Stella Kyriakides Archives - European Industrial Pharmacists Group (EIPG)

Real-world evidence for regulatory decision-making


by Giuliana Miglierini Digitalisation is rapidly advancing also in the regulatory field, as a tool to improve the efficiency and accuracy of processes used for the generation and use of data to inform the regulatory decision-making. To this instance, real-world Read more

Webinar: Implementation of Contamination Control Strategy Using the ECA template


The next EIPG webinar will be held in conjunction with PIER and University College Cork on Friday 21st of October 2022 (16.00 CEST), on the implementation of Contamination Control Strategy (CCS) using the ECA* template. This is the second Read more

ACT EU’s Workplan 2022-2026


by Giuliana Miglierini The implementation phase of the Accelerating Clinical Trials in the EU (ACT EU) initiative, launched in January 2022 by the European Commission, started with the publication of the2022-2026 Workplan jointly drafted by the Commission, the European Medicines Read more

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

, , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.


Commission establishes portfolio of 10 most promising treatments for Covid-19

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The second phase in the development of new medicines to treat Covid-19 – a part of the EU Strategy on Covid-19 Therapeutics launched in May 2021 – has reached a cornerstone with the announcement made by the European Commission of a first portfolio list of ten potential Covid-19 therapeutic candidates likely to be authorised by the European Medicines Agency (EMA). The only medicine authorised up to now at EU-level to treat Covid-19 is remdesivir.

The choice of the molecules to be included in the list was based on independent scientific advice by an expert group, and it is aimed to offer new treatment opportunities for patients affected by the disease in a way complementary to the preventive action of the already available vaccines. The strategy shall contribute to the achievement of the European Health Union, and it has been modelled on the example of the EU Vaccines Strategy.

Once available in the European market, the new medicines are expected to contribute to the reduction of hospitalisations and deaths from Covid-19. “We have already signed four joint procurement contracts for different Covid-19 treatments and we stand ready to negotiate more. Our goal is to authorise at least three therapeutics in the coming weeks and possibly two more by the end of the year and help Member States gain access to them as soon as possible.”, said the Commissioner for Health and Food Safety, Stella Kyriakides.

Three different categories of therapeutics

The initial list of ten candidates includes three different categories of therapeutics, and it may evolve in future according to the emerging of new scientific evidence.

Antiviral monoclonal antibodies have been identified as the most efficacious approach to be used in the earliest stages of infection. This category includes the following medicinal products under development:

  • Ronapreve, a combination of two monocolonal antibodies casirivimab and imdevimab from Regeneron Pharmaceuticals and Roche.
  • Xevudy (sotrovimab) from Vir Biotechnology and GlaxoSmithKline.
  • Evusheld, a combination of two monoclonal antibodies tixagevimab and cilgavimab from Astra-Zeneca.

The second category refers to oral antivirals, in this case too for early treatment; it includes the following candidates:

  • Molnupiravir from Ridgeback Biotherapeutics and MSD.
  • PF-07321332 from Pfizer.
  • AT-527 from Atea Pharmaceuticals and Roche.

Hospitalised patients may also benefit from the use of immunomodulators; four different possible candidates have been selected within this category:

  • Actemra (tocilizumab) from Roche Holding.
  • Kineret (anakinra) from Swedish Orphan Biovitrum.
  • Olumiant (baricitinib) from Eli Lilly.
  • Lenzilumab from Humanigen.

The scrutiny and selection of the most promising therapeutic options took into consideration 82 different molecules in late-stage clinical development. The analysis assumed that different types of products are needed for different patient populations and at different stages and severity of the disease. This scrutiny exercise was completely separate from the standard scientific assessment of the regulatory dossiers submitted for the candidates, that will be performed by EMA in order to issue the recommendation for final marketing authorisation by the EU Commission.

Steps towards the approval of the selected candidates

As announced by Commissioner Stella Kyriakides, half of the selected candidate therapeutics may reach approval by EMA by the end of 2021. These include products for which the rolling review is already ongoing or that have applied for marketing authorisation to the European Medicines Agency. Pre-requisite for the approval is the final demonstration of their quality, safety, and efficacy; there is still the possibility some of the products in the list shall not be authorized should the scientific evidence provided to EMA be considered not enough robust to meet the regulatory requirements.

