lack in transparency Archives - European Industrial Pharmacists Group (EIPG)

A new member within EIPG

The European Industrial Pharmacists Group (EIPG) is pleased to announce the Romanian Association (AFFI) as its newest member following the annual General Assembly of EIPG in Rome (20th-21st April 2024). Commenting on the continued growth of EIPG’s membership, EIPG President Read more

The EU Parliament voted its position on the Unitary SPC

by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection

by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

HERA reports on stockpiling of antimicrobials

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By Giuliana Miglierini

The European Health Emergency Preparedness and Response Authority (HERA) has published the two final reports, prepared by McKinsey Solutions for the European Commission, describing respectively the results obtained during the first and second phases of the antimicrobial resistance (AMR) feasibility study on stockpiling.

Antibiotic resistance represents a major threat for human health, as many active substances are losing efficacy towards many bacterial species. The first report (deliverables D1–D5) focuses on the mapping exercise run during the project and aimed to assessing the current situation, identifying vulnerabilities, and reviewing the stockpiling systems currently available in the EU and at the global level.

The second report (deliverables D6-D7) discusses the vulnerabilities identified in the previous phase and the potential tools and solutions to address them, including the assessment of available options for stockpiling of antimicrobials at EU level.

Mapping of the current situation

According to the first report, 32 classes of antibiotics were identified as critical with respect to the need to ensure continued access to patients in order to offer sufficient therapeutic and prophylactic options against systemic bacterial infections.

The analysis proceeded further to identify narrower sets of antibiotics most useful to treat infections due to common pathogens with acquired antibiotic resistance: a first subset of 20 substances was indicated as specially relevant as first- or last-line/reserve therapies against AMR pathogens, and from this a shorter sublist of 13 was identified as last-line/reserve therapies for severe and potentially lethal infections.

The report did not identified any critical market withdrawal of antibiotic substances from the EU market, even though some criticalities may occur in some member states. Alternatives with better efficacy and/or safety profiles are still available on the market for the six substances identified as fully withdrawn.

According to the report, stockpiling at the EU level might not have a direct impact on the mitigation of market-driven trends. Improved monitoring of potentially critical future withdrawals would be needed to enable early detection of shortages and establishment of counteractions.

Innovation in the field of new antibiotics is still largely insufficient, with only six substances currently in phase 3 clinical development. These might prove useful especially as the ultimate reserve line of therapy after exhaustion of the currently available therapeutic options. The report suggests that, upon reaching approval, these innovative substances could be considered for future stockpiling or incentives to facilitate launch in the EU.

The analysis of supply chain vulnerabilities aimed to identify higher priority antibiotics as possible candidates for stockpiling. The report highlights that the analysis was “significantly limited by a lack of outside-in transparency”. Potential single points of failure and/or past disruptions in most supply chains were identified for the 32 critical antimicrobial classes, but the lack of capacity data made the in-depth analysis particularly difficult.

Six representative sets of antibiotic substances were assessed, for five of which less than 25% of API manufacturing occurs in the EU. Similar trends have been also observed for the remaining 26 classes. The supply of critical intermediates (i.e., 6-APA and 7-ACA) appears particularly worrying and may potentially lead to a future shortage of that specific antibiotic/class in the case of a shock. HERA report warns against the possible risks related to potential vulnerability to trade disruptions and unforeseen geopolitical shocks, which may lead to a significant shortage in case of failure of just a single manufacturing site, independent of its location.

The feasibility study also mapped the already existing or planned stockpiling systems, so to use this information to better design the new, EU-level stockpiling system. Four different levels were identified, ranging from the EU’s and member states’ systems to multilateral and/or international NGO stockpiles, stockpiles/inventories in the commercial value chain, and extra-EU national stockpiles.

At the EU and EFTA national level, 13 countries reported a national stockpile that includes antimicrobials, even if greatly differing as for the chosen model. The rescEU system was identified at the EU level as the most relevant mechanism potentially useful to complement and/or integrate with a publicly managed physical stockpile of antibiotics.

