New EC report dives deep to better understand shortages of critical medicines

Background on medicines shortages and recent policy making regarding 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 “note[d] with concern that the EU lags behind the USA” since it did not have a “standardized and transparent reporting mechanism on the causes of medicines shortages.”
• Things have not improved since the time that resolution was published. A 2020 European Parliament resolution said 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). Notably, the trend was worsening even before the Covid-19 pandemic exacerbated issued.
• In response to even more acute drug shortages during the Covid-19 pandemic, the European Commission issued proposals to set up a “European Health Union” meant to address drug shortages in several ways. Regulation (EU) 2022/123, which called for a “reinforced role for EMA in crisis preparedness and management for medicinal products and medical devices,” expanded EMA’s mandate to monitor and mitigate shortages at the E.U.-level, including the development of lists of critical medicines during major events that affect public health. Following this regulation, the EMA now coordinates shortage prevention, management and communication efforts among Member States. The regulator also consults with industry and Member States to determine if a situation requires specific recommendations. [See AgencyIQ’s analysis of EMA’s milestones.]
• The regulation established an Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG) within the EMA to support E.U.-level coordination when addressing critical shortages and ensure a “robust response.” The group provides advice and recommendations to ensure the continued supply of safe and effective medicines. During the pandemic, the MSSG was tasked with developing a list of medicines critical for addressing the public health emergency. Subsequently, the Commission directed the MSSG to develop a Union list of critical medicines outside of public health emergencies and major events. [Read AgencyIQ’s analysis of the list of critical medicines.]
• In May 2023, a non-paper drafted by the Belgian government, 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 were in short supply. The non-paper (an informal document used in closed negotiations within E.U. institutions) then reviewed the multifactorial causes for these shortages across the E.U.
• The non-paper also suggested three potential actions to address drug shortages. In the short term, the non-paper called for the installation of a solidarity mechanism within the MSSG allowing member states to request drug supplies from other states. For the mid-term, the non-paper proposed monitoring the supply and production chain of a list of critical medicines. And in the long-term, it recommended a “Critical Medicines Act” to reduce dependency on only a few suppliers of critical medicines and their ingredients. [Read AgencyIQ’s analysis of the non-paper.]
• In October 2024, the European Commission published a communication putting forth a package of reforms to address medicines shortages. The Commission’s communication was accompanied by a Q&A document defining key terms and ideas, including how the effort was related to ongoing efforts to overhaul the pharmaceuticals legislation. The tools introduced included developing a Union list of critical medicines, demand forecasting, a Union rapid alert system, and joint procurement. [Read AgencyIQ’s analysis of the Parliament discussion, the communication and establishment of the list of critical medicines.]
• The European Commission communication required the EMA to compile a new list of critical medicines. Version 1 of the list (XLS download link) contained about 300 medicines and was intended to help the EMA, the Commission and the Heads of Medicines Agencies (HMA) work together on proactive measures. 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 concept of an essential medicines list is not new, however – the World Health Organization maintains an extensive list that is updated annually, and FDA maintains a list of both critical medicines and precursor “critical input” chemicals. [Read AgencyIQ’s analysis of EMA list of critical medicines.]

The European Commission just published a report assessing supply chain issues for a select set of medicines.

• One of the things required by the Commissioner in October 2023 was an analysis of the E.U. medicines supply chain and its vulnerabilities. This analysis was intended to be based on a select set of medicine on the list of critical medicines compiled by the EMA.
• The European Commission has just published a report assessing the first 11 of those critical medicines. The commission – and specifically its Health Emergency Preparedness and Response Authority (HERA) and the DG Internal Market, Industry, Entrepreneurship and SMEs (GROW) – wrote that the report was presented to the EC’s Critical Medicines Alliance, a group launched in April 2024 as a “consultative mechanism” to bring together various stakeholders, including the European Commission, Member State representatives, industry, patients and healthcare providers in April 2024. [See AgencyIQ’s analysis of the Critical Medicines Alliance launch.]

