Source | New York Times

By Louise Story

Could a widely praised approach to drug marketing now be at risk of backfiring? That is a question confronting GlaxoSmithKline and its diabetes treatment Avandia, which is now clouded by concerns over the drug’s safety.

Della Reese, the jazz singer and actress, seemed a natural choice to star in ads for Avandia, when Glaxo signed her on in 2004. Not only does Ms. Reese have broad appeal, known most recently for her role in the television series “Touched by an Angel,” but she has Type 2 diabetes.

And while she was Avandia’s main spokeswoman, from 2004 to 2006, Ms. Reese represented an important target in Avandia’s marketing: African-American consumers.

Because Type 2 diabetes is a disease twice as likely to affect black Americans as non-Hispanic white people in this country, Avandia’s maker, GlaxoSmithKline, has long placed a marketing focus on African-Americans — much more so than any other maker of diabetes drugs, according to industry executives.

In the eight years that Avandia has been for sale, becoming a $3-billion-a-year worldwide best seller, Glaxo’s African-American focus in the United States has won the company praise in the advertising industry and from some black doctors. They credit the campaigns for putting a friendly face on a drug for a disease that too often goes untreated, particularly among minority groups.

But now that Avandia is dogged by safety questions — a Congressional hearing today will address concerns that the drug may increase the risk of heart attacks — some black advertising executives wonder if Glaxo’s advertising strategy could end up working against the company.

“Avandia has such a large African-American niche, I’d expect competitors now to step up their outreach to African-Americans,” said Howard Buford, the founder and chief executive of Prime Access, a multicultural advertising agency in New York.

Alternatives to Avandia include Byetta, which is marketed by Amylin Pharmaceuticals and Eli Lilly. It and others could benefit if doctors started encouraging patients to drop Avandia. So far, though, many doctors seem to be playing wait and see.

Avandia’s main competitor in this country is a drug called Actos, which had a comparable number of total prescriptions written last year, about 11.3 million, according to Verispan, a health care information company based in Yardley, Pa.

Actos is made by Takeda Pharmaceuticals of Japan, which does not conduct significant consumer advertising in the United States. A spokesman for Takeda said the company had no plans to increase its advertising to consumers in light of safety concerns about Avandia. So, the competitive issue raised by Mr. Buford could be largely theoretical.

Still, Mr. Buford said it would be incongruous if Glaxo’s black outreach did come back to haunt the company, because Glaxo had worked to overcome what he described as a deep distrust of the drug industry among many African-Americans, particularly older people. He said the skepticism traces in part to the notorious Tuskegee syphilis experiment from the 1930’s to 1970’s in which the federal government allowed black sharecroppers to go untreated in order to study the disease’s physical effects.

“There’s still a lot of distrust,” Mr. Buford said.

And yet, some other ad industry executives said that because Glaxo had helped raise diabetes awareness in recent years among African-Americans, the company might now have a reservoir of good will that it could draw upon.

“For them to advertise a drug to African-Americans that could help save lives and provide information, that is important,” said Jo Muse, the chairman and chief creative officer of Muse Communications, a multicultural agency in Hollywood. “Thousands of African-American men, in particular, have been affected in a positive way by direct-to-patient advertising.”

A spokeswoman for Glaxo said she could not comment on the company’s marketing strategy.

Ahead of today’s hearing by the House Committee on Oversight and Government Reform where Moncef Slaoui, Glaxo’s chairman of research and development, is scheduled to testify, the company has been scrambling to address safety questions about Avandia that were raised on May 21 in a New England Journal of Medicine article.

The company has posted a video on its Web site featuring an executive, Dr. Anne Phillips, addressing the health concerns. And on Tuesday, the company ran a full-page ad in more than a dozen newspapers, including The New York Times, with an open letter to patients from Dr. Ronald L. Krall, its chief medical officer.

“As leaders in diabetes, we understand that managing your Type 2 diabetes is not easy,” the letter said, in part. “We also understand the confusion and concern you may have experienced following recent press coverage about the safety of Avandia. GlaxoSmithKline stands firmly behind Avandia.”

Glaxo, which spent a total of $25.7 million on Avandia advertising last year, according to TNS Media Intelligence, has by no means ignored potential white customers.

After all, black Americans represent only about 13 percent of the population. And although they are more likely to develop Type 2 diabetes, the number of non-Hispanic white Americans in this country with the disease outnumbers African-American patients, 13.1 million to 3.2 million, according to the American Diabetes Association.

Latinos have been another important group for diabetes drugs, and an audience that Glaxo has also made a target with some of its Avandia advertising. The American Diabetes Association does not have national figures on the percentage of Type 2 diabetes patients in this country who are Hispanic.

Caucasians featured in Avandia ads have included the actress Jane Seymour, who was in a 2001 television spot, just a few years after she starred in the TV series “Dr. Quinn, Medicine Woman.”

And currently, a Glaxo-sponsored Web site about health, www.stepitupdiabetes.com, features the white fitness coach Bob Harper, who is the exercise guru on the NBC reality series “The Biggest Loser.” Various Avandia advertisements depicting everyday people feature Caucasians.

But there is no disputing that Glaxo has made a special effort to reach African-Americans with its Avandia advertising, ad executives say.

“You see in the broad diabetes category an acknowledgment or nod toward the African-American community, but GlaxoSmithKline was definitely a leader and one of the first groups to really use a more targeted effort,” said Croom Lawrence, the vice president for strategy and insight at RTC Relationship Marketing, a direct marketing advertising agency in the WPP Group. “That was really the face of this brand.”

And it was a brand-building effort that at least until now had been considered generally effective, as evident in the awards for multicultural marketing in 2001 and 2002 that Glaxo won at the DTC National Conference, an annual conference about marketing drugs to consumers.

Generally among marketers, efforts to reach black audiences often include ads featuring African-Americans that run in magazines like Ebony, Essence and Jet or on the Black Entertainment Television network. But those ads do not always run in mainstream media.

With Avandia, however, ads featuring a black couple or a black grandfather with his grandson also ran in mass-market magazines like Sports Illustrated, Reader’s Digest and Ladies’ Home Journal. Direct mail and outdoor advertising have also promoted Avandia to potential black patients. And African-Americans appear as prominently, if not more so, than any other group on Avandia’s Web site.

