Reform of pharma legislation: the debate on regulatory data protection

April 1, 2024

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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.

PGEU annual medicine shortages report

March 4, 2024

adequate supply of medicines, adjustment of therapy and posology, alternative treatments, Annual Report, anti-infective for systemic use, antineoplastics, Aris Prins, Class I medical devices, Class IIa medical devices, co-payments, compliance to public service obligations, compounding formulations, data transparency, definition of medicine shortages, Electronic Health Records, employee satisfaction, financial losses, generic substitution, immunomodulating agents, increase in demand of medicines, interruption of therapeutic treatments, joint notification, medicine shortages community pharmacists, medicines for alimentary tract and metabolism, medicines for the cardiovascular systems, medicines for the nervous system, medicines for the respiratory system, national pricing, non-reimbursable medicines, patients distress, PGEU, pricing policies, private expenditure, procurement strategies, reduced efficacy, reporting systems for medicine shortages, revision of the pharmaceutical legislation, security of the supply chain, shared electronic communication tools, shortage of medical devices, suboptimal treatment, survey, suspension of the manufacturing process, trust in the pharmacy, valorisation of investments

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 to find suitable solutions to provide patients with the products they need to treat their diseases.

“Despite pharmacists continued best efforts to find solutions, shortages still leave many patients without their prescribed treatment – said PGEU President Aris Prins. – This situation causes frustration and inconvenience for patients and erodes their trust in pharmacists and in the healthcare system. They also cause stress for pharmacy staff and impose an additional administrative burden on pharmacies daily work”.

The main outcomes of the yearly survey
As every year, PGEU (the association representing community pharmacists at the European level) run a survey among its members to assess the current situation of medicine shortages. The survey was run between 4 December 2023 and 17 January 2024; 26 PGEU’s members provided their contribution to the 15 questions (1 answer per country).

All respondent countries experienced medicines shortages in 2023. Only three respondents reported positive improvements over the previous year (Cyprus, Greece and North Macedonia, representing 12% of the total), some other a stable situation (23%). In the great majority of cases (65%), shortages increased with respect to 2022, confirming the already known trend. Among the more significant data, the Netherlands reported 2.292 medicine shortages in 2023 (in comparison the 1.514 registered in 2022), a negative trend that impacted on 5 out of 13 million medicine users. A similar situation was reported by Sweden, where 2.457 packages were reported to be in shortage in September 2023, compared to the 1.615 in 2022. Spain also reported an increase in 36% of medicine shortages compared to the previous year.

The time spent by community pharmacies to deal with shortages almost tripled over the last 10 years, reaching an average of 10 hours per week in 2023.

The lack of anti-infective for systemic use (i.e. antibiotics) is particularly worrying, as it was experienced in 100% of the respondent countries. Slightly lower are data on shortages of medicines for the respiratory system (96% of countries impacted) and cardiovascular systems (92%). Other therapeutic classes often impacted at a European level are medicines for alimentary tract and metabolism, the nervous system, and antineoplastic and immunomodulating agents (77% of countries impacted, respectively). It is significant to note that, according to the report, there are no categories of medicinal products exempt from shortage issues.

The worsening of this trend is also acknowledged by the fact that in many responding countries (27%) the list of medicines facing shortages exceeded 600 references at the time of the survey, and was between 500-600 references in another 15% of countries.

The problem is not only referred to medicines: medical devices are also concerned, with shortages in community pharmacies reported by 69% (+3% vs 2022) of the countries participating to the survey. In this case too, all classes of medical devices are touched by the problem, with higher percentages for Class I (low risk devices – e.g. bandages, thermometers, surgical face masks) (27%) and Class IIa (medium risk devices – e.g. lancets, needles, short-term contact lenses) (23%). In the case of medical devices, only two countries reported the existence of a specific system to monitor shortages.

The impact for patients and community pharmacies
Patients are hardly impacted by medicine shortages. According to the PGEU report, distress (100% of respondent countries) and interruption of therapeutic treatments (88%) are the more frequent inconvenience. In many cases, patients have no other alternative than to buy other more expensive or non-reimbursable medicines (73%), thus increasing the rate of private expenditure for co-payments. The survey also highlights the occurrence of suboptimal treatment with reduced efficacy (73%), a practice that might negatively impact on patients’ health.

