As FDA considers how best to address continued concerns about generics for Wellbutrin XL (bupropion extended-release tablets), one issue it may wrestle with is whether it should conduct bioequivalence studies at the highest dose, 300 mg, which has a higher risk of seizures.

The agency said it has "agreed to look into doing a study that would test the drug in patients that have reported problems with the product," but "there is no information available yet on what type of study may be done."

Industry sources say the study hinges on funding from the manufacturer. Teva, who distributes the generic for manufacturer Impax, may be willing to participate in a study, the sources said. Teva officials had no comment.

The potential collaborative study stems from a meeting this summer with the agency, requested by People's Pharmacy co-founder Joe Graedon, to address the hundreds of reports Graedon's Web site had received from patients experiencing adverse events and loss of effectiveness when switching from GlaxoSmithKline's antidepressant Wellbutrin XL to Budeprion XL , the brand name of the generic.

Post-marketing Reports Continue

FDA was already aware of post-marketing events with the two drugs. The agency reviewed the therapeutic equivalence of Teva's Budeprion XL to Wellbutrin XL in April after receiving 85 post-marketing reports in the first half of 2007 (¹ Also see "Teva’s Generic Bupropion XL Meets Bioequivalence To Wellbutrin XL, FDA Finds" - Pink Sheet, 16 April, 2008.). The agency concluded the generic is bioequivalent and therapeutically equivalent to the brand, despite reports that more than half the patients who switched back to Wellbutrin XL from the generic reported an improvement in depression.

"The question is whether the reported lack of efficacy and/or new onset side effects in these patients who switched suggests a problem with the generic product, i.e., lack of bioequivalence to the branded product, or have some other explanation," FDA said in the ² review.

Yet Tod Cooperman, president of ConsumerLab, who was also present at the meeting and conducted tests of the formulations last October, noted that FDA only tested the 150 mg dose of the drugs - whereas the majority of complaints centered on the 300 mg dose.

FDA explained that the smaller dose was used because of a potential risk of seizures. "The 300 mg strength was not studied, since the pharmacokinetic profile between the 300 mg and 150 mg doses of bupropion are not expected to differ."

Graedon questioned whether generics are truly bioequivalent in a meaningful way for the patient. The clinical trials are a "non-real life environment," he said, and patients are not "clinical trial types."

"In the real world, what we have seen on our Web site ... is that these are people who had very good success with the brand name ... and they stayed on it, not for weeks or months but in some cases for years."

"So the notion that bupropion wore out seems to fade if people go back on the brand name and it works," Graedon added.

A Different Extended-Release Mechanism

A possible reason for the loss of effectiveness, Cooperman says, could result from the patients getting too much of the drug too quickly.

ConsumerLab's analysis showed that the tested products contained the claimed amount of bupropion hydrochloride, but the dissolution rates were "quite different."

The active pharmaceutical ingredient is no longer protected by patent, but the drug delivery technology is; Teva's system leads to much more rapid dissolution.

At two hours, 34 percent of Budeprion XL was in solution, while only 8 percent of Wellbutrin XL had dissolved. At four hours, 50 percent of the Teva drug had dissolved, versus 25 percent of Wellbutrin XL. The drug concentrations were approximately equivalent after eight hours, ConsumerLab says.

The dissolution rate is more similar to the immediate-release formulation, thrice-daily Wellbutrin, than once-daily extended-release Wellbutrin XL, ConsumerLab said in their report. Teva says the dissolution test for its product is still protected by proprietary information, but ConsumerLab said they were able to obtain the method.

FDA redacted bioequivalence or dissolution data for the product in the approval letter. While results from the April review suggest there is some difference in rate and extent of absorption at the 150 mg level, the variation is within FDA's established bioequivalence limits. Whether the results extend to the 300 mg dose is the linchpin in the argument, Cooperman says, calling the agency's assumption "a leap of faith."

FDA has been challenged on its approval standards for generic bupropion in the past. In 2005, Biovail, which developed the brand's extended-release technology, filed a citizen's petition against FDA, "intending to protect the public against the potentially harmful effects of generic versions of Wellbutrin XL that may not, in fact, be bioequivalent to Biovail's branded product, or that may be misleadingly labeled" (³ Also see "Biovail Sues FDA Over Wellbutrin XL Generics" - Pink Sheet, 24 August, 2006.).

