Biotech Drugs' Generic Future Debated

Biotech Drugs' Generic Future Debated Medications Are Hard to Afford -- but May Also Be Hard to Copy
By Marc KaufmanWashington Post Staff WriterThursday, February 10, 2005; Page A01
MALVERN, Pa. -- To more than half a million patients suffering from rheumatoid arthritis or Crohn's disease, Remicade has brought life-changing treatment and relief.
But the drug, a genetically engineered protein produced not by chemistry but by living cells in a manufacturing process that requires 310 discrete steps, also brings a heavy financial burden. The manufacturer estimates that each patient will pay $14,000 to $16,000 a year for Remicade, and that people generally will take it indefinitely.
For those helped by Remicade, made by Centocor Inc., a biotech subsidiary of Johnson & Johnson, the drug represents a realization of the promise of biotechnology -- to treat disease with laboratory-created versions of proteins and other essential building blocks of the body's cells. But for employers, health insurers and the already stressed Medicaid and Medicare programs that pay the bills, the drug represents something else -- a serious threat to their financial well-being.
With complicated and costly "biologics" such as Remicade increasingly seen as the wave of the pharmaceutical future, health care experts warn that they will drive the nation's fast-growing bill for drugs far higher. And that prospect has set off a fierce battle in Washington over the multibillion-dollar question of whether to open the door to lower-cost generic or "follow-on" versions of the pricey biologics.
Faced with a similar problem 20 years ago, when the prices for an earlier generation of drugs skyrocketed, Congress passed the Hatch-Waxman Act -- which allowed makers of generic drugs to copy medications after the expiration of their patents and to sell them without conducting many of the expensive clinical trials and testing procedures that can make brand-name drugs so expensive. Last year, about half of all U.S. prescriptions were for generic drugs, yet those low-priced products accounted for only 8 percent of the nation's drug bill.
Biotech drugs were in early development then, and nobody thought to give the Food and Drug Administration the authority to establish a similarly abbreviated review process for their generic versions.
Now, many believe the science of biopharmaceuticals -- which has produced more than 150 FDA-approved drugs and has another 350 in human clinical trials -- has advanced enough to make possible a parallel shortcut that would get lower-cost biologics onto the market. But others say that because newer biologics are much more difficult to manufacture and pose more safety risks, that prospect should worry the public.
Johnson & Johnson is pointing to its own experience with another product as a cautionary tale: Some patients taking its genetically engineered anemia drug, Eprex, experienced serious side effects after the company started using a new stabilizing chemical, and it took years to fully diagnose the problem.
This issue and more will be debated at an FDA conference next week, one designed to assess whether the expertise of generic-drug makers has progressed far enough to take on biologics.
The major trade associations of brand-name drugmakers say it probably has not. "It's a very different process to reverse-engineer a pill than a biologic," said James C. Greenwood, president of the Biotechnology Information Organization. "With a pill, you can pretty easily discern the chemical makeup and then duplicate the product. But with the larger, more complicated and more variable proteins that make up the biologics, you can very easily get small but significant differences that have clinical effects."
But generic-drug makers -- as well as some insurers and government programs that pay the bills -- argue that the industry is foot-dragging as the science speeds ahead.
"I feel very strongly that we have the science and systems in place to manufacture safe and effective biologics," said Marvin Samson, a vice president of Teva Pharmaceutical Industries Ltd., a generic maker that already produces biologics in Eastern Europe for countries where patent protection is not enforced. "The situation is like in the 1980s with Hatch-Waxman, where the brand-name industry said we didn't have the science and capabilities to analyze their products and reproduce them. We did have the ability then, and we do now."
The Generic Pharmaceutical Association, which represents 120 companies, wants Congress to create a review process for generic biologics soon. "We think that as policymakers understand better what biologics without competition are going to do to Medicaid and Medicare budgets, they'll definitely want a generic option," said Kathleen Jaeger, the GPhA's president.
That opinion is not widely shared in Congress. Both Sen. Orrin G. Hatch (R-Utah) and Rep. Henry A. Waxman (D-Calif.), sponsors of the 1984 law, are not convinced a scientific consensus exists.
Waxman is also skeptical that the Republican-controlled Congress would do anything to displease the brand-name drug industry, a major financial supporter of the GOP. "I think it would be fair to say the big drug companies don't want competition and will do whatever they can to stop it," he said. But others, including Sen. Charles E. Schumer (D-N.Y.), are seeking action this year.
The European Union is already moving forward with a regulatory process that would allow the simplest biologics to be copied. Regulators there are not reviewing applications yet, but their planning is conceded to be several years ahead of the United States'.
The crux of the argument centers on how biologics and traditional drugs are made. Most drugs invented before the last decade of the 20th century were discovered through chemistry and are made of small molecules that interact with living cells. The advent of biotechnology and the explosion of knowledge about genetics and the life sciences have begun to produce very different products -- large-molecule proteins and peptides that change the workings of a patient's body in complex and often variable ways.
Since passage of the Hatch-Waxman Act, generic-drug companies have analyzed thousands of small-molecule drugs that no longer have patent protection and have learned to manufacture them safely and cheaply. But making a large-molecule biologic is, by all accounts, more complicated, especially because many of the technologies involved are trade secrets. What's more, protein-based drugs can cause immune reactions that are more serious and long-lasting than the allergic reactions that chemistry-based drugs sometimes cause.
To create a pure and dependable drug, Centocor runs its biologics through nine major stages of processing. The healing proteins are first grown in sealed "bioreactors" of live cells and then spun out of the growth medium that sustains the cells exactly when ready about 60 days later, and refined several times over.
"We're using a unique line of living cells to make our product," said John Dingerdissen, who runs global biologics manufacturing for Centocor. "You make the slightest change with them or with our process, and you can end up with a very different result."
Johnson & Johnson decided to publicly discuss its own disturbing experience as a contribution to the debate: In 1998, the company changed a stabilizing chemical in Eprex, a protein drug that was marketed only outside the United States. The change was made to remove any cow-based material.
Within a year, reports began to trickle in of a small but significant number of patients who were not getting better with the drug but were developing a severe and rare form of anemia called pure red cell aplasia. It took almost four years, a team of about 100 researchers and many millions of dollars to figure out what had happened. It turned out that the new stabilizer was interacting with some rubber stoppers used in the syringes to inject the drug, creating a compound that stimulated the body to produce antibodies to Eprex.
"Only an innovator company has a deep enough knowledge of its product to know where to look effectively when there's a problem like this," said Audrey Phillips, a biopharmaceutical executive with Johnson & Johnson.
Gordon Johnston, GPhA vice president for regulatory affairs, acknowledged the Eprex lesson but said "it's never a good idea to set policy based on one problem or one success."
Some biotech companies are also skeptical that generic biologics would save consumers much money. That is because -- unlike chemistry-based drugs -- biologics require costly testing on a continuing basis. Generic-drug makers agree but say they can still reduce prices by 20 to 30 percent, said the GPhA's Jaeger, unless Congress and the FDA require too much testing.
But Johnson & Johnson's Phillips says that testing has to be extensive to make sure any follow-on product is safe and effective. "Given what we've experienced, we believe that standard has to be very high," she said.
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