US Drug and Nutritional Supplement Makers
Use Material With Possible Mad Cow Link

FDA Tries to Downplay US Drug & Nutritional Supplements
Scandal Surrounding Use of Risky Bovine Parts from UK
and Other Countries

http://www.nytimes.com/2001/02/08/health/08COW.html?printpage=yes

New York Times, Thursday, February 8, 2001
5 Drug Makers Use Material With Possible Mad Cow Link
By MELODY PETERSEN and GREG WINTER

For the last eight years, the Food and Drug Administration has
repeatedly asked pharmaceutical companies not to use materials from
cattle raised in countries where there is a risk of mad cow disease.

But regulators discovered last year that five companies, including some
of the world's largest drug concerns, were still using ingredients from
those countries to make nine widely used vaccines.

Some of the companies say that they found the F.D.A.'s request unclear
and do not believe they did anything wrong. Others say they could not
keep up with the government's expanding list of countries where cattle
could be infected. One, however, acknowledged that it could have moved
more quickly.

The nine vaccines include some regularly given to millions of American
children, including common vaccines to prevent polio, diphtheria and
tetanus. They also include the anthrax vaccine, which the government
requires for soldiers serving in the Persian Gulf.

Federal health officials stress that the vaccines are still considered
safe. They calculate that the odds of these vaccines passing on the
disease, in the worst eventualities, are between one in 40 million and
one in 40 billion doses.

The officials say that the very slight chance that someone could be
infected is far outweighed by the benefits that these vaccines bring in
fighting disease and preventing death. Indeed, it is now only a
scientific theory that a vaccine could infect someone with the human
form of mad cow disease - called new variant Creutzfeldt- Jakob disease.
No one is known to have contracted the disease this way.

"Any risk is very remote," said Dr. Karen Midthune, director of the
F.D.A.'s Office of Vaccine Research and Review. "But if we have the
ability to bring this remote risk to zero, that is something we want to
do."

Nonetheless, the fact that these suspect materials slipped into the
nation's vaccine supply - and that the F.D.A. did not discover it for
seven years - raises questions about the agency's ability to ensure that
all medicines are free of the infectious proteins that can cause mad cow
disease.

The F.D.A. so far has only investigated the vaccine makers and has not
looked to see whether other medicine is free of possible mad cow
contaminants. Some experts say they worry more about dietary
supplements. Unlike drugs, supplements are largely unregulated. The
F.D.A. is not even sure how many supplement makers there are.

"It's just insane not to have greater safeguards" for supplements, said
Dr. Paul W. Brown, chairman of the F.D.A.'s advisory committee on mad
cow disease. "The potential exists for abuse."

All five vaccine makers, which include GlaxoSmithKline, Aventis and
American Home Products, have now agreed to stop using the suspect
materials, which include blood, fetal calf serum and meat broth.

But it will take a year or more to replace existing supplies with
reformulated products, because it can take many months to grow cultures
used in making vaccines. Both the companies and the F.D.A. say that the
current products are safe and should remain on pharmacy shelves.

They point out that the suspect ingredients, for the most part, are used
only in the early stages of manufacturing, when cultures are grown.
Blood, for instance, may be used to feed the bacteria and viruses in
these cultures. The cultures are then significantly diluted in the final
vaccine.

The F.D.A. first asked the vaccine makers in a 1993 letter to stop using
materials from cattle raised in Britain and other countries where there
was a threat of mad cow disease. Regulators followed up with another
letter in 1996 in which the agency "strongly" recommended that drug
companies take "immediate and concrete steps" to make sure they were not
using the materials.

In interviews, regulators said it was not until last year that they
learned that some vaccine makers were not complying. During a routine
review of a company's application for a license, the F.D.A. discovered
that the company, which it will not identify, was using cattle parts
from a high-risk country.

Regulators immediately demanded that all vaccine makers identify where
their biologic ingredients were coming from. That review found the nine
vaccines.

Dr. Murray M. Lumpkin, a senior medical adviser at the F.D.A., said his
agency's investigative resources were limited.

"You have to prioritize where the greater risk is," Dr. Lumpkin said.
For example, the F.D.A. now has inspectors visiting animal feed
companies, he said, after it found that many of them were not following
regulations adopted in 1997. Those rules, in part, prohibit using beef
parts to make cattle feed. Scientists contend that cattle in Britain
were infected after eating feed that contained parts of other infected
cows.

"That is where we think the greatest risk for Americans is at this
time," Dr. Lumpkin said.

But critics including doctors, scientists and consumer advocates say
that the F.D.A. should have acted more aggressively by ordering, rather
than asking, companies to follow the agency's recommendations.

"The companies acted recklessly because, in part, the F.D.A. failed to
regulate them," said Dr. Peter G. Lurie, another member of the F.D.A's
advisory committee on the disease.

Dr. Lurie, a researcher at Public Citizen, the consumer group, said he
agreed that the vaccines should stay on pharmacy shelves. But he faulted
both the companies and the F.D.A. for possibly undermining public
confidence in the safety of vaccines.

In their defense, F.D.A. officials said they expected companies to heed
their requests.

"The expectation," Dr. Lumpkin said, "is that people will behave
responsibly."