These issues can also lead to patients losing trust in the pharmacy, a negative effect reported by 77% of participating countries; employee satisfaction may be also impacted (73%). A very high percentage of countries (92%) indicated that community pharmacies may experience financial losses linked to medicine shortages, due to the dedicated amount of time needed and increased administrative responsibilities.

According to the report, disruption/suspension of the manufacturing process (65%), national pricing and procurement strategies (62%), and unexpected/high increase in demand of medicines (50%) are the main causes identified by pharmacists leading to medicine shortages. In the majority of countries (69%) there are already reporting systems in place for community pharmacists to report shortages.

Different solutions for different countries
It is worthwhile to note that only 46% of countries participating to PGEU’s survey have a commonly accepted definition of medicine shortages at the national level. This definition is incorporated in the national legislation in 19% of cases. Significantly, 35% of respondent countries still do not apply a standardised definition for shortages.

The PGEU annual report also assessed the solutions available to community pharmacists in different countries. Generic substitution is a very diffuse practice across Europe (92% of respondent countries), while far less often encountered are the preparation of compounding formulations (50%), or the adjustment of therapy and posology with a different strength of the same medicine (50%). Both these practices may require the issuing of a new prescription by the doctor in charge of the patient. Some countries are experiencing new approaches to simplify the process. In Germany, for example, a new legal basis was created to allow pharmacists to deviate from the medical prescription without consulting the prescribing doctor upon certain conditions in case of a shortage.

PGEU also calls the European and national institutions to adopt urgent and ambitious measures to better address medicine shortages. The availability of a timely and adequate supply of medicines to patients should be the first priority, to be included in the ongoing revision of the pharmaceutical legislation. This last one should put patients’ interests over commercial ones. An improved compliance to public service obligations of supply chain actors would be also required, as well as the impact of pricing policies on medicines availability and on the security of the supply chain.

Shared electronic communication tools between pharmacists and prescribers (i.e. electronic health records) may prove important to possibly expand the role of pharmacists to handle shortages, by allowing them to substitute the missing product with the most appropriate alternative. Reporting, monitoring, and communication on medicine shortages should be also improved according to PGEU, with action to be taken both at the central (EMA) and national level, e.g. working at increasing the efficiency and effectiveness of joint notification and assessment practices. A greater transparency on shortages data would be also appreciated by community pharmacists, to be achieved in each country through the connection of all medicine supply chain actors and national competent authorities in consistent reporting systems. Last, but not least, PGEU asks for a better recognition and valorisation of investments made by pharmacists and pharmacies to manage shortages.

Some perspectives on green pharmaceuticals

January 20, 2023

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by Giuliana Miglierini

The central role the green agenda plays within the EU Commission’s transformative policies impacts also on the development and availability of pharmaceutical products characterised by a improved sustainability. The concept of “Pharmaceuticals in the environment” (PiE) is entering the new legislative framework; the undergoing revision of the pharmaceutical legislation, for example, may include among other the request of environmental risk assessment and urban wastewater treatment. But also, the goal of a circular economy at net zero emission and the revision of the chemical legislation.

As explained by Dr Bengt Mattson, Policy Manager at the Swedish research-based pharmaceutical industry association Läkemedelsindustriföreningen (Lif) during a recent EIPG’s webinar, the EU Commission Action plan on environment for years 2021-2023 includes twenty legislative and non-legislative files impacting also the pharma sector.

The theme of the so-called “green pharmaceuticals” is also part of the broader approach to environmental sustainability of the chemical industry. The topic is not new, for example the EU and IMI-funded CHEM21 project in years 2012-2017 focused on the development of new manufacturing processes for the pharmaceutical industry to reduce the use of expensive and toxic materials. Another target of the project included the development of environmentally friendly methods useful to save time and costs, while reducing waste.

Activities focused on the antimicrobial drug flucytosine, with the final goal to use flow chemistry and biocatalyst techniques to make it more easily available also in lower income countries to treat a fungal form of meningitis in HIV/AIDS patients. The new, cleaner and safer method developed under the project allowed to reduce the need for expensive toxic chemicals and other raw materials, with a corresponding decrease both in costs and wastes. As a side activity, the CHEM21 project also explored more efficient screening methods to find new enzymes potentially useful as biocatalysts in industrial chemical reactions.

