French JA, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004 Apr 27;62(8):1252-60.

The two major organizations for healthcare professionals with an interest in epilepsy have come to a consensus on the use of newer antiepileptic drugs (AEDs) for new-onset epilepsy. Their report describes how they reviewed reports of clinical trials (testing in groups of patients) of the new generation of AEDs to determine whether the results support the use of each drug as first-line treatment for patients. The method, called ”evidence-based,” uses established definitions to rate the quality and reliability of “evidence” from clinical trials. The desirable “Level A” rating requires either one very well designed study or two somewhat lesser studies, all with positive results showing that the AED is effective.

This type of analysis differs both from reports of the results of individual clinical trials and from approval by the U.S. Food and Drug Administration (FDA) of claims from drug manufacturers that the drug is effective for a specific diagnosis in patients who are in a certain age group or who are taking other medications, for instance. Individual clinical trials can show highly significant differences between treatment groups but be biased by poor design (such as ill-chosen comparison groups or doses, use of non-standard endpoints, analysis planned only after seeing the main result) or suffer from small numbers of patients starting or completing the study.

Most clinical trials sponsored by the pharmaceutical industry meet the criteria for good design and careful statistical analysis. They are designed specifically to meet regulatory standards set by the FDA in order to gain approval to market the drug. However, current FDA standards have been interpreted as requiring a placebo-treated group for comparison with the AED-treated group. The standard requiring a placebo creates a dilemma for doctors conducting clinical trials, who generally will not put patients with partial-onset seizures at risk by leaving them untreated. The possibility of progression to a generalized tonic-clonic seizure that could result in injury or job loss is too great a burden to be considered ethical.

With mild seizure types, the situation is different. Children often experience absence or myoclonic seizures for months before the diagnosis of epilepsy is made, so a brief additional delay before treatment with an AED begins may be viewed as ethically acceptable. Parents often are willing to wait through a brief placebo-treatment period before starting their child on an AED because of concerns about the possible effect of drugs on growth and development.

Interestingly, most AEDs widely used to treat newly diagnosed epilepsy do not meet the current FDA criterion of proven superiority to placebo! Phenobarbital, for instance, remains the most widely prescribed drug for seizures worldwide, but no placebo-controlled clinical trial ever proved its efficacy. Phenytoin (Dilantin, Phenytek) also has not been proven more effective than a placebo in a controlled study. Neither has carbamazepine (Tegretol, Carbatrol), which often is used in studies of other AEDs, where the study design is planned to demonstrate equivalence to carbamazepine. It has proven superior to another AED in only one clinical trial. (Brodie MJ et al: Efficacy and safety of remacemide versus carbamazepine in newly diagnosed epilepsy: Comparison by sequential analysis. Epilepsy & Behavior. 2002;3:140-146.)

These older, standard AEDs are allowed to indicate that they are FDA-approved for initial treatment of new-onset epilepsy based on old regulations, grandfathered into current practice. Newer AEDs cannot achieve comparable approval status because studies using a placebo for partial-onset epilepsy are unfeasible because of ethical constraints. Doctors are in a Catch-22 situation.

Evidence-based guidelines like those recently published are helpful to clinicians because the FDA restricts what a pharmaceutical company can claim is an effective and safe use for a drug. The new guidelines offer doctors a way out of their dilemma into clinical reality, presenting good evidence on which to base their selection of the most appropriate AED for each patient. With the publication of these carefully developed guidelines, doctors now can feel comfortable prescribing any of the AEDs that meet Level A criteria, as appropriate for each patient's situation.

Why does this matter if the FDA still has not approved these drugs for newly diagnosed partial-onset epilepsy?
Doctors may use “evidence-based” standards in addition to FDA approval as the basis for clinical practice. Insurers and pharmacy formularies may be more likely to accept these prescriptions as meeting the standard of appropriate care when deciding on reimbursement.

Why do epilepsy specialists care about this issue?
Insurers and pharmacy formularies often limit doctors’ selection of an appropriate AED. These limitations may prevent doctors from considering the use of medications that do not have FDA approval for the patient's specific situation. The new guidelines therefore may broaden the options available.

Why does epilepsy.com care about this issue?
We advocate for more treatment options to be made available for patients, when appropriate and supported by clinical evidence. We believe that if a doctor considers the safety profile of a newer AED to be preferable for a patient, then that decision should be allowed by insurers and pharmacy formularies.

To determine the efficacy and safety of new AEDs for initial treatment of newly diagnosed epilepsy, we support the use of clinical trials comparing the new AEDs to other active drugs instead of a placebo, which under certain circumstances (as noted above) may be unethical.

French JA, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004 Apr 27;62(8):1261-73.

A similar consensus on the use of AEDs for medically refractory epilepsy raises a paradox. Evidence shows all seven of the new AEDs to be effective for use as adjunctive (add-on) therapy in patients with refractory partial or mixed seizure disorders. Yet only four of these new AEDs were judged effective when used alone (monotherapy) for new-onset epilepsy, which is mostly not refractory. As the authors clearly state, the lack of recommendation for the other three drugs is based on a lack of evidence. None were studied for monotherapy and found to be ineffective.

Indeed, no study has been published in which an AED that was effective as adjunctive therapy in refractory partial epilepsy was not found to be effective as monotherapy in new-onset partial epilepsy. Common sense suggests that if a drug is helpful in the most difficult cases, it should also be effective for the mildest cases. We cannot make recommendations without data from well designed clinical trials, however, so we are left to rely on clinical judgment—an invaluable but potentially misleading guide.

Many epilepsy specialists pay careful attention to side-effect profiles when selecting an AED for newly diagnosed epilepsy. Many use AEDs as monotherapy that are indicated only for adjunctive therapy. Whether this clinical practice is correct remains uncertain. We sorely lack head-to-head studies that compare the effectiveness or toxicity of new AEDs. Nevertheless, most epileptologists favor newer AEDs over older, potentially toxic ones such as phenobarbital and phenytoin. Bottom line, we need more data.

By the way…
The approval process for developing AEDs in the United States is far more restrictive (because of FDA requirements) than the process in Europe. The European regulatory agency encourages testing of AEDs without placebo controls. The agency wants to see comparisons between a new AED and a standard AED (often carbamazepine or valproate). These clinical trials provide evidence for direct comparisons of efficacy and typical adverse effects. Fortunately, data from these trials can be included as credible evidence in the preparation of guidelines in the United States.

Elsewhere on this site you will find an eloquent editorial called "The Placebo Debate," recommending that readers address these ethical concerns. Congress can advise the FDA to consider epilepsy to be a special disorder for which placebo controls are not appropriate. The requirements for drug approval can potentially be modified if physicians and other interested parties can demonstrate the special ethical issues of AED testing.

See links to the new 2004 guidelines.