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EMA, new features for the PRIority Medicines (PRIME) scheme


By Giuliana Miglierini Based on the review of results obtained in the first five years of implementation of the PRIority Medicines (PRIME) scheme, the European Medicines Agency has launched a set of new features to further enhance the support to Read more

The proposals of the EU Commission for the revision of the IP legislation


By Giuliana Miglierini In parallel to the new pharmaceutical legislation, on 27 April 2023 the EU Commission issued the proposal for the new framework protecting intellectual property (IP). The reform package impacts on the pharmaceutical industry, as it contains proposals Read more

Webinar: Pharmacovigilance as a specialization and the role of the Pharmacovigilance Risk Assessment Committee (PRAC)


EIPG webinar Next EIPG webinar is to be held on Wednesday 31st of May 2023 at 17.00 CEST (16.00 BST) in conjunction with PIER and University College Cork. Sofia Trantza, a pharmacist with long experience as a Qualified Person for Pharmacovigilance Read more

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The Windsor Framework

March 3, 2023 , , , , , , , , , , ,

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 effect since 1 January 2021 requiring that all goods coming into Northern Ireland from Great Britain comply with EU regulations. The UK Government and EU Commission have both made proposals in relation to the operation of the Protocol over the last two years. One approach adopted by the UK Government was to introduce the Northern Ireland Protocol Bill on 13 June 2022 providing UK with power to make further changes to it. In response to the Bill being introduced, the European Commission announced it was proceeding with legal action against the UK. Since then, negotiations between the UK Government and the European Commission increased in intensity and this led to the announcement of the agreement called “Windsor Framework”. Part of the new Windsor Framework is a political declaration published by both parties which confirms that the UK Government will not be proceeding with the Northern Ireland Protocol Bill and that the European Commission will halt its legal proceedings relating to the Protocol against the UK.

The Framework (This publication is available at www.gov.uk/official-documents)

The original Protocol applied all EU rules and authorisation requirements for medicines, notwithstanding that medicine supply is an essential state function. This meant that for novel medicines, including innovative cancer drugs, it was the EMA, not the MHRA, which approved medicines for the Northern Ireland market. This failed to recognise or accommodate for the fact that the overwhelming flow of medicines to Northern Ireland is from Great Britain, with medicines provided for the UK market as a whole.

The EU made a series of changes to its rules last year to address some of these issues, addressing regulatory requirements which prevented medicines flows and supporting the MHRAs continued ability to authorise generic drugs under a single licence for the whole UK. This, combined with the UKs own Northern Ireland Medicines Authorisation Route (NIMAR), has ensured that medicines have continued to flow uninterrupted into Northern Ireland. But these arrangements were not a complete solution for the long-term and did not address the EMAs role in licensing novel medicines, leaving Northern Ireland exposed to divergence as UK and EU rules changed into the future.

This uncertainty, as well as the requirement for Northern Ireland drugs to meet various EU labelling requirements, risked discontinuations if firms were unwilling to maintain two sets of labels and packs for Great Britain and Northern Ireland. This was not a sustainable way forward and has been addressed by this deal.

Under the agreement, both UK and EU have listened to the needs of industry and the healthcare sector and secured an unprecedented settlement that provides a comprehensive carve-out from EU rules: fully safeguarding the supply of medicines from Great Britain into Northern Ireland, and once again asserting the primacy of UK regulation.

As a result, it will be for the MHRA to approve all drugs for the whole UK market. This will enable all types of medicines to be supplied in single packs, within UK supply chains, with a single licence for the whole UK. This will provide a long-term, durable basis for medicines supplies into Northern Ireland.

  • Specifically, the whole of the Falsified Medicines Directive has been disapplied for medicines supplied to Northern Ireland, ending the unnecessary situation in which – even with grace periods – wholesalers and pharmacies in Northern Ireland were expected to keep barcode scanners to check individual labels.
  • And for the provision of innovative drugs to patients, Northern Ireland will be reintegrated back into a UK-only regulatory environment, with the European Medicines Agency removed from having any role.
  • This responds to the overwhelming calls from industry for stability and certainty, and can give reassurance to patients and clinicians in Northern Ireland well into the future.

