Lisa Nainggolan, Sue Hughes

September 24, 2010

September 24, 2010 (Stockholm, Sweden)— Doctors at the European Association for the Study of Diabetes (EASD) 2010 Meeting yesterday said they were surprised by the fact that the European Medicines Agency (EMA) and the US FDA had made different decisions with regard to rosiglitazone (Avandia, GlaxoSmithKline) but that they would respect these differing decisions and work to ensure that they were carefully communicated to physicians and patients.

Diabetologists from both the EASD and the American Diabetes Association (ADA) spent yesterday afternoon at the European meeting conferring on the subject of rosiglitazone and had hoped to issue a joint statement because they knew the two regulatory agencies were due to issue their verdicts on the drug simultaneously.

The FDA and EMA had coordinated with each other and knew what each other's decision would be; in two telebriefings carefully scheduled to coincide with each other, the agencies "put the cat among the pigeons" when the Europeans announced the drug would be suspended while the Americans chose to keep it on the market, albeit under a restricted access program, as reported by heartwire .

Dr Steven Nissen

Some of the experts polled felt the agencies should have come to the same conclusion, while others said they understood that such decisions were "not black and white." Officially, however, the ADA and EASD stood behind the decisions made by their respective regulatory bodies.

Meanwhile, Dr Steven Nissen (Cleveland Clinic, OH), the physician who has spearheaded the campaign against rosiglitazone after conducting the first meta-analysis that suggested harm, said he was "very pleased" with the European decision and that the FDA action was a "reasonable outcome."

Experts Agree, Why Should Regulatory Agencies Differ?

The executive director of the EASD, Dr Viktor Jorgens,told heartwire that he is personally perplexed by the split. "In the diabetes world, we have the ADA and our research-oriented organization EASD. It makes sense for the patients, the community, and the politicians that we sit together, put all the facts together, and make a recommendation, and this is feasible in many aspects. The experts are able to agree on something, and it doesn't really make sense that these two regulatory institutions should differ substantially."

He added that it was unfortunate that "we could not make a statement together with ADA--which we would have liked to do because we are such good friends. But they have commended what the FDA says, and we have to commend what the EMA states."

It doesn't really make sense that these two regulatory institutions should differ substantially.

Dr David Matthews

Dr David Matthews (University of Oxford, UK), who is chair of the panel on global statements for EASD, told heartwire : "It's quite interesting that they have agreed to disagree. And it's surprising, because I know the FDA and EMA have conversed about announcing their decisions, so there was some expectation that they might be concordant." But, he added that "there is no opprobrium attached" to the decisions differing.

"The problem that the regulators face is that information about drugs is not black or white," Matthews continued. "So it's reasonable when you've got drugs where there is that level of uncertainty that people can move in either direction. I think the published evidence for rosiglitazone is very much on the midpoint; if you take the RECORD study, is it doing you any harm? Or is it doing you good? Or you can take another view . . . saying there's no point in marketing something if it's not doing any good, but on the other hand, there is no point in withdrawing something if it's not doing any harm. "

There's no point in marketing something if it's not doing any good, but on the other hand, there is no point in withdrawing something if it's not doing any harm.

Dr Ulf Smith

EASD president Dr Ulf Smith, unsurprisingly, would not be drawn on who had made the "right" decision: "This is the evaluation by the agencies, and obviously they differ, but it's not a very easy decision," he told heartwire . "The FDA wants patients to be well-informed about the potential risks and also they want to see a follow-up evaluation of the RECORD study to see if there is any signal that would be more convincing in terms of withdrawing or continuing [to market rosiglitazone]."

However, earlier in the week at a press conference here, Smith had said: "Everyone is apprehensive [about Avandia], so perhaps we shouldn't use it, and there are alternatives." And many doctors discussing rosiglitazone here before the regulatory decisions were announced said they didn't initiate use of it anymore, although they said they also did not stop patients from taking it if they were doing well on it, without any sign of problems.

But Are the Decisions That Different?

In a hastily convened joint ADA/EASD press conference just minutes after the decisions were announced yesterday, doctors strongly urged patients everywhere to consult with their physicians before making any decisions about therapy and that they should not, under any circumstances, simply stop taking their medication.

"We've not had time to study all the documents, but it's very important for us at EASD to promote the information that patients should contact their physician in order to get a different prescription. It's vital that all patients who have diabetes continue with antidiabetic therapy," Smith said.

Dr David Kendall

Dr David Kendall (chief scientific and medical officer, American Diabetes Association) concurred. "All patients who have concerns should seek the counsel of their healthcare provider and be aware that there are a number of effective treatment alternatives to rosiglitazone," he said.

Kendall said the ADA will, together with its sibling endocrinology organizations in the US, "obviously defer" to the FDA for regulatory decisions, while Matthews said official EASD position "is that it is for the regulators to make the rules.

"Two agencies with great expertise have come up with . . . what appear to be discrepant decisions," Kendall added, but "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."

Kendall also pointed out that, when closely examined, the advice from each respective agency is perhaps not as divergent as it might first appear. Patients will be allowed to take rosiglitazone in the US only if alternatives are not available, he stressed, urging journalists, "as you report this, to look closely at the wording [on the FDA documentation] and the similarities [with the EMA] in how the data are interpreted, even if the final decision in the US remains between provider and patient."

