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Draft ICH M13A guideline on bioequivalence open for consultation


By Giuliana Miglierini The draft ICH M13A harmonised guideline “Bioequivalence for immediate-release solid oral dosage forms” was endorsed by the International Council for Harmonisation on 20 December 2022 and is now open for consultation. Comments can be forwarded until 26 Read more

The Windsor Framework


On 27 February 2023, UK Prime Minister Rishi Sunak and the European Commission President Ursula von der Leyen announced that agreement had been reached on changes to the operation of the Protocol on Ireland/Northern Ireland. The Protocol has been in Read more

HERA reports on stockpiling of antimicrobials


By Giuliana Miglierini The European Health Emergency Preparedness and Response Authority (HERA) has published the two final reports, prepared by McKinsey Solutions for the European Commission, describing respectively the results obtained during the first and second phases of the antimicrobial Read more

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MDCG, a position paper on the capacity of notified bodies

October 14, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The lack of a suitable capacity of notified bodies (NBs) is one of the main issues still pending after the entry into force of the new Medical Device Regulation (MDR) (EU) 2017/745 and In Vitro Diagnostic Regulation (IVDR) (EU) 2017/746. The Medical Devices Coordination Group (MDCG) discussed some suggestions on how to address the problem within a position paper published in August 2022.

Even if the document does not represent an official guideline, it describes some critical points to be considered by manufacturers and notified bodies in order to face the great challenge of the re-certification of medical devices and in vitro diagnostics according to the new rules. Should this not occur in time, many products may exit the market at the end of the transition period, potentially leading to a supply crisis greatly impacting on the health of patients and the normal functioning of healthcare institutions.

The MDCG position paper answers the request of EU Health ministers advanced during the EPSCO Council meeting on 14 June 2022 to figure out some immediate measures to face the problem. The final goal of the document is to improve the efficiency in the application of the current regulatory framework, with no reduction of requirements to be fulfilled by manufacturers. Waivers from applicable conformity assessments procedures should be considered only in relation to an interest of public health, patient’s safety, or health.

The position paper consists of nineteen points addressing the issue under its different perspectives, the first eleven of which refer to the increase of notified bodies’ capacity. The MDCG calls on all stakeholders to collaborate in order to smoothly implement the suggested actions, a process that will be monitored by the MDCG itself.

How to increase the capacity of NBs

Hybrid audits should be the elective tool notified bodies may use where appropriate to timely and efficiently run conformity assessment. Duplication of activities should be also avoided. To this instance, the suggestion is to “develop a framework for leveraging evidence, or components thereof, from previous assessments” run according to previous Directives. A pre-condition to activate this possibility is that the previous assessment has been judged “valid and properly substantiated also with regard to the MDR/IVDR requirements and the device” by a duly qualified notified body personnel.

A flexible approach may also apply to the combination of audits for legacy devices and actions needed to guarantee their ‘appropriate surveillance’. Combined audits may be used particularly for legacy devices whose application for MDR/IVDR certification is under review by a NB, thus moving the focus more towards the assessment of compliance with the new rules. To this instance, the MDCG also announced the intention to produce a specific guidance on ‘appropriate surveillance’ under Article 110(3) IVDR and to update MDCG 2022-4.

Already existing guidance may also be reviewed to reduce the administrative burden for NBs, and remove limitations related to the scope of documentation not required by MDR/IVDR.

A fundamental piece of the new European infrastructure for medical devices and IVDs is represented by the centralised Eudamed database, which should be timely fed by NBs with all relevant information using machine-to-machine procedures. Double registrations should be avoided as much as possible.

New notified bodies are essential in order to increase capacity. To this instance, the MDCG suggests supporting training, coaching and internship activities for their personnel. The rationalisation of internal administrative procedures is also deemed important.

Time for re-assessment of NBs is undergoing a review by the European Commission, which is expected to result in the publication of new Delegated Acts. The proposal is to move from the current first re-assessment at three years after notification (and then every 4th year) to up to five years after notification, on the basis of a flexible approach. There are currently ten re-assessments planned in 2022, twelve in 2023 and 11 in 2024. According to the MDCG, the new timeframe for re-assessment would allow national designating authorities to free resources to assess new NBs, while existing ones could process higher numbers of first MDR/ IVDR certifications.

Assessment, designation and notification of conformity assessment bodies (including the European Commission) are also called to reduce their timeframes and improve the efficiency of their processes, keeping unaltered the requirements to be met. The possibility to add specific codes to the designation of NBs shall be also explored by the MDCG. The Group is also committed to prioritise some ongoing actions which may impact on NB’s capacity (i.e. revision of section III.6. of MDCG 2019-6 revision 3).

MDCG’s guidance documents should be seen as an aid “to apply the legal requirements in a harmonised way, providing possible solutions endorsed by the MDCG”. Nevertheless, demonstration of the compliance to requirements should always benefit of a certain flexibility. A reasonable time should also be granted to integrate the new guidance in the relevant systems and/ or to apply them, suggests the MDCG.

Suggestions for the manufacturers

Under the perspective of manufacturers of MDs and IVDs, costs to access NBs may play an important role, especially for small-and-medium companies (SMEs). The MDCG position paper recalls NBs to the obligation to make their standard fees publicly available, possibly in a way that might be easily compared. Specific access schemes should be also in place to make available some capacity to SMEs and other first-time applicants for conformity assessment.

Manufacturers should also refer to notice MDCG 2022-11 to ensure timely compliance with MDR requirements. IVDs should not left behind, even if this category of products benefits of one more year for the transition to new rules compered to medical devices.

Structured dialogue is the suggested tool to improve the collaboration between manufacturers and notified bodies along the entire process of conformity assessment aimed at regulatory procedures, should this approach turn to be useful in order to improve the overall efficiency and predictability.

