The Bulgarian presidency of the Council of Europe saw the organisation, on 6 March, of the “Conference on Options to Provide Better Medicines for all European citizens”: an occasion to deeply discuss important issues regarding rapid access to therapies, such as how dealing with medicines shortages.

A question to the European Parliament

This specific topic has been declared a priority of the Bulgarian presidency and it has been object of a question for written answer on parallel trade to the European Parliament made on March 1st by deputy Andrey Kovatchev (PPE). According to Mr Kovatchev, in early 2018, patients’ organisations in Bulgaria reported that around 60% of the medicines imported into the country were re-exported to other European markets. The Bulgarian deputy thus asked the Commission for a new analysis of the reasons for the shortages of medicines and the impact of parallel trade, the introduction of a pan‐European system for monitoring movements of medicines along the supply chain and the establishment of an electronic EU register of prescriptions.
The answer to the question was provided on 25 April by EU’s Health and Food Safety Commissioner, Vytenis Andriukaitis, who declined any further analysis of the issue claiming that shortage of medicines has been already widely studied and discussed. The Commission, wrote Andriukaitis, is currently working to draft the final report based on the 2017 questionnaire on the measures implemented by the Member States for appropriate and continued supplies of medicines, that will be followed by an expert meeting aimed to identify and share the best practices to ensure continuity of supply and restrict parallel trade.
Commissioner Andriukaitis also rejected the possibility of a pan-European system for monitoring medicines, as a similar project is already in place and involves 22 Member States with the final goal of a Digital Service Infrastructure for the cross border exchange of electronic prescriptions and short forms of electronic health records. The first exchange of data between a limited group of countries is expected to start in 2018, to be then expanded in 2019. “This system will allow for medicinal prescriptions to be issued and transmitted electronically for citizens travelling inside the EU; it does not however foresee a central register for storage of ePrescriptions”, wrote Mr Andriukaitis in his answer.

The main outcomes of the Bulgarian presidency’s Conference

Medicinal products are specific commodities and the trade activities performed with them, and the control over shortages of medicinal products should be regulated by sustainable solutions” is the key message emerged from the Conference organised by the Bulgarian presidency.
The four panels of the Conference examined different aspects related to fair access to therapies. At the base of pharmaceutical shortages is the principle of proportionality, that should guide every new legislative act. “This is where law and fact become intertwined. Application in practice can be challenging….”, explained the representative of the Council Legal Service, Matthew Moore. Proportionality in the legislative action is governed by article 5 of the TEU and Protocol No. 2 on the application of the principles of subsidiarity and proportionality. Application of the principle, explained Mr Moore, can lead to annulment of national and EU regulations, thus its proper understanding is fundamental.

The application of the principle of proportionality to shortages on medicines in Spain has been illustrated by Ms. Belén Escribano Romero, Head of Department, Pharmaceutical Inspection and Enforcement Department at the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). In 2010 the Spanish law (Article 54.5 of RD 824/2010) introduced the requirement of a prior notification to the AEMPS for shipments of medicinal products of human use to other Members States. After a pilot phase, the notification system started to be fully operative in July 2012: wholesale distributors have to notify the Agency at least 3 days before the shipment departure through an electronic system; notification is required only for products whose lack may cause a healthcare problem. The current list includes 14 medicinal products and 38 pharmaceutical presentations. Data for the concerned products have to be updated by MAHs every 6 months; in case of a possible shortage, AEMPS notifies the wholesaler and customs inspectors to stop the shipment, explained Ms Escribano Romero. Only 11 shipments (2% of total) were not allowed in the period 2012-2017; the number of shortages due to parallel trade decreased in Spain from 103 in 2007 to 11 in 2017.

The EU Commission’s questionnaire to Member States on the legal obligations and the  proposed measures received up to now a feedback from 23 countries, said Agnès Mathieu-Mendes, Deputy Head of Unit B4 of the DG Santé. Export restrictions are legitimate, according to the European Court of Justice, “in cases where parallel trade would effectively lead to a shortage of medicines on a given national market”. According to Ms Mathieu-Mendes, such measures might be based on negative lists of medicines, to be periodically revised and that do not include non-justified, large amount of products.

The industrial position was illustrated by the representative on the European Association of the Euro-Pharmaceutical Companies (EAEPC), Oliver Luksic, speaking of about 120-140 million estimates for parallel distributed medicines packages in Europe. According to Mr Luksic, parallel distribution is run according to GDP and GMP requirements and it is thus safe. Repackaging companies are at all effects considered MAHs. Parallel trade also allow to achieve lower prices, with more than € 500 million direct savings per year and indirect savings much higher, said Mr Luksic. Export restriction might deserve a negative real effect on the medium/long term, was the opinion of the EAEPC representative, as the result of negative price effects. A more effective mean to regulate the process of parallel trade, according to Oliver Luksic, would see the full implementation of the Public Service Obligations (PSO) by both wholesaler and MAHs.

The future of the European pharmaceutical industry

The main challenge, according to the Director General of Medicines for Europe, Adrian van den Hoven, relates to the need to provide answers to the ageing of population. Over-65 people currently represent 18,5% of the EU-28 populations, with estimates to reach 28% by 2050; this trend correlates to a corresponding increase in the prevalence of chronic diseases. Generic medicines currently cover 62% of the dispensed ones and represents a cornerstone of sustainability, thanks to the € 100 billion less spending achieved through generic competition. Biosimilars are expected to follow a similar trend of development, even though their market penetration is still far behind. Medicines for Europe also support the new concept of “value added medicines”, based on the use of known molecules to generate new products through drug repositioning (to treat new indications), reformulation (to develop new delivery systems) and availability of complex combinations (to allow new regimens of treatment).

