Diabetes Alert: Avandia Warnings Updated To Reflect Restrictions on Use

GlaxoSmithKline has finalized an update for the warning label and medication guide of their diabetes drug Avandia, which includes information on new FDA required restrictions on use and concerns about potential heart problems with Avandia.

In a press release issued Monday, the company said that the changes will affect all rosiglitazone-based drugs; including Avandia, Avandamet and Avandaryl.

The labels and guides will note that Avandia is only available to patients who are already taking the drug or who have failed to control their diabetes with other medications. It also includes an updated black box warning that notes that clinical trials show a “statistically significant” increased risk of myocardial infarction and notes that trials have indicated that Takeda Pharmaceuticals’ Actos, a competing drug, does not appear to carry the same risks.

Avandia (rosiglitazone) was first approved in the United States in 1998 to treat type 2 diabetes by helping control blood sugar levels. The drug has been used by millions of diabetics, but sales plummeted following the concerns about potential Avandia heart risks.

In September 2010, the FDA determined that the black box warning added in 2007 was not enough and issued stronger warnings about Avandia and restricted use. The agency determined that only patients who have failed to control their diabetes through every other available medication should be given access to the medication, and ordered the drug’s maker, GlaxoSmithKline, to develop a risk evaluation and mitigation strategy (REMS) to make sure the drug is adequately restricted. The decision came after an FDA advisory committee narrowly voted this summer not to issue an Avandia recall.

GlaxoSmithKline said in its press release that it continues to work with the FDA on developing a REMS program.

The drug maker faces thousands of Avandia suits filed by people who allege that they suffered an injury as a result of the drug maker’s failure to adequately warn about the risk of heart problems.

A number of Avandia settlements have reportedly been reached by GlaxoSmithKline in an effort to resolve the Avandia litigation.

Diabetes Alert: Avandia May Be Banned In Europe

European regulators will decide by September if Avandia will be allowed to stay on the market there. The European Medicines Agency (EMEA) said on July 23 that it is still reviewing GlaxoSmithKline’s controversial diabetes drug, which has been linked to an increased risk of heart attacks.

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 a 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.

As I reported yesterday, the FDA has 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.

Incidentally, India has already suspended all participation in the TIDE trial in the country. In India, at least 20 cities including Mumbai, Bangalore, Chennai and Hyderabad had enrolled over 150-200 subjects earlier this year for conducting these clinical trials, which are part of the global post-marketing studies to asses its safety risks.

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 has not indicated how long the enrollment halt would last.

Diabetes: Safety Concerns Force FDA To Halt Enrollment For Avandia Trials

The FDA On July 21 ordered drug maker GlaxoSmithKline to stop enrolling new patients in a controversial clinical trial of its widely marketed diabetes drug, Avandia (rosiglitazone).

The clinical trial, called TIDE, was mandated by the FDA to assess safety risks of the drug, which is prescribed to treat type-2 diabetes.

But it has been highly controversial because Avandia has been linked in a variety of studies to an increased risk of heart attack and other adverse cardiovascular effects.

Critics, including one of the Food and Drug Administration’s own safety researchers, have said publicly that the trial should be stopped immediately, asserting that it is unethical to expose patients to risks that have been shown statistically to be quite real.

GlaxoSmithKline recently announced that India has already suspended all participation in the TIDE trial in the country.

In India, at least 20 cities including Mumbai, Bangalore, Chennai and Hyderabad had enrolled over 150-200 subjects earlier this year for conducting these clinical trials, which are part of the global post-marketing studies to asses its safety risks.

This development is significant in the wake of the fact that a total of around 2,000 diabetics were to be enrolled from India.

A debate has been raging on the blockbuster drug, Avandia since studies reported serious side-effects like heart attacks and strokes associated with its use, in 2007. It is widely-prescribed by doctors here in India, with 9-10 companies marketing it.

The country's drug controller general recently halted the trials, for which subjects were being enrolled since February, across various hospitals and clinics all over.

Dr Anoop Misra, director and head diabetes, Fortis Hospitals in New Delhi said: "This step taken by FDA of stopping this unethical trial is welcome, though belated. I hope further step of banning this drug is taken soon. I am also happy to note that DCGI (India) stopped this trial in India before FDA decision, and such efficient steps and regulations are required in India."

The FDA on its part said its action does not mean the drug will be removed from the market. But the agency is demanding that GlaxoSmithKline update physicians and ethics oversight boards involved in the trial regarding all new safety information about the drug.

It said the information "can be used’’ to update consent forms for new patients and current participants. Critics, including members of Congress, have said the current consent forms in use in the trial are inadequate given the extent of the scientific warning signs.

The potential dangers of Avandia have already discouraged enrollment in the trial.

The trial’s design called for global enrollment of 16,000 patients, with about a third in the United States. But the trial’s lead investigator, Hertzel Gerstein, of McMaster University in Ontario, Canada, said last week only about 1,120 patients had been recruited worldwide, because of the widespread safety concerns.

