Questions and Hopes on New EU Drug Legislation

The European Union (EU) claimed last month that the new pharmacovigilance rules that came into effect in July 2012 have been a success. A just-issued report from the European Medicines Agency (EMA) says that the legislation "offers better promotion and protection of public health." It provides, it continues, "more clearly defined roles and responsibilities for the many stakeholders involved, simplified tasks, decreased duplication of effort, and targeted administrative simplification."

Not everyone agrees. The costs to industry of the new rules remain a hot topic. Fees will be charged to companies to meet the expense of the new activities—and the first bills are due to land on company desks this summer. Criticisms came loudly from German firms last month, highlighting failures to arrange some form of co-funding from the EU budget for what is seen as an EU responsibility. Although the new rules include some exemptions for smaller firms, industry says that they are inadequate. In February, an almost unprecedented coalition of leading European drug industry associations issued a joint expression of concern over the increasingly regulatory costs from the new rules. The signatories to the statement included the European Federation of Pharmaceutical Industries and Associations, the European Generic Medicines Association, EuropaBio, the Association of the European Self-Medication Industry, and the European Confederation of Pharmaceutical Entrepreneurs.

Misplaced focus

The focus on assessing reported side effects may be misplaced, some safety experts argue. They say not enough is being done at ground level, to keep doctors up-to-date with safety changes or alerts outlined in product information. It would be valuable to ensure that a cultural shift takes place among prescribing doctors. There are also siren voices cautioning that the increased centralization of pharmacovigilance at EU level risks robbing national authorities of their role and skills. But the view from the EMA is that the trend towards centralized adverse drug reaction reporting is not only inevitable, but desirable.

There is no doubt that the EU is determined to clamp down on any slackness in postmarketing monitoring. European drug authorities are still smarting from suggestions that they have been insufficiently vigilant in putting a stop to risky products, suggestions that crystallized in recent years around the scandal over adverse effects and deaths from decades of unchallenged use of Servier Laboratories' drug, Mediator (Jacques Servier, the company's founder and president, who died in April at age 92, is accused of concealing the risks of the drug). While investigations are still ongoing into alleged malpractice, they have done nothing to ease the authorities' discomfort. EU officials recently warned Denmark, Italy, the Netherlands, and Slovenia that their failure to put the pharmacovigilance rules into effect could lead to action against them at the Court of Justice of the EU. And officials are still pondering whether to fine Roche over shortcomings discovered in its safety reporting and drug monitoring standards.

Major shift in legislation

The pharmacovigilance legislation was perhaps the biggest change to the regulation of human medicines in the EU since 1995. The EMA, which is responsible for much of the implementation, has had to rejig its own priorities to deal with the tasks. The agency already flagged up the implementation of the pharmacovigilance legislation as a major part of its work program for 2014—including improvements to its EudraVigilance database on adverse drug reactions, development of a repository for periodic safety update reports, and a system for monitoring scientific literature for signal detection. Current plans include further reflection on measuring performance, especially in changes of behavior and impacts on public health and industry.

The agency's report, which is based on evidence collected between July 2012 and July 2013, states that it "has demonstrated positive results." Among the key achievements, it lists the introduction of risk management plans as a matter of routine in product evaluations, clearer understanding of the role of periodic safety update report assessment, more rapid and timely risk-minimization and restriction of indications, and increased transparency of studies for patients and healthcare professionals. Adverse-drug-reaction reporting has increased, with more than 9,000 more patient reports received and about 175,000 more individual case safety reports to EudraVigilance. Adverse drug reaction data are also more accessible to the public.

Nearly half the confirmed signals detected led to label changes, and one in ten led to products being further investigated at EU level (including codeine overdose in children treated for pain, and hydroxy-ethyl starch infusions associated with fatal outcomes). Special labelling (with a conspicuous black triangle) was applied to more than 100 products under investigation. And public health reviews have been initiated on all combined hormonal contraceptives and venous thromboembolism, on Diane-35 and venous thrombo-embolism, on tetrazepam and serious and fatal skin reactions, and on diclofenac and cardiovascular risk. This, says the report, "will change the labelling and use of medicines taken by millions of EU citizens." The EMA has also trained about 10,400 individuals in pharmacovigilance, and in 2013 developed and published a catalog containing all the training material prepared in the context of the implementation of this legislation.

A global leader?

The EU likes to depict itself as "a global leader in pharmacovigilance," and the EMA's report compliments its own "leadership in putting into operation its tasks through collaboration, consultation, and concentration," concluding that "there is concrete evidence that major change has been delivered, which should lead to better public health." It says that "ensuring that regulators can respond to emerging or urgent health issues in a timely and efficient way is a key deliverable," and the new legislation "increases the opportunities for quick and robust regulatory action" through a new committee structure "and new procedures that fast-track the decision-making process when public health is at risk." The newly-created Pharmacovigilance Risk Assessment Committee now issues recommendations to the Committee for Medicinal Products for Human Use (CHMP), and has dealt with 918 total procedures. In addition, a new referral procedure, known as the urgent Union procedure, allows an EU member state or the European Commission to trigger a rapid assessment of "significant, emerging safety concerns resulting from the evaluation of data from pharmacovigilance activities."

Guarded optimism on clinical trials

Meanwhile, commentary continues to fly thick and fast about the prospects for Europe's new clinical trials rules. Latest to enter the fray is the energetic BioIndustry Association (BIA) in the UK, which puts a broadly positive spin on developments. In a recent briefing paper, it says the new regulation "will provide a harmonized regulatory framework for clinical trials in the EU, allowing patients timely access to innovative treatments and reducing bureaucracy and costs for clinical trials sponsors. The new rules will also improve Europe's attractiveness as a location for the research and development of new medicines, the group says. It sees the main benefits as the single EU portal, one submission, joint assessment, and one decision at member-state level.

The BIA notes that "the expected benefits will only be achieved if the IT infrastructure, secondary legislation, and guidelines (to be developed and requiring input from member states and stakeholders) serve the primary objectives of simplification, efficiency, standardization and speed." But, overall, it concludes that, "While it is recognized that the timelines are not as ambitious as originally proposed by the Commission, we need to look at the benefits of the regulation as a whole, in particular a single authorization process and the timelines for ethics committees' review."

A leading UK role?

The BIA sees the UK as "well placed for the implementation of this regulation," with partnerships already well-established at the level of national authorities, "a good track record," and every expectation that the country will assess clinical trial applications "much quicker than the target timeline, especially for single country trials and early stage clinical research."

The BIA also boasts a little of its own contribution to the evolution of the new rules. It says it helped ensure the legislative process stayed on track, that it addressed "unhelpful amendments to the proposed regulation prior to adoption," and provided the life sciences industry view to legislators to keep the final legislation "balanced." The BIA promises to remain closely attentive during 2015–2016, as the EU develops the necessary secondary legislation, on cooperation in safety-data assessment, good manufacturing practice (GMP) principles, and inspection modalities. The group will also remain alert to the emergence in the UK of the necessary national legislation concerning ethics committees, enforcement, damage compensation, cluster trials, and arrangements for consent interviews with patients.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.