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Workshop on Antiepileptic Drug (AED) Monotherapy Indication

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March 8-9, 2001

Sponsored by:
National Institute of Neurological Disorders and Stroke/National Institutes of Health (NINDS/NIH), American Epilepsy Society (AES), Citizens United for Research in Epilepsy (CURE), Epilepsy Foundation (EF)

The purpose of this workshop was to attempt to reach consensus on the best method to obtain Food and Drug Administration (FDA) approval for monotherapy labeling for antiepileptic drugs (AEDs). Approximately 120 participants attended the workshop, including epileptologists, statisticians, and researchers from the United States, Belgium, France, Germany, Spain and the United Kingdom, as well as representatives from the FDA, sponsoring organizations, and sixteen pharmaceutical companies.

There is a long tradition of treating epilepsy patients with two or more AEDs. However, in the past decade monotherapy has emerged as the ultimate treatment strategy for both newly-diagnosed and long-term patients because of fewer side effects, better compliance, less teratogencity and lower cost. Furthermore, the evidence does not exist that additional drugs improve seizure control in most patients.

Obtaining FDA approval for monotherapy use is particularly important since the AEDs marketed in the past several years have the potential advantages of better tolerability, improved safety, less teratogenicity, and simpler pharmacokinetics than the older drugs. Because of current FDA requirements, however, most of these medications have not received monotherapy indications and are being prescribed "off-label," which increases physician concern regarding legal liability and can result in problems with insurance reimbursement.

The FDA currently requires demonstration of a difference in treatment effect between active drug and placebo. Most AEDs obtain initial FDA approval through an "add-on" clinical trial design, which means adding the investigational medication or placebo to one or more baseline medications. Efficacy information obtained from this type of trial is considered insufficient for FDA monotherapy approval, however, since an "add-on" trial may exaggerate the side effect profile of a new AED because of drug-drug interactions and additive toxicity.

The problem with monotherapy placebo-control trials is that this approach leaves at least half the patients in the trial without AED protection and exposes them to the risk of additional seizures and their consequences. Those AEDs with monotherapy indications have received them as a result of trials conducted while patients are hospitalized and their medications withdrawn for evaluation for surgery; or on an outpatient basis using what is called a pseudo-placebo design which compares the study medication with a sub-therapeutic dose of another medication. There are problems with these designs, both ethically and scientifically. Pharmaceutical companies are also reluctant to pursue these trials not only for the ethical issues, but also because recruitment is difficult, many patients drop out, and the trials are costly and time-consuming.

European Drug Regulatory Agencies allow active control equivalence trials for monotherapy approval. In these trials, the new AED is compared to a well-established AED that has "substantial evidence" of effectiveness. These trials have been used successfully in therapeutic areas such as treatments for cancer, infectious disease, and some cardiovascular conditions. The advantage of these trials is that all patients are treated with the active compound; the disadvantage is that they are designed to demonstrate equivalence and could therefore be comparing mediocre drugs.

Considering the ethical issues of placebo-controlled trials and the benefits of monotherapy treatment, however, there was considerable support at the workshop for consideration of active-control equivalence trials for monotherapy approval of AEDs. This resulted in substantial debates between participants and representatives from the FDA as to this approach. The FDA did indicate willingness to considering experiences from historical controls, if the data exist to support them. These data would have to be based on previous trials of active control vs. placebo under similar conditions with respect to study population, endpoints, dose of active control and other important design features.

The workshop ended with the draft of a brief consensus statement. A task force will be set up to look at the issue of historical control and to see what data exist. Most participants indicated that the workshop had been a good start in addressing the monotherapy issue.

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Last updated February 09, 2005