Jackie Mulryne
Morgan, Lewis & Bockius, London
jackie.mulryne@morganlewis.com

Janine Reudt-Demont
Niederer Kraft Frey, Zurich
janine.reudt-demont@nkf.ch

Introduction

The new European Union General Pharmaceutical Legislation (GPL) will introduce wholesale changes to the pharmaceutical regulatory framework, and has been framed as the most significant overhaul of medicines regulation in two decades. Together with proposed changes to the EU Medical Devices Regulation (MDR) and other initiatives, the regulatory framework in the EU will be fundamentally changed in the coming years.

Combination products are products that may not fit neatly into the definition of medicine or device, and often have to comply with both regimes. The regulatory framework is therefore complex and is set to become even more so with these changes.

This article examines the implications of the GPL for combination products in both the United Kingdom and Switzerland, two jurisdictions which often align with EU rules but retain separate regulatory frameworks. The divergence resulting from changes in EU law potentially increases complexity, requiring careful consideration by those placing combination products on the market in these countries.

EU provisions on combination products

Definitions and classification

The key factor for classification of a product as either a medicine or a device is the principal mode of action: whether the medicinal product is ancillary to the mode of action of the medical device, or vice versa. The GPL retains this approach; however, it introduces legal definitions for various combination products that are regulated as medicines, formalising terms that were previously defined through European Medicines Agency (EMA) guidance:

• An ‘Integral combination of a medicinal product with a medical device’ means a combination of a medicinal product with a medical device, as defined by the MDR, where: (1) the two form an integral product and where the action of the medicinal product is principal and not ancillary to that of the medical device (such as bone cement containing antibiotics to treat infection); or (2) the medicinal product is intended to be administered by the medical device and the two are placed on the market as a single integral product that is intended exclusively for use in the given combination and where the medical device is not reusable (such as pre-filled syringes).
• ‘Medicinal products in exclusive use with a medical device’, means a medicinal product presented in a package with a medical device or to be used with a specific medical device, as defined by the MDR and referenced in the summary of product characteristics (such as a measuring cup for cough medicine).

These align with existing definitions in the MDR, thus providing additional legal certainty and consistency between medicines and devices rules, but do not fundamentally alter current practice. Note that where the action of the device is primarily and the medicinal substance is ancillary, the product is regulated as a medical device under the MDR.

Obligations for marketing authorisation applicants

For integral combinations, applicants must submit data showing the safety and efficacy of the entire combination, considering both the medicinal product and the medical device. The device element must meet the general safety and performance requirements of the MDR, and the EMA or national authorities will recognise assessments from notified bodies responsible for the device component. Similarly, for medicinal products in exclusive use with a device, evidence must be submitted of safe and effective use, and the device must comply with MDR requirements. The EU MDR notes that, in the absence of a European Commission certificate, a Notified Body Opinion on the conformity of the integral medical device component should be included.

Device performance and conformity data will form a key part of authorisation dossiers. The authorities will recognise the device-element assessment, with the aim of achieving coordinated (but still regime-specific) assessments for combination products. This approach does not significantly depart from current practice but aims to define expectations and processes more clearly.

Practical considerations and authority coordination

The GPL also codifies practical aspects of cooperation between medicines and device authorities. For example, there is the possibility for parallel scientific advice that considers the views of both medicines and device authorities, and provisions in relation to information and pooling of information with the Medical Devices Coordination Group. Coordination between the two regimes is complex and it is hoped that these provisions, and the procedures that are put in place to manage them, will streamline the process or manufacturers.

Implications for the UK

Regulatory framework in the UK

Following Brexit, the UK operates a standalone regulatory regime. The UK’s framework has remained closely based on EU law, with differences to date being mostly organisational and administrative rather than substantive. Due to agreements with the Commission about the regulation of products post-Brexit, certain products are on the UK market in line with UK law only (broadly including most innovative medicinal products), while others comply with both EU and UK law (broadly medicinal products authorised through national pathways and devices). In relation to devices, the MDR applies in Northern Ireland, but not in Great Britain.

In addition, the MHRA has introduced various reliance and recognition routes, that permit products that are on the market in the EU to be placed on the market in the UK through a streamlined process, with a substantial number of products currently placed on the UK market under such arrangements.

However, as the EU embarks on significant reform, regulatory divergence will increase. Changes to EU legislation will not directly affect products governed only by UK law, but shared systems and reliance/recognition approaches may be complicated by increased divergence. Further, for products that are on the market under both UK and EU rules, companies will need to apply both regimes. In addition, it will be important to monitor whether the changes to the EU regime impact the UK’s approach to recognition of EU authorisations.

Combination product-specific implications

The principles on classification of medicines and devices remain consistent between the UK and the EU; the Medicines and Healthcare products Regulatory Agency (MHRA) follows existing EU guidance, much of which is now codified in the GPL. Thus, immediate differences that are specific to these products are likely to be practical (relating to clarification and coordination) rather than substantive (relating to definitions and data requirements). However, if the EMA’s approach and guidance change in the future, these differences may increase.

