A British Medical Journal (BMJ) probe just learned that, in July, the UK Commission on Human Medicines told the drug regulator in the UK—the Medicines and Healthcare products Regulatory Agency (MHRA)—to withdraw the drug because its benefits are outweighed by its risks, said the Journal.
The probe also revealed that members of a European panel reviewing Avandia, before it received approval in Europe in 2000, questioned the drug’s longer-term risks and benefits as well as GlaxoSmithKline PLC’s data indicating that the medication does not lead to increased cardiac issues versus other diabetes medications said the Journal.
Now, the European Medicines Agency is looking at the diabetes medication and will follow with a recommendation on whether the drug should remain or be taken off of the market, said the Journal, which noted that, in the United States, the US Food and Drug Administration (FDA) is making a similar decision following an advisory panel vote this summer to keep Avandia on the market with additional warnings.
As expected, GlaxoSmithKline PLC refuted BMJ’s assertions, arguing that it conducted broad research with over 50,000 patients, saying: "We have rigorously shared our data relating to the cardiovascular safety of Avandia in a timely and transparent manner and have made extensive efforts to publish our clinical trial findings in peer review journals, at scientific meetings and via our own clinical trials website," quoted the Journal.
Regardless, Avandia has long been surrounded with debate concerning cardiovascular risks. Avandia is in a class of medications called thizolidinediones, which reduce body tissue insulin resistance and adjust cholesterol levels and are considered some of the strongest medications for treatment of Type 2 diabetes, noted the LA Times, previously.
A 2007 study with over 200,000 Medicare patients pointed to Avandia’s increased heart attack risks, “cardiovascular disease, stroke, and death by 30-to-40 percent,” versus other, older diabetes medications, said the LA Times. The study prompted stronger FDA label warnings, with even stronger warnings following more reports of increased risks with Avandia, said the LA Times.
It was then that the FDA panel concluded that the benefits of Avandia outweighed its risks and that it should remain on the market, but that no more patients are to be enrolled in a prospective study comparing the two drugs directly.
We previously wrote that another study linked Avandia to an increased risk of fractures. The research, which appeared in the Journal of Clinical Endocrinology & Metabolism, found Avandia increased the risk of fractures in postmenopausal women with Type 2 diabetes, as well as in men prescribed either drug with a loop diuretic. Many of the people included in the study suffered lower limb, arm, and leg fractures.
Avandia has long been surrounded with debate concerning cardiovascular risks, while Actos was believed a safer alternative, causing sales of Actos to increase and Avandia seeing significant declines, explained the LA Times. Now, emerging research suggest that similar heart risks are being seen in both drugs, said the LA Times, which explained that both are part of the class called thizolidinediones. Thizolidinediones reduce body tissue insulin resistance and adjust cholesterol levels and are considered some of the strongest medications for treatment of Type 2 diabetes, noted the LA Times.
A 2007 study with over 200,000 Medicare patients pointed to Avandia’s (generic: rosiglitazone) increased heart attack risks, “cardiovascular disease, stroke, and death by 30-to-40 percent,” versus other, older diabetes medications, said the LA Times. That study indicated that the risk was not seen with Actos (generic: pioglitazone), added the LA Times.
The study prompted stronger U.S. Food and Drug Administration (FDA) label warnings, with even stronger warnings following more reports of increased risks with Avandia, said the LA Times; an FDA panel found the benefits of Avandia outweighed its risks and that it should remain on the market, but that no more patients be enrolled in a prospective study comparing the two drugs directly.
The team, led by Debra Wertz—an outcomes research manager at HealthCore Inc., a Wellpoint Inc. research subsidiary—analyzed 28,938 patient records for people who took either medication from 2001 to 2005, obtaining company data, said the LA Times. Death information was derived from the National Death Index, which is managed by the National Center for Health Statistics. The research appears in the journal Circulation: Cardiovascular Quality and Outcomes.
When accounting age gender, and prior heart disease, about four percent per group either suffered a heart attack or heart failure or died, said the LA Times. The figures break down to 96 Avandia, versus 121 Actos patients suffering a heart attack and 265 Avandia and 243 Actos patients suffering from heart failure, said the LA Times; 217 in each group died.
"What distinguishes this latest study from other claims-based analyses is its analysis of death records, which include out-of-hospital deaths," Wertz said in a statement, quoted the LA Times, and that the study followed younger patients longer than in prior studies. Earlier studies did not include stroke data, which could affect outcomes.
We previously wrote that another study linked Avandia and Actos to an increased risk of fractures. The research appeared in the Journal of Clinical Endocrinology & Metabolism and found that the drugs increased the risk of fractures in postmenopausal women with Type 2 diabetes, as well as in men prescribed either drug with a loop diuretic.
Women over 50 who had broken bones were 71 percent likelier to have been prescribed a thiazolidinedione. In men, the increased risk (more than triple) was seen among those taking both a thiazolidinedione and loop diuretics, like Lasix, but not in just one or the other. The researchers pointed out that loop diuretics have been linked with bone density decreases. In both genders, the fracture risk went up the longer a person was on the medication. According to the researchers, the fractures seen in the study weren’t just the spine and hip fractures most often seen in people with osteoporosis. Many of the people included in the study suffered lower limb, arm, and leg fractures.
As we've reported previously, that advisory panel voted 20-12 to recommend that Avandia be allowed to stay on the market. However, 10 panel members voted that its sales should be restricted and that warnings on its label regarding heart risks be strengthened.
Since November 2007, Avandia’s label has included a black box warning – the Food & Drug Administration's (FDA) strongest safety alert – detailing its association with myocardial ischemia. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack. Since the addition of the black box, evidence linking Avandia to an increased risk of heart attacks has continued to accumulate.
