European Notebook: UK To Leave EU; Prices Attract Political Attention; Advanced Therapies Revamp

European politicians and regulators moved forward on a clutch of issues over the past four weeks that will affect pharmaceutical and biotech companies, including discussing a new five-year action plan to tackle antimicrobial resistance, asking for a European Commission report on whether ever-higher drug prices are tipping the regulatory balance against incentives and innovation support, and nurturing the nascent cell and gene therapy sectors.

But the UK vote to leave the EU on June 23 and the decision by Prime Minister David Cameron to stand down in October will have multiple ramifications, including the likely relocation of the European Medicines Agency to another European country, the loss of the chemistry and pharmaceuticals offices for the Unified Patent Court, and the prospect of years of negotiations over trade relationships with countries across the globe ( (Also see "UK Votes To Leave The EU – Where Next For The Life Sciences?" - Pink Sheet, 27 Jun, 2016.) and ( (Also see "Brexit Timebomb: Expect Effects On Drug Regulation, IP, Research And Trade" - Pink Sheet, 24 Jun, 2016.)). There will also likely be uncertainty over regulations governing medicine development and supply, many of which are based on EU laws. Companies involved in European markets may eventually face having to satisfy separate EU and UK regulations.

The immediate reaction from UK life science companies was one of disappointment: the pharma trade association, the Association of the British Pharmaceutical Industry (ABPI), said the vote would create immediate challenges for future investment, research and jobs in the the UK. Numerous UK pharma company executives signed a letter June 22 calling for the country to remain in the EU, including GlaxoSmithKline PLC's CEO Sir Andrew Witty and AstraZeneca PLC CEO Pascal Soriot. Head of the BioIndustry Association Steve Bate said the vote was not the outcome the biotech sector wanted, but that the fundamentals of UK bioscience remain strong.

Antibiotic Use Falls

In other news, the consumption of antibiotics has fallen by 6% in Europe over the past seven years, according to a June 16 special Eurobarometer survey published by the European Commission. Antibiotic consumption has declined in Romania by nine percentage points, and by eight percentage points in Latvia, Denmark and the Netherlands. However, the decline is not universal: in Spain, the proportion of people using antibiotics increased by 9 percentage points, and in Italy by 7 percentage points.

Around a third of Europeans said they had used antibiotics in the past 12 months, the Eurobarometer survey found, even though such use might have been unnecessary; 57% of Europeans said they didn’t know antibiotics were ineffective against viruses. The European Commission’s current five-year action plan to tackle antimicrobial resistance (AMR) runs out this year, and the commission is now considering what to do about the issue in 2017 and subsequent years.

Meanwhile, an antibiotic of last resort for patients, colistin, is surprisingly also used widely in animals, and the European Medicines Agency proposed May 26 that its use in animals should be restricted to last-resort use too. There are increasing concerns about a colistin resistance gene, mcr-1, first spotted in bacteria in China, that has now also been found in the EU. The EMA is keen to make sure the use of other antimicrobials does not increase to compensate for any reduction in colistin use.

Striking A Balance On Pricing

In Europe, like in the US, very high drug prices are attracting increasing attention from politicians and health ministers, who through the Council of the EU asked the European Commission June 17 to prepare an analysis of how high drug prices might be affecting patient access to treatment, and to analyze if the “balance” is correct between pharmaceutical company incentives such as data/marketing exclusivity and extended patent terms on the one hand, and patient access, pricing and innovation on the other (Also see "EU Exclusivity Review: Commission To Assess Impact On 'Skyrocketing' Drug Prices" - Pink Sheet, 21 Jun, 2016.).

The health ministers noted the increasing number of examples of market failure in EU countries, where patient access to effective and affordable essential medicines has been endangered by very high prices, the market withdrawal of products that are out-of-patent, or by companies not introducing drugs in certain countries for entirely business economic reasons.

There’s also the trend for companies to seek approvals in small indications and segmented patient groups within a disease area, and then seek very high prices while the added value of these products is not always clear. Post-marketing obligations have not really worked, and some incentives may encourage inappropriate behavior that delays generic availability, the ministers complained.

Countries should consider voluntarily cooperating on shared interests they have in the pricing and reimbursement arena, the ministers suggest. These interests could include joint horizon scanning for new products likely to have a significant impact on health systems; the exchange of information by national pricing and reimbursement authorities while respecting business confidentiality; and exploring voluntary joint price negotiations – some countries have already expressed an interest in jointly procuring expensive drugs (Also see "European Notebook: Clinical Trial Fatality; Affordable Medicines Debate; Physician Payment Disclosure" - Pink Sheet, 25 Jan, 2016.).

