The U.S. Food and Drug Administration, to assist in its mission to protect and promote the public health, uses 50 committees and panels to obtain independent expert advice on scientific, technical, and policy matters. This page features select Advisory Committee meetings where Sentinel data have been presented or discussed.
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Sentinel Data in Action: Accounts from FDA
Sentinel Data on the Risk of Diabetic Ketoacidosis with Off-Label Use of SGLT2 Inhibitors Featured at Recent FDA Advisory Committee
Christian Hampp PhD; Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD
January 15, 2019
In January 2019, the FDA held a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee to discuss the benefits and risks of sotagliflozin, as the first sodium-glucose-contransporter-2 inhibitor (SGLT2 inhibitor) seeking indication for the treatment of adults with type-1 diabetes mellitus (T1DM), as an adjunct to insulin. Clinical trials in type-1 diabetic patients showed an increased risk of diabetic ketoacidosis (DKA) with sotagliflozin, compared with placebo, amid a background of insulin therapy. Other SGLT2 inhibitors are currently approved for the treatment of adults with T2DM.
We analyzed data from 17 Sentinel Data Partners to help the committee understand the frequency of off-label utilization of SGLT2 inhibitors for T1DM and associated real-world rates of DKA. We also conducted a formal age- and sex standardized comparison of observed DKA event counts in Sentinel with counts that would be expected if the sotagliflozin clinical trials incidence rates were present in the Sentinel population. With these analyses, we showed that SGLT2 inhibitors are used off-label in the treatment for T1DM, albeit at low overall rates but at higher rates among younger patients. Rates for DKA during off-label use of SGLT2 inhibitors were high, especially among younger patients, and especially among younger women. Real-world rates for DKA in Sentinel were higher than expected based on clinical trials.
The committee followed the Sentinel data presentation and posed several questions, including about drug utilization by age. In the discussion of sotagliflozin's benefits and risks, members of the committee expressed concern that DKA rates in the real world could be higher than in the clinical trial setting, which is what the Sentinel data suggested. The committee was split 8-8 on the question as to whether sotagliflozin's benefits outweigh the risks when used for T1DM.
Sentinel Data Contextualizes Results from a Post-Market Cardiovascular Risk Trial
Marie Bradley PhD, MPharm, MSc.PH; Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD
January 9, 2019
Febuxostat (Uloric) is a urate lowering therapy (ULT) used in the management of hyperuricemia in gout that was FDA approved in 2009. It is the only alternative xanthine oxidase inhibitor (XOI) for patients who cannot take allopurinol due to hypersensitivity reactions, or the presence of chronic kidney disease. FDA’s Arthritis Advisory Committee (AAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM) met on January 11, 2019 to discuss the results from the post-marketing safety trial “Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities” (CARES) which evaluated the cardiovascular safety of febuxostat.
The CARES trial was a multicenter double-blind cardiovascular risk trial published in March 2018. CARES reported a 34% (HR 1.34; 95% 1.03 – 1.73) increase in cardiovascular mortality among febuxostat users compared to allopurinol users. However, since the clinical trial enrolled a high-risk population, it was not clear how generalizable the CARES trial findings were to patients in real world settings. Moreover, 45% of trial patients had incomplete data across the 7-year study and 57% discontinued their assigned medication, casting uncertainty over the estimated magnitude of risk. FDA set out to use Sentinel to examine the characteristics of patients with gout and characterize the utilization of XOIs, including switching patterns of febuxostat and allopurinol.
We identified over 5 million patients with gout between 2009 and 2016 in Sentinel. Allopurinol was the most commonly used ULT (46.4%), while only a small proportion were febuxostat users (4.3%). Cardiovascular disease risk at baseline was similar between febuxostat and allopurinol initiators, and febuxostat initiators had more severe gout, and were more likely to have chronic kidney disease. Allopurinol initiators also tended to adhere longer to ULT therapy compared to febuxostat initiators. Switching between ULTs was generally low. Compared to CARES, febuxostat users in Sentinel had lower rates of prior myocardial infarction (1.5% vs. 38.6%) and stroke (2.7% vs. 14.8%) and had fewer males (62% vs. 84%).
The panel remarked that Sentinel provided important real-world data on ULT utilization patterns. Compared to the CARES trial population, Sentinel data suggested that ULT users were older, less likely to be male and had lower gout severity and lower cardiovascular disease risk. This helped support the advisory panel’s determination (19:2 vote, 1 abstain) that there is a patient population in which benefit-risk profile for febuxostat is favorable, and that stronger labeling (a boxed warning for cardiovascular risk), a restricted indication as second-line agent, updating professional society treatment guidelines, and issuing “Dear Healthcare Provider” letters to communicate the risk to patients and their providers, could adequately manage this risk.
 White WB, Saag KG, Becker MA, Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout, N Engl J Med. 2018 Mar 29;378(13):1200-1210