FDA Approval Process for Generics Sound, Say Officials

Pam Harrison

December 05, 2012

The US Food and Drug Administration's (FDA's) recent recommendation to the manufacturers of generic extended-release bupropion (Budeprion XL 300 mg, Impax Laboratories and Teva Pharmaceuticals) that resulted in its being voluntarily withdrawn from the market should not diminish public confidence in the agency's approval process for generic drugs.

In a Perspective article published online December 5 in the New England Journal of Medicine, FDA officials note that the basis for approving the 300-mg dose of the generic drug was data that had been extrapolated from of an earlier bioequivalence study of the 150-mg dose of both the generic and the brand-name formulation.

"We do not believe that the results of the FDA study should cause concern regarding the overall reliability of the agency's approval process for generic drugs, including the use of extrapolation, when scientifically appropriate," the officials, led by Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, write.

Not Bioequivalent

As reported by Medscape Medical News, on October 4, the generic antidepressant was voluntarily withdrawn from the market on the basis of results of an FDA head-to-head bioequivalence study that showed that the generic agent was not therapeutically equivalent to Wellbutrin XL 300 mg, the brand-name extended-release formulation.

The FDA study included 24 healthy fasting volunteers who were treated with a single 300-mg dose of the generic extended-release formulation and were then crossed over to the brand-name formulation, Wellbutrin 300 mg.

"The extent of bupropion absorption after the administration of the generic product, as reflected in the area under the curve of the plasma concentrations plotted over time, was 86% of the absorption with the brand-name product," investigators write.

The investigators note that bioequivalence of 2 drug products should reflect significant agreement in pharmacokinetic parameters such that the entire 90% confidence interval associated with the generic-to-reference ratio of geometric means should fall within the bioequivalence limits of 80% to 125%.

The corresponding 90% confidence interval was 77% to 96%, they add.

Furthermore, mean peak plasma concentrations recorded after the administration of the generic 300-mg dose was only 75% of that observed after administration of the same dose of the brand-name drug.

In some participants, the peak plasma concentrations as well as the area under the plasma concentration curve for Budeprion XL were less than 40% of the values seen with Wellbutrin XL.

Peak plasma concentrations for the major active metabolite of bupropion hydrochloride, hydroxybupropion, also failed to meet FDA bioequivalence criteria.

Major pharmacokinetic differences between the generic and the brand-name dose of the drug were also seen in time to peak drug concentration in the blood at 4 hours for Budeprion XL compared with 5 hours for Wellbutrin XL.

Extrapolation "Generally Successful"

According to the investigators, "technical aspects of the Budeprion formulation may have led to the failure of extrapolation in this case." They note that "other 300-mg generic bupropion products do not use the same technology as Budeprion."

The authors add that the FDA will continue to use extrapolation for the approval of multiple strengths of generic drugs because it has been "generally successful."

"The agency will also move more aggressively to perform its own studies when data are urgently needed," they write.

N Engl J Med. Published online December 5, 2012. Full article