Petition Denied on Tacrolimus Bioequivalence
FDA has denied a 4/2020 Belcher Pharmaceuticals citizen petition that sought a requirement that generic drug makers of pre-12/2012-approved tacrolimus oral capsules conduct product testing pursuant to a rigorous 2012 draft product-specific guidance. This would demand both fasting and fed bioequivalence studies designed as single-dose, four-way, fully replicated crossover studies in vivo. In the petition, Belcher said tacrolimus ANDAs approved before 12/2012 needed to update their bioequivalence testing because FDA made substantial changes to its position on bioequivalence testing for narrow-therapeutic ingredient drugs.
Denying the petition, FDA told Belcher that prior to 12/2012 it approved ANDAs and made determinationd at the time of approval that those ANDAs were bioequivalent and therapeutically equivalent to the reference-listed drug (RLD). “The agency generally does not expect application holders of approved ANDAs to re-demonstrate bioequivalence according to bioequivalence recommendations revised after approval of that ANDA unless the agency becomes aware of evidence indicating that the ANDA drug product(s) may not be therapeutically equivalent to the respective RLD or an application-holder proposes to make a change to the approved drug product(s) that necessitates new bioequivalence studies to support approval of the change,” the agency wrote.
FDA’s denial letter acknowledged that its post-marketing surveillance of generic tacrolimus products did raise concerns with the bioequivalence of Accord Healthcare’s ANDA 091195, which led the agency to investigate further. A 3/2020 FDA-contracted study of Accord’s product found it had a higher rate of absorption compared to the RLD, Prograf. The agency concluded afterward that there is insufficient data to determine that the Accord’s drug is bioequivalent and therapeutically equivalent to the RLD, and it consequently changed its therapeutic equivalence code from an AB to a BX (insufficient data to confirm bioequivalence).
In a separate move, an FDA drug alert issued on the same day (9/18) says Accord's tacrolimus oral capsule products are "no longer recommended as automatically substitutable at the pharmacy for Prograf (tacrolimus) oral capsules. Tacrolimus is indicated for the prevention of organ rejection in adult patients receiving kidney, liver, or heart transplants, and in pediatric patients receiving liver transplants.