The Stop TB Partnership’s Global Drug Facility (GDF) was identified as one of the international models of interest, together with the US Strategic National Stockpile (SNS). The GDF includes more than 2,000 partners and acts as the largest purchaser and supplier of medicines to treat tuberculosis in the public sector globally. The suggestion is for HERA and the European Commission to collaborate with the GDF in case of a TB-related demand spike. The SNS may represent a significant example of how to address many of the criticalities highlighted by the report.

How to better address stockpiling of antibiotics

The second report builds on the above-mentioned observations to go deeper in analysing from different perspectives and targets the possible approaches to the stockpiling of antibiotics. The indication is for HERA to consider using existing initiatives (e.g., rescEU, the EU’s Joint Procurement Agreement and the Emergency Response Coordination Centre) and to work closely with EU member states and other EU agencies (i.e., EMA and the ECDC).

An important warning was also made: stockpiling is just “a short-term mechanism. It does not alter the fundamental market environment. It can only represent one part of any answer to the challenges faced by health agencies including HERA, whether AMR-related or otherwise”.

A sudden and unpredictable surge in demand and an interruption to supply are the two archetypes analysed to better identify how to address stockpiling.

More than 30 potential demand scenarios were considered, leading to the identification of one high priority stockpiling candidate (higher demand for anti-mycobacterial medicines due to a surge of imported tuberculosis cases) and other three important, but not yet prioritised scenarios. These include stockpiling against the accidental or deliberate release of a bacterial pathogen, treating bacterial super-infections due to a viral pandemic, and the potential rapid spread of an AMR pathogen in the current European context.

Stockpiling for supply chain disruptions was also assessed, leading to the conclusion that alternative products are available as substitutes in the great majority of cases. A point of attention is represented by cross-class substitution, that might provoke different side effects for different groups of patients and could represent a potential factor for the promotion of AMR. More complex treatment procedures (e.g., i.m. vs oral administration), higher costs for healthcare systems and organisational issues for providers should also be considered.

Virtual stockpiling to be managed through the new European Shortages Monitoring Platform (ESMP) or the existing European Medicines Verification System (EMVS) would increase transparency of the system. A mandate or incentives to support private sector physical stockpiling was considered as the most feasible option available. Efforts should be made by the EU Commission to better characterise the relationships between the economic sustainability of limited generics productions (e.g. oral formulations for paediatric use of narrow-spectrum genericised penicillins) and the risk of shortages.

Five lines of possible action

The second report identifies five possible lines for future action aimed to strengthen the antibiotic supply chain and improve the stockpiling feasibility. At first instance, it would be important to improve transparency and reporting, so to better enable the availability of targeted preparedness and response measures.

This might include the harmonisation and extension of mandatory reporting of medicine shortages across the EU, the possibility for HERA to access regulatory data from agencies and information from marketing authorisation holders on supply chain setup and inventories in the case of a healthcare emergency situation, the implementation of an opt-out mechanism from stockpiling obligations at final product level, and the introduction of a general extension of reporting requirements for the supply chain of antibiotic products sold in the EU.

The second line of possible action addresses how to lower wastage in existing private and public inventories and stockpiles. Available options include regulatory measures and limited financial support for drug stability studies or for packaging options able to maintain product quality over longer periods of time.

Facilitation and regulatory support for mutual recognition of national level approvals for antibiotics might help to improve the flexibility of existing inventories and stockpiles, so as to better mitigate the shortages occurring in some member states.

Other two complementary approaches have been identified as potentially useful to improve the supply chain resilience of the EU antibiotics market. On one hand, diversified and in-market antibiotic manufacturing capacities and capabilities could be supported by targeted incentives and investments. On the other, the maintenance of reserve/convertible manufacturing capacity for hard-to-make substances might be also supported, so to better face the need to rapidly compensate the increased requests from patients should disruptions occur.