People reported night sweats, crying they could not control, the return of anxiety and suicidal tendencies that erupted after successful years on medication. What brought this on? Most were convinced the timing was related to being switched from a medicine they had been taking for years to a new agent.

These stories, which were pouring into People’s Pharmacy, were more than web-site hosts Joe and Terry Graedon could bear. In an effort to learn what they could about the two drugs, Budeprion XL 300, a generic new to the market, versus Wellbutrin 300 XL, coming off patent yet still more expensive, they contacted the FDA. When that yielded no results, they asked ConsumerLab.com to do a dissolution test. The results,

Six months later, and armed with its own complaints about “adverse events” – also known as side effects, or bad things which shouldn’t happen -- the FDA conducted tests to determine if the drugs were indeed identical. Review of Therapeutic Equivalence: Generic Bupropion XL 300mg and Wellbutrin 300 XL was issued in April. But it did not say what some consumers or watchdogs wanted to hear.

Based on the results of its standard testing, the agency concluded that "there was no significant difference in the rate and extent of absorption." The drugs met criteria for equivalence. And after discounting any importance to the documented differences in the speed of release times, the agency attributed the renewed symptoms to the normal expression of depression.

Skeptics disagree.

People’s Pharmacy and ConsumerLab.com argue the FDA’s report is inadequate. They point to agency’s actual review of a 150 mg. drug and not the 300 mg. in the title, the dose which brought the complaints.

When asked if there was a reason the FDA didn’t use the strength for which there were complaints, a spokesperson said the higher dose was associated with dangerous side effects, notably seizures. Dale Conner, Director of the Division of Bioequivalence I, explained that the agency is allowed to substitute a lesser strength, something which happens in testing strong cancer drugs, for example, rather than subject healthy volunteers to an undesirable risk.

Symptoms of an illness or surge in drug?

At the heart of this controversial report ruling on an antidepressant is the question of what caused the symptoms? And what does it have to do with the most important recorded difference, the release time of the ingredients in the different drugs. Wellbutrin released more slowly over the extended period than did Budeprion in both tests.

Graedon and Cooperman point to the surge in ingredients in Budeprion XL 300 as the likely cause of side effects, certainly the ones they were hearing about. “[H]eadache, tremor, nausea, irritability and insomnia. These are classic complaints of excessive levels of bupropion, the active ingredient,” Graedon said.

Conner explains the FDA’s understanding differently. Because the ingredients are identical, the symptoms emerged because the effect was less than it should have been. Hence, the FDA contends that the drug “was not working well enough” to treat depression. And, for patients, this meant that “parts of their disease came back.” According to the official report:

These rates of recurrence of depression in treated patients offer a fully satisfactory explanation for why some patients experience worsening of their depression following a switch to a generic product, just as some patients would have experienced recurrence without any such switch.

Conner says this is to be expected. There are often reports about side effects or lack of efficacy with the release of a new generic. “There is a certain psychological component to believing this product can’t be as good.” Conner added, “it looks different, it’s cheaper.”

That does not persuade Graedon. “People have learned their bodies,” he said. And complaints came from people who had been symptom-free for many years, at least until the drug they were using was changed. Once they were returned to Wellbutrin 300 XL, their symptoms abated. The explanation he finds most convincing is that the drug’s speed led to symptoms.

Which drug works?

At the heart of this issue is which drug should people take? Clearly generics are a staple in today’s medicine chest, and are likely to grow proportionally as more drugs come off patent. Too, they’re affordable, making them an attractive choice. And, for most people, they seem to be working just fine. But, in addition to unwanted symptoms, what are the consequences when they don’t? The policy implications can be substantial.

A recent Supreme Court decision gives immunity to medical device makers after the FDA has given its stamp of approval. Soon, the Court will decide Wyeth v. Levine, a product liability case having to do with labeling, which could have far reaching consequences for everybody taking any medicine from aspirin to zyprexa.

These rulings are particularly noteworthy at this moment when the agency’s flaws – insufficient monitoring of off-shore production, weak post-market follow-up, an undifferentiated system for collecting "voluntary complaints," and an outdated infrastructure -- are being exposed in government reports and congressional hearings. These are not directly linked to generics but clearly could easily affect them. They are a reminder that this is an agency in serious need of an overhaul to restore accountability and with it, the trust of American consumers.

It is useful to observe, what a recent op-ed in USA Today noted, “When the Food and Drug Administration approves a new drug as safe and effective, that isn't always the end of the story.”

One could go further: in some cases it is the beginning.



