The importance of Article 117 of the MDR, for Drug-Device Combination (DDC) products

Last updated: 10 November 2021

See section on updates at the end of the post.

The importance of Article 117 of the MDR, for Drug-Device Combination (DDC) products should not be underestimated. Anyone in regulatory affairs working on Drug-Device combination (DDC) products in the EU should at the very least be aware of Article 117 of the Medical Devices Regulation (EU) 2017/745 (MDR) as its requirements could have a potentially significant impact on the timelines of the assessment and outcomes of Marketing Authorisation Applications, variations or line extensions for such products.

From 26 May 2021 when the MDR became applicable, manufacturers intending to place integral (or Drug-Device Combination (DDC)) products (regulated as medicinal products) onto the market will be required to seek a Notified Body Opinion (NBOp) for those devices that are not CE marked.

About MDR Article 117

The Medical Devices Regulation (EU) 2017/745 (MDR) came into force on 26 May 2017 and became applicable on 26 May 2021, but provides for a transitional period for certain devices until 26 May 2024.

By way of Article 117, the MDR introduces an amendment to Annex I, Directive 2001/83/EC concerning supportive information to be submitted to competent authorities with e.g. marketing authorisation applications, variations or extension applications, i.e. evidence of the conformity of the device (part) with the relevant GSPRs set out in Annex I of Regulation (EU) 2017/7451.

The term ‘device (part)’ should be understood to refer to a medical device, or parts of a medical device, that are used in an integral or co-packaged configurations1. Both of the latter, highlighted terms are described elsewhere in this post.

What is the impact of the amendment to Annex I of Directive 2001/83/EC introduced by Article 117 of the MDR?

The impact is that from 26 May 2021, in accordance with Article 117 of the MDR, marketing authorisation applications submitted for an integral (or Drug Device Combination (DDC)) product, must demonstrate that the device part meets the relevant requirements of Annex I of Regulation (EU) 2017/745 as follows:

  • If the device part has a CE marking, then the applicant has to provide either of the following which allow the manufacturer to affix CE marking:
    • a Declaration of Conformity or, where applicable,
    • an EU certificate issued by a notified body designated for the type of device part in question
  • If the device part does not hold a CE marking and the dossier does not include a declaration of conformity or where applicable, an EU certificate issued by a notified body designated for the type of device part which has a risk classification of sterile class I, measuring class I, class IIa, class IIb or class III medical device, then the applicant must provide an opinion from a notified body (known as a Notified Body Opinion or NBOp) on the conformity of the device part with the relevant general safety and performance requirements (GSPRs) set out in Annex I to Regulation (EU) 2017/745.

It is the responsibility of the applicant to ensure that the Notified Body is appropriately designated (see EU commission website) for the issuance of such an opinion.

What are integral (or Drug-Device Combination (DDC)) products?

A drug-device product where the medical device (part) falls under the second sub-paragraph of either Article 1(8) or Article 1(9) of Regulation (EU) 2017/745, where the action of the medicinal product is principal is known as an integral product.1

Integral products for which the principal mode of action is pharmacologic, metabolic or immunologic, are regulated under the medicinal products framework (under Directive 2001/83/EC or regulation (EC No) 726/2004 as appropriate) and are referred to as Drug-Device Combination (DDC) products. 2

The two types of integral (or Drug Device Combination (DDC) products

The second sub-paragraph of Article 1(8) and Article 1(9) of Regulation (EU) 2017/745 describe two types of integral (or Drug Device Combination (DDC) products. They are:

i) second sub-paragraph of Article 1(8) of the MDR

Devices that when placed on the market or put into service, incorporate, as an integral part, a substance that, if used separately, would be considered as a medicinal product and has an action that is principal and not ancillary to the action of the device.

The relevant General Safety and Performance Requirements (GSPRs), as set out in Annex I of the MDR) apply with respect to the safety and performance of the device (part).

Examples include medicinal products with an embedded sensor where the sensor is a medical device and its action is ancillary to the medicinal product.

ii) second sub-paragraph of Article 1(9) of the MDR

Devices intended to administer a medicinal product, where the device and the medicinal product are placed on the market in such a way that they form a single integral product intended exclusively for use in the given combination and which is not reusable.

