incentives Archives - European Industrial Pharmacists Group (EIPG)

Generative AI in drug development


by Giuliana Miglierini Generative AI is perhaps the more advanced form of artificial intelligence available today, as it is able to create new contents (texts, images, audio, video, objects, etc) based on data used to train it. Applications of generative Read more

PGEU annual medicine shortages report


by Giuliana Miglierini The situation of medicine shortages is getting worse, with many countries which in 2023 experienced more issues than the previous years, according to the PGEU annual report on medicine shortages. Community pharmacists are on the front line Read more

EMA’s pilot scheme for academic and non-profit development of ATMPs


by Giuliana Miglierini Advanced therapy medicinal products (ATMPs) are often developed by academic and non-profit organisations, because of their high level expertise in the biotechnological techniques that underpin many new therapeutic approaches. On the other hand, these organisations often lack Read more

The risk of a biosimilar void in Europe

, , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The undergoing revision of the pharmaceutical legislation aims, among others, to redefine data protection to better support competitiveness of generics and biosimilars and to favour the timely access of patients to treatments.

While the innovator pharma industry is claiming the proposed reform would reduce the attractiveness of Europe for R&D activities, a recent report from Iqvia analysed the status of biosimilar competition. According to the document, not all biological medicines experiencing loss of exclusivity (LoE) in the next decade would automatically face competition by the corresponding biosimilars. This would result in the creation of a “biosimilar void” on the market, with many originators losing protection without seeing the parallel development of their biosimilar versions.

Competition is not guaranteed

Biosimilar competition is not necessarily guaranteed, and emerging dynamics pose a risk to conventional notions of medicines lifecycles, states the report since its very beginning. The analysis refers to biological medicines that will lose protection in the period 2023-2032.

Despite the approx. 8-fold expected increase in LoE opportunity by value between 2012 and 2032 (from €4.4 billion to €32.2 bln, as result of loss of exclusivity for 110 biological medicines), data show a declining trend for years 2021-2023 (€4.3 bln). According to Iqvia, more than a half (55%) of biologics with LoE in the period 2023-2027 might experience the lack of a biosimilar in development.

The report highlights five areas of common perception to be addressed to better define the issue. The increasing complexity of many biological medicines coupled to new barriers to entry is one of the factors making the development of biosimilars interesting only for products referred to originators with large market shares. According to Iqvia, 27% of the 26 high-sales products that will reach loss of exclusivity by the end of 2032 do not have yet a biosimilar candidate in development in Europe (vs 45% at the global level), corresponding to a potential loss of approx. €8 bln market opportunity. The number of biosimilar candidates in the pipeline for high-sales biologics is also expected to decrease from 2027 onwards.

Regulatory hurdles, therapeutic classes, and disease indication are expected to play a greater role in guiding decisions on biosimilar development, indicates the report. The attractiveness of the European market should also be considered. Oncology will remain the more interesting area, with 44% of all candidates in early to late development for LoE events occurring between 2023 and 2027. Immunology and ophthalmology are other therapeutic areas that might experience growing competition.

The current barriers to biosimilar development

According to Iqvia, the main constraints limiting the decision on biosimilars development are represented by cost and time. In the oncology area, for example, high costs have to be considered to purchase the reference comparator biologic medicine, and large patients populations are required to demonstrate relevant clinical endpoints. New therapeutic classes, i.e., PD-L1/PD-1 inhibitors, may also pose challenges for the design of pharmacokinetic and equivalence studies. From the manufacturing perspective, the increasing use of antibody-drug conjugates (ADC) would result in new barriers to entry.

According to Iqvia, the least attractive products for biosimilars development are those with less than €500 million annual sales in Europe. The report shows 93% of these products might fail to see biosimilar competition, compared to 27% of high-sales medicines. This negative trend would result in a “biosimilar void” corresponding to approx. €15 bln in lost savings. Iqvia also identified some exceptions that might experience a niche development, on the basis of specific technological and manufacturing know-how, platforms and market access excellence.

Another factor to be considered is reimbursement rate, that the report identifies in 51% for low-sales biologics with no biosimilar pipeline (approx. 30% lower than for products with a biosimilar pipeline). The management of the intellectual property referred to the originator should be also taken into consideration.

