EU Surprises Itself by Agreeing to Pharma Rules

They made it! Despite everything you may have read about the European Union being unable to agree on anythingfrom a new constitution to how to keep budgetary deficits in checkthe 15 current EU member states managed to agree just before the year-end on its new regulatory framework for pharmaceuticals. After more than two years debate, consensus was reached in late December on the major points of divergence among the key players. The result is that the new rules will come into effect about the same time that the 15-member EU enlarges to become a 25-member EU, with 10 new countries from the former Soviet bloc and the Mediterranean.

The new rules are extensive in their scope, so they will have many indirect effects on the clinical trials community. They also contain some specific changes that relate directly to clinical trials.

Comprehensive impact
First, the big picture. The likely principal consequence will be a more efficient authorization system for innovative medicines. The role of scientific advice in the authorization process will be strengthened, and in the European Agency for the Evaluation of Medicinal Products (EMEA), increased flexibility will come from the creation of different specialized groups and the possibility of using experts from outside the EU.

Erkki Liikanen, the European Commissioner responsible for the pharmaceutical industry, greeted the vote as an important day for European patients and the European pharmaceutical industry. He said it will ensure a high level of protection for public health, while improving access to medicines and boosting the competitiveness of the European pharmaceutical industry.

The basic principles of the existing system are retained, with the co-existence of two regulatory procedures, one centralized and one decentralized, based on mutual recognition. The changes will open the centralized procedure to new types of medicines: it will become mandatory for medicines to treat AIDS, cancer, diabetes, neurodegenerative disorders, and orphan diseases, and after four years this will be further extended to cover medicines for autoimmune and viral diseases. A general review clause could also allow for further extension to other conditions.

The new rules will also introduce a new fast-track authorization procedure for products of significant therapeutic interest. In addition, there is the possibility of a conditional one-year authorization where there is an important expected health benefit for the patients concerned, and a pan-EU compassionate use provision for products before authorization.

The fast-track registration procedure for these products of significant therapeutic interest is a mirror of the similar accelerated process in the United States. It will reduce review time by at least two months30 days faster than the U.S. system for priority review, claimed Liikanen.

The conditional marketing authorization will allow for a one-year authorization to be granted, provided that there is an important expected health benefit for the patients concerned, and provided the company agrees to carry out additional monitoring and clinical studies, which will be reviewed at the end of the year. The new provisions for compassionate use will allow the supply of medicines for compassionate reasons to a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily by an authorized medicinal product. The medicinal product concerned must either be the subject of an application for a marketing authorization...or must be undergoing clinical trials.

According to Commissioner Liikanen, this will help to ensure that patients are not discriminated against on the basis, in particular, of the location of the clinical trials performed by a particular company. He said it will allow patients successfully treated in a clinical trial to continue treatment during authorization assessment.The changes should also improve the transparency of procedures and decision-making. More access will be provided to the results of the EUs decision-making process on pharmaceuticals.

And there will be some tighter monitoring of medicines on the market, in response to widespread criticisms of failings in the European system. Just before the final vote on the package of proposals, the influential European consumers association, BEUC, issued a statement claiming: Throughout Europe, only around 1025% of adverse reactions experienced by patients are reported to the relevant authorities. The system of reporting by health professionals is not working as it should. It is essential to allow patients to report directly about the side effects they experienced.

During the first five market years of a new medicine, side effects must be closely monitored, it went on. Often we do not know enough about the safety of a medicine until it has been exposed on a longer term to a much wider range of people than is possible through clinical trials. The surveillance of side effects will become even more important with new fast track procedures.

European citizens are being unnecessarily exposed to medicines that may not always be safe for them, said Jim Murray, BEUC Director, adding: It is in everybodys interest that medicines are closely monitored. The actual experience of patients is the first and essential step to a more effective monitoring system that facilitates swift action where necessary and better information sharing. Direct reporting of side effects would allow patients and doctors to make better choices.

Additional protection will be provided to data generated in support of marketing authorization applications. Protection of data submitted by companies for the approval of medicines will be harmonized so that it will not be possible to market generic copies of a product anywhere in the EU until 10 years have elapsed from its first EU authorization. This can be extended by an additional year if a further innovative indication for the medicine is authorized. One year of data exclusivity will also be granted on the studies that allowed the switch of medicinal products from prescription only to nonprescription status.

But there will be more vigorous competition from copy products, since the new rules will allow the generic pharmaceutical industry to start testing their products in Europe two years before the end of the data exclusivity period for the reference product.There will also be clearer rules for copyingwith new definitions of generic medicines and of biosimilars, as copies of biological products have been termed. Even the U.S.-based Biotechnology Industry Organization took the unprecedented step of issuing a comment on this aspect of the agreement.

