AES Calls for Definitive Study to Examine Antiepileptic Drug Substitution

Caroline Cassels

December 03, 2007

December 3, 2007 (Philadelphia, PA) -- The American Epilepsy Society (AES) is calling for a definitive study to determine once and for all whether substitution of brand-name antiepileptic drugs (AEDs) with generic agents may put some patients with epilepsy at undue risk of breakthrough seizures and/or toxicity.

Here at the AES 61st Annual Meeting, Michael Privitera, MD, from the University of Cincinnati, in Ohio, announced that the AES is in discussions with the US Food and Drug Administration (FDA) to get agreement on a protocol for the development and completion of a valid, controlled, prospective clinical trial.

The FDA's current policy is that approved AED formulations can be used interchangeably, without concern for safety and efficacy, and that no additional testing is needed when formulations of the same AED are substituted.

Further, the FDA's current bioequivalence standard requires that the calculated 90% confidence interval of a generic agent fall within 80% to 125% of the brand-name drug. To ensure medications meet this standard, the FDA then tests drugs according to plasma concentrations in healthy volunteers.

According to Dr. Privitera, there are 2 potential hazards to this approach. First, bioequivalence studies in normal individuals may not provide all of the necessary information to assess risk in epilepsy patients. Second, he said, bioequivalence does not necessarily equal therapeutic equivalence.

"We don't know what the acceptable bioequivalence range is that would sufficiently protect [epilepsy] patients from seizure risk and toxicity, but we strongly suspect that the current range used by the FDA is not sufficient," Dr. Privitera told Medscape Neurology & Neurosurgery.

Multiple surveys indicate that the majority of patients and physicians have concerns over AED substitution and seizure risk. "Physicians believe that people with epilepsy have an unacceptable incidence of seizures or side effects when switching formulations," said Dr. Privitera.

Generic-to-Generic Switching Also Problematic?

He added that it is important to note that this could apply not only when patients are switched from a brand-name agent to a generic drug but also when they are switched from 1 generic drug to another.

Two recent studies presented at the AES 2006 annual meeting and reported by Medscape Neurology & Neurosurgery at that time highlighted both physician and patient concerns about generic AED substitution.

The first study, a national online survey led by Michel Berg, MD, from the University of Rochester School of Medicine, in New York, explored US physicians' and patients' attitudes toward generic AED substitution and reported that 75% of physicians and 65% of patients reported concern over the safety of generic medications.

Furthermore, 90% of physicians reported a specific concern that generic substitution in controlled patients could result in a breakthrough seizure, with 65% reporting they had cared for a patient who had experienced a breakthrough seizure caused by a switch from a branded to a generic agent.

In addition, a Canadian study led by Frederick Andermann, MD, from the Montreal Neurological Institute, in Quebec, compared switchback rates from generic to brand-name AEDs ( Lamictal, GlaxoSmithKline; Frisium, Aventis Pharmaceuticals; Depakene, Abbott Laboratories) and compared them with drugs for other chronic conditions, including hypercholesterolemia and depression ( Zocor, Merck; Prozac, Eli Lilly).

The study showed the switchback rates from generic to brand-name AEDS ranged from 12% to 19%, compared with just 2% to 3% in drugs for depression or hypercholesterolemia.

Dr. Privitera acknowledged that while this research does not prove substitution with generic AEDs is problematic, it does give credence to the idea that patients with epilepsy may be more sensitive to changes in drug formulations and indicates a strong need for further study.

Is Epilepsy Different?

"It is the FDA's position that epilepsy is no different from other disorders. It is our position that bioequivalent standards may not be appropriate for all classes of medicine for all diseases and for all patient populations.

"We believe epilepsy is different and that an unexpected seizure in someone who was previously well-controlled can produce loss of driving privileges, loss of job, or severe injury. In addition, people with epilepsy can experience serious adverse effects if their antiepileptic drug levels change abruptly," he said.

In general, the cost of brand-name drugs is higher than generic agents. However, any potential cost saving derived from switching AEDs must be balanced against the potential risk to the patient and take into account potential additional costs of adverse events to the individual and society as a whole.

The AES is proposing a controlled prospective clinical trial with a protocol approved by the FDA studying the impact of differences between the same AED formulations of different manufacturers in an "enriched" patient population of epilepsy patients who have experienced previous problems with generics.

"We want to bring all the players to the table — the FDA as well as the pharmaceutical manufacturers of brand-name and generic drugs -- so we can answer the question of whether the bioequivalent standards are adequate for people with epilepsy," said Dr. Privitera.

"We're still early in the planning phase, and we don't want to move ahead until we have an agreement with the FDA over the trial protocol, but we hope that we may be able to start enrolling patients in a trial by mid-2008."

In the interim, until the completion of such a study, the AES has released a position statement that calls for no formulation substitution of AEDs without physician and patient approval and that opposes all state and federal legislation and formularies that limit physicians' choice of AED formulations.

Dr. Privitera declares he has received funding support, honoraria, and/or consulting fees from the following sources: the National Institutes of Health, Ortho McNeil, UCB Pharma, the Neuroscience Institute, Johnson & Johnson, American Epilepsy Society, Schwarz Pharma Pfizer, GlaxoSmithKline, Shire Pharmaceuticals, the Janssen-Cilag EpiFellows Foundation, and the Shor Foundation.  

American Epilepsy Society 61st Annual Meeting. Presented December 1, 2007.

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