http://www.washingtonpost.com/ac2/wp-dyn/A20349-2001Mar17?language=printer

Drug Giant's Spin May Obscure Risk
Researcher Says GlaxoSmithKline Plays Down Problems in Hepatitis Treatment

By Deborah Nelson
Washington Post Staff Writer
Sunday, March 18, 2001; Page A14

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 deadly 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 world. 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 have 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."

Early 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 slides 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 the 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 medical profession need to dress up in bikinis to counter them?"

© 2001 The Washington Post Company

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