The relevant General Safety and Performance Requirements (GSPRs), as set out in Annex I of the MDR) apply with respect to the safety and performance of the device (part).

Examples include1:

  • Single-use pre-filled syringes, single-use pre-filled pens and single-use pre-filled injectors (including autoinjectors) used for the delivery of one or more doses of medicine and which are not intended to be re-used or refilled once the initial doses provided are exhausted.
  • Drug-releasing intra-uterine devices and pre-assembled, non-reusable applicators for vaginal tablets.
  • Dry powder inhalers and pressurised metered dose inhalers that are preassembled with the medicinal product and ready for use with single or multiple doses but cannot be refilled when all doses are exhausted.
  • Implants containing medicinal products whose primary purpose is to release the medicinal product.
What are non-integral drug-device products?

There are configurations where a medicinal product and a medical device are not placed on the market as a single integral unit, but the medicinal product is intended for use with a device.1 Such products are not considered a drug-device combination as the medical device falls under the first subparagraph of Article 1(9) of the MDR.

Below are examples of two such configurations:

i) Co-packaged: A medicinal product and a medical device are packed together into a single pack (e.g. carton), which is placed on the market by the Marketing Authorisation Holder.

Examples include1:

  • Oral administration devices (e.g. spoons, syringes).
  • Injection needles.
  • Refillable/reusable (e.g. using cartridges) pens and injectors (including autoinjectors).

ii) Referenced: The product information (SmPC and/or package leaflet) of the medicinal product refers to a specific medical device to be used (e.g. identified by its brand name and/or specific description), and the specified medical device is obtained separately by the user of the medicinal product.

Examples include1:

  • Refillable/reusable dry powder inhalers and metered dose inhalers; spacers for inhalation sprays.
  • Nebulisers and vaporisers.
  • Single use or reusable pumps for medicinal product delivery.

In both co-packaged and referenced configurations, the medical device should comply with the requirements as laid down by the applicable medical device legal framework.

The table below is an attempt to summarise the salient points from the content above.

Product typeApplicable
article of the MDR
Legislation under which regulatedDoes Article 117 of the MDR apply?Supplementary documentation to be submitted to competent authority
Medical Device incorporating as an integral part, a substance which if used separately is considered a medicinal product, but with action principal to that of the device.Article 1(8) second sub paragraphRegulated under Directive 2001/83/EC or Regulation (EC) No 726/2004 as applicable.

The relevant GSPRs set out in Annex I of the MDR shall apply as far as the safety and performance of the device part are concerned.
Yes it does.
The product is an integral or Drug-Device Combination product
Applications should include either of the following:
i) the EU Declaration of Conformity or ii) the relevant EU certificate issued by a Notified Body.


In the absence of either of the above, a Notified Body Opinion or (NBOp) should be included.
Medicinal product medical device configurations where the is intended to administer the medicinal product i.e. it is an administration device.
Co-packaged
A medicinal product and a medical device are packed together into a single pack (e.g. carton), which is placed on the market by the MAH.


Article 1(9) first sub paragraph
Device must be CE marked in accordance with the relevant legislation on medical devices i.e. Directives 93/42/EEC or 90/385/EEC or Regulation (EU) 2017/745 (MDR) as appropriate, except for Self-CE marked Class I devices which must be in compliance with the MDR since 26 May 2021 No it does not This is a non-integral drug-device product and therefore not a drug-device combination.
Referenced
The product information (SmPC and/or package leaflet) of the medicinal product refers to a specific medical device to be used (e.g. identified by its brand name and/or specific description), and the specified medical device is obtained separately by the user of the medicinal product.


Article 1(9) first sub paragraph
As aboveNo it does not.
This is a non-integral drug-device product and therefore not a drug-device combination
Configurations where a medicinal product and medical device are placed on the market as a single integral unit and the device is an administration device.
The device intended to administer a medicinal product and the medicinal product are placed on the market in such a way that they meet the following three conditions:
i) Device and medicinal product form a single integral product
ii) Product is intended for use exclusively in the given combination
iii) Product is not reusable
Article 1(9) second sub paragraph Regulated under Directive 2001/83/EC or Regulation (EC) No 726/2004 as applicable.

