IVDR Archives - European Industrial Pharmacists Group (EIPG)

The drug shortage situation - EIPG's point of view


by Maurizio Battistini The shortage of medicines has been a major concern in the countries of the European Union, and elsewhere, for more than 10 years, so much so that the Economic Community has devoted a great deal of effort Read more

EP’s draft position on Unitary SPC and SPC Regulation revision


by Giuliana Miglierini The Committee for Legal Affairs (JURI) of the European Parliament released the draft amendments to the Commission’s proposals aimed to establish a Unitary Supplementary Protection Certificate (SPC) (links to the document and to the procedure) and to Read more

Reactions to the proposed ban of PFAS


by Giuliana Miglierini A proposal to ban around 10,000 per- and polyfluoroalkyl substances (PFAS) was submitted in January 2023 to the European Chemicals Agency (ECHA) by authorities of Germany, Denmark, the Netherlands, Norway, and Sweden. The proposal was published on Read more

MDCG, a position paper on the capacity of notified bodies

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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 surveillanceunder 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.


IVD regulation in force: new MDCG guidelines and criticalities for innovation in diagnostics

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by Giuliana Miglierini

The new regulation on in vitro diagnostic medical devices (IVDR, Regulation (EU) 2017/746) entered into force on 26 May 2022. The new rules define a completely renewed framework for the development, validation and use of these important tools supporting the diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of a disease, in line with technological advances and progress in medical science. “Diagnostic medical devices are key for lifesaving and innovative healthcare solutions. Today we are marking a big step forward for the patients and the diagnostics industry in the EU. The COVID-19 pandemic has underlined the importance of accurate and safe diagnostics, and having stronger rules in place is a key element in ensuring this is the case for EU patients.”, said Stella Kyriakides, Commissioner for Health and Food Safety

The European Commission also published a Q&A document to facilitate the comprehension of the new framework.

The main contents of the IVDR

The risk-based approach for the classification and development of in vitro diagnostics is at the core of the IVDR. There are four different classes of IVDs: class A (low individual risk and low public health risk), class B (moderate individual risk and/or low public health risk), class C (high individual risk and/or moderate public health risk) and class D (high individual risk and high public health risk). The assessment of the quality, safety and performance of IVDs by independent notified bodies shall be based on more detailed and stringent rules. Higher-risk categories will also be subject to further assessment by newly created scientific bodies acting under the auspices of the European Commission, such as the expert panels and the network of EU reference laboratories. Twelve expert panels have been established up to now.

Each single IVD will be associated to a Unique Device Identifier (UDI), so to facilitate its traceability along the entire life cycle. The identifier will also serve to locate the relevant information about a diagnostic marketed in the EU within the European database of medical devices (EUDAMED), where also a summary of safety and performance will be publicly available for medium- and high-risk devices. The database will also contain information about all economic operators and provide a repository for the certificates issued by notified bodies.

The new regulation strengthened the framework for post-marketing surveillance of IVDs, asking for a closer coordination of the vigilance activities by all member countries. The IVDR also introduced reinforced rules on clinical evidence and performance evaluation, including an EU-wide coordinated procedure for authorising multi-centre performance studies, and a specific regime for devices manufactured and used in the same health institution (in-house devices).

Difficulties in the timely implementation of the (EU) 2017/746 regulation may still be possible due to the lack of a sufficient number of notified bodies, as only seven have been designated up to now, established in only four countries (Germany, France, the Netherlands and Slovakia), while eleven other applications were pending in May 2022. To solve this issue, Regulation (EU) 2022/112 was adopted. A transition period up to May 2025 applies to devices that require a notified body certificate already under the previous Directive (around 8%, vs about 80% according to the IVDR); other classes of IVDs benefit of different transition periods (May 2025 for class D, May 2026 for class C and May 2027 for class B and A sterile).

Q&As on the interface with the Clinical Trial regulation and UDI

The Medical Devices Coordination Group (MDCG) published a Q&A document (MDCG 2022-10) to provide guidance on the interface between Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and the IVDR.

