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ROCKVILLE, Md. -- Type 2 diabetes drug empagliflozin (Jardiance) got an effectively null recommendation from an FDA advisory panel for expanding the indications to include prevention of cardiovascular events.
The Endocrine and Metabolic Drug Advisory Committee (EMDAC) voted 12-11 Tuesday on whether a large postmarket study offered "substantial evidence to establish that the drug reduced cardiovascular mortality in the population studied."
The vote followed an in-depth discussion of the design and conduct of the EMPA-REG trial, which included criticisms involving interim unblinding, changes to the protocol and the primary endpoint definition, and duplicative as well as missing data.
On a less controversial question, the panel voted unanimously that the drug did not show an "unacceptable increase in cardiovascular risk."
Empagliflozin is a sodium glucose co-transporter 2 (SGLT-2) inhibitor that lowers blood glucose by increasing urinary sugar excretion.
In August 2014, the FDA approved empagliflozin with the caveat that the developer, Boehringer Ingelheim, conduct a postmarket trial in accordance with the for all new diabetes drugs. The study was submitted to the agency in November 2014.
The EMPA-REG study was initially intended merely to rule out an increase in cardiovascular risk. However, the sponsor chose to develop a randomized, double-blind, placebo-controlled trial with a broader sample of patients -- 7,020 in total -- with type 2 diabetes and heightened cardiovascular risk to concurrently pursue a claim of event reduction.
In its application, Boehringer Ingelheim proposed the following additional indication for empagliflozin: "In adult patients with type 2 diabetes mellitus and established cardiovascular diseases, empagliflozin is indicated to reduce the incidence of cardiovascular death."
EMDAC member , who expressed skepticism about the expanded indication at the start of the meeting, said he was won over by the reduction in cardiovascular deaths, which "withstood all sensitivity analyses, including the worst cases.
"I would hate to deny a claim based on the unique way this trial was run, and how this claim was evolved, because I believe that, at the end of the day, the result is true," said Hiatt, of the University of Colorado School of Medicine in Aurora, referring to a study protocol that was amended multiple times.
On the other hand, , at the University of Washington in Seattle, voted not to support the indication, based on "substantial evidence" of reduced cardiovascular deaths.
Heckbert said she was concerned about the number of "inassessible" deaths and the fact that cardiovascular deaths were not the primary endpoint; and she stressed that the agency generally requires 2 well-designed clinical trials.
"Although these data are intriguing and promising, a second study is needed" before the indication can be considered valid, she said.
In opening remarks at the meeting, , director of the FDA's division of Metabolism and Endocrinology Products, noted that while the legal standard for "substantial evidence" of effectiveness calls for "evidence consisting of adequate and well-controlled investigations" -- and that definition has been interpreted by the agency to indicate a requirement of at least 2 trials -- although under certain circumstances, a single study could constitute "substantial evidence."
As the FDA noted, the EMPA-REG study results were the first to show that a type 2 diabetes drug produces a cardiovascular benefit.
The trial's stated primary endpoint compared the drug against placebo while monitoring the time to occurrence of 3 major adverse cardiovascular events (3-point MACE):
- Adjudicated cardiovascular death;
- Nonfatal myocardial infarction (MI;) and
- Nonfatal stroke.
The sponsor chose "MACE-plus" as its secondary endpoint, incorporating all 3-point MACE events as well as hospitalization for unstable angina. The trial found that empagliflozin was both non-inferior and superior to placebo for 3-point MACE (HR 0.86, 95% CI 0.74-0.99). The results also showed that empagliflozin was noninferior, but not superior, to placebo for the secondary endpoint of MACE-plus (HR 0.89, 95% CI 0.78-1.01).
Importantly, the study showed a relative risk reduction of cardiovascular death of 38% and a relative risk reduction in all-cause mortality of 32%. The agency noted that the greatest differences between the two treatment arms were driven by cardiovascular death, which also heavily influenced all-cause death.
However, the FDA's technical staff called into question much of the data collection and its interpretation.
The panel discussion highlighted concerns around missing patient data -- 211 participants discontinued the trial before its completion -- and the decision to exclude silent myocardial infarction (MI) from the primary endpoint. The panel also explored the impact of the study being unblinded for 230 individuals.
"It's kind of inconceivable to me that 230 people can keep their mouths shut [about that] for 2 years, or whatever," said EMDAC member . But Konstam, from Tufts Medical Center in Boston, ultimately voted in support of the drug's cardiovascular benefit.
The FDA staff said that the composite primary endpoint initially included silent MIs until a protocol amendment removed them.
"Anytime the sea changes, there are red flags that go up," said , an FDA medical officer. She was highly critical of how the sponsor conducted the trial and the data-collection processes.
The issue of "inassessible" or undetermined deaths was another problem, Hicks stated, pointing out that "124 patients with an undetermined death is not a small number of patients. When we see this many undetermined deaths, we know there are missing data.
"Still, all of that said, if you do extreme analysis and exclude all of these uninterpretable deaths from the analysis, the effect on cardiovascular deaths remains robust."