Food and Drug Administration advisory committee members have recommended lamotrigine extended-release tablets as a monotherapy for partial seizures, relying on the knowledge that the immediate-release version of the drug works for the indication.

The Peripheral and Central Nervous System Drugs Advisory Committee found that substantial evidence had been submitted to support the recommendation, but not because of the novel clinical trial design GlaxoSmithKline (GSK) utilized for the supplemental indication. It was the fact that the immediate-release (IR) version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The committee voted 10 to 2 in favor of the evidence of effectiveness for Lamictal XR (extended release). There was one abstention and one member absent for the vote. All the committee members who voted in favor said knowing the immediate-release version was effective affected their decision.

Acting Committee Chairman Dr. Britt Anderson, an assistant professor in the psychology department at the University of Waterloo, Ontario, said knowing about the immediate-release version was a factor, but not critical to his "yes" vote.

Dr. Phillip Pearl, division chief of general child neurology at Children’s National Medical Center, Washington, D.C., said after the vote that "the [immediate release] made my decision feel rational, and I could not come up with a strong-enough feeling to refute that."

The Food and Drug Administration, in a sense, held the same belief about Lamictal XR as did the committee members: In its premeeting briefing documents, Division of Neurology Products Director Dr. Russell Katz said the agency’s prior belief is high that Lamictal XR likely will be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy.

Historical design okay, but data still a problem. Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had utilized in an effort to prove safety and efficacy of the extended-release version as monotherapy.

The study design relied on a historical control, and most of the concerns from the FDA reviewers and committee members focused on the differences between the patient populations of the new study and the control dataset.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European nations, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical control.

Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria, that is, they did not see reduced symptoms on the study drug, than did non-U.S. patients.

Committee members did decide the historical trial design was acceptable, voting 14 to 0 in favor of a positive recommendation.

But when it came time to decide on Lamictal XR’s effectiveness, most committee members could not reach a recommendation based on the evidence that had been submitted. They relied on their clinical experience.

Dr. William Theodore, chief of the clinical epilepsy section at the National Institute of Neurological Disorders and Stroke, said there was an enormous bias among clinicians when voting because they already know the drug works.

"It would be hard to come up with a rational argument to say that ... the controlled release doesn’t work as monotherapy," Dr. Theodore said. "I can’t come up with a reasonable doubt in this context."

The committee strongly reiterated its feelings about the trial’s problems shortly after the vote was taken, when Dr. Norman Hershkowitz, a team leader in the Division of Neurology Products, asked the members whether their thinking would have been different if there were not so many problems with GSK’s clinical trial.

Committee members resoundingly said they would not have had to rely on their prior knowledge of the immediate-release version of the drug. Dr. David Treiman, epilepsy center director at the Barrow Neurological Institute in Phoenix, who voted "no," said he would have changed his vote on the question to "yes."

Neurology division has never accepted a historical control design. GSK submitted its supplemental new drug application (sNDA) for Lamictal XR as a monotherapy treatment for partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties.

The FDA has been considering the historical controls question for several years, and its decision could affect approval of several other drugs in late-stage trials seeking similar monotherapy indications.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

FDA Advisory Panel Recommends Lamictal XR for Partial Seizures