Three years after the once-popular diabetes drug Avandia (rosiglitazone) largely disappeared from medicine cabinets following a dramatic reappraisal of its cardiovascular risk, the drug’s partial vindication on June 6, 2013, by a US Food and Drug Administration (FDA) advisory panel1 has come too late to revive its fortunes, experts say.
But the controversy that engulfed Avandia and its roller coaster ride through the regulatory process continue to have farreaching implications for clinical practice and drug development.
“Now that the water has cleared, we look back and see that it never was a problem. There was no cardiovascular benefit, but no problem either,” said Fernando Ovalle, MD, director of the Multidisciplinary Comprehensive Diabetes Clinic at the University of Alabama-Birmingham. Ovalle was referring to the findings of an independent team of researchers from the Duke Clinical Research Institute commissioned by the FDA to analyze, or readjudicate, data from drug maker GlaxoSmithKline’s RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) trial.
The Duke team concluded that Avandia did not present a serious cardiovascular risk to diabetes patients, although it pointed out flaws in the trial’s design, noting that its unblinded nature could have affected the outcome. Based on that readjudication, the FDA panel voted in June to ease the tight restrictions on the drug put in place by the agency in 2010 and 2011.2,3
“This has put the FDA in something of a bad spot, because the agency can’t really admit it was wrong, although that is what the advisory panel said,” Ovalle noted. But Ovalle, who stopped prescribing the drug more than 2 years ago, said the findings have come too late to sway public opinion.
“Avandia’s reputation has been irreparably damaged,” he said. The drug’s maker, GlaxoSmithKline, awaits a final ruling from the FDA, but does not plan to relaunch it in the United States. “There is no news yet from the FDA, and so nothing’s changed since the adcom (advisory committee) meeting in June. The committee’s recommendations were not definitive, and the FDA takes them under advisement, and so we’re in a holding pattern,” said company spokeswoman Heidi Siegel, adding, however, “There are no plans to promote it again in the US.”
But the readjudication was not pointless, some FDA observers say. Rather, it provided a forum for the agency to scrutinizei ts own practices, while furthering public debate on wide-ranging issues related to drug review and development.
“The review was done not so much to save or damn the drug, but rather to have a thoughtful look back at what happened, recognizing that the way the saga unfolded had negative effects on the environment in which drugs are developed,”said G. Alexander Fleming, MD, the president and CEO of healthcare consulting firm Kinexum and a former FDA regulator who led the review of metabolic therapies such as Metformin. “And I think the agency’s objective was accomplished: to air the process warts and all, and to demonstrate that the FDA has a responsibility to be data-driven.”
He added, however, “In part, the review and hearing also reflect the FDA saying ‘mea culpa’ for stopping a head-tohead comparison trial of Avandia and Actos. based on the Agency’s safety concerns about Avandia. At the recent hearing, FDA acknowledged that the trial probably was justified and the results would have been valuable.” Actos (pioglitazone), manufactured by Takeda Pharmaceuticals, was Avandia’s leading competitor at the time.
Ovalle still vividly recalls Avandia’s promising debut in 1999 and its subsequent fall from grace a decade later, saying the dramatic turn of events was “hard to believe” at the time.
“The drug took off. It was one of the few agents available to type 2 diabetes (T2DM) patients, and we liked the effect it had on glucose for people who had never had it under control,” he said, adding, “There was some concern early on about possible liver toxicity, given the history of Rezulin—a similar drug—at that time, so we did liver exams every 3 months, but we didn’t find anything and we were very happy about that. In fact, we kind of fell in love with it.”
The drug was an important tool in states with high diabetes rates, such as Alabama, where 11.1% of adults were diagnosed with the disease in 2010, putting the state second only to Mississippi, with a rate of 11.3%, according to data from the Centers for Disease Control and Prevention (CDC).4
In a class of drugs called thiazolidinediones, or TZDs, Avandia works as an insulin sensitizer, reducing the body’s resistance to insulin. Ovalle said clinicians had some new concerns about the drug after a few years, noting that some of their patients gained weight and developed problems with edema. A few ended up in the hospital, although he said that was rare.
