Analysis of the Eastern District of Pennsylvania’s recent ruling in  In re Budeprion XL Marketing & Sales Litigation has properly focused on the trial judge’s rejection of the generic manufacturer’s preemption argument.  Preemption in the wake of Wyeth v. Levine has been a hot topic, and how the opinion applies in the context of failure-to-warn suits against generics could be soon headed to the Supreme Court.

The suit itself, and its adverse outcome for generics, also highlights significant and troubling concerns over how FDA’s Office of Generic Drugs (OGD) determines whether a generic drug is “bioequivalent” to the branded drug it is meant to duplicate.  Concern with buproprion XL reflects the “rising tide of skepticism” over generic approvals which one senior FDA official identified last year.  Buproprion XL is a controlled or extended release drug, one that is designed to release medication in a patient’s body over a period of time. In his In re Budeprion XL opinion, Judge Schiller related how FDA and consumer advocates have received scores of complaints from depression patients who switched (most likely for insurance reasons) from the branded Wellbutrin XL to the generic buproprion XL.  Those complaints ranged from returned symptoms to suicide attempts.  The differences between the branded and generic apparently lie in how the active ingredient, buproprion, is released into the blood stream.  Judge Schiller wrote, “studies showed that Budeprion XL released 34% of its Buproprion within the first hour, compared to only 8% for Wellbutrin XL.”

As noted in a May 2009 Washington Legal Foundation Legal Backgrounder, FDA studied the matter and in its report reiterated that Wellbutrin XL and buproprion XL were bioequivalent and deemed buproprion XL was still safe and effective.  Not mentioned in FDA’s reassessment, however, was the agency’s original failure to examine the bioequivalence of the 300 mg versions of buproprion XL and Wellbutrin XL.  Instead, as the plaintiffs pointed out in In re Budeprion XL, the agency only tested the bioequivalence of the 150 mg versions of the branded and generic antidepressants.  The majority of those complaining about buproprion XL side effects had taken the 300 mg version.

The WLF Legal Backgrounder also documented patients’ and doctors’ concerns over the equivalence of other controlled-release generic drugs, as well as generic drugs for epilepsy, acute skin pain, and a deadly gastrointestinal bacteria.

Buproprion XL’s manufacturer argued that the state failure-to-warn suit would directly undermine FDA’s authority and its bioequivalence process, which requires generic makers to provide warnings on the label identical to those on the branded drug.  The court replied that the defendants could submit information to FDA to change the label and in fact implement warnings themselves under the “changes being effected” process while FDA considers the request.  Judge Schiller boldly declared, “this Court finds it difficult to believe that FDA would balk at a drug maker seeking to strengthen the warning label on its product.”

To which anyone who follows FDA’s Office of Generic Drugs would reply, “Oh really?”  OGD devotes considerable resources to upholding the credibility of its generic-equal-branded mantra, including an extensive public relations campaign targeting pharmacies and consumers.  The office consistently rebuffs the pleas of branded producers and patients’ groups to apply more rigorous testing standards in judging bioequivalence.  FDA in essence would be acknowledging flaws in its testing if it allowed the producer of buproprion XL to add a warning that its drug dissolves differently than Wellbutrin XL.

The judge’s reasoning in In re Budeprion XL places generic drug makers and FDA in quite a bind.  In order to curtail some state tort litigation, generics may have to seek a warning which shows that its drug is different from the branded on which it’s based.  FDA may be put in a position where it has to either admit that patient use revealed that its bioequivalence determination as basically wrong, or reject a warning which might protect the public.  At a minimum, the In re Budeprion XL decision should increase pressure on FDA and its Office of Generic Drugs to palce more emphasis on ensuring patient safety than on preserving its credibility or lowering health care costs.