Other collaborative efforts between countries could include exchanging the methods and outcomes of health technology assessments, informal meetings about pharmaceutical policies and their effects on health systems, and exploring synergies between regulators, HTA bodies and payers. An initial timetable for the analysis is expected from the Commission before the end of 2016.

Europe’s pharma trade association, the European Federation of Pharmaceutical Industries and Associations (EFPIA), said it understood the desire of countries to collaborate with each other, and that it would come up with its own proposals. But because of the diverse nature of health care systems across Europe, it said it supported the continuation of each country deciding which medicines to reimburse, and at what price. The generics association also said it would contribute to the review, adding it would support any move to allow European manufacturers to export generics during the term of the supplementary protection certificate (SPC) on the originator.

High Prices Attacked In France

The pharmaceutical industry in France is already being targeted by health activists expressing outrage at high drug prices. Following high-profile campaigns by the League Against Cancer and Médecins du Monde on the issue, the industry is calling for a calm and reasoned debate.

Drug prices are set by the state, noted an open letter published by the French trade association LEEM (Les Entreprises du Médicament) on June 20, and signed by a cross-section of business leaders at local and multinational companies based in France. The letter also noted that gastric ulcers can now be cured with drugs costing less than €10 in total, and new drugs are now available to fight AIDS, hepatitis C, diabetes and high blood pressure.

Biotech companies in France are also under attack: the association France Biotech said June 2 it was alarmed at proposed legislation that would increase taxation on the allocation of free shares to executives who achieve their objectives. Biotech companies will be adversely affected by the taxation measures that are designed to address the remuneration practices of some large French businesses, France Biotech complains.

Supporting New Clinical Trials Regulations

Europe’s new rules on conducting clinical trials will come into effect in late 2018 – when a clinical trial submissions portal and database has been set up and tested – and the European Commission has just released four public consultations on how some of the new rules will be applied (Also see "European Notebook: EMA’s 2016 Work Agenda; Clinical Trial Rule Delay; Ireland Benefits From Pfizer Merger" - Pink Sheet, 4 Jan, 2016.).

These include defining an investigational medicinal product (IMP) and an auxillary medicinal product (AMP), the latter for example being rescue medication or challenge agents used to define an endpoint, and not concomitant medication. The second consultation was on ethical considerations in conducting pediatric clinical trials, including taking into account the evolving maturity of children, who can reach a point where they refuse to participate in clinical studies.

The third consultation provides recommendations and templates on how to summarize clinical trial results for the general public. These include the use of short sentences and succinct explanations, rather than scientific jargon, clear and simple graphics and visual aids, the avoidance of long lists of adverse reactions, and the absence of any promotional content.

The fourth consultation, on taking a risk-proportionate approach to clinical trials, acknowledges that many clinical trials are associated with potential risks that are only slightly greater than risks associated with normal clinical practice. Factors that could be taken into account when evaluating risk could include the status and nature of the investigational substance, the indication, the trial population, the level of difference between the trial-related intervention and normal clinical practice, and the complexity of the protocol.

Better Regulations Needed For Gene And Cell Therapies

EU regulations on gaining marketing approvals for so-called advanced therapies including gene- and cell-based products came into effect in 2008, but only five ATMPs (advanced therapy medicinal products) are currently authorized. EMA is evaluating ideas to support the sector that holds promise to reshape treatment of a wide range of conditions.

Potential solutions emerging after a May 27 meeting involving regulators, companies and researchers include flexibility in manufacturing regulations, particularly if a product is manufactured at a patient’s bedside requiring the hospital to have a manufacturing license. Some European countries allow hospitals to hold manufacturing licenses and others do not, suggesting some harmonization is required.

Existing rules on genetically modified organisms also are not specifically designed for medicines, and are interpreted differently in different countries, again requiring harmonization.

One other major area of contention is hospital exemptions, a process whereby custom-made ATMPs can be given to specific patients in hospitals without the product or procedure having a marketing authorization. It was suggested that once an ATMP gains a marketing approval in a specific indication, the equivalent hospital exemption products should, after a set period of time, cease to exist. The regulators are now considering the views of the various stakeholders and will decide on the appropriate actions needed.

Simplified IPOs?

A new, potentially simplified process for issuing a prospectus for investment offerings was backed by UE member states on June 8, and the proposed regulation will now be discussed with the European Parliament after the summer. The regulation is expected to benefit small companies like biotechs that want to raise money, entrepreneurs and investors, and is part of the commission’s push to establish a unified market for capital in Europe.

The EU Directive on trade secrets, that will provide minimum standards for their protection, was adopted by the European Council at the end of May, and after its text is published in the EU Official Journal, countries will have up to two years to implement national legislation in line with the directive. And over the next few days, European companies will start releasing details of their payments to health care professionals during 2015, for speaking at educational meetings and for working on advisory boards or in consultancies, in order to increase transparency.