• How did the European Commission narrow their analysis down to the first 11 medicines? Officials used a stepwise approach, they said. In the first step, critical medicines on the EMA’s list were ranked based on “quantitative criteria.” Only medicines that experienced at least one shortage between 2019 and 2023 were kept on the list. This reduced the number of critical medicines to 90. The second step looked at the risk of a supply chain disruption and the impact a shortage would have on public health for each medicine. The EC’s assessment of the risk to the supply chain included the number of actual shortages for each medicine, as well as a public health impact assessment conducted by Member States (based on EMA’s guideline using two criteria: the therapeutic indication and availability of alternative treatment options).
• This initial ranking was then augmented with qualitative factors to “increase sample diversity across various dimensions.” These qualitative factors included manufacturing and supply chain considerations such as the geographical location of manufacturing sites, the characteristics of the manufacturing process (aseptic requirements, storage specifications), and whether products had only a single source of manufacture. Other product-specific characteristics included whether the target population was adult or pediatric, whether the product was chemical or a biologic, and the cost of the product to health systems. The final list of medicines for evaluation was selected based on these characteristics from the top-ranking medicines.
• This process eventually resulted in a final list of eleven medicines: alteplase, amoxicillin, amoxicillin/clavulanic acid, benzathine benzylpenicillin, clonazepam, fludarabine, glucagon, hepatitis B vaccine, rifampicin, verteporfin and vincristine. The report notes that these products cover “a broad set of supply chain specifics.” The report also points out that the selection doesn’t reflect the risk of shortages. Instead, the selected medicines are a “diversified sample” based on qualitative factors.
• Next, the European Commission collected data from marketing authorization holders, suppliers and national competent authorities for the selected medicines. This information included manufacturing, supply chain and shortages information. The information requested about manufacturing and the supply chain included the location of sites for the product’s active pharmaceutical ingredient manufacturing, the fill and finish process, and the labeling and packaging of the final product. Recent shortages of the product (within the last 3 years) were then assessed for the duration and root cause(s) of the shortage, as well as information regarding the extent to which the supply chain was interrupted (i.e., points of disruption). Member States also needed to provide information on shortage mitigation measures they used to try to resolve the shortage. Marketing authorization holders also were asked to provide a supply chain risk assessment evaluating potential vulnerabilities and the expected economic viability of the medicine.
• Each information point was converted into a risk factor graded on a three-point scale (i.e., high, medium and low risk) based on specified thresholds in six different areas (EU industrial presence, supplier diversification, supply chain risks, market concentration, unpredictable demand, and economic viability). This scale was applied to each medicine and information point for the overall assessment of shortage root causes. (See figure below)

European Commission Risk Thresholds for Drug Supply Chains

Manufacturing issues not related to the quality of products appear to be the highest risk to supply chains

• “Manufacturing issues not related to quality” account for 38% of the evaluated shortages for the 11 products, according to Figure 10 in the report. However, the information collected from Member States and by the EMA lacked the specific information to narrow the root cause. 31% of shortages were caused by “unexpected increased demand,” 22% were caused by “another reason,” and the remaining 9% was a combination of quality issues (1%), commercial reasons (2%), distribution issues (4%), and an unlabeled category (2%) that isn’t explained.
• More than 30% of production for all 11 medicines was found to be limited to either one supplier or concentrated in one country. This market concentration applies to all assessed manufacturing steps (i.e., active pharmaceutical ingredient, fill/finish, packaging/labeling). However, most individual manufacturing steps indicate more than 70% production within the E.U. The report explained that while “there is a considerable reliance on API providers located outside the EU … MAHs are relatively less dependent on non-EU-located fill and finish manufacturers compared to their dependency on non-EU API sources.”
• The report’s data also show a troubling amount of identified risk for the eleven medicines. Three medicines were assessed to be at high risk for all stages of manufacturing (API, fill and finish, and packaging and labeling) of their medicine, and only two drugs were assessed to be at low risk because they are made at more than six manufacturing sites. In addition, marketing authorization holders for three products suggested a high risk to the supply chain in their self-assessment based on the shortage prevention plans they currently have in place. MAHs for the remaining eight products indicated a medium level of risk to their supply chains.
• This isn’t the first time that supply chain diversification has been identified as being an issue. The EMA’s Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG) previously recognized limited supply chain diversification as an issue in April 2024 when it published recommendations on strengthening supply chains for critical medicines. MSSG suggested that adding alternative manufacturing sites could be an option to ensure robust supply chains. Another recommendation asked marketing authorization holders to assess geopolitical risks (e.g., trade barriers or conflict zones) when choosing manufacturing sites.
• The second key issue highlighted in the EC’s report is the unexpected increase in demand. Data from the Member States and the EMA showed that unexpectedly increased demand accounts for 27% of shortages. The risk level of unexpected demand was considered high for four medicines, while no conclusion was drawn for the rest of the medicines assessed. One issue may be the process used to plan future manufacturing capacity. The report notes that the manufacturing planning for generics for the next three to six months is commonly based on current sales, which would not accommodate unexpected demand increases (e.g., during a public health emergency).
• It should also be noted that the report points out several limitations regarding the data collected: Missing data was one issue as not all respondents answered all questions. The sales data evaluated was from 2022, which. This means that key marketing authorization holders supplying the evaluated medicines may have changed. The access to up-to-date information, standardization of terminology to obtain consistent responses, and the benefit of a standardized platform for reporting shortages are considerations for future improvement of these evaluations.