The FDA restrictions will essentially result in the same outcome as suspending the drug. . . . It is effectively gone."

Nissen agreed. He told heartwire : "The FDA restrictions will essentially result in the same outcome as suspending the drug. Doctors will have to do so much paperwork to allow a patient to take it that that alone will keep 99% of prescriptions from being written. So the drug is effectively gone."

Asked during the press conference whether the EMA had ever allowed a drug back on to the market that had previously been suspended, the EASD representative to the EMA, Dr Clive Bailey (University of Aston, Birmingham, UK), said he did not think this had ever happened.

Readjudicating RECORD "Is Ridiculous"

Nissen is, not surprisingly, still extremely critical of the way the rosiglitazone issue has been handled by the regulatory agencies. "This drug should never have been approved. It has shown no evidence of benefit other than a reduction in blood sugar; even at the time of approval it was known that it increased cholesterol. But regulatory authorities worldwide allowed it to be marketed for 11 years, during which time it became the world's best-selling diabetes drug, with peak sales of more than $3 billion.

"And we have known for five years that this drug has been harming people," he added. "The company and the FDA both knew there was an increase in MI but failed to issue sufficient warnings or act to remove it, until now. There are still one million prescriptions a month being written for rosiglitazone. It just shows the power of marketing." However, he conceded that GlaxoSmithKline has agreed to stop marketing the drug from now on.

And on the readjudication of the RECORD trial, Nissen called this a "face-saving exercise for the FDA" and said he saw no way that the drug could be resurrected from this activity. "You have to keep in mind that you can't appropriately evaluate the safety and efficacy of a drug from an open-label trial. The idea of readjudicating events from almost a decade ago is frankly a little bit ridiculous."

At a press conference earlier this week at the EASD meeting, Matthews said the "scrutiny of the RECORD study has revealed some worrying issues," and he said it has prompted a big push from the EASD--which it is conferring with the EMA on--to seek more access to clinical-trial data. "This is something that came very clearly out of the FDA hearing," he noted. "Data must be open to scrutiny."

It's Vital That Diabetes Research Does Not Suffer

However, the doctors in Stockholm also stressed that it is vital for the development of new diabetes drugs that research continues unfettered.

"You can't do cardiovascular-outcomes trials on every single new therapy for diabetes," Matthews said, because the complexity of the disorder, which now has six different ways to be treated, with 64 possible permutations of combination therapy, means that outcomes trials would need too many patients and take too long. Industry would never fund such studies because the patents on the new compounds would expire before the trials were finished, he added.

"We need to be open to new ideas about therapeutics, because we haven't solved diabetes in any sensible way yet. There are real issues about inhibiting research if the regulations are so onerous that no new therapeutics are brought to market," Matthews said.

You can't do cardiovascular-outcomes trials on every single new therapy for diabetes.

Dr Jonathan Bodansky (St James University Hospital, Leeds, UK), who runs a large diabetes clinic in the UK, told heartwire : "Cardiologists need to know that these new drugs come out, and to get outcomes data takes a long time; this was exemplified by rosiglitazone. And the event rate in people with diabetes is progressively going down, due to a number of reasons, so it is going to be difficult to demonstrate [effects on] cardiovascular end points and outcomes. . . . It may take a decade or more.

"Drugs are usually licensed or allowed onto the market not because they've got long-term end points but because they do the job they are supposed to do, which is control diabetes or lower BP or cholesterol," Bodansky noted. "So one can only extrapolate as to what these drugs do, and the most useful thing is whether they lower HbA1c, although that was shown with glitazones, but the difference was that they tended to cause weight increase and fluid retention, and those have been the major disadvantages of that class of drugs."

Cardiovascular Outcomes Are Not the Only Ones That Are Important

"You also have to remember that cardiovascular outcomes are not the only thing under consideration here," Matthews added to heartwire . "We all agree, death is not the worst event in any of our lives. People say, 'If drugs stop you from going blind and so on, they would be drugs that I would rather like to take, even if it was demonstrated that my longevity was not changed.'

"Drugs should not be abandoned just because they have a neutral effect on cardiovascular outcome," which in any case is only important in certain groups of people, he stressed. "If I have drug trials where I'm only interested in those who have a heart attack, I forget about most of you in this room. If you say it's all about cardiovascular disease, you might run into trouble, and you will have a tendency to recruit high-risk patients [into trials] who might not reflect the general diabetes population. We need drugs to be safe, but we need to think about the different patient groups. Should we do outcomes trials in teenagers, for example?"

In fact, all the diabetes doctors at EASD were keen to point out that the key to good diabetes treatment is personalizing therapy and that it should never be forgotten that, as well as the evidence base and expert-prompted guidelines, two other things must be taken into account: physician and, above all, patient preference. "I have some patients who say, 'I'd rather die than take insulin, and I will die,' " Matthews said."So I say, 'Well, you need insulin because your blood sugar is so high, but I'm going to try to find some other ways to manage this.'

"We are debating with the EMA to have rational thresholds for cardiovascular safety, while pressing for much more openness with regard to data; there shouldn't be a huge locked archive at the end of a trial," he concluded.

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