FDA advisory committee members decided substantial evidence had been submitted to recommend Lamictal XR as an effective monotherapy for partial seizures, but it was not because of the novel clinical trial design GlaxoSmithKline employed for the supplemental indication.

It was the fact that the immediate release version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The Peripheral and Central Nervous System Drugs Advisory Committee voted 10-2 in favor of the evidence of effectiveness for Lamictal XR (lamotrigine extended-release tablets), including 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 Britt Anderson, assistant professor in the University of Waterloo, Ontario Department of Psychology, said knowing about the immediate release version was a factor, but not critical to his "Yes" vote.

Phillip Pearl, division chief of general child neurology at Children's National Medical Center in Washington D.C., said following 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."

FDA in a sense held the same belief about Lamictal XR as the committee members. In its pre-meeting briefing documents, Division of Neurology Products Director 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 OK, But Data Still A Problem

Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had employed 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 states, as well as the U.S. 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 did not see reduced symptoms on study drug, than non-U.S. patients (Also see "Lamictal XR Monotherapy: Will Ex-U.S. Data Invalidate Historical Comparison?" - Pink Sheet, 8 March, 2011.).

Committee members did decide the historical trial design was acceptable, voting 14-0 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.

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," 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 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. 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."

Review Division Has Never Accepted A Historical Control Design

GSK submitted its 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 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.

FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications ('Historical Controls For Epilepsy Studies To Be Considered By Advisory Committee,' 'The Pink Sheet,' Jan. 25, 2011).

-Derrick Gingery (d.gingery@elsevier.com)

Lamictal IR Experience Impresses Advisory Committee, Not XR Trial Design

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