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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

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Reform of pharma legislation: the debate on regulatory data protection

April 1, 2024 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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 on the entire European pharmaceutical and healthcare sectors. In the meantime, the Committee for Legal Affairs of the European Parliament approved the amendment to the Regulation proposed by the Commission to govern the issuing of Union compulsory licences for the manufacturing of medicinal products during crisis.

The initial proposal on regulatory data protection

To resume the main features of the EU Commission proposal on incentives referred to regulatory data protection (RDP), the current 8+2(+1) scheme would be remodulated to grant a standard 6-year period of regulatory data protection, valid for all newly approved medicines. This might be followed by extension periods of different length, depending on specific conditions (see here the impact report, Chap. VII).

The proposed additional criteria may support an RDP duration up to 12 years, as for example in the case of medicines for orphan diseases or unmet medical needs. But the more debated criteria proposed by the Commission is perhaps the request to the holders of marketing authorisations (MAH) to market newly approved medicinal products in all EU members states at the same time, within 2 years from the date of the MA. Should this occur, the MAH may benefit from a 2-year extension of the RDP.

New chemical substances undergoing clinical testing against a relevant and evidence-based comparator may also benefit of a 6-month extension of the RDP. Should the product be already in the market, the approval of a new indication coupled to the provision of a significant clinical benefit may extend regulatory data protection for 1 year. The same extension applies to products that changed their prescription status on the basis of significant non-clinical tests or clinical studies. Repurposed medicinal products may benefit from a 4-year extension of regulatory data protection in case of a new therapeutic indication not previously authorised in the EU.

The RDP is critical for the EU’s competitiveness

According to the Director General of EFPIA, Nathalie Moll, there are three key areas to be kept in mind while reaching the final decision: the positive net financial impact of regulatory data protection for both patients, the EU and member states, the R&D attractiveness at the EU and national level, and the fact the US has currently a more attractive RDP than the EU (see here more).

The regulatory data protection scheme proposed by the Commission might greatly reduce the number of new medicines available in Europe in the next 15 years, says EFPIA. The Commission’s estimate of €1.2 billion/year of additional costs for members states for every additional year of regulatory data protection would be wrong, it adds, as it is based on the List Prices of medicines. But many EU countries have clawback-type mechanisms to reduce this type of impact, which should be added to the indirect impact innovative medicines may exert in reducing other costs supported by healthcare systems. Thus, the final economic impact calculated by EFPIA would be €2 billion/year.

The attractiveness for R&D investments of a certain geographical area may prove also important, especially in the case of advanced therapies and complex types of therapeutics or to support research targeted to unmet medical needs.

As for the duration of regulatory data protection in the US, according to EFPIA this reaches 12 years (including market protection) for biologics and around 6-7 years of market protection for small molecules. ”RDP for non-biologics is the only element of IP where Europe leads on the US and is in the control of EU policy makers”, wrote Nathalie Moll.

On the other side of the game, Medicines for Europe on behalf of the generic and biosimilar industry also addressed a note to the rapporteur and shadow-rapporteur of the EU pharmaceutical legislation.

The key message is that there might have been a misunderstanding about the concrete impact of the extensions of regulatory data protection proposed by the EU Parliament, which received a strong political support, due to the complex interactions between the pharma legislation and the IP and SPC legislations.

The correct understanding of the dual track of pharmaceutical incentives (regulatory and patent/ SPCs) should be thus the key area of attention during the final set up of the new provisions. According to Medicines for Europe, some parliamentary amendment would extend the duration of regulatory data protection well beyond the duration of SPC, thus further extending the global protection (up to 13.5 or 18 years, depending on the specific proposal) and preventing the entry of generics and biosimilars in the European market.

The analysis run by the industrial association also calculated the potential impact on pharmaceutical budgets corresponding to the possible different lengths of regulatory data protection, and how the same budget might be used to potentiate the resources of healthcare system in terms of available nurses and doctors. The calculated range spans from €2.5-5.35 bln for the three countries considered (France, Germany, Spain) up to €19.5 bln to the entire EU in the case of 13.5 year extension, and it reaches, respectively, €13.2-24 bln and €99.5 bln in the case of the 18 years extension.

A strong critical voice in support of a true competition

The European Social Insurance Platform (ESIP) published a note at the end of February signed by its Director, Yannis Natsis. “Let us be clear that these protection periods are not companies’ rights, but privileges granted to the manufacturers by the European legislators, and they come at a significant cost for public budgets”, wrote Mr. Natsis.