According to the Times, Glaxo sent the memo, dated July 29, at the behest of the FDA. It discussed the TIDE trial, an Avandia study funded by the drug maker. After the advisory panel meeting, the FDA ordered Glaxo to stop enrolling patients in TIDE to give the agency time to study new evidence of Avandia’s risks. Glaxo was also ordered to update physicians and ethics oversight boards involved in the trial regarding all new safety information about the drug, thus the July 29 memo.
TIDE compared the safety of Avandia to another drug, Actos, which has not been associated with as many safety concerns as Glaxo's drug. As we've reported previously, scientists inside and outside the FDA have opposed TIDE, saying it is unethical to compare Avandia, with its known cardiac risks, with a seemingly safer alternative.
According to The New York Times, none of the arguments presented at last month's advisory panel meeting were included in the memo. Dr. David Graham, an FDA medical who argued against the study during that meeting told the Times that Glaxo's memo is "biased, misleading and not truthful."
Several members of the advisory committee also complained that the company’s letter was biased, the Times said.
Dr. Steven Nissen, a Cleveland Clinic cardiologist who made a presentation before the committee arguing for Avandia’s withdrawal, said that GlaxoSmithKline’s letter failed to mention that the committee concluded that Avandia carries a higher risk of heart attack than Actos.
“Since the TIDE trial compares these two alternative therapies, this omission does not meet any reasonable ethical standards,” Dr. Nissen told the Times.
Since November 2007, Avandia’s label has included a black box warning – the FDA’s strongest safety alert – detailing its association with myocardial ischemia. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack. Since the addition of the black box, evidence linking Avandia to an increased risk of heart attacks has continued to accumulate.
Earlier this summer, an FDA advisory panel voted 20-12 to recommend that Avandia be allowed to stay on the market. However, 10 panel members voted that its sales should be restricted and that warnings on its label regarding heart risks be strengthened.
According to the TIME Magazine report, prior to its approval, Glaxo defended Avandia to the FDA, even as a debate over its heart risks raged within the company. After the drug came on the market in 1999, two analysis produced by Glaxo in 2005 and 2006 found an 29 percent and 31 percent increase in heart side effects among patients taking the drug. The company did not provided the FDA with the results of those analysis until May 2006. The agency did not make them public.
The TIME report goes on:
"It was seven years after the drug was approved, and the dangers of Avandia had still not been made sufficiently clear to the public. The FDA was sitting on the new analyses, and GSK (Glaxo), the FDA discovered during an investigation by its inspections unit in the fall of 2007, had failed to report clinical data and other material from 15 tests of Avandia by the end of 2006, according to a March 25, 2008, warning letter to the company. With the company and the FDA maintaining tight control over the full database of information on Avandia's effectiveness and safety, there was little independent scientists could do to assuage their growing concerns about the drug."
Deputy FDA commissioner Dr. Joshua Sharfstein told TIME that the agency is trying to if Glaxo's failure to fully inform the agency of Avandia's heart risks broke the law.
However, the report doesn't hold the FDA blameless in the Avandia debacle. After all, it withheld the 2005 and 2006 Glaxo Avandia studies from the public. The TIME report suggests that the FDA is too cozy with the industry it regulates, something that allowed Glaxo "to perpetuate the uncertainty about (Avandia's) safety rather than clarify it."
Avandia and Actos both belong to class of diabetes drugs known as thiazolidinediones. This new study used data from a large study known as TRIAD, identifying 786 cases of fractures and comparing them to 2,657 patients who had diabetes but no fracture history. Of the 786 patients with fractures, only 54 were women less than 50 years old, while 457 were women 50 and older and 275 were men.
The researchers looked at prescriptions participants had filled during the 90 days prior to the fracture date or 90 days before a designated study date for those without fractures.
Women over 50 who had broken bones were 71 percent more likely to have been prescribed a thiazolidinedione. In men, the increased risk (more than triple) was seen among those taking both a thiazolidinedione and loop diuretics like Lasix, but not in just one or the other. The researchers pointed out that loop diuretics have been linked with bone density decreases.
In both genders, the fracture risk went up the longer a person was on the medication.
According to the researchers, the fractures seen in the study weren't just the spine and hip fractures most often seen in people with osteoporosis. Many of the people included in the study suffered lower limb, arm, and leg fractures.
The study authors do point out that it does have some limitations, including that it a was randomized controlled study. Also, the TRIAD study they utilized was not designed to look at this fracture risk. The researchers called for larger, randomized trials.
We previously reported that it was later discovered that one member of that panel, Endocrinologist David Capuzzi of Philadelphia, was a paid speaker for GlaxoSmithKline, the maker of Avandia. Glaxo’s website shows that he received $3,750 from the company as a speaker between April 2009 and March 2010. A spokesperson for the company also told The Wall Street Journal that he was paid $8,000 in speaking fees from the company before that period and an additional $3,000 in the second quarter of this year.
Dr. Capuzzi confirmed the relationship to the Journal, but said he never gave talks about Avandia. Since then, however, Glaxo has said Dr. Capuzzi once served on an advisory board on Avandia and received $750 for doing so, according to the Journal.
Dr. Capuzzi defended Avandia during the two-day meeting, and was among the three members who voted to allow the drug to stay on the market with no additional warnings or restrictions.
Dr. Capuzzi told the Journal he informed the FDA of his payments from Glaxo prior to the advisory panel meeting. However, others on the advisory panel were not made aware of them.
On Friday, the FDA issued a statement on the matter, saying "The FDA has completed its fact-gathering process and has referred the Dr. Capuzzi matter to the HHS Office of Inspector General." According to the Journal, the agency did not release any other information.
Since November 2007, Avandia’s label has included a black box warning – the FDA’s strongest safety alert – detailing its association with myocardial ischemia. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack. Since the addition of the black box, evidence linking Avandia to an increased risk of heart attacks has continued to accumulate.
The FDA is not required to follow the recommendations of such panels, but does so in most cases. However, the lack of unity among panel members in the case of Avandia makes it hard to predict what the agency will do.
