At the FDA advisory panel empagliflozin enjoyed strong support from the cardiologists and statisticians but not from the endocrinologists.
An FDA advisory panel last week turned out to be a much more contentious and divided than many had expected. Based on the FDA’s own analysis of last year’s Empa-Reg Outcome trial I had predicted that the Endocrinologic and Metabolic Drugs Advisory Committee would strongly endorse an important new expanded indication for empagliflozin (Jardiance, Boehringer Ingelheim).
Ultimately the committee did support the new indication, but the vote, 12-11, was surprisingly close. The new indication– to reduce the incidence of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease– gained strong support from the cardiologists and statisticians on the panel but not from the endocrinologists.
Milton Packer and Sanjay Kaul, two highly prominent cardiologists who are experts in clinical trials and have substantial experience with the FDA, were shocked and disappointed by the endocrinologists’ votes.
Milton Packer (Baylor University, Dallas) focused on the apparent reasons for the divergent view of the endocrinologists. Here is what he said:
The EMDAC meeting on empagliflozin taught us a great deal about the challenges patients with diabetes face when they seek to receive proper treatment for their disease.
The meeting focused on the results of the EMPA-REG trial, the first trial to show that treatment with a drug given for diabetes can reduce the risk of cardiovascular death.
The challenge to the committee was to understand that the benefit of the drug on reducing the risk of cardiovascular death was real, even though it was not related to the drug’s ability to improve glycemic control.
The cardiologists and statisticians on the panel recognized that EMPA-REG was a robust trial; they did not care whether the mechanism of benefit was related to changes in blood glucose; and they uniformly voted to approve the drug to reduce the risk of cardiovascular death.
In contrast, the endocrinologists did not want to believe that a drug with hypoglycemic effects exerted benefits on cardiovascular death that were not related to its actions on blood glucose, and they uniformly voted against providing a claim for the reduction of cardiovascular death.
An observer came away from the meeting with the strong impression that the endocrinologists did not want to accept any evidence that empagliflozin could reduce the risk of cardiovascular death; were not prepared to acknowledge that drugs might work in diabetes by effects that were independent of blood glucose; and wanted to be left in peace to be allowed to micromanage hemoglobin A1c without being reminded that doing so does not change the cardiovascular risk of patients with diabetes.
Therefore, they had to find a reason to vote “no”, and the only reason that they could come up with was that the result was seen robustly in only one trial, and they believed the effect should be replicated to gain FDA approval.
In truth, the benefit of empagliflozin was replicated in the EMPA-REG trial, since it was seen with two different doses of the drug; each dose reduced the risk of cardiovascular death.
The discussion during the committee meeting indicated that patients with diabetes now face a major challenge receiving proper treatment from the physicians they rely on for specialist care. Diabetologists seem unwilling to accept evidence that empagliflozin can reduce the risk of cardiovascular death, independently of what it might do to glycemic control. They accept that fact for statins and for ACE inhibitors, but they will not accept it for a drug that has an effect on blood glucose. If empagliflozin had no effect on glycemic control, there would be no problem. But since it does act to lower blood glucose, diabetologists refuse to give the drug the credit it deserves.
What will happen when the FDA provides empagliflozin with an indication for the reduction of cardiovascular death? Will diabetologists simply not prescribe it because it does not fit neatly into the model of the disease they have inside their heads? When will endocrinologists recognize that the treatment of diabetic patients should be based on clinical trial evidence and not on unreliable surrogate measures?
Sanjay Kaul (Cedars-Sinai, Los Angeles) focused on the robust evidence of benefit in the trial. Here is what he said:
‘Substantial evidence of effectiveness’ criterion based on a single trial (i.e., p < 0.001) applies to all-cause mortality (ACM) and cardiovascular mortality (CVM), but not to MACE-3, the primary endpoint. The p value for both ACM and CVM is statistically robust or ‘persuasive’ implying that the probability of replicating the positive results in a second trial is higher than 92%.
Not only is the mortality reduction statistically robust, the 2.6% absolute or 32% relative risk reduction in ACM and 2.2% absolute or 38% relative risk reduction in CVM is clinically important.
The mortality results hold up to even the worst-case sensitivity analyses that account for non-assessable CV deaths or missing data.
It is legitimate to ask why silent MIs were not ascertained. Many, but not all, contemporary diabetes CVOTs have excluded it because it is difficult to assess reliably. However, this is not a deal breaker.
Data regarding heart failure and renal outcomes were not systematically and rigorously collected, therefore these results are not actionable for regulator decision making. This is tacitly acknowledged by the sponsor’s proposal for conducting 2 heart failure trials in the future. Hence, they were appropriately not part of the voting questions.
It is reassuring to note that the expert statisticians and cardiologists on the panel voted in favor of the label update, an inference also drawn by the reviewers within CardioRenal Division at the FDA.
I hope the discussion at the AdCom panel will help the FDA make the correct decision regarding label update.