EMA publishes Union list of critical medicines

Today, the European Commission published the Union list of critical medicines, developed in collaboration with the EMA and the Heads of Medicines Agencies (HMA). This list is one of the first steps in the Commission’s action plan to address medicine shortages and will provide a jumping off point for assessing supply chain vulnerabilities. Here AgencyIQ analyzes the new list and its accompanying methodology and Q&A documents.

Background: E.U. medicines shortages

• Medicines shortages have been identified as a major health concern in Europe for many years now. A 2017 European Parliament resolution called on the European Commission and the European Council “to formulate a better definition of the concept – and analyse the causes – of shortages of medicines.” The European Parliament also “notes with concern that the EU lags behind the USA as regards a standardised and transparent reporting mechanism on the causes of medicines shortages.” A 2020 European Parliament resolution said that the problem had “worsened exponentially in recent years.” Shortages increased by 60% between 2017 and 2019 in select European countries, the U.S., and Canada, according to a report from the Organisation for Economic Cooperation and Development (OECD).
• In 2020, the European Commission adopted the Pharmaceutical Strategy for Europe, noting that medicines shortages “have been a serious concern in the EU for several years.” Pillar three of the strategy addresses this concern directly, calling for better crisis preparedness and response mechanisms, as well as diversified and secure supply chains. The Pharmaceutical Strategy document notes that the Covid-19 pandemic compounded medicines shortages that had already impacted patient health and the E.U. healthcare systems for years. Currently, only Article 23a and Article 81 of Directive 2001/83/EC address medicines supply across the E.U.
• The Pharmaceutical Group of the European Union (PGEU) conducted a survey finding shortages worsened in 2022 compared to 2021 in most European countries. All but one of the 29 countries surveyed reported shortages of more than 50 medicines, with seven reporting more than 600 medicines in shortage.

Several legislative efforts to curb shortages are currently underway

• In response to challenges brought to light during the Covid-19 pandemic, the European Commission issued proposals to establish a “European Health Union.” Regulation (EU) 2022/123 became applicable on March 1, 2022, with the exception of most provisions related to medical devices. The regulation expanded the European Medicines Agency (EMA)’s mandate to monitor and mitigate shortages, as well as establish lists of critical medicines during major events that affect public health. It also established the Health Emergency and Preparedness and Response Agency (HERA). [See AgencyIQ’s analysis of the expanded EMA mandate here.]
• In April, the European Commission unveiled its proposed revision to the pharmaceutical legislation, which contains extensive provisions to address and prevent shortages. Under the proposal, these elements would be addressed within the revised pharmaceutical regulation, thereby addressing drug shortages at a consistent, E.U.-wide level. [See AgencyIQ’s analysis of the proposed regulation here.]
• A non-paper drafted by the Belgian government in May 2023, obtained by POLITICO Pro EU, called attention to the continuing issue of medicine supply shortages. The document, titled “Improving the security of medicines supply in Europe,” noted that antibiotics, thrombolytics and insulin have been “difficult to obtain” and that antipyretics and painkillers are in short supply. The non-paper (an informal document used in closed negotiations within E.U. institutions) then reviewed the multi-factorial causes for these shortages across the E.U.
• The non-paper suggested three action points complementary to current legislation. In the short-term: Install a solidarity mechanism within the Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG) as a temporary bridge strategy. For the mid-term: Monitor the supply and production chain of a list of critical medicines. In the long-term: Create a “Critical Medicines Act” to reduce dependency on only a few suppliers of critical medicines and ingredients. [Read AgencyIQ’s analysis of the non-paper here.]
• On October 3, the European Commission presented its stance on ensuring medicines supply in a European Parliament plenary meeting. STELLA KYRIAKIDES, European Commissioner for Health, emphasized that addressing ongoing issues with availability of safe, effective and affordable medicines has been a priority since the beginning of the mandate. The European Commission promised to release a communication providing a toolbox of actions to enhance security and availability of medicines at all times. [See AgencyIQ’s analysis of the Parliament discussion here.]
• Finally, in late October, the Commission released a Communication that, in the absence of legislation, puts forth imminent and longer-term structural changes to address medicines shortages. Among the immediate actions assigned to the EMA included the development of a Union list of critical medicines, completion of which was by the end of this year. [See AgencyIQ’s analysis of the EC Communication here.]