At the same time, the agreement safeguards frictionless access to the EU market for world-leading Northern Ireland pharmaceutical and medical technology firms. This pragmatic dual-regulatory system protects business, patients and healthcare services, and reflects that it is an essential state function to maintain and oversee the supply of medicines within the whole United Kingdom.

Proposal for a Regulation (This publication is available at EU commision website here)

The European Commission has published a proposal for a Regulation that in essence carves-out medicinal products destined for the UK internal market from the EU pharmaceutical rules. Article 4(1) of the proposed Regulation provides that centrally-authorised products cannot be placed on the market in Northern Ireland. Such medicines may be placed on the market in Northern Ireland if all the following conditions are met:

  • the competent authorities of the UK have authorised the placing on the market of the product in accordance with the law of the UK and under the terms of the authorisation granted by the competent authorities of the UK;
  • the medicinal product concerned shall bear an individual label which shall be attached to the packaging of the medicinal product in a conspicuous place in such a way as to be easily visible, clearly legible, and indelible; it shall not be in any way be hidden, obscured, detracted from, or interrupted by any other written or pictorial matter or any other intervening material. it shall state the following words: “UK only”.
  • the UK shall provide the European Commission with written guarantees that the placing on the market of the medicinal products does not increase the risk to public health in the internal market and that those medicinal products will not be moved to a Member State.

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The transition towards EMA’s new Digital Application Dataset Integration (DADI) user interface

June 17, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The Digital Application Dataset Integration (DADI) network project is aimed to replace the current PDF-based electronic applications forms (eAFs) used for regulatory submissions with new web-forms accessible through the DADI user interface.

The European Medicines Agency (EMA) has released the updated timeline for the implementation of the project, which will at first affect variation forms for human medicinal products. The ongoing phase of User Acceptance Testing (UAT) by members of the DADI Subject Matter Expert (SME) Group (including representatives of EMA, national competent authorities and the industry) is expected to close in August 2022, followed by a second round of testing with external users, representatives of the different stakeholders.

The final release of the new form is currently scheduled for October 2022; a six month transition period shall then apply, during which both the PDF eAF and the web-based form can be used in parallel. Further information of the scope and implementation of the new DADI interface is available in the Q&A document published by EMA. An updated Fast Healthcare Interoperability Resources (FHIR) mapping spreadsheet is also available, containing all attributes that are required by the Notice to Applicants; the attributes have been made consistent with the ISO Identification of Medicinal Products (IDMP), so that the DADI form also supports the submission of structured data to EMA’s Product Management Service (PMS).

A short history of the project

The DADI project is aimed to improve the interoperability of data; it builds upon the Common European Single Submission Portal (CESSP) Phase 1 project (2016-2020). Seven national competent authorities (NCAs), from Austria, Germany, Spain, Ireland, the Netherlands, Norway and Sweden are also collaborating to the setting up of the DADI project.

Some results from the Horizon 2020’s UNICOM project (with no contractual obligations for EMA towards the UNICOM Consortium and the European Commission) also supported the DADI’s development; UNICOM is specifically targeted to ensure the availability of pan-European ISO IDMP compliant forms and IDMP implementation at national agencies.

The use of ISO IDMP rules is compulsory as for Commission Implementing Regulation (EU) 520/2012 (articles 25 and 26) for both marketing authorisation holders (MAHs), EMA and member states. These standardised definitions for the identification and description of medicinal products for human use shall facilitate the reliable exchange of information between the different parties involved in the regulatory processes. However, it should be noted that ISO IDMP covers human medicinal products only, not veterinary ones, and refers to the entire product lifecycle, including development. This differs from the PMS module, which covers only the Authorised Medicinal product part of IDMP.

How the DADI interface works

EMA’s plan is to gradually replace during 2022 and 2023 all the eAF forms for the various types of regulatory procedures, starting with the variation form for human medicinal products, so to achieve the availability of standard product master data for human and veterinary medicinal products. It is important to note that both the old forms based on the PDF format and the new web-forms are “electronic application forms”; EMA warns to expect that “the web-based forms will still be called electronic application forms (eAF)”, while in DADI communications, reference can be made to web-based application forms to distinguish them from the current PDF-based eAFs.

The implementation of the FHIR data exchange standard shall make possible to generate human- readable output (PDF files, with an attached FHIR XML) as well as machine-readable output for digital processing. Exchangeable contents based on FHIR are called “resources”. They all share some common characteristics, including how they are defined and represented on the basis of reusable patterns of elements, a common set of metadata, and a human readable part.

