BY Nick Lane
EMEA- ON THE BRINK OF THE NEW EU
The EMEA is something like quantum physics, everyone has heard of it, but very few people know how it actually works. Nick Lane PhD looks at the changing climate of medical regulation in Europe and how impending changes at the EMEA could affect ophthalmologists. The European Union is set to welcome ten new accession countries in May 2004, expanding its membership to 25. Another two states could join in 2007. This expansion challenges integration at every level, and pharmaceutical regulation is no exception.
New legislation, coming into force over the next few years is intended to narrow the regulatory gulf that threatens the enlarged EU. The brunt of the new legislation will be borne by the European Agency for the Evaluation of Medicinal Products (EMEA), the EU equivalent to the Food and Drug Administration (FDA) in the US .
What is the EMEA?
The EMEA is the centralised pharmaceutical regulatory body of the EU, responsible for "coordinating scientific resources existing in member states, with a view to evaluating and supervising medicinal products for both human and veterinary use."
Unlike the FDA, the EMEA does not stand alone but alongside national agencies (Competent Authorities in Eurospeak) responsible for pharmaceutical regulation in individual EU countries. This messy situation is a characteristic Euro fudge, but also has some advantages – it allows choice; small companies can gain approval in single countries or regions of Europe, while multinational companies can gain direct access to a single European market. Regulation of the pharmaceutical industry in Europe dates back to the thalidomide disaster in the early 1960s. In response, the member states introduced national regulatory agencies, to ensure that nothing of the kind ever happened again.
The need for a pan-European outlook became more pressing with the development of the Common Market. Better collaboration between agencies was needed to avoid unnecessary duplication, to share data and information on drug safety and efficacy, and to promote the competitiveness of the European pharmaceuticals industry, which has been lagging behind the US industry for more than a decade.In 1995, two new systems were put in place to strengthen pan-European cooperation: a mutual recognition procedure, in which medicines approved in one member state gain semi-automatic approval in other nominated countries (but not necessarily the whole EU); and a centralised procedure, in which new medicines are approved for marketing throughout the EU on the basis of a single central decision. A third possibility – application for approval in several countries simultaneously (parallel licensing) – was phased out in 1998.
The European Agency for the Evaluation of Medicinal Products was established in 1995, after two years of planning, to coordinate the centralised procedure for pharmaceutical regulation. It sits in London . Gossip at the time of the decision said it was a consolation prize to the British, who failed to persuade the EU to locate the European Central Bank in London , despite an avowed intent never to join the Euro. (The ECB went to Frankfurt .) In the confusing tradition of clinical trials, the acronym EMEA doesn't actually match its full name in any European language. This discrepancy at least expires with a name-change to the EMA, the European Medicines Agency, planned for 2004.
What does the EMEA do?
At its inception, the stated aims of the EMEA were to "protect public health by assuring safe and efficacious medicines; to create a single market for pharmaceuticals; and to reduce regulatory costs to the industry." Already a polarity is evident in these objectives, between the interests of patients and those of the pharmaceutical industry. Aspirations for the EMEA were initially set low. Innovative biotechnology products (List A medicines) had to be approved through the centralised procedure, but all other innovative pharma products (List B medicines) could be approved either through the mutual recognition procedure, or via the centralised procedure (or in single individual countries). These limits on the EMEA's jurisdiction were intended to offset the chances of failure through over-ambition, and to safeguard the interests and authority of the national regulatory agencies, for political reasons. The EMEA comprises a management board; committees responsible for preparing opinions on medicinal products for human use (the CPMP), veterinary use (CVMP) and the designation of ‘orphan drugs' status (COMP); and a secretariat responsible for coordinating pre-authorisation evaluation of human medicines, post-authorisation evaluation of human medicines, and veterinary medicines and inspections, supported by communications, networking, and administration personnel. It coordinates a network of more than 3000 European experts and associated scientific resources.