The relevant GSPRs set out in Annex I of the MDR shall apply as far as the safety and performance of the device part are concerned.
Yes it does.
The product is an integral or Drug-Device Combination product.
Applications should include either of the following:
i) the EU Declaration of Conformity or ii) the relevant EU certificate issued by a Notified Body.


In the absence of either of the above, a Notified Body Opinion or (NBOp) should be included

What is a Notified Body Opinion (NBOp)?

A Notified Body Opinion (NBOp) is an opinion provided by a Notified Body on the conformity of a device (part) with the relevant GSPRs set out in Annex I of Regulation 2017/745, as required by Article 117 of the MDR1.

How long does it take to obtain a Notified Body Opinion (NBOp)?

This depends on the initial quality of documentation submitted to the Notified Body (NB) and the number of clock stops required for further clarification of the information provided. Discussing this with a NB should provide a better/clearer idea of how long it would take. Whether an NBOp is sought to accompany an MAA or a variation or line extension, it seems prudent to engage with a NB as early as is possible in order to understand and establish clear timelines for assessment and grant of an NBOp as this could  potentially have a significant impact on the timelines of the assessment and outcomes of any of these application types.

The Notified Body, BSI suggests in its brochure3 that the process is typically expected to take two to six months to complete. Whilst the brochure does not explicitly say so, it seems that the time range provided could be for an NBOp to support an MAA application.

Is there anything that can be done to facilitate the assessment of an integral (or Drug Device Combination (DDC)) product?

Yes there is. The EMA Guideline on quality documentation for medicinal products when used with a medical device1 states the following:

The assessment of the integral medicinal product can be facilitated when the NBOp is presented as a summary technical report. This enables both assessor and applicant to determine how the opinion was derived, minimise duplication and avoid gaps in assessment, and to identify aspects to be considered during the MAA/variation.

For integral (or Drug Device Combination (DDC)) products already licensed, is there a requirement (from 26 May 2021) to provide a (new or updated) EU certificate/declaration of conformity/NBOp if there are changes to the device (part) after grant of the initial marketing authorisation?

Yes, as per the EMA guideline Questions & Answers for applicants, marketing authorisation holders of medicinal products and notified bodies with respect to the implementation of the Medical Devices and In Vitro Diagnostic Medical Devices Regulations2 ((EU) 2017/745 and (EU) 2017/746), there are two situations where a (new or updated) EU declaration of conformity / EU certificate issued by a notified body /notified body opinion (NBOp) must be submitted in a post-authorisation setting of the medicinal product. They are:

a) Addition or full replacement of the device (part)

Where a device (or device part) is replaced or a new device is added, a new EU declaration of conformity/ EU certificate issued by a notified body / notified body opinion must be provided as part of a variation or extension application2.

b) Changes to the device (part)

Where the medical device manufacturer plans to introduce changes that may affect the safety and performance of the device part or the conditions prescribed for the intended use of the device part, there are three possible situations2:

  • For devices covered under a manufacturer’s EU declaration of conformity only (no involvement of a notified body): the device part manufacturer is responsible to ensure compliance with the MDR, including changes to the device part. The EU declaration of conformity should be updated accordingly, if necessary.
  • For devices covered under an MDR EU certificate issued by a notified body: if the assessment of changes leads to the issuance of a new/supplemented EU certificate according to the requirements established in the relevant annexes (Annexes IX, X, XI) of the MDR, the EU certificate must be provided as part of an appropriate post-authorisation regulatory procedure.
  • For devices holding a notified body opinion (NBOp): if the assessment of changes lead to the issuance of a new notified body opinion, the new notified body opinion must be provided as part of an appropriate post-authorisation regulatory procedure.
Regarding the submission of variations for changes to the device (part)2

As for any other changes, the MAH should determine whether there is a potential impact on quality, safety and/or efficacy of the DDC.

  • If the MAH determines that the change impacts the registered information, a variation application according to the variation guideline will be required.
  • If the change does not impact the registered information but the MAH concludes that there is an impact on the quality, safety and/or efficacy of the DDC, a variation application must also be submitted.

In cases where the need for a variation and/or the category of the change is unclear, it is recommended that the medicines competent authority that issued the MA be consulted.

