FDA Restricts Rosiglitazone; EMA Pulls the Plug

Shelley Wood, Lisa Nainggolan, Sue Hughes

September 23, 2010

September 23, 2010 (Updated September 24, 2010) (Silver Springs, Maryland and London, United Kingdom) — The US FDA has decided that rosiglitazone (Avandia, GlaxoSmithKline) can remain available, but only under a very stringent restricted-access program. However, the European Medicines Agency (EMA) has recommended the suspension of the marketing authorizations for all rosiglitazone-containing antidiabetes medications licensed in the EU--Avandia, Avandamet, and Avaglim.

"These medicines will stop being available in Europe within the next few months," the agency said in a statement. "Patients are advised not to stop their treatment without speaking to their doctor. Doctors should stop prescribing rosiglitazone-containing medicines, and patients taking rosiglitazone-containing medicines should be reviewed in a timely manner to amend their treatment."

As previously reported by heartwire , rosiglitazone has been under mounting scrutiny both in the US and Europe, culminating in an FDA advisory hearing where 12 out of 33 panel members voted to recommend removal of the drug from the US market and an additional 10 panelists voted to recommend that rosiglitazone stay on the market, but with severe restrictions on its use.

In response to both the FDA and EMA statements issued today, GlaxoSmithKline said that the EMA has "stated that the suspension will remain in place unless convincing data are provided that identify a group of patients in whom the benefits of the medicine outweigh its risks." In the US, all rosiglitazone-containing medicines will remain available with additional safety labeling and restrictions for use, which includes the FDA requiring a risk evaluation and mitigation strategy (REMS) program with additional measures to ensure the safe use of the medicine.

TIDE Trial on Hold, RECORD to Be Readjudicated

In a second surprise decision, the FDA has put the TIDE trial on full clinical hold and rescinded the regulatory deadlines for its conduct, while the RECORD trial is to be readjudicated.

The agency says that although there is a "signal of harm" with rosiglitazone, confirmation of the existence and magnitude of this harm has not been possible with available data. In trying to make the correct decision to deal with this situation, the FDA says the REMS program will be designed to severely restrict use of the drug to patients with no other options; meanwhile, the agency is hoping to ascertain more information on the MI risk from readjudication of the RECORD study at the individual patient-data level.

"If reliable information on ischemic risk can be obtained from the readjudication of RECORD, the benefit/risk information for rosiglitazone should be reevaluated and the conduct of further safety studies (including studies vs pioglitazone) reconsidered," the FDA decision reads.

GlaxoSmithKline said: "The company continues to believe that Avandia is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions."

EMA Explains Its Decision

At a telephone press briefing, EMA senior medical officer Prof Hans-Georg Eichler explained that the agency had now concluded that the benefits of rosiglitazone no longer outweighed its risks, so that is why it has decided to suspend the drug.

He said the recommendation for suspension would now be passed onto the European Commission, who will make a formal legally binding decision. That would happen in the next couple of weeks. The drug would then not be available anymore. Letters would go out to advise doctors to discuss with patients on a case-by-case basis the best therapeutic alternatives to use.

Eichler noted that a suspension is different from a withdrawal. "Suspension can be a temporary measure. It can be lifted if a company comes up with convincing and robust data that rosiglitazone benefits outweigh its risks in certain populations."

Why Different Decisions by EMA and FDA?

Commenting on the different decisions taken by the EMA and the FDA, Eichler said there were two different stages of dealing with drug safety: risk assessment and management of that risk. "The FDA and EMA have had access to the same data and risk assessments are similar. But we have chosen different courses of risk management. The FDA has chosen to restrict the drug further, while we have chosen to suspend."

He attributed this different decision to "differences in healthcare environments" between the US and Europe, noting that the FDA does not have the legal tool of suspension that is available in Europe. "We concluded that we each took the appropriate action for our particular countries." He added that the EMA considered further restricting usage of rosiglitazone but that the drug was already severely restricted and there was not much opportunity to restrict further. The agency also took into account data on drug utilization, which showed that although the majority of the drug's use was for on-label indications, a small group of patients were being prescribed the agent for off-label use. "So for these reasons we felt the best way forward was suspension."

Asked to comment on how the FDA can justify leaving the drug on the market, Eichler said, "We are not here to comment on our colleagues' assessment in the US. Both agencies are managing the risks/benefits of this drug the way they think best in their respective populations."

How Come It Took So Long?