Since 2000, the EMEA has contra-indicated Avandia for anyone with heart failure or a history of heart failure. Since then, use of Avandia, as well as Avandame (Avandia in combination with metformin) and Avaglim (Avandia in combination with glimepiride), has been further restricted several times by the EMA by new warnings and contra-indications on their use in patients with heart problems.
The EMEA initiated a new review of Avandia earlier this month on the request of the European Commission following publication of studies questioning the cardiovascular safety of the medicine.
In the US, a Food & Drug Administration (FDA) advisory panel took up Avandia last week. Since 2007, Avandia has borne a black box label – the FDA’s most urgent safety warning – regarding its heart attack risks. An FDA advisory panel met last week to consider further restrictions on the controversial diabetes drug.
According to an earlier report in The New York Times, 12 of the panel’s 33 members voted that Avandia should be withdrawn; 10 voted that its sales should be restricted and the warnings on its label enhanced; 7 voted only to support enhanced warnings on the drug’s label; and 3 voted that the drug should continue to be sold with its present warnings unchanged.
The FDA is not required to follow the recommendations of such panels, but does so in most cases. However, the lack of unity among panel members in the case of Avandia makes it hard to predict what the agency will do, The Times said.
Yesterday, we reported that the FDA had ordered GlaxoSmithKline to halt enrollment in a study called TIDE (Thiazolidinedione Intervention With Vitamin D Evaluation) over safety concerns. TIDE was designed to compare the long-term effects of Avandia with another diabetes drug called Actos.
Actos has not raised as many safety concerns as Avandia. For some time now, scientists inside and outside the FDA have opposed TIDE, saying it is unethical to compare Avandia, with its known cardiac risks, with a seemingly safer alternative.
According to The Boston Globe, the FDA said it halted recruitment in TIDE because it needs time to study new evidence of the Avandia’s risks. The agency is demanding that Glaxo update physicians and ethics oversight boards involved in the trial regarding all new safety information about the drug. The agency did not say how long the enrollment halt would last.
The decision by the Food & Drug Administration (FDA) comes a week after one of its advisory panels voted 20-12 to recommend that Avandia be allowed to stay on the market. However, 10 panel members voted that its sales should be restricted and that warnings on its label regarding heart risks be strengthened. Nineteen panelists said TIDE should continue, and 11 opposed it.
Since November 2007, Avandia's label has included a black box warning - the FDA's strongest safety alert – detailing its association with myocardial ischemia. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack. Since the addition of the black box, evidence linking Avandia to an increased risk of heart attacks has continued to accumulate.
Actos has not raised as many safety concerns as Avandia. For some time now, scientists inside and outside the FDA have opposed TIDE, saying it is unethical to compare Avandia, with its known cardiac risks, with a seemingly safer alternative.
According to The Boston Globe, the FDA said it halted recruitment in TIDE because it needs time to study new evidence of the Avandia’s risks. The agency is demanding that Glaxo update physicians and ethics oversight boards involved in the trial regarding all new safety information about the drug. The agency did not say how long the enrollment halt would last.
The people already participating in the trial will be allowed to continue with it, the FDA said.
As we reported in May, TIDE was already having trouble recruiting new members. At that time, two research sites had dropped out of TIDE because of enrollment issues. An official with one of them – Wake Forest University Baptist Medical Center in North Carolina – told The Wall Street Journal that it was “not succeeding in recruiting anybody.”
In April, Glaxo opened up a dozen research sites overseas, some in developing countries including Pakistan, India, Mexico, Latvia and Colombia.
According to The Boston Globe, TIDE called for the enrollment of 16,000 patients, but so far, only 1,120 patients had been recruited worldwide. Recently, India had suspended all participation in the trial.
A Food & Drug Administration (FDA) advisory panel took up Avandia last week. Since 2007, Avandia has borne a black box label - the FDA's most urgent safety warning - regarding its heart attack risks. An FDA advisory panel met last week to consider further restrictions on the controversial diabetes drug.
According to an earlier report in The New York Times, 12 of the panel’s 33 members voted that Avandia should be withdrawn; 10 voted that its sales should be restricted and the warnings on its label enhanced; 7 voted only to support enhanced warnings on the drug’s label; and 3 voted that the drug should continue to be sold with its present warnings unchanged.
The FDA is not required to follow the recommendations of such panels, but does so in most cases. However, the lack of unity among panel members in the case of Avandia makes it hard to predict what the agency will do, The Times said.
According to The Wall Street Journal, Dr. Capuzzi defended Avandia during the two-day meeting, and was among the three members who voted to allow the drug to stay on the market with no additional warnings or restrictions.
Glaxo's website shows that he received $3,750 from the company as a speaker between April 2009 and March 2010. A spokesperson for the company also told the Journal that he was paid $8,000 in speaking fees from the company before that period and an additional $3,000 in the second quarter of this year. No one else on the panel received any money from Glaxo during that same time frame.
According to the Journal, Dr. Capuzzi has confirmed his relationship with Avandia's maker. While he said he has given talks on another Glaxo drug called Lovaza, Dr. Capuzzi said he has never spoken on Avandia.
Dr. Capuzzi also said he told the FDA about his payments from Glaxo. But apparently, this was not made known to other members of the advisory panel. One panel member, Cardiologist Arthur Moss of the University of Rochester Medical Center in New York, told the Journal he would have liked to have known about it, and was "surprised" the panel wasn't told. Dr. Moss also voted with Dr. Capuzzi to allow Avandia to stay on the market without further warnings or restrictions.
According to the Journal, the FDA is looking into whether there was disclosure to the agency and, if so, why it wasn't conveyed to the committee.
The votes came at the end of a two-day meeting where GlaxoSmithKline, Avandia's maker faced tough criticism for the way it handled the drug and its cardiovascular risks.
