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LEGAL-EASE: THE WAITING GAME — Eisai Files Lawsuit Over DEA Scheduling Delay for Approved Epilepsy Drug

Samson, Kurt

doi: 10.1097/01.NT.0000436542.81463.53

The manufacturer of a promising new epilepsy medication filed a petition with the US Court of Appeals for the District of Columbia on Aug. 19, asking the court to order the US Drug Enforcement Agency (DEA) to promptly schedule the drug under the Controlled Substances Act. The legislation authorizes the DEA to categorize drugs for their risks, health benefits, and potential for abuse.

In interviews with Neurology Today, epileptogists also expressed their alarm over the delays in scheduling this and other antiepileptic drugs (AEDs).

The US Food and Drug Administration (FDA) approved perampanel (Fycompa) in October 2012 as an adjunct therapy for partial onset seizures with or without secondarily generalized seizures. In January, the FDA formally asked the DEA to schedule the drug, but the agency has yet to do so. The DEA needs to classify the drug as a controlled substance before it can be made available to epilepsy patients.

In its petition for a writ of mandamus, or court order, Japanese pharmaceutical company Eisai Inc. asserted the DEA has “unreasonably” and “egregiously” delayed perampanel scheduling, and challenged justification for the delay. The company cited a lack of any scheduling timetable, predictability, or transparency related to the agency's scheduling procedures.

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FDA approval of perampanel was based on results from three phase 3 clinical trials involving 1,480 patients with partial-onset seizures. The randomized, double-blind, placebo-controlled, dose-escalation studies found the drug to be effective as an adjunct therapy by significantly reducing seizure frequency in patients with or without secondary generalized seizures.

Perampanel is a non-competitive AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist that works by reducing neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at post-synaptic AMPA receptors. It is the first antiepileptic drug (AED) that works in this manner to be approved by the FDA.

Glutamate is the primary excitatory neurotransmitter in the central nervous system and is involved in a number of neurological disorders caused by neuronal over-excitation. The AMPA receptor is widely present in almost all excitatory neurons.

The FDA approved the AED pregabalin (Lyrica) as an add-on for partial onset seizures on June 13, 2005, and it was assigned a Schedule V classification — meaning it has very low abuse potential and minor health risks despite containing small amounts of narcotics — by the DEA one month later. Ezogabine (Potiga) was approved on June 13, 2011, but was not assigned a Schedule V classification by the DEA until December 16, 2011.

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According to the labeling information from the FDA, the new drug application submitted by Eisai included study data on the abuse potential of perampanel when compared with alprazolam (Xanax) and oral ketamine, both widely abused recreationally.

The researchers found that supra-therapeutic doses of perampanel (24 mg and 36 mg) produced responses for “euphoria” similar to those reported with the use of ketamine 100 mg and alprazolam 3 mg. The incidence of euphoria after administration of 8 mg, 24 mg, and 36 mg was 37 percent, 46 percent, and 46 percent, respectively, which was 13 percent greater than with alprazolam 3 mg but 89 percent less that with ketamine 100 mg.

Users also said the drug produced a “high” at 24 mg and 36 mg that was comparable with ketamine 100 mg, but significantly greater on a visual analog scale than either dose of alprazolam.

On tests to measure dissociative phenomena, supra-therapeutic doses of perampanel produced responses similar to ketamine 100 mg, but greater than both doses of alprazolam tested. In addition, the duration of the effects of higher doses of perampanel for the majority of measures was much longer than with either alprazolam 3 mg or ketamine 100 mg.

In its petition, Eisai noted that between 1997-1999 and 2009-2013, there was an almost five-fold increase in the average time between FDA approval and DEA's final ruling, from an average of 49.3 days to 237.6 days.







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“For patients with intractable epilepsy, new medications offer their only hope,” said Michel J. Berg, MD, associate professor of neurology and medical director of the Strong Epilepsy Center at the University of Rochester Medical Center in New York. “They have tried all the old ones without success. It's very frustrating.”

Although only a small number of intractable patients might respond to a new AED, the chance of some improvement, or even a dramatic improvement, is a paramount concern when there are such delays, he told Neurology Today in a telephone interview.

“After the FDA approves a drug there are already inherent delays in the system. The agency and the manufacturer then have to reach a labeling agreement and the actual manufacturing and distribution process take time,” he noted.

“Add another six or more months for the DEA to schedule a drug and patients have a long wait. That is six months or more out of a patient's life. They come to me and ask when it will be available, and I don't have an answer.”

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Perampanel's delay is part of a larger problem with DEA's scheduling of new drugs, added Jacqueline A. French, MD, professor of neurology at the New York University (NYU) Comprehensive Epilepsy Center of NYU Langone Medical Center, in New York City, and president of the American Epilepsy Society. Dr. French is also a member of the editorial advisory board of Neurology Today.

“It's not just [perampanel], it is other antiepileptic drugs as well,” she told Neurology Today in a telephone interview. “Some people felt that [pregabalin] might have some potential for abuse, and since then every time the word 'euphoria' appears as a side effect in an AED trial, there seems to be a scheduling problem, and this entire class of medications comes under special scrutiny.”

Delays not only pose problems for epilepsy patients awaiting new therapies, but uncertainty about which category a new drug like perampanel will be placed in by the DEA is a concern for epileptologists as well, she said.

“It is very problematic if physicians cannot e-prescribe drugs due to their DEA schedule status. Usually such drugs fall under the lower Schedule V category, but in some states this means that every time a patient needs a refill they have to have a monthly written prescription, and if that does not make it in the mail, it requires a trip to the office. Most of these patients cannot drive, so patients are constantly worried that they will run out of their AED and start having seizures again.”

Another issue is the potenial effect of post-approval DEA delays on new drug development, according to Dr. French.

“The clock starts ticking on their exclusive patent once a drug is approved by the FDA, and we worry that if manufacturers start to view this class of medications as more likely to have problems with the DEA, they might be less inclined to continue developing them, or start developing them for other indications,” she said.

Selim Benbadis, MD, professor of neurology and director of the Comprehensive Epilepsy Program at the University of South Florida School of Medicine and Tampa General Hospital, in Tampa, FL, told Neurology Today that he is puzzled by why DEA scheduling appears to be taking longer for new AEDs.

“I have never heard of a situation like this before,” he said. “Assessment of the potential for drug abuse is part of the systematic testing that goes on during new drug trials, so this data is available to the DEA. I am not sure why there are such delays unless it is just an administrative issue.”

The DEA did not respond to Neurology Today's request for comment, but has said elsewhere that it does not comment on pending litigation.

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•. Petition for a writ of mandamus to redress unreasonable delay by the Drug Enforcement Administration. In Re Eisai Incorporated No. 13-1243. U.S. District Court of Appeals for the District of Columbia:
    •. DEA Schedules:
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