The report also assessed how Member States mitigated shortages, and found three measures to be most common:

• Medicines shortages are generally addressed by the individual Member States, but the EMA was also given more responsibility for oversight during the pandemic. Article 23a of the Directive 2001/81/EC requires marketing authorization holders to inform the national authorities when they plan to temporarily or permanently cease to market a product. Article 81 of the same directive requires the marketing authorization holder to “ensure appropriate and continued supplies” of an authorized medicine. The European Commission explained in a 2018 paper on shortages that Articles 81 and 23a require marketing authorization holders to provide information on sales volumes and supply issues. Also, Member States can request certain additional information from the marketing authorization holder as needed. Most recently, Regulation (EU) 2022/123 requires the EMA to monitor shortages that could lead to crisis situations. The agency also publishes information on critical shortages including links to national shortage catalogs.
• Because national regulators can implement different measures to address shortages in their countries, the report wanted to look at how regulators have actually used their authority to address shortages associated with the 11 selected drugs between 2021 and 2023. The report groups these measures into three main categories: regulatory flexibility, controlled distribution and dose-sparing measures.
• Regulatory flexibility commonly enabled the approval of labeling in a foreign language or approval of an authorized medicine. The report notes that 50% of Member State authorities addressed shortages by approving exemptions – for example, for using foreign language packages or unlicensed medicines. Other regulatory flexibilities applied include accelerated processes for regulatory approval of changes to the manufacturing process or the authorization of parallel import. Parallel import refers to the import of an E.U.-approved product “into one Member State from another and then distributing it outside the distribution network set up by the manufacturer or his/her distributor.”
• As a second option, Member States used measures to control the distribution of the product to patients with the highest levels of need. Additionally, prescriptions were limited in doses to prevent dispensing unnecessary doses. On some occasions, Member States also facilitated the redistribution of available doses between hospitals and pharmacies. Export bans were a measure to keep available doses within a Member State, although this was one of the least-common measures used.
• Alternative protocols or dose-sparing measures were also used in some cases, with Member States reporting allowing substitution of the product for an equivalent treatment or changing the dosage (e.g., reducing the frequency of a dose) or pharmaceutical form (e.g., from a tablet to a capsule).