According to The New York Times, 12 of the panel's 33 members voted that Avandia should be withdrawn; 10 voted that its sales should be restricted and the warnings on its label enhanced; 7 voted only to support enhanced warnings on the drug’s label; and 3 voted that the drug should continue to be sold with its present warnings unchanged.
The FDA is not required to follow the recommendations of such panels, but does so in most cases. However, the lack of unity among panel members in the case of Avandia makes it hard to predict what the agency will do, The Times said.
Avandia was the biggest selling diabetes drug in the world, until 2007 when a Cleveland Clinic study raised questions about its heart risks. The study, conducted by Dr. Stephen Nissan, showed patients taking Avandia had a 43-percent higher risk of having a heart attack. The drug's label has borne a black box warning - the FDA's most serious safety alert - regarding its heart attack risk since November of that year.
Last month, Nissan released a follow-up to that study, which found an increased heart attack risk of 28 percent. The update was among the evidence presented to the FDA advisory panel.
Also considered by the panel was a study conducted by Dr. David Graham, an FDA researcher. That study, which involved 227,500 Medicare patients, found that those who took Avandia were 27 percent more likely to suffer a stroke, 25 percent more likely to develop heart failure and 14 percent more likely to die compared with those who took another drug called Actos.
An Avandia study called RECORD, which was funded by Glaxo and used to tout the drug's safety, was sharply criticized during the two-day meeting, with Graham telling the panel: "You can’t trust it, and if we do trust it, we’re engaging in the willing suspension of disbelief." He also characterized RECORD as "garbage".
Last week, a memo in a 756-page briefing document posted to the FDA Web site characterized RECORD as “inadequately designed and conducted to provide any reassurance about the CV (cardiovascular safety) of rosiglitazone.” The memo further states that the RECORD results “confirm and extend the recognized concerns regarding heart failure” and possibly suggest an increased risk for heart attacks.
According to an earlier New York Times report, the FDA review of RECORD found at least a dozen instances in which patients taking Avandia suffered serious heart problems that were not counted in the trial’s tally of adverse events, mistakes that further obscured Avandia’s heart risks.
According to CNN, a Glaxo-funded study called RECORD was highly criticized by Dr. David Graham, an FDA researcher. "You can't trust it, and if we do trust it, we're engaging in the willing suspension of disbelief," he said of RECORD.
RECORD, which was released in 2009, did not find increased heart risks, as other Avandia studies have. It was touted by Glaxo as evidence of the drug's safety.
Graham said the RECORD study would have been dismissed as "garbage" if it had been used to seek the drug's original approval.
Graham's own recently-released Avandia study of 227,500 Medicare patients found that those who took the controversial diabetes drug were 27 percent more likely to suffer a stroke, 25 percent more likely to develop heart failure and 14 percent more likely to die compared with those who took another drug called Actos.
Graham is only the latest Avandia critic to tear into RECORD. Last week, a memo in a 756-page briefing document posted to the FDA Web site characterized RECORD as “inadequately designed and conducted to provide any reassurance about the CV (cardiovasular safety) of rosiglitazone.” The memo further states that the RECORD results “confirm and extend the recognized concerns regarding heart failure” and possibly suggest an increased risk for heart attacks.
According to a New York Times report, the FDA review of RECORD found at least a dozen instances in which patients taking Avandia suffered serious heart problems that were not counted in the trial’s tally of adverse events, mistakes that further obscured Avandia’s heart risks.
Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning – the FDA’s strongest safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack.
Last week, Dr. Stephen Nissan, who conducted that study, released a follow-up to it. The update looked at 56 clinical studies involving 35,500 patients, including RECORD, and found an increased heart attack risk of 28 percent. Without RECORD, the risk of heart attacks rose to 39 percent, according to study.
That update is also among the evidence being considered by the FDA advisory panel. Dr. Nissan, who was also present at the meeting, criticized Glaxo for failing to run any adequate trials of its safety.
"We have a drug that has been on the market for 11 years. The company had every opportunity to do large-outcome trials, adequately powered and properly run, to answer this question. They didn't do it," Nissan said.
Today, the advisory panel could vote to recommend that Avandia be removed from the market. While the FDA isn't required to follow advisory panel recommendations, it usually does so.
That study, completed in 1999, showed Avandia held no benefit over Actos, and could be more dangerous to the heart. However, according to the Times, SmithKline Beecham did not post the results on its Web site or submit them to federal drug regulators, as is required in most cases by law.
“This was done for the U.S. business, way under the radar,” Dr. Martin I. Freed, a SmithKline executive, wrote in an e-mail message dated March 29, 2001, about the study results that was obtained by The Times. “Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK.”
Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning – the Food & Drug Administration's (FDA) strongest safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack.
Today, an FDA advisory panel is taking up Avandia, and will be asked to make a recommendation on whether or not it should stay on the market. Last week, we reported that in anticipation of that meeting, FDA staff had posted a 756-page briefing document to the agency's Web site that is critical of the drug. One of the documents included in the posting is a memo highly critical of the so-called RECORD trial, another Avandia study paid for by GlaxoSmithKline. RECORD, which involved 4,500 patients, compared Avandia to patients receiving other diabetes drugs, metformin and sulfonylurea, for an average of 5.5 years. Released in 2009, RECORD did not show an increased heart-attack risk that has been seen in some other Avandia studies, and was used by Glaxo to tout its safety.
The memo included in the FDA briefing was written by Thomas Marciniak, a medical team leader in FDA’s division of cardiovascular and renal products. He writes that RECORD was “inadequately designed and conducted to provide any reassurance about the CV (cardiovasular safety) of rosiglitazone.” He goes on to write that the RECORD results “confirm and extend the recognized concerns regarding heart failure” and possibly suggest an increased risk for heart attacks.
According to today's New York Times report, the FDA review of RECORD found at least a dozen instances in which patients taking Avandia suffered serious heart problems that were not counted in the trial’s tally of adverse events, mistakes that further obscured Avandia’s heart risks.
