BioWorld International Correspondent

LONDON - Biopharmaceuticals with global sales of $10 billion will lose patent protection by 2007, but pharmaceutical and biotechnology companies with ambitions to market generic versions now find themselves in limbo after the FDA joined the European Union in refusing to approve biogeneric human growth hormone, despite finding nothing wrong with the application.

After completing its review of Omnitrope, a recombinant human growth hormone, the FDA told Sandoz Ltd., a subsidiary of Novartis AG, there weren't "any deficiencies in the application," but stated it could not reach a decision because of uncertainty regarding scientific and legal issues.

A spokesman for Novartis said the FDA has not asked for additional data, adding, "We will be taking part in the continuing discussion about the development of an appropriate pathway for follow-on biologics, and discussing Omnitrope in particular."

At issue is whether or not the FDA can determine if Omnitrope is equivalent to the existing marketed product. The Novartis spokesman said that is not a scientific or a medical issue, but "a policy issue."

The crux of that policy issue is whether biogenerics should be required to complete the same range of clinical trials as the original product. (That is not a requirement for small-molecule generics.)

Sandoz said it agreed that rigorous scientific criteria should be applied, but said there should be no unnecessary, or unethical, duplication of pre-approval studies or clinical trials.

Companies that have biogenerics reaching the end of their patent protection argue that it will be impossible to prove equivalence without access to commercially confidential data contained in the original filings. The U.S. Biotechnology Industry Organization supports that view, saying the FDA should not rely on an innovator's proprietary data to approve a follow-on biologic, and arguing that the science is such that clinical trials are necessary in order to demonstrate safety and effectiveness of a follow-on biological product.

Alexander Berghout, head of clinical development and regulatory affairs, biopharmaceuticals at Sandoz, said advances in the technologies to make biologics should be factored into the regulatory process. "It is critical that advancements be made in regulatory requirements to improve patient access to high-quality, cost-effective alternatives to branded products that have lost patent protection," he said.

European regulators turned down Omnitrope late in 2003, despite the European Medicines Evaluation Agency recommending its approval in July 2003. Novartis subsequently filed a lawsuit to contest the decision. The Novartis spokesman said the company is continuing to consult with the European Commission to seek marketing authorization but is pursuing the legal case in parallel. There is no indication as yet to when the case will be heard.

In some sense, the impasse in Europe is harder to fathom than that in the U.S. Unlike the FDA, the EU has passed a law to allow biogenerics (or biosimilars, as it has called them) to be approved on the basis of an abbreviated approval package that can reference data from other approved products. Omnitrope is regarded as being the test case for the legislation, and until it was rejected, Europe was seen as leading the way in developing a regulatory framework for biogenerics.

The FDA is committed to developing draft guidance over the coming year on how to demonstrate that a protein pharmaceutical is similar enough to a licensed product. This week the agency is holding a workshop to determine the state of science as it relates to protein characterization, production and assessment of similarity. However, it noted that the workshop will not be looking at any legal or regulatory issues.

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