Sometimes in our haste to get a product to market, we take some “logical” shortcuts. We extrapolate data. Whenever we do this, we must make sure that we’re not putting patients at risk. The human body is not a black box, and straight extrapolation won’t always mimic what happens in reality.
Recently, the industry, and the regulatory community, learned this lesson the hard way, in the critical area of generic drugs. The result was an FDA report, released late last year, that shows how taking shortcuts can lead to errors in assessing bioavailability, the rate at which a given drug becomes available to the human body.
FDA’s report focused on the generic drug, Budeprion XL 300mg, manufactured by Impax and distributed by Teva. Impax already had FDA approval for its 150mg dosage form of that drug but wanted FDA approval for its 300mg form. Following approved procedures that other generics companies had already been used to approve five generic drugs, the company used two 150mg Budeprion XL tablets to extrapolate blood levels for a single 300mg XL tablet.
Subsequent tests, however, showed that 300mg of Budeprion XL was not therapeutically equivalent to that of the name brand Wellbutrin XL 300mg.1 Impax has since requested that the FDA withdraw its approval on the 300mg XL tablets.
The FDA has since revised its guidance, and it no longer allows such extrapolations. This was based on reports that patients receiving the generic Budeprion XL 300mg experienced reduced efficacy compared to when they were on the Wellbutrin. These reports were just for the Impax/Teva product. When the companies began actual bioequivanlence studies, the FDA asked patients who had the reduced effect to be included, but there were not enough responses, and the study was terminated in late 2011.
When the FDA performed its own study on healthy volunteers in 2010, it found that the Budeprion 300mg XL tabs failed to release active pharmaceutical ingredient (API) into the blood at the same rate as the Wellbutrin 300mg XL. While there were no adverse physiological effects reported, the product did not achieve the same therapeutic levels and was removed from the market. The FDA then asked the other four generic companies producing analogs of the Wellbutrin 300mg XL product (Anchen, Actavis, Watson, and Mylan) to conduct similar studies for which data had not yet been reported.
This problem with bioequivalency had already been documented back in 2007 in a research paper.2 In this case, simply changing the sugar used to bulk up the dosage form caused major bioavailability differences. The same could be true when changing a dosage level, for instance, from 150mg to 300mg.
The impact of excipient on bioequivalence.
The case confirms the fact that any formulation will seldom remain exactly the same. Out of necessity, the ratios of ingredients change, tablet weights change, hardness changes, and even some excipients change.
It is an overdue change that clinical trials be performed on the actual dosage forms intended for sale by the company involved.
With generic pharmaceuticals, it seems that less stringent acceptance criteria may have been motivated by cost (specifically, HMOs and Medicare), rather than science.
With generic drugs accounting for almost 80 percent of all the prescriptions written in the US, it is clear that the acceptance criteria for generics should be every bit as stringent as they are for branded drugs. The public’s safety demands no less.
- FDA Post-Market Safety Information
- “A Modern View of Excipient Effects on Bioequivalence: Case Study of Sorbitol,” M-L. Chen, A.B. Straughn, N. Sadrich, M. Meyer, P.J. Faustino, A.B. Ciaverella, B. Meibohn, C.R. Yates, and A.S. Hussain, Pharmaceutical Research, 24 (1), January 2007