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FDA significantly restricts access to the diabetes drug Avandia
  Makes regulatory decisions on RECORD and TIDE trials
The U.S. Food and Drug Administration today announced that it will significantly restrict the use of the diabetes drug Avandia (rosiglitazone) to patients with Type 2 diabetes who cannot control their diabetes on other medications. These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia.
"The FDA is taking this action today to protect patients, after a careful effort to weigh benefits and risks," said FDA Commissioner Margaret A. Hamburg, M.D. "We are seeking to strike the right balance to support clinical care."
Rosiglitazone also is available in combination with other diabetes medications, metformin under the brand name Avandamet or glimepiride under the brand name Avandaryl.
Avandia, manufactured by GlaxoSmithKline (GSK), is in a class of drugs known as thiazolidinediones, or TZDs. It is intended to be used in conjunction with diet and exercise to improve glucose (blood sugar) control in patients with Type 2 diabetes mellitus.
The FDA will require that GSK develop a restricted access program for Avandia under a risk evaluation and mitigation strategy, or REMS. Under the REMS, Avandia will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take Actos (pioglitazone), the only other drug in this class. Current users of Avandia who are benefiting from the drug will be able to continue using the medication if they choose to do so.
Doctors will have to attest to and document their patients' eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge they understand the risks. The agency anticipates that the REMS will limit use of Avandia significantly.
"Allowing Avandia to remain on the market, but under restrictions, is an appropriate response, given the significant safety concerns and the scientific uncertainty still remaining about this drug," said Janet Woodcock, M.D., director of the FDA's Center for Drug Evaluation and Research.
Also today, the FDA ordered GSK to convene an independent group of scientists to review key aspects of the company's clinical trial known as RECORD, which studied the cardiovascular safety of Avandia compared to standard diabetes drugs. During the course of the FDA's review of the RECORD study, important questions arose about potential bias in the identification of cardiovascular events. The FDA is requiring this independent review to provide additional clarity about the findings.
In addition, the agency halted the GSK's clinical trial known as TIDE and rescinded all of the regulatory deadlines for completion of the trial. The TIDE trial compares Avandia to Actos and to standard diabetes drugs.
The FDA may take additional actions after the independent re-analysis of RECORD is completed.
Avandia: Reaction and implications World News | September 24, 2010
Kevin Grogan
Following the regulators' moves against GlaxoSmithKline's Avandia, industry observers have been reacting to the news and considering the impact of suspension in Europe and further restrictions in the USA.
Steve Nissen of the Cleveland Clinic and a critic of Avandia (rosiglitazone) who authored a much-publicised meta-analysis linking the drug to a 43% increased risk of heart attack in May 2007, is pretty pleased with the outcomes. He told the Wall Street Journal that the US Food and Drug Administration's decision to keep Avandia on the market with severe restrictions is "a reasonable course of action and compromise. It will limit 99% of its use".
He added that doctors will be forced to document in detail that their patients are benefiting from Avandia and patients "will have to read and sign documents saying they understand the cardiovascular risks". That is "such a barrier to its use", Dr Nissen said, and between the FDA and the European Medicines Agency "it essentially means the drug is gone".
Other observers believe the FDA has not gone far enough and Sidney Wolfe, director of the influential consumer organisation's Public Citizen's Health Research Group, said the agency has "again caved to industry pressure". He added that "too many people could still be exposed to this dangerous product", arguing that the FDA "should have acted with its European counterpart and outright banned Avandia from the market".
Dr Wolfe went on to say that more than three years ago at an FDA advisory committee meeting, Public Citizen urged the FDA to ban Avandia. "Since then, 9 million prescriptions for the drug have been filled in the USA. This means that, just in the past three years alone, tens of thousands more patients have needlessly suffered hospitalisations for heart failure or deaths" than would have had they taken Takeda's Actos (pioglitazone), "a comparable, but safer drug".
Speaking of Actos, Takeda issued a statement saying that it offers "an established safety profile regarding the risk of CV events", saying that controlled clinical studies, conducted over the past 11 years in more than 20,000 patients globally, "show no evidence that Actos is associated with an increased risk of heart attack, stroke or death".
Analysts believe that Takeda will benefit from Avandia's travails but possibly only in the short-term as Actos goes off-patent in the USA in January next year. BMO Capital Markets' Robert Hazlett believes that doctors are more likely to prescribe Merck & Co's dipeptidyl peptidase-4 (DPP-4) inhibitor Januvia (sitagliptin).
Others believe that the glucagon-like peptide-1 (GLP-1) analogues, namely Novo Nordisk's Voctoza (liraglutide) and Eli Lilly/Amylin's Byetta (exenatide). will be the main beneficiaries, which have been shown to reduce weight while lowering blood sugar.
FDA Restricts Rosiglitazone Use: Stays, but Only for Some
MedPage Today
Published: September 23, 2010
The controversial diabetes drug rosiglitazone (Avandia) can remain on the market but new patients can receive it only if their blood sugar can't be controlled with pioglitazone (Actos) or other medications, the FDA announced today.
