Set up in January 1995 to be responsible for the scientific evaluation of applications for drug marketing authorizations for the entire European Union, the European Medicines Evaluation Agency (now the European Medicines Agency, but it still maintains the acronym EMEA) faced enormous challenges from the start. Not the least of these challenges was dealing with the well-established regulatory bodies that existed in the 15 member countries of the European Union at the time who were reluctant to give up their independence.
"EMEA set out not to be an alien body, overlooking and dominating the network of national agencies, but as a common building, designed to mutualize the best skills of the European club and put them at the service of European patients and citizens," said Jean Marimbert, director general of the French drug regulatory body.
In the decade since its inception, the EMEA has overcome several other challenges and along the way has earned the trust of both the E.U. member states and the pharmaceutical industry. And much like EMEA's U.S. equivalent, the U.S. Food and Drug Administration, the agency already has a long list of issues to tackle in the next few years.
An EMEA approval for a new drug holds good for all E.U. member states. But for many classes of drugs, the preexisting "mutual recognition procedure," whereby approval by a single national regulatory body is accepted by other countries, is still used.
"The challenge in the beginning was to convince companies to use new procedures, operated by a small and very young agency," said Brian Ager, director general of the European Federation of Pharmaceutical Industries and Associations. Companies initially seemed reluctant to go through the EMEA's centralized approvals procedure, which was voluntary (other than for products derived from biotechnology, such as -interferon). But by October 1995, 22 new applications had been made, of which two-thirds were for nonbiological drugsand therefore could have followed the decentralized procedure.
"Ten years ago there was a mixture of feelings in the industry. This ranged from positive but nervous anticipation to fear of the unknown," said Ager. But the industry now has a high level of confidence in the function of the EMEA, he said. "Its primary public health function is established and recognized, and it has a road map for its future evolution which should, among other things, ensure that regulatory structures keep pace with scientific developments."
Among the major issues the agency has had to deal with in its first 10 years have been a major review of the European pharmaceutical legislation, which has the overarching aim of giving patients quicker access to new drugs. One product of that review, a new procedure for fast-tracking drugs, will be implemented in November. But the whole process was lengthy and characterized by much disagreement, and it failed to come up with the totally centralized system for drug approval that some had hoped for. In the end, two approval routesnational and centralizedwere permitted to exist side by side for many classes of drugs. There are some in both academia and industry who argue that, instead of simplifying the process, the new pharmaceutical legislation has simply made everything far more complicated.
This effect is reflected in some of the criticism of the EMEA's work to date. "Approval times are still not great, particularly for cancer drugs," said Kathy Redmond, a former president of the European Oncology Nursing Society. Between 1995 and July 2003, the average time taken to approve cancer drugs was 471 days. "Even if the EMEA pulls out all the stops, time is wasted with translation (30 days) plus the European Commission decision-making process (23 months)."
Transparency is also a problem, she said, particularly in the Committee for Medicinal Products for Human Use's (CHMP) Scientific Advisory Group on Oncology (SAG-O), which advises EMEA on oncology drugs. "The agency does not reveal who the members are. The pharmaceutical industry certainly knows, as do people on the inside track, but what about the man in the street who the agency is supposed to protect?" Redmond said. "And there are no published minutes of SAG-O meetings, unlike the FDA, which publishes transcripts of proceedings of [the FDA's Oncologic Drugs Advisory Committee] meetings."
One of the biggest challenges the EMEA is currently facing is how to proceed with the authorization of biosimilar drugs (generic versions of biotechnology-derived drugs). The very name that has been chosen for these products points toward the major difficulty. It is not possible to make an exact copy of a biotech medicine in the same way that a traditional chemical molecule can be copied. Because these products are derived from cell culture or whole living organisms, there is bound to be a degree of variability in any attempt to copy them. In addition, the analytical tools for biotech medical products are not yet good enough to allow complete characterization. But with many patents on biotech drugs ready to expire, it is essential that some way of licensing these biosimilar drugs be found.
So far the CHMP has issued six consultation papers on biosimilar products, including two on medicines frequently used in oncologyerythropoietin, used to treat cancer-related anemia, and granulocyte colony-stimulating factor, used in the treatment of neutropenia. Already, several questions have been raised about the contents of both papers. "The problem is that no definition is given of a biosimilar. To qualify as a biosimilar, biosimilarity has to be shown in all three parts of the dossier: quality, safety, and efficacy. But how similar should the product be to the innovator product?" said Huub Schellekens, director of the Central Laboratory Animal Institute at the University of Utrecht, the Netherlands, who has made a particular study of the similarity, or otherwise, of biosimilar drugs.
Overall, the agency has had a good start, but major challenges lie ahead and there's still much to be done. Given that at least some of the EMEA's difficulties appear to be built in and unlikely to change in the near future, are there new roles that it could play that would not be hampered by the problems of representing 25 different countries with 20 official languages?
"I think that the role of regulatory bodies is exceedingly important not only in regard to which drugs are ultimately registered but also as to which kinds of trials, in a globalized market, are being planned all over the world," said Paolo Casali, M.D., head of the Adult Sarcoma Medical Treatment Unit at the Istituto Nazionale Tumori, Milan, Italy. "The design of clinical studies of new medicines will be greatly affected by the policies of regulatory bodies and to some extent, at least, they have the opportunity to shape the future of clinical research."
Casali noted that the most innovative drugs of the future will likely be very selective and have a limited patient target. "Thus, industry will more and more frequently face the choice of starting a large trial in a wide patient population, giving up any sophisticated selection through molecular biology, or to select patients on biological criteria, with the consequence that the trial may have limited statistical power," he said. "What regulatory bodies will do in this regard is crucial. The challenge ahead for EMEA is to encourage mew methodological attempts without jeopardizing its role as a regulator."
Currently, the lack of methodological improvements may lead to clinical trials that do not fully exploit the potential of a drug, says Casali. "The paradoxical consequence might be that we have the drug, but we do not have a method to show that it is effective."
He believes that the clinical oncology community should be doing all it can to help regulatory bodies tackle these problems. "We should be offering help to advance methodological research on new statistical techniques, as well as providing the ability to put new drugs into perspective through independent expertise which is focused on the disease, where the expertise currently available to regulatory bodies is focused on the drug," he said.
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