Orphan and one-off medicines

Despite the growing number of new biologics reaching marketing authorisation as orphan medicines, according to Iqvia biosimilar development is undergoing by now for only one product (eculizumab). No other orphan biologics are expected to face biosimilar competition in future, as annual sales of the 39 orphan medicines currently on the market are too low (approx. €105 mln).

A major factor limiting the development of biosimilars for orphan medicines is linked to the fact many of these therapies fall in the antibody-drug conjugates (ADC) and cell- or gene-therapies (ATMPs) categories (wave 3 biologics). This implies many challenges from the development and manufacturing point of view, higher upfront investments and a more complex setup for analytical and clinical testing.

According to Iqvia, there are currently 16 non-orphan biosimilar candidates under development, corresponding to wave 3 biologics. A limiting factor for this pipeline is identified in the still present fragmentation of the European regulatory system, e.g., reimbursement policies, incentives, and clinical standards. ATMPs, also referred to as one-off therapies, represent a particular case, being relatively young on the market. This leads to no expectation of LoE events in the next five years. The trend would then change, with some 10 products losing protection by 2040, but it should be considered together with the parallel declining of the number of eligible patients, as many of them might have been already treated with the one-off originator medicine.

Shifting standards of care

Another factor analysed by Iqvia is the impact on biosimilars development of the possible changes in the current standards of care, for example resulting from the availability of new and more user-friendly formulations of the originator (i.e., subcutaneous vs intravenous injections). The availability of second- and third generation versions of the original biologic should be considered as another factor limiting the possible market share of a biosimilar of the first-generation product. The picture is indeed furthermore complicated, as another frequent possibility, especially in the oncology area, sees the development of combination therapies based on the use of two or more biologics. As already said, some of them might be very costly (i.e. monoclonal antibodies and PD-1 inhibitors), and require a larger study population to demonstrate equivalence of the add-off effect.

The proposed solutions to fill the biosimilar void

The Iqvia report proposes several possible solutions to overcome the expected biosimilar void, starting from horizon scanning activities aimed at early identification of upcoming LoE events in order to prevent contractions in biosimilar development. Horizon scanning may also support market entry and granting of incentives based on demand. The development of biosimilars of orphan medicines might benefit of a default waiver of comparative efficacy studies, a suggested measure that according to Iqvia would not compromise the demonstration of biosimilarity. Improvements at the regulatory level might also help to streamline development, together with global convergence of regulatory guidance. Iqvia also suggests the adoption of clear regulatory pathways to incentivise the development of the next-generation, one-off biosimilar gene- and cellular treatments. Access might be improved by optimisation of market conditions, with incentives for clinicians combined with the introduction of prescription targets. New tender models would also be needed to favour multi-winner procurement practices.


EP’s draft position on Unitary SPC and SPC Regulation revision

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The Committee for Legal Affairs (JURI) of the European Parliament released the draft amendments to the Commission’s proposals aimed to establish a Unitary Supplementary Protection Certificate (SPC) (links to the document and to the procedure) and to revise the current SPC Regulation (links to the document and the procedure).

On the dedicated pages of EP’s website, you can also find the opinion issued by the Consultative Working Party, according to the Inter-institutional agreement of 28 November 2001 on a more structured use of the recasting technique for legal acts.

A document analysing the potential impact of the Unitary SPC on access to health technologies was also prepared by the Policy Department for Citizens’ Rights and Constitutional Affairs Directorate-General for Internal Policies in September 2023.

We summarise the main features of the EP’s draft positions, which were discussed in the 7 November meeting of the JURI Committee.

The revision of the current SPC Regulation

The JURI Committee (Rapporteur Tiemo Wölken) moved to Recital 2 the statement that “medicinal products, in particular those that are the result of long, costly research will not continue to be developed in the Union unless they are covered by favourable rules that provide for sufficient protection to encourage such research”. Recitals 3 and 5 of the original proposal have been deleted, the last one referring to the risk research centres located within the EU might move to countries offering greater protection. The new Recital 2 makes now reference to the difficulty of establishing a direct link between favourable protection rules and EU competitiveness. If, on the one hand, it would be true that the attractiveness of EU markets might benefit from favourable protection, on the other it should be taken into account that European incentives can be granted also to authorised medicines from third countries. Furthermore, UE-based innovative companies can equally benefit from incentives in third countries.

Recital 13, referring to the request of a marketing authorisation for a biological medicinal pro-duct identified by its International Nonproprietary Name (INN), has been amended to indicate that the protection conferred by the SPC should extend to all biosimilars (and not to therapeutically equivalent products, as previously indicated).

