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EMEA Tackles "Generic" Biologic Drug Issues
The regulation of biosimilar drugs—generic copies of biotechnology-derived products—is one of the most contentious issues the European Medicines Agency (EMEA) has had to deal with in its 11-year existence. Not only is proving similarity of such products scientifically complex, but many interested parties are lobbying energetically on various issues surrounding biosimilar drugs. And with many patents on biotech drugs ready to expire, there is increasing pressure to find some way of licensing these products. The U.S. Food and Drug Administration is tackling the same issue for what it calls "follow-on" biologics (see story, p. 435).
The major difficulty is reflected in the term "biosimilar." 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 issue 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 these products are not yet good enough to allow complete characterization of the original drug.
The first guidelines on quality and non-clinical and clinical issues relating to biosimilar products were adopted by the agency's Committee on Human Medicinal Products (CHMP) in December 2003. The committee also issued general regulatory guidelines on such products in September 2005. Following a consultation exercise, including a large public conference in Paris in December 2005, guidelines on quality, non-clinical and clinical issues were issued on March 8. These guidelines, which will come into effect on June 1, 2006, included specific regulations for classes of medicines that contain insulin, somatropin, and recombinant granulocyte colony-stimulating factor. Further guidelines on medicines containing epoetin, widely used in the treatment of cancer-related anemia, will be published soon, the agency said.
In January, CHMP gave a positive opinion on the application of the first candidate—a growth hormone called Omnitrope. (The European Commission will make the final decision on the application.) In studies, Omnitrope demonstrated quality, safety, and efficacy comparable to that of a similar medical product already authorized in the European Union, the agency said.
This was Sandoz's second attempt at getting approval; the European Commission rejected the first application the company submitted in 2001. Will the same thing happen this time? It's unlikely, says Huub Schellekens, M.D., 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.
"The first opinion of the EMEA was taken on the [application] submitted by Sandoz, the manufacturer, which was based partly on the concept of well-established use," Schellekens said. "Well-established use" refers to the standard route used to approve generic drugs. That process was set up to avoid generic versions of well-established and effective medicines having to go through a lengthy approval procedure. Now, EMEA requires substantial additional data on biosimilar drugs, in particular regarding their toxicological and clinical profiles.
The Pharmaceuticals Unit of DG Enterprise and Industry, the branch of the European Commission concerned with medicines regulation, did not accept Sandoz's first application. "They reasoned that in the case of proteins you are never sure whether a product referred to in a paper is really similar to another—a much more scientific position than the EMEA at the time," said Schellekens.
But now with a clear legal basis—new EU pharmaceutical legislation, which makes reference to the special case of biosimilars, and the EMEA guidelines—the situation has changed.
But if differences between protein products will always be found, how can regulators ever be sure that they are doing the right thing? "It will all come down to a matter of choice as to whether these differences are considered relevant or not," said Schellekens. Of course, such differences could eventually be monitored through post-marketing surveillance, and the EMEA guidelines will stipulate that there be product-specific prescribing to allow this to happen. But in some European countries, product-specific prescribing is discouraged and generic substitution is automatic or even obligatory for financial reasons. So national laws will need to change, too.
There also is the problem of recruitment to the trials that are required before an application can be submitted. A high degree of altruism among patients would be needed for them to enroll in a trial where it was clear that they were unlikely to get a better treatment than that offered by the existing reference drug.
Despite these complexities, experts say that EMEA has made progress. Nicolas Rossignol, a European Commission official who has been heavily involved in the subject, thinks that things have gone well up to now. "Much has been achieved by the Commission and the EMEA in clarifying the EU regulatory framework on similar biological medicinal products," he said. "But we need to continue the scientific work, both through developing specific guidelines for new product classes, and by reviewing existing guidelines as regulatory experience is gained."
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