International Herald Tribune
November 2, 2012
The U.S. Food and Drug Administration (FDA) has said it is looking more closely at the way generic companies made extended-release drugs after it found one such medicine failed to work as well as its brand-name counterpart. The finding is a rare departure for the agency, which for years has insisted generic drugs are just as effective as generally more expensive brand-name versions.
The medication, a 300-milligram dose of bupropion, was manufactured by Impax Laboratories and was intended to mimic the popular antidepressant Wellbutrin XL, which was sold by GlaxoSmithKline. But soon after it was introduced in 2006, patients who switched to it from Wellbutrin began complaining their depression returned. Impax and Teva Pharmaceuticals Industries, which marketed the drug, have stopped selling the 300-milligram dose.
Although regulators have said the episode appears to be limited to one dosage level of a single drug, an FDA official said last month the agency was now looking more closely at the techniques used by makers of generic drugs to create the extended-release drugs. “This has actually prompted us to change our policy,” said Gregory P. Geba, the director of the FDA office of generic drugs.
Generic drugs now account for the overwhelming majority of medicines prescribed in the United States, and extended-release drugs are a rapidly growing segment of the generic market. But they can be tricky to make. While the active ingredient is the same as in the brand-name version, the mechanism for gradually releasing the drug into a person’s body can vary.
The FDA’s decision that a generic was not the equivalent of the brand provides fodder to some critics who say the regulator and generic drug companies have been reluctant to acknowledge that sometimes generics do not work as well as the brand-name originals.
Others dismissed such arguments, saying the recent criticism was just the latest effort in a longstanding campaign to discredit generics unfairly. “I think there’s still a cloud hanging over generic drugs,” said Joe Graedon, a pharmacologist who runs a consumer website, the People’s Pharmacy, which raised questions five years ago about Teva and Impax’s version of Wellbutrin XL. “This may be far more common than the FDA had realized.”
Ralph G. Neas, president and chief executive of the Generic Pharmaceutical Association, the industry trade group, said in an email the “FDA’s science surrounding the approval criteria for all drug products, including extended-release products, is well grounded and rigorous.”
The popularity of extended-release drugs has increased rapidly in the past decade or so in the United States. In 2001, 84 extended-release drugs were sold in the country; by 2011, the number had grown to 120, according to IMS Health, a healthcare information company.
Patients like the drugs because they can take them less frequently. But developing a longer-acting version of a best-selling medicine is a classic strategy for extending the time a company can sell a drug exclusively.
Besides patenting the drug itself, brand-name companies also can acquire a patent for the way the drug is released into the body. Those methods can include complex technologies that employ tiny pellets, special coatings or laser-cut holes. The patent for the method can often outlast the patent for the drug itself.
When a brand-name drug does lose its patent protection, a generic company often seeks to make its own extended-release version, one that dissolves the drug at the same rate as the branded product but does not infringe on the other company’s patent.
Generic drugs must contain the same active ingredient as their brand-name counterparts but can differ in other ways, such as inert ingredients and size, shape and color. But some critics say the generic companies do not always succeed in mimicking the longer-lasting effects of the brands, and the FDA does not do a good enough job of evaluating them.
“I tell my patients I’m not against generic drugs, but I tell them that if they’re stable in whatever they’re taking, don’t let the pharmacy change them,” said Harry M. Lever, M.D., a cardiologist at the Cleveland Clinic. He said patients had complained for years about problems when they switched between generic brands or from brand-name drugs to generics. Often, those drugs are extended-release versions, he said.
Complaints about the bupropion pill surfaced soon after the drug was approved in December 2006. Patients who took the 300-milligram dose claimed their depression had returned after they switched from Wellbutrin XL.
The FDA approved the 300-milligram dose of bupropion without requiring a direct study in patients. Instead, it extrapolated from the results from an earlier study of a 150-milligram dose. Impax and Teva’s 150-milligram dose remains on the market.
The FDA and representatives for Impax and Teva declined to comment on the mechanism used in the extended-release bupropion tablets or why it did not work well in the 300-milligram dose, saying it was a trade secret.
The agency initially dismissed the patients’ concerns, saying the symptoms were likely because of the “natural course” of depression and not a failure of the drug. Still, it asked Teva and Impax to conduct a study of people who used the higher dose and complained of problems. But the companies canceled the study in late 2011, saying they could not recruit enough participants.
In 2010, the FDA took the rare step of conducting its own study of the 300-milligram strength. In early October, it announced the drug did not, in fact, perform as well as the brand-name version. Representatives for Teva and Impax declined to comment on whether they intended to sell the higher dose in the future.
Geba said he wished the agency had uncovered the problem sooner, but the issue was clouded by the fact depression is difficult to treat. “It’s understanding the adverse events—are they real or are they part of someone’s actual illness?” he said. “That’s not an easy thing to assess.”
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