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Drug Giant's Spin May Obscure Risk

HONG KONG -- When pharmaceutical giant Glaxo Wellcome Inc. came to this
crowded Asian city several years ago to test a new drug for hepatitis B,
researcher Nancy Leung was pleased with the early results. In a short course of
treatment, the drug showed positive effects on many liver patients at her
university hospital. But over time, she began detecting mutant viruses in the
blood of participants who stayed on the drug longer than a year. She promptly
reported the disturbing development to Glaxo. "Most virologists," Leung said,
"do not want to create a new virus." Glaxo assured her that the new viruses,
though drug-resistant, appeared to be relatively benign, she said. Then, in
the summer of 1997, a 36-year-old patient, She Yun-Ki, fell mortally ill while
taking the drug. Glaxo listed his cause of death as peritonitis, but Leung said
that was misleading. He had developed mutant viruses, she said, and his liver
failed. The peritonitis was the last in a cascade of deadl!
y ailments that followed, she said. The death left her shaken, and she took a
more critical view of the rapidly spreading mutant viruses among patients
receiving long-term treatment, joining a growing number of liver specialists who
say the drug should not be used for more than a year. But that view is on a
collision course with Glaxo's efforts to promote more and longer use of the
drug, lamivudine, which is now sold in 60 countries and last year accounted for
$108 million in sales. Glaxo officials say long-term treatment is safe and
effective for most patients. Leung said Glaxo has tried to suppress concerns
about the drug, attaching her name to upbeat research reports that she didn't
approve and churning out data that mask the drug's problems. Glaxo's failure to
adequately acknowledge lamivudine's problems has led to a "mood of mistrust and
discontent" among Asian liver specialists, she said. Fraser Gray, who leads
Glaxo's lamivudine development team, said he was not!
aware of any unhappiness among Asian researchers over the company's
interpretation of their data. Glaxo works closely with all outside researchers
to make sure they agree with the company's scientific claims of success, he
said. Leung sees it differently. "We are too much controlled by them," she
said. "I feel like I've been constantly, positively spun." The mutant virus
controversy illustrates a new global twist in an ongoing debate in U.S.
scientific circles over whether drug companies with massive research budgets
exert too much control over human testing and the publication of findings in
medical journals. Academic researchers who rely on industry money to stay
afloat are being pressured by drug companies to put a favorable spin on clinical
trial results, said Marcia Angell, former editor in chief of the New England
Journal of Medicine. Lamivudine is prescribed for chronic hepatitis B, a
potentially fatal liver disease that infects 350 million people around the wo!
rld. In the United States, the virus spreads largely through illegal drug use
and unprotected sex. In Asia, where three-quarters of the hepatitis B population
resides, the disease is primarily passed from mother to baby. Chronic carriers
may live normal lives, but they suffer periodic attacks that can eventually
cause liver failure or cancer. Glaxo, now GlaxoSmithKline, began worldwide
lamivudine testing in the mid-1990s and is still studying its long-term
usefulness. The FDA approved lamivudine for hepatitis B in 1998, based on
one-year results from research carried out by Leung and others in Asia, Europe
and the United States. Since then, there has been good and bad news on
lamivudine. While there is evidence that long-term treatment produces lasting
improvement in some patients, the mutant virus risk rises dramatically over time
-- infecting one-fourth of study participants after one year of treatment and 67
percent after four years. Patients with the mutant viruses h!
ave suffered relapses and several have died. Some have had to forgo liver
transplants, because the risk of complications is higher. On the other hand,
many appear no worse off initially and continue to show improvement on
lamivudine, leading Glaxo to recommend they stay on the drug. The long-term
consequences of the mutant viruses are not yet known. A recent study by Liaw
Yun-San, a leading Taiwan hepatologist, uncovered more frequent and severe liver
attacks in lamivudine patients with the mutant than Glaxo had been reporting. He
said his own and other studies led him to conclude that the mutant viruses
should be avoided until an effective treatment is developed. Yet Glaxo has
portrayed Liaw's research as an endorsement of lamivudine, citing the
improvement seen in some of his patients after their serious liver attacks.
"They always want to look on the bright side," Leung said. "It's a milestone
drug. But it's not a perfect milestone. That is where we part ways." Earl!
y on in her dealings with Glaxo, Leung said, there was a puzzling incident that
set the tone for her relationship with the company. It occurred in 1998, after
Glaxo applied for U.S. marketing approval, when an FDA inspector conducted a
routine spot check of clinical trial records in Hong Kong. She said Yun-Ki's
death was mentioned in a memo that the inspector wanted to review. But the copy
of the document that Glaxo gave the inspector was missing the reference to the
dead patient, according to Leung and an FDA official. The alteration was
discovered after Leung's hospital provided the inspector with an unaltered
version of the document, they said. It is unclear why the document was
altered, since Glaxo had reported the death to the FDA at the time it happened.
A Glaxo spokeswoman said its Hong Kong staff did it to protect patient privacy,
but Leung said the FDA inspector had free access to patient names. Subsequent
incidents haven't been as ambiguous, she said. The slide!
s Glaxo gave her for an international science meeting presented misleading
information about her findings, she said. Some lamivudine patients had shown
dramatic spikes in liver inflammation. Yet the company's chart showed a flat,
steady line that hovered near normal liver enzyme levels. The company flattened
the spikes by using averages rather than individual readings, arguing that
approach was easier to understand. Last summer, Leung said she received an
e-mail with several study abstracts that Glaxo had written under her name,
without her input, for distribution at a conference at the National Institutes
of Health in Bethesda. Her reservations about long-term treatment weren't
reflected in Glaxo's upbeat conclusions. Leung said she tried to correct the
written record in her oral presentation, but the damage had been done, because
the abstracts are read and cited internationally. "It doesn't matter if Nancy
creates a fuss at a presentation, because the whole world reads t!
he abstract," she said. Glaxo spokeswoman Nancy Jo Pekarek said there may have
been a "breakdown in the process" in the rush to get the abstracts done for the
NIH conference. "This unfortunate incident has not disrupted the good working
relationship we have with her," Pekarek said. In December, Glaxo sought
Leung's signature for this year's updated research report for the FDA. She read
the report and, four days later, fired back a dozen questions. Later the same
day, she said, the company informed her that it was too late to address her
concerns, because the report had already been "signed off internally" and
submitted. Pekarek confirmed that the company had given the FDA the long-term
treatment data on lamivudine, including the Asian study results. Other
lamivudine researchers described varying degrees of company influence. Another
Hong Kong researcher said Glaxo routinely writes abstracts and scientific papers
under his name, although he usually reviews them first. A!
Taiwan scientist said he has asked Glaxo to remove his name from a paper that
he considered too positive. In the United States, one researcher said he does
his own analyses, while another said the company often writes the first draft of
papers but he revises them. "Some people work better doing a draft on their
own, and some prefer that we do it," said Gray of Glaxo, who called Leung's
experience a "rare occurrence." Pekarek said the company doesn't skew research
data in its favor. The company conducts symposia and distributes treatment
guidelines addressing the mutant virus risk, she said. Potential problems are
disclosed in all scientific and marketing materials, she said. Leung said she
gets those materials but disagrees that the risks are adequately presented. A
Glaxo flier last month promoted a four-year regimen of lamivudine, with
favorable statistics superimposed on a Pacific island scene. "And only small
print on drug resistance," Leung said. "Do we as a medic!
al profession need to dress up in bikinis to counter them?"