By a vote of 20 to 12, an FDA advisory panel last week recommended that the drug be permitted to remain on the market. But half of the members who voted to keep it on the market also supported strong restrictions on prescribing, including education programs about the risks for doctors and patients, which specialists predict will dramatically cut into GSK sales figures.

GlaxoSmithKline said in a statement that new enrollment in the trial would be stopped "pending FDA review of recommendations from its Advisory Committee meeting July 13-14. Patients already enrolled may continue in the trial."

"This pause in enrollment will give clinical trial investigators and patients time to learn about the data presented to the FDA Advisory Committee and the Committee’s recommendations," said Dr Ellen Strahlman, GSK’s Chief Medical Officer. "We are committed to working with the FDA in the best interest of diabetic patients."

Avandia, which was approved for the market in 1999, was prescribed 2 million times by US doctors in 2009. It was once the largest-selling drug in its class, with more than $3 billion in global sales. It sold around $1 billion in 2009, with half of that revenue in the US.

Killer Drug Gets Safety Certificate From FDA - GSK Claims "Victory"

This week the US Food and Drug Administration voted not to ban GlaxoSmithKline's diabetes drug rosiglitazone (brand name Avandia). Their vote has been reported as a victory for the company. I don't think so: this saga tells an ugly story about our collective medical incompetence.

Rosiglitazone was first marketed in 1999. From the outset it was a magnet for disappointing behaviour. That first year Dr John Buse discussed an increased risk of heart problems at a pair of academic meetings. He was silenced. GSK made direct contact, then moved on to his head of department.

Buse felt pressured to sign various legal documents and after wading through documents for several months, in 2007 the US Senate committee on finance released a report describing the treatment of Dr Buse as "intimidation".

In 2003, the Uppsala drug monitoring group of the World Health Organisation contacted GSK about an unusually large number of reports associating rosiglitazone with heart problems. GSK conducted two internal meta-analyses of their data in 2005 and 2006.

These showed the risk was real, but although both GSK and the FDA had these results, neither made any public statement, and they were not published until 2008.

Why then? In 2004 GSK were caught ‑ famously - hiding data showing side effects of the antidepressant paroxetine in children: a court settlement required them to post all clinical trial results voluntarily on a public website.

Using this data source, cardiologist Prof Steve Nissen and colleagues published a landmark meta-analysis in 2007 showing a 43% increase in the risk of heart attack on rosiglitazone. People with diabetes are already at increased risk of heart problems.

The FDA found a similar risk in their own calculations, but voted in 2007 to keep the drug on the market. This is not insane: diabetes is tricky, 300 million people have it worldwide, a great many die from it, and rosiglitazone is unusually good at controlling blood sugar. Lots of dangerous drugs are kept on the market and then used less frequently, in extreme circumstances.

A consensus algorithm from the American Diabetes Association and the European Association for the Study of Diabetes, meanwhile, unanimously recommended against rosiglitazone. Although annual sales for rosiglitazone fell, they still remained over $1bn (£650m). Concerns continued to mount. So did the bad behaviour. In 2007, Nissen caught GSK out discussing a copy of his unpublished paper, which they had obtained improperly.

Then on 28 June this year Nissen published an updated meta-analysis of 56 trials in over 35,000 patients. Again it found an increased risk of heart problems. GSK's response to all this has been like the responses you get from homeopaths.

There are seven trials since 2007, they said, showing no excess risk: fine, except there are 56 which collectively do show an excess risk. There is this other meta-analysis, they said, which looked at 164 trials: fine, except it's published in a fairly obscure journal, and it looked at trials lasting more than four weeks, when the others set the bar at trials over 24 weeks, because a heart risk takes time to develop.

In any case, this other meta-analysis is not brilliant for GSK's case, since it points out that the company denied access to data from six trials which we know to have taken place. There is no excuse for companies withholding data from academics and doctors. But most revealingare the deep-rooted flaws this story exposes in our rather ad hoc systems for gathering, analysing, and disseminating evidence on risks and benefits of treatments.

This drug has been on the market since 1999, and it has seen billions of dollars of sales every year. There has been plenty of real patient experience of this treatment, but we have failed to capture it for analysis. Most of the trials included in these meta-analyses were not specifically designed to look at heart problems, and so the data on these is unpredictably inaccurate.

In an ideal world, for every patient, wherever possible, we could be gathering anonymised outcome data and comparing this against medication history. In an ideal world, wherever there is genuine uncertainty about which treatment is best, a patient would be randomised to one treatment, and their progress monitored. In an ideal world, these notions would be so embedded in our notion of what healthcare looks like that no patient would be bothered by it.

This isn't fanciful, or difficult, or disproportionately expensive. Instead we have a hotchpotch of incomplete monitoring systems and unforgivable secrecy.

Courtesy: Ben Goldacre/The Guardian