The extension of regulatory data protection would thus result in a possible distortion of competition, and in a delay of patients’ access to treatments. Mr. Natsis also identified the “elephant in the room” of the European healthcare system, i.e. the extremely high prices of medicines in many therapeutic areas. An issue that ESIP’s Director considers a systemic problem.

The note supports the proposed 6-year standard regulatory data protection, with extensions that should not exceed the current situation. Incentives for orphan medicines should go in favour of truly rare diseases and unmet medical needs. ESIP also supports the availability of alternative incentive mechanisms to reward development of new antibiotics, instead of the Transferable exclusivity vouchers (TEVs) that should be replaced.

ESIP’s Director also wrote that “Put simply, we need to take these industry threats with a pinch of salt”, with reference to the pharmaceutical industry having repeatedly threatened to leave Europe since the beginning of the revision of the pharma legislation. “In any case, we cannot afford to end up with a reform which hands a free-for-all incentives “menu” to the companies. These are very expensive “carrots”. Such an outcome will be counter-productive for patients and self-defeating for healthcare systems across Europe”, commented Yannis Natsis.

From the perspective of statutory payers, a well-functioning generic competition allows to treat larger groups of patients at lower prices, while the pricing and business strategies of pharma companies often would limit the possibility to treat patients with most severe conditions. The request for the Parliament is thus to reach a well-balanced text. “There needs to be a renewed social contract between the pharmaceutical industries and the society at large”, wrote Yannis Natsis.

The JURI Committee amendments to the proposed Regulation on the Union compulsory licensing

In the meantime, the Committee for Legal Affairs (JURI) of the EU Parliament approved on 13 February 2024 (17 votes in favour, 6 against) the report detailing the amendments to the proposed Regulation on the Union compulsory licensing during crisis and emergencies for the public health.

The Report also include the opinion given by the Committee on International Trade, and the list of entities or persons that provided input to the rapporteur (Adrián Vázquez Lázara) in the preparation of the report, among which are many industrial associations.

The Explanatory Note by the rapporteur highlights the need to maintain the equilibrium between innovation and rapid access to essential products. The JURI Committee has identified several aspects of the proposed Regulation that should be better clarified to ensure legal certainty, and which were addressed within the approved amendments.

The definition of “crisis” raised many concerns; the proposed amendments refer to a cross-border effect in the UE with involvement of two or more member states. Measures put in place should be proportionate, and not unnecessarily and disproportionally affecting the rights of citizens or the protection of intellectual property rights of businesses.

Union compulsory licenses might be issued only after the rights-holder has the time to negotiate a voluntary license with a potential licensee. To this instance, the Parliament has indicated 4 weeks as a suitable period for the Commission to wait for the results of ongoing negotiations. Furthermore, the Union compulsory licensing should remain a last resort instance and should have a duration strictly in line with that of the crisis, with a maximum of 12 months unless otherwise needed.

According to the JURI Committee, the definition of the know-how necessary for the manufacturing of certain products should be also clarified, as it is key to activate an expanded production capacity during crises. A new proposed recital indicates the Commission should have the authority to oblige rights-holders to provide all needed information, including know-how, especially for highly complex pharmaceuticals such as vaccines.

The Committee also highlighted the need for a better definition of the role of the advisory board. The proposed amendment indicates the inclusion as observers of other crisis relevant bodies at the UE level to ensure consistency with the measure, and of representatives of national authorities responsible for issuing compulsory licenses under the national patent laws.

Rights-holders should be able to provide their comments and other pertinent information to the advisory board prior to the final issuing of the Union compulsory licence. The procedure should start with the identification of the intellectual property rights concerned, and of potential licensees. The Commission should not grant any compulsory licences should the rights-holders not have been completely identified.

The JURI Committee also amended the text of the proposal to indicate the remuneration for the rights-holders should be determined, among others, considering the total gross revenue gene-rated by the licensee from the pertinent activities governed by the Union compulsory licence.

Remuneration should be also provided in cases where the rights-holder should disclose the trade secrets strictly necessary to achieve the purpose of the licence. A new amendment asks the Commission to assess the list of crisis modes or emergency modes reported in the Annex to the Regulation every two years from its entry into force, or without undue delay in case of exceptional threats to public safety or national security.


The risk of a biosimilar void in Europe

December 1, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.


The drug shortage situation – EIPG’s point of view

November 24, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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


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

November 17, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.