Today, the EMA published the first Union list of critical medicines

• This new critical medicines list enables collaboration to avoid medicines shortages and is intended to help the EMA, the Commission and the Heads of Medicines Agencies (HMA) work together on proactive measures. Future actions to strengthen E.U. supply chains and avoid supply disruption will focus on these priority medicines. The list will likely not reduce shortages in the near future but the stated intent is “to ultimately prevent and mitigate shortages.”
• The Commission’s Q&A document defines critical medicines as those “for which no appropriate alternative is available and for which insufficient supply would result in a serious harm or risk of harm to patients. These medicines are considered to be essential to ensure the continuity of care, the provision of quality healthcare and guarantee a high level of public health protection in Europe.”
• The first iteration of the list contains over 300 medicines covering more than 200 active substances. EMA notes that it reviewed over 600 active substances currently on national critical medicines lists for six countries: Finland, France, Germany, Portugal, Spain and Sweden. In 2024, the regulator plans to continue review of additional medicines not found on these lists.
• In conjunction with the medicines list, the Commission also released a methodology document clarifying the process for risk assignment and plans for governance. While the HMA/EMA Task Force on the Availability of Authorized Medicines (HMA/EMA TF-AAM) finalized the list of critical medicines, the EC’s DG GROW will conduct the assessment of supply chain vulnerabilities.
• To create the list, criticality was assessed based on two criteria: Therapeutic indication and the availability of appropriate alternatives. For each of these two criteria, a risk level of either low, medium or high was assigned, forming a “risk matrix” that placed medicines into three categories: 1) Critical medicines, 2) Medicines at risk, and 3) Other medicines.
• High-risk therapeutic indications include those medicines that have a “very serious implication for the health of individual patients or public health” and treat patients with “general life-threatening acute conditions, specific life-threatening acute conditions or irreversible progressive conditions.” Additionally, medicines that treat a potentially fatal condition, require immediate administration, for which an interruption of treatment would jeopardize outcomes, or are part of a national disease control program (e.g., vaccination campaign) also qualify for the high-risk category.
• Medium-risk therapeutic indications have “serious implications for the health of individual patients or public health.” Conditions that qualify a medicine as medium-risk include being indicated for a chronic and severely debilitating disease, treating vulnerable patient populations, preventing relapse of a condition, or treating a condition which turns into an irreversible disease when left untreated. Medicines not meeting the high-or medium-risk categories are considered low-risk.
• As part of the methodology, “appropriate alternatives” were defined as medicines which fulfilled four criteria: 1) Authorized for the same indication, 2) Marketed in the Member State, 3) Clinically feasible, and 4) Presents no negative impacts for the patient.
• To stratify medicines in accordance with available alternatives, multiple factors were considered. First, medicines with either zero or one appropriate alternatives fall into the high-risk category, whereas products with two alternatives are considered medium risk. However, cases in which switching to the alternative treatment would “require extensive clinical consultations” also garner a high-risk classification. Similarly, cases in which the “alternative treatment is clinically possible but requires input from medical personnel” yield a medium-risk classification.
• Once a medicine is stratified by both criteria, it is placed into the appropriate final category using the following matrix:

Analysis

• Measures to address or prevent shortages for critical medicines are still to be determined. The Commission will be responsible for developing measures required to prevent or address shortages for critical medicines, and it is not yet clear what those measures might be. However, the Q&A document notes that these may include recommendations such as diversification of the supply chain or increased E.U. production, which will be determined by the upcoming supply chain vulnerability assessment. Other measures could include investment incentives, additional regulatory obligations and strong contractual obligations for delivery. Of note, marketing authorization holder obligations are also being updated through the revision of the pharmaceutical legislation.
• The Union list may include medicines not found on a national list. Medicines may not be regarded as critical in a particular Member State, either because it is not marketed there, alternatives are available, or it does not meet national criticality criteria. Similarly, medicines considered critical in only one or a few Member States will not meet criticality criteria for the Union list. Therefore, there will likely be some mismatch between the medicines found on the Union list and individual national lists.
• There is also notable mismatch between the E.U. list and the World Health Organization (WHO) Model List of Essential Medicines. This discrepancy is evident in the numbers alone, with the E.U. list containing 200 medicines and the WHO list containing 634 medicines. However, much of this difference is owed to the very different goals of the two lists – the WHO list is intended to identify those medicines which are needed for a basic healthcare system to provide “efficacious, safe and cost-effective” care, whereas the E.U. list is intended to identify those medicines for which a shortage would cause acute disruptions to individual and public health, often due to the lack of an available alternative.
• A comparison of medicines for mental health conditions reveals a snapshot of the competing priorities between these lists. Whereas the WHO list contains multiple common medicines for depression, anxiety, bipolar disorder and schizophrenia, the E.U. list contains only one medicine for depression. However, considering the methodology used to develop the E.U. list, this is likely due to the fact that many medicines used for the treatment of mental health disorders have available alternatives. In fact, the one antidepressant medicine included on the E.U. list is Spravato (esketamine), a fast-acting treatment for which there are currently no comparable alternatives. In contrast, this medication is not included on the WHO list, possibly due to the fact that it is not considered a necessity for a basic health-care system and, due to its proprietary status, may also not have been considered adequately cost-effective.
• The list contains biologics, traditional drugs and vaccines, with an apparent focus on public health. It is worth clarifying that this list includes more than 20 vaccines and five immunoglobulins, which are often used for preventive purposes and may not immediately come to mind when considering medicines that are considered critical for treatment. Additionally, the list contains more than 50 antivirals and antibiotics, suggesting a focus on public health and continued access to anti-infectives, even during major disruptive events. There are also more than 30 chemotherapeutic agents included on this list, aligning with the high-risk therapeutic criterion, “If the treatment is unavailable or interrupted, it will jeopardise the vital prognosis of patients in the short or medium term or represent a significant loss of opportunity for patients regarding the severity or potential evolution of the disease.”

What’s next

• The Union list of critical medicines is a work in progress and is not yet complete. Currently, only a fraction of E.U. authorized medicines have been evaluated and the list published today is based on the national lists of just six of the 27 E.U. and 30 European Economic Area countries. The Q&A document indicates that the list will be completed in 2024.
• The next step for medicines on the list: An assessment of supply chain vulnerabilities. According to the Commission, the goal of this assessment will be to de-risk “but not decouple from the global economy.” A vulnerabilities analysis of the medicines found on this list will serve to identify potential bottlenecks, which include dependency on only a few consolidated markets outside of the E.U. and a low diversification of suppliers. The Commission notes that some possible solutions will include “stockpiling, public procurement, increased and modernised manufacturing, strategic partnerships, etc.” The completion of this assessment is anticipated in April 2024.

To contact the author of this item, please email Kirsten Messmer ( [email protected]).
To contact the editor of this item, please email Chelsey McIntyre ( [email protected]).

Key Documents and Dates

• EMA website – Availability of Critical Medicines, updated December 12, 2023
• Union list of critical medicines – version 1, published December 12, 2023
• Methodology to identify critical medicines for the “Union list of critical medicines”, published December 12, 2023
• Questions and answers on the Union list of critical medicines, published December 12, 2023