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For ophthalmologists, the most important elements of the EMEA are probably the CPMP (the Committee for Proprietary Medicinal Products) and the EMEA Secretariat that support it. (see graphic for the approval process for travoprost (Travatan, Alcon Laboratories). The CPMP is a scientific committee composed of experts nominated by each member state, with two members from each state. The CPMP appoints two of its members as Rapporteur and Co-rapporteur, who then enlist teams from their national agencies (or draw on other experts maintained by the EMEA) to carry out the scientific review for each product. The assessment teams conduct a thorough review of the quality, safety, and efficacy of the product, based on the dossier of clinical data submitted by the company. On the basis of this review, the CPMP prepares an ‘opinion' on whether the EU should grant marketing authorisation for the product. Their ‘opinion' is Eurospeak for ‘decision' in all but name, as the Commission is legally prohibited from delegating decision-making to bodies such as the EMEA. In practice, the Commission has never overturned the ‘opinion' of the CPMP. Part of the EMEA Secretariat is concerned with pharmacovigilance – surveillance of the safety and efficacy of medicines on the market, to detect any side-effects that might be related to a medicinal product and, if necessary, to recommend withdrawal of marketing authorisation.
The earliest procedures to monitor drug safety on the market were the spontaneous adverse drug reaction (ADR) schemes, established in many member states soon after the thalidomide disaster, and still going strong. However, pharmacovigilance is a designated priority area under the new legislation and is changing rapidly. The EMEA is building and coordinating a new Europe-wide drug safety database, called EudraVigilance, which enables the electronic exchange of individual case safety reports (ICSRs).
According to Dr Panos Tsintis MD, Head of Sector for Pharmacovigilance at the EMEA, "We're expecting over 300,000 ICSRs to be transmitted via EudraVigilance every year. EMEA will also collect SUSARs (serious unexpected suspected adverse reactions) from clinical trials."We're trying to look at pharmacovigilance more proactively" he told EuroTimes. "Traditionally, pharmacovigilance has reacted to problems as they arise. We looked for harm instead of looking for safety of a medicine. Now we're trying to get involved earlier, by designing better ways of detecting safety signals and tackling them as early as the clinical trial stage."
To assist the accession countries in achieving the same operating standards as the existing EU member states, the EMEA has taken initiatives such as the Pan-European Regulatory Forum (PERF), to help candidate countries prepare their regulatory systems before their accession to the EU. PERF was set up in 1999 and includes good manufacturing practices, pharmacovigilance, veterinary topics, and quality management. From April 2003, observers from the 10 accession countries have been sitting on scientific committees and working parties.
How does the EMEA compare with the FDA?
The obvious comparator for the EMEA is the FDA, although the latter is a larger and more ambitious organisation, covering food products and medical devices as well as medicines. One study, by the Tufts Centre for the Study of Drug Development, made a direct comparison of approval times for medicines approved by both the EMEA and the FDA. Times were similar but slightly faster for the EMEA. Biotechnology product approvals in Europe took 417 days, versus 452 days in the US for the same products, although one can't help wondering whether this merely reflects the greater volume of traffic at the FDA.
Impressively, the EMEA beat its own benchmarks. The mean CPMP active review time for biotech drugs was 183 days, compared to a targeted maximum of 210 days. The mean stop-clock time (when questions from the CPMP are being addressed by the applicant) was 140 days versus a targeted maximum of 182 days. However, once the EMEA sends a new drug application to the EU for final ratification, the process slows down. Mean EC review time was 82 days versus a benchmark of 60. At present, the EMEA is not able to offer priority approvals, as does the FDA. However, this is set to change with the new legislation, which provides for accelerated (‘fast-track') authorisations, in which active processing is targeted for completion within 150 days instead of 210 days.
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Other planned changes will build the regulatory importance of the EMEA. In future it will be mandatory for all medicines used in HIV disease, oncology, diabetes and neurodegenerative disorders to be authorised via the centralised procedure. The EMEA will also be given more flexibility. If there is a pressing need for medicine, and data are insufficient for full authorisation, conditional authorisations can be made subject to annual reappraisal. Compassionate use of medicines not yet authorised will be allowed according to the clinical need of patients. So is the EMEA, in accreting all this new power, attempting to compete with the FDA? Not according to Dr Tsintis.
