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.
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
Sentinel Data on the Risk of Diabetic Ketoacidosis with Off-Label Use of SGLT2 Inhibitors Featured at Recent FDA Advisory Committee
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 on use of Higher Dosage Strength Opioid Analgesics Featured at Recent FDA Advisory Committee
In June 2019, FDA held a joint meeting of the Drug Safety and Risk Management Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee to discuss the clinical utility of and safety concerns associated with the higher range of opioid analgesic dosing (both in terms of higher strength products and higher daily doses) in the outpatient setting. FDA was interested in better understanding current clinical use and situations that may warrant use of higher doses of opioid analgesics. FDA was also interested in discussing the magnitude and frequency of harms associated with higher doses of opioid analgesics relative to lower doses, as well as optimal strategies for managing these risks while ensuring access to appropriate pain management for patients. At the Advisory Committee meeting, FDA presented utilization data, including analyses of Sentinel data.
FDA analyzed results from 17 Sentinel Data Partners to help the committee understand the utilization of higher dosage strength opioid analgesic products when compared to lower dosage strength opioid analgesic products and transdermal opioid analgesics. FDA evaluated utilization patterns, patients’ cumulative durations of therapy for the opioid analgesic categories, comorbidities, and the presence of claims with diagnoses of interest, such as pain-related diagnosis codes, mental illness, or substance use disorder. The results showed that the use of higher dosage strength opioid analgesic products comprised a small portion of all opioid analgesic use and has declined in recent years. Compared to patients on lower dosage strength opioid analgesic products, patients on higher dose opioid analgesic products had longer therapy with any of the higher dosage strength products. They also appeared to have higher prevalence of comorbidities, mental health conditions, or substance abuse. Patients on higher dose opioid analgesic products appeared clinically similar to patients on transdermal opioid analgesic therapy.
A verbatim transcript is available approximately 10-12 weeks following the meeting date, in most instances.
Sentinel Data on Pediatric-Focused Neuropsychiatric Events with Use of Singulair (montelukast) Featured at Recent FDA Advisory Committee
In September 2019, FDA convened a joint meeting of the Pediatric Advisory Committee (PAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee. The objective of the meeting was to discuss a pediatric-focused safety review of neuropsychiatric events (NAE) with the use of montelukast.
Using data from January 1, 2000 to September 30, 2015 in the Sentinel Distributed Database (SDD), FDA investigated if there is an increased risk of depressive disorders, self-harm and suicides associated with montelukast use compared to inhaled corticosteroids (ICS), and if the risk of NAEs with montelukast compared to ICS was modified by the 2008 Drug Safety Communication and subsequent montelukast labeling changes, or is affected by age, sex, and psychiatric history. Patients aged 6 years and older with a diagnosis of asthma were included, excluding patients with a diagnosis of chronic obstructive pulmonary disease (COPD). Rates of depressive disorders and self-harm from montelukast patients were compared to ICS patients, adjusting for several potential confounders.
Our study did not find any associations between montelukast use and inpatient depressive disorder or self-harm, compared to ICS use, either overall or across subgroups of age, sex, or calendar time. We observed a decreased risk of treated outpatient depressive disorder with montelukast use compared with ICS use. We do note plausible explanations for the decreased risk observed, including early termination of montelukast use to resolve depressive symptoms and that patients already receiving treatment for depression may have been more likely to have received ICS than montelukast after the 2008 Drug Safety Communication and labeling changes.
The AC panel remarked that the Sentinel study provided additional data on the neuropsychiatric risk and montelukast but noted the challenges associated with studying these adverse events in observational data.