IHS Global Insight Perspective | |
Significance | GlaxoSmithKline's (GSK; U.K.) Avandia woes appear to have reached an all-time high after the U.S. FDA released briefing documents discarding the validity of the result of the main trial, which looked at the drug's cardiovascular risks. In addition to FDA scrutiny, the European Medicines Agency (EMA) is also due to review the safety profile of Avandia. |
Implications | The FDA is due to hold a vote to decide on the future of the drug on 13–14 July, and the EMA meeting is due to be held on 19–22 July. |
Outlook | The tone of the FDA's briefing documents suggests that the agency is very critical of GSK's assessment of the drug's cardiovascular risks; however, it falls short of suggesting strongly that the drug should be withdrawn. Nevertheless, the scrutiny the drug has faced over the last few months suggests that the odds are stacked against GSK, not just in the United States, but also in the European market. |
Summary of Clinical Data on Avandia
Long-term controlled clinical trials for U.K. pharma major GlaxoSmithKline's (GSK's) Avandia (rosiglitazone) include the DREAM, ADOPT, and RECORD trials. These three trials involved over 14,000 patients, with a mean duration of exposure to the drug of 41 months.
- DREAM: This trial included 56,269 patients with impaired glucose tolerance or impaired fasting glucose in order to evaluate the efficacy of placebo, Avandia monotherapy, ramipril monotherapy, and Avandia plus ramipril.
- ADOPT: The ADOPT trial evaluated Avandia monotherapy, metformin monotherapy, and SU monotherapy in 4,351 patients with Type 2 diabetes whose condition was previously managed by diet and exercise alone.
- RECORD: This trial evaluated Avandia as an add-on therapy to either metformin or sulfonylurea, in comparison with metformin and a sulfonylurea; the primary endpoints of the trial were cardiovascular death, hospitalisation, and CHF.
When the U.S. FDA evaluated the results from these trials in 2007, it concluded that the results did not indicate that Avandia was associated with a statistically significant increase in unexpected cardiovascular adverse events. However, it noted that a higher rate of myocardial infarctions was observed in the Avandia arm of the trials.
The RECORD study sparked a wider debate about the potential cardiovascular risks of Avandia. According to the FDA briefing documents, the main sticking point about the study is that its limitations in terms of its design conduct and evidence point to biased findings. In response to various issues highlighted about Avandia's cardiovascular profile, the FDA has revealed details on a comprehensive review of the RECORD trial that focuses on the trial design and conduct, endpoint adjudication, analysis issues, and cardiovascular results.
- Trial design: The RECORD trial was conducted as part of a post-marketing obligation that was requested by European regulators. According to the FDA, three issues in the trial design may have led to biased results, and a further 13 issues were raised that may have led to bias towards Avandia being non-inferior in terms of its cardiovascular risks. In light of this, the FDA has concluded that the RECORD trial does not accurately reflect Avandia's cardiovascular risks.
- Trial conduct: The FDA highlighted that the protocol designs for the RECORD trial also adversely affected the reliability of the study. The issues raised in terms of trial conduct that resulted in bias include failures to refer events for adjudication, and other adjudication issues including missed endpoints, adjudication disagreements, and insufficient information.
- Endpoint, adjudication, and analysis issues: The primary endpoints in the RECORD trial, which include cardiovascular death and hospitalisation, have been disregarded by the FDA due to the fact that these endpoints may be affected by a number of other factors. The most appropriate safety endpoints for RECORD were identified as myocardial infarction, stroke, and cardiovascular death. Referrals for adjudication and the adjudications themselves have been described as "erratic". Additional evidence shows that the cardiovascular follow-up in RECORD was low.
Following the publication of this 765-page briefing document, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting will meet on 13–14 July to make a decision on what course of action the FDA should take on Avandia, in light of the available evidence. Members of the two groups will be asked to vote for one of the following options:
- Allow continued marketing and revise the current label to remove the boxed warning and other warnings regarding an increased risk of ischemic cardiovascular events
- Allow continued marketing and make no changes to the current label
- Allow continued marketing and revise the current label to add additional warnings (for example, contraindications for certain patient populations, recommendation for second-line use in patients intolerant of, or uncontrolled on, other anti-diabetic agents)
- Allow continued marketing, revise the current label to add additional warnings, and add additional restrictions on use (such as restricting prescribing to certain physicians or requiring special physician and patient education)
- Withdrawal from the U.S. market
EMA Review of Avandia
As the FDA prepares to makes a decision on the fate of Avandia, GSK has announced that the European Medicines Agency (EMA) is due to evaluate the safety profile of the drug. The Committee for Medicinal Products for Human Use is due to convene for a meeting over 19–22 July to discuss the risk/benefit profile of the drug, based on available data.
Outlook and Implications
Based on this FDA briefing document, it is likely that GSK will go into the advisory committee meeting hoping for a positive outcome, but also prepared for the worst. Since the publication of the Senate finance committee report on Avandia, evidence against the drug and calls for its withdrawal have been coming hard and fast. Two peer-reviewed studies published in Archives of Internal Medicine and the Journal of the American Medical Association (JAMA) linked the drug to cardiovascular adverse effects. The study in Archives of Internal Medicine, which evaluated 56 clinical trials, showed that patients on Avandia increased their risk of heart attack by up to 39%. The JAMA study of 227,571 Medicare patients over the age of 65 that were treated with either Avandia or rival drug Actos (pioglitazone; Takeda, Japan) showed that in comparison with Actos, Avandia increased the risk of stroke by 27%, heart failure by 25%, and death by up to 3%. Separately, powerful pressure groups such as United States-based health research group Public Citizen have lobbied U.S. lawmakers to withdraw the drug immediately. GSK has also been hit by Avandia-related lawsuits, some of which the company is in the process of settling. The number of settlements remains unclear, but the timing has been described as suspicious, as it appears that GSK is keen to stave off legal threats to the drug around the time of the FDA meeting. The briefing document is available here.
The EMA review of Avandia is not surprising. Although the decisions of the FDA and EMA remain independent, a negative verdict by the FDA could possibly put pressure on the EMA to take similar steps, especially in light of the media attention the Avandia saga has attracted.