The UK’s statutory scheme revision for branded medicines

October 20, 2023 , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The amendment of the statutory schemeregulating the increase in pricing and consequent clawback payments of branded medicines proposed by the Department of Health and Social Care (DHSC) of UK’s government attracted the strong criticism of the pharmaceutical industry. The proposal aims to supersede the current scheme, established in 2018 by The Branded Health Service Medicines (Costs) Regulations. UK’s framework for pricing and clawback payments is completed by the 2019 voluntary scheme for branded medicines pricing and access (VPAS). Under the current framework, should a pharmaceutical company decide to opt out and not to join the voluntary scheme, then it becomes automatically subject to the statutory one. The current VPAS scheme, which in its original form dates to 1957, will end in December 2023. The DHSC is thus negotiating a new deal with the industrial counterparts to be effective starting 1 January 2024. Negotiations on the voluntary scheme are independent from the consultation on the statutory scheme, claims the DHSC.

The main features of the proposal

The statutory and voluntary schemes are administered by the DHSC on behalf of England, Wales, Scotland and Northern Ireland. The so received clawback payments from the pharmaceutical industry are then annually back allocated to each of the four countries on an agreed basis. According to the DHSC’s proposal, the ongoing negotiation should result in the two schemes – statutory and voluntary – continuing to operate in a complementary way. Should the negotiation on the voluntary scheme close without results, then the statutory scheme would continue to apply from 2024 onwards to all branded medicinal products. “With negotiations ongoing, there cannot currently be a default assumption of continuing alignment with any potential voluntary scheme provisions”, wrote the government. The proposed reform of the statutory scheme is comprehensive of an increase of the allowed annual growth rate, which is expected to impact on the back payment percentages. A revision of current exemptions from scheme payments should also occur.

A structure similar to that of the current statutory scheme should be used to manage these amendments, while a new lifecycle adjustment should be put in place to rebalance the payment percentages referred to medicines at different stages of their product lifecycle. As for unbranded biological products, which should be always prescribed by brand name according to MHRA’s guidance, the government aims to clarify that the statutory scheme should be applied to all biological medicines, irrespective to the fact they are marketed or not under a brand name. The government’s goal is to achieve a balance between these three objectives, “in a way that is consistent with supporting both the life sciences sector and broader economy”.

Comments from the ABPI

According to the Association of British Pharmaceutical Industries (ABPI), there is no equivalent in the world to UK’s voluntary scheme. The version agreed for the period 2018-2023 is based on a 2% per annum rise in pricing: pharmaceutical companies are called to pay back to the NHS rebates on their sales on all expenditure above the capped limit. On their side, the current voluntary scheme also requires the DHSC and NHS England to improve medicines access environment over the period 2019-2023.

ABPI mentions the dramatic rise in payments linked to the unforeseen circumstances of increased post pandemic NHS demand, which is posing major challenges for the UK life science sector. The members of the association more specifically criticise the cap growth mechanism, as well as the proposed lifecycle adjustment. The top management of leading pharma companies operating in the UK also expressed their views (read more, on the European Pharmaceutical Review).

More details on the proposals UK’s government confirmed its commitment to working with the pharmaceutical industry to facilitate the development of medicines in the UK and to support rapid NHS’s patients access to innovative medicines. The current form of the statutory scheme allows for a growth rate of 1.1% (nominal) per year for sales of branded medicines subject to the scheme. The payment percentage for 2023 and all subsequent years was set in April 2023 at 27.5%. The main exemptions refer to sales of pharmacy only and general sales list medicines, small companies with under £5 million sales to the NHS each year, sales of low-cost presentations costing less than £2, and parallel imports. The continuation of the policy of broad commercial equivalence between the statutory and voluntary schemes is the criterion chosen by the DHSC to protect the stability and efficacy of both: payment percentages in the statutory scheme would be thus comparable (but not necessarily identical) to those in the voluntary scheme. The new payment percentages in the statutory scheme proposed for 2024 would be based on a higher allowed growth rate of 2% (nominal). According to the DHSC, the maintenance of the current growth rate of 1.1% per year, in the absence of a newly agreed VPAS, would result in an effective decrease in allowed growth for most companies and might give rise to “a commercial environment for the life sciences sector that may not fully reflect the objective of supporting the sector and the broader economy”. On the other hand, an increase above 2% per year may lead to a unsustainable budget pressure on the NHS. As for the exemptions, the proposal aims to include in the statutory scheme some additional exemptions from payment which are currently part of the VPAS, namely referred to sales of medicines containing a new active substance (NAS) for 36 months from the date of their first marketing authorisation. According to the consultation document, this would incentivise companies to launch innovative medicines in the UK more rapidly than in other countries. An exemption from scheme payments for centrally procured vaccines (CPVs) is also part of the proposed package, and it would include vaccines for national immunisation programmes recommended by the Joint Committee on Vaccination and Immunisation (JCVI), procured by a central government body, or managed by the UK Health Security Agency (UKHSA) or a successor body. The third exemption to be included in the statutory scheme refers to payments for exceptional central procurements (ECPs). The measure would cover medicines related to purposes of emergency preparedness (i.e. national stockpiles) conducted by a central government body, or managed by UKHSA or a successor body. The lifecycle adjustment Innovative medicines are typically characterised by higher prices at launch, to then lower it while approaching the end of intellectual property protection. According to the DHSC’s proposal, initial prices are typically above the opportunity cost to the NHS, and older medicines would in general also benefit from greater price competition from generics and biosimilars. In some instances, states the document, this competition would be insufficient, thus resulting in prices not low enough to reflect the later stage in the product’s lifecycle. This especially applies to single supplier markets, where no competition at all is available. The proposal aims to overcome the current one-size-fits-all approach to the statutory scheme, and to introduce additional payments for older products with no competition, or a flat, lower payment for older products in more competitive markets. The so-generated additional income would then be used to reduce the headline payment percentage paid by newer products. According to the consultation document, these latter ones would refer to any product where the active substance has been marketed in the UK for less than 12 years.


