NY TIMES, Feb 22nd, 2003
Papers Indicate That Bayer Knew of Dangers of Its Cholesterol Drug
Newly disclosed company documents indicate that some senior executives at Bayer were aware that their anticholesterol drug had serious problems long before the company pulled it from the market.
The documents, made public by lawyers suing Bayer, include e-mail messages, memos and sworn depositions of executives that suggest that Bayer promoted the drug, Baycol, even as a company analysis found that patients on Baycol were falling ill or dying from a rare muscle condition much more often than patients on similar drugs.
The lawyers are suing Bayer, which is based in Germany, and its British marketing partner, GlaxoSmithKline, in federal court in Minneapolis and in dozens of other cases around the country. Though the documents do not paint a full picture of what the companies knew, or how early they knew it before Baycol was pulled from the market in 2001, they provide a rare glimpse inside a major drug company's marketing efforts in the face of mounting indications of trouble.
Bayer, which developed Baycol, says the drug was marketed appropriately and is safe when used properly.
But approximately 100 deaths and 1,600 injuries worldwide have been linked to a muscle disorder caused by the drug, according to regulatory filings by the company. Similar drugs are at least as effective as Baycol but cause the disorder much less frequently, according to the Food and Drug Administration.
The F.D.A., which allowed the sale of two higher doses of Baycol in the years after initially approving the drug, said it did not see a rapid increase in deaths until the spring of 2001, and Bayer took the drug off the market shortly after the agency raised serious concerns about it with company executives in late July.
The drug, which studies found to be less effective at its initially approved strength than competing medicines, caused more problems at higher doses. Senior executives at Bayer and GlaxoSmithKline were aware that this might be possible as early as 1997, according to a letter that is part of the court filings.
Philip S. Beck, a lawyer with Bartlit Beck Herman Palenchar & Scott, who is representing Bayer, said the company monitored reports on Baycol from doctors, shared those reports with regulators and repeatedly added to the written warnings on the drug's label. "We did what companies should do," he said.
Patricia Seif, a spokeswoman for GlaxoSmithKline, said the company's "promotion of Baycol was fully consistent with the product label that the F.D.A. approved."
More than 10,000 patients who took Baycol or the families of those who died have filed lawsuits against Bayer and GlaxoSmithKline. The first trial, in Corpus Christi, Tex., began Tuesday.
Bayer and GlaxoSmithKline have settled more than 400 of the cases for individual amounts ranging from $200,000 to $1.2 million, according to lawyers for the patients. At that rate, the drug makers could pay billions of dollars to resolve all the lawsuits. The companies deny the allegations in the lawsuits, and Bayer says that no more than 15 percent of the patients who have sued actually suffered any injury and that it is trying to settle most of those claims. Lawyers for the plaintiffs dispute that estimate.
The companies have agreed that Bayer, which discovered the drug and played the biggest role in marketing it, will pay 95 percent of the cost of settling cases.
Mr. Beck said that the company still believed that Baycol was safe when prescribed according to the instructions and warnings in its label. Bayer took the drug off the market, he said, because doctors were not using it as directed by the label.
The company was also being pressured by the F.D.A. The agency had allowed Bayer to sell higher doses of Baycol because it did not notice unusual rates of complications from the drug. But Dr. David G. Orloff, director of the F.D.A. division that reviewed Baycol, said that in the spring of 2001, less than a year after approving a higher dosage of Baycol, the agency noticed a sharp jump in reports of deaths and serious injuries in patients using Baycol, and after investigating the reports it pressed Bayer to pull the drug. "It took time and tragedy to understand it was different," he said.
The drug makers have demanded that many documents in the cases remain sealed, and judges have acceded to the request. The documents that have become public have been introduced in court by lawyers for plaintiffs trying to broaden the lawsuit against Bayer and seek additional damages. The available documents show how the companies responded as they received reports of a dangerous side effect called rhabdomyolysis, which causes muscle cells to break down and their contents to flow into the blood.
Even mild cases of rhabdo, as doctors commonly call the condition, can cause severe pain and muscle weakness. In more serious cases, rhabdo can cause paralysis or death as the kidneys shut down.
John Nahay, 71, said he "just got weaker and weaker" after beginning to take Baycol in the summer of 2001, shortly before it was pulled from the market. Mr. Nahay, who lives in Langhorne, Pa., and is among the thousands who have sued Bayer, must now undergo dialysis treatments three times a week and is largely confined to his house. "It's hard to believe that that little pill could do that," he said.
Regulators approved Baycol in June 1997, making it the sixth of a group of popular cholesterol reducers called statins. By August 2001, when Baycol was removed from the market, at least six million people worldwide had taken the drug, including 700,000 Americans, according to Bayer. With sales that year expected to exceed $600 million, it had become one of the company's fastest-growing products.
