by Maurizio Battistini

The shortage of medicines has been a major concern in the countries of the European Union, and elsewhere, for more than 10 years, so much so that the Economic Community has devoted a great deal of effort and increasing attention to this problem in an attempt to mitigate its impact on patient health.

Several factors can be identified as being at the root of the shortage of medicines, some of which intersect with each other, mainly concerning aspects with technical, qualitative, regulatory, forecasting, supply, speculative and economic implications.

EIPG has made its contribution to the various attempts to contain the phenomenon by participating in task forces, round tables and convenings dedicated to identifying the root causes of the issue and, through gap analysis, the consequent mitigation measures. Overall, strengthening the risk-assessment approach to assess and define the risk level of individual deficiencies or the causes to which they pertain in order to rationalize and focus mitigation interventions and identify their level of acceptance with a proactive approach.

Before defining the particularly deserving aspects to be emphasised and consequently acted upon, it is important to mention those that represent, in the opinion of EIPG, but are not limited to, the elements on which priority action should be taken. In analysing the problem, one cannot in fact fail to take proper account of the fact that medicines are not such without their active ingredients and that, for diseases with the widest spread, there are equivalent medicines and alternative therapies. On the basis of the latter assumption, it is understandable that the definition of a shortage of medicines should be restricted to cases where no equivalent medicines or alternative therapies with different medicines are available, so as to concentrate efforts to solve the problem only on those conditions that are worthy of attention because they are not limited to the unavailability of a specific product or to situations for which it is possible to identify an alternative treatment (defining a list of critical medicines and defining risk assessment criteria for assessing whether a product should be on the list or not).

The operation required to bring the production of active ingredients back to Europe, recognising their strategic and central role in the composition of medicines for the entire community and patients, takes longer. The relocation of the manufacturing of active ingredients to third countries, which has been taking place for several years now for mainly economic reasons, has led to the dependence of many other countries, including mainly those of the Union, on supplies that today has the occasional impact that we know of, but which could become much more serious if not systemic. We have been hearing about reshoring the production of active pharmaceutical ingredients for some time now, but so far there do not seem to be any concrete initiatives for its implementation.

As mentioned above, EIPG identified the revision of the definition of drug shortages and the reallocation of strategic production of active pharmaceutical ingredients in Europe as a main key action to mitigate the impact of drug shortages.

Although it is not an aspect of primary interest to the European industrial pharmacist community, EIPG recognises the economic aspects as playing an important role in the origin of shortages, particularly with regard to the low price paid for certain categories of medicines, which induces manufacturers to abandon the manufacture of low-profit products, and the discrepancies in the price of medicines that exist in the different countries of the Union, discrepancies that, coincidentally, make the countries where prices are the lowest or even where volumes are not so attractive as to devote production to shortages.

Having made this necessary digression on the aspects requiring corrective action at source, there are, however, other, mostly ‘occasional’ causes on which to intervene, where possible, in a proactive manner or by means of reaction instruments capable of reducing the impact of shortages. In this regard, some of the elements covered in the introductory part of this discussion, namely: technical-qualitative, regulatory, forecasting and speculative, are taken up and detailed.

As far as the technical quality aspects are concerned, given the vastness of such occasional events in the production cycle of a medicine, a separate, dedicated discussion should be devoted to them. In addition to a few examples, please refer to the chapter ‘Shortages Originating from Manufacturing‘ in the text ‘Pharmaceutical Supply Chains – Medicines Shortages‘ published by Springer and written by the same author as this article. The book, authored by experts in the field, provides an insight of relevant case studies and updated practices in Pharmaceutical Supply Chains (PharmSC) while addressing the most relevant topics within the COST Action Medicines Shortages (CA15105) and it covers uncertainty and risk aspects of supply chain management, carefully combining the scientific level with a pedagogical approach. In industry, proactive strategies such as the adoption of reserve stocks or back-up establishments can be adopted to make up for medicine shortages on an emergency basis, although the expense of sustaining these prudential approaches remains the main problem.

In a number of situations, shortages can occur due to underestimated sales forecasts or problems with the supply of raw materials, and in particular APIs.

A particular case in point is parallel trade, which by its very nature can have such contrasting effects that it has been dubbed ‘The double face of the parallel trade’. While on the one hand, this method is useful in dealing with shortages in a relatively short time (import in the country where the shortage needs to be filled and export from the country where the availability exists), on the other hand, it has often encouraged the migration of products from countries where they are cheap to others where they guarantee a higher margin, in which case it could be the source of the problem and not its solution.