Some form fields could also be pre-populated with available product master data from the PMS for human medicines and the Union Product Database (UPD) for veterinary ones, so to facilitate applicants with the filling of the form. Additional metadata may be included in the FHIR XML backbone in order to facilitate regulatory activities.

Users will be able to download forms containing relevant product data, but it won’t be possible to export only product data nor to perform bulk exports in the web UI. Digital signature tools should be used to sign the PDF rendition of the web-form (details will follow from EMA).

Other expected benefits include shorter times to load substances drop down lists and a lower administrative burden for regulators, so to speed up the validation of applications and lowering the number of errors and discrepancies.

The main expected changes

No changes in the process to apply for or submit marketing authorisation applications will occur following the implementation of the DADI project. The current PDF output will remain, as well as the content of the output form included in the application.

The DADI project was developed on the basis of the Safe Agile principles of the Network Portfolio, and it will impact both centralised, decentralised, mutual recognition and national procedures. Ownership of the new web-forms is shared between EMA and NCAs, to acknowledge the collaborative work done to develop them.

At the level of national competent authorities, the new FHIR compliant XML shall be implemented by NCAs which are currently using the PDF forms’ Extensible Markup Language (XML) functionalities.

Specific guidance, training and webinars on the use of the new variation form should be made available by EMA close to its final adoption. Support in the use of the new web-forms will be available through the EMA Service Desk; the existing eAF Maintenance Group shall also continue its activities and act as an expert body.

Access to the new DADI interface should be based on EMA’s Identity and Access Management (IAM) system, and make use of specific access privileges. Consultants may be granted access by marketing authorisation holders (MAHs) to all products from that MAH, or only to specific applications containing products.

EMA also clarifies that the new DADI portal will remain distinct from the IRIS platform supporting product-related scientific and regulatory procedures, and it will be governed differently.

The challenges for the industry

The challenges and opportunities for the pharmaceutical industry linked to the implementation of the new DADI interface by April 2023, at the end of the transition period, has been addressed by an article by Amy Williams in Pharmaceutical Online.

Namely, the decision to implement the DADI has overwritten the expected publication of the IDMP’s EU Implementation Guide 2.2, thus asking the industry an effort to redefine its priorities along its entire regulatory portfolio to include all types of EU procedures. Submission of structured PMS data should also be accelerated by the adoption of the DADI, thus asking for an improved approach to data capture and alignment across the entire company. The need to resubmit post-approval data using EMA’s Extended EudraVigilance Medicinal Product Dictionary (xEVMPD) should be also considered.

The new phase of the DADI implementation indicates that “full IDMP-based regulatory data exchange, via a system-to-system interface between pharmaceutical companies and EMA, now won’t come into effect any time soon”, writes Renato Rjavec in Pharmaceutical Technology Europe. Compliance to data granularity requirements of IDMP should also be ensured, together with the availability of tools to extract relevant information from complex IDMP data model to appropriately generate the xEVPRM format of data exchange.


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

November 19, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.


A new role for EMA and a pilot project for the repurposing of medicines

November 12, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

A draft agreement was reached at the end of October between the Council of the European Union and the European Parliament to reinforce the mandate of the European Medicines Agency (EMA) with reference to crisis preparedness and management for medicinal products and medical devices. “EU-level preparation and coordination are two essential ingredients to fight future health crises. Thanks to this deal we are adding an essential new building block to upgrade the EU’s health architecture. It will allow the EU’s Medicines Agency to make sure we have the medicines needed to deal with public health emergencies”, said Janez Poklukar, the Slovenian minister for health.

The revision of EMA mandate is part of the broader activities announced by the EU Commission in November 2020 to achieve the European Health Union; these also include the reinforcement of the European Centre for Disease Prevention and Control and a draft law on cross-border health threats. The establishment of the new Health Emergency Preparedness and Response Authority (HERA), announced in September 2021, is also part of the package. The draft agreement shall now be endorsed both by the Council and the Parliament before entering into force.

Three new key targets for EMA

The draft agreement reached by the Council and Parliament negotiators focuses on three main areas. The first one refers to the definition of a major event and how to recognise it: these shall be events likely to pose a serious risk to public health in relation to medicinal products, as acknowledged by a positive opinion from the Medicines Shortages Steering Group, and which may trigger specific actions such as the adoption of a list of critical medicinal products to fight the health threat.