President Carl B. Feldbaum said of the new rules requiring tests for biosimilars: The EU recognizes that biosimilars are different from existing biological therapies in terms of their raw materials and manufacturing processes and that even slight differences can significantly alter a biological therapys safety and effectiveness. Therefore, the EU will require companies that produce biosimilars to conduct appropriate tests. BIO supports the EU in its decision to require extensive tests for biosimilar medicines. Biological therapies are vastly different and more complex than conventional chemical drugs. As the EU correctly concluded, even slight changes in the therapies themselves or the processes used to create them can create significant differences in their safety and effectiveness. Without adequate clinical tests, patients cannot be assured that their biological therapies are safe and effective.

Clinical trials-specific
Greater focus on the quality of testing and trials will direct more attention to the conduct of clinical trials. The starting point for this initiative is agreement on the need to provide for the ethical requirements of the EU Clinical Trials Directive1 to apply to all medicines authorized in the EU.

So, the European Commission and the EMEA will be given additional responsibilities for checking on how industry and trial centers behave. They are to be given the task of coordinating the execution of the various supervisory responsibilities vested in the Member States, and in particular with the tasks of providing information on medicinal products and of checking the observance of good manufacturing, laboratory, and clinical practices.

The new rules will also lead to increased attention to the conduct of clinical trials outside the EU.

In particular, the new rules say,
with respect to clinical trials conducted outside the EU on medicinal products destined to be authorised within the EU, at the time of the evaluation of the application for authorisation, it should be verified that these trials were conducted in accordance with the principles of good clinical practice and the ethical requirements equivalent to the provisions of the directive.

Initial reactions
After vigorous debates in Europe over two years, which had increasingly focused on the question of intellectual property protection in a battle between the research-based and generic sectors of the pharmaceutical industry, the EU members agreement was met with an outbreak of unaccustomed consensus among most of the European lobby groups.

The principal associations representing the European biotechnology and innovative pharmaceutical industry were critical of concessions made to the copy industry, saying the signal given to research was not encouraging. But the criticism was mutedand Commissioner Liikanen said he was happy at their moderate reactions.

European producers of generic medicines endorsed the new rules. The European Generic Medicines Association said whilst there could be delays in patient access to affordable healthcare caused by increased periods of data exclusivity, the law will nonetheless create the foundation for a more efficient regulatory system for the authorisation of all medicines in the European Union.

It was among patient organizations and health insurance corporations that the most criticism emerged: they spoke of a sell-out to big pharmatheir term for the lobby of the international pharmaceutical industry. The European Medicines Forum, a coalition of health activists and patient groups, lamented what it claimed was the inadequacy of compassionate use provisions, the failure to give patients a bigger role in pharmacovigilance, and the huge costs that would result from allowing more intellectual property protection to big pharma. They were particularly hostile to the outrageous prolongation of clinical data protection.

An alternative voice
Meanwhile, at the same time the EU was agreeing its new pharmaceutical rules, an influential health-sector think tank in one of the most influential EU member states was expressing radically alternative views on the future of pharmaceutical research.

The UK Kings Fund put out a provocative report2 which claimed that research in the United Kingdomone of the European beacons of hope for the pharmaceutical industry-was badly focused and did not serve the interests of citizens. The current agreement between the U.K. government and the U.K. pharmaceutical industry is focused on the wrong areas, says the report: by concentrating on researching new medicines, it neglects some other research areas that may be potentially beneficial for promoting peoples health, such as alternative therapies. Research designed to protect and promote health currently attracts far fewer resources than research focused on the search for new pharmaceuticals.

In addition, the arrangement does not fully take the needs of some major groups, including children and older people, into account. The strategic objective should be shifted towards achieving better health for the U.K. population, the report says. A reshaping of the framework...is needed if users of the health care system are to get a better deal. It needs to be widened to include citizens and service users more effectively in decision-making, and to undertake research into areas of potential health benefit other than new forms of drugs treatment.

Among the Kings Funds proposed remedies: the roles of the private sector, public sector, the scientific and clinical professions and health service users need to be reworked; the benefits of expanding the public role needs examining in the areas of basic research, precompetitive research, neglected therapeutic areas, care delivery, and clinical research and trials in areas that attract no commercial funding; and the regulatory role should be modified to ensure openness, absence of bias, high scientific standards, and the promotion of trials that promise the greatest health gains.

It is a curious coincidence that just as the EU is agreeing on a new regulatory framework to promote a research-based pharmaceutical industry, influential figures in one of the most research-oriented EU member states should be arguing so forcefully for a diametrically opposed approach.

References
1. Directive 2001/20/EC of 4 April 2001 of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.
2. Getting the right medicines?, Kings Fund, London, 2003.