Combination products will undergo to a substantial change under the EU MDR 2017/745 and new regulatory challenges are at the horizon. Drug-device combinations (DDC) became an essential tool for the delivery of medicinal products and in the last years the number of marketing authorisation for these types of device increased significantly. From market point of view, the global drug device combination product market size is expected to reach USD 177.7 billion by 2024, against USD 81,374 billion estimated for 2017. Thus, the industry is expecting a huge increased.
The new EU MDR 2017/745 introduces big changes in Europe for these types of products. Before EU MDR, in general, manufacturers needed to have EMA market authorisation for the drug but no specific process was in place for the device part of the products and, for the Medical Device Directive MDD, the conformity to Essential Requirements was usually demonstrated through a self declaration or compliance was directly checked by the competent authorities during the review to the Marketing Authorisation Application. Things have changed as with the Article 117 of new EU MDR 2017/745.
Characteristic of Combination Products
There are mainly two types of combination products:
- integral: the medicinal product and device form a single integrated product e.g. pre-filled syringes and pens, patches for transdermal drug delivery and pre-filled inhalers.
- co-packaged: the medicinal product and the device are separate items contained in the same pack e.g. reusable pen for insulin cartridges, tablet delivery system with controller for pain management.
Article 117 of EU MDR 2017/745
The main regulatory challenge is related to article 117 of EU MDR, that introduces a new concept for combination products (typically drug-device combinations). With this article, the marketing authorisation application should include a CE certificate for the device or, if it is not CE marked but would need to be certified if marketed separately, the applicant must include an opinion from a notified body (NOBp) on the conformity of the device. With this process, the notified body shall evaluate whether the device is compliant with General Safety and Performance Requirements and provide the NBOp report that can be included the in Market Authorisation Application.
In the framework of the Article 117 of EU MDR 2017/745, competent authority for the regulation of medicines will evaluate the device specific aspects of safety and performance relevant to the quality, safety and efficacy of the medicinal product, whereas the NB will assess the relevant GSPRs.
What type of Documentation shall be provided to the Notified Body?
When the manufacturers seek for a Notified Body Opinion Report for a drug combination product, it shall provide to the notified body the technical documentation defined in the Annex II of the EU MDR 2017/745.
As mentioned bore, the manufacturer shall demonstrate conformity to General Safety and Performance Requirements, taking in consideration that some GSPR won’t be applicable (for example the ones related to active medical devices).
A comprehensive guideline is currently under preparation by EMA in order to define the quality requirements for drug-device combination products; this guideline is currently in draft: Guideline on the quality requirements for drug-device combinations.
Rule Classification 14 and Combination Products with Ancillary Medicinal Substance
A medical device may contain an ancillary medicinal substance to support the proper functioning of the device. These products fall under the medical devices legislation and must be CE marked. An ancillary medical substances is defined as a medicine that is incorporated within a medical device where the main mode of action is due to the device.
Rule 14 for device classification according to the EU MDR states:
All devices incorporating, as an integral part, a substance which, if used separately, can 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 devices, are classified as class III.
The process for ancillary device did not substantially changed from the EU MDD. All class III Rule 14 devices must have a medicinal dossier, in Common Technical Documentation format (CTD format) on the ancillary medicinal substance.
In conclusions, in this post the new approach for the regulation of combination products according to EU MDR 2017/745 has been discussed. The necessity to have a CE marking or a Notified Body Opinion for the device part of a drug combination product is the main change which has been introduced with the European Medical Device Regulations.