Solid funding from the Union budget shall be also provided to EMA in order to support the work of the new steering groups, task force, working parties and expert panels. The availability of provisions for adequate data protection is important to guarantee the full compliance to the GDPR regulation and other EU data protection rules, and the safe transfer of personal data relevant to EMA’s activities (e.g. data from clinical trials).

EMA shall play an improved role in the monitoring and management of shortages of medicines and medical devices, a critical activity for the availability of the products needed during public health emergencies. Other points of the agreement include the timely development of high-quality, safe and efficacious medicinal products, and the creation of a new EMA’s structure specific for expert panels in charge of the assessment of high-risk medical devices and of essential advice on crisis preparedness and management.

How to tackle shortages of medicines

According to the EU Parliament, two “shortages steering groups” (for medicines and medical devices, respectively) shall be created by EMA; if needed, these groups may also include expert advice from relevant stakeholders (e.g. patients and medical professionals, marketing authorization holders, wholesale distributors, etc.).

Parliament negotiators highlighted the importance to achieve a high transparency of the process, including avoidance of interests related to industry sectors for members of the two groups; summaries of the proceedings and recommendations shall be also made publicly available.

A European Shortages Monitoring Platform shall be created by EMA to facilitate the collection of information on shortages, supply and demand of medicinal products; a public webpage with information on shortages of critical medicines and medical devices shall be also made available.

As already occurred during the Covid pandemic, future public health emergencies may boost the development of new medicines and medical devices. Sponsors of clinical trials conducted during health emergencies will be required to make the study protocol publicly available in the EU clinical trials register at the start of the trial, as well as a summary of the results. Following the granting of the marketing authorisation, EMA will also publish product information with details of the conditions of use and clinical data received (e.g. anonymised personal data and no commercially confidential information).

“With this agreement, Parliament makes both the Agency and all actors in the supply chain more transparent, involving them more in the process and fostering synergies between EU agencies. Moreover, we pave the way to promoting clinical trials for the development of vaccines and treatments, boosting transparency on those issues. In short, more transparency, more participation, more coordination, more effective monitoring and more prevention”, said Rapporteur Nicolás González Casares (S&D, ES).

EMA’s pilot project for the repurposing of medicines

The repurposing of already approved and marketed medicines is another key action put in place to ensure improved response capacity in case of future health emergencies.

A new pilot project to support the repurposing of off-patent medicines has been launched by EMA and the Heads of Medicines Agencies (HMA), with special focus on not-for-profit organisations and the academia as the main actors to carry out research activities needed to support the regulatory submission for the new indication. The initiative follows the outcomes reached by the European Commission’s Expert Group on Safe and Timely Access to Medicines for Patients (STAMP).

Interested sponsors may access EMA’s specific scientific advice upon submission of the drug repurposing submission form to the e-mail address [email protected] by 28 February 2022. More information is available in a Question-and-Answer document. The pilot will last until scientific advice for the selected repurposing candidate projects; filing of an application by a pharmaceutical company for the new indication is another target. Final results of the project will be published by EMA.

Comments from the industry

The European Federation of Pharmaceutical Industry Associations (EFPIA) welcomed the proposed framework for the repurposing of authorised medicines. “This pilot launch comes at a timely moment to test whether a streamlined and more transparent regulatory pathway for repurposing of off-patent established products increases the chances of including existing scientific evidence into regulatory assessment. One of the goals of the pilot is to raise awareness regarding the standards required for regulatory-ready evidence on the road to further increase availability of authorised therapeutic use”, said the chair of EFPIA’s Regulatory Strategy Committee Alan Morrison.

Innovation on existing, well-known molecules through repurposing can deliver huge benefits for patients, according to Medicines for Europe. The Association of the generic and biosimilar industry supports the pilot project as a way to generate robust data packages and to translate research into access for patients. A sustainable innovation ecosystem for off-patent medicine is the expected final outcome, possibly including also reformulation of existing medicines, new strengths or adaptation for specific patient groups (i.e. paediatric populations). “These investments must also be recognised in pricing and reimbursement policies to make access a reality for all patients”, writes Medicines for Europe.