Whenever safety questions start clouding a drug, pharmaceutical companies tend to expend most of their crisis-control effort trying to persuade current customers to keep refilling their prescriptions. Any thought of acquiring new patients tends to be deferred until the controversy is resolved.

And so, for Glaxo, maintaining Avandia customers will probably involve continuing its strategy of mainstream ads, with an African-American emphasis, outside ad executives said.

And some advertising industry executives say Glaxo may now be able to build on a reputation with Avandia for having provided important information to black consumers. “This is an audience that has not had the benefit of advertising in the past,” said Byron E. Lewis, chairman and chief executive of the Uniworld Group, an agency in New York that created the multicultural ads for Avandia from 2001 to 2004.

Pharmaceutical companies in general have been seeing a higher return on direct-to-consumer advertising for minority groups, because many of the people in those audiences might not otherwise go to a doctor about a problem, said Mr. Muse of Muse Communications.

Dr. Gerald L. DeVaughn, president of the Association of Black Cardiologists, said he was awaiting more evidence before deciding whether to advise his patients to stop taking Avandia in light of the concerns about potential cardiac risks. Patients have not been asking him about the news reports about the suspected risks, Dr. DeVaughn said.

While some ad executives said the new concerns about Avandia’s level of cardiac risk may cause Glaxo to lose customers, others said that the company could hold onto many of its black customers if Glaxo is now seen as having effectively communicated the pros and cons of Avandia over the years — and having encouraged people to seek out medical help in their decisions.

“None of this exists in a vacuum,” said Mark A. Robertson, the director of business development for UniWorld, the former Avandia agency. “Glaxo has always promoted and motivated people to see their doctors to ask what is best for them.”

Source | New York Times

By Stephanie Saul

When a Congressional committee holds a hearing next Wednesday, the subject will be the safety of the diabetes drug Avandia and whether federal drug regulators have paid close enough attention to its potential risks.

But for one witness who is scheduled to appear, Dr. John B. Buse, a nationally noted diabetes specialist, the hearing will take a different turn, focusing on whether he was the target of an effort by the drug’s maker, GlaxoSmithKline, to silence his criticism of the drug.

In a statement last night, Dr. Buse said his full story would be told at the hearing, including the account of how he was intimidated by Glaxo. But he said the company apologized and he later reported his concerns about the drug to the Food and Drug Administration.

“It was upsetting, but it was not life-altering,” Dr. Buse’s statement said. “I hold no ill will toward Glaxo or any of its employees.”

Congressional investigators have been looking into what they have called “very serious” claims that Avandia’s maker “silenced one or more medical professionals who attempted to speak out about the potential for cardiovascular problems with Avandia,” according to a letter to Glaxo last week from the Senate Finance Committee.

Glaxo denied yesterday that it made any effort to stifle a scientific discussion of its drug, used for Type 2 diabetes. Avandia is the company’s second-largest product with more than $3 billion in sales last year.

Dr. Buse has declined to discuss any details of his story, saying he wanted them to come out during sworn testimony. But one of his friends, a University of Michigan diabetes expert, Dr. Charles F. Burant, said that Dr. Buse had been troubled by the pressure he had received from Glaxo.

Dr. Burant said he was not familiar with specifics, but that the pressure had included Glaxo’s contacting the University of North Carolina medical school, where Dr. Buse was then on the faculty and is now the head of endocrinology.

Although Glaxo is based in London, it has major operations in Research Triangle Park, N.C., and the company’s foundation has donated millions of dollars to the University of North Carolina.

Dr. Buse, who is about to become the president of the American Diabetes Association, was an early and frequent critic of Avandia after it reached the market in 1999. In a March 2000 letter to the F.D.A., he said Avandia might raise patients’ risk of heart attacks, and he criticized the company’s marketing, saying it employed “blatant selective manipulation of data” to overstate the drug’s benefits and understate its risks.

The following year, after demanding that Glaxo strengthen the language on Avandia’s label describing its potential heart risks, the F.D.A. sent Glaxo a letter reprimanding the company for playing down those risks in discussions between sales representatives and undercover investigators at a medical conference.

Dr. Buse, meanwhile, had also raised his concerns about Avandia in speeches to other doctors. Avandia, an oral medication, is used for a patient population already at increased risk for heart disease.

More recent questions about Avandia’s potential risks, as outlined in a New England Journal of Medicine article last week, have prompted the Congressional hearing. The author of that article, Dr. Steven E. Nissen, a heart specialist at the Cleveland Clinic, has also been called to testify.

In an interview this week, Glaxo’s president of United States operations, Chris Viehbacher, acknowledged that the company was looking for any records that would shed light on the accusations that it tried to suppress Dr. Buse’s criticisms. Mr. Viehbacher said that the events occurred years ago and that the employee who was thought to have been involved had left the company.

In that interview, Mr. Viehbacher repeated Glaxo’s ’s contention that Avandia’s risks were in line with those of other diabetes medications.

Yesterday, in a written statement issued by a spokeswoman, Mary Anne Rhyne, the company said: “Discussions occurred with Dr. John Buse in 1999 and 2000 regarding his views on Avandia, and we had a scientific disagreement that was later resolved. We regret if, at any time, Dr. Buse felt the conduct of any GSK employee was contrary to the spirit of open, scientific debate regarding his views on Avandia.” The statement also said that the company “does not condone any efforts by GSK’s staff to limit an individual’s ability to discuss or publish adverse events related to Avandia.”

Dr. Buse’s friend, Dr. Burant, said in a telephone interview, “I never wrote a prescription for Avandia because of the heavy-handed way Glaxo treated John Buse.”

When Glaxo sales representatives have asked him why he was not prescribing Avandia, “I was very straight with them,” Dr. Burant recalled.

“When they were giving John a hard time, I just told them that if this is the way you’re going to treat people who are doing their usual scientific review of the product, it’s not the kind of company I’m going to support,” Dr. Burant said. “I just told them flat-out.”

