Generic Drug Safety

Are Generics Really the Same?

Between 2000 and 2008, the number of new generic drugs put forth for FDA approval went up 40 percent and approvals doubled, with roughly 600 cleared to be sold last year. "Generic companies are popular on Capitol Hill because the industry is powerful and voters are anxious for cheaper drugs. There was always pressure on us to reduce barriers to entry," says Scott Gottlieb, M.D., deputy commissioner for medical and scientific affairs for the FDA from 2005 to 2007. (Dr. Gottlieb is now a resident fellow at the American Enterprise Institute, a conservative think tank in Washington, D.C., and also advises brand-name-drug companies.)

Because brand-name medications have already been clinically tested, generic companies applying for FDA approval don’t have to repeat that process on their versions. Instead, they must test their medicine on a minimum of 20 people; subjects take a single dose, so the drug is not tested over time. If tests show the generic contains the same active ingredient that the original does and delivers about the same dose, then the FDA considers it "bio­equivalent" and clears it to be sold.

But as Beth Hubbard discovered, patients are finding stark differences among drugs the FDA has deemed equivalent. Pharmacologist Joe Graedon and his wife, Terry, cohosts of the public radio show "The People’s Pharmacy," have fielded complaints about dozens of generics for depression, hypertension, high cholesterol and more. Consumers described drugs that had no effect, caused bizarre side effects or made conditions worse. Joe Graedon says he has been "astounded" by the outpouring.

"I’m not in the back pocket of the pharmaceutical companies—I want generics to be good," he says. "But the more we dug, the more we realized nobody is monitoring the equivalence of these drugs."

After her ordeal, Hubbard hit the Internet. Amazed, she scrolled through hundreds of comments at PeoplesPharmacy.org, many from patients who had switched to the same drug she had—Budeprion XL 300 milligrams, which Impax Laboratories makes and Teva Pharmaceutical Industries distributes. One patient wrote, "I have no history of suicidality, but a day after switching to the generic, I went into a week of steadily rising panic…. I was psychotic, self-loathing way way beyond anything I have ever experienced. I made it through the worst of it, called a suicide hotline, took two Ativan and didn’t take any more of the Budeprion. The next day I felt much better, and today I’m back to my normal self."

If the drugs were truly bioequivalent, what could account for such divergent reactions? Last fall, the Graedons collaborated with ConsumerLab.com, an independent testing laboratory in White Plains, New York, to find out. Testing revealed that the 300 mg Budeprion XL dose Hubbard had taken dumped four times as much active ingredient during the first two hours as the brand name did. Graedon compares the effect to guzzling alcohol. “If you sip a glass of wine over the course of two or three hours, you’re not going to feel drunk,” he explains. "But if you drink the whole thing in 15 minutes, you’re getting too much too fast."

Release formulas, which control how quickly a drug dissolves in your bloodstream, are something drug companies carefully develop and patent. And these release-formula patents often remain in place after the patent on a drug’s active ingredient has expired. That means generic companies must sometimes engineer their own release mechanism, as happened in the case of Budeprion XL. After complaints started rolling in, the FDA concluded in a 2008 report that patients’ problems were more likely caused by normal relapses of depression than by differences in the drugs, and Teva stressed that it followed all the FDA’s rules.

But that report—and the original approval of the 300 mg pill—was based solely on data Teva had submitted for the 150 mg pill; the agency’s judgment was that the doses were proportional and would behave similarly in the body. "Neither the FDA nor Teva did the required bioequivalence studies for this pill," counters Tod Cooperman, M.D., president of ConsumerLab.com.

Buehler notes that the FDA won’t approve generics that its scientists deem to have "clinically significant" differences in release rates compared to the original. But the bioequivalence studies they base this judgment on aren’t public, so doctors and patients have no way of knowing when the FDA has found a difference and how dramatic it is. Nor can they easily find out about differences in fillers and additives, which might change the release rate or in rare cases trigger allergic reactions. "It’s scary to think the FDA would approve something it knows is different and still call it equivalent," Dr. Cooperman says.

Some physicians are concerned not only with how fast generics deliver their dose but also about the strength of the dose itself. Because for some drugs, such as those that treat epilepsy and heart disease, even small differences in potency can mean the difference between an ineffective underdose and a toxic overdose.

Stephanie Bornice, a 22-year-old stay-at-home mother of two in Bristol, Pennsylvania, and an epilepsy sufferer since 2002, says she hadn’t had a seizure in six years, thanks to the medication Trileptal. But last year, after about a month on the generic, oxcarbazepine, Bornice began to have frightening and familiar symptoms, like tremors before an earthquake. "Someone would be talking, and I wouldn’t understand him, or my sight would blur," she remembers. One afternoon, a seizure came on suddenly. She rushed to put her newborn son safely in his crib before, she says, "everything turned black."

Bornice’s doctor at the time, Jacqueline French, M.D., professor of neurology at New York University Comprehensive Epilepsy Center in New York City, quickly confirmed Bornice’s suspicions that the generic was causing the problem and switched her back. Dr. French describes the case as a "clear-cut failure" of the generic—and not the only one she has seen. "The FDA is telling us that the drugs [dosages] are the same within a certain margin and that should be OK," Dr. French says. "But there are patients holding off seizures by the skin of their teeth."

Ensuring the correct dose becomes even trickier when pharmacists switch customers from one generic version of a drug to another, says John S. Antalis, M.D., a family physician in Dalton, Georgia, who has served on the safe-medication-use committee of U.S. Pharmacopeia, a nonprofit organization in Rockville, Maryland, that sets official standards for all medications. Dr. Antalis cites the dozens of versions of warfarin, the generic for the blood thinner Coumadin. It’s a drug that requires patients to have regular blood tests; they risk blood clots if they have too small a dose and internal bleeding if they get too much. It became much harder to monitor the clotting in patients’ blood, Dr. Antalis says, because they were being shifted between so many versions of warfarin that it was hard to say which drug was having what effect. "I try to stay on top of any subtle hint of change, but it’s difficult," he says.

Physicians’ groups, including the American Academy of Neurology in St. Paul, Minnesota; the American Heart Association in Dallas; and the Endocrine Society in Chevy Chase, Maryland—all of whose members prescribe drugs that require delicate dosing—have warned doctors to look out for reactions to generics. They’ve also called on the FDA to study the issue in more detail. (Many medical societies have ties to brand-name companies; for instance, Abbott Laboratories, maker of the popular brand-name thyroid drug Synthroid, has donated to the American Association of Clinical Endo­crinologists in Jacksonville, Florida.)

Some experts chalk up complaints to the fulfillment of expectations: We believe a generic will be worse, so it is. "People hear the word generic, and they think about generic cornflakes or plastic wrap," Dr. Kesselheim says. Others dispute that notion. "Patients look forward to having a lower co-pay," says Adam Keller Ashton, M.D., clinical professor of psychiatry at the State University of New York at Buffalo School of Medicine and Biomedical Sciences. (Dr. Ashton says he has earned money from the makers of Wellbutrin in the past but not for the previous two years, and he has no ties to generics.)

He estimates that at least 75 of his patients have complained about the 300 mg generic version of Wellbutrin XL. "If it was in their head, why wasn’t it in their head when other brands went generic?" he says, adding that many of his patients felt so bad that if he hadn’t intervened, "it might have progressed to the point to where lives were in jeopardy."

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