Ensure that the (new/updated) EU declaration of conformity / EU certificate issued by a designated notified body / notified body opinion for medical devices is included in the variation package at the time of submission of the application in order to avoid any delays of the procedure.

When should a variation to include a notified body opinion be submitted, for a Mutual Recognition Procedure (MRP)/Repeat Use Procedure (RUP)?

According to section 3.6 of the minutes of the CMDh meeting of 14-15 September 2021:

  • The CMDh agreed that the variation to include the notified body opinion has to be submitted before the start of an MRP/RUP.
  • If it is submitted as a type IA variation, the variation can be finalised during the MRP/RUP (as the change should already be implemented).
  • If it is submitted as a type IB variation, the variation has to be finalised before the start of the MRP/RUP.
  • The change could also be included in case the MAH needs to submit a type II, C.I.z variation to update the dossier before the start of the MRP/RUP.
Is there a Notified Body Opinion template available?

On 7 October 2021, Team NB has made available, a position paper5 which includes a proposal for a Notified Body Opinion Template.

The position paper is intended to provide a template for the opinion of the Notified Body (NBOp) with respect to the conformity of device part of a combination product to the GSPRs of Annex I of the Medical Device Regulation 2017/745 and in accordance with article 117 of MDR 2017/745.

This template is a proposal for the content of a notified body opinion (NBOp) and is created in order to obtain a harmonised reporting method. It does consider the minimum content for a notified body opinion as proposed in Annex I and Annex II of EMA/CHMP/QWP/BWP/259165/2019 Guideline on the quality requirements for drug-device combinations. The information contained in the template can be adapted to the individual company layout as required by an individual notified body. As further feedback is received from Competent Authorities on the layout and contents of submitted NBOps this template may be updated to ensure efficient communication of this regulatory information.

Where can you find more information about Article 117 of the MDR?

References:

  1. EMA Draft Guideline on the quality requirements for drug-device combinations  (29 May 2019 EMA/CHMP/QWP/BWP/259165/2019 CHMP) on the EMA website. On 22 July 2021, the guideline was adopted for publication, with its name changed to Guideline on quality documentation for medicinal products when used with a medical device (22 July 2021 EMA/CHMP/QWP/BWP/259165/2019). The guideline will come into effect from 1 January 2022. Please note that there are differences between the draft and adopted guidelines.
  2. Document entitled Questions & Answers on Implementation of the Medical Devices and In Vitro Diagnostic Medical Devices Regulations ((EU) 2017/745 and (EU) 2017/746)  (23 June 2021 Rev.2 EMA/37991/2019) on the EMA website.
  3. Drug-Device combination products – MDR Article 117: Drug Device combination products application process, on the BSIgroup website.
  4. A Notified Body’s perspective on the requirements for new interactions with Notified bodies under the MDR with respect to combination products – Journal of Medical Device Regulation, 2020, 17(2), 21-27 on the BSIgroup website.
  5. Team-NB Position Paper: Team-NB Position Paper (6 October 2021)
Webinars:
  1. On demand webinar: BSI’s perspectives on Article 117 and drug device combinations on the BSIgroup website
  2. Article 117: Bear the challenge of MDR requirement on the TUV SUD website.
  3. Multi-stakeholder webinar to support implementation of the Medical Device Regulation on Drug-device combinations on the EMA website.

I can confirm that I do not have any affiliation with either BSI or TUV SUD notified bodies.

Disclaimer:
The aim of this post is simply to provide information on some of the salient points about Article 117 of the MDR and to reinforce some of the points in the guideline and Q&A on the subject(References 1 and 2 above).

For all regulatory submissions, please consult appropriate sources such as regulatory authorities or regulatory agency websites and other appropriate websites for the latest guidance and/or guidance documents, and other experts/consultants as appropriate/necessary.

Updates
DateUpdate
10 November 2021New section entitled When should a variation to include a notified body opinion be submitted, for a Mutual Recognition Procedure (MRP)/Repeat Use Procedure (RUP)? added.
16 October 2021New section entitled Is there a Notified Body Opinion template available?
added.

Section entitled Where can you find more information about Article 117 of the MDR? updated with the addition of reference no 5.

Photo by Towfiqu barbhuiya on Unsplash