Four other candidates are still in early phase of development and have already received scientific advice from the Agency; their rolling review shall begin as soon as enough clinical data will be available. The further development of these products will benefit by an innovation booster to support development activities.

As said, this is just a first list of promising therapeutics to treat Covid-19; some other approaches are expected to be identified as a consequence of the activation of several new initiatives by the EU Commission. Among these are the setting up of the interactive mapping platform for promising therapeutics which represents one of the first targets of action for the newly created Health Emergency Preparedness and Response Authority (HERA) (we wrote about this in October’s newsletter). The Commission also announced the activation within few weeks of the HERA website, where contact details and practical guidance for interested companies shall be found.

A pan-European matchmaking event for therapeutics industrial production has been also announced; this effort will focus on the development of new and repurposed Covid-19 therapeutics and it is aimed to mobilise the EU’s pharmaceutical manufacturing capacity.

The criteria used to select the candidate therapeutics

The European Commission published also a Q&A note to better explain the process that led to the selection of the ten promising therapeutics to be included in the list.

The portfolio of the selected products (authorised and under development) has been established by the expert sub-group on Covid-19 therapeutics (part of the expert group on SARS-CoV-2 variants) upon request of the Commission. The criteria used to run the analysis were approved by Member States in the Human Pharmaceutical Committee.

They include the evaluation of the pharmacological rationale on the basis of the available evidence of the potential role played by the single medicinal product in the treatment of Covid-19, its stage of development and availability of relevant data from clinical trials, the absence of (new) major identified safety issues, and the ability to answer to unmet clinical need and/or bring therapeutic added value. For some product categories, the efficacy against new SARSCoV-2 variants has been also evaluated.

Other points included in the assessment refer to the route of administration, treatment regimen, and formulation, and the company’s intention to access EMA’s early stage scientific advice procedures. The analysis run by the expert group did not focused on more industrial aspects, i.e. manufacturing, production volumes, prices and access conditions; these will be part of the considerations made by the Commission in order to activate its support instruments.

As for the three different categories of selected products, antiviral monoclonal antibodies are intended to mimic the action of natural antibodies generated by the immune system against coronavirus. They can exert both a curative and a preventive action against the infection, in particular in the earliest stages of the disease. They are usually administered by injection.

Oral antivirals are small molecules aimed to block the activity and replication of the virus. These too are early interventions targeted to prevent damage in tissues and organs and offer the advantage of administration as tablets or capsules, thus favouring compliance. Other plus identified by the expert group are a higher resistance to variants, and the therapeutic action maintained also in vaccinated patients.

Immunomodulators aim to regulate the excessive reaction of the immune systems against the virus, thus preventing the risk of hospitalisation. They represent a symptomatic treatment option for patients at severe stage of progression of the disease despite vaccination and antiviral therapy.


First steps of the HERA Authority and comments from industrial and medical associations

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The new European Health Emergency preparedness and Response Authority (HERA) has started its operative phase. Initially launched in February 2021, HERA has been modelled by the European Commission on the example of the US’s DARPA agency, and it will be in charge of anticipating threats and potential health crises.

The first three calls for tender to support HERA’s setup have been published on the Commission’s website and will remain open until 29 October 2021. They are targeted towards addressing different aspects of the management of Covid-19 therapeutics and antimicrobial resistance.

A total sum of €7 million from the EU4Health programme will fund these activities. An info session on the three calls was delivered on 14 October 2021 by European Health and Digital Executive Agency (HaDEA) in collaboration with DG Santé (see more at this link). A summary of HERA’s activities in the field of crisis preparedness and emergency response is also available here. A budget of €6 billion from the current Multiannual Financial Framework 2022-2027 is available to fund HERA’s setup and activities, plus additional support from other EU programmes, for a total of almost €30 billion. HERA will be part of the internal Commission structure, and it is expected to become fully operational in early 2022.