When Dr. Buse addressed his concerns about Avandia to the F.D.A. in early 2000, he was one of several physicians who had been outspoken supporters of Rezulin, a diabetes drug that was taken off the market that year after being linked to liver disease. After viewing early data on Avandia, he said, he concluded that it might be just as hazardous as Rezulin, if for different reasons.

Dr. Buse has served as a consultant to Parke-Davis, the maker of Rezulin, as well as Takeda Pharmaceutical and Eli Lilly, which make a competing oral diabetes medication called Actos. In the past, however, he had also been a consultant for SmithKline Beecham, which merged with Glaxo Wellcome in 2000 to become GlaxoSmithKline.

In a recent interview, Dr. Buse identified himself as a member of a “gang of three” — a group of endocrinologists who raised early questions about Avandia after evidence that the drug had negative effects on fats in the blood and the emergence of signals that it increased the risk of heart attack.

Another member of the “gang,” according to Dr. Buse, was Dr. Anne L. Peters, a diabetes expert who runs a clinic for Los Angeles County and is affiliated with the Keck School of Medicine at the University of Southern California.

In a recent interview, Dr. Peters said that she had previously received money from Glaxo as a speaker on behalf of Avandia, but had resigned because she was worried about the drug’s risks.

About five years ago, she said, she helped change the formulary — or list of preferred drugs — for Los Angeles County so that patients in her clinic would get prescriptions for Actos rather than Avandia.

“The Avandia people, it was just so surprising, they asked me what I wanted to keep Avandia on the formulary,” Dr. Peters said, recounting events that occurred sometime in the 2000-to-2002 period. “They asked me, “What can we give you that will have you keep it on the formulary?’ ”

Dr. Peters said that she asked the company to establish a database at the clinic that would track the outcomes of patients on both drugs.

When she asked for the database, which would have cost several thousand dollars, she said, a company representative replied: “That’s all you want? Other doctors ask to go to the Caribbean.”

Dr. Peters said that Glaxo representatives first asked her to write a proposal, then asked her to go to Philadelphia to meet with company officials before the database could be approved. She decided to purchase it herself.

“They wanted to give me everything but approve my request,” said Dr. Peters, who has served as an adviser or consultant to Takeda and Eli Lilly. During a recent interview, Dr. Buse said that although he was outspoken in criticism of Avandia in the early days, he now argues that the drug should remain on the market until Glaxo completes a large clinical trial, which the company says will answer questions about Avandia’s cardiovascular risk.

“A few times I was over the top, I just got carried away,” he said of his early warnings about Avandia. “The truth of the matter is, it was pretty much a statement of the facts with a little bit of imploring to not stick your head in the sand.”

Source | New York Times

By Stephanie Saul 

A large clinical study meant to test the heart safety of the diabetes treatment Avandia may be in jeopardy as a result of recent reports of the drug’s risks, according to an executive for its maker, GlaxoSmithKline.

Dr. Ronald L. Krall, the medical director for GlaxoSmithKline, said in a telephone interview yesterday that some of the 4,450 patients enrolled in the drug trial, called Record, have dropped out this week because of safety concerns about Avandia.

Dr. Krall said he did not yet know how many patients have withdrawn, but said Glaxo was now worried about whether it could complete the drug trial, which has been scheduled to run through next year. The company has been counting on a successful outcome from the study to dispel widespread concerns that Avandia carries a higher risk of heart attacks than other diabetes drugs.

Now, though, the independent research committees overseeing the study “are concerned about the ability of the study to continue” and are “considering what to do to prevent people from dropping out of the trial,” Dr. Krall said.

The safety concerns were ignited by an analysis published Monday in The New England Journal of Medicine suggesting that Avandia, used to treat Type 2 diabetes, carries an increased risk of heart attack, estimated at 43 percent, compared with other diabetes drugs or placebos.

In response to the medical journal article, the Food and Drug Administration issued a safety alert for Avandia and advised patients who take it to consult their doctors.

Avandia, which was approved by the F.D.A. in 1999, has been used by an estimated seven million people, six million of them in the United States.

Yesterday, the F.D.A. said its own recent analysis of more than 40 clinical studies of Avandia seemed to confirm the findings in The New England Journal of Medicine’s study, whose lead author was the influential Cleveland Clinic heart specialist Steven E. Nissen.

But an agency spokeswoman yesterday urged caution in interpreting those results.

“Dr. Nissen’s meta-analysis and the F.D.A.’s meta-analysis both arrived at a similar figure of 40 percent” the F.D.A. spokeswoman, Julie Zawisza, wrote in an e-mail message. “But this alone, is not conclusive of anything. What it does mean is that we need to try to reconcile the meta-analysis finding with clinical trial data that DO NOT show this increased risk.”

People with Type 2 diabetes are already at risk of heart attacks, facing a 20.2 percent chance of such an attack over seven years. One of the main reasons for controlling blood sugar in diabetic patients is to manage that risk.

But if Dr. Nissen’s analysis is an accurate reflection of Avandia’s increased risk, it appears the drug would do more cardiovascular harm than good. Diabetics taking Avandia would run a 28.9 percent chance of heart attack over the same seven-year period, according to his analysis.

GlaxoSmithKline’s own meta-analysis, submitted to the F.D.A. last August, showed a slightly lower 31 percent increased risk of heart attack.

A meta-analysis, which involves comparing the results of disparate clinical trials, is not considered as definitive as a uniform, controlled patient study of the sort GlaxoSmithKline has been counting on with its Record trial. Both GlaxoSmithKline and the F.D.A. have said that the meta-analyses indicating a heart risk with Avandia are contradicted by an interim look at Record, as well as data from an analysis of more than 20,000 patients enrolled in a UnitedHealthcare plan.

But neither GlaxoSmithKline nor the F.D.A. has released results from that interim assessment of Record, which was conducted within the last month.

The F.D.A. has received heavy criticism this week from Capitol Hill, where members of Congress have suggested that Avandia is shaping up as another Vioxx — a painkiller that became a bestseller, despite periodic questions about its safety, before being taken off the market in 2004 when its heart risks became irrefutable.

The F.D.A. plans to ask an advisory panel to review the Avandia data. Such panels, if they find safety risks with a drug, can recommend that the agency require a stronger warning label or ban the drug altogether.