Mad cow disease, which is always fatal, is believed to be caused by an
infectious protein called a prion. In sick animals or humans, the prion
twists into an abnormal shape, often in the brain. These misfolded
prions accumulate in toxic clumps, eventually destroying normal brain
tissue and creating spongelike holes.

Cattle ingredients are used in a myriad of drugs other than vaccines.
But the F.D.A. says it cannot release a list of these drugs because many
details of how a product is manufactured are proprietary corporate
information.

But regulators say, for instance, that many drugs contain gelatin, made
from the bones or hooves of cattle. And calf lungs are used to make
surfactants, which help premature infants breathe.

As for dietary supplements, the industry's trade groups say that
hundreds of products use an array of cow tissues, from ground prostate
glands and testicles in pills that supposedly bolster sexual vitality to
thymus extract for healthy skin.

Many organs that scientists consider particularly risky for the
transmission of mad cow disease are also used, including freeze-dried
brain and pituitary glands in supplements that manufacturers say
stimulate memory, adrenal extract for energy, even powdered spleen to
help clear the sinuses.

As with vaccines, the F.D.A. has urged supplement makers not to use cow
tissue from certain countries. But the F.D.A., which has no specific
manufacturing rules for supplements, cannot say whether products sold in
the United States are free of such ingredients.

"The F.D.A. is toothless," Dr. Brown said. "Their purview over dietary
supplements is infinitesimally small."

Without comprehensive federal guidelines, the Natural Nutritional Foods
Association, the largest trade group, started a voluntary program in
1999 to test whether its members' products are free of contaminants,
including mad cow disease. But of about 500 companies eligible, only 20
have gone through the review.

For its part, the F.D.A. inspects only about 60 of the more than 1,000
supplement manufacturers each year. "We rely on the industry to do the
right thing," said Dr. Christine Lewis, director of the F.D.A.'s dietary
supplement division.

In 1995, the F.D.A. told its border agents to detain any imports of
suspect cattle parts or products made from them. Regulators say they
have not found any supplements sold in the United States that contain
the materials.

And one industry executive said there was little incentive to even try
to import such materials. "These glands are not very expensive," said
Matt Schueller, vice president at Enzymatic Therapy, a supplement maker
in Green Bay, Wis.

Even so, Dr. Brown and others say that the border controls are not
enough.

Every year, more than $1 billion of supplements are imported from high-
risk countries, according to a 1999 F.D.A. study. Only about 7 percent
of these products say on their labels that they contain animal parts,
but there could be more, Dr. Brown said. Foreign labeling laws vary
widely, he said, making it hard to know what some imports contain.

The companies that make the nine vaccines say they have tried to comply
with the F.D.A.'s requests and, over the years, have provided regulators
with any information they asked for.

They say that in most of the vaccines, the ingredients that regulators
have questioned are in the cultures used to start each batch. They say
that some of these cultures, which are used year after year, were
created in the 1980's, before the F.D.A. told them to stop using
material from certain countries.

American Home Products has been working for five years to change the
material used in bacterial seed cultures for its vaccine, Pnu- Imune 23,
which prevents pneumonia, said Dr. Peter R. Paradiso, a top researcher
in the company's Lederle Vaccine subsidiary. The 23 cultures making up
the vaccine must be modified one at a time, he said, with regulators
approving each one.

"The risk is very, very minuscule," Dr. Paradiso said. He calculates the
risk of Pnu-Imune passing on the disease, in a worst case situation, at
one in 2.4 trillion doses.

At Aventis, Len Lavenda, a spokesman, said that the company had believed
that IPOL, its polio vaccine, complied with the F.D.A.'s request. But
last year, regulators disagreed, he said, because the company cannot
trace the origin of some ingredients purchased in the 1980's.

In ActHIB, Aventis's vaccine to protect against haemophilus influenzae
Type B bacterium, the company used small amounts of hemin, a blood
derivative, from cattle in the Netherlands. Material from the
Netherlands was banned in 1997, but Aventis decided not to change its
supplier, he said, because its scientists believed that infectious
material could not survive the production process.

"That was probably a mistake," Mr. Lavenda said. The vaccines are safe,
he said, but the company fears its decision could weaken the public's
confidence in the vaccines.

BioPort, which makes vaccines against rabies and anthrax, said that it
did not understand until last year that the F.D.A. wanted the companies
to change seed cultures created before 1993.

GlaxoSmithKline, the British pharmaceutical giant that sells three of
the vaccines cited by the F.D.A., declined to answer specific questions.
Carmel M. Hogan, a company spokeswoman, said the company had been trying
since 1990 "to move away from using bovine materials from infected
countries."

The F.D.A. said the problem with Infanrix, one of GlaxoSmithKline's
vaccines, which prevents diphtheria, tetanus and pertussis, stems from
an ingredient made for it by Chiron Behring in Germany. Chiron stopped
using material from German cows in September, said Thomas Schick, a
Chiron spokesman, after American regulators visited its factory.

The final vaccine, Certiva, also for children, was made by North
American Vaccines until 1999 when there were production problems. Baxter
International, which purchased North American last year, said the
company did not intend to sell Certiva again.