[e-drug] Riskier Bayer drug sold overseas

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E-drug: Riskier Bayer drug sold overseas
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Paths of Bayer Drug in 80's: Riskier Type Went Overseas
New York Times May 22, 20032 

By Walt Bogdanich and Eric Koli

A division of the pharmaceutical company Bayer sold millions of
dollars of blood-clotting medicine for hemophiliacs - medicine that
carried a high risk of transmitting AIDS - to Asia and Latin America
in the mid-1980's while selling a new, safer product in the West,
according to documents obtained by The New York Times. 

The Bayer unit, Cutter Biological, introduced its safer medicine in
late February 1984 as evidence mounted that the earlier version
was infecting hemophiliacs with HIV. Yet for over a year, the
company continued to sell the old medicine overseas, prompting a
United States regulator to accuse Cutter of breaking its promise to
stop selling the product.

By continuing to sell the old version of the life-saving medicine, the
records show, Cutter officials were trying to avoid being stuck with
large stores of a product that was proving increasingly
unmarketable in the United States and Europe. 

Yet even after it began selling the new product, the company kept
making the old medicine for several months more. A telex from
Cutter to a distributor suggests one reason behind that decision,
too: the company had several fixed-price contracts and believed
that the old product would be cheaper to produce. 

Nearly two decades later, the precise human toll of these marketing
decisions is difficult, if not impossible, to document. Many patient
records are now unavailable, and because an AIDS test was not
developed until later in the epidemic, it is difficult to pinpoint when
foreign hemophiliacs were infected with HIV - before Cutter began
selling its safer medicine or afterward. 

But in Hong Kong and Taiwan alone, more than 100 hemophiliacs
got HIV after using Cutter's old medicine, according to records and
interviews. Many have since died. Cutter also continued to sell the
older product after February 1984 in Malaysia, Singapore,
Indonesia, Japan and Argentina, records show. The Cutter
documents, which were produced in connection with lawsuits filed
by American hemophiliacs, went largely unnoticed until The Times
began asking about them.

"These are the most incriminating internal pharmaceutical industry
documents I have ever seen," said Dr. Sidney M. Wolfe, who as
director of the Public Citizen Health Research Group has been
investigating the industry's practices for three decades. 

Bayer officials, responding on behalf of Cutter and its president at
the time, Jack Ryan, declined to be interviewed but did answer
written questions. In a statement, Bayer said that Cutter had
"behaved responsibly, ethically and humanely" in selling the old
product overseas. 

Cutter had continued to sell the old medicine, the statement said,
because some customers doubted the new drug's effectiveness,
and because some countries were slow to approve its sale. The
company also said that a shortage of plasma, used to make the
medicine, had kept Cutter from manufacturing more of the new
product. 

"Decisions made nearly two decades ago were based on the best
scientific information of the time and were consistent with the
regulations in place," the statement said. 

The medicine, called Factor VIII concentrate, essentially provides
the missing ingredient without which hemophiliacs' blood cannot
clot. By injecting themselves with it, hemophiliacs can stop bleeding
or prevent bleeds from starting; some use it as many as three
times a week. It has helped hemophiliacs lead normal lives. 

But in the early years of the AIDS epidemic, it became a killer. The
medicine was made using pools of plasma from 10,000 or more
donors, and since there was still no screening test for the AIDS
virus, it carried a high risk of passing along the disease; even a tiny
number of HIV-positive donors could contaminate an entire pool. 

In the United States, AIDS was passed on to thousands of
hemophiliacs, many of whom died, in one of the worst drug-related
medical disasters in history. While admitting no wrongdoing, Bayer
and three other companies that made the concentrate have paid
hemophiliacs about $600 million to settle more than 15 years of
lawsuits accusing them of making a dangerous
product. 

The Cutter documents - a few of them have surfaced in recent
years in television and newspaper reports about Cutter's marketing
practices - were gleaned from that litigation. But because the
documents did not relate directly to the suits, most went
uninvestigated.

