Friday, October 19, 2012

FDA says Wellbutrin Generic really isn’t generic after all


By Bob Rouder and Saul Perloff


The federal government both grants and restricts marketing advantages. For example, the patent protection and market exclusivity the government affords some pharmaceutical compounds lays the groundwork for a new drug to become a blockbuster brand. On the other hand, FDA approval of a generic can presage the demise of a brand drug. Pharmaceutical companies and consumers alike depend upon the government getting it right in both granting and eliminating market exclusivity. The story of Wellbutrin XL illustrates this point.

Wellbutrin becomes a blockbuster drug


Wellbutrin (bupropion HCl) was a blockbuster brand for GlaxoSmithKline (GSK). Invented in 1969 and first approved for use in treating clinical depression in 1985, it has generated brand sales in excess of $10 billion. Originally, Wellbutrin was formulated as an immediate release drug requiring thrice daily administration. A sustained release version introduced in 1996 permitted twice daily dosing. In 2003, an extended release formulation, Wellbutrin XL (bupropion HCl extended-release tablets), reduced the dosing to once per day.

Wellbutrin XL is dispensed in both 150 mg. and 300 mg. strengths. The dosing is significant, insofar as the compound is considered to have a “narrow therapeutic index”: Too low a dose is ineffective in addressing the disease state while too high a dose can promote seizures.

Welllbutrin yields the market to generic competition


In December 2006, FDA approved several generic versions of Wellbutrin XL. One of these was Budaprion XL, made by Impax Laboratories and marketed by Teva Pharmaceuticals. FDA News Release. The FDA approves a drug as a generic provided that it and the innovator drug are therapeutically equivalent wherein (i) the proposed generic is pharmaceutically equivalent to the innovator drug (e.g. has the same active ingredients, dosage form, route of administration, quality and labeling); and (ii) the proposed generic is bio-equivalent to the brand (i.e. exhibits a similar rate and degree of bioavailability to the body). FDA Facts About Generic Drugs.

Once the patent(s) applicable to the brand drug have expired, it is difficult for a brand company to challenge the FDA’s decision to approve a generic version of the drug in court. Not surprisingly, by 2008 most of the twenty million prescriptions written for Wellbutrin XL were filled with an FDA-approved generic version of the drug.

Patients report treatment failures


In early 2007, patients began reporting treatment failures after taking the 300 mg dose of Budaprion XL. An online consumer newsletter – The People’s Pharmacy –publicized these failures. Oct. 3, 2012 Commentary. This lead to comparative dissolution testing of Wellbutrin XL 300 mg. and Budaprion XL 300 mg. by Consumer Lab. Testing Results.

Those tests seemed to demonstrate that Impax/Teva’s approved generic released its active ingredient in an amount and at a rate different from Wellbutrin XL 300 mg.

The testing and treatment failures were brought to the attention of FDA. The agency cited the relatively small numbers of reported adverse events and the fact that the nature of the disease state lends itself to intermittent return, as reasons to uphold its original assessment of therapeutic equivalence.

In response to inquiries the FDA stated at the time it “cannot offer any examples where generics have been shown to not perform as expected. FDA has many years of experience in the review of generic drugs and has great confidence in the quality and equivalence of generic drug products.” See Pharmalot Article.

However, FDA did ask Impax/Teva to study its 300 mg. product to compare its bioequivalence to Wellbutrin XL 300 mg. According to FDA, Impax/Teva began the study, but terminated it in late 2011, “reporting that, despite efforts to enroll patients, Impax/Teva was unable to recruit a significant number of affected patients to generate the necessary data.” See FDA Update

FDA withdraws its approval of impax’s generic Wellbutrin


In 2010, “in light of the public health interest in obtaining bioequivalence data” FDA undertook its own testing. It found that Budaprion XL 300 mg. was not in fact bioequivalent to Wellbutrin XL 300 mg. See FDA Review.

That finding was accompanied by an admission: The original approval did not involve testing of the 300 mg. dosage form. Rather, only the 150 mg. version was tested and the results, which showed bioequivalence, were extrapolated to the higher dose. That methodology was chosen because it was viewed as unethical to expose volunteers to the higher dose – and the possibility of seizure – when dose proportional testing had always been deemed valid. See FDA Update. In this instance, however, it was not scientifically appropriate to extrapolate the results. This month, Teva voluntarily ceased marketing the 300 mg. product. See FDA Withdrawal Q&A.

Further fallout


Although FDA has stated that it believes that the failure of the Impax/Teva product “may reflect the product’s formulation, which is unique,” the agency has nevertheless asked the other manufacturers of 300 mg. extended-release bupropion tablets to conduct their own studies to assess the bioequivalence of their products to Wellbutrin XL 300 mg. The results of these studies should be available early next year.” FDA is also revising its guidance to industry for how to conduct premarket bioequivalence studies in generic bupropion products. Exactly how the testing standards will change and whether FDA applies them to other drug compounds remains to be seen.

Sources: FDA News Release: FDA Approves First Generic Bupropion Hydrochloride Extended-Release Tablets (Dec. 14, 2006); FDA Questions and Answers Regarding Market Withdrawal of Budeprion XL 300 mg Manufactured by Impax and Marketed by Teva (Oct. 3, 2012); FDA Update: Budeprion XL 300 mg Not Therapeutically Equivalent to Wellbutrin XL 300 mg (Oct. 3, 2012); FDA Website: Review of Therapeutic Equivalence Generic Bupropion XL 300 mg and Wellbutrin XL 300 mg (Oct. 3, 2012); http://www.wellbutrin.com/; Consumer Lab website; Pharmalot website.

This article was prepared by Bob Rouder (rrouder@fulbright.com / 512 536 2491) and Saul Perloff (sperloff@fulbright.com / 210 270 7166) of Fulbright’s False Advertising Practice.