IHS Global Insight Perspective | |
Significance | The report concluded that GSK was aware of the cardiac risks associated with Avandia "years before" it became public, but failed to convey the risks adequately to the U.S. FDA or patients. The legislators were also equally critical of the FDA, noting that the agency had allowed the continuation of a clinical trial for Avandia even after it had been described by the agency's own officials as "unethical" and "exploitative" to patients. |
Implications | At the heart of the report is the debate over whether post-marketing surveillance efforts by the FDA have been successful, and the conclusion was they have not. |
Outlook | The report will lead to intensified calls to push for a withdrawal of Avandia from the U.S. market, while the FDA will look to implement the recommendation of the Institute of Medicine, which has underlined the need for increasing independence for the post-marketing drug-surveillance team. |
Senate Finance Committee on Avandia
The key conclusions have been revealed of a probe initiated in 2007 by the U.S. Senate Finance Committee after the emergence of concerns over adverse risk associated with diabetes drug Avandia (rosiglitazone), and the related response from the U.S. FDA and the drug's manufacturer, GlaxoSmithKline (GSK; U.K.). The report's findings were announced by Senator Max Baucus, chairman of the Committee on Finance, and Senator Chuck Grassley. Avandia is indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus; the franchise garnered sales of £771 million (US$1.19 billion)—a 16% drop—for the year ended 31 December 2009.
Given the objectives of the investigation, the conclusions relate to the actions of GSK and the FDA. The authors of the report were very critical of the U.K. pharma major's conduct in pushing the marketing of the drug despite having knowledge of the associated risks "years before" the evidence reached the public domain. Furthermore, it found that GSK's personnel "intimidated independent physicians, focused on strategies to minimise findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that rival drug Actos might reduce cardiovascular risk".
The drug is linked to 83,000 excess heart attacks during an 8-year period between 1999 and 2007. In the third quarter of 2009 itself, it was associated with 304 deaths. The figures come from a 2007 FDA report on the drug which concluded that there were safer alternatives to Avandia, pointing towards Takeda (Japan)'s Actos (pioglitazone).
In response, GSK has sought to refute the conclusions of the Senate report, noting that the Avandia safety analysis is not based on consistent rigorous scientific evidence. Furthermore, the pharma firm found that the report "cherry picks" information from documents, mischaracterising the company's efforts to research Avandia, and communicated findings to consumers and regulators.
FDA's Responsibilities
The FDA's position on the drug's adverse risks and the manner in which the regulator conducted the post-marketing surveillance was also under scrutiny by the Senate Finance Committee. Essentially, the report found that the post-marketing surveillance system involves the FDA personnel who originally approved the drugs also reviewing the drugs once they are on the market. This, the legislators suggest, implies a conflict of interest, as drug reviewers would have a natural tendency to protect their decision in originally approving the drug. Referring to the ongoing TIDE (Thiazolidinedione Intervention with Vitamin D Evaluation) clinical trial comparing Avandia to Actos which is currently recruiting patients, the report highlights the FDA's own officials questioning the basis of the trial. The FDA officials noted that "there is no evidence that rosiglitazone confers any unique health benefits over pioglitazone, while there is strong evidence that rosiglitazone confers an increased risk of heart attacks and heart failure compared to pioglitazone". Further, ther report points out that any proposed head-to-head trial would be "unethical and exploitative".
The full report can be accessed here.
Outlook and Implications
The findings of the report will prompt legislators to revisit the issue of drug safety and responsibility on the part of pharmaceutical companies in terms of providing information on drugs' adverse risks. Not surprisingly, the FDA is once again in the spotlight and the subject of much debate on whether earlier legislation on drug safety have indeed been successfully implemented and effective. The regulator has been found wanting in many aspects of implementation. Pivotal among these is the issue of surveillance of marketed drugs. The report's findings will urge legislators to consider tougher measures relating to inspecting marketed drugs, including an independent body to monitor drugs.
The overhaul of the FDA is expected to be part of the health reform legislation, which could not come sooner given that the agency is clearly unable to take a balanced stance when conflicting opinions emerge over a drug, as has been the case with Avandia. The agency has said it will be waiting for recommendations from an advisory panel in a few days to take a final decision on the marketing of Avandia in the United States. This decision will be crucial for the future of Avandia, as withdrawal would impact GSK's revenues adversely.
The pharma major's woes are not expected to be minimised if the FDA does not support withdrawal. The probe has alleged GSK's actions to be unethical and exploitative, among other criticisms, and the firm could face questions on corporate and ethical conduct with respect to consumers and regulators. Avandia's case will also be relevant in the larger context of the pharmaceutical industry post withdrawal of Merck's Vioxx (rofecoxib) following emergence of adverse reactions. Pharma firms can expect further tightening of legislation relating to drug safety. The Institute of Medicine's recommendations on this issue are likely to be examined for implementation shortly.
Related Articles
- United States: 18 December 2008: FDA Issues New Guidance for Experimental Diabetes Drugs
- United Kingdom: 22 May 2007: GSK Strongly Defends Avandia After Study Links It to Increased Heart Attack Risk