A reference to Article [86] of the new Directive (EU) …/… [2023/0132(COD)] to be approved has been introduced in Recital 24, concerning fees that can be charged by the European Union Intellectual Property Office (EUIPO) with reference to centralised application for SPCs for paediatric medicinal products.

The newly inserted Recital 41 a highlights the importance of the timely entry of generics and biosimilars in the EU market, as it may support competition, reduction of prices, sustainability of national healthcare systems and access to affordable medicines.

Several amendments have been proposed for Recital 45. Among the main ones is the reference to the opportunity “to restrict the protection conferred by a supplementary protection certificate in accordance with Regulation (EU) 2019/933 so as to allow making for the exclusive purpose of export to third countries and any related acts in the Union strictly necessary for making or for the actual export itself […]”. The JURI Committee referred to “related acts” as those that “could include the possession, supply, offering to supply, import, using or synthesis of an active ingredient for the purpose of making a medicinal product containing that product, or temporary storage of the product or advertising for the exclusive purpose of export to third-country destinations”.

A phrase was added to Recital 60 on the centralised SPC register to deny the possibility to use the hereby contained information to support patent linkage, regulatory or administrative decisions related to generic or biosimilars, pricing and reimbursement decisions or tender bids. Article 35 – paragraph 11 a further emphasises this concept with reference to public authorities, that should not use such information for refusal, suspension, delay, withdrawal or revocation of marketing authorisations.

The JURI Committee also modified the definition of medicinal product contained in Article 2 – paragraph 1 – point 1 of the proposed Regulation, making reference to “‘any substance or com-bination of substances that fulfils at least one of the following conditions”. These include properties for treating or preventing disease in humans, the possibility to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.

The new Article 2 – paragraph 1 – point 12 a defines the meaning of the wording ‘economically linked’ with reference to “different holders of two or more basic patents protecting the same product, that one holder, directly or indirectly through one or more intermediaries, controls, is controlled by or is under common control with another holder”.

The JURI Committee also introduced the new Article 8 – paragraph 1 – point d b, stating the need to provide information on any direct public financial support received for research related to the development of the product.

The new Article 26 – paragraph 4 – point c a mentions the inclusion of any evidence in the notice of opposition in support of the opposition itself. According to the amended Article 26 – paragraph 6, the opposition panel should communicate its decision together with the reasoning for it. The same applies to the EUIPO (Article 26 – paragraph 9). The Office should also issue a single decision with reference to several oppositions filed against an examination opinion (Article 26 – paragraph 9 a). Undue delays are repeatedly discouraged.

Article 28 – paragraph 3 – point a was amended to indicate that examiners of patents and SPCs should possess relevant expertise and sufficient experience in the assigned tasks. Article 45 – paragraph 3 adds experts shall be verified for the absence of any conflict of interest.

Amendments of the Unitary SPC proposal

Many of the amendments made by the JURI Committee to the Unitary SPC proposal correspond to the ones seen above for the SPC recast. Among the distinctive ones is the new Recital 14 a, focusing on the “digital by default” principle and consequent electronic applications for unitary and combined applications for supplementary protection certificates. Article 8 – paragraph 4 a adds that the electronic application for a unitary SPC should use the formats made available by EUIPO. Other articles regulate the entire procedure to occur by exchange of electronic documentation.

Amended Recital 22 now makes explicit reference to the possibility to produce and store in the EU “in view of entering the market of any Member State upon expiry of the corresponding certificate (‘EU Day-one entry’) and any acts related thereto”.

The new Article 22 – paragraph 1 – point c b defines cases where the applicant shall waive the SPC rights for markets where the medicinal product has not been launched, i.e., the medicinal product is not placed on all Member States or a Member State market covered by the unitary certificate or combined centralised SPCs.

Comments from Medicines for Europe

The first drafts of the EP position on the SPC and SPC Regulation recast are a step in the right direction for access to medicines across Europe, according to Medicines for Europe. The association particularly appreciated the identification of the necessary safeguards for scrutiny of the SPC application before granting, to prevent invalid (non-innovative) SPCs from delaying access to generic and biosimilar medicines. The undue use of SPC expiry dates in the register to implement unlawful and anti-competitive patent linkage strategies were also deemed positive.


HERA reports on stockpiling of antimicrobials

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.