FDA is asking an advisory panel for help in resolving longstanding questions about the usefulness of historical data in clinical trials of antiepileptic drugs, an issue that directly affects a supplemental application for GlaxoSmithKline's Lamictal XR (lamotrigine extended-release tablets) and may affect several other drugs now in late-stage trials.

The Peripheral and Central Nervous System Drugs Advisory Committee will address the issue at its March 10 meeting, focusing on how historically controlled trials, such as the one GSK conducted for its sNDA, can be used in supplemental applications of AEDs to treat seizures of partial origin, where the drugs in question already are approved for adjunctive therapy.

Such is the case with Lamictal XR, which is indicated as adjunctive therapy for primary generalized tonic-seizures and partial onset seizures with or without secondary generalization in patients age 13 and up. The trial GSK submitted in support of the sNDA was a double-blind, randomized study conducted at 65 sites in the U.S. and six other countries, in which a historic control was used for "aggregated pseudoplacebo data." Patients were randomized to receive either a 250 mg dose or a 300 mg dose of Lamictal XR; 113 patients enrolled in each arm, with 79 completing the lower-dose arm and 94 completing the higher-dose arm.

"For both dose groups, the upper 95% confidence limit for the proportion of subjects discontinuing the double-blind treatment phase did not overlap the lower 95% confidence limit of the historic data," the company says in its publicly posted summary of the trial. "In the continuation phase, seizure frequency was reduced 70% compared to baseline. Headache and dizziness were the most frequent AEs. Four subjects experienced five SAEs during the continuation phase."

The extended-release version of lamotrigine was first approved May 29, 2009, and GSK submitted the sNDA for monotherapy treatment of partial seizures in patients 13 and up on March 31, 2010. The expected user fee date would have been around the end of January, but FDA extended it to April 30.

"In mid-November, GSK responded to a request from FDA for information that required additional analyses and datasets," the company explained in an e-mail. "Because this solicited major amendment was received within three months of the original 10-month review goal date of Jan. 31, 2011, FDA extended the PDUFA goal date by three months to provide time for a full review of the submission."

A Crowded Pipeline

The pipeline for AEDs seeking similar monotherapy indications is a crowded one. According to the NIH clinical trial registry, ClinicalTrials.gov, several industry-sponsored Phase III studies are under way:

# UCB is studying conversion to its Vimpat (lacosamide) as monotherapy in subjects with partial-onset seizures, in a trial specifically listed as having historical controls;

# Separately, UCB is conducting a head-to-head trial of Vimpat versus carbamazepine (Novartis' Tegretol and generics) as monotherapy in epilepsy patients experiencing partial-onset or general tonic-clonic seizures;

# Sunovion is studying eslicarbazepine, which currently has no approved U.S. indication, for epilepsy with simple or complex partial onset seizures;

# Nial-Portela is studying eslicarbazepine as monotherapy for patients with newly diagnosed partial-onset seizures;

# Eisai is comparing its Zonegran (zonisamide, which also is available generically) to carbamazepine as monotherapy in newly diagnosed partial epilepsy; and

# Pfizer is studying its Lyrica (pregabalin) as monotherapy in patients with partial seizures.

Not A New Idea

FDA has been mulling over the historical control issue for several years. "We started accepting historical control trials in approximately 2007 in support of applications for monotherapy indications for antiepileptic drugs that already had adjunctive therapy indications," the agency said in an e-mail. "The decision to bring it to the community as part of an advisory committee meeting, however, was deferred until the first submission of an application containing such data."

In the January 2006 issue of Epilepsy Research, Michel Baulac noted that there are several possible ways of using historical controls in such trials. "A simple way would be to design a superiority trial where the test drug would have to be superior to the historical placebo group," he wrote. Alternatively, the historical data could serve as a third arm in designs comparing two active drugs. "Non-inferiority would be validated by showing that both established comparator and test drug remain superior to the virtual, historical placebo."

The problem with these and other approaches is that the International Conference on Harmonisation recommended against using historical controls for regulatory purposes in 2000, except when the treatment effect is dramatic or the course of the disease highly predictable, which is not the case with newly diagnosed epilepsy, Baulac noted.

"The major issue is that a strict similarity between historical populations and newly recruited populations cannot be ensured. The historical control group can be dissimilar with respect to a wide range of factors that could affect outcome, including: demographic characteristics, diagnosis criteria, stage or severity, concomitant treatments, observational conditions, evolution of practice. It can be also dissimilar regarding the conditions of blinding of the patients and/or of the investigators." These issues are sure to come up at the advisory panel meeting.

Meanwhile, other safety issues are likely to hover in the background when the panel considers the Lamictal XR sNDA. There is the unresolved question of whether AEDs in general increase the risk of suicidality, which has led FDA to impose a class-wide Risk Evaluation and Mitigation Strategy (Also see "FDA Opts For MedGuide, Not Black Box For Anti-Epileptic Suicidality" - Pink Sheet, 24 November, 2008.). This remains even though a recent article in the New England Journal of Medicine called this link into question ('Antiepileptic Drugs May Not Raise Suicide Risk,' Health News Daily, Aug. 5, 2010).

For products containing lamotrigine, including immediate-release Lamictal, which is now generic, FDA has warned about a risk of aseptic meningitis (Also see "GSK Lamictal's New Warning On Aseptic Meningitis May Help Pfizer's Lyrica" - Pink Sheet, 12 August, 2010.).

-Martin Berman-Gorvine ( m.berman-gorvine@elsevier.com )

Historical Controls For Epilepsy Studies To Be Considered By Advisory Cmte.

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