Combination products became an essential tool for the delivery of medicinal products and in the last years the number of marketing authorisation for these types of devices increased significantly.

Combination products are composed of any combination of an ancillary drug, device, and biologically active product. Examples include drug-eluting stents and medicated dressings, both in which a medicinal component contained within the device coating has an ancillary purpose to that of the device. Other types of combination products are insulin injector pens and metered-dose inhalers, which function as prefilled drug-delivery systems.

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.

With the EU Regulation 2017/745 on medical devices (EU MDR), new requirements have been imposed on combination products regarding their medical device component, that not only involve medical device manufacturers, but also pharmaceutical and biopharmaceutical companies. Pharmaceutical companies that manufacture combination products or companion diagnostics, also find their products undergoing greater clinical scrutiny than before as laid out in the new Regulation. The EU MDR’s inclusion of combination products results from their increasing design and production complexities. The strategy also ensures that combination products and standalone devices undergo equivalent risk management and safety scrutiny. Ancillary-device components are now examined with the same care as standard medical-device products.

Before EU MDR, in general, manufacturers needed to have market authorisation for the drug, however no specific process was in place for the medical 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 dramatically changed as with the Article 117 of new EU MDR 2017/745.

Article 117 of EU MDR introduces the notion of risk-classification, and accordingly to involve a Notified Body as a new stakeholder in the medicinal product’s Marketing Authorization application (MAA) process in Europe. 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 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 (GSPRs) and provide the Notified Body 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 Notified Bodies will assess the relevant GSPRs. When the manufacturer seeks 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 to demonstrate conformity to GSPRs. A comprehensive guideline was prepared by EMA in order to define the quality requirements for drug-device combination products; Guideline on the quality requirements for drug-device combinations.

On the other hand, the process for ancillary device (a medical device may contain an ancillary medicinal substance to support the proper functioning of the device) did not substantially change from the EU Medical Devices Directive (EU MDD). These products fall under the medical devices legislation, must be CE marked and as class III Rule 14 devices a medicinal dossier, in Common Technical Documentation format (CTD format) on the ancillary medicinal substance. 

Obstacles observed by manufacturers: 

• Limited Notified Body capacity; there are many pharmaceutical companies with full pipelines and few designated bodies (all Notified Bodies had to reapply) to review new devices. Pharmaceuticals companies with a portfolio that does not include medical devices sold in the EU may not have a standing relationship with a Notified Body and find application queues are long.
• Unfamiliar process; each Notified Body is a separate organization with an independent process and variation in staff support for this new type of review. There is uncertainty with the level of detail needed and how to submit information. Unlike the MAA, Technical Files are not in eCTD format, and each Notified Body must design and implement their own interface for handling submissions. Team Notified Body, the European Association of Medical Devices-Notified Bodies, issued a Position paper on Documentation Requirements for Drug Device Combination Products recommending documentation structure.
• Critical path; unless there is prior agreement with the Committee for Medicinal Products for Human Use (CHMP), the device CE certification or Notified Body Opinion must be included in the MAA, meaning that device development work has to be complete earlier in the overall product development process. The CE mark or Notified Body Opinion is anticipated to take 2-6 months. Since device decisions are often made late in the drug development cycle, Article 117 requirements put additional pressure on an already accelerated timeline.

Billev Pharma East has expertise in regulatory, medical and safety of medicinal products and medical devices and can assist you with the preparation of the whole dossier package, obtain CE certificate and marketing authorisation. This is a great advantage for our partners in terms of time to market and costs.