Addressing the impact of the EU medical devices regulation on combination products

Published on: Mar 30, 2019

An inter-regulatory and stakeholder workshop on combination products, organised by TOPRA and RAPS, was held in Brussels in November 2018. Reported by Stéphanie Francard, Senior Regulatory Scientist, VCLS, and Chris Wilson, Senior Director, Regulatory Science, Drugs and Biologics, VCLS.

The Medical Device Regulation (MDR) (EU) 2017/745 entered into force on 25 May 2017 and, after a three-year transition period, it will fully apply and supersede the medical device directive 93/ 42/EEC (MDD) in EU member states from 26 May 2020. Among other items, it introduces new requirements and changes for combination products, i.e., medical devices incorporating an ancillary medicinal substance, and medicinal products which incorporate a device component as an integral part (known as drug-device combination products), which impact respectively CE certification and drug market authorisation dossier content, as related to the device’s component data.

The workshop, panel discussions and Q&A primarily focused on Article 117 of the MDR, which amends Directive 2001/83/EC Annex I point 12, Section 3.2, and which sets out to clarify and reinforce the dossier requirements for medicinal products which incorporate a device component as a single integral final product:

• “where[… ] a product is governed by this Directive, the marketing authorization dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements […] contained in the manufacturer’s EU declaration of conformity or the relevant certificate issued by o notified body[…]”

• If the dossier does not include the results of the conformity assess­ment[…]and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required[… ], the authority shall require the applicant to provide an opinion on the conformity of the device part [… ]issued by a notified body[… ]”

Notably, expectations for device-related data in the marketing authorisation application (MAA) dossier are currently captured in the medical devices and medicinal products directives, [1] but changes introduced by the MDR will result in clarified and reinforced requirements and procedure which will need to be addressed by Pharma and Medtech industry.

The workshop comprised three sessions, with speakers coming from the European Commission, EU member state medicinal and medical device competent authorities, notified bodies and industry.

SESSION 1: Legislative background and state of play guidance and interpretation

The first presentation was given by Vincent Houdry, European Commission, DG GROW, and addressed the transitional period for the MDR, together with Article 117 implementation. It was noted that there are currently 33 notified body (NB) designation applications covering he entirety of MDR and In Vitro Diagnostic Regulation (IVDR) codes. The first designation of NB under the MDR is expected in丿anuary 2019.

MDR classification Rule 14 _(Ex MDD Rule 13) concerns 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. One new procedure is that the NB shall not deliver a certificate if the scientific opinion is negative. In addition, due to the removal of the term ‘liable to act on the body’, an increase in the number of class Ill devices under this Rule are expected.

Elizabeth Baker, UK Medicines and Healthcare products Regulatory Agency (MHRA), then provided a valuable overview of the impact of the MDR on combination products from a national competent authority (NCA) perspective. She reminded the audience that the role of the competent authorities is to protect public health and facilitate the single market. From a historical perspective, NCAs have been arranging NB consultations since 1995, originally with no guidance and consequently little consistency between NCAs and NBs. Over time, there has been a gradual improvement, culminating in the MDR and associated guidance documents. Some challenges remain, including timing and NB resources and the number of regulatory bodies to be involved. A request was made for additional flexibility from the EC.

However, progress is being made, and for drug-device combinations that are ruled as medicinal products, the Quality Working Party/ Biotech Working Party (QWP/BWP) guidance on integral and non­integral device components of medicines will prove valuable, although some further discussion is needed, eg., can a master file concept be used to reduce resource, and how can life cycle management be better handled to reduce regulatory burden – for example, not everything in a NB report should trigger a variation. The development of a specific guidance on well-established device technologies was also suggested. In addition, there is existing clear European Medicines Agency (EMA)/ NCA guidance on NB consultations for ancillary medicinal substances integrated in combination products ruled as medical devices, which could be harmonised to a single document. Elizabeth also stressed additional complexities that will arise from NB changes and Brexit.

Armin Ritzhaupt, EMA, then covered NB consultations, combined ATMPs and Article 117 transition and implementation. Regarding consultations, he highlighted that the MDR will lead to new or revised roles and responsibilities for the EMA and NCAs. These include new areas for consultation including the fact that a MAA dossier for medicinal products which incorporates a device component will now have to contain a Declaration of Conformity, CE certification or NB opinion, to comply with MDR Article 117.

ATMPs may also incorporate, as an integral part, one or more medical devices, referred to as Combined ATMPs, for which similar regulatory provisions already exist (Article 9 of ATMP EU Regulation 1394/2007).

The next presentation was given by Dr Abigail Moran, MHRA, UK, when she gave a short update from the perspective of a NCA on the guideline on the “quality requirements for medicinal products containing a device component for delivery or use of the medicinal product”, covering integrated and non-integrated devices. In summary, good progress on this drug-device combination (DDC) guideline has been made and is continuing. A draft has been developed, and its structure was presented during the workshop. In addition, a work plan is in place. The draft release for consultation is expected to be by the end of Q2 2019, followed by a further six months’ consultation ending Q4 2019.

