European regulators explain why they suspended rosiglitazone

December 14, 2010

London, UK - In an era of increased transparency, a new paper published this week helps explain the recent European decision to suspend the marketing authorization of rosiglitazone (Avandia, GlaxoSmithKline) and all rosiglitazone-containing antidiabetes medications licensed in the European Union—Avandia, Avandamet, and Avaglim[1].

The controversial drug, as reported extensively by heartwire , was pulled from the European market after the European Medicines Agency (EMA) recommended the suspension of its marketing authorization. The decision, made September 22, 2010, followed the conclusions of the EMA's Committee for Medicinal Products for Human Use (CHMP) that "the benefits of rosiglitazone no longer outweigh the risks."

In the paper, published online December 14, 2010 in the journal Diabetologia, representatives of the European agencies, including the EMA, the Swedish Medical Products Agency, the Dutch Medicines Evaluation Board, and the Agence Fran ç aise de S é curit é Sanitaire des Produits de Sant é, summarize the available evidence considered by the national regulatory agencies within the European Union and their representatives in the CHMP.

"We wanted to give physicians a better understanding of how the evaluation process actually works because we might be seen sometimes as a bit of a black box," Dr Eberhard Blind, head of endocrinology, metabolism, and cardiovascular safety and efficacy of medicines at the EMA, told heart wire . "It's probably not completely transparent how our decision processes work, such as the scientific advisory groups that we consult in the decision process and what information we received and when we received it. The purpose is to make this a little more understandable to people outside the regulatory field."

A brief history of
rosiglitazone's time

In their review, Blind and colleagues attempt to get a handle on all that has gone on, and wrong, with rosiglitazone since it became available in Europe in 2000. At that time, one of the safety concerns was fluid retention and higher rates of congestive heart failure compared with insulin alone, and as a result rosiglitazone was contraindicated in patients with heart failure and in patients also taking insulin.

In 2006, however, the risks of cardiac ischemia associated with rosiglitazone were starting to surface, and information was included in the product information based on data provided by the marketing authorization holder (MAH). Still, it was the meta-analysis performed by Dr Steven Nissen and Kathy Wolski (Cleveland Clinic, OH), which suggested an increased risk of MI and a numeric, but not statistically significant, increase in cardiovascular death that really generated the discussion and controversy about the benefits and risks of rosiglitazone.

In their paper, Blind and colleagues highlight the results from the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, a trial previously reported by heart wire , and discuss its limitations. That large morbidity and mortality trial of rosiglitazone, published nearly 10 years after the drug was approved, showed no overall cardiovascular risk, but methodologic questions dogged the trial, making the findings controversial. Officials from the Food and Drug Administration (FDA) have criticized this trial, as have other experts, and the EMA concluded the study was "inconclusive with regard to cardiovascular events, neither showing definite proof of an increased rate [of cardiovascular events] nor rejecting its hypothesis."

The regulatory representatives also discuss some of the other major rosiglitazone trials that emerged since 2007, including an updated meta-analysis that included the RECORD trial and that strengthened the original results, and a study performed by FDA scientist Dr David Graham showing an increased risk of cardiovascular events with rosiglitazone compared with pioglitazone (Actos, Takeda Pharmaceuticals) in Medicare subjects. They also cite an FDA meta-analysis of 52 studies with rosiglitazone showing an increased risk of adverse cardiovascular outcomes.

During this time, the EMA's scientific committee, CHMP, repeatedly deliberated on the rosiglitazone issue, and the EMA consulted with the various European regulatory agencies. In addition, the EMA met twice with its own scientific advisory group on diabetes/endocrinology and cardiovascular issues. In 2008, the scientific advisory group stated rosiglitazone had a small but diminishing role in clinical practice, but by July 2010 they felt that the available evidence had shifted against rosiglitazone, ultimately leading to the September 2010 recommendation from the CHMP that marketing authorization be suspended.

To heart wire , Blind said rosiglitazone is a "complex story," but the decision to suspend marketing authorization was undertaken "very carefully and utilized a large amount of resources this past summer." He said, and it is noted in the paper, that despite the wide array of clinical data, the evidence of cardiovascular risk with rosiglitazone is not unequivocal and was at times conflicting. Despite this, however, the evidence of harm could not be refuted, he said.

Different from the FDA

As reported previously by heart wire , the decision reached by the EMA differs from the FDA judgment. In the US, rosiglitazone remains on the market, but with heavy restrictions. All rosiglitazone-containing medicines are available but have safety labeling and restrictions for use, including a risk evaluation and mitigation strategy (REMS) program that requires additional measures be taken by the prescribing physician so that the medicine is used properly.

Explaining the decision in a September 22, 2010 briefing document, Dr Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, stated that the evidence of cardiovascular ischemic risk with rosiglitazone is not "robust or consistent," but there were multiple signals of concern. The agency chose to keep the drug on the market because of this open question, until a detailed readjudication of events and analysis of RECORD could be performed. The FDA also stated that there are diabetic patients who would benefit from glucose control but are unable to tolerate pioglitazone.

Blind chose not to comment on the FDA decision, stating the different regulatory, legal, and healthcare environments make such comparisons difficult. The purpose of their paper, he said, was simply to explain the EMA decision on rosiglitazone. He added that the opinions expressed in the paper are his and his coauthors and not made on behalf of the EMA, although their thinking largely reflects the opinions of the agency.

The assessment of rosiglitazone, however, took place with the involvement of the entire European Union regulatory network, including all national agencies. The EMA plans to publish a detailed European Public Assessment Report (EPAR) shortly on the rosiglitazone decision.

No conflicts of interest to report.

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