Facing Criticism, FDA Rethinking Some Therapeutic Equivalence Standards

US regulators are taking a second look at the way generic drug applications for extended-release generic drug obtain approval several weeks after finding that Teva Pharmaceuticals and Impax Laboratories' Budeprion XL 300mg, supposedly generic to GlaxoSmithKlines' Wellbutrin 300mg, was in fact not therapeutically equivalent.

The finding was a setback for the US Food and Drug Administration (FDA), which has fastidiously maintained that nearly all drugs approved through its generic drug pathways are, within acceptable tolerances, the same as their original counterparts.

Testing problems may have been at the core of Budeprion's equivalence issues. The 300mg dose version of Budeprion was approved in 2006 with the use of bioequivalence testing, but that testing was on the 150mg version of the drug-not the 300mg version.

Explained FDA, "This methodology was based on FDA's guidance at the time the products were approved." In addition, FDA said it had concerns that the 300mg dose could cause seizures in otherwise healthy adults, providing additional justification for approval based on the 150mg version. After granting Teva approval for Budeprion, FDA said it asked the company to provide BE testing based on the 300mg dose level, but that Teva said it was unable to recruit a sufficient number of study participants.

Despite concerns about the drug, it took FDA until 2010 to initiate its own Phase 1 testing regarding the drug's BE profile-an unusual step in and of itself. The agency's findings, released in October 2012, showed that the two products did not have the same rate of release, and were thus not therapeutically equivalent.

The case received a fair bit of attention, including from Forbes contributor David Maris, who said it cast doubt on FDA's entire system of approving generic drug products. "How could the FDA know if a drug is bioequivalent if it doesn't even test it?" asked Maris. "It can't."

At FDA, the episode is leading to changes, announced Gregory Geba, director of FDA's Office of Generic Drugs, in an interview with the New York Times. "This has actually prompted us to change our policy," he said. The agency, he said, is now re-evaluating how it conducts equivalence testing for generic drug products, particularly for extended release drugs.

As for criticism against the agency, Geba said FDA faces a great deal of difficulty in determining whether adverse event reports from generic drugs are the result of the product or a result of the illness. "That's not an easy thing to assess," he concluded.