Febuxostat from Takeda Receives Expanded FDA Approval
Drug/Device: Febuxostat
Sponsor: Takeda Pharmaceuticals USA
Committee: Arthritis Advisory Committee And Drug Safety And Risk Management Advisory Committee
Indications：the second line therapy for the treatment of hyperuricemia in patients with gout who have failed allopurinol
Question: Based upon the available data, is there a patient population in which the benefit-risk profile for Febuxostat is favorable for the treatment of hyperuricemia in patients with gout?
Vote Results: Yes 19 No 2 Abstain 1
Related Documents:
Febuxostat Background:
Febuxostat was approved on 13 February 2009 in US at doses of 40 and 80 mg once daily (QD) for the chronic management of hyperuricemia in patients with gout, with a post-marketing requirement (PMR) to further assess the CV risk associated with the drug. This application is to respond to FDA PMR requirement.
The applicant submitted CARES postmarket CV outcome study for AC meeting. This safety study results showed no difference in overall major adverse CV event(MACE) rates between treatment and placebo arms. However, the treatment (febuxostat) group had elevated risks for CV death and all-cause death, compared to allopurinol group. As results, committee approved febuxostat , but put limit use of the drug to second line therapy for the treatment of hyperuricemia in patients with gout who have failed allopurinol, and with labeled warnings and precautions on CV death events.
Unique Challenges :
1) Timeline extension given due to difficulties in study enrollment. In 2009 approval letter, FDA issued the timeline for postmarket safety study, January 2014 for the study completion and January 2015 for final report submission. The safety study was required with adequate sample size and long enough duration to measure the risk of CV events of Febuxostat. Due to challenges with enrollment, CARES added sites in Mexico and Canada, the milestones were modified with a Final Report Submission date of May 2019.
2) Benefit-risk analysis. In spite of 34% increased risk for CV death and a 22% increased risk for all-cause mortality, Febuxostat was approved mainly due to the benefits overweighing risks for the following specific points . Gout has been growing to epidemic, Febuxostat is the only alternative XOI to allopurinol, and there is unmet medical need for the patients who are unable to tolerate allopurinol. Therefore it is convincible to conclude that there is a patient population in which the benefit-risk profile for Febuxostat is favorable for the treatment of hyperuricemia in patients with gout.
3) Generalizability to gout patients in real world settings is unclear. The key concern is whether the patient population settings in CARES study is similar with real world population or not. FDA employed Sentinel System to analyze and compare gout population with CARES population. The data used in Sentinel System were from Sentinel Distributed Database (SDD) from Jan 1, 2009 to Sept 30, 2016 with 17 health plans over 122 million enrollees (RWD). The conclusion form Sentinel Analysis was not favorable to Febuxostat.