The concept of repurposing towards new indications may offers important opportunities also for Olga Solomon, Head of DG Santé Unit B5, who highlighted the new holistic regulatory approach to facilitate early access to medicines. But repurposing, she commented, often suffers from a certain industry’s reluctance to include new indications. According to Solomon, this might be addressed by improving the knowledge of non-industry organisations and academics about the regulatory framework, a mechanism to provide advice or support on data quality and by bringing stakeholders together on a platform.
As for the Supplementary Protection Certificates (SPC), Solomon said that the DG Grow is assessing the possibility of a “unitary” SPC title, updating the scope of the EU patent Bolar and research exemptions and introducing an SPC manufacturing waiver.

Scientific advances and unmet medical needs are the key drivers of pharmaceutical innovation, but governments need to put in place strong incentives, rapid access to market and a stable pricing environment to facilitate the activities of R&D-focused pharmaceutical companies, said on behalf of EFPIA Boris Azaïs, Director of Public Policy at MSD. The roadmap to be follow to achieve the goal is similar to the one used to progressively develop and use innovative treatments for HIV and HCV. A roadmap that faced many failures, as demonstrated for example by the 123 candidates that failed clinical trials for Alzheimer’s disease since 1998 compared to the only 4 new medicinal products approved by the FDA in the same period. Neurological disorders together with cancer, immunological and infectious diseases are the main areas of investments in R&D and innovation.

Tools to provide early access

The term ‘benefit’ doesn’t necessarily have the same meaning for HTA and regulatory approvals, explained Stefan Lange, Deputy Director at the Institute for Quality and Efficiency in Health Care (Germany), commenting the different priorities to be taken into account during the two types of evaluations.

Various special programmes have been developed by the regulators to facilitate research and development and early access, e.g. the EMA Early Access Toolbox illustrated by the Agency’s Head of Human Medicines Evaluation Division, Zaide Frias. The number of parallel advises greatly increased since 2015, according to Ms Frias, with a level of alignment raging from 77% (with respect to the population considered in the studies) to 44% (with respect to the choice of the comparator). Artificial intelligence and new technologies such as wearables devices and smart home technologies today pose new challenges to the regulators and are changing the scene of pharmaceutical development; digital transformation will affect also regulatory activities, explained Zaide Frias.

The delicate limit between the action of regulators and the affordability of prices of innovative medicines has been explored by Yannis Natsis, Policy Manager, Universal Access & Affordable Medicines at EPHA. According to him, the key points to be addressed are the signals sent by EMA to the market, the position of the Agency towards imitation and over meaningful innovation, priorities posed by regulators to safeguard competitiveness of a business sector over public health needs and the relationship with pharmaceutical companies. EPHA asked EMA to be less dogmatic and defensive, to encourage a dialogue with the critical voices on all issues, to stop hiding behind the legislation while enforcing existing tools properly, to prevent further orphanisation of pharma regulation and to discourage abuse, overuse and misuse of incentives by manufacturers. A proactive position on issues of transparency and independence are other points requiring a major attention by the Agency, according to Natsis, as well as a better collaboration with the FDA and HTA bodies and actions intended to break down silos between national medicines agencies and Health Ministries.

The main grey issues linked to early access have been exposed by Josef Probst, Director General of the main Association of Austrian Social Security Institutions, who remembered the Council conclusions on strengthening the balance in the pharmaceutical systems highlighting concerns about very high and unsustainable price levels and the not always clear added value of some innovative products. No evidence of improvement in overall survival or quality of life was found at the time of MA for 39 of the 68 oncological indications authorised by EMA in the period 2009-2013, a number decreased to 33 after three years from the MA, said Dr. Probst. Just 33% of the 72 trials for market authorisation of cancer drugs in the period 2009-2013 were run against an active comparator, he added, while 35% were placebo controlled, 22% referred to add-on therapy and 10% had no comparator. The representative of payers also indicated that just 18% of the products which received EMA conditional approval in years 2006-2014 offered an advantage, another 18% were considered possibly helpful; judgement has been reserved in 28% of cases, while 27% of products were found not acceptable and 9% “add nothing new”.

How to achieve a better accessibility

Some of the many cases of massive overcharging of drug prices have been illustrated by Andrew Hill (Department of Translational Medicine, University of Liverpool, UK) on the basis of the initial prices of the active pharmaceutical ingredients used. The phenomenon involves also some generics medicines, said Dr Hill, those analysis indicated that almost all medicines are very cheap to manufacture. The suggestions advanced by the expert included the checking of prices and overcharging by countries, and the update every two years of the lists of drug costs and prices, in parallel with updates of the list of essential medicines. Dr Hill also suggested countries to buy all generic drugs at close-to-cost prices, maximising their use in national treatment campaigns. It would also be important to identify high quality generic suppliers and to act proactively to induce price reduction by a re-evaluation of the cost-effectiveness of all patented drugs vs. cheap generic alternatives, he said. Finally, according to Andrew Hill, if companies refuse to lower prices, countries might use TRIPS flexibilities to ensure access through compulsory licenses, personal importation and patent challenges.

Governments should know the actual numbers related to drug pricing and negotiate with pharmaceutical companies according to actual (not inflated) costs, added Fernando Lamata, representing the Association for Fair Access to Medicines, and ex-Secretary General of Health of Spain and ex-Regional Minister of Health of Castilla-La Mancha. Dr Lamata discussed the concept of value-based price vs. fair and sustainable price, this last one based on transparency of R&D costs and return on investments. Joint procurement, and the possibility of considering compulsory/mandatory licensing or manufacturing through private non-profit companies or public companies, as well as strengthening industry-independent EMA and HTA evaluations, are other suggestions advanced by Fernando Lamata.

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