Recently, we wrote that, based on a 756-page briefing posted on its Website, Avandia has continued to raise safety concerns with staff there. Recent FDA analyses criticized the drug, noted the Journal.
Avandia, known generically as rosiglitazone, has been the subject of safety concerns for several years. In November 2007, a black box warning—the FDA’s strongest safety warning—detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta-analysis of 42 clinical trials that revealed that patients taking Avandia experienced a 43-percent increased risk of having a heart attack.
Now, the drug is at the center of a dispute that could change how the agency responds to drug safety, specifically concerning medications and devices that have been approved and are on the market, noted the Journal.
Type 2 diabetes affects some 23 million Americans, said the Journal and the panel meeting is considered significant. "This is a defining moment" for [FDA Commissioner] Peggy Hamburg and [Deputy Commissioner] Josh Sharfstein, said former FDA Commissioner David Kessler in an interview, quoted the Journal. "Who at the FDA will decide what happens to Avandia?" Kessler asked, noting that whoever makes the decision will also be the group managing how the FDA handles drug safety, approvals, and withdrawals going forward, wrote the Journal. When asked about who would decide Avandia’s fate, Dr. Sharfstein said, "The FDA is going to make a decision on behalf of the public," reported the Journal.
The FDA advisory panel will also look at a study conducted by Dr. David Graham of the FDA’s Center for Drug Evaluation and Research that found that patients in the U.S. Medicare system who took Avandia may have suffered as many as 48,000 heart attacks, strokes, and other problems between 1999 and 2009. Graham’s study involved 227,500 patients, making it the largest to date, and found that patients who took Avandia were 27 percent likelier to suffer a stroke, 25 percent likelier to develop heart failure, and 14 percent likelier to die versus those who took another drug called Actos.
According to a prior Journal article, the FDA advisory panel will be asked to vote on several actions the FDA could take regarding Avandia, including allowing Avandia to stay on the market or adding restrictions on its use, such as only allowing certain doctors to prescribe the medication. The meeting will take place over two days; the vote will occur Wednesday. The FDA is not required to follow the advise of such panels, but usually does so.
Actos, made by Takeda, has been found in some studies to be equally effective in lowering glucose levels as Avandia without the same cardiac risk, said the Journal. Meanwhile, according to some experts, proving Avandia causes cardiovascular problems could be challenging given that diabetes can lead to such issues, noted the Journal.
According to The Wall Street Journal, one of the documents included in the posting is a memo discussing the RECORD trial, an Avandia study paid for by GlaxoSmithKline, the manufacturer of the controversial diabetes drug. RECORD, which involved 4,500 patients, compared Avandia to patients receiving other diabetes drugs, metformin and sulfonylurea, for an average of 5.5 years. Released in 2009, RECORD did not show an increased heart-attack risk that has been seen in some other Avandia studies.
According to the Journal, the memo included in the FDA briefing was written by Thomas Marciniak, a medical team leader in FDA's division of cardiovascular and renal products. He writes that RECORD was "inadequately designed and conducted to provide any reassurance about the CV (cardiovasular safety) of rosiglitazone." He goes on to write that the RECORD results "confirm and extend the recognized concerns regarding heart failure" and possibly suggest an increased risk for heart attacks, the Journal said.
In addition to the RECORD study, the FDA advisory panel scheduled to meet next week will also look at a study conducted by Dr. David Graham of the FDA’s Center for Drug Evaluation and Research. It found that patients in the U .S. Medicare system who took the drug may have suffered as many as 48,000 heart attacks, strokes and other problems between 1999 and 2009. Graham's study involved 227,500 patients, making it the largest to date, and found that patients who took Avandia were 27 percent more likely to suffer a stroke, 25 percent more likely to develop heart failure and 14 percent more likely to die compared with those who took another drug called Actos.
According to The Wall Street Journal, the FDA advisory panel will be asked to vote on several actions the FDA could take in regards to Avandia. These include allowing the product to stay on the market or adding restrictions on the use of the product such as only allowing certain doctors to prescribe the medication. The meeting will take place over two days, and the vote will occur next Wednesday. While the FDA is not required to follow the advise of such panels, it usually does so.
Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning – the FDA’s strongest safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack.
Last week, Dr. Stephen Nissan, who conducted that study, released a follow-up to it. The update looked at 56 clinical studies involving 35,500 patients, including RECORD, and found an increased heart attack risk of 28 percent. Without RECORD, the risk of heart attacks rose to 39 percent, according to study.
Since November 2007, Avandia's label has included a black box warning – the FDA’s strongest safety warning – detailing Avandia’s association with heart attacks. The black box didn’t satisfy many Avandia critics, however, who continue to advocate that it be pulled from the market.
In November 2007, a black box warning – the FDA’s strongest safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack.
That black box didn't satisfy many Avandia critics, who wanted the drug pulled from the market. But when it voted to require the stronger warning, the FDA's Drug Safety Oversight Board also voted 8-to-7 to keep Avandia on the market. That board does not meet in public, and it doesn't disclose its deliberations.
Earlier this year, the Senate Finance Committee released a report detailing its 2-year Avandia investigation. According to the report, in July 2007 the FDA’s own scientists estimated that Avandia was responsible for more than 80,000 heart attacks.
Since then, two new studies have been published pointing to Avandia heart risks. One, conducted by the Cleveland Clinic's Dr. Steven Nissan, was an update to the 2007 study that sparked worry. According to a report in the Wall Street Journal, Nissan’s updated analysis looked at 56 clinical studies involving 35,500 patients, including a Glaxo-funded study known as Record, and shows an increased heart attack risk of 28 percent. If the Record study is removed from the analysis, the risk of heart attacks rises to 39 percent, the Journal said.
