Biotech Drugs' Generic Future Debated (washingtonpost.com)

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Biotech Drugs' Generic Future Debated

Medications Are Hard to Afford -- but May Also Be Hard to Copy

By Marc Kaufman

Washington Post Staff Writer

Thursday, 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

& , 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.

& 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 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. 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

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. "

& 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 , a biopharmaceutical executive with & .

Gordon ston, 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 & 's 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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