Avandia is Glaxo’s second-largest selling drug, with more than $3 billion in sales last year worldwide. The company’s American depository receipts fell nearly $5 this week on news of safety concerns about the drug. The shares closed yesterday at $52.43.

GlaxoSmithKline has urged regulators and the public not to rush to judgment based on the New England Journal of Medicine article and has said that the Record trial, which began in 2000, would be a more reliable way to estimate the drug’s cardiovascular risks.

In that study, half of the 4,450 patients are being treated with Avandia in combination with another diabetes drug, while the others are being treated with two other drugs.

The trial is designed to determine whether patients taking Avandia are more likely to have a range of cardiovascular problems, including heart attack and stroke.

Federal regulators did not act on a recommendation from their safety reviewers several months ago that GlaxoSmithKline’s diabetes drug Avandia should carry the strongest possible caution about heart attacks, Senator Charles Grassley said Thursday in a statement.

Mr. Grassley, Republican of Iowa, said in a statement that some Food and Drug Administration staff members had concluded that prescribing information for the medicine should include a warning framed by a black box, the most serious type of alert.

Lawmakers have raised questions about the F.D.A.’s handling of Avandia since May 21, when an analysis released by The New England Journal of Medicine found patients on Avandia were 43 percent more likely to have a heart attack. Mr. Grassley has repeatedly criticized the agency for ignoring safety reviewers’ advice about other products, including Merck’s Vioxx painkiller, which was linked to increased heart risk.

‘’Over the last few days there have been countless articles about the popular diabetes drug Avandia,'’ Mr. Grassley said in the statement. ‘’For me, some of the most important questions that need to be answered here are what did F.D.A. know, when did it know it, and what did it do with the information.'’

The F.D.A. is still reviewing data on Avandia’s heart attack risks and says it has not reached conclusions. Glaxo said more reliable, longer-term studies found no greater risks than for other diabetes drugs. Avandia, approved in the United States in 1999, was the world’s top-selling diabetes pill and had $3 billion in sales last year.

The recommendation for Avandia was made by the division of drug risk evaluation within the agency’s Office of Surveillance and Epidemiology, which monitors safety, Mr. Grassley said. His statement did not say why the agency took no action on the advice.

The F.D.A. would not comment on Grassley’s statement about the heart attack warning because of ‘’ongoing regulatory matters,'’ an agency spokeswoman, Julie Zawisza, said in an e-mail message.

Source | New York Times

By Stephanie Saul and Gardiner Harris

GlaxoSmithKline has said that it was too early to draw conclusions that Avandia raises the risk of heart attacks in patients with Type 2 diabetes.

A leading diabetes doctor sent the Food and Drug Administration a letter seven years ago that warned of the heart risks of the drug Avandia. And in the next year, the F.D.A. reprimanded the drug’s maker for playing down safety concerns, according to documents from 2000 and 2001.

The documents, found in a reporter’s search of the F.D.A.’s database, indicate that the agency had been warned of safety concerns with the Type 2 diabetes treatment Avandia, and that the drug’s maker, GlaxoSmithKline, was seeking to minimize Avandia’s risks, before some of the same cardiovascular concerns were brought to public attention on Monday in an article and an editorial in The New England Journal of Medicine.

The F.D.A. has acknowledged that the company alerted the agency to concerns about a cardiovascular risk as early as 2005, based on the company’s analysis.

Glaxo has challenged the significance of the data cited in the medical journal. And, along with the F.D.A., the company has said that it was too soon to draw conclusions that Avandia raises a Type 2 diabetes patient’s risk of heart attacks. But the documents from 2000 and 2001 indicate that concerns about the drug’s safety are by no means new.

The letter in 2000 to the F.D.A. was written by Dr. John B. Buse, chief of endocrinology at the University of North Carolina in Chapel Hill, who is about to become the president of the American Diabetes Association. His letter from seven years ago sounded an alarm about Avandia, citing “a worrisome trend in cardiovascular deaths and severe adverse events” among patients using the drug.

In a telephone interview yesterday, Dr. Buse said that his opinion of Avandia had not changed since he wrote that letter. But he added yesterday that regulators should not rush to judgment by withdrawing Avandia from the market. Instead, he said, they should wait for the results of a larger study now being conducted by Glaxo that is meant to study the drug’s cardiovascular risks.

Avandia has been used by an estimated six million people in the United States since the agency approved it 1999. At the time, the company promoted Avandia as a safer alternative to a similar diabetes drug, Rezulin, which was withdrawn from the market in 2000 because it caused serious liver damage in some patients.

A Harvard professor who is a critic of the nation’s drug approval process, Dr. Jerome L. Avorn, yesterday drew parallels between the regulatory histories of Avandia and Rezulin, which had been a popular drug in its day.

With both drugs, “there were signals of a very dangerous side effect that were ignored,” he said. “Then massive marketing created a tremendous uptake of the drug.”

Last year, worldwide sales of Avandia exceeded $3 billion, making it one of Glaxo’s top-selling drugs.

The New England Journal of Medicine article, by the influential Cleveland Clinic heart specialist Dr. Steven E. Nissen, warned that the use of Avandia might significantly increase the risk of heart attacks. The extent of those possible risks had not been previously identified to the public.

Dr. Nissen has said that, according to his analysis, any person with Type 2 diabetes has a 20.2 percent chance of having a heart attack during a seven-year period. But with Avandia, he says, that seven-year risk would increase to 28.9 percent.

Glaxo has challenged the significance of Dr. Nissen’s analysis, which was developed by combining the results of more than 40 studies of the drug. Dr. Nissen has acknowledged that such studies, called meta-analyses, have limitations and are not as valid as controlled clinical trials.

As a result of Dr. Nissen’s article, the F.D.A. issued a safety advisory on Monday, suggesting that patients taking the drug consult their doctors. The agency also said that it planned to hold a meeting of outside advisers to review the drug’s safety. Among the options would be leaving it on the market with an even stronger warning — the drug’s label already alludes to the possibility of heart risks — or blocking its sale.

