By Giuliana Miglierini

The Staff Working Document on “Vulnerabilities of the global supply chains of medicines” published by the European Commission on 17 October 2022 identified several issues related to the current, often difficult situation experienced by pharmaceutical supply chains. Among these are the increasing complexity and specialisation, challenges linked to the production process and technologies, the lack of geographical diversification and other dependencies, the need to unlock the potential of data to improve supply and demand predictability, and a perceived regulatory complexity.

The same issues have been widely debated under different perspectives during recent months as a possible contribution to the current revision of the pharmaceutical legislation, a major goal of the EU Commission’s Pharmaceutical Strategy for Europe together with the New Industrial Strategy for Europe.

The structured dialogue with stakeholders has been the tool chosen to facilitate the interaction and exchange of opinions in order to optimise the development and implementation of the new pieces of legislation. We resume some of the latest proposals arising from the main industrial associations on how to better achieve this very challenging objective.

EFPIA proposals for action

In November 2022, the European Federation of Pharmaceutical Industry Associations published a report to illustrate its proposals for action to tackle shortages of medicines and to improve the efficiency and robustness of the supply chain.

Five key principles form the basis of nine operative proposals. A standard definition of a shortage and an interoperable IT European monitoring/notification system would be needed in order to build a harmonised EU prevention and mitigation system. Epidemiological data are deemed essential to better analyse patient demand, so to improve transparency in the overall supply chain by means of the European Medicines Verification System (EMVS). Targeted shortage prevention plans (SPP) should be developed to prevent the risk of shortages for critical products and to manage safety stocks on a risk-based approach. Regulatory mitigation measures for shortages would also be of help in improving flexibility. At the global level, the maintenance of global open supply chains should be the goal, supported by the strong existing EU manufacturing and R&D footprint, and where appropriate, targeted incentives for the diversification of supply chains.

“The current revision of EU pharmaceutical legislation is a golden opportunity to reverse the trends of the last 25 years. It is our once-in-a-generation chance to reinvent the regulatory framework to ensure we have a modern approach that matches our ambition to be a hub of medical innovation”, writes EFPIA’s director general Nathalie Moll in a recent post, published on the association’s website.

In its Regulatory roadmap to Innovation of January 2023, EFPIA focused on how to achieve a more agile and streamlined regulatory framework, so to shorten the period needed for approval of a new active substance (currently 426 days, vs 244 days in the USA, 306 in Canada, 313 in Japan or 315 in Australia). Innovative approaches to clinical trials, including complex clinical trials (CCTs) and decentralised trials (DCTs), and the development of clear guidance on the use and regulatory acceptance of real-world data (RWD) and real-world evidence (RWE) are among the eight areas of possible immediate actions identified by EFPIA.

A dynamic regulatory assessment pathway based on early and iterative dialogue on data, international data standards and technology, and cloud-based submission modalities would support EMA and HTAs in accepting iterative data generation as part of the evaluation procedures.

As for drug-device combinations and in-vitro diagnostics, EFPIA suggests adopting an integrated EU pathway for the assessment, including the possibility for parallel advice with Notified Bodies. A clearer definition of unmet medical need would also be needed, as well as the full digitalisation of regulatory processes. A common definition of shortage coupled to the setting up of a European reporting system (possibly the already existing EMVS) would support the collection of real-time information and activation of alerts. Epidemiological data should be elaborated and released by the European Centre for Disease Control (ECDC).

The Variation Regulation is also under review by the EU Commission. EFPIA’s proposal is to incorporate the considerations for pharmaceutical product lifecycle management set forth by the ICH Q12 guideline, and to develop a vaccine-specific annex to the Variation guideline.

EFPIA also identified four areas requiring legislative change to accelerate pharmaceutical innovation in Europe. These include the possibility to redesign EMA’s committee structure in order to speed up the efficiency of regulatory assessment and decision-making process from EMA approval to EC decision.

Expedited regulatory pathways (ERP) are still of limited use in the EU, according to EFPIA. The suggestion is to embed the PRIME scheme in the new legislation to ensure its optimal use and allocation of sufficient resources. The creation of a new legal category for drug-device combination products, to be regulated as medicinal products, would also accelerate the approval of this increasingly important type of therapeutic option.

The transition from paper leaflets to electronic product information (ePI) should be also supported within the new pharmaceutical legislation, while considering the still present difficulties that may be experienced by elders and people not having access to computers or mobile devices. A new, centralised ePI repository/database would also be needed.