“We still defended the drug because there was nothing like it that improved glucose numbers the way it did. In terms of cardiovascular risk, we saw LDL numbers go up a little bit, and so we said we’d watch that closely,” he recalled.
“On the other hand, small studies of Avandia and Actos, another TZD insulin sensitizer, showed signs of improvement as well— cardiovascular benefits in all markers except LDL, from blood pressure, to inflammatory markers, to C-reactive protein— and so it looked like these drugs were going to lower cardiovascular events significantly. But then the studies turned out negative, showing no effect. It was disappointing to learn there were no benefits,but there weren’t clear bad effects either.”
He added that most physicians believed that it would be hard for these drugs to show definitive beneficial effect from a cardiovascular perspective given that statins were of proven benefit and standard of care therapy, and had to be given to patients during clinical trials. Despite some of these uncertainties, however, he said clinicians were stunned in 2007 when Steven Nissen, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic, published in The New England Journal of Medicine the results of a meta-analysis of Avandia trial data that showed a 43% increase in heart attacks for those taking the drug.5
Three years later after Nissen’s report, the FDA announced it would restrict use of Avandia to patients unable to control their diabetes on other medications, ultimately requiring them to enroll in the agency’s Risk Evaluation and Mitigation Strategy program in order to receive it.2,3 “Steve Nissen’s paper came as a complete surprise to many of us who thought the opposite. He said the drug caused heart attacks. And while the medical community was given the impression with his meta-analysis that the drug was dangerous, to be fair, the meta-analysis was incomplete and heavily criticized by statisticians, but that didn’t matter in the ensuing public controversy. Things became politicized, and the debate was no longer based on science,” he recalled.
“The FDA responded by making the ‘safe’ move in sharply restricting Avandia and that killed the drug. The perception was so poor that patients were asking to be taken off it. As a doctor, if you tried to reassure them, you put yourself in a bad position. Lawyers were out there advertising, saying, ‘If you took Avandia, call us.’ I stopped prescribing it.” Fleming described Avandia’s situation as “almost unique along the spectrum of what happens in drug development and regulation.”
Nissen took a look at the publically available Avandia trial data and added up the cardiovascular events associated with Avandia and the control treatment. This approach is called a meta-analysis and is generally regarded as “hypothesisgenerating, never definitive because of some significant limitations,” Fleming said. “There was nothing wrong with Nissen performing the meta-analysis or even the Journal publishing it, though it rarely publishes meta-analyses. The problem was with Nissen’s over-reaching conclusions and the editors allowing the title of the article itself, which implied both definitiveness and that higher death rates were caused by Avandia,” he said.
“Nissen went on to publish conclusions that the closely related and competing drug, pioglitazone (Actos), provided cardiovascular benefits, making Avandia even more untenable.” Multiple FDA advisory panels were called—including one the resulted in the FDA “guidance,” published in record time, that cardiovascular safety trials would have to be completed before any therapy for T2DM could be approved. This requirement suddenly added years and perhaps as much as $500 million to the cost of developing a drug for T2DM, Fleming said.. The controversy around Avandia itself escalated. In the wake of the Nissen paper, at FDA there was a storm of additional reviews and different opinions reached about Avandia.
“In the FDA drug review process, data, analyses, and interpretations are verified by a host of well-qualified professionals. The FDA reviews of Avandia went beyond this standard approval process. It added not 1 but 2 rounds of adjudicating which patients in the Avandia RECORD trial had serious cardiovascular events. Event adjudication is generally the responsibility of an expert panel independent of the FDA and the company (though the company selects the panel). Adjudication during the initial review process may be done when there is a particular reason. What is more unusual is to have the adjudication process come after the drug approval. Even rarer, if not unique, is to have a second adjudication process as occurred with FDA’s commissioning of the Duke Clinical Research Institute. The Duke report absolved Avandia from showing increased cardiovascular risk in the RECORD trial. This undoubtedly led to FDA’s soul-searching.” he said.