A Green-by-design future for pharmaceutical processes

At the EIPG’s webinar, Dr Mattson discussed from many different perspectives how R&D initiatives may influence green manufacturing. The attention moved from packaging and energy in the ’90-ies to APIs released in the environment at the beginning of the new millennium. The ’20-ies shows a greater attention to API-related emission and to aspects linked to the efficient use of resources and the resulting carbon footprint. From this point of view, it may result not easy to correctly estimate the expected environmental impact of a pharmaceutical product. Biological substances, for example, may be more easily biodegradable than synthetic small molecules, but they may also require more energy to ensure the correct storage conditions.

The development of green processes represents a great challenge for chemists and pharmacists working in the pharmaceutical industry. A possible approach to Green Drug Design has been explored, for example, by another IMI project, Premier. Results have been recently published in the Environmental Science & Technology Letters.

The “Greneer” approach includes among others, criteria aimed to achieve avoidance of non-target effects and of use of persistent, bioaccumulative, and toxic (PBT) substances, and exposure reduction. The final goal would be the development of “green-by-design” active pharmaceutical ingredients.

Green pharmaceutical processes should also prefer more eco-friendly, renewable raw materials, with a particular attention to the choice of solvents and reagents. Waste water treatment to eliminate residues of pharmaceuticals is a typical example of downstream measures put in place at the industrial level to reduce the environmental impact of manufacturing activities. As noted during the webinar, the main source of this type of pollutants remains excretion by patients, followed by inappropriate disposal.

The pharmaceutical supply chain, and in particular community pharmacists represented by PGEU, is also active to inform patients, develop national and regional collection schemes for expired and unused medicines, and to make available more sustainable packing materials and transports.

A call to action from the UK

In the UK, the request emerging from a report by the Office of Health Economics (OHE), commissioned by the Association of the British Pharmaceutical Industry (ABPI) is for the government and other stakeholders to take immediate action “to secure the era of green pharmaceuticals”.

The report highlights the challenges for the pharmaceutical industry in order to reach the ambitious target of net zero carbon. Among these is the difficulty to quickly change processes to increase sustainability while maintaining product safety, the need to collaborate at all levels along the complex global pharmaceutical supply chain, the high waste-to-product ratio on the supply side of the medicines market, the new environmental impact profile of innovative drug products compared to established small molecule technologies, and the lack of reward for sustainability.

The report also suggests high-priority activities, including investment in decarbonisation and a long-term energy strategy for transition away from fossil fuels. Common regulatory standards and environmental reporting standards should be agreed upon by regulators of different geographic areas, including the EU and US. Financial support for the adoption of greener technologies by both the industry and the NHS is also suggested. Improvements to the NHS’s supply chain may come by the Supplier Roadmap and more sustainable procurement processes and health technology assessment methods. Public-private partnerships may represent the tool to launch proof of concept pilots for sustainability schemes or co-invest on key infrastructure projects.

Standardised metrics to be used to publicly disclose emissions and progress against targets are suggested as a useful tool for the industry, together with the life cycle analysis (LCA) of products, and the development of innovative solutions for waste management and efficiency improvement.

Other insights on green pharmaceuticals

Many other things may be said on green pharmaceuticals, but we are running out of space. We then highlight some useful links readers may refer to deepen the topic.

An outcome of the CHEM21 project is represented by the CHEM21 online learning platform, managed by the ACS Green Chemistry Institute. The platform offers many free educational and training materials in the field of the sustainable synthesis of pharmaceuticals.

The Green Chemistry Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) has elaborated a Green Aspirational Level (GAL) metrics to assess the green efficiency for a given API’s manufacturing process, based on the complexity of its ideal synthesis route.

The industrial associations also committed to take action in the field of Environment, Health, Safety and Sustainability (EHS&S). The three main European groups representing, respectively, the research-based industry (EFPIA), the auto-cure (AESGP) and the generic and biosimilar sectors (Medicines for Europe) have developed the Eco-Pharmaco-Stewardship (EPS) framework. The initiative takes into consideration the entire life-cycle of a medicinal product, including roles and responsibilities of all parties involved.

The Medicine Maker’s editor Stephanie Sutton interviewed some industrial experts on different aspects of sustainability (here the link to the article). Some other comments from industrial representatives have been reported by Cynthia A. Challener in an article published on PharmTech.com

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PGEU annual medicine shortages report

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