The guideline addresses the requirements for assays used in clinical trials, that may include IVDs carrying a CE mark for the intended purpose, IVDs developed in-house and devices for performance studies. Only the devices falling on the definition of an IVD with regards to their intended purpose are subject to the IVD legislation. The guideline also provides suggestions on assays likely to be considered IVDs, as they are used for medical management decisions of trial subjects within the trial.

Another Q&A guideline (MDCG 2022-7) provides clarifications on how to apply the Unique Device Identification system to both medical devices and in vitro diagnostics.

Topics covered by the document include the need for a new UDI-DI assignment in case the number of items in a device package changes or for single-use reprocessed devices, the requirement for economic operators to maintain a registry of all UDIs of the devices which they have supplied or with which they have been supplied, or the requirement of a new UDI-DI for substance-based medical devices, in case of formula quantity changes or additional claims.

The MDCG also addressed the assignment and use of the Basic UDI-DI and the determination of the ‘grouping’ for design or manufacturing characteristics, including the case of devices comprising a patient and a physician facing module, and the contents of the Declaration of Conformity (DoC). Labelling is also addressed, as well as rules for systems and procedure packs (SPPs) and configurable devices, as well as those applying to retail point of sale, promotional packs and marketing related samples.

The impact of the IVDR on innovation

The issues linked to the IVDR implementation and their impact on innovation and diagnostic laboratories, including the development and use of in-house devices, have been analysed by the BioMed Alliance In Vitro Diagnostics Task Force, and published in HemaSphere.

The Task Force identified two main challenges to be faced by the academic diagnostic sector. The first one impacts on the possibility to use in-house IVDs, based on the demonstration that no equivalent CE-IVD kit is present on the market or when the specific needs cannot be met at the appropriate level of performance by an equivalent CE-IVD. The strict exemptions applying to in-house IVDs (e.g. prohibition of transferring to other legal entities, compliance with EN ISO 15189 and justification of use, etc.) may impact also on the potential for innovation in the diagnostic sector.

The second challenge refers to the not so clearly defined boundaries between CE marked-IVDs, modified CE-IVDs, Research Use Only (RUO) tests, and in-house IVDs. The Task Force recalls the immediate applicability of the General Safety and Performance Requirements specified in Annex I of the IVDR, as they have not been included in the approved amendment of the implementation timeline.

Furthermore, only tests meeting economic viability may in the future be transferred from the academia to the industry, while rare or complex tests would probably remain excluded. According to the paper, the cost of diagnostics shall likely increase, and the academa should carefully consider how to support further research into rare or complex diagnostics in order to ensure their availability to patients.

Following the results of a survey among medical societies on current diagnostic practices, several suggestions are made to better support the implementation of the IVDR, namely by mean of the availability of diagnostic equivalents of the European Reference Networks for rare diseases and a concerted action involving all stakeholders. A joint biomarker-to-test pipeline between the IVD industry and research/academic labs would also be useful to facilitate the initial development and local application of innovative diagnostics within healthcare institutions or diagnostic reference networks with specific expertise, to then transfer them to manufacturers above a certain production volume.


ACT EU: the EU’s vision for the future of clinical trials

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by Giuliana Miglierini

Just few days before the entry into force of the new Clinical Trials Regulation and of the Clinical Trials Information System (CTIS) on 31 January 2022, a new initiative has been announced to completely renew the European framework governing how clinical trials are designed and run. The strategic document ACT EU (Accelerating Clinical Trials in the EU) has been jointly developed by the European Commission, the European Medicines Agency (EMA), the Heads of Medicines Agencies (HMA) and national regulators with the aim to strengthen the European Union as a leading “focal point” for clinical research at the international level.