Since then, however, new health concerns about the entire class of TZDs have emerged, making the debate over cardiovascular risk essentially a moot point. “There is an even larger story about this class: it’s going away and not because of the CV issue. Over the past several years, data have emerged that point to increased risks of bladder cancer and osteoporosis associated with pioglitazone and ongoing concern about fluid retention caused by TZDs, which could worsen congestive heart failure, TZDs have already been removed from the market in Germany and France,” Fleming said.
“Over the past decade there has been a lot of progress on the drug review and the clinical development process. One of the key lessons learned is that long-term clinical outcomes do need to be verified and not just assumed. Rather than just relying on treating a number such as blood sugar, we now more often look at the longer term measure of a drug in preventing complications of the disease,” he said.
“We won’t see TZDs any more, although perhaps for the wrong reasons,” Ovalle commented. “They are gone and we have moved on.” He said that TZDs have been replaced by new drugs that are working well, including GLP-1 (glucagon-like peptide-1) receptor agonists, DPP-IV (dipeptidyl peptidase IV) inhibitors, and most recently, SGLT-2 (sodium-glucose transport 2) inhibitors, “with no weight gain or edema, and no bad press.” The new drugs accomplish some of what the insulin sensitizers did but through different mechanisms, he noted, including through weight loss. “GLP-1 agonists are drugs that are focused on anti-hyperglycemia, and a nice side effect is that they help people lose weight. Another class of drugs, SGLT-2 inhibitors, also look like good drugs but these are new and we always have to be careful with new drugs as there may be things we don’t know about them yet,” he said.
“In general, when I prescribe a newer drug like any of these, I now say to patients that I think it’s a safe drug, but I now have to include a disclaimer on the possibility of yet unknown side effects. That’s something I never did before.”
Ovalle said that Avandia’s dramatic regulatory reversal, among other controversies in recent years, has left him with a somewhat jaundiced view of the agency’s review process. “I think the FDA is heavily influenced by the media. Regulators probably feel under pressure to protect their jobs,” he said. “On the other hand, people who sit on the FDA’s advisory panels often have close ties to the pharmaceutical industry and to particular drugs, and disclosure of these conflicts of interest is probably not sufficient.”
Fleming described the controversy’s legacy as mixed. The controversy over Avandia, he said, led directly to diabetes drugs having to undergo cardiovascular safety trials. “This is not necessarily a bad idea, but it’s expensive and adds 3 to 4 more years to the drug review. However, the question remains: Should this be a slavish requirement? If no other drug in the class has shown a problem, it’s probably not a good idea, not just from the standpoint of cost but in terms of consuming patients who are a scarce resource. Drug companies can afford to do the trial, but they are tapping out a resource that is under pressure. The negative effect of that may be that important trials are suffering from competition for this resource from trials that are not important and take a substantial amount of time to process.”
By contrast, he noted, anti-obesity drugs have not been required to do cardiovascular safety trials. “They are done on a case-by-case basis for cause. With type 2 diabetes drugs, we are headed in that direction, but it’s unclear how quickly.” “Going forward, I think we need to look to a stepwise process, which should be formalized by the agency, in which products make it out of review sooner but under more restrictive use. We shouldn’t have a one-size-fits-all approach or set the bar so high that it impedes development of important therapies.”1. FDA panel votes narrowly to modify Avandia restrictions, June 6, 2013. http://www.reuters.com/ article/2013/06/06/avandia-fda-idUSL1N0EH1XH20130606. Accessed September 10, 2013.
2. FDA website. FDA significantly restricts access to the diabetes drug Avandia. Press release, September 23, 2010. http://www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ ucm226975.htm Accessed September 10, 2013.
3. FDA website. FDA Drug Safety Communication: Updated Risk Evaluation and Mitigation Strategy (REMS) to Restrict Access to Rosiglitazone-containing Medicines including Avandia, Avandamet, and Avandaryl. Press release, May 18, 2011. http:// www.fda.gov/Drugs/DrugSafety/ucm255005. htm. Accessed September 10, 2013.
4. CDC website. Percentage of US adults with diagnosed diabetes, by State 2010. http://www. cdc.gov/diabetes/atlas/countydata/atlas.html, Accessed June 20, 2013.
5. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes [published online May 21, 2007]. N Eng J Med. 2007;356(24):2457-2471.