A Generic Conundrum: How do you Study a Drug that has Been Withdrawn from the Market?

| 13 August 2013 |  By 

In March 2013, the US Food and Drug Administration (FDA) formally withdrew approval for Impax Laboratory's buproprion hydrochloride extended release 300 mg (Budeprion XL 300 mg), saying the drug had been found to not be bioequivalent to its reference listed drug, Wellbutrin XL 300 mg. Soon thereafter, the agency announced it was looking for a company to further study the issue of why Impax's drug wasn't bioequivalent when several other generic products did not exhibit similar problems despite being approved through the same testing regimen. Now, though, that plan has run into something of a conundrum: Just how do you study a product that has been withdrawn from the market?


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," 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, Actavis, Watson and Mylan-to conduct similar bioequivalency testing on their drugs. FDA has not called for any of those drugs to be withdrawn from the market, though it has re-issued bioequivalency standards for the drug at the 100, 200, 300, 450 and 522 mg dose levels.

The drug was formally withdrawn by FDA in a 15 March 2013 Federal Register notice, removing its new drug application (ANDA #77-415) from the list of approved generic drugs, but leaving a related 150 mg formulation on the market.

A Search for Answers

But the question remained: Could other drugs exhibit the same issues seen in the case of Impax's Budeprion? FDA said it remained open but initially skeptical of that idea.

"The Agency … 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 wrote in a response to Valeant Pharmaceuticals in April 2013. "Based on the information available to us, we do not believe it is necessary to withdraw approval of [other buproprion generic] products prior to completing our review of the results of the confirmatory bioequivalency studies. Once our review of the study data is complete, FDA will take any appropriate regulatory action."

And while those other sponsors continue to conduct their own testing, FDA quietly announced in April 2013 that it wants to direct its own study on the issue-"a two-year pharmacokinetic study of bupropion HCl products with different release patterns."

"Understanding the scientific basis causing the failure of the 300 mg tablets is important for future guidance development and review processes," FDA explained in its announcement on the Federal Business Opportunities website. "It is noted that the generic version had different formulation design as the reference product so that the generic product releases earlier in the gastrointestinal (GI) tract," FDA wrote.

Continued FDA: "One of the hypotheses for the failure of bioequivalence study on the 300 mg tablets is that bupropion is eliminated differently in the GI tract due to the different in vivo release patterns. In addition, subjects with different metabolic genotypes may have different sensitivity ... Pharmacokinetic study of bupropion HCl products with different release patterns at different dose levels will help understand the underlying mechanisms."

Studying … What, Exactly?

But in withdrawing the drug from the market, FDA may have introduced new complexities into conducting this study.

In a new posting on the Federal Business Opportunities website in August 2013, the agency noted that "Budeprion XL 300 mg will not be part of the study because it has been withdrawn from the market."

In other words, the drug that was the cause of the agency's concerns-Impax's Budeprion XL 300 mg-won't even be tested, despite the agency's contention that its particular formulation may have contributed to its failure-a formulation that presumably isn't present in still-approved generic variants of Wellbutrin XL 300 mg since those products still remain on the market.

What will be studied, FDA's notice explains, are other bupropion 300 mg generic variants to determine whether different release patterns (immediate, sustained and extended release) are affected by enzymes during the digestion process.

The response deadline for FDA's proposed study is 19 August 2013.

FBO Notice


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