A recent report from the Agency for Healthcare Research and Quality (AHRQ), a U.S. governmental entity in the Department of Health and Human Services, concluded that there are "no significant differences in the risk of maintaining seizure freedom" or safety between old and new antiepileptic drugs. But this conclusion is fraught with problems brought on by the choice of drugs and studies to compare, as well as an apparent lack of input from experts in the field.
Comparative effectiveness studies such as this often have potential high-stakes implications for people with epilepsy (PWE), health care providers, pharmaceutical companies, lawyers, health care payers, politicians, and, ultimately, society in general. They typically pose specific questions and mine pooled data from previously published studies in the specialty literature using statistical reanalysis in an effort to reach an evidenced-based conclusion.
By Dr. Joseph F. Drazkowski
In this case, the pooled data on antiepileptic drugs (AEDs) came from studies that were originally conducted to evaluate the AEDs in a regulatory environment to obtain drug approval, and thus they were not specifically designed to address the concerns of a comparative effectiveness review, which is the professed focus of the AHRQ report.
Seizure control is an important aspect of epilepsy therapy, but it is clearly not the only one to be considered. Epilepsy is heterogeneous in clinical presentations, etiology, and response to therapies, and so it is disappointing that the report’s comparative effectiveness review of AEDs did not take into account many of the considerations made in selecting an AED. Drug therapy for PWE is typically highly individualized – and rightly so – and often regards multiple influencing factors, including age, sex, seizure type/syndrome, seizure burden/frequency, comorbidities, concurrent therapy for other conditions, psychological and psychiatric effects, family planning, ability to work, and ability to drive. All of these must be considered in addition to the specific side effects of AEDs.
The goal of AED therapy is to achieve good seizure control while avoiding adverse side effects in order to maximize quality of life. The consequences of uncontrolled seizures or unexpected seizure recurrence may range from social embarrassment to sudden unexpected death. PWE must have confidence that their AED regimen will provide consistent and sustained effectiveness given the unique facts of their individual circumstance.
The original objectives of the report were to "perform a comparative effectiveness review of the efficacy, safety, and tolerability of AEDs" and "address the issue of generic substitution" of older versus newer medication and generic versus innovator (proprietary/trade name) medication. Multiple other "Key Questions" also were proposed within the report, suggesting that answers would be forthcoming for questions revolving around the individual concerns of PWE. Little, if any, of the individual concerns in the questions proposed as part of the research found their way into the conclusion.
The panel of authors who wrote the final report appears to consist primarily of pharmacists and statistical specialists. The report also lists numerous "informants," including nationally and internationally recognized experts from the epilepsy community. Listing the names of these experts from the epilepsy community implies that they had a significant influence on the report’s design, analysis, results, and recommendations. However, the extent of actual participation and influence of the epilepsy experts’ role and contribution to the final product is not clearly elucidated or defined in the published report.
Unfortunately, the review includes the two drugs vigabatrin (Sabril) and gabapentin (Neurontin) in the "new group," which likely adversely influence the reported results. Vigabatrin is used in a very limited subset of PWE who have a severe refractory or catastrophic epilepsy syndrome. Gabapentin is commonly felt to be a marginal AED, at best. No consideration for the teratogenicity of AEDs is mentioned in the report. A comparison of "new" AEDs to carbamazepine did not account for either the varied mechanisms of action or the side-effect profiles of the newer agents. The pharmacokinetic interactions of AEDs in patients taking other medications were not specifically considered. Additionally, risk and tolerability in special populations and comorbid diseases were not explicitly discussed. It is noteworthy that the section of the report discussing the review’s limitations is physically lengthier then the conclusion section.
Since the AHRQ report was released, official responses from organizations interested in epilepsy advocacy have universally been critical of the process and result. Organizations including the American Academy of Neurology, American Epilepsy Society, North American Regional Commission of the International League Against Epilepsy, Epilepsy Foundation of America, and National Association of Epilepsy Centers have crafted a joint letter to the agency and its leaders enumerating significant criticisms of the process, methods, and conclusions of the published work. At least one well-respected epilepsy expert who is listed as an informant on the report later became a signatory on one of the letters that were critical of the report, raising questions about the