[Ip-health] WP on Generic Biologics

[James Love]

This article, which goes pretty far in reporting the Bio spin on the
difficulties of generic biologics, could have explored also some of the
proposals for broader disclosures of know-how as a condition of
registration, in order to promote competition (to the degree that this
is an issue).  One might also revisit some early policy decisions
regarding the granting of patents for some biologic products, in favor
of a sui generis regime that would better facilitate technology
transfer.   Jamie

http://www.washingtonpost.com/wp-dyn/articles/A12377-2005Feb9.html

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 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.

Biotech Drugs' Generic Future Debated

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.