HERA’s role is to improve the EU’s development, manufacturing, procurement and distribution of key medical countermeasures said the Commissioner for Health, Stella Kyriakides, following the recent Informal Meeting of Health Ministers in Ljubljana, Slovenia -. HERA will also be crucial in ensuring accessibility and availability of medicines. As I said to Ministers today, HERA is a joint undertaking, with Member States, EU Agencies, the European Parliament and other concerned stakeholders, including industry and civil society. HERA’s strength and success will come from our joint preparedness and joint response, and our capacity to bringing joint solutions. HERA is now operational and should be fully up and running early next year.

HERA’s first activities

The call for tender on antimicrobial resistancerefers to a service contract to run a study comprehensive of a technological review of the latest AMR medical-countermeasures (e.g.; medicines, medical devices, vaccines) and a gap analysis and assessment of needs amongst the EU Member States and key stakeholders. The study shall also include options for possible actions, funding and provision of support mechanisms, and exploration of available tools suitable to ensure the availability of safe and effective products in the European market. These products are expected to be immediately available to the EU and member states in the event of a public health emergency. The estimated total value of the tender is €1 million.

Stockpiling of medical countermeasures in the area of AMR is the subject of the second feasibility study (estimated total value €1 million). The study shall analyse physical stockpiling solutions compared to other options, providing identification and assessment of all available opportunities. The needs and availability of AMR countermeasures shall be also assessing, both at member states and EU level, as well as the mapping of relevant stockpiling systems currently operated at EU and/or global level (e.g. WHO). Possible funding mechanisms (including procurement options), identification and assessment of operational deployment mechanisms and considerations on liability and regulatory aspects and/or constraints are also to be included in the study.

The third feasibility study has the higher estimated total value (€5 million) and will focus on the design and prototype development for a mapping platform on Covid-19 therapeutics in the EU. The platform is expected to map the production capacity and supply of products intended to treat Covid-19, both already on the market and in R&D phases. Possible examples include ICU medicines, heparin, dexamethasone and antibiotics, in vitro diagnostics devices and/or companion diagnostics.

Comments from stakeholders

Many stakeholders released their comments to welcome the creation of the new Authority.

The creation of HERA is a first step to putting Europe on the front foot in addressing global health threats.”, said EFPIA Director General, Nathalie Moll. “The speed at which Europe became the epicentre of the Covid-19 crisis meant, as a region, we were simply reacting to issues as they arose, working together to find solutions as quickly as possible”.

The lessons learnt during the pandemic revealed a number of weaknesses in Europe’s ability to respond to a public health crisis. HERA’s ability to balance coordination and unity with agility and responsiveness as threats emerge shall be central to its success, according to EFPIA. The Federation, together with Vaccines Europe, supports an end-to-end approach to govern HERA’s activities, and a collaborative, partnership-based model to maximise the strength of each stakeholder in a highly coordinated approach.

The association representing the generic and biosimilar industry, Medicines for Europe, wrote in a note that HERA should “be an efficient agency with strong links to healthcare industries”. A joint industrial cooperation forum to coordinate interactions of manufacturing associations and EU authorities, a regulatory framework able to prioritise the supply of essential medicines and the elimination of the proposal for redundant manufacturing capacity are just some suggestions made by the Association, which is more favourable towards manufacturing investment in a wide range of medicine production types, as outlined in the Structured Dialogue.

Reserve policies should be also revised in order to avoid waste, costly destruction, and distorting supplies of medicines to certain (smaller) EU countries. The functioning of joint procurement system should be also addressed and improved by the Commission, to avoid distortions in the internal market and provide accurate demand estimates.

The Federation of the European Academies of Medicine (FEAM) published in May 2021 a report jointly prepared with the Wellcome Trust, highlighting the opportunity in the short term not to overstep HERA’s role in relation to others European authorities (e.g. the European Centre for Disease Prevention and Control) as a pre-requirement to ensure its success.

The new-born Authority should also try to harmonise the European research and development landscape for pandemic preparedness and response, in order to remain “relevant and active between emergencies”.