By Naomi Aoki, Globe Staff
The patents on the first generation of biotechnology drugs are nearing expiration, raising the specter of competition from cheaper generics. But unlike their pharmaceutical counterparts, biotech drugs may be difficult - even impossible - for generic makers to copy.
The roadblocks are both regulatory and scientific. The rules allowing generic versions of more traditional drugs, a category that includes most of the pills sold by large pharmaceutical companies, don't apply to biologics, drugs made by biological processes.
Legally, manufacturers are free to copy the drugs as their patents expire. But regulations mandate that copies of biologics undergo the same battery of clinical tests required of new drugs, driving up costs and defeating the purpose of making generics. At the time the rules for generics were established in 1984, biotechnology was a fledgling industry and its drugs were not covered.
With patents on some of the biotech industry's top-selling drugs - worth more than $10 billion in sales - set to expire in the next few years, however, generic drug makers are lobbying to change the rules. They argue that the safety and effectiveness of generic biologics could be tested in less rigorous and time-consuming studies.
Today, there are roughly 100 biotech drugs on the market and three times as many in development. A patent on the industry's top-selling anemia drug, EPO, which generates more than $4 billion in sales a year for Amgen and its licensee Johnson & Johnson, is set to expire in the United States in 2004.
Human insulin for diabetes, alpha interferon for hepatitis and cancer, beta interferon for multiple sclerosis, and growth hormone for dwarfism will also lose their market exclusivity in coming years. Each of these markets exceeds $1 billion in worldwide sales.
''Patient safety is of utmost importance to us,'' said Dr. Carole S. Ben-Maimon, president and chief operating officer of Barr Research, a division of generic drug maker Barr Laboratories. ''We're not looking to make drugs that we don't have the science to copy. We want to make drugs that achieve the identical outcome and perform in an identical fashion to the brand-name drug.''
The biotech industry claims, however, that achieving such a goal is not possible. Even if a regulatory path were established to bring generic biologics to market, industry officials say, the science simply doesn't exist to copy complex biotech products. The drugs are made from living cells, mainly proteins cultured in bacteria or hamster cells. As a result, the process is highly unpredictable; the slightest change can result in significant differences in a drug's safety and potency.
Biotech companies spend years refining the processes as they gear up for commercial production. Without that experience and intimate knowledge of the specific processes, they say, generic drug makers can not make equivalent products. Even one of the industry's oldest and best-understood drugs, human growth hormone, has proven difficult to reproduce. No two versions of the hormone, made by six different brand-name drug companies, are the same.
''The issue for us is based on science,'' said Stephan Lawton, vice president and general counsel for the Biotechnology Industry Organization. ''It hasn't been demonstrated here or elsewhere that a shortcut that does not involve clinical trials is fair to patients. We're just not there yet.''
Drug makers need only show that generics of traditional pharmaceuticals are the same chemical compound and act the same in the body as their brand-name counterparts. But those rules apply to drugs made using chemistry. At the time the Hatch-Waxman Act governing generic drugs was passed in 1984, there didn't seem to be a need for provisions to cover biologics.
Although the issue has been pushed aside for more pressing legislative matters of national security, industry observers say, it promises to resurface. Generic drugs are an important tool in combating the high cost of prescription drugs, and biotech drugs include some of the most expensive products in the world.
''It's going to happen,'' said Bruce Downey, chairman and chief executive of New-York based Barr Laboratories. ''The costs of not doing it are just too extreme. The question is when is going to happen.''
Regulatory changes in the United States are still at least a few years away, and generic versions of biotech drugs are more likely to appear first in other parts of the world. The task will no doubt be daunting. Barr and other generic companies will have to invest millions in people and manufacturing plants to make biologics.
Negotiating the patent landscape could prove difficult since many biotech drugs are protected by layers of patents. Amgen's earliest US patent for EPO expires in 2004, but others last into the next decade. With notable exceptions, biotech drugs also serve smaller markets than pharmaceuticals. And companies will try to protect their brands from generic competition by developing improved versions.
The investments and the risks will likely be too great for many generic drug makers, Downey said. The industry acknowledges that copies of some of the more complicated biotech drugs may require the full gamut of clinical testing to ensure their safety and effectiveness. But generics of better-understood biologics could be brought to market without such rigorous testing, he said.
The branded companies themselves make changes to manufacturing without triggering new approval processes, Downey said. Cambridge's Biogen moved manufacturing of Avonex, a multiple sclerosis drug, to a new plant and changed the raw material in which the protein is produced. Before marketing the drug, the company proved the new version of Avonex was comparable to the old without undergoing a new round of clinical testing.
''Why not use a similar standard to approve generic biologics or another reasonable standard?'' Downey asked. ''Solving the regulatory problem is prerequisite to solving the more complicated scientific issues. Without the regulatory pathway in place, companies won't invest in generic biologics.''
The biotech industry counters, however, that the scientific questions need to be answered before a regulatory procedure can be established. Biogen could make changes to its manufacturing process only because it had years of experience and detailed data about the drug. Additionally, the same team of specialists offered both continuity and expertise.
Even then, said Jim Green, the company's vice president of preclinical development, there was no sure-fire way of knowing if the drug might behave differently. Biotech drugs are made up of thousands of atoms, as opposed to the hundreds that make up most pharmaceuticals. Folds and layers in the structure of the proteins make it impossible to analyze each atom.
At the time Biogen made the changes to Avonex, Green said, it postulated that the new version might cause a slight increase in side effects. As it turns out, the new version actually reduced side effects. The result worked in the company's favor, Green said, but it speaks to the difficulty of predicting how subtle changes in manufacturing might effect the resulting drug.
''We're not saying it's an impossible task,'' Green said. ''But the path is very different. Safety concerns are much more complicated with biologics and the conditions need to be more rigorous. Something like interferon beta for multiple sclerosis is very complex. We still don't know exactly how it works. Other molecules are relatively well-understood. Ultimately, the process will need to be very molecule specific.''
Naomi Aoki can be reached by e-mail
This story ran on page D1 of the
Boston Globe on 10/31/2001.
© Copyright 2001 Globe Newspaper Company