certificate issued by a NB for the medical device component, or
- Notified Body Opinion (NBO) on the conformity of the device
Scenario 1 would require manufacturers of the medical devices to obtain CE marking with the aid of an appropriate conformity assessment process applicable to the device. The CE certificate would then need to be submitted to the MAA.
Scenario 2 where a CE mark has not been issued to the device component on its own, the manufacturer must reach out to an NB and seek their opinion on the conformity of the device, and provide the NBO report in the MAA.