Challenges still remain (as identified by several other speakers) and will be addressed in the guidance. Examples include the potential overlap of roles, responsibilities, expectations and processes between NCAs and NBs, the content and format of the notified body opinion (NBO), clarification of potential ways of working, requirements and expectations for compatibility, accuracy and stability, technical interpretation of general safety and performance requirements (GSPRs), and lifecycle management.

Session 1 was completed with a presentation from Guy Buijzen, DEKRA Certification, President TEAM NB. We were informed that, to give a NBO as per Article 117, NB assessment will be based on scientific data that demonstrate conformance to the GSPRs (Annex I of the MDR), which constitute evidence to support claimed safety and performance for the intended use.

As is currently the case under the MDD, the NB must have qualified staff available to conduct the assessment and be able to demonstrate competence, be designated to assess the technology and have procedures in place for the conduct of such assessments, and to provide information on costs and timescales involved for device changes.

Technical documentation should be standalone and provide evidence to support the claims made, including safety and performance data as detailed in Annex II of MDR. Key areas include but are not limited to: answers to GSPRs, risk management documentation, safety and performance data, including clinical data, functionality testing up to claimed shelf life (accuracy, reproducibility of dosage), usability/human factors by target patient population, training for users, compatibility of drug with device, sterilisation and packaging validation and impacts on the medicinal product.

A brief update was then provided on the activities of the QWP/ BWP drafting group and the evolution of the guideline on “Quality Requirements for Medicinal Products containing a Device Component for Delivery or Use of the Medicinal Product”.

In summary, a wide variety of topics have already been discussed (as addressed by several other speakers) and good progress has been made, but several challenges remain, including the need for clear legal definition of “single integral product”, how to handle devices relating post-marketing data, whether a negative opinion from a NB can be overruled, and how to address a second opinion from another NB where there are divergent opinions.

SESSION 2: Devices incorporating ancillary medicinal products

Dr Jon Sutch, BSI, UK, opened the second session with a talk on a NB’s experience of working with different CAs, from the perspective that BSI has a significant amount of experience with devices containing ancillary medicinal substances. He made the point that consultation is between the NB and CA, and it is up to the NB to choose the CA. As BSI has experience of working with several CAs, he was able to highlight significant variability between CAs in their approach which leads to difficulties for NBs and device manufacturers, which in turn could have implications for patient safety. Examples of inconsistencies included what changes need a supplementary consultation, data requirements for changes in shelf life, and the impact of changes in device size with associated changes in drug content.
Other challenges identified were: 60-day assessment of variations under the MDR, compared with 210 in the MDD; possible variability issues between device versus pharma reviewers; data submission format (CESP/Eudralink/CD); timelines; and the need for a comprehensive final report, which is crucial to allow transfers/assessment of changes by NBs. Finally, the need for harmonisation of procedures across EU was stressed, echoing requests made by several other speakers.

Waldo Weijer, Dutch Medicines Evaulation Board (MEB), then took the example of a variation on an ancillary medicinal substance to discuss the re-consultation procedures (existing and potential improvements), from the perspective of a medicines CA, based on different scenarios.

Oliver Bisazza, MedTech Europe, presented an industry perspective, reinforcing the messages from earlier speakers regarding the expected impact of the changes introduced by the MDR for medical devices incorporating an ancillary medicinal substance. He also proposed a flow-chart for MDR clinical evaluation consultation procedure (CECP/ scrutiny) for high-risk devices, and he finished his presentation by raising the following remaining issues:

• As the number of products affected by the up-classification to class Ill (eg., wound care products with antimicrobial preservatives) is expected to increase, what impact might this have on products’ availability?

• For legacy products being transitioned from MDD to MDR, if a new opinion from a medicinal product CA is required but it has not received a timely or favourable opinion, again, what impact will this have on product availability?

• Will the scrutiny expert panel also give an opinion on the ‘safety, quality and usefulness’ of the medicinal substance and its incorporation, and could this lead to divergent opinions?

Cary Percy, Boston Scientific, US, then discussed several scenarios based on industry experience. Specifically, Cary raised some potential concerns regarding CA consultation time and possible variations between different CAs regarding data requirements. To address this, a request was made for predictability and consistency between each NB and each CA. In addition, a proposal was made for an Implementing Act to address risk-based considerations of the significance of change – essentially a “Least burdensome approach”.

SESSION 3: Medicinal products incorporating medical devices

Ann Jans, Federal Agency for Medicines and Health Products (FAM HP), Belgium, opened Session 3 with a presentation focused on the MDR from the perspective of a medicines NCA. As part of the evaluation of DDCs at FAMHP, there is always close collaboration between medicinal product and medical device assessors.

The required information on the device component can already be found in Directive 2001/83/EC and an example was given of a pre-filled syringe. The determination of dose accuracy is based on MDD ER 10.1 and MDR GSPR 15.1, although ISO standard 11608-1:2014 should also be considered.