The documents - internal memorandums, minutes of company
marketing meetings and telexes to foreign distributors - reveal and
chronicle Cutter's decision to keep exporting the older product after
it began making the new one, which was heat-treated to kill HIV.
The heat treatment rendered the virus "undetectable" in the
product, according to a government study. (There are few available
records documenting the actions and decisions of the three other
American-based companies that also sold unheated concentrate
after offering a heated product.) 

Doctors and patients contacted overseas said they had not known
of the contents of the Cutter documents. Bayer and other
blood-product companies, though admitting no wrongdoing, have
already made some payments to foreign hemophiliacs. It is unclear
if Bayer could now face legal liability specifically for selling the older
product after a safer one was available. 

Federal regulators helped keep the overseas sales out of the public
eye, the documents indicate. In May of 1985, believing that the
companies had broken a voluntary agreement to withdraw the old
medicine from the market, the Food and Drug Administration's
regulator of blood products, Dr. Harry M. Meyer Jr., summoned
officials of the companies to a meeting and ordered them to
comply. "It was unacceptable for them to ship that material
overseas," he said later in legal papers. 

Even so, Dr. Meyer asked that the issue be "quietly solved without
alerting the Congress, the medical community and the public,"
according to Cutter's account of the 1985 meeting. Dr. Meyer said
later that he could not recall making that statement, but another
blood-product company's summary of the meeting also noted that
the F.D.A. wanted the matter settled "quickly and quietly." Dr.
Meyer died in 2001. 

Whether Cutter was behaving ethically became an issue in internal
company discussions. "Can we in good faith continue to ship
nonheat-treated coagulation products to Japan?" a company task
force asked in February 1985, fearing that some of its plasma
donors might be HIV positive. The decision, records show, was
yes. 

Taken together, the documents provide an inside view of Cutter's
bottom-line strategizing and efforts to manage the flow of
information amid growing public anxiety about the safety of its
product. 

When a Hong Kong distributor in late 1984 expressed an interest in
the new product, the records show, Cutter asked the distributor to
"use up stocks" of the old medicine before switching to its "safer,
better" product. Several months later, as hemophiliacs in Hong
Kong began testing positive for HIV, some local doctors questioned
whether Cutter was dumping "AIDS tainted" medicine into
less-developed countries. 

Still, Cutter assured the distributor that the unheated product posed
"no severe hazard" and was the "same fine product we have
supplied for years." 

Li Wei-chun said her son, who died in 1996 at the age of 23, was
one of the hemophiliacs in Hong Kong who got AIDS after using
that product. "They did not care about the lives in Asia," Ms. Li said
in a recent interview. "It was racial discrimination." 

How It Started
Discovery That Blood Spreads the Disease 

At the beginning of the epidemic, more than two decades ago, fear
over what would later be known as AIDS was centered mostly
among gays and intravenous drug users. But that changed on July
16, 1982, when the federal Centers for Disease Control reported
that three hemophiliacs had acquired the disease. 

This gave epidemiologists a strong reason to believe that the
disease was being spread through blood products. And that belief
carried grave implications for the many thousands of hemophiliacs
who routinely injected themselves with concentrate made from
giant pools of donated plasma. 

Because an AIDS test had not yet been developed, federal health
officials had no idea how many plasma donors carried the disease.

By March of 1983, the CDC went so far as to warn that blood
products "appear responsible for AIDS among hemophilia
patients." 

The unfolding story had not gone unnoticed at Cutter headquarters.
Back in January, Cutter's manager of plasma procurement had
acknowledged in a letter: "There is strong evidence to suggest that
AIDS is passed on to other people through . . . plasma products." 

With sales of concentrate beginning to slip, Cutter got more bad
news in May 1983: after learning that a Cutter rival had begun to
make heated concentrate, France decided to halt all imports of
clotting concentrate until it could figure out what to do.

Fearing a loss of customers, Cutter conceived a marketing plan
that stopped well short of full disclosure. "We want to give the
impression that we are continuously improving our product without
telling them we expect soon to also have a heat-treated"
concentrate, an internal memo said.

Several weeks later, Cutter tried to minimize the danger
hemophiliacs faced when using blood products. "AIDS has become
the center of irrational response in many countries," the company
said in a June 1983 letter to distributors in France and 20 other
countries. "This is of particular concern to us because of
unsubstantiated speculations that this syndrome may be
transmitted by certain blood products." 