Even before Dr. Nissen had started working on his paper, Glaxo alerted the agency in 2005 and in 2006 that internal analyses had shown an increased risk of heart attacks. But the company also submitted a study of patients that it said showed Avandia was no riskier than other diabetes drugs. None of this analysis was specifically communicated to the public or doctors, although the company posted it on a Web site.

On Capitol Hill yesterday, agency officials explained their handling of Avandia to more than a dozen House and Senate staff members.

The briefing did little to settle concerns among some in Congress that the F.D.A. had been slow to alert patients about the drug’s potential risks to the heart, according to several staff members who were present and who spoke on condition of anonymity because the briefing was confidential.

Dr. Gerald J. Dal Pan, who leads the F.D.A.’s office of surveillance and epidemiology, told Congressional staff members that some in his office had disagreed with the agency’s actions regarding Avandia’s potential heart risk, several of those present said. Agency safety reviewers had been overruled by those in charge of drug approvals, staff members said.

No senators attended the meeting, but some commented afterward on the F.D.A.’s handling of Avandia.

“It’s unconscionable that F.D.A. found serious medical risks arising with Avandia and raised no red flags,” said Senator Max S. Baucus, Democrat of Montana and chairman of the Senate Finance Committee.

Senator Charles E. Grassley, Republican of Iowa, said that the agency’s inaction and internal dissension was further proof that legislation was needed to separate the agency’s approval and safety-assessment functions. Mr. Grassley had proposed such an amendment to a drug-safety bill that recently passed the Senate, but it lost by one vote.

The House will soon take up its version of F.D.A. legislation. Several staff members said that Mr. Grassley’s amendment has won new life.

In his letter to the agency, dated March 15, 2000, Dr. Buse was highly critical of the drug maker’s marketing of Avandia, accusing the company of “pervasive and systemic” efforts to play down the drug’s risks and overstate its benefits.

The F.D.A. was conducting its own investigation of Avandia marketing and found that company representatives were denying the existence of changes on the drug’s label that the F.D.A. had already ordered, which were meant to flag Avandia’s risks to the heart and liver.

The agency sent the drug maker a warning letter in July 2001, citing misleading statements made by company representatives at a recent meeting of the American Academy of Clinical Endocrinologists, where the agency had sent undercover investigators. The F.D.A’s letter criticized company posters displayed at the meeting, saying they did not carry adequate warnings.

It was the third time that the agency had chastised the company about its promotion of Avandia. Because of the repeated warnings, the agency demanded that the company send out a letter to doctors specifically warning them of the risks. The company subsequently sent out that “Dear Doctor” letter on Sept. 6, 2001.

In statement yesterday, a Glaxo spokeswoman, Mary Anne Rhyne, said that the company had “strongly disagreed” with the allegations in Dr. Buse’s March 2000 letter, “which we found to be unbalanced and unsubstantiated.”

“We took the time to meet and talk with Dr. Buse at length about his concerns,” Ms. Rhyne’s statement continued. “We explained our reasons for why we disagreed with his characterization of the cardiovascular safety profile of Avandia.”

As for the F.D.A.’s July 2001 warning letter, Ms. Rhyne said, “Action was taken at the time to ensure representatives of the company were accurately reflecting the label for the product in any commercial activity.”

Dr. Buse, as one of two incoming presidents of the diabetes association set to take office in September, has been widely quoted in media reports this week on Avandia. In that role, he has struck a neutral tone on the drug and urged patients not to panic. And yesterday, he said that the F.D.A. and doctors should wait for Glaxo’s study of Avandia’s cardiovascular effects.

But as a private doctor, Dr. Buse said that he does not generally prescribe Avandia to patients. He has been an outspoken critic of the drug in medical education meetings, some of them sponsored by Takeda and Eli Lilly, which jointly market a competing drug, Actos.

He was also an investigator in a study comparing Avandia with Actos, sponsored by Eli Lilly, that showed Actos had better effects on cholesterol than Avandia.

Dr. Buse said yesterday that he wrote the letter in 2000 in response to an F.D.A. petition filed by Dr. Sidney Wolfe, a consumer activist, who had asked the agency to place warning labels on Rezulin, Avandia and Actos.

Dr. Wolfe’s Health Research Group, a part of Public Citizen, has long warned patients not to use any of those drugs. At the time, the F.D.A. was considering removing Rezulin from the market, and Dr. Buse objected. Rezulin was made by Parke-Davis, a division of the Warner Lambert Company.

“The way I felt about it, after several years of clinical availability of Rezulin, we kind of understood the problems with it,” he said, “and we didn’t understand the problems of Actos and Avandia.”

Dr. Buse analyzed data submitted to the F.D.A. in support of Actos and Avandia and came to the conclusion that there was a “hint, a whisper” of cardiac-related deaths with Avandia as well as evidence of negative effects on cholesterol.

Referring to Avandia by its generic name, rosiglitazone, and to Rezulin as troglitazone, Dr. Buse wrote in the letter, “I do not believe that rosiglitazone will be proven safer than troglitazone in clinical use under current labeling of the two products.” He added: “In fact, rosiglitazone may be associated with less beneficial cardiac effects or even adverse cardiac outcomes.”

In the 2000 letter, Dr. Buse asked the agency to call for head-to-head studies of all the drugs.

Yesterday, he said, “I would say that in the last several years, there has not been a study that’s made me feel better about this.”

Source | New York Times

By Stephanie Saul

When GlaxoSmithKline settled a lawsuit three years ago with the State of New York over the antidepressant medication Paxil, the company agreed to take an unusual step: publicly disclosing the results of its clinical trials for Paxil and other drugs.

The company, which was criticized at the time for failing to publicize all pediatric trials of Paxil, not just the positive ones, made good on its promise. The first posting on a new Web site was about 65 studies involving its popular diabetes drug, Avandia.

This week, GlaxoSmithKline learned what that greater disclosure could mean.

A cardiologist at the Cleveland Clinic, Dr. Steven Nissen, stumbled onto the Glaxo Web site while researching Avandia last April. He and a colleague quickly analyzed the data, and on Monday, The New England Journal of Medicine released its finding that Avandia posed a heightened cardiac risk.