"We've always had a different context in Europe – there's a different ethnic balance, different health-care delivery systems, and so on. And a different attitude. We tend to be more conservative about the safety aspects, and we tend to take actions first, before the FDA. Just to give a single example, we took troglitazone (an antidiabetic agent) off the market a year before the FDA did. This is not surprising because the legal tools available to us differ somewhat from the FDA's. We have the option to either suspend temporarily or revoke marketing, a more permanent option, whilst the FDA can only revoke in some situations."
On the approvals side there are more similarities, and overall there is a need for better collaboration between the EMEA and the FDA. "We're beginning to do this" said Dr Tsintis. "This month we've completed a confidentiality agreement with the FDA, which will allow us to share information on our regulatory processes, including scientific advice, orphan drug designation and inspection reports, as well as our pharmacovigilance data. We do need to strengthen communication between the agencies to reinforce public health protection and to optimise resources." Unlike the FDA and several national agencies (such as the new Medicines and Healthcare products Regulatory Agency in the UK ) there are no plans to merge regulation of medical devices with medicines at the EMEA. Crossover cases, such as photodynamic therapy, are regulated by the EMEA if they make use of innovative medicines; but devices such as lenses, impregnated with small doses of approved drugs, won't need approval from the EMEA. "We're sometimes consulted informally, and this may happen more often with new crossover products" said Dr Tsintis "but at the moment I'm not aware of plans to formalise these arrangements. And I don't think that's really needed."
Funding and the Internal Market
One cause for concern is the source of regulatory funding. Many national agencies receive their funding directly from the companies they regulate in return for regulation services. In addition to being part-subsidised by the EU, the EMEA also receives fees directly from the industry. This sets up a potential conflict of interest, in which the regulators are funded by the industry they regulate. The mutual recognition procedure devolves power to the countries, maintaining the autonomy of the national agencies, but the freedom of choice offered by competing agencies also encourages the development of an internal market.
Pharma companies approach a national agency of their choice to act as the Reference Member State , which performs the lead assessment and receives its fees directly from the company in question. The danger is that national agencies compete to shorten approval times or offer consultation services.As John Abraham, at the Centre for Research in Health and Medicine at the University of Sussex put it: "An internal market of regulatory agencies chasing industry fees poses a threat to public health and regulators' independence."
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Conversely, the mutual recognition procedure lays itself open to inefficiencies when member states' interests are infringed and they register their dissent as Concerned Member States. One study showed that more than 30% of applications (mostly for generic drugs) were withdrawn in at least one Concerned Member State in the year 2000. France was responsible for almost half the withdrawals. Because it stands alongside the national agencies, the EMEA itself is also part of the internal market for regulation services, at least for List B medicines, where there is no obligation to use the centralised procedure. However, for List A medicines marketing authorisation via the centralised procedure is mandatory, and this limits the workings of the internal market. With the expansion of List A drugs to include four major therapeutic areas, the internal market is shrinking. Moreover, as the EMEA makes decisions centrally, it is less prone to inefficiencies such as the dissent of Concerned Member States.
Nonetheless, the growing power of the EMEA is still coupled with direct funding from the pharma companies it regulates, inevitably raising the question of independence. "We are bound by a strict code of conduct, which ensures that there is no conflict of interest" Dr Tsintis told EuroTimes. "It covers all the experts, committees and staff of the EMEA. But for the EMEA to be recognised as fair and unbiased in the outside world, transparency is absolutely critical. We're making a big effort to publicise our decisions, and the reasons behind them. For example, we're making reports available to the general public online. In future we'll be publishing negative reports as well as positive ones."How well the EMEA's efficiency and probity hold out in the expanded EU, with its unequal wealth distribution and high pressure to turn a blind eye to parallel imports and soft-patent generics, remains to be seen. But the agency has a clear vision of its role in protecting public health in the new Europe , and is honour-bound to succeed.
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