Establishing Therapeutic Equivalence of Complex Pharmaceuticals: The Case of Dabigatran.

Dabigatran is widely used for stroke prevention in atrial fibrillation. Dabigatran is no longer patent-protected in Canada and 2 generic formulations were recently approved by Health Canada. Branded dabigatran uses a complex formulation to maintain the acidic microenvironment required for maximal absorption. Consequently, food does not influence its bioavailability and the efficacy and safety of dabigatran are similar with or without concomitant intake of proton pump inhibitors (PPIs). Unfortunately, current bioequivalence criteria do not mandate testing of the generic formulations with food or with concomitant intake of PPIs; thus, the only data available for the approved generic products are in fasted, healthy volunteers. Without confirmation that the bioavailability of the generic dabigatran products is maintained in the presence of food or with coadministration of PPIs, it is uncertain whether they will afford patients the same protection from stroke as the branded product. Clinicians and patients must be made aware of this limitation to make informed prescribing decisions. The rules for establishing bioequivalence have not kept pace with the increasing complexity of pharmaceutical products; we urge regulators to update the regulatory process to ensure the therapeutic equivalence of generic products.