Last but not least, it should be pointed out that the phenomenon of shortages has an economic implication, as it is more likely to affect drugs with low profitability or movements of drugs from countries with low margins or sales volumes to those with high margins or higher market shares.

Heads of Medicines Agencies and the European Medicines Agency on improving availability of human and veterinary medicines invited the EIPG to attend the key stakeholders’ table at the Workshop on Shortages Prevention Plan held on 1 and 2 March 2023. The EIPG was represented by Jane Nicholson and Maurizio Battistini. Staff from the EMA, the European Commission and members of national authorities presented their current initiatives and future plans. Representatives from the research and generics industry, wholesalers, pharmacists from the EIPG and PGEU, and several organizations representing patient groups had the opportunity to present and discuss ideas for shortage prevention, permanent market withdrawals, and shortage communication and transparency.

The meeting had breakthrough sessions on biosimilars (the EMA is publicly encouraging their use) immunoglobulins and veterinary medicines. The EIPG commented on the low prices of medicines that cause shortages and called for more accurate definitions of ‘medicine shortages’ and to focus efforts on essential product shortages where there is no equivalent medicine or alternative therapy to ensure patient access to adequate treatment.

Shown below is the action plan that EIPG submitted to the group at the meeting; an action plan that largely reflects what is the topic of this article.

• Establish pro-active risk management plan
• Prepare list of medicinal products of clinical importance that lack therapeutic alternatives • Undertake regular checks on market availability of alternative products especially those with low pricing due to cap measures
• Criticality in the procurement of all starting materials with particular attention to APIs
  • How to mitigate?
• Quality and manufacturing aspects that could have an impact on medicines’ shortages
  • How to manage them preventively?
• Appropriate agreements on quality and capacity of CMOs
• Need to review quality management systems throughout life cycle (including those for older products)
• Consideration of batch release and transportation impact on the time to deliver products to the market
• Review impact on production planning of potential weaknesses in sales forecasting

Everyone in industry agrees that problems of shortages are complex with no quick solutions, and it was interesting to hear staff from Agencies agree that one of the main problems of shortages for older products is the impact of low pricing of products by national healthcare systems. Also, product dumping of medicines at an extremely low price was mentioned as occurring in some countries and everyone present agreed this must not be tolerated. There were 100 participants in the main meeting room at the EMA and 200 who were connected online.

In opening the meeting, Emer Cooke Executive (Director EMA) explained the aim was to inform stakeholders about the HMA/EMA Task Force activities and deliverables and share stakeholders’ perspectives on ongoing and planned initiatives to address availability issues. She explained the long-term position of the EMA is to focus on prevention and to become more proactive, particularly since the EMA after Covid was given an extended mandate for emergency situations. The EU joint action for shortages has been launched to improve capacity at national level and the single point of contact (SPOC) working party is really helping to ensure suitable structures are in place to assist with shortages. The EMA is working with the European Commission, DG SANTE (medicinal products unit, quality, safety and innovation) and DG HERA (intelligence gathering, analysis and innovation unit) both of whom made presentations during the meeting.

In October 2023, released documents about Commission steps up actions to address critical shortages of medicines and strengthen security of supply in the EU.

The work done by the European community is aimed at addressing the shortages of the most critical medicines by emphasising the role of logistical aspects but overlooking certain critical elements that go beyond supply chain management and concern the upstream management of the concrete problems for which medicine shortages continue to occur (root causes). For the time being, the Commission seems to be oriented towards a predominantly top-down approach, even if there are spaces where opportunities for a multidisciplinary discussion involving all stakeholders in the supply chain are offered. However, it remains important to note that the Community is taking an active interest in the problem albeit adopting containment measures aimed at containing the problem rather than solving it at its root.

Given the role entrusted to Italy to find solutions to this important problem, the author is convinced that the face-to-face meeting that EIPG will have in Rome with the Italian Medicines’ Agency, on the occasion of the EIPG’s Annual General Assembly, will serve as a constructive basis for working together to find longer-term solutions to medicines’ shortages main causes.

Reference: Battistini, M. (2019). Shortages of Medicines Originating from Manufacturing. In: Barbosa-Povoa, A., Jenzer, H., de Miranda, J. (eds) Pharmaceutical Supply Chains – Medicines Shortages. Lecture Notes in Logistics. Springer, Cham. https://doi.org/10.1007/978-3-030-15398-4_5