“It was a treasure trove,” Dr. Nissen said about the Web site.

GlaxoSmithKline has disputed the journal’s interpretation. Officials with the Food and Drug Administration said they were reviewing whether to take any action on Avandia.

Whatever the drug’s fate, the episode is likely to fuel efforts by some medical experts, including Dr. Nissen, to persuade lawmakers to require makers of drugs and medical devices to disclose study results publicly. Currently, producers are not required to do so, but Congress is considering legislating a requirement.

Many companies besides GlaxoSmithKline already post results from some studies or trials on their Web sites, or one operated by the Pharmaceutical Research and Manufacturers Association, a trade group in Washington.

Dr. Bruce M. Psaty, a cardiologist at the University of Washington, said that having such information can play a critical role, as the case of Avandia suggests, in spotting signals of a drug’s possible dangers.

Other experts have argued that the relative efficacy or cost of competing drugs can be compared only when all study results, rather simply those that a company chooses to publicize, are available.

Studies have found that the vast majority of drug and medical device studies are never published in medical journals.

“The more information, the better,” Dr. Psaty said.

Dr. Ronald L. Krall, chief medical officer for Glaxo, said his company sharply disputed the methodology of Dr. Nissen’s study, and a top F.D.A. official said that the agency had previously informed doctors about Avandia’s heart risks.

Dr. Krall said his company was aware when it created its database of study results a few years ago that it might lead to controversy. Other scientists might look at its data or choose to analyze it differently than company officials did, he said.

“We are committed to the principle of transparency,” Dr. Krall added. “But we knew that when starting this, by putting the data in the public, many things could happen, some of which could be trouble.”

Some experts also believe that releasing the results of hundreds of studies involving drugs or medical devices might create confusion and anxiety for patients who are typically not well prepared to understand the studies or to put them in context.

“I would be very concerned about wholesale posting of thousands of clinical trials leading to mass confusion,” said Dr. Steven Galson, the director for the Center for Drug Evaluation and Research at the F.D.A.

Roughly a decade ago, some experts raised concerns that doctors were not getting the full picture about a drug’s risks and benefits because they tended to hear or read about only those trials in which the medication showed a benefit.

Companies and researchers typically did not seek publication of studies that showed that a drug had little benefit or might even cause harm. In some cases, trials that were started and stopped before completion were not disclosed.

As a result, outside researchers could not learn what trials of a drug had been performed so they could put findings in context or compare studies of competing drugs.

That issue caught the public’s attention after it was disclosed that Glaxo had not publicized trials of Paxil in children in which the drug showed little, if any, benefit. The company was subsequently sued by Eliot Spitzer, who was then the attorney general and who is now the governor of New York. The drug maker, as part of the lawsuit’s settlement, created a public Web site for trial results. Glaxo was by no means the only drug company that came under scrutiny. In late 2004, a group of leading medical journals, including The New England Journal of Medicine, said that they would no longer publish articles about study results unless producers publicly registered the tests on Web sites like ClinicalTrials.gov, which is run by the National Library of Medicine.

As a result, the number of drug trials registered on that site has sharply increased, said Dr. Deborah Zarin, its director. (Currently, drug manufacturers are required to register trials of new drugs for serious or life-threatening conditions).

But even before the recent Avandia episode, advocates for greater study transparency like Dr. Nissen were pushing lawmakers to take the next step by requiring that producers of drugs and makers of devices not only register trials but also publicly disclose study findings.

“It is critical, but this raises the question of how many other drug safety issues are out there,” Dr. Nissen said. Recently, the Senate passed an F.D.A.-related bill that would set up a process for developing a mechanism that experts expect would result in a government-run database where companies and others would post the results of clinical trials. The House is currently considering a bill that has somewhat different provisions.

Dr. Alan Goldhammer, a senior executive at the Pharmaceutical Research and Manufacturers Association, said the organization supported the disclosure provision in the Senate bill that had passed.

He said the group, however, was concerned that some states may be trying to get ahead of the federal government on the issue; for instance, Maine recently passed a bill that mandates the release of study findings.

“We want to make sure it is done in a reasonable way,” Dr. Goldhammer said.

Recently, a report issued by the Institute of Medicine, a part of the National Academy of Sciences, recommended that the F.D.A. release all summaries of study data it had collected in the process of approving new drugs as well as all post-marketing studies of those products.

The F.D.A. rejected the first recommendation as overly burdensome and Dr. Galson, the director of the F.D.A.’s drug evaluation and research, said that the agency already released much of this information. “It is not that we are philosophically opposed to it, but the work would be enormous,” he said.

Even those supporting mandatory results disclosure acknowledge that finding uniform ways to disclose complex scientific information would prove difficult and time-consuming. For example, Dr. Zarin of ClinicalTrials.gov said that reviewing a study’s results to make sure that it was free of any biases interjected by researchers involved in a study or by its sponsor was a major undertaking.

Then, there is also the question of who the audience for such information should be — scientists, consumers or both?

Dr. Zarin said that there had been significant discussion among experts over the last year about that issue. Most have agreed that data is best understood by experts, a view that might not prove popular with patients.

Dr. Krall of Glaxo agreed, saying the drug maker had considered providing summaries of its studies for patients, but then dropped the efforts after deciding it would require making subjective decisions about trial results.

“There is not a uniform view about how to interpret results,” he said. “It is quite problematic to go that next step.”

Source | New York Times

By Stephanie Saul

The Food and Drug Administration is trying to estimate the number of heart attacks that may be linked to GlaxoSmithKline’s Avandia.

An article in a leading medical journal yesterday raised serious safety questions about the widely used diabetes pill Avandia and renewed skepticism about the vigilance of federal drug regulators.

The analysis, based on a review of more than 40 existing clinical studies involving nearly 28,000 patients, showed that Avandia significantly increased the risk of heart attacks, compared with other diabetes drugs or a placebo.

Both the study’s lead author and the editors of The New England Journal of Medicine, in which the article appeared, cautioned that the research method used left the findings open to interpretation. But they said the study nevertheless raised important concerns.

