Late in 2012, the US Food and Drug Administration (FDA) faced a rare and potentially problematic dilemma: Despite its repeated assurances that generic products were therapeutically equivalent to their reference product, it was forced to admit that several generic versions of the antidepressant Wellbutrin XL 300 mg (bupropion) were, in fact, different. Now, in response to criticism and its own promises to take another look at some of its therapeutic standards, the agency is making changes.
In September 2012, FDA announced that it had asked Israel-based manufacturer Teva Pharmaceuticals to stop distributing Budeprion XL 300 mg after it conducted testing and found that significant differences existed between Budeprion and Welbutrin XL 300 mg, its RLD. Teva marketed Budeprion, on behalf of Impax, which owned its application and manufactured the drug.
Though a similar review in 2007 had found the drugs existed within acceptable tolerances of one another, a 2012 review by FDA found the opposite. "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg," the agency wrote in its findings.
One of the most basic problems may have come from how the drug underwent bioequivalence testing. FDA said the product was approved at the 300 mg dose based on studies conducted using the 150 mg dose. "This methodology was based on FDA's guidance at the time the products were approved," explained FDA. The agency also noted the lower dose was used as the basis of approval due to concerns that the higher dosage could cause seizures in otherwise healthy adults, and this concern caused FDA to grant Teva/Impax a waiver for the studies-a process it refers to as "waiving up."
At the time of FDA's October 2012 announcement, the agency said it had asked four other manufacturers-Anchen (ANDA # 77-284), Actavis (ANDA # 77-285), Watson (ANDA # 77-715) and Mylan (ANDA #77-415)-to conduct similar bioequivalency testing on their drugs. As of 1 April 2013, only Impax's ANDA has been withdrawn.
Therapeutic Standards Are Changing
But FDA also made another little-noticed announcement in November 2012 explaining that it intended to take a second look at the way generic drug applications for extended-release generic drugs obtain approval, likely in response to the bioequivalence testing problems that exhibited themselves in the bupropion case.
Then-head of the Office of Generic Drugs Gregory Geba explained to the New York Times that, "This has actually prompted us to change our policy." The agency, he continued, was planning to re-evaluate how it conducts equivalence testing for generic drug products, particularly for extended release drugs.
The status of that review has flown mostly under the radar until now, with FDA's 1 April 2013 response to a citizen petition by Valeant Pharmaceuticals. In it, FDA explains much of its rationale for not requiring the 300 mg dose for bioequivalence studies.
"Until recently, FDA was concerned about a dose-related seizure risk with the 300 mg bupropion products," FDA explained. "As such, the Agency recommended, in a draft product specific bioequivalence (BE) guidance for bupropion HCl ER tablets first issued in 2007, that BE testing be conducted using the 150 mg strength, and waived the requirement to show in vivo BE for the 300 mg strength if there was: acceptable bioequivalence studies on the 150 mg strength, proportional similarity across all strengths and acceptable in vitro dissolution testing of all strengths."
With that testing now known to be inadequate, FDA said it had withdrawn all bioequivalence standards for bupropion, replacing them instead with updated BE guidance. The agency posted five new draft BE guidances on its website on 29 March 2013: 100 mg tablets, 200 mg extended release tablets, 300 mg extended release tablets, 450 mg extended release tablets, and 522 mg extended release tablets.
Those standards show that FDA no longer accepts testing on lower doses of the drug as the basis of approval for a higher dosage, such as a 150 mg dose used to approve the 300 mg extended release dose form.
What of the Missing Four?
FDA's response to Valeant also provides new information on the status of the four remaining ANDAs on the market for bupropion. FDA said that while it agrees that those four manufacturers used the same bioequivalence standards as Teva/Impax and used the same BE waivers, it has "Asked these sponsors to conduct additional studies to confirm the BE of their 300 mg bupropion HCl ER tablets and to submit the results to FDA."
"The Agency also believes that the bioequivalence issues with the Impax/Teva 300 mg product may have been the result of that product's particular formulation and thus limited to that product," it added. "Based on the information available to us, we do not believe it is necessary to withdraw approval of these products prior to completing our review of the results of the confirmatory BE studies. Once our review of the study data is complete, FDA will take any appropriate regulatory action."
FDA also rejected a call from Valeant that it convene an advisory committee to study the BE issues raised, saying that its Center for Drug Evaluation and Research (CDER) is uniquely qualified to study those issues and that it does not believe there are any "outstanding issues that are sufficiently controversial or scientifically novel to warrant input from an advisory committee at this time."