Although the upper bound of the 95% confidence interval was below 1.3, falling shy of the cut point for a mandatory postapproval CV outcomes trial, the FDA nevertheless has decided such a study will be required.
“The applicant has proposed to conduct a CV outcomes trial whose primary objective is to demonstrate a cardioprotective effect of dapagliflozin,” Dr. Parks writes. “FDA concurs with the applicant that a CV outcomes trial is necessary to better characterize the CV safety of this drug and to evaluate safety issues that have arisen in the course of this [new drug application] review. If approved, this CV outcomes trial will be a required postmarketing trial.”
But Hepatic, Cancer Concerns Worry
Although dapagliflozin’s premarketing CV profile looks clean, “several unexpected safety issues identified in this clinical development program were of sufficient concern to FDA to merit discussion of their impact on the overall benefit-risk consideration,” Dr. Parks writes.
Among these are the drug’s hepatic effects. There were a total of five dapagliflozin-treated patients in the phase IIb/III trials who met the laboratory criteria for Hy’s Law (AST or ALT levels greater than three times the upper limit of normal and elevation of total bilirubin level greater than two times the upper limit of normal). One of these was classified as a “probable” case of drug-induced liver injury.
In their review, Office of Surveillance and Epidemiology hepatologists Leonard Seeff and John Senior noted that in many cases the data were too limited to make a linkage between dapagliflozin and liver damage. Given the importance of recognizing sentinel cases of drug-induced liver injury in registrational trials, “it is prudent to gather more information on all relevant cases as part of an in-depth review of the dapagliflozin [new drug application] in order to assess whether this agent may be hepatotoxic,” they say, adding that careful hepatic monitoring should be performed in any future studies.
The FDA also calls the committee’s attention to numerical imbalances in cases of breast and bladder cancer among dapagliflozin-treated patients.
There were seven bladder cancer cases in dapagliflozin-treated patients at the time of the 4-month safety update, compared with none in the control group. Subsequently, two more cases were reported with dapagliflozin and one with controls. “This can be extrapolated to 207 cases per 100,000 person-year exposure in dapagliflozin-treated patients versus 53 cases per 100,000 person-year exposure in control[s],” the clinical review states.
The findings suggest dapagliflozin could be in for the same type of bladder cancer cloud currently hanging over Actos.
The FDA questions whether detection bias resulting from dapagliflozin’s mechanism of action and related genitourinary adverse effects could have contributed to the imbalance observed.
“More frequent assessments of urinalysis in the dapagliflozin group might result in postbaseline detection of hematuria requiring further work-up and higher rate of cancer diagnosis than control group, which might not have received as extensive monitoring,” the FDA reviewers state.
“In this regard, it is interesting to note that concerns of bladder cancer associated with pioglitazone use arose during premarketing development due to nonclinical findings of bladder cancer in male rodents. This led to a prospective assessment of urine cytology in approximately 1,800 patients in clinical trials up to 1 year [in] duration. Despite similar active surveillance for bladder cancer in pioglitazone and control groups, no clinical cases were detected premarketing. Imbalance of clinical bladder cancer risk with pioglitazone was not observed until after approval.”
There also was an imbalance in the number of breast cancer cases, with nine reported in the dapagliflozin-treated group and none in the control group.
For both types of cancer, the FDA concludes that the numbers observed exceeded the expected number of cases in the type 2 diabetic population. It asks the advisory committee whether any imbalance in baseline factors may have contributed to the findings and whether detection bias was a factor.
The FDA also wants the committee to consider the increase in genital and urinary infections associated with dapagliflozin. Such infections have become a well-known side effect of this class of drugs, given their mechanism of action.
This coverage is provided by “The Pink Sheet.” This news organization and “The Pink Sheet” are owned by Elsevier.