What’s next

• The key causes of medicines shortages highlighted in the report are ongoing issues that are unlikely to be solved any time soon. For example, many of the causes identified in the report have previously been identified by industry groups, such as the European Federation for Pharmaceutical Industry and Associations’ (EFPIA) July 2022 report on shortages. Key recommendations in EFPIA’s report include the development of an interoperable system to report shortages in a harmonized way, better transparency on patient demand, and the implementation of shortage prevention plans. It is not enough to simply identify the problems causing shortages – especially when those problems are known. Rather, regulators and legislators need to identify and implement policy solutions if some of these problems are to be alleviated.
• At present, E.U. law only requires limited information from MAHs when they report shortages and supply issues, but doesn’t provide mechanisms to address shortages. The directive only requires marketing authorization holders to fulfill a public obligation of informing applicable regulatory agencies of supply issues or planned discontinuation of supply. In a February 2023 report, the EMA highlighted several shortcomings in the current practice of reporting and issued recommendations including that potential or actual shortages be reported as soon as possible, that shortage information be transparent and more accurate, that companies have shortage prevention plans in place and that shortage management plans be enacted to address actual shortages.
• Similarly, recent legislative developments in the U.S. and guidance issued by the FDA indicate a shift to a more proactive and authoritative role of the regulator in shortage management. For example, the Coronavirus Aid, Relief, and Economic Security (CARES) Act of 2020 requires application sponsors to notify the FDA of any “permanent discontinuation” or “an interruption” in the manufacture of the finished product or the active ingredient. The FDA released draft guidance with the reporting expectations for drug shortages in April 2023. Additionally, a 2023 Homeland Security & Governmental Affairs report included recommendations for additional data collection and greater collaboration between the FDA’s Centers. [Read AgencyIQ’s analysis of the report and guideline.]
• However, the FDA highlighted consistent authority limitations concerning shortages at a recent meeting hosted by the Food and Drug Law Institute. “Now, we have very limited authorities at FDA,” said PATRICIA CAVAZONNI, CDER director at FDA, during a recent Food & Drug Law Institute meeting. “We cannot tell manufacturers what to do, what to manufacture, where to manufacture and so on. So, we fundamentally only have one authority: the manufacturers have to tell us when they are anticipating a disruption in manufacturing—or when the disruption has taken place, if they cannot anticipate it.” Cavazzoni reminded attendees that “Everything else we do is voluntary, through collaboration by manufacturers who are really incredible at stepping up most of the time.” The FDA was tracking 111 drugs in shortage as of the beginning of May 2024, according to Cavazzoni. [See AgencyIQ’s analysis of this meeting.]
• The limitation in authority is similar in the E.U. where legislation calls on a public obligation for the marketing authorization holder. However, current legislation doesn’t include specific provisions for reporting and addressing shortages. Articles 23a and 81 implement a general requirement but are not specific concerning shortages. This issue was identified during the examination of the current legislation by the European Commission.
• But a proposed revised regulation, published in April 2023 as part of the proposed Pharmaceutical Regulation, would give EMA additional authority to tackle medicines shortages and impose new obligations on the MAH and regulators. Two key provisions would specify the reporting requirements for shortages depending on whether the interruption in supply is temporary or permanent; it would also require marketing authorization holders to implement a shortage prevention plan. National regulators and the EMA would need to monitor shortages based on data provided by the MAH. Perhaps most importantly, the reporting requirements would be harmonized across the E.U. – a marked change from the current system in which Member States may set their own reporting requirements. [See AgencyIQ’s analysis of the regulation.]
• The European Commission proposal will likely be further modified. Most recently, the European Parliament’s compromise on the regulation expanded reporting requirements to wholesale distributors and would require regulatory authorities to develop a system that enables patients to report shortages. The European Council has not yet provided its stance on mitigating medicines shortages. Once the council issues its own approach, the trilogue among the three E.U. institutions can begin. The European Council’s position and following trilogue could be impacted by the findings of this first (and potential future) iteration of the assessment.
• The new report provides the assessment of the “first tranche” of medicines but further iterations are planned with improvements. There is currently no timeline given for the next selection of medicines and surveys to gather data, though the report suggests that the next iteration of the project will likely implement some changes to obtain more recent and complete data as well as comparable data from all respondents. However, there is one major warning in the report: “Overall, refinement and extension of this exercise beyond its pilot phase is challenging within the limitations of the present legal framework and the constraints imposed by the existing data collection tools and formats,” its authors write.

To contact the author of this item, please email Kirsten Messmer ( kmessmer@agencyiq.com).
To contact the editor of this item, please email Alexander Gaffney ( agaffney@agencyiq.com)

Key Documents and Dates

• European Commission press release – Commission assessment shows the need to reinforce resilience of critical medicines supply chains, July 10, 2024
• Technical report – Assessment of supply chain vulnerabilities for the first tranche of the Union list of critical medicines, July 10, 2024