The assessment of drug-device compatibility is based on MDR GSPR 10.3 and MDD ER 7.3. When considering drug-device compat­ibility, it is important not to forget there could be more than one function. For example, in the case of a pre-filled injection device, this has two functions: as the primary container closure system, and as a device designed to facilitate the administration of a drug product.

The primary container closure system’s inherent characteristics and integrity can impact the quality of the drug product through leakage/ingress, sorption, chemical reaction and leaching.

And contact with medicinal substance, inherent properties of the medicinal product, conditions of use including storage duration or conditions and handling conditions can all potentially impact the performance of the device in administering drug product.

Theresa Jeary, LRQA, UK, then gave a short presentation from a NB perspective on the impact of Article 117. She began her presentation by identifying some current challenges for NBs. These include the number of NBs and their staffing, together with a significant increase in the number of clients. She then focused on Article 117 and confirmed that a NB will be responsible for assessing the device component of single integral combination products, such as devices pre-filled with medicine.

To give a NBO, the NB expects to receive the scientific data that demonstrate conformance to the MDR GSPR, and evidence to support claimed safety and performance for the intended use.

Documentation to be provided should be “standalone” and should include safety and performance data together with the technical documentation as detailed in Annex II of the MDR, to provide evidence to support the claims made.

The NB report was then discussed. Although product approval is the medicines agency’s responsibility, the NB assessment report must provide details on the evidence assessed by the NB, the technical characteristics of the device, summarise how the manufacturer has demonstrated conformity with requirements, and finally provide a clear conclusion with confirmation of acceptability or not, together with a reference to the applicable requirements.

When it comes to the management of device changes, MAA holders are advised to consider what impacts there could be. For example, will the NB be involved in the assessment of changes? This would be the case for changes that impact device safety or performance, device design change impacting usability, product formulation changes and intended use of the device/change to medicinal product.

Finally, delegates were reminded of the possible impact of Article 117 on quality system expectations, legacy product assessment requirements, clinical data requirements and vigilance reporting and requirements.

Serge Mathonet, Sanofi, representing European Biopharmaceutical Enterprises (EBE), began his presentation by highlighting the various forums, workshops and meetings that have recently been held and that have allowed industry to voice its concerns related to the MDR and Article 117, which lead to additional considerations and timelines for the MA. He then went on to discuss DOC products and licensing trends.

Regarding recent numbers, it is interesting to see the increasing number of MAAs for DOC products.

CAMD [competent authorities for medical devices] plays a key role on the NB assessment procedure as per Article 117 and the level of interaction among relevant authorities, but it seems CAMD has still to establish a work plan/deliverables/timeline.

Further industry engagement/proposals were then examined. These include establishing a transition period until NB numbers reach steady state, promoting the need for pharma industry experts or representatives in device working groups, setting up a CAMD IVD/ MDR implementation task force, reviewing the requirements for an Article 117 Briefing Book (EBE/EFPIA), and drafting a new Reflection Paper (EBE) – medicinal product incorporating a drug delivery device component: “An Industry Perspective on developing an efficient ‘End to End’ Control Strategy”.

Mark Chipperfield, Corvus Device Limited, UK, finished the session with a discussion of a few industry example scenarios. His take-home message was that it is seen as critical to clarify ‘single’ ‘integral’, ‘exclusively for use in given combination’, ‘non-reusable’ definitions, and the responsibility for ‘system-level considerations’ for non-INPs. In addition, he asked for clear, risk-based, proportionate and consistent approaches that will help both SMEs and large companies, will cover both originator and generic/biosimilar products, address new submissions and post-marketing changes/variations and ensure NB opinion on satisfaction of Annex I does not incurbroader requirements of the MDR.

Specific examples of drug-device combination products were also discussed to illustrate the need for definitions and qualification guidance. These included vial and non-integrated transfer syringes, staked-needle pre-filled syringes (integrated), changing configuration for the same medicinal product [disposable auto-injector (integrated) and loadable patch injector], and pre-filled syringe.

Conclusion

This workshop was a great opportunity to hear from, and interact with, all the various stakeholders, to be informed on what progress has been made, what is still required and where the challenges are. Several speakers noted that a harmonised and pragmatic approach for the transition and application of Article 117 is required. This will become increasingly important as more and more combination products are expected in the future, and the implementation of the MDR is intended to provide benefit to patients. It is therefore critical to ensure the availability of healthcare products is not compromised.

Manufacturers are therefore encouraged to anticipate and start to verify the compliance of their device components to the MDR GSPR. After the implementation of the MDR, discussions between all stakeholders (NBs, CAs with scientific advices, the medical device and pharma industries, etc.) at the early stages of a product’s development are recommended.

References

[1] Directive 93/42/EEC Article 1.3. If, (…) such a device [intended to administer a medicinal product within the meaning of Article 1 of Directive 2001/83/ EC] is placed on the market in such a way that the device and the medicinal product form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single product shall be governed by Directive 2001/83/EC. The relevant essential requirements of Annex I to this Directive shall apply as far as safety and performance-related device features are concerned.