As under the current guidance, EU CE or UKCA marking or an opinion from an EU notified bodies or a UK approved body will remain a requirement, and MHRA assessors will need to consider both the UK and EU device regimes when evaluating device aspects of combination products – this is, however, already the case.

Moreover, wider changes introduced by the GPL, particularly in relation to supply chains and shortages, will also impact applicants for combination products, and so companies will need to comply with evolving provisions on both sides of the Channel.

Future developments

The UK medical device regulation is currently being updated to bring it more into line with the EU MRD. As part of this, there are proposals to maintain indefinite recognition for EU CE marks and to introduce reliance/recognition routes for devices. In consultations, stakeholders noted that combination products (such as co-packaged products) should be allowed to use reliance routes with fewer requirements to avoid excessive burdens. The UK will need to consider the new EU processes as it adapts its own reliance frameworks.

Implications for Switzerland

Regulatory framework in Switzerland: definitions and classification

Under Swiss law, combination products are categorised as follows:

• Non-separable combinations (‘integral’), where the medicinal product and the medical device form a non-separable unit, and the combination product may not be reused. The medicinal product constitutes the primary mode of action. Examples include prefilled syringes, autoinjectors, preloaded powder inhalers and prefilled infusion pumps.
• Non-separable combinations (‘co-packaged’), where the medicinal product and the medical device are contained within the same packaging and are intended to be used exclusively in that combination. The medicinal product constitutes the primary mode of action. The medical device serves, for example, for dosing and/or administration purposes. An example is cough syrup supplied with a measuring cup.
• Separable combinations (‘referenced’), where the medical device is not enclosed in the packaging with the medicinal product but is available separately. The medicinal product information refers to a specific medical device for combined use. The medicinal product constitutes the primary mode of action.

In order to be placed on the Swiss market, combination products require an authorisation as a medicinal product from Swissmedic. The medical device component forms part of the authorisation application. The marketing authorisation holder bears responsibility for the pharmaceutical quality and safety-related issues connected with placing the combination product on the market and assumes full responsibility for the medical device component. Accordingly, the marketing of a combination product is essentially governed by the regulatory framework for medicinal products. This framework is not harmonised with EU legislation.

However, the regulation of medical devices is harmonised, as the Swiss Medical Devices Ordinance (MedDO) is closely modelled on the EU MDR and frequently refers to its provisions. Although the MedDO does not apply to non-separable combination products (whether ‘integral’ or ‘co-packaged’), Switzerland has, with respect to the device component, adopted the EU’s regulations on combination products. This has been achieved by providing that the part of the combination deemed to constitute a device must satisfy the general safety and performance requirements in the MedDO. In the case of separable combinations (‘referenced’), the medical device component is treated as a stand-alone device and must meet all conformity requirements of the MedDO (ie, be CE-certified).

Obligations for marketing authorisation applicants

The authorisation of combination products in Switzerland is similar to the EU regime. The Notified Body Opinion constitutes an essential element of the authorisation documentation for the assessment of an integral combination product. Swissmedic has recently indicated that these opinions are often unsatisfactory and do not enable Swissmedic to conduct an assessment of compliance with the device requirements. Swissmedic accordingly clarified that it is the responsibility of the applicant for the combination product to ensure that the Opinion demonstrates the conformity of the medical device components, and failure to do so may lead to delays.

Combination product-specific implications of the GPL

As set out above, the definitions of combination products do not fundamentally change, and the EU MDR legislation is not essentially amended by the GPL. Furthermore, Switzerland follows its own regulatory framework with respect to the authorisation of medicinal products for the Swiss market. Accordingly, no fundamental changes to the requirements governing the marketing of combination products in Switzerland are to be expected. It is likely for this reason that Swissmedic has not (yet), commented on the changes under EU law as they pertain to combination products.

However, given that the MedDO is closely modelled on the MDR and that Swissmedic’s current practice closely follows EU practice, it is reasonable to assume that the EU’s new approach to combination products will also be adopted by Swissmedic, at least with respect to the requirements of the medical device component. Therefore, as Swissmedic closely monitors developments, changes to the approach in the EU may in practice influence Swissmedic's assessment procedure.

Therefore, as set out in relation to the UK, the differences with the Swiss regulatory framework in this area will be more practical than substantive. However, should the EMA’s approach and guidance change in the future as a result of the GPL, Switzerland – and Swissmedic – may well adapt its practice accordingly.

Conclusions

While the GPL introduces fundamental changes to the regulation of medicinal products, the changes in relation to combination products are more limited, and do not fundamentally change the framework for classification or approval of such products. Therefore, the impact in the UK and Switzerland is also limited, being mainly procedural in nature. However, if the EMA’s approach changes, the UK or Swiss system may follow, or this may lead to divergence between the countries. Manufacturers are advised to closely follow the implementation of the GPL and updates in EMA practice, especially given product developments are usually not country specific.