FDA Approval Process: The case of Rosiglitazone (Avandia)

Rosiglitazone (Avandia) is an antidiabetic drug in the thiazolidinedione class of drugs. It works as an insulin sensitizer, by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with metformin or with glimepiride.

Released in 1999, annual sales peaked at approximately $2.5-billion in 2006; however, following a meta-analysis published in the New England Journal of Medicine in 2007 that linked the drug’s use to an increased risk of heart attack, sales plummeted to just $9.5-million in 2012. The drug’s patent expired in 2012. Despite rosiglitazone’s effectiveness at decreasing blood sugar in type 2 diabetes mellitus, its use decreased dramatically as studies showed apparent associations with increased risks of heart attacks and death. Adverse effects alleged to be caused by rosiglitazone were the subject of over 13,000 lawsuits against GSK; as of July 2010, GSK had agreed to settlements on more than 11,500 of these suits.

Some reviewers recommended rosiglitazone be taken off the market, but an FDA panel disagreed, and it remained available in the U.S. From November 2011 until November 2013, the federal government did not allow Avandia to be sold without a prescription from a certified doctor; moreover, patients were required to be informed of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies. In November 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of the 2009 RECORD clinical trial (a six-year, open label randomized control trial), which failed to show the heart infarct risks associated with the drug. How could this case or another like it, happen in the modern FDA process? – question posed by Dr. Jeff Talbert, University of Kentucky College of Pharmacy.

Avanda - Casualty of the scientific process?

Avanda – Casualty of the scientific process?

Given the current system of drug approval in the United States, it is actually surprising more cases similar to rosiglitazone do not occur. Studying a drug’s safety and efficacy profile through a basic research lens in a Randomized Controlled Trial (RCT) allows the researcher to control the environment and eliminate many confounding variables. While this might allow the researcher to demonstrate a relationship between use of the drug and a set of target endpoints compared to placebo in a controlled environment, the external validity is rarely this cut and dry. The initial RCT’s used to get a drug approved usually do not have large enough enrollments to statistically identify differences in rare adverse events compared to placebo. Unfortunately, large post-market observational studies are then the usual breeding ground for such research, leading to the exact situation described with rosiglitazone.

Whether or not the FDA should revise their policy for drug approval and review sparks an interesting debate. The current process is already arguably too slow in terms of getting potential life-saving or outcome-improving drugs to market. In fact, the controversial approval of anti-retroviral drugs in the 1980’s created so much unrest in the communities affected by the AIDS virus that underground networks formed to smuggle drugs into the United States from Mexico to treat the disease (See: Ron Woodroof famously known for the Dallas Buyer’s Club). Adding requirements to the drug approval process would likely extend the time to market, decrease the available years before patent expiration, and increase costs making the investment in new drugs more risky for pharmaceutical manufacturers. The ability to predict all of the potential adverse events or long term side effects of taking a medication is impossible in the stages of development. If a drug has only been in existence for 6 months, then it is impossible to know whether or not it statistically raises your risk for cancer after you have taken the drug routinely for 20 years.

Rather than changing FDA policies, pharmaceutical companies would be better served donating to public schools to increase math and statistics education in the United States so that the general population would have a better chance in understanding “why” a researcher is unable to account for all potential adverse events. Common and significant drug reactions are usually found in the initial trials, but the rare ones do slip through the cracks due to the insufficient power in these trials. The case of rosiglitazone demonstrates the need for post-market observational studies and quasi-experimental protocols to identify “potential” links to adverse events. Then once a potential side effect is discovered, the drug company should immediately invest in a RCT that looks specifically at that side effect and the use of their drug versus placebo (in this case they might actually even compare against a competitor, because if they found a link they could say “Hey, this is just a side effect of the drug class”). The RCT is needed because it would have a higher internal validity and likelihood of identifying a true connection between drug and adverse event. Both basic and applied research should be used, but practitioners need to understand the difference.

The swings of support for rosiglitazone would best be described by the Punctuated-Equilibrium policy framework by Baumgartner and Jones. From approval of rosiglitazone up until the release of the NEJM meta-analysis, speculation about the drug’s relationship to heart attack risk would have existed in the medical community. Peer-reviewed publications in NEJM do not happen at random or overnight, so the years prior to 2007 it is likely that some practitioners were calling for additional studies or investigation into a possible heart attack linkage. Then after the journal publication and drop in utilization of the drug, scientists (especially ones from GSK) were working to answer the question if the drug was truly related to the adverse event. These policy shifts were punctuated by major events, but were the result of a lot of work and gradual steps. Unfortunately for GSK, the Punctuated-Equilibrium model only explains the policy shifts, but does nothing to help the brand image for Avandia® and the damage done by the NEJM article. At this point (especially with lack of patent exclusivity), GSK is better off moving on to other drugs in the pipeline.

The complexity of the pharmaceutical industry adds another challenge for those who want to bring pharmaceutical products to market. In the case of rosiglitazone, newspaper editors are not likely to publish the headline:

“According to a meta-analysis published in the New England Journal of Medicine, researchers may have found a link between heart attacks and the use of Avandia, but before you stop taking your diabetes medication please wait for the results of a controlled clinical trial to determine if Avandia actually causes heart attacks.”

Instead, a newspaper might read:

“Avandia found to cause heart attacks according to the New England Journal of Medicine.”

Or even more simply a Tweet that reads:

Avandia = Heart Attack #thanksGSK”

The media and general public are unable to fully grasp the complexity behind the research that lead to these conclusions, but are quick to coalesce behind a blurb of 140 characters or less that can be digested from our smartphone while driving down the road. Being able to dumb down the process into bite-sized chunks and the sensationalism of negative events (notice that the media didn’t have the same “Oops, my bad GSK” moment after 2009), puts added pressure to companies in this environment. The best strategy may be to accept the current reality and focus efforts on controlling the media message and continuing to spend a lot of money on media campaigns (Enter direct-to-consumer advertising). Welcome to the world of pharmaceutical manufacturing and drug approval in the United States. While it is not ideal for the patient, I would still argue that it is a pretty good process that has evolved substantially in the last half century.


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Joey Mattingly, PharmD, MBA is an assistant professor at the University of Maryland School of Pharmacy located in Baltimore, Maryland. Joey has managed retail and long-term care pharmacy operations in Kentucky, Illinois and Indiana. Leading Over The Counter is a blog of Joey's views and opinions on the topics of pharmacy leadership and management and do not represent the University of Maryland, Baltimore. Joey can be followed on Twitter @joeymattingly.

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