Biovail had alleged that if non-bioequivalent generic versions of Wellbutrin XL reach the market and some patients suffer from grand mal seizures, the drug's reputation would suffer (⁴ Also see "Federal Court Ruling Clears Way For Wellbutrin XL Generic" - Pink Sheet, 12 September, 2006.).

Casting A Cloud Over Generics

Graedon believes that the approval process is rigorous and generic manufacturers meet the same quality standards as Rx products, but the post-marketing monitoring is "spotty at best."

"How do you know these aren't problems in the pipeline? How do you know the active pharmaceutical ingredients are the same? What about quality control?"

Cooperman also supports the generics industry, saying "everyone sees a great role to be played by generics - if they are truly behaving like the brand drug." He says quality control is an area needing closer scrutiny.

More stringent enforcement "might cause the removal of a few drugs on the market now, but in the long run it would be better for the generic industry and its reputation going forward."

The questions about bupropion come at a difficult time for FDA, which is under fire for its inspections of foreign and domestic generic manufacturers. Taking on the re-evaluation of a generic drug - for the second time this year - can only add to the resource crunch, even if the study is supported by outside funding.

Adding to the pressure are investigations by the Justice Department and members of the House Energy and Commerce Committee. Both are looking into allegations of fraud related to Ranbaxy manufacturing in India and questioning why it took FDA so long to crack down after it became aware of problems (⁵ Also see "Ranbaxy’s Ripples: Generic Drug Integrity Returns As Focus For Congress, FDA" - Pink Sheet, 21 July, 2008., p. 9).

Even as FDA moved to block imports of some of Ranbaxy's products, the concerns are likely driving Commerce Committee Chairman John Dingell, D-Mich., to add more stringent measures in the inspections bill he is developing (⁶ Also see "Dingell May Tighten Inspection Provisions In Safety Bill, After Ranbaxy Alert" - Pink Sheet, 22 September, 2008., p. 3).

Adding Fuel To The Fire

Other companies adding to the cloud over generics include Actavis, who recalled all 65 products manufactured at its Little Falls, N.J., plant Aug. 1 following a series of inspections (⁷ Also see "GMP Storm Cloud: Generic Firms May Get Further Scrutiny After Actavis Recall" - Pink Sheet, 11 August, 2008., p. 24), and Sandoz, which appears to be continuing to release generic metoprolol succinate ER (AstraZeneca's Toprol XL ) despite FDA's concern that it is in violation of good manufacturing practices (⁸ Also see "GMP Warning To Sandoz Questions Continued Lot Release; Will FDA Block It?" - Pink Sheet, 1 September, 2008., p. 23).

ConsumerLab and People's Pharmacy had reported an increased adverse cardiovascular signal in the metoprolol generic in March, five months before FDA sent a warning letter.

As with extended-release Wellbutrin, Toprol's delivery method was still covered by patent; Par Pharmaceutical also markets an authorized generic as the only truly identical product on the market.

Whether these reports create any widespread doubts about generics in general remains to be seen, but in the short term, news that brings into question FDA's oversight ability certainly makes it harder for the generics industry to argue that the agency should be given more discretion in legislation that would create a follow-on biologics pathway (⁹ Also see "Editor’s Perspective: Is The Ketek Scandal Good For Big Pharma? Generic Biologic Bill Could Suffer" - Pink Sheet, 25 February, 2008., p. 4).

What steps industry and FDA could take to allay general fears about generics remains unclear. There's no suggestion that the agency is being hasty in its approval of ANDAs (see ¹⁰ Also see "Generic Firms Object To Policy Behind Residual Solvents Deficiency Letters" - Pink Sheet, 29 September, 2008.) and while FDA seems obliged to investigate questions about particular products, a new slew of studies about products that were supposed to be safe in the first place will not be particularly reassuring.

- Becky Jungbauer (r.jungbauer@elsevier.com)

FDA Revisits Wellbutrin Generics – Again; Will Teva Fund A High-Dose Study?

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