Comments to the draft ICH guidelines Q2(R2) and ICH Q14

November 25, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The public consultation on the two draft guidelines ICH Q2(R2) on the validation of analytical procedures and ICH Q14 on analytical procedure development closed at the end of July 2022.The European Medicines Agency published in August two documents summarising comments received (ICH Q2(R2) and ICH Q14).

Many industrial organisations contributed to the consultation with their point of view on the two draft guidelines. In the next phase of the procedure (step 3 of the ICH process), comments will be reviewed by the ICH Q2(R2)/ICH Q14 Expert Working Group (EWG). We summarise for readers some of the main comments received from industrial stakeholders. A webinar organised byEIPG on the implications and opportunities of the revision of ICHQ2 and the ICHQ14 was presented by Dr Phil Borman, Senior Fellow & Director Product Quality at GSK on 15thJune 2022 (recording and slides are available at the webinars page of EIPG’s website).

Key principles from the EIPG’s webinar

During the webinar, Dr Borman gave a comprehensive picture of the process of Analytical Quality by Design (QbD). The systematic approach to method development starts with the identification of the predefined objectives (Analytical Target Profile, ATP). The understanding and control of the analytical procedure are at the core of the process, and they should be pursued according to principles of ICH Q8. Analytical QbD covers both the drug product (ICH Q8) and the active ingredient (Q11). This means that a similar framework to ICH Q8 and Q11 can be applied also for analytical procedures. The ATP is made up of the sum of performance characteristics, precision, range (including sensitivity), and bias/accuracy.

According to ICH Q2(R1), published in 1994, the objective of validation of an analytical procedure is to demonstrate its suitability for the intended scope. Revision of both guidelines started in 2019, based on a Concept paper published in 2018. ICH Q2(R2) covers the validation of the analytical protocols and reports, while ICH Q14 refers to the development of the analytical procedure and its lifecycle management.

Key features of the new drafts include the fact that no additional expectations / mandated requirements for pharmaceutical analytical scientists are present, the possible use of “enhanced approaches” and the clear link between performance characteristics and their related criteria and the validation study. The Q2(R2) guideline shall apply to both small molecules and biologics and includes the possibility to use prior knowledge (e.g., from development or previous validation) as a part of the validation exercise. Assay for the determination of robustness can be conducted, for example, during development. Other key features highlighted by Dr Borman include the possible use of Platform analytical procedures to reduce the number of validation tests and the possibility to use any type of calibration model (including multivariate calibration).

The expected benefits refer to the possibility to reduce the existing burden associated with post-approval changes to analytical procedures and the use of Established Conditions.

As Dr Borman explained, the ATP could form the basis of a Post Approval Change Management Protocol (PACMP), thus favouring the reporting of changes between technologies at a lower reporting category. A more performance driven and flexible approach to validation is expected following the entry into force of the new ICH Q2(R2) guideline. The selection of validation tests shall be based on the concrete objective of the analytical procedure.

Comments to ICH Q2(R2)

The overview of comments relative to the draft ICH Q2(R2) published by EMA consists of a 72-page document, divided into a first section containing general comments and a second focused on specific comments.

