The FDA's reversal earlier this week of its approval of a generic equivalent of the popular antidepressant Wellbutrin XL 300 ends a five-year saga that began with consumer complaints and a crusade by Joe Graedon, the cofounder of the consumer advocacy group the People's Pharmacy.
In 2007, Graedon began receiving disturbing complaints on his website from patients who had been taking the 300 mg dose of Wellbutrin and had recently switched over to the generic equivalent Budeprion XL 300. Budeprion products are sold by Teva Pharmaceuticals and made by Impax Laboratories, both headquartered in Philadelphia.
"People were saying, 'I've been on Wellbutrin for several years and things were fine and dandy, but once I was switched I started experiencing headaches, anxiety, depression and sleeplessness'," he said. "People who had never been suicidal were all of a sudden reporting suicidal thoughts."
At first Graedon said he was skeptical. But after he had received a few dozen messages, he decided to write about it in his syndicated newspaper column. That's when the floodgates opened: Soon more than a thousand messages poured into the People's Pharmacy website describing the same symptoms, in intimate detail.
Alarmed, Graedon contacted Consumer Lab, an independent testing group based in White Plains, N.Y, and asked them to evaluate the 300 mg dose of the generic pill. The findings of the Consumer Lab tests suggested that while the active ingredient in the generic Budeprion XL 300 mg and brand-name Wellbutrin XL 300 mg products was identical, the rate at which it was released differed.
"In the first two hours of a dissolution test, we found Budeprion released 34 percent of the drug, while Wellbutrin released 8 percent. At four hours, the Teva product released nearly half of its ingredients, while original Wellbutrin released 25 percent. The generic did not act like a once-a-day formula but more like an immediate release formula," Dr. Todd Cooperman, Consumer Lab's president, stated.
Cooperman said the problems arose because of an unusual circumstance where the patent on the drug itself had expired, making it available in generic form, but the time-release mechanism used in the original did not. The original pill has a membrane so that the drug seeps out over time. The Teva pill simply breaks apart.
Consumer Labs and the People's Pharmacy took their concerns to the Food and Drug Administration and requested information on the human drug trials that companies are typically required to submit for drug approval. After what Graedon described as "a lot of back and forth," the FDA revealed that the 300 mg product had never undergone bioequivalence testing even though this is typical agency protocol. Instead, their approval was based on tests of a 150 mg version of the drug.
Graedon said although it's well understood that different dosages of drugs frequently don't have the same results and can produce varied side effects, the agency stood by its approval of the 300 mg dose of the generic. However, they asked Teva to voluntarily perform its own trials involving people who had reported problems.
Citing difficulty recruiting subjects, the company never performed the tests. Then in 2010, the FDA took the unusual step of conducting its own independent trial of 24 subjects. It found that the maximum concentration of Budeprion XL 300 in the blood reached only 75 percent of the amount Wellbutrin XL 300 released.
"This discrepancy in dosage could render the drug less effective in treating depression and could explain the side effects we were hearing about," Graedon said.
When results of the trials became available recently, the agency sent both Teva and Impax communications asking them to voluntarily withdraw the drug from the market. Both companies have complied with the request.
FDA spokesperson Sandy Walsh stressed that this is not a recall, which is typically done when a drug is unsafe.
"This is a voluntary market withdraw by the company for a drug that may not work well for some people. It is one type of generic Wellbutrin XL in the 300mg strength only, made by Teva. This does not impact the other manufacturers or the 150 mg strength pills," Wash said.
The agency estimates that only about 2 percent of people taking a 300 mg dose of a generic version of the antidepressant take the Teva pill. They have asked other manufacturers of generic 300 mg dose versions of Wellbutrin to conduct their own studies and submit their data no later than March 2013.
But is this voluntary recall just the tip of the iceberg? Does it mean there could be other generics in wide use that are either unsafe or ineffective? Dr. Harold Koenig, associate professor of psychiatry and medicine at Duke University said he doesn't believe this is the case.
"Most generics work just fine and are as effective as the name brand. And they are a lot cheaper. So you cannot say, based on what happened with this one drug, that we should throw out all generics," he said.
However, Koenig said he thought the FDA's actions were significant. "It might open up a can of worms if this is the first time the FDA took their own look at the effectiveness of generic versus name brand. It could lead to a lot of other drugs being studied," he said.
For his part, Graedon said he is happy with the result even if it was a long time in coming.
"It took us five years and an awful lot of arm wrestling to help the FDA make this decision, but this is really a historic moment. If you think of prescription drug use in America, generics account for about 75 percent of them, and until yesterday the FDA has maintained they are identical to brand names."