But on June 27, 1997, the day after Baycol was approved by the Food and Drug Administration, Jerry Karabelas, executive vice president for pharmaceuticals at SmithKline Beecham, which later merged with Glaxo, wrote to David Ebsworth, president of Bayer's North American pharmaceutical operations, saying he had "serious concerns" about using the drug with some other medicines, according to excerpts of the letter included in court papers.
Mr. Karabelas said that Baycol appeared to be no stronger than a competing drug called Lescol. But, he said, Baycol also caused "drug interactions that could be magnified at higher doses."
"Simple and safe," Mr. Karabelas wrote, "no longer appears to be a viable promotional platform."
Fred T. Magaziner, a lawyer with the Dechert law firm that is representing GlaxoSmithKline, said that Mr. Karabelas was writing about drug interactions that were later proved not to be a problem with Baycol.
Still, the e-mail message indicates that some top executives had concerns about the drug's safety early on.
Bayer began marketing Baycol in early 1998, and doctors soon began reporting serious side effects. In April 1999, Dr. William Pogson, a cardiologist in Independence, Mo., wrote in The American Journal of Cardiology that a patient had developed "profound muscle weakness, and the inability to walk" in September 1998 after taking Baycol for three weeks alongside Lopid, another type of cholesterol drug. A few months later, a second patient of his developed rhabdo while taking Baycol, but not Lopid. "It made me want to stay away from the drug," Dr. Pogson said in an interview.
Nonetheless, the F.D.A. approved a stronger dosage of 0.4 milligram of Baycol in May 1999.
That October the F.D.A. expressed its first public concerns about Bayer's marketing, warning the company in a letter that its sales materials were "false, lacking in fair balance or otherwise misleading" and that they underplayed "the most important risk information" on rhabdomyolysis.
Mr. Beck said the warning was isolated and similar to dozens of others received by drug companies, including the makers of other anticholesterol drugs.
In December 1999, Bayer added a warning to the drug's label saying that Baycol should not be prescribed with Lopid a warning stronger than those on the labels of similar drugs. A drug's label, which is approved by the F.D.A., is a document included in a drug's package that often spans many pages, and doctors rely on these labels when they prescribe medicines.
Some Bayer executives, however, were aware that doctors might ignore the label change. In August 2000, Laurie Simpson, a manager in Bayer's strategic analysis division, wrote to Tig Conger, vice president for cardiovascular and metabolic marketing, saying, "If the physician's experience is that he/she has safely used combinations in the past, tendency would be to discount the contraindication."
Mr. Beck, Bayer's lawyer, said the warning about drug combinations was emphasized in all sales material.
As the drug became more widely used, more doctors reported problems. In April 2000, three Spanish doctors reported in The Annals of Internal Medicine a case of rhabdo in a woman who had taken Baycol but not Lopid.
At the same time, Bayer was preparing to introduce another new, higher dosage of Baycol. At least one health official of the company expressed concerns about the new stronger version.
In May 2000, when Bayer was anticipating F.D.A. approval of the stronger version of Baycol in July, Dr. Richard Goodstein, vice president for scientific relations at Bayer, sent an e-mail message to Patricia Stenger, a manager in Bayer's scientific affairs division, about a meeting of the "Baycol Project team." Dr. Goodstein told Ms. Stenger that he saw "a false comfort factor in place across the company" about the drug.
Reached at her home, Ms. Stenger said she could not comment. Dr. Goodstein did not return telephone calls, but Mr. Beck said Dr. Goodstein was concerned about Bayer's reputation in the medical community and not about Baycol's safety.
"With the stronger medicine there is always a chance of more adverse reactions," Mr. Beck said, "but some people need the stronger medicine." He said that Bayer warned doctors of the risks of the higher dose but believed that it could be safely prescribed.
The new tablet was approved by the Food and Drug Administration in July 2000. The label on the new 0.8 milligram tablets stated that doctors should start patients on a lower dose.
At the same time, reports of problems were increasing. In an August 2000 article in the journal Angiology, Turkish doctors reported a death after a patient took Baycol and Lopid.
That November, Bayer analyzed reports of side effects and found that patients taking Baycol alone had 5 to 10 times the chance of developing rhabdo as patients on the other medicines.
Mr. Beck said Bayer then hired Pacificare, a managed care company, to more thoroughly analyze Baycol's risks among its members. The study did not include patients taking the highest dose of Baycol. It found that the drug at lower doses was no more risky than other statins as long as it was prescribed according to the label directions, Mr. Beck said.
Still, the reports of problems with Baycol continued. In December 2000, the Harris County public hospital system in Houston stopped using Baycol after seeing six cases of rhabdo in just nine months in patients taking the drug. The increase in rhabdo cases "was a noticeable thing in a hospital system our size," said Dr. David Hyman, chief of general internal medicine at Ben Taub General Hospital in Houston. "We made a decision we were uncomfortable with the drug."
Eight months later, in August 2001, Bayer pulled Baycol from the market
By MELODY PETERSEN and ALEX BERENSON