And the publication of the study on the journal’s Web site prompted the Food and Drug Administration to issue a public safety alert and advise users of the drug — an estimated million people in this country and two million worldwide — to consult their doctors about the potential cardiovascular risks.

The journal’s editor in chief, Dr. Jeffrey M. Drazen, said: “We view this as the best publicly available data on a very important question. It shows what we regard as a preliminary, but worrisome, signal about cardiovascular toxicity of this drug.”

The drug’s maker, GlaxoSmithKline, issued a news release defending Avandia’s safety and saying it “strongly disagrees” with the conclusions of the journal article, which it said was based on incomplete evidence.

Glaxo’s stock fell by nearly 8 percent on the news.

While the analysis took Wall Street and many doctors by surprise, Glaxo and the F.D.A. disclosed yesterday that they had known about the signs of potential cardiovascular risk since last August, when the company, on its own initiative, submitted a similar analysis to the agency. That disclosure prompted questions on Capitol Hill about why patients and doctors had not been informed earlier.

Explaining its delay, the F.D.A. said the significance of the studies had not been confirmed and in fact was contradicted by some other studies of the drug.

“We decided we needed to reanalyze the complex dataset ourselves to make a better informed decision,” Dr. Robert J. Meyer, a director of the agency’s office of drug evaluation, said in a news conference yesterday.

Dr. Meyer said that the agency was close to completing its analysis and would convene an advisory panel as soon as possible to review the drug. The F.D.A. is conducting an estimate of excess heart attacks that might be attributed to the drug, but Dr. Meyer said that the results were not final, declining to disclose the number. He noted that Avandia’s label already carries a warning of cardiovascular risks.

Meanwhile, the F.D.A. advised Avandia patients to check with their doctors.

“We’re expecting dozens if not hundreds of phone calls tomorrow,” said Dr. John B. Buse, chief of endocrinology at the University of North Carolina in Chapel Hill. “I’ve told our staff to tell people who call that this is not cause for panic. We can discuss it further at their next visit.”

But Dr. Buse, a president-elect of the American Diabetes Association, said he would not be surprised if some doctors ultimately switched patients to an alternative drug unless additional details were released supporting Avandia’s safety.

The New England Journal of Medicine posted the paper on its Web site, ahead of its planned print publication on June 14. Early Web postings are made by the journal’s editors in matters that they consider to have public health importance.

The study was not supposed to be released until 5 p.m. yesterday, after the closing bell on Wall Street, but it was inadvertently published yesterday morning by two wire services. The company’s stock began falling almost immediately and was down more than 8 percent by midafternoon, before finishing down 7.85 percent, at $53.18.

The research method employed by the lead author, Dr. Steven E. Nissen of the Cleveland Clinic, was a so-called meta-analysis, which combines the data of various studies. Such analyses, generally used to develop hypotheses, are seen as less reliable than uniform controlled studies.

In an interview, Dr. Nissen said that the average diabetic has a 20.2 percent risk of a heart attack over a seven-year period. A diabetic taking Avandia has a 28.9 percent risk during that same seven-year period, according to his analysis.

“It’s a huge risk,” he said, estimating that “tens of thousands of people” had heart attacks as a result of taking the drug.

An editorial that accompanied the article questioned why doctors would continue to prescribe Avandia, which is known generically as rosiglitazone. But the editorial cautioned patients not to stop taking the medication without discussing it with their doctors.

In its news release, Glaxo defended Avandia’s safety.

“The totality of the data show that Avandia has a comparable cardiovascular profile to other oral antidiabetic medicines,” the release said. “GSK stands firmly behind the safety of Avandia when used appropriately, and we believe its significant benefits continue to outweigh any treatment risks.”

In a conference call with reporters yesterday, the company’s chief medical officer, Dr. Ronald L. Krall, said that Glaxo had submitted similar data to the F.D.A. last August after noticing a signal of increased cardiovascular risk. Its data indicated a 31 percent increased risk, based on a similar meta-analysis. That information was also posted on the company’s Web site last year, Glaxo said.

But the company submitted its analysis along with another study that supported the drug’s safety — a look at 30,000 patients taking Avandia and other diabetes drugs enrolled in an unidentified insurer’s managed care plan. And the company also said that a drug safety monitoring committee overseeing a continuing study of the drug’s cardiovascular risks had not raised any red flags.

Avandia, a pill on the market since 1999, is used for the treatment of Type 2, or adult-onset, diabetes. It is sold alone as Avandia and in combination with other drugs as Avandamet and Avandryl. With $3 billion in worldwide sales last year, it was Glaxo’s second-biggest product after the asthma inhalant Advair.

Patients who are newly discovered to have Type 2 diabetes generally receive another oral drug, metformin, as the first-line treatment, with Avandia among several medications recommended when metformin alone no longer works. If those treatments fail, patients typically move to insulin injections.

Some doctors contend that another drug that works by a similar mechanism to Avandia — Actos, made by the Takeda Pharmaceutical Company and jointly marketed by Eli Lilly — has been shown in studies to have a superior cardiovascular risk profile.

The journal editorial, by Dr. Bruce M. Psaty of the University of Washington and Dr. Curt D. Furberg of Wake Forest University, said that they could see no reason doctors would prescribe Avandia, given the alternative treatments available.

“In view of the potential cardiovascular risks,” the editorial said, “and in the absence of evidence of other related advantages, except for laboratory measures of glycemic control, the rationale for prescribing rosiglitazone at this time is unclear.” Glycemic refers to blood sugar.

The editorial said that problems with Avandia had once again spotlighted flaws in the nation’s drug approval and monitoring system. They asserted that those problems had not been fully addressed by legislation recently passed by the Senate that is meant to strengthen the agency’s powers. Both Dr. Psaty and Dr. Furberg have been critical of the F.D.A.’s drug approval process in the past.

On Capitol Hill, several lawmakers questioned whether Avandia could be another Vioxx — a painkiller that Merck pulled off the market in 2004 after it was shown to cause heart attacks in some patients.

Rep. John D. Dingell, the Michigan Democrat who is chairman of the House Energy and Commerce Committee, said the agency’s handling of questions about Avandia might reflect dangerous shortcomings in its drug safety monitoring. Those questions, he said, would figure in his committee’s efforts to force the agency to be a tougher regulator.

