Same, same but different Wellbutrin could cause problems for generics companies

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Although the FDA’s decision to ask Teva Pharmaceutical Industries and Impax Laboratories to pull Budeprion XL 300mg, their generic version of Wellbutrin XL 300mg, from the shelves owing to ineffectiveness may have had little impact on the share price of either company, it could have much deeper and wider implications for the rest of the generics industry.

There could now be calls for the regulator to tighten its rules on equivalency standards and also re-examine the policy of “waiving up”, whereby higher doses of drugs can in certain cases be approved by extrapolating data from a lower dose. But ultimately, and more worryingly for generics companies, these results might call into question the idea that all generics are identical to named brands.

In it together

In a statement published yesterday the FDA said it had asked Impax, which manufactures the drug that is distributed by Teva, to withdraw voluntarily the 300mg dose of the major depressive disorder product because it was not “therapeutically equivalent” to GlaxoSmithKline’s Wellbutrin XL 300mg.

After the news Teva’s US shares fell by 1% to $40.79 and Impax was off 2% at $26.39. UBS analysts estimate that Teva and Impax only have 2% of the generic 300mg market and have put a sales figure of $9m during 2011 for Teva, with Impax getting a small royalty, hence the lack of any significant movement in either group’s stock.

But this could start to move if, as expected, patients who experienced worsening of their symptoms launch multiple lawsuits. Teva and Impax might also not be alone in finding their drugs pulled. The four other companies currently providing higher doses of the drug, including Watson Pharmaceuticals, Mylan, Actavis and Anchen Pharmaceuticals have been asked by the regulator to conduct their own bioequivalence studies and have a deadline of March 2013 to come up with the results.

Testing times

The withdrawal of Budeprion XL 300mg initially came about as a result of 85 complaints from consumers during a six-month period in 2007. The regulator continued to monitor reports of lack of efficacy and in November of that year asked Impax and Teva to conduct a bioequivalence story comparing Budeprion XL and Wellbutrin XL at the 300mg dose.

However, Teva and Impax terminated the study in late 2011, claiming they were unable to recruit enough patients who had made the switch between the two products. In parallel the FDA had in 2010 launched its own investigation due to the public health interest of obtaining bioequivalence data.

That trial in healthy volunteers measured the rate and absorption of the two drugs, and when it reported last month it showed that Budeprion XL 300mg was not bioequivalent to Wellbutrin XL 300mg.

Scaling up

The reason why the FDA found itself in this position is the practice of “waiving up” approval of doses for certain generic products.

When the generic version of Wellbutrin came before it, the FDA had allowed Impax and other filers to extrapolate the results from bioequivalence studies of the 150mg dose of the drug to the 300mg dose.

Usually the regulator recommends that all doses of a drug be used to establish bioequivalence, but in the case of Wellbutrin the risk of seizure occurs at higher doses – something that would not have been acceptable in the healthy adult volunteers used in testing.

Instead the drug was approved on bioequivalence of the next strength down, the 150mg dose, which remains on the market.

Tightening up procedures

This is not the first time that a generic drug has been found to be inferior to the original and the FDA has previously looked into versions of the blood thinner warfarin and phenytoin for seizures.

What the regulations of bioequivalence currently do is ensure that generics are absorbed at the same rate and to the same extent as the reference drug. This, however, does not always translate into actual efficacy and it is rare that generics are tested against the reference drug for efficacy.

The agency itself has also admitted in the past that the occasional gaps in efficacy were leading it to look into tightening standards to align the efficacy of generics more closely to their branded counterparts. And in April 2010 a group of independent advisors to the FDA voted 11-2 that the regulator’s equivalence standards were not robust enough for certain medicines.

After this latest hiccup in ensuring similarity, the regulator will once again be asked to look at this issue, which has read through to the coming of biosimilars, whose similarity to their reference drugs is going to prove even more difficult to assess.

To contact the writer of this story email Lisa Urquhart in London at lisau@epvantage.com

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