Edoxaban: Comparative Effectiveness and the FDA

The October 27, 2014 issue of The Medical Letter on Antithrombotic Drugs included, on the advice of its reviewers, edoxaban (Savaysa – Daichhi Sankyo) among the new oral anticoagulants competing with warfarin for use in nonvalvular atrial fibrillation or venous thromboembolism, even though it had not yet been approved for any indication by the FDA. Edoxaban probably will be approved, but an article in the November 10, 2014 issue of The Pink Sheet, a trade publication that covers the pharmaceutical industry, reveals that its path to approval has not been smooth and tells us a few things about the approval process that some of us may not have known.

The FDA’s standard of approval for new drugs included at first only safety, then safety and efficacy for the indication for which approval was sought, and then in 1995, according to The Pink Sheet, a comparison with the standard of care. The FDA-approved new oral anticoagulants, dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis), have been heavily advertised and widely used, but warfarin is still considered the standard of care, and edoxaban was non-inferior to warfarin in clinical trials. But in patients with normal renal function (about one-third of the subjects in the clinical trials), it was inferior to warfarin.

In most circumstances, if a new drug up for approval is non-inferior to the standard of care in achieving the primary endpoint, that would be good enough, even if it was inferior in some subgroups, but in this case there are already 3 similar drugs on the market that are also non-inferior (or superior) to warfarin and have not demonstrated any problem in patients with normal renal function. The FDA does not want to require each new drug to be better than all of the old drugs for the sought indication, but it does consider, in analyzing the new drug’s benefit/risk ratio, what treatment options are available, so the bar may be higher for the fourth new drug than it is for the first.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee finally recommended approval of edoxaban, but expressed some reservations about the dose and the appropriate patient population, which raises the possibility that the agency will not approve its use in patients with normal renal function or will require testing of a higher dose before approval for those patients. If and when edoxaban is approved, with or without extraordinary limitations on its use, we will publish a full review in The Medical Letter.

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