The revised version of the Questions & Answers for applicants, marketing  authorisation holders of medicinal products and notified  bodies with respect to the implementation of the MDR and IVDR  (hereafter the “EMA revised guidance”) covers in details the following cases:

• integral drug-device combinations (medical devices that form an integral product with a medicine, such as pre-filled syringes) and their lifecycle management;
• medicinal products that include a medical device in their packaging (referred to as co-packaged) and how these should be labelled;
• the consultation procedure for medical devices with an ancillary medicinal substance; and the consultation procedure for companion diagnostics.

 We have summarised below key aspects brought by this revision:

Insights on integral drug-device combinations and their lifecycle management

• The EMA clarifies that there are cases where a medicinal product and a medical device are placed on the market in the same packaging but do not form an integral product (e.g. vial containing a medicinal product solution with an empty CE marked sterile syringe). These are referred as medicine with a co-packaged device.

• The EMA recommends turning to national competent authorities for medicinal products and/or devices in EU Member States to obtain advice on the qualification/classification of drug-device combination, especially in case of borderline products (those products where it is not clear which regulatory framework applies, medical device framework or pharmaceutical framework). However, to support innovative drug-device combinations and early dialogue, the EMA states that informal input can be requested from the Innovative Task Force (ITF). While the ITF may offer scientific opinions on product classification, it is the Applicant's responsibility to seek formal advice from a national authority on product qualification or risk classification before submitting an application.

• The EMA offers detailed guidance on when a new or updated EU declaration of conformity or certificate of conformity is required due to changes to the device (or device part) after the initial marketing authorisation of the integral drug-device combination. A new or revised Notified Body opinion for the device part of an integral drug device combination is required when a new device is introduced with a line extension or variation. It is expected when major changes are introduced to an existing device, such as: (i) change to its design; (ii) addition or replacement of an integral device (part), (iii) change to its performance characteristics; and (iv) change to its intended purpose such as a different patient population and/or new user (e.g. home versus hospital setting) and/or new usability study, and/or significantly different instructions for use which may have a significant impact on the delivery or the quality, safety, or efficacy of the medicinal product. It is also expected in case of changes to the medicinal product which may impact the performance or safety of a device, for example, the introduction of a new finished product formulation resulting in different viscosity significantly affecting device performance.

• The EMA clarifies how to submit minor changes to the terms of the marketing authorisation for integral drug device combination following the changes to the device (or device part) and  provides examples of minor changes to the marketing authorisation, such as change in suppliers of a device (part), change in dimension to a device (part), change in qualitative/ quantitative composition of a device (part) and change in the sterilisation method for a device.

• Finally, the EMA explains to Marketing Authorisation Holders whether they will need to provide a new/updated notified body opinion for changes related to their medicinal products (for example, in cases where there is an extension of indication, a new strength or a new pharmaceutical form or a new route of administration) in an integral drug-device combination. Changes to the medicinal product may have an impact on the safety or performance of the device or on its intended purpose. The EMA provides the following recommendations but advises that each case should be assessed individually: 

  • In case of an extension of indication, if there is no change to the device or the user, the Marketing Authorisation Holders should evaluate and justify that the new indication does not significantly impact the safety and performance of the device. In such cases, a new or updated notified body opinion may not be required in support of the variation to the marketing authorisation.

  • In case of a new strength to an existing integral drug-device combination with no change to the device, the Marketing Authorisation Holders should assess and justify that the new strength does not significantly impact the safety and performance of the device. In such case, a new or updated notified body opinion may not be required in support of the regulatory procedure to change the marketing authorisation.

  • In case the new pharmaceutical form is combined with the introduction of a device, depending on whether the device is integral or co-packaged, evidence of compliance with the MDR will be required. If a new pharmaceutical form is combined with an already CE marked device, the Marketing Authorisation Holders should assess whether it significantly impacts the safety and performance of the device. If so, a new or updated notified body opinion will be required.

  • In case of new route of administration, which may impact the device's safety or performance, a new or updated notified body opinion is likely to be required to support the variation to the marketing authorisation.

Labelling requirements for medical devices co-packaged with medicinal products

• The EMA provides specific guidance in cases where co-packaged medical devices Class I and Class IIa (such as dosing devices like measuring spoons, measuring cups, or measuring syringes…), are supplied without an individual packaging and where it is not technically feasible to implement the labelling requirements on the device itself. These devices are often provided by bulk by the device manufacturer without an individual packaging and will not contain their own packaging or IFU (this is permitted under Annex I, Section 23.1(d) of the MDR). The EMA provides that the medicinal product information (such as the SmPC, labelling and package leaflet) must not include the required information for the device. However, the EMA proposes these alternative solutions. This includes:

  • To include a separate leaflet with the required medical device information inside the packaging of the medicinal product. This leaflet should cross-reference the medicinal product's package leaflet to avoid confusion.

  • To attach the medical device information leaflet to the medicinal product's package leaflet, forming one single folded component. The medical device section should be clearly differentiated, possibly as a tear-off section, and titled with a relevant subheading.

  • Affix a fold-out vignette or sticker containing the device-specific information directly onto the device or its packaging. Ensure the information is indelible, legible, and comprehensible.

Information on the consultation procedures for companion diagnostics

• A companion diagnostic is defined as an in vitro diagnostic test essential for the safe and effective use of a specific medicinal product, identifying patients who will benefit or are at risk from the treatment. Annex II of MDCG 2020-16 provides a flowchart to determine whether an in vitro diagnostic test fulfils the definition of a companion diagnostic under IVDR.

• Companion diagnostics require conformity assessment by a notified body and a consultation with a medicinal products authority to assess the device's suitability for the related medicinal product. The notified body must seek a scientific opinion from the European Medicines Agency (EMA) if the medicinal product is under the centralised authorisation procedure, already authorised through it, or has a pending marketing authorisation application via this procedure. For medicinal products not under the centralised procedure, the notified body may consult either a national competent authority or the EMA for the scientific opinion.

In addition, the EMA provides that this revised guidance should be read in conjunction with the EMA Guideline on quality documentation for medicinal products when used with a medical device.

Authored by Fabien Roy and Hélène Boland.