The second study, conducted by Dr. David Graham of the FDA’s Center for Drug Evaluation and Research, found that patients in the U .S. Medicare system who took the drug may have suffered as many as 48,000 heart attacks, strokes and other problems between 1999 and 2009. It involved 227,500 patients, making it the largest to date, and found that patients who took Avandia were 27 percent more likely to suffer a stroke, 25 percent more likely to develop heart failure and 14 percent more likely to die compared with those who took Actos.
Both Nissan and Graham will present their findings at the public advisory panel meeting scheduled for July 13 and 14. Both researchers have called for Avandia to be removed from the market.
They aren't the only ones with concerns about the drug. The consumer advocacy group Public Citizen petitioned the FDA two years ago to remove Avandia from the market. The American Diabetes Association and its European counterpart have advised doctors against using Avandia.
Dr. David Juurlink of the Institute for Clinical Evaluative Sciences in Ontario, who wrote an editorial for the Journal of the American Medical Association (JAMA) that accompanies the Graham and Nissan studies, recently told NPR that he thinks the accumulating evidence "make it difficult to advance a cogent argument regarding why, exactly, a patient might want to receive the drug or why a physician would choose to prescribe it."
The first study is an update of the 2007 analysis of 47 Avandia clinical trials conducted by Dr. Steven Nissan of the Cleveland Clinic. Nissan's earlier analysis was the first to link Avandia to a higher risk - 43% - of heart attack and stroke, and kicked off the controversy that has dogged the drug ever since. Following publication of Nissan's 2007 analysis, a black box warning – the FDA’s strongest s safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling.
According to the Journal, Nissan's updated analysis looks at 56 clinical studies involving 35,500 patients, including a Glaxo-funded study known as Record, and shows an increased heart attack risk of 28 percent. If the Record study is removed from the analysis, the risk of heart attacks rises to 39 percent, the Journal said.
The second study, conducted by Dr. David Graham of the FDA's Center for Drug Evaluation and Research, found that patients in the U .S. Medicare system who took the drug may have suffered as many as 48,000 heart attacks, strokes and other problems between 1999 and 2009.
Dr. Graham's study involved 227,500 patients, making it the largest to date. It found that patients who took Avandia were 27 percent more likely to suffer a stroke, 25 percent more likely to develop heart failure and 14 percent more likely to die compared with those who took Actos.
Both Nissan and Graham have renewed their calls for Avandia to be pulled from the market, according to report in The Washington Post.
"I'm hoping with a new administration and new leadership they will act differently. This is a defining moment for the new administration," Nissen said.
For his part, Graham told the Post that he was not hopeful the FDA would change its Avandia stance.
"FDA, unfortunately, has not changed. It has not improved its approach to drug safety. It does not value drug safety," Graham said.
Both Avandia studies are published online in the Journal of the American Medical Association and its sister publication, the Archives of Internal Medicine.
According to Reuters, Germany's Federal Joint Committee of doctors and health insurers cited bone fracture and heart risks associated with Avandia's class of drugs. The ban on glitazone medicines also include Actos, sold by Japan's largest drugmaker Takeda.
"There are other pharmaceuticals that have no such side effects and long-term risks," The committee's chairman Rainer Hess said. "We believe that patients should be protected against useless and, more importantly, harmful therapies."
Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning – the FDA’s strongest safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack.
Earlier this year, the Senate Finance Committee released a report detailing its 2-year Avandia investigation. According to the report, in July 2007 the FDA’s own scientists estimated that Avandia was responsible for more than 80,000 heart attacks.
Earlier this month, we reported that an unpublished Avandia study had found that patients in the U .S. Medicare system who took the drug may have suffered as many as 48,000 heart attacks, strokes and other problems between 1999 and 2009. According to the study’s author, Dr. David Graham, a safety official with the FDA, the problems could have been averted had the patients taken a different drug.
Dr. Graham is a long-time critic of Avandia. The findings of his study will be included in data presented at next month's FDA advisory panel meeting. Dr. Graham and others have argued that Avandia should be withdrawn from the market.
According to The Wall Street Journal, Dr. Graham is a long-time critic of the controversial diabetes drug. The findings of his study will be included in data presented at a meeting next month to review Avandia's safety. Dr. Graham and others have argued that Avandia should be withdrawn from the market.
For the study, which was authenticated for the Journal by the FDA, Dr. Graham and colleagues from the FDA and Centers for Medicare and Medicaid Services retrospectively examined the medical records of 227,000 patients 65 and older. The patients took either Avandia or a competing drug, Actos, between 2006 and 2009. Many of the patients also took other diabetes drug treatments. Patients taking Avandia had a 27 percent greater chance of suffering a stroke, a 25 percent increased risk of suffering heart failure and a 13 percent greater chance of dying, the study found.
"There is no rationale for [Avandia's] continued availability on the market or its use by prescribing physicians or patients," the researchers conclude.
According to the Journal, the unpublished study was first reported by the blog, Pharmalot, in May. The blog also published an email from Dr. Graham to the FDA's senior leaders, in which he complained that the agency was holding up his efforts to publish his work in the Journal of the American Medical Association (JAMA).
An FDA official confirmed the email, but said the agency wasn't preventing publication of the study. A JAMA spokeswoman said the journal doesn't ever confirm or deny receipt or acceptance of any manuscript until publication, The Wall Street Journal said.
Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning – the FDA's strongest safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack.
Earlier this year, the Senate Finance Committee released a report detailing its 2-year Avandia investigation. According to the report, in July 2007 the FDA’s own scientists estimated that Avandia was responsible for more than 80,000 heart attacks.
There were around 5,000 Avandia lawsuits consolidated in the Philadelphia case, which was scheduled to go to trial yesterday. A GlaxoSmithKline spokesperson told The Wall Street Journal that the next case slated for trial in that court and is to begin in October 2010. None of the Avandia cases consolidated in federal court have been resolved.
