An overview of drug-device combination products in the EU

For the purpose of this blog post, drug-device combination products are therapeutic and diagnostic products that may combine medicinal products, including biological products, with a medical device. From a regulatory perspective, the intermixing of device technologies and pharmaceutical innovation associated with combination products requires greater coordination and communication between the various stakeholders.

An important point to note is that in the EU, unlike the USA, there is no single definition of a combination product in the legal framework of either medicinal products or medical devices. EU products combining a medical device and medicinal product are either regulated as a medicinal product or a medical device with the primary mode of action governing the regulatory pathway. In Europe, the agencies involved in these assessments include the EMA, the national competent authorities for the medicinal product part and the Notified Bodies for the device part. A Notified Body is an organization designated by the EU Commission to assess the conformity of medical devices before being placed on the market.

In 2019 the EMA published draft guidelines on quality requirements for medical devices in human medicines specific to drug-device combinations. The guidelines were a response to a growing number of requests for advice, cover the main aspects of the quality requirements. Among the key challenges in developing drug-device combination therapies are those associated with addressing human factors studies and studies in representative user populations. These are particularly pertinent to patient administered drug-device combinations. New requirements for post-market surveillance also present an important consideration for developers as they prepare applications.

The regulatory framework for medical devices incorporating medicinal substances as an ‘integral part’ is described in Article 1(8) of MDR[1]:

1. Where the action of the medicinal substance is ancillary, the product is regulated as a medical device and must be CE marked. As the action of the medicinal product is considered ancillary, a scientific opinion must be provided from a medicines authority before a notified body can issue a certificate for the combined product. Although the majority of digital trends are being driven and implemented in the developed world, developing economies will be further left behind if they cannot progress in areas that will benefit them.
2. Where the action of the medicinal substance is principal, the combination product is regulated under the medicinal products framework. In this case, the relevant general safety and performance requirements (GSPR) of the MDR apply to the device part.

The regulatory framework for administration devices is described in Article 1(9) MDR[2]:

1. If the administration device is marketed as a single integral product intended exclusively for use in the given combination and is not reusable, the combination product is regulated under the medicinal products framework. In this case, the relevant GSPR requirements of the MDR apply to the device part.
2. In all other cases, the administration device is regulated under the medical device framework. When the medical device is not physically combined with the medicinal product the device will need to be CE marked. The (separate) medicinal product must be licensed for use under the medicinal product directives.
3. Different types of combination product have different regulatory requirements. The combination type and requirements are discussed in more detail below.

For all the above, adhering to the foundations of effective combination product development is essential to meet regulatory requirements. Those foundations rest on the integration of quality by design, design controls, human factors, risk management and standards. While developers may be accustomed to considering the suitability of the device for drug delivery, the intended use, product configuration, intended user(s), risks and controls; mapping a cascade of controls and sharing information about each GSPR through the product lifecycle is an added dimension of complexity. Effective purchasing controls and supplier quality agreements are another critical tenet in a successful strategy for control of combination products.

The combination product category encompasses a wide variety of products. Changes in EU policy seek to introduce greater transparency to the process and encourage combination product developers to engage in early dialogue with the pertinent regulatory agencies. For example, one category of combination product to consider is known as Drug/ Device Combinations or DDCs, although this is not a regulatory term. In the EU, combination products that are integral, exclusively for use and not reusable, can be considered DDCs and their regulation now described in Article 117 of the MDR[3]. If the device is intended to administer a medicinal product and the product is placed on the market in such a way that it forms a single integral product intended exclusively for one-time use in the given combination, that single integral product is governed by Directive 2001/83/EC or Regulation (EC) No 726/2004, as applicable.[4] [5] In that case, the relevant GSPRs set out in Annex I to this Regulation apply as far as the safety and performance of the device part of the single integral product are concerned.

Article 117 of the MDR also introduced additional requirements for the manufacturers of such combinations in requiring the involvement of a Notified Body in the process to provide an opinion on the conformity of the device aspects against MDR Annex I, GSPRs, in the cases where the device itself has not been CE marked in its own right.[6]

This is an excerpt from the forthcoming BSI medical devices white paper, The convergence of the pharmaceutical and medical devices industries. To browse our collection of medical device white papers, please visit the Insight page on the Compliance Navigator website.