ACT EU shall support the achievement of the goals established by the European Pharmaceutical Strategy and the European medicines agencies network strategy (EMANS) to 2025. The initiative will be co-led by the European Commission, EMA and HMA; the proposed governance shall find inspiration on the model already in use by the Clinical Trials Information System, with an EUCTR Coordination Group with an adapted mandate and composition. The individual domains which form the overall matrix will be coordinated by the relevant functions available within the network. The formal public communication phase on ACT EU will start after the official endorsement of the initiative by HMA and EMA.

Six objectives and ten priorities of action for 2022-2023

The ACT EU strategy identifies six different goals for the future of European clinical research. Its leading role shall be optimised through a unified European position on clinical trials at the international level, a better ethical oversight and integration of ethics committees into the clinical trial and medicines regulatory lifecycle. Large-scale multinational clinical trials with broader geographical scope shall be incentivised, while reducing the administrative burden for sponsors and investigators.

A special attention will be paid to the generation of decisional evidence for unmet medical needs, rare diseases, and on vaccines and therapeutics for public health crises and pandemics. A truly high level and coordinated scientific advice is indicated as an important element in order to support the trial and marketing authorisation processes. The strategy confirms the need to adopt new patient-oriented medicines development and delivery models with pro-active engagement of all the stakeholders. The availability of an improved capacity both at the development and regulatory level is also deemed important to achieve the goals of the initiative.

These challenging objectives shall be pursued in years 2022-2023 through the activation of a set of ten specific priority lines of action. An initial exercise to map already existing initiatives within the European medicines regulatory network (EMRN) will be run, that will represent the basis for the consequent development of a governance rationalisation strategy. This might include, for example, the alignment of different expert groups and working parties in the EMRN and ethics infrastructure.

The smooth implementation of the Clinical Trials Regulation shall be monitored using a set of Key Performance Indicators (KPI), still to be developed; the modernisation of the good clinical practices (GCPs) should occur under specific ICH’s guidance. The attractiveness of Europe for larger, multinational trials should specifically address studies run in the academic setting. Furthermore, the academics and non-profit organisations may also play a leading role in the analysis of data arising from clinical trials.

Further actions will include the availability of a multi-stakeholder platform, including patients, and the engagement in the initiative of all enablers by mean of a targeted communication campaign. A tighter coordination of different aspects relevant to the planning of new clinical trials, i.e. the scientific advice on the trial approval and the design of the study, has been also announced. The increasing use of artificial intelligence and/or machine learning technologies in the clinical domain and issues pertaining complex and decentralised trials, as well as the interface between the In Vitro Diagnostics Regulation (IVDR) and the Clinical Trials Regulation will benefit of new targeted methodological guidelines.

As for safety monitoring of clinical trials, the priority is to start its integration into a pre- and post-marketing safety monitoring framework. At the educational level, the competences needed to face this challenging scenario for the future of clinical trials in the EU will require the activation of specific training curricula, inclusive of modules on drug development and regulatory science with links to universities and SMEs.

Four principles to guide all actions

The complexity of the ACT EU initiative will require also the development of a new approach to make available the resources needed to smoothly run all the planned activities, possibly including the exploitation of the expertise external to the European medicines regulatory network. The strategy indicates the intention to adopt a collaborative and integrative approach, so to achieve a large research impact in the EU.

To this instance, the four principles “Do, Require, Influence, Support” have been identified to guide the execution and coordination of the projects, the requirement of specific guidance to address the expectations on applicants/developers/researchers, the availability of key publications and leadership to support the transformation phase at all levels (including patient, the academic, etc.), and stakeholders interactions suited to support all the above mentioned objectives.

The initial mapping of existing activities should also led to the identification of the budget needed for meetings, inclusive also of the activities relative to stakeholder engagement, training, and communication. Any other activities falling outside the optimisation of the already existing ones would be self-funded by the respective organisations (EC/NCA/EMA).

Comments from EFPIA

According to EFPIA, the announcement of ACT EU represents the beginning of an exciting new phase for clinical research in Europe. The industrial association highlights that the innovative design of many clinical trials, especially the complex ones, requires an increased efficiency.