FDA Officials Offer Explanation For Absence of Low Dose Dabigatran

Following the approval last October of dabigatran some observers  criticized the FDA’s decision not to approve the lower 110 mg dose of the drug in addition to the higher 150 mg dose. Now, in a perspective in the New England Journal of Medicine, 3 FDA officials, B. Nhi Beasley, Ellis Unger, and Robert Temple, explain that their decision “was based on our inability to identify any subgroup in which use of the lower dose would not represent a substantial disadvantage.”

The FDA officials acknowledge that there were several good reasons for approving the lower dose, including the finding of safety and efficacy and the ability to individualize treatment. However, the FDA review team was unable to identify a patient population in which the lower dose might be superior to the higher dose, including older patients, patients with renal function, and patients with previous bleeding episodes.

The authors also express concern about physicians and patients who fear the bleeding risk of warfarin and dabigatran: “we concluded that encouraging the ‘play it safe’ option for patients and physicians represented an undesirable stimulus to use a less-effective regimen and would lead to unnecessary strokes and disability.”

Sanjay Kaul, who was a member of the advisory committee, provided the following comment:

The arguments put forward in the paper are right on target. As the authors outlined, there is no compelling reason to use 110 mg over 150 mg dabigatran. In addition, if one were to focus on ischemic strokes only, the point estimate of the hazard ratio for the dabigatran 110 mg vs warfarin is 1.13 with 95% upper limit of the confidence interval of 1.42 (which would not have met the FDA noninferiority criterion). Although major bleeding is significantly reduced with 110 mg dabigatran compared with warfarin, I don’t think there will be any disagreement that avoiding disabling strokes outweighs reduced bleeding risk. Thus, I agree with the FDA’s opinion that the 110 mg dabigatran dose does not offer a favorable benefit-risk balance.