APIC, representing manufacturers of active ingredients and API intermediates, focused on the fact that “uncertainty is not part of the validation whereas it has a reality in practice and part of the discussion between laboratories”. The measurement of uncertainty is also considered linked to the Total analytical error (TAE), a concept that would not be adequately addressed in the guideline.

EFPIA, on behalf of the biopharmaceutical industry, asked for a better connection between the two guidelines ICH Q2 and Q14, starting from the alignment of the respective titles. Improved consistency in the use of some terms was also suggested (e.g. ‘performance criteria’). Improved clarity and greater flexibility should be applied to the concept of working and reportable ranges. The association also asked to provide more examples for multivariate analytical procedures using different models to facilitate the understanding of their validation and lifecycle management.

Medicines for Europe, representing manufacturers of generic and biosimilars, asked to provide a more specific methodology for reportable range validation. The association requested some clarification about the possibility of using the minimal requirements of the performance characteristics for the addendum method validation strategy.

The European Association of Nuclear Medicine (EANM) focused its intervention of radiopharmaceuticals, a class of substances that should be considered a special case and therefore be excluded from the scope of the guidance. The request assumes that other approaches different that those discussed may be applicable and “acceptable with appropriate science-based justification”. The same request also applies to the draft ICH Q14 guideline. The EANM contribution also highlighted aspects specific to radiopharmaceuticals that should be considered, including the strength of the radioactivity content, the unavailability of radioactive standards of the active substance, and the need of specific techniques for radioactivity determination. The suggestion is to refer to the specific guideline on the validation of analytical methods for radiopharmaceuticals jointly developed by the EANM and the EDQM.

According to the International Society for Pharmaceutical Engineering (ISPE), there are many sections of the draft Q2(R2) guideline that may pose challenges due to lack of alignment and fragmentation of contents. A revision of the structure is thus suggested, together with the harmonisation of terms with those listed in the Glossary. ISPE also highlighted the opportunity to better clarify the distinction between validation elements and recommended data applicable to multivariate analytical procedures vs traditional analytical methods.

The ECA Foundation/European QP Association reported a very critical position on the two draft guidelines, clearly stating that ICH Q2 and Q14 should integrate with one another. According to ECA, the corresponding US guideline “USP <1220> is far superior”. Many of the points reported above with respect to the general section of the overview are discussed in more deep detail within the part of the document listing specific comments.

Comments to ICH Q14

The same structure of the document also applies to the 54-page overview summarising the results of the consultation on ICH Q14 guideline.

According to the Plasma Protein Therapeutics Association (PPTA), representing manufacturers of plasma-derived and recombinant analog therapies, the draft would be too focused on chemical methods, with just a residual attention to biological methods.

APIC asked for improved discussion of the capability (and uncertainty) of the method of analysis, a fundamental parameter to assess its appropriateness for the intended use within the defined specification range. According to the association, more specific reference should be made in relation to development data that can be/cannot be used as validation data.

ISPE suggested adopting a more detailed title for the guideline; something similar has also been suggested by EFPIA. ISPE also addressed the issue of reproducibility, that may be influenced by external factors across multiple laboratories. Multivariate analysis is also discussed, suggesting adopting additional requirements for the multivariate elements while maintaining the same approach to other analytical procedures.

EFPIA would prefer to avoid the use of the term “minimal” in favour of other expressions denoted by a less negative connotation (e.g., traditional, suitable/historic, classical, fit for purpose) with reference to the validation approach. The availability of training case studies is considered important to support the alignment between industry and regulatory agencies on expectations for regulatory change management, especially with reference to multivariate models. EFPIA asked that the paragraph discussing the relationship between ICH Q2 and Q14 should not address what should be submitted to regulatory agencies. Discussion of OMICS methods used in quality control of complex biological products should be included in the annexes.

ISPE asked to avoid reference to geographic regions, as the final goal is to reach harmonisation. A clearer statement of the scope would be advisable (a possible example is provided), as well as a better linkage to the ICH Q12 guideline on pharmaceutical product lifecycle management.

Specific comments include the suggestion of the PPTA to define all acronyms at first use in text and to include them in the Glossary. According to Medicines for Europe, it would be advisable to add characterisational assays (other than release/stability) for biosimilars. Furthermore, the scope of the guideline should focus on the risk assessment and availability of the analytical knowledge needed to select the most appropriate method for a specific application. Activities deemed to the submission of the regulatory CTD dossier should remain confined to the complementaryQ2 guideline.