A timely communication to manufacturers by mean of webinars, workshops, targeted feedback and informative sessions is also deemed important in order to allow for a better preparedness, with a particular attention to SMEs and first-time applicants. The MDCG also suggest NBs to develop common guidelines for manufacturers to assist them in the application phase, containing explicative examples of typical non-conformities and details on he preparation and content of technical documentation. National authorities and industry associations are called as well to contribute to the dissemination of relevant information across their stakeholders.

Specific guidance should be issued by the MDCG to support a simpler conformity assessment of some aspects of legacy and orphan devices denoted by a demonstrable track record of safety. The development of a specific definition of “orphan devices” is also planned.

An improved dialogue between NBs and medicines authorities, and cases where expedited review would be possible is also supported in order to speed up consultations on medical devices incorporating an ancillary medicinal substance and companion diagnostics.


The new guideline on combination products between medicines and medical devices

October 1, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The new “Guideline on quality documentation for medicinal products when used with a medical device” (EMA/CHMP/QWP/BWP/259165/2019), adopted by the European Medicines Agency in July 2021, will come into force starting 1st January 2022.

The first draft of the guideline was presented in May 2019; according to EMA, the document aims to solve the often observed issues of inconsistent and/or incomplete data submitted to competent authorities. It also considers the amendment to Annex I of Directive 2001/83/EC introduced by Article 117 of the new Medical Devices Regulation ((EU)2017/745, MDR).

A Questions and Answers document to support in the implementation of the MDR and In Vitro Diagnostic Medical Devices Regulations ((EU) 2017/746) was also published by EMA in June 2021.

Three different combinations with medical devices

The guideline applies to the product-specific quality aspects of a medical device/device part, that may have an impact on the quality, safety and/or efficacy of the associated medicinal product, as defined by a specific risk assessment. The submitted documentation is part of the Quality part of a marketing authorisation dossier. Makers has also to prove the conformity of the device/device part to MDR’s requirements by mean of a EU Declaration of Conformity or CE certification released by the Notified Body that assessed the device.

The products covered by the new guideline include integral products made up of an integral and not reusable combination of the medical device/device part and the medicinal product (where the action of the medicinal product is principal), medical devices placed on the market co-packaged with a medicinal product, and referenced medicinal products to be used in conjunction with a specific medical device described in the product information (SmPC and/or package leaflet) and obtained separately by the user. The classification in one of the above mentioned categories of medicine/device combination impacts the information that should be submitted to competent authorities.

The guideline applies also to medicinal products intended to be used with a Class I medical devices, with electromechanical devices (including active implantable devices), electronic add-ons and digital elements of devices (if expected to impact the benefit-risk assessment of the medicinal product from a quality perspective). Combined advanced therapy products defined under Article 2(1)(d) of the ATMP Regulation fall out of the scope of Article 117, as well as veterinary products, in-vitro diagnostic devices (including companion diagnostics), system and procedure packs regulated under Article 22 of the MDR.

Examples of integral products include medicinal products with an embedded sensor performing an ancillary action, single-use prefilled syringes, pens or injectors, drug-releasing intrauterine devices or pre-assembled, non-reusable applicators for vaginal tablets, dry powder inhalers and preassembled, ready-to-use pressurised metered dose inhalers, implants containing medicinal products whose primary purpose is to release the medicinal product. For this type of products, the safety and performance of the device/device part has to reflect the relevant General Safety and Performance Requirements (GSPRs) described in Annex I of the MDR.

Examples of co-packaged or specifically referenced medical devices include spoons and syringes used for oral administration, injectors needles, refillable or reusable pens/injectors, dry powder inhalers and metered dose inhalers, nebulisers and vaporisers and single use or reusable pumps for medicinal product delivery. These two categories of products should comply with the requirements of the applicable medical device legal framework.

The approach to the overall product quality

The discussion of the quality of the device/device part on the Quality Target Product Profile (QTPP), Critical Quality Attributes (CQA) and overall control strategy of the medicinal product has to be included in the regulatory dossier.

More specifically, for integral products the EU Declaration of Conformity or the relevant EU certificate issued by a Notified Body for the device/device part has to be produced. Should this not be possible, the applicant has to provide an opinion (NBO) on the conformity of the device/device part with the relevant GSPRs, issued by a Notified Body enlisted in the NANDO website.

The information provided with the authorisation dossier shall be assessed by the competent authority to determine the overall benefit/risk ratio of the medicinal product. All information relevant to the device/device part has to be submitted using the usual eCTD format. Data on preexisting combination of the device/device part with an already approved medicinal product can be provided on a case-by-case basis and needs to be adequately justified. Early scientific and/or regulatory advice can be activated in the case of particularly innovative and emerging technologies.

The guideline provides a detailed description of the information to be submitted to competent authorities in relation to each of the different types of device/medicinal products combinations.

Reference is made to Module 1 (Product Information), Module 3.2.P (Drug Product), Module 3.2.A.2 (Adventitious Agents Safety Evaluation) and Module 3.2.R (Regional Information, Medical Device). This last section includes the Notified Body Opinion for integral medicinal products in the form of a summary technical report. Usability studies should be also available in the case supporting information is not included in the dossier, and the device/device part has not been used in the intended user population before, or where other aspects of the intended use, including changes to the clinical setting or use environment, are new or different from the intended use as confirmed by the EU certificate issued by a Notified Body or NBO.

The guideline also highlights the need the device/device part should be as advanced as possible in the development process (e.g. meets relevant GSPRs) by the time pivotal clinical trials commence. Any change to the device occurred during the trials has to be described, evaluated and justified with respect to the potential impact on the quality, safety and/or efficacy of the medicinal product. The guideline also provides information on how to manage the life cycle of the integral, co-packaged or referenced medicinal products.