The French decided to keep using unheated concentrate, and
Cutter said it sold them more of the unheated product in August
1983. Later, two French health officials were sent to prison for
continuing to use up old stocks of unheated concentrate in 1985,
when a heated product was available. 

Cutter finally received United States approval to sell heated
concentrate on Feb. 29, 1984, the last of the four major blood
product companies to do so. Though some doctors and patients
held out against the heated product, a safer era had clearly begun
for hemophiliacs in the United States.

Market Considerations
Bayer Says Some Wanted Old Product 

For five months more, until August 1984, Cutter said it continued to
make the old, unheated medicine. The records suggest that the
company hoped to preserve the profit margin from "several large
fixed-price contracts." But in its statements to The Times, Bayer
also said that some customers still wanted the old medicine, initially
believing - incorrectly, it turned out - that heating the concentrate
could leave it less effective and possibly dangerous. 

The new product, meanwhile, was selling briskly, leaving Cutter
with a problem: "There is excess nonheated inventory," the
company noted in minutes of a meeting on Nov. 15, 1984. 

"They needed to get the return for what they invested," explained
Michael Baum, a Los Angeles lawyer who has represented dozens
of United States hemophiliacs in suits against blood-product
companies. "They paid the donors. They had processed the
plasma, put it into vials, kept it in warehouses - and all that expense
had already been incurred." (One vial is roughly equivalent to a
small dose, though more may be needed to stop severe bleeding.) 

At the November meeting, the minutes show, Cutter said it planned
to "review international markets again to determine if more of this
product can be sold." And in the months that followed, it had some
success, exporting more than 5 million units (a typical vial might
contain 250 units) in the first three months of 1985, documents
show. 

"Argentina has been sold 300,000 units and will possibly order
more, and the Far East has ordered 400,000 units," according to a
March 1985 Cutter report. Two months later, the company reported
that "in Taiwan, Singapore, Malaysia and Indonesia, doctors are
primarily dispensing nonheated Cutter" concentrate. 

By then, while there were still a small number of buyers in the
United States, nearly all of the unheated concentrate was being
sold abroad, available records show. All told, Cutter appears to
have exported more than 100,000 vials of unheated concentrate,
worth more than $4 million, after it began selling its safer product. 

Gary Mull, an international product manager for Cutter at the time,
said no one at the company had ordered him to sell the unheated
concentrate as a way of avoiding a write-off. "If I had reason to
personally believe, let alone the company" that any of the material
was highly infectious, "we wouldn't have sent it out," he said.

Mr. Mull, who now works for another blood-product company,
added, "I wasn't the shipping person, but I would still be the person
in charge of queueing it up." 

Bayer, which is based in Germany, said in its statement that an
overall plasma shortage in 1985 had kept Cutter from making more
heated medicine. But Cutter may actually have contributed to that
shortage - by using some its limited plasma supplies to continue
making the old product.

Bayer's response also emphasized that some countries were slow
to approve its new product. For example, Bayer said "procedural
requirements" imposed by Taiwan had delayed its "ability to apply
for registration" and had led to other delays as well. 

But an official at Taiwan's health department, Hsu Chien-wen, said
recently that Cutter had not applied for permission to sell the new,
safer medicine until July 1985, about a year and a half after it
began doing so in the United States. 

In one case, records show, Cutter officials even discussed trying to
delay Japan's approval of heated concentrate so the company
could shed stocks of the older product. Bayer said Cutter did not
act on that idea.

Officials from the three other American-based companies that
continued to sell unheated concentrate - Armour Pharmaceutical,
Baxter International and Alpha Therapeutic - either declined to be
interviewed or denied wrongdoing, in some cases citing the same
reasons Bayer did for its decisions. 

Still, what is not in dispute is that by the spring of 1985, few
researchers doubted the connection between AIDS and unheated
concentrate. The previous October, the federal Centers for Disease
Control, using a prototype HIV test, had reported that 74 percent of
hemophiliacs who used unheated concentrate had tested positive
for HIV In the same report, the agency said a study done with
Cutter had shown that heat treatment rendered the virus
"undetectable." 