Medicines for Europe, focus on access and prevention of shortages

The 2022 of Medicines for Europe (MfE), representing the generic, biosimilar and value-added medicines industry, focused its lobbying activities mainly on access to medicines and prevention/ mitigation of shortages.

The economic and geopolitical crisis highly impacted the sector, which suffers strict price caps requirements in market policies. In a recent letter to the EU institutions, Medicines for Europe highlights the possible link between the shortages of amoxicillin and amoxiclav antibiotics and the low pricing and procurement policies in place in many EU member states.

“There are significant risks of more medicine shortages in 2023”, writes the association, which may be tackled by concrete policy reforms and industry commitments.

The economic model for generic medicines in Europe is identified as the structural root cause of shortages, requiring manufacturers to run their plants at the maximum capacity in order to “remain profitable as GMP rules require continuous investment in manufacturing plant upgrades”. This leaves little space to accommodate requests for increased production in order to face shortages. Other measures that, for MfE, impacted on the consolidation of supply chains and generic markets include the requests set forth by the Falsified medicines directive, as well as the Brexit, the Covid emergency and the current war scenarios.

The letter also identifies some possible short- and medium-term measures useful to mitigate the risk of shortages and improve the efficiency of the generic’s supply chains.

The first ones include the request for more regulatory flexibility for packaging, to facilitate the distribution of the available products in different member states. Clearer thresholds for nitrosamines and the need to avoid new regulations that may have a disproportionate impact on low margin medicines are also suggested. A better dialogue on immediate measures to tackle the cost of inflation on generic medicines would also be beneficial, says MfE, which also agrees on the need to better estimate demand surges on the basis of available data and epidemiological analysis.

The association of the generic and biosimilar industry shares also the importance of a rapid digitalisation of the medicines regulatory network in order to fully exploit the potential of big data. On the medium-term (2025), this may prove important to achieve objective related to the implementation of the ePI, the reduction of variations, the management of API sources, the harmonisation of packs and a better handling of requirements at national level.

Suggested actions at the legislative level include the introduction of legal guidance on the implementation of the criteria established by the Public Procurement Directive. The Transparency Directive may take example from Canada, where prices for generics varies according to the variation of the demand. A Medicine Security Act might represent the legislative tool to support investments in manufacturing diversification and greener technologies.

MfE also highlights some threats resulting from political choices such as national stockpiling requirements, that can increase costs and reduce cross-country solidarity. A preferred approach would be that of the European strategic reserve concept, based on rolling reserves. The real usefulness of joint procurement should also be better evaluated, especially with reference to OTC and other medicines directly dispensed by community pharmacies.

A note published in November 2022 focused on the still greatly unused potential of value-added medicines, a sector which according to MfE may benefit by a re-evaluation of the current innovation model, leading to a increased attention to the entire lifecycle of a medicine and on off-patent molecules. The request to the EU Commission is to fully acknowledge value added medicines in the EU pharmaceutical legislation as a separate group of medicines, with its own dedicated regulatory pathway and proportionate data exclusivity incentives.

The vision of the ATMP sector

The vision of the advanced therapies (ATMPs) sector, represented by the Alliance for Regenerative Medice (ARM), was illustrated in an event held in November 2022 at the European Parliament.

The declining competitiveness of the EU and how to ensure patients’ access to transformative treatments have been subjects of the debate. Many of the newly approved treatments fall under the ATMP categories of medicinal products (cell and gene therapies, tissue therapies), that according to ARM would require a better suited policy and regulatory framework to fully exploit their potential. “The same policies and approaches that brought us yesterday’s biomedical innovation simply will not work for the cell and gene therapies of today and tomorrow. The EU has led before — and can lead once again — but the time to act is now.” said Timothy D. Hunt, chief executive officer of ARM.

According to data by ARM, the number of ongoing industry clinical trials in Europe involving ATMPs is increasing very slowly (just 2% at the end of June 2022). More in detail, only one phase 1 study was initiated in Europe in the first half of 2022, says the association, and the region accounted for just 11% of new trials involving ATMPs and started in the same period. Many EU’s approved advanced therapies are also suffering, with 23 ATMPs withdrawn from the market. The reduced interest of the sector towards Europe is also acknowledged by the declining number of developers headquarters (-2% vs the previous five years): a trend opposite to that of North America and, especially, the Asia-Pacific region