“We learned from an F.D.A. briefing that the agency has known about this problem for at least eight months and perhaps even longer,” Mr. Dingell said in a prepared statement yesterday. “What we don’t know is why diabetics and their doctors haven’t been notified of the substantial risk to the heart from a drug prescribed to protect the cardiovascular system.”

Henry A. Waxman, the California Democrat who is chairman of the Committee on Oversight and Government Reform, said yesterday that he had started an investigation of Avandia and would call Glaxo officials and Dr. Andrew C. von Eschenbach, the F.D.A. commissioner, to testify at a hearing on June 6.

The finding — that Avandia raises the risk of heart attack by 43 percent — was based on a review of 44 studies of the drug. The review was conducted by Dr. Nissen and Kathy Wolski of the Cleveland Clinic, where Dr. Nissen is the chief of cardiovascular medicine.

Dr. Nissen, who had been among the first doctors to raise questions about the cardiovascular safety of Vioxx, first publicly raised concerns about Avandia in a letter published last December in the British medical journal Lancet.

Dr. Nissen’s letter noted increased cardiovascular problems in a 5,000-patient clinical study, called Dream. Glaxo had sponsored the Dream trial in an effort to expand the product beyond a treatment for diabetes by using it to prevent the disease.

In the Dream trial, intended to determine if Avandia could prevent diabetes, patients taking Avandia had 66 percent more heart attacks, 39 percent more strokes and 20 percent more deaths from cardiovascular-related problems compared with a placebo. That outcome, Dr. Nissen wrote, “virtually precludes the possibility of an overall benefit and suggest an unexpected mechanism for harm.”

Both Avandia and Actos, the Takeda drug, are members of a class of compounds with a troubled history. One drug in the group, Rezulin , was withdrawn in 2000 because it caused liver problems.

Source | The Los Angeles Times

By Thomas H. Maugh II

December 5, 2006

The first major head-to-head study comparing the newer diabetes drug Avandia with older medicines metformin and glyburide shows that Avandia provides better glucose control than metformin but carries more serious side effects and a higher cost, researchers said Monday.

For newly diagnosed type 2 diabetics, “metformin is still the first drug of choice,” said Dr. Steven Kahn of the University of Washington and the Puget Sound Veterans Affairs Health Care System, who led the study.

Both Avandia and metformin — a generic also sold under the brand names Glucophage and Fortamet — performed substantially better than glyburide, however.

“People who use glyburide will have to think about changing drugs,” Kahn said.

The results of the study were reported Monday at the 19th World Diabetes Congress in Cape Town, South Africa, and will be published Thursday in the New England Journal of Medicine.

The study was funded by Avandia’s manufacturer, GlaxoSmithKline. Kahn reported receiving consulting fees, grants and lecture fees from the company.

The study enrolled 4,360 newly diagnosed diabetics who never had received drug therapy for the disorder. The patients were divided randomly into three groups, each of which received one of the drugs. The main goal of the study was to determine the time until the therapy stopped working and the patients required the addition of a second drug for glucose control.

At the end of five years, 15 percent of patients receiving Avandia needed a second drug, compared with 21 percent of those receiving metformin and 32 percent of those receiving glyburide.

But 62 patients taking Avandia developed a heart problem, compared with 58 taking metformin and 41 taking glyburide.

Source | Bloomberg

January 5, 2006 

GlaxoSmithKline Plc’s Avandia diabetes drug has been linked to swelling in the back of the eye, which can reduce vision, U.S. regulators said.

The Food and Drug Administration sent an e-mail notice today about the complication, known as macular edema, to about 54,000 subscribers of MedWatch, the agency’s alert system. The FDA also forwarded a letter that Glaxo sent last month to doctors, saying the company received reports of both new and worsening cases of swelling in people taking Avandia.

People with diabetes already are at higher risk of eye complications because of the disorder, which results in the blood vessels at the back of the eye, or retina, becoming leaky and swelling. European regulators last month also said they are reviewing macular edema reports in people using Avandia and Takeda Pharmaceutical Co.’s similar Actos drug.

“Even though the reported incidence is very rare, we felt a need to alert doctors,'’ said Bernadette King, a Glaxo spokeswoman, in a telephone interview. She said the cause of the swelling is not clear.

The swelling can cause blurred vision and changes in how color and darkness are perceived, the Glaxo letter said.

There is less than one report of macular edema for every 10,000 patients estimated to have taken Avandia, King said. The FDA has said that complications often are not reported to the agency or doctors, making it difficult to get a true estimate how often injuries occur in people taking specific drugs.

4 Million Users

About 4 million people have used Avandia in the U.S., King said. Avandia and Actos are used by people with Type 2 diabetes, the most common form, in which the body fails to produce enough insulin to keep blood sugar well controlled. The medicines make the body more sensitive to the insulin it has available.

Third-quarter Avandia sales rose 29 percent to 299 pounds ($525 million).

London-based Glaxo is the world’s second-largest drugmaker, behind Pfizer Inc. American depositary receipts of Glaxo were unchanged at $51.95 as of 3:02 p.m. in New York Stock Exchange composite trading.

Calls to Takeda’s U.S. offices in Lincolnshire, Illinois, were not immediately returned.

Source | Market Watch

By Brickates Kennedy

January 5, 2006

GlaxoSmithKline has issued a warning that its diabetes drug Avandia can cause serious eye problems in some users.

According to a statement released by the U.S. Food and Drug Administration, Avandia may cause the worsening of macular edema, an eye condition that can lead to blurred vision and even blindness. The condition is associated with diabetes.

Avandia, known generically as rosiglitazone, also is marketed under the name Avandamet. The drug is used to treat type 2 diabetes, the most common form of the disease.

Over 6 million patients have taken the drug since it’s been on the market, according to Glaxo.

In a letter sent in December, Glaxo advised healthcare professionals that in rare cases, rosiglitazone has been associated with the worsening of macular edema, especially in patients who had edema, or swelling caused by excess bodily fluid, in their extremities.

Glaxo added that in some cases the macular edema improved or disappeared after rosiglitazone was discontinued.