Is the FDA Broken? — Uloric Cardiac Risk Issues

Was Uloric Approval the Safe Decision?

Attempts in 2005 and 2006 to obtain government-approval to sell Uloric were denied by the FDA due to concerns about research data that showed a slight elevation in the risks of death and heart problems (including acute coronary syndrome, myocardial infarction or heart attacks, and angina) in patients taking Uloric over other common grout drugs, including allopurinol. Takeda (and its subsidiary TAP), the manufacturer of Uloric, overcame this initial denial by providing additional safety data from expanded clinical trials to the FDA.

Additional clinical trials were then completed by the manufacturer of Uloric. These new studies did not contain the same cardiac safety signals as the earlier studies.  In February of 2009, Uloric (also known as febuxostat) was approved for sale in the United States by the Food & Drug Administration following the November 2008 recommendation of approval by an FDA Advisory Committee. The FDA found that the benefits of the drug outweighed its risks to patients.  However, the FDA did require as a condition of the approval that the drug company conduct post-marketing safety studies to further evaluate whether there was an unacceptable risk of heart injuries or death in patients taking Uloric. The initial approval required that Takeda complete the additional safety studies before January 31, 2015.

Uloric was heralded as the first new medication approved in over 45 years for the chronic management of hyperuricemia (or elevated levels of uric acid) associated with gout, a painful condition that occurs when patients cannot properly breakdown uric acid in their bloodstream which helps to form inflammatory arthritis due to uric crystals in their joints.   It is estimated that over 3 to 8 million American adults suffer gout attacks each year, with the condition being more likely to occur in male patients.  It is estimated that the drug has been ingested by hundreds of thousands of patients in the United States since 2009.

On November 15, 2017, over eight years after patients took Uloric, the FDA issued a drug safety alert indicating that preliminary data from the post-marketing clinical studies (which involved over 6,000 patients) did show an increased risk of cardiac-related deaths in patients taking Uloric, and this risk was higher than what was seen in other patients taking allopurinol to treat their gout symptoms.  The FDA permitted the drug to remain on the market and awaited the final results of Takeda’s post-marketing safety studies.  Prescribing physicians were warned to consider this potential increased risk of myocardial infarctions, cerebrovascular events, and heart-related deaths in determining the best medications to prescribe to their patients with gout, but did not recall the product from the market or even require a black box warning, the most prominent warning usually indicated for drugs that potential the risks of serious injury or death.

In June of 2018, Public Citizen, an international consumer advocacy organization founded by Ralph Nader, filed a Citizen Petition with the FDA seeking the withdrawal of Uloric from the market.  This 23-page Petition outlines the rocky course leading to approval of the drug initially by the FDA in 2009 due to concerns about adverse effects of the drug on patients’ hearts and also criticizes the reliability of the studies that ultimately led to the FDA’s approval of the drug on the manufacturer’s third attempt.  The Petition seeks the removal of Uloric from the market based upon concerns that the risks of death and heart injuries allegedly associated with Uloric outweigh the benefits of the drug in treating patients with gout, especially with a lack of strong evidence that Uloric is more effective than alternative treatments.

On August 22, 2018, the FDA announced that it had received the final results of the post-marketing study (which is also called CARES – Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities trial) and that an advisory committee meeting of external experts would be convened to discuss the safety of the drug once the FDA completed its internal review of the data.  The results of the study were also published in March of 2018 in the New England Journal of Medicine.

On January 11, 2019, an FDA Advisory Committee of experts will be meeting to discuss recently published medical studies relating to a potential increased risk of heart-related deaths in patients taking Uloric for gout and whether the warning label for the drug should be changed or the use of the medicine be limited due to this potential safety concern.

So, while we wait for a final determination from the FDA, several questions arise.  Should we be troubled that a drug company has marketed a medicine for over 10 years in the face of safety concerns?  Should the FDA continue to study potential safety issues for years while doctors are prescribing the drugs without adequate information about potential safety issues?  And, what about the patients?  Don’t they have a right to know when a drug they are taking is under a potential cloud of suspicion?  If so, how should this information be communicated, as our system is failing to do the job.  In the coming months, will Uloric continue to be widely sold, limited in its availability, recalled, or perhaps just quietly disappear from the market as its appeal to consumers and physicians diminishes due to potential safety concerns?  And, most important, how many patients might die or suffer serious harm because of this?

Additional Resources on Uloric Heart Safety Issues:

• FDA Approval Documents for Uloric
• Manufacturer’s Web Site for Uloric
• Prescribing Information and Warning Label for Uloric
• Public Citizen Petition to Remove Uloric from the Market
• New England Journal of Medicine Reports on Heart-Related Uloric Safety Issues