The latest settlement follows the separate resolution of some 700 cases for about $60 million that we reported last month.
Most Avandia lawsuits have been filed by people who claim the diabetes drug caused them to suffer a heart attack or stroke. Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning – the Food & Drug Administration's (FDA) strongest safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack.
Earlier this year, the Senate Finance Committee released a report detailing its 2-year Avandia investigation. According to the report, in July 2007 the FDA’s own scientists estimated that Avandia was responsible for more than 80,000 heart attacks.
Since the release of the Senate report, calls have increased for the FDA to pull Avandia off the market. The FDA is conducting another safety review of Avandia, the results of which will be discussed at a public meeting in July.
Avandia, made by GlaxoSmithKline, has been the subject of several studies linking it to an increased risk of heart problems. The TIDE trial is comparing Avandia with another diabetes drug called Actos. Actos has not raised as many safety concerns as Avandia, and some scientists inside and outside the FDA have said it is unethical to compare a drug with known cardiac risks with a seemingly safer alternative.
In March, FDA Commissioner Margaret Hamburg wrote to Senator Charles Grassley (R-Iowa), one of the signatories of the senate Finance Committee report, telling him that the agency is reassessing the Avandia versus Actos trial “based on expert input and our own analysis.” The study is also expected to be discussed at an advisory panel meeting on Avandia this summer.
According to The Wall Street Journal, two research sites have dropped out of TIDE because of enrollment issues. An official with one of them - Wake Forest University Baptist Medical Center in North Carolina - told the Journal that it is "not succeeding in recruiting anybody."
In April, GlaxoSmithKline, which is paying for TIDE, opened up a dozen research sites overseas, some in developing countries including Pakistan, India, Mexico, Latvia and Colombia. That move has some critics of the company uneasy.
Dr. Sidney Wolf of the consumer advocacy Public Citizen told the Journal he was concerned patients at some of these overseas sites might not be aware of the safety questions surrounding Avandia. Dr. Wolf's group is on record calling for the end of the TIDE trial.
Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning – the FDA’s strongest safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack. Earlier this year, the Senate Finance Committee released a report detailing its 2-year Avandia investigation. According to the report, in July 2007 the FDA’s own scientists estimated that Avandia was responsible for more than 80,000 heart attacks.
Since the release of the Senate report, calls have increased for the FDA to pull Avandia off the market.
While more than 4,000 Avandia lawsuits already have been filed, the company faces at least another 9,000 claims over the drugs that haven’t yet been filed under an agreement with Glaxo. Glaxo is scheduled to face its first Avandia trial in state court in Philadelphia in July, Bloomberg said.
Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning – the FDA’s strongest safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack.
Earlier this year, the Senate Finance Committee released a report detailing its 2-year Avandia investigation. According to the report, in July 2007 the FDA’s own scientists estimated that Avandia was responsible for more than 80,000 heart attacks. Since the release of the Senate report, calls have increased for the FDA to pull Avandia off the market. The FDA is conducting another safety review of Avandia, the results of which will be discussed at a public meeting in July.
There is also speculation that the FDA could soon halt a large Avandia study called TIDE, which is comparing it to another drug called Actos. As we've reported previously, Actos has not raised as many safety concerns as Avandia, and some scientists inside and outside the FDA have said it is unethical to compare a drug with known cardiac risks with a seemingly safer alternative. In March, FDA Commissioner Margaret Hamburg wrote to Senator Charles Grassley (R-Iowa), one of the signatories of the senate Finance Committee report, telling him that the agency is reassessing the Avandia versus Actos trial “based on expert input and our own analysis."
Last month, Joshua Sharfstein, Hamburg’s principle deputy, told The Wall Street Journal that whatever decision is made regarding TIDE, it “cannot be de-linked from the agency’s view of Avandia.” This, the Journal said, indicates that if the FDA halts TIDE, it could also ask Glaxo to halt sales of Avandia.
Reuters pointed out that, in 2007, the FDA asked Glaxo, maker of Avandia (generically known as rosiglitazone), to conduct a trial comparing the long-term effects of Avandia against those of Takeda Pharmaceutical Co. Ltd.’s Actos when prevailing data pointed to an increased risk of heart attack and chest pain in Avandia.
Since that time, increasing data have linked Avandia to increased cardiac risks, according to Public Citizen, a science-focused consumer advocacy interest group, said Reuters. Public Citizen said it wants the study to end, noting that continuing to involve patients in a trial that seeks 16,000 global participants by 2015 is placing diabetics at unnecessary risk, reported Reuters.
TIDE, said Public Citizen's Health Research Group Director Sidney Wolfe and Canadian researcher David Juurlink in a letter to FDA Commissioner Margaret Hamburg, is "exposing thousands of high-risk patients with diabetes to a drug with an unfavorable safety profile and no clinical advantage over its comparator," quoted Reuters. "A wealth of data now suggests" Avandia carries increased risks over Actos, the two added.
Wolfe and Juurlink also mentioned that patients apparently do not receive sufficient information regarding safety differences between the two drugs when they are making decisions to enter or not be involved in the trial, said Reuters. Actos has not raised as many safety concerns as Avandia and some scientists inside and outside the FDA have said it is unethical to compare a drug with known cardiac risks with a seemingly safer alternative.
According to Reuters, officials at the FDA confirm that they are looking at the drug; however, the agency is not moving as quickly as consumer advocates would like. "The TIDE trial will be discussed at a joint advisory committee in July," FDA spokeswoman Karen Riley said in an emailed statement, quoted Reuters. "Based on expert input and our own analysis, FDA will reassess the rationale for the TIDE trial, review the trial's enrollment and respond accordingly," Riley said. The FDA has not yet reached a conclusion. Meanwhile, diabetes continue to be enrolled in TIDE and continue to be prescribed Avandia.
Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning—the FDA’s strongest safety warning—detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta-analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack.