Patients already taking rosiglitazone who are doing well may stay on the drug, the agency said, but they should discuss alternatives with their physicians. FDA officials also promised that the drug's label warnings on cardiovascular risk would be revised, although the specific language has not been worked out yet.
The new restrictions also apply to products that combine rosiglitazone with other diabetes medications (Avandamet, Avandaryl).
"The FDA is taking this action today to protect patients, after a careful effort to weigh benefits and risks," said FDA Commissioner Margaret A. Hamburg, MD, in a statement. "We are seeking to strike the right balance to support clinical care."
However, in a nearly simultaneous announcement, the European Medicines Agency (EMA) took the opposite tack, suspending the drug's marketing authorization in Europe.
The EMA said that the currently available forms of rosiglitazone would cease to be available in Europe "within the next few months."
Several studies have indicated that cardiovascular events and deaths have been more common with rosiglitazone than other diabetes medications, including pioglitazone, the only other approved thiazolidinedione drug. But others, notably the manufacturer-sponsored RECORD trial, appeared to exonerate the drug.
In a conference call with reporters, Janet Woodcock, MD, head of the FDA's Center for Drug Evaluation and Research, said the FDA believes that the adverse-event data now in hand did not justify yanking the drug entirely.
"We feel there is considerable uncertainty about the existence and magnitude of the cardiovascular risk," she said.
An FDA advisory committee meeting in July reached essentially the same conclusion, with 20 of 33 panelists voting to keep the drug on the market but with more restrictions.
In the U.S., the FDA is demanding a restricted access program under which doctors must document that patients have not responded adequately to other medications and cannot take pioglitazone before they can receive a new prescription for rosiglitazone. Patients will have to sign a statement indicating that they have reviewed the cardiovascular safety concerns about the drug.
FDA Deputy Commissioner Joshua Sharfstein, MD, said physicians should consult with patients now taking rosiglitazone about whether to stay on the drug. "They may want to consider switching patients to another medication," he said during the conference call.
Woodcock said the agency has also ordered a halt to the ongoing safety study called TIDE that sought to compare adverse event rates for rosiglitazone versus pioglitazone.
In addition, the FDA is seeking "independent readjudication" of findings from the controversial RECORD study, which the agency's staff attacked at the July advisory committee meeting, she said.
Hamburg said during the call that the FDA had coordinated with EMA and each knew what the other's final decision would be.
She said the two agencies largely agreed on the risk data, but differed in how the risks should be managed. She noted that both the FDA and EMA would continue to monitor new data (including the reinterpreted RECORD findings) and could revisit their decisions.
The three FDA officials also elaborated on their rationale for keeping rosiglitazone on the market in a Perspective published online today in the New England Journal of Medicine.
Woodcock, Hamburg, and Sharfstein noted that rosiglitazone is clearly effective. "Against these benefits, we must assess the evidence of rosiglitazone's cardiovascular risks," they wrote.
"This evidence is concerning, but it is not definitive. There are patients with severe type 2 diabetes whose disease may not be controlled on other medications and either may not tolerate pioglitazone or, in consultation with their healthcare professional, decide not to take pioglitazone for other medical reasons."
They noted that the FDA had just recently started a safety review of pioglitazone for potential bladder cancer risk.
"When there are just two drugs in a class, and many outstanding uncertainties, maintaining some flexibility may have value for patient care," the officials argued.
A statement from rosiglitazone's manufacturer, GlaxoSmithKline, reiterated the company's position that rosiglitazone "is an important treatment for type 2 diabetes."
It said the company would nevertheless comply with regulators' decisions. The company also promised to stop promoting the drug in all markets, including the U.S.
The consumer advocacy group Public Citizen, which had previously called for rosiglitazone's removal from the market, slammed the FDA decision.
"Although the FDA has made progress highlighting the risks of using Avandia by severely restricting the drug, it did not go far enough," said the group's medical director, Sidney Wolfe, MD, in a statement.
"Too many people could still be exposed to this dangerous product. Rather, the FDA should have acted with its European counterpart and outright banned Avandia from the market," he said.
But in a joint statement, the American Diabetes Association, the Endocrine Society, and the American Association of Clinical Endocrinologists declined to second-guess the agency's decision, although they also stopped short of endorsing it.
The groups "continue to support the FDA in its role as the regulatory agency that makes decisions regarding drug safety and efficacy," the statement said.
They urged patients currently taking rosiglitazone not to stop the drug without first talking to their doctors, and pointed out that several alternatives are available.
However, an ADA official gave a bit more backing to the FDA's decision in remarks at a press conference, held by the European Association for the Study of Diabetes in Stockholm shortly after the decisions were announced.
"Despite what appear to be discrepant decisions, we believe both the EMA and the FDA have used the available evidence to provide clinical counsel to clinicians and patients in the best fashion possible," said David Kendall, MD, the ADA's chief scientific and medical officer.
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