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Biosimilars Could Face Data Extrapolation Challenges

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By Marie Powers
Staff Writer

The FDA's decision last week that an approved generic bupropion wasn't comparable to GlaxoSmithKline plc's antidepressant Wellbutrin XL 300 mg (bupropion) raises questions about the hurdles biosimilar developers may face along the new regulatory path.

The FDA determined that Budeprion XL 300-mg (bupropion hydrochloride extended-release) tablets, manufactured by Impax Laboratories Inc. and marketed by Teva Pharmaceuticals USA Inc., are not therapeutically equivalent to Wellbutrin XL 300 mg. The decision affected only the 300-mg formulation manufactured by Impax and marketed by Teva and addressed only the bioequivalence rating of the product. Four additional manufacturers – Anchen Pharmaceuticals Inc., Actavis Group, Watson Pharmaceuticals Inc. and Mylan Pharmaceuticals Inc. – still market approved generic versions of Wellbutrin XL 300 mg, and Impax/Teva continues to market Budeprion 150 mg.

The decision, and the reasons behind it, left unsettling questions about the hurdles biosimilars developers may face when bringing compounds before the agency. One of the first questions for industry is whether, and to what extent, the agency will revisit the use of extrapolated data.

Like other generic versions of Wellbutrin XL 300, Impax/Teva's Budeprion XL 300 mg was approved in December 2006 on the basis of data comparing bioavailability of the 150-mg versions of the branded and generic drugs, extrapolated to the 300-mg extended-release strength. Within six months of the Impax/Teva Budeprion XL 300-mg approval, however, the FDA received 85 postmarketing reports describing adverse events or lack of efficacy after patients switched from Wellbutrin XL 300 mg, including worsening of depression symptoms.

The FDA re-examined the bioavailability data for the 150-mg versions, concluding the compounds were bioequivalent and therapeutically equivalent, but continued to review postmarketing reports. In November 2007, the agency asked Impax/Teva to conduct a bioequivalence study directly comparing Budeprion XL 300 mg to Wellbutrin XL 300 mg, stipulating the study enroll patients who reported problems after switching from the branded version to the generic. Impax/Teva began the study but terminated it late last year after the companies were unable to recruit a significant number of affected patients.

In the meantime, in 2010 the FDA sponsored its own bioequivalence study, enrolling 24 healthy adult volunteers to examine the rate and extent of absorption of the two drug products under fasting conditions. In August, data from that study showed the Impax/Teva version of Budeprion XL 300 mg failed to demonstrate bioequivalence to Wellbutrin XL 300 mg.

Consequently, the FDA said it is revising its guidance to industry for how to conduct premarket bioequivalence studies in generic bupropion products.

'A Billion Times More Complicated'

Extrapolating data for various reasons, including dosage, administration, formulation and indication, looms large as a challenge for biosimilars developers, said Peter Pitts, president of the Center for Medicine in the Public Interest and a former FDA associate commissioner. Once a biosimilar is approved, it could be used off label, posing a number of complex scientific and regulatory problems.

Those challenges likely would be exacerbated when developing biosimilars to drugs such as antidepressants, which fall into a narrow therapeutic index, according to Pitts. In April 2010, the Pharmaceutical Science and Clinical Pharmacology Advisory Committee voted unanimously, with one abstention, that critical dose drugs constitute a distinct group and that the FDA should develop a formal list of those drugs, he pointed out. In an 11-2 vote, the committee also concluded that existing bioequivalence standards were not sufficient for drugs in the narrow therapeutic index group.

"The issue with biosimilars is interchangeability," Pitts told BioWorld Today. Differences between small-molecule drugs like Wellbutrin and biosimilars are iteratively more complicated than they are with generics because they involve not just the chemical composition of the product but also the manufacturing process.

"When it comes to biosimilars, you're talking about molecules that are between 5,000 and 20,000 atoms," he added. "The question is whether a 5,000-atom biosimilar is less difficult than a 20,000-atom biosimilar. Of course it is."

Thus, biosimilars developers must prepare to contend with "many, many more ways to cut safety and efficacy" data, Pitts added.

Moreover, if biosimilars developers are asked by the FDA to conduct additional trials, they may face the same problem as Impax/Teva and fail to recruit sufficient enrollment because patients are not willing to consider switching drugs.

The FDA recently asked the other manufacturers to conduct their own bioequivalence studies and to submit data from the studies no later than March 2013. The agency did not indicate how quickly it could review the new studies or what penalties, if any, would be levied if the manufacturers are unable to generate the data on time.

The FDA isn't likely to cut biosimilars developers any slack in addressing those issues, either. A spokesman said the agency is "fully cognizant of the scientific, regulatory and legal challenges" associated with establishing the biosimilars pathway but emphasized that "any product licensed under this new pathway will meet the same very rigorous standards for approval as current products."

The Budeprion/Wellbutrin decision indicated the FDA now realizes that issues of similarity exist even with small molecules, Pitts said.

"With biosimilars, it's going to be a billion times more complicated," he cautioned.

Ironically, Teva may be among the first pharmas rethinking its biosimilars approach, at least in the U.S. Although company spokeswoman Denise Bradley said the firm "is firmly committed to the development of biosimilars" and – through its joint venture with Lonza Group AG, of Basel, Switzerland – continues to evaluate the path forward for rituximab (Rituxan/MabThera, Roche AG/Biogen Idec Inc.), "given the changes in the regulatory and competitive environment," the company recently suspended plans for a Phase III trial. Bradley said Teva plans to provide an update on its review of its research and development portfolio during investor day presentations on Dec. 11.

The FDA's decision on the Impax/Teva version of Budeprion XL 300 mg had "absolutely no relation" to the standstill on rituximab, Bradley added.

Still, the fact that the FDA is feeling its way along the biosimilars regulatory pathway and potentially revisiting its general approach to extrapolation should give biosimilars developers pause, Pitts suggested.

"Ten years from now, when the FDA has more experience dealing with this, [the pathway] will be more predictable," he said. "But now, every biosimilar that comes before the FDA for review is going to be a de novo experience. It's going to be a very difficult, very risky and very problematic process. From a business standpoint, you have to ask yourself: Is this a worthwhile proposition?"