(Bayer said no one knew "definitively" that its heat treatment killed
the AIDS virus until eight months later.)

By May 1985, as the AIDS scare reached hemophiliacs in Hong
Kong, Cutter's distributor there placed an urgent call to Cutter
headquarters, records show. Sounding distraught, he told of an
impending medical emergency. Hemophiliacs were frightened.
Children were being infected with HIV. Parents were hysterical.
Couldn't the company send the new, safer product? 

Cutter replied that most of the new medicine was going to the
United States and Europe, and that there was not enough left for
Hong Kong, though a small amount was available for the "most
vocal patients." 

Dr. Chan Tai-kwong, who treated hemophiliacs at Queen Mary
Hospital in Hong Kong, said doctors asked Cutter's distributor for
the heated concentrate but could not get it; 40 percent of his
patients were HIV- positive, Dr. Chan said.

Dr. Patrick Yuen, who worked at another hospital, gave a similar
account. "The local distributor asked us to keep using it," he said.
"They said not to be afraid." 

Even so, Cutter knew the market for the older medicine had all but
dried up.

"It appears there are no longer any markets in the Far East where
we can expect to sell substantial quantities of nonheat-treated," a
Cutter official wrote in May 1985. Bayer said Cutter stopped
shipping unheated concentrate in July 1985. 

Later, in the early 1990's, two members of a Hong Kong
government commission that concluded the tragedy could not have
been avoided, expressed concern when told of the internal Cutter
documents. Dr. Yuen, a member of the panel, said Cutter failed to
warn doctors and hemophiliacs in Hong Kong about the dangers of
unheated concentrate. "It should tell the whole world, not just
Europe and America," he said.

Bayer also said Cutter did fully inform foreign customers about the
heated product. And Bayer said it took more than a year to get
Hong Kong's approval to sell it. But Dr. Cindy Lai, assistant director
of Hong Kong's health department, said that in the 1980's Cutter
needed only to get an import license. "It normally took one week,"
she said. 

The delay harmed more than just the hemophiliacs, said Mrs. Li,
the mother of the young hemophiliac who died of AIDS in 1993.
Infected with a terrible and still mysterious disease, hemophiliacs
were often shunned by family, friends and employers.

"It was the immoral drug company that caused some families to fall
apart," she said. "They blamed and tortured each other. It was
better to die than to live." 

The Message Gap
Many Slow to Hear of the Problems

Today, in the Internet age, vast amounts of the most
up-to-the-minute medical information are available at the click of a
mouse. News moved less efficiently in 1985. 

In Taiwan, Dr. Shen Ming-ching, who ran the country's largest clinic
for hemophiliacs, recalled in a recent interview that it was not until
he travelled to the United States for a conference in July 1985 that
he learned for certain that heat treatment killed HIV Upon returning
home, he said, he immediately insisted that Taiwan authorities stop
importing the old concentrate. 

For his efforts on behalf of the hemophiliacs in Taiwan, Dr. Shen
said, the government gave him a certificate and "a beautiful
medal." As for the hemophiliacs themselves, 44 of Dr. Shen's
patients got AIDS, including a 2-year-old. He said 23 had died.

None of the Taiwan patients interviewed by The Times said they
knew that Cutter had begun selling the safer medicine in the United
States in early 1984.

One Taiwan patient who received Cutter's old concentrate was Lee
Ching-chang. Mr. Lee said he got his first concentrate in November
1983 at age 22, and continued receiving the unheated type into
1985. 

Mr. Lee said he tested positive for HIV in 1986. "I am bitterly
angry," he said. Mr. Lee said he was too sick to work. 

Six other hemophiliacs with HIV or their families spoke to The
Times about despair, discrimination, job loss or in some cases
thoughts of suicide. Mr. Lee was the only hemophiliac with HIV
willing to be photographed. 

Tang Fu-kuo helps AIDS patients in Taiwan. "I cannot tell myself
that it's just history; let's forget it," Mr. Tang said. "Nobody wants to
acknowledge fault." 
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