Earlier this year, the Senate Finance Committee released a report detailing its two-year Avandia investigation. According to the report, in July 2007, the FDA’s own scientists estimated that Avandia was responsible for more than 80,000 heart attacks.
Since the release of the Senate report, calls have increased for the FDA to pull Avandia off the market. The FDA is conducting another safety review of Avandia, the results of which will be discussed at a public meeting in July.
Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning – the FDA's strongest safety warning – detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta- analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack. Earlier this year, the Senate Finance Committee released a report detailing its 2-year Avandia investigation. According to the report, in July 2007 the FDA’s own scientists estimated that Avandia was responsible for more than 80,000 heart attacks.
Since the release of the Senate report, calls have increased for the FDA to pull Avandia off the market. The FDA is conducting another safety review of Avandia, the results of which will be discussed at a public meeting in July.
The TIDE trial is comparing Avandia with another diabetes drug called Actos. Actos has not raised as many safety concerns as Avandia, and according to the Journal, some scientists inside and outside the FDA have said it is unethical to compare a drug with known cardiac risks with a seemingly safer alternative.
In March, FDA Commissioner Margaret Hamburg wrote to Senator Charles Grassley (R-Iowa), one of the signatories of the senate Finance Committee report, telling him that the agency is reassessing the Avandia versus Actos trial "based on expert input and our own analysis.”
Hamburg has also asked the Institute of Medicine, a government scientific panel, to review the ethics of such head-to-head studies like TIDE. In addition, Hamburg has asked a senior advisor to review the FDA's decision-making on drug safety, including how much evidence the agency needs to pull a drug from the market.
Though neither of these reviews targets Avandia specifically, the Journal points out that both will be completed before the July advisory committee meeting on Avandia. It is likely that that their conclusions will be considered by the advisory panel.
As to Avandia’s future, Joshua Sharfstein, Hamburg’s principle deputy, told The Wall Street Journal that whatever decision is made regarding TIDE, it "cannot be de-linked from the agency's view of Avandia.” This, the Journal said, indicates that if the FDA halts TIDE, it could also ask Glaxo to halt sales of Avandia.
To reach their conclusions, researchers performed a review of 202 articles that addressed the possible association between the risk of heart attacks and use of Avandia in diabetes patients. Two reviewers who were blinded to the authors' financial relationships evaluated each article and classified it as being favorable (supporting the argument that the drug does not increase the risk of heart attack), neutral, or unfavorable (questioning Avandia's safety). Of the articles reviewed, 107 (53%) included a conflict-of-interest statement and 90 (45%) had a conflicting financial relationship.
Ninety-one percent of the authors who reached favorable conclusions on Avandia and heart risks had financial relationships with antihyperglycemic agent manufacturers. What's more, 86% had a financial relationship with GlaxoSmithKline, the maker of Avandia. Contrast this with the authors who presented unfavorable conclusions: Only 5% had financial relationships with antihyperglycemic agent manufacturers and 18% had such a relationship with Glaxo that was disclosed.
However, the researchers also found through an online search that some authors listed financial conflicts in other publications that were not disclosed in their Avandia paper.
The study reached no conclusions about Avandia's safety.
HealthDay News points out that it remains unclear if drug maker payments are fully linked to the so-called “supportive” research; however, the review pointed out that a massive 94-percent of the researchers authoring positive study results on Avandia were paid by drug companies.
The researchers looked at over 200 studies and wrote that "there was a clear and strong link between the orientation of authors' expressed views on the rosiglitazone controversy and their financial conflicts of interest with pharmaceutical companies," quoted HealthDay News. According to the review, 45-percent of the study authors had financial conflicts of interest, with about 25-percent of those not having disclosed that information, according to the Mayo Clinic researchers, wrote HealthDay News. The review was published online March 19 in BMJ.
Avandia has been the subject of safety concerns for several years. In November 2007, a black box warning—the Food & Drug Administration (FDA’s) strongest safety warning—detailing Avandia’s association with myocardial ischemia was added to the drug’s labeling. The black box was added after the Cleveland Clinic published a meta-analysis of 42 clinical trails that showed patients taking Avandia had a 43-percent higher risk of having a heart attack.
Meanwhile, last month, the FDA announced it was looking at information regarding Avandia’s risks for heart attack and heart failure to determine if the medication should be removed from the market, wrote HealthDay News. The FDA is scheduling a public meeting on the information in July.
Liability for Avandia lawsuits could total as much as $6 billion, according to a UBS analyst. GlaxoSmithKline, the maker of Avandia, faces more than 13,000 U.S. lawsuits over the controversial diabetes drug.
Last month, the Senate Finance Committee released a report detailing its two-year Avandia investigation. According to the report, in July 2007, the FDA’s own scientists estimated that Avandia was responsible for more than 80,000 heart attacks. Two FDA doctors wrote in an October 2008 memo that Avandia should be removed from the market because it poses serious heart-related dangers to patients, the report said. The Senate report also claimed that Glaxo tried to undermine criticism of the drug. The report drew on 250,000 pages of documents, including emails from GlaxoSmithKline officials and interviews with Glaxo and FDA officials, and anonymous whistleblowers. Since the release of the Senate report, calls have increased for the FDA to pull Avandia off the market.
In a UBS note just made public, the brokerage said Glaxo’s Avandia lawsuit liability was in the range of $1 billion to $6 billion. Avandia lawsuits allege that GlaxoSmithKline failed to adequately warn users about the increased risk of serious and potentially life-threatening injuries, such as heart attack, stroke, congestive heart failure, liver failure, bone fractures, macular edema (vision loss), and death. Federal Avandia lawsuits have been consolidated for pretrial proceedings in an MDL, or multidistrict litigation, in the U.S. District Court for the Eastern District of Pennsylvania. The first bellwether, or test trials, in that litigation are expected to begin in June.