Asked if this decision should have been reached sooner, Eichler said the EMA was aware that there had been criticism that the regulatory system should have "clicked in" earlier. "We have been receiving signals of cardiovascular adverse effects for some time. But we receive similar signals for all drugs every day. Most are false leads. If we heeded all these signals, there would be no drugs left on the market. A knee-jerk reaction is not in order. We follow up the signals, request further studies, and then act appropriately. That is what has happened here. We have issued several previous restrictions on rosiglitazone usage. The evidence was accumulating, and now we have enough evidence that the risks do outweigh the benefits. This is the latest step in a chain of regulatory steps."

He added that cardiovascular events were a difficult safety issue to evaluate with a diabetes drug, as diabetics tend to experience cardiac events anyway. "So we don't know if they are a consequence of the drug or a coincidence. This has been reflected in the ongoing debate that has been going back and forth for 10 tears. There is no perfect tool for evaluating this risk. And we have to consider the risk that we will lose a valuable drug. We are happy with our current decision. Are we happy that it took 10 years? Of course not, but I don't know how we could have done it faster."

Dr Kristina Dunder, a member of the EMA's Committee for Medicinal Products for Human Use (CHMP), estimated the increased risk of cardiovascular events with rosiglitazone at between 20% and 40%.

What About Pioglitazone?

Asked about the safety profile of pioglitazone, Dunder noted that "there is large probability that the cardiovascular safety of pioglitazone is different from rosiglitazone, and we have biological plausibility to confirm that." She added that the risk of bladder cancer with pioglitazone has now been raised and is being investigated. "For the time being, there is absolutely no reason to think that bladder cancer is a real risk, but a question has been raised about this, and we are consistently reviewing this with the FDA."

Details of FDA Restrictions

At an FDA telephone briefing, FDA Commissioner Dr Margaret Hamburg explained that the REMS restriction on rosiglitazone will allow new patients access to the drug only if they are unable to achieve glycemic control using other medications and, in consultation with their healthcare professional, decide not to take pioglitazone for medical reasons. Current users of rosiglitazone will be able to continue using the medication, again through a REMS program, only if they appear to be benefiting from it and they acknowledge that they understand these risks. Doctors will have to attest to and document their patients' eligibility; patients will have to review statements describing the cardiovascular safety concerns.

The FDA's explanation of its action is also detailed in a "Perspective" published online earlier today in the New England Journal of Medicine [1].

The agency anticipates that the REMS will limit use of rosiglitazone significantly. Hamburg estimated that about 600 000 patients are currently taking rosiglitazone in the US, but this number is now expected to "fall significantly," she said. However, the REMS programs will take several months to set up.

The rosiglitazone label will also be strengthened to include even stronger warnings of cardiac risk, but Hamburg said that because new label warnings are not always read, the "significant questions" about the drug’s cardiovascular safety justified stronger measures to support good clinical decision making and protect patients--hence the REMS program.

Echoing the EMA's comments on the different action in Europe, Hamburg said both the FDA and EMA had reached similar conclusions about the safety of rosiglitazone, but the different actions taken reflected different tools available in Europe and the US. She added: "We [the FDA and EMA] are taking somewhat different strategies, but both are trying to ensure the goal of safety."

Dr Janet Woodcock (director, FDA Center for Drug Evaluation and Research) elaborated: "We have a signal of increased cardiovascular risk with rosiglitazone from the meta-analyses, but there is still considerable uncertainty about the existence and magnitude of that risk. Data from randomized studies have not provided enough reassurance that the drug meets the required standard of safety. Therefore, as a matter of prudence, we have decided to restrict access to the drug. But we have heard very clearly from patients and doctors that some patients were unable to tolerate other diabetes medications and this drug was effective for them. Our approach will enable those patients to continue taking rosiglitazone as long as they are fully informed of the risks."

RECORD to Be Readjudicated

On the readjudication of the RECORD trial, Hamburg noted that this study has the potential to help address the question of the cardiovascular safety of rosiglitazone, but during the course of the FDA's review of the RECORD study, serious questions arose about potential bias in identification of cardiovascular events arising from the study's open-label design. The FDA is therefore requiring the readjudication of end points to provide additional clarity about the findings. "In this way, we hope to catch events that might have occurred but not been referred to the adjudication committee."

Woodcock added: "We hope that readjudication of the RECORD data will help address the cardiovascular safety issue raised by the meta-analyses."


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