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Engineered Drugs Open New Issue of Regulation as Patents Expire

August 9, 2003
Alison Langley
New York Times

Somatropin, a hormone that sends a message to the pituitary gland to stimulate growth in the human body, is not a new discovery. And its synthesis is not a new technological advance somatropin products have been on the market for more than a decade, each protected by patents covering varying things, like the way the hormone is made and how it is administered.

But the basic patent on the copy of the hormone produced naturally in most people has expired. And Sandoz, the generic drug division of the Swiss pharmaceutical giant Novartis, has applied for permission to market Omnitrop, its own somatropin copy, in Europe.

If it is approved as expected this fall, Omnitrop will be the first generic version of a genetically engineered medicine allowed to be sold in Europe. And the comfortable world of biotechnology may be violently shaken by losing its hold on an industry that has $30 billion in annual global sales and is growing nearly 10 percent a year.

Though no generic version of genetically engineered drugs has been approved in the United States, executives at Sandoz say they will soon ask the Food and Drug Administration for the right to market Omnitrop there, too, probably early next year.

Until now, biotechnology companies have never thought it possible to make a generic version of their medicines because the molecules and the manufacturing process are so complex. Laws in the United States and Europe that cover generics of traditional chemical drugs do not cover this new breed of medicines, often called biologics products made from living cells, blood factors and genetically engineered proteins.

But now, as the first patents on biologics are beginning to expire, pressure for updated laws is coming from generic drug makers wanting a piece of the pie and from patients and consumer groups hoping to cut the price of these products, which can cost more than $100,000 a year.

Two months ago, the European Union passed legislation allowing companies to apply for permission to sell generic versions of genetically engineered drugs. While regulators fine-tune the guidelines, generic biologics will be evaluated on individually.

The European Union's approval of Omnitrop, which has already received support from an advisory committee, would make it more likely that the F.D.A. would also allow generic competition for biologics, perhaps announcing rules as early as next year.

"In the future, biotech companies will have to potentially suffer from the same patent-expiry threat as other companies," said Birgit Kulhoff, an analyst at Bank Sal. Oppenheim Jr. "They can no longer rely on the idea that it's difficult or impossible to come up with generics."

Biologics often carry multiple patents; for example, a therapy can have 14 different patents on everything from a particular cell line to the manufacturing process.

Most biologics will start to lose their patent protection and be open to competition beginning in 2005. But human growth hormones and a handful of other drugs using recombinant gene technology are already off patent. They include insulin for diabetes, beta interferon for multiple sclerosis and alpha interferon for hepatitis and cancer. Together, they have annual global sales of $13.5 billion.

Still, just a handful of generic drug makers have the expertise and other resources to develop, test and manufacture a comparable biologic, though the number may grow. Early on, at least, probably only the larger concerns with both biotechnology and generic expertise will be able to enter the generic market for biologics companies like Novartis, Teva Pharmaceutical Industries of Israel and the Merck Group of Germany.

"Novartis is scary; Merck could become scary, Teva as well," Ms. Kulhoff said, noting the threat they pose to the companies that do the initial development of biologics. "All these companies have a lot of experience in getting drugs on the market and in marketing generics."

A big unanswered question is whether generic biologics can be sold at the big discounts normally seen on other generic drugs, given the extraordinary expenses involved in a biologic's creation.

Generic versions of traditional chemical drugs can be approved for sale without lengthy, and expensive, clinical testing to show they are safe and effective, because the chemical processes can be standardized and the drugs copied easily. But with living things it is hard to verify sameness and prove that a product is as effective or safe.

These issues are now being pondered by regulators.

In considering Omnitrop's application, European Union authorities required Sandoz to conduct clinical trials first on healthy volunteers to test for side effects and then on patients with a growth hormone deficiency to prove its safety and efficacy tests routinely required on any new drug.

But unlike the companies that developed the original drug, Sandoz did not have to show that the active ingredient, somatropin, was effective at treating growth deficiencies because that already has been proved.

"As the E.U. is still only preparing the respective regulatory rules, we had to go through a case-specific process with the authorities," Patrick Vink, head of Sandoz's biopharmaceutical division, wrote in an e-mail reply to a reporter's questions.

He would not say whether the trials were of the same scope as those required for any new drug, nor would he divulge how much money his company spent on the tests. (European Union regulators are not allowed to answer questions about drug approvals.)

Omnitrop would be manufactured in Sandoz's main plant in Kundl, Austria, which has been making biotechnology medicines for years, Dr. Vink wrote.

Still, "the price will have to reflect the high investments in development and manufacturing," he acknowledged, adding, "We feel there will be cost-saving benefits for patients and health care systems, freeing up resources for new breakthrough therapies."

Scientists at two companies that currently sell somatropin products, Serono of Geneva and Genentech of California, say that generic biologics need to go through exactly the same testing as the original biologics.

Even the slightest change in a bioengineered product, they say, can elicit a different and sometimes harmful response. An example often pointed to is a bioengineered anemia medicine made under license by two companies; one version had no serious side effects while the other did. No one has figured out why.

"On the patient health side, I have a lot of concern," Walter Moore, vice president for governmental affairs at Genentech, said in a telephone interview from his office in South San Francisco.

"The crux is, if the process defines the product, I don't see how we can skip any human clinical trials," he said.

Thomas D. Szucs, a professor at the European Center for Pharmaceutical Medicine at the University of Basel, agreed. "Good manufacturing practice is basically becoming in biotechnology sometimes the even greater hurdle than the technology," Professor Szucs said. "That's what I'm seeing now." For example, human insulin no longer is protected by patents but has faced no generic competition because it is too hard to make, he said.

He is also skeptical that a large market for generic biologics will ever be developed because of the complexity of the molecules involved.

In the United States, there are additional obstacles. Mark B. McClellan, the F.D.A. commissioner since November, has said it will take federal legislation to establish a mechanism for approving generic biologics. And another F.D.A. official said that even the definition of a biologic was under consideration.

Meantime, generic drug makers have been pushing to get comparable biologics approved through the Hatch-Waxman Act, a 1984 statute governing generic drugs.

But in April, the Biotechnology Industry Organization, a trade group based in Washington, petitioned the F.D.A. to withdraw draft rules that would have allowed comparable biologics to be eligible for approval.

The agency is expected to conclude its examination of generic biologics by year's end.

The European Union is working with authorities in the United States and Japan to harmonize the approval processes for all drugs, so it is very likely that generic biologics in the United States will also be decided case by case, one European Union official said.

In the meantime, the companies that originate biologics are trying to keep competition at bay by introducing improved versions that make their older drugs outdated. Both Roche and Schering-Plough, for instance, have developed more effective forms of alpha interferon, which is off patent, that need fewer injections.

Besides, Mr. Szucs said, technology is moving so fast that a medicine is often obsolete before its patent even expires.

Copyright © 2003, New York Times