BETHESDA, MD 24 June 2009—A patient advocacy group’s campaign and the media’s recent focus on generic drug substitution have increased the need for pharmacists to judge FDA-declared bioequivalent products by more than just price, say two pharmacists who work at epilepsy clinics.
"At the dispensing end . . . there’s frankly a sort of naiveté that, ‘Well, it’s an FDA-approved product and we’re able to buy it, it must be OK,’ " said Barry E. Gidal, who cares for adult epilepsy patients at William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. "That’s putting a lot of faith in a system that I’m not sure is that functional."
Brian K. Alldredge, with the Epilepsy Center at the University of California, San Francisco (UCSF), said FDA needs to change how it looks at data from generic drug products.
"What I think is necessary is for the Food and Drug Administration to narrow the confidence interval for the differences in the bioequivalence parameters that they look at," Alldredge said.
One of the criteria by which the FDA’s Office of Generic Drugs deems a generic product bioequivalent, or AB rated, to the brand-name product entails statistical analysis—90% confidence intervals and point estimates of population means.
For example, FDA’s guidance for establishing the bioequivalence of a generic 600-mg oxcarbazepine tablet to the brand-name product states that bioequivalence is based on 90% confidence intervals of the active metabolite. In vivo testing of the 150- and 300-mg tablets is not necessary under certain circumstances.
In the public eye. Generic oxcarbazepine was one of the drug products named in Self magazine’s article "Are Generic Drugs a Bad Bargain?," which included the experience of a 22-year-old mother with epilepsy who had a seizure about a month after starting to use a generic oxcarbazepine product. According to the article, the woman had been seizure free for the previous six years while taking Trileptal, the brand-name oxcarbazepine product.
NBC used the article as the basis for a May 28 segment on the Today Show.
Generic antiepileptic drugs were also the target of an online patient survey conducted by the Epilepsy Foundation and promoted to news reporters.
About two weeks before the Today Show segment on generic drugs, the foundation announced that 59% of patients with epilepsy reported a worsening in their seizures after their brand-name antiepileptic drug had been switched to a generic version. Adverse effects had increased for 49% of the patients.
The survey, which was posted at the foundation’s website for more than two years, attracted responses from 1086 people.
Alldredge and Gidal are members of the foundation’s professional advisory board.
Sensitivity by a minority. "While I think that the methodology and the guidelines for approval or disapproval of an AB-rated generic are probably fine for most drugs," said Gidal, chair of the Pharmacy Practice Division at University of Wisconsin—Madison, "I think for a lot of patients with epilepsy, they may not be."
Gidal is on the speaker’s bureaus for Abbott Laboratories, GlaxoSmithKline, and UCB—all of which market antiepileptic drugs that compete with generics.
The number of patients with seizure disorders that he treats has risen in recent years, he said, because of traumatic brain injuries and other issues resulting from military deployments in Iraq and Afghanistan.
He estimated that one fourth of his patients are very sensitive to changes in drug exposure.
Alldredge, a clinical professor in the neurology department at the UCSF School of Medicine, expressed uncertainty about trusting all of FDA’s decisions on AB ratings. But he remained unconvinced that brand-to-generic switches and generic-to-generic switches are problematic for a great number of patients with epilepsy.
"We see associations in clinical practice, and we make clinical inferences based on those associations," he said. "So, I see a product change in a patient, and they say they have an increase in the frequency of seizures, and I might associate the two in a causal way."
Indeed he did. In late May, one of his patients reported a substantial increase in the frequency of seizures after a change from Keppra to a generic levetiracetam product.
In this isolated case, Alldredge said, the most plausible explanation for the increase in seizure frequency was the change in the drug products.
He asserted that the manufacturers of brand-name antiepileptic drugs have stressed to health care providers the existence of "bioinequivalence" between brand-name and AB-rated generic products.
Suggestions. Alldredge and Gidal agreed that pharmacists should tell patients that a generic version of an antiepileptic drug can save them money but also warn them that they may be sensitive to allowable differences between products. Good communication is key, they said.
The possibility that the generic antiepileptic drug product received by a patient one month may not be the same one received the next month, Gidal said, "is a big crux of the whole issue."
For hospitals and health systems, he said, the solution is not necessarily to stock only brand-name products.
"I think the most prudent approach . . . is that we should ask patients to bring their supply of [antiepileptic] drug in with them," Gidal said.
Then, if the hospital’s pharmacy does not normally stock the exact same drug product, consideration should be given to having the patient use his or her personal supply while in the hospital.
Gidal said he is impressed by how the Department of Veterans Affairs (VA), which serves inpatients and outpatients alike, is approaching the problem.
He said he received a notice from VA that in mid-June it would convert to generic lamotrigine and topiramate products from the brand-name products for contracting reasons. The letter listed his patients whom VA knew received lamotrigine therapy and suggested that he plan to monitor those patients.
Gidal said he is determining patients’ lamotrigine blood levels before the product conversion. After the conversion, he plans to determine blood levels again and ask patients whether their clinical status has changed.
VA, he added, also informed him that it would make the effort to use a single source long-term for each generic product.
Alldredge said he tells patients in the outpatient setting that it is a good idea to check the drug level when changing products having the same antiepileptic drug.
In the hospital setting, however, the cost of the laboratory test may exceed the savings from the product switch, he said.
As for his patient who had an increase in seizure frequency soon after switching levetiracetam products, Alldredge said he offered three possible reasons: there could be a problem with the particular manufacturer’s generic product; the patient is exquisitely sensitive to changes in drug concentration; or this was a coincidence.
Alldredge said he went on to tell the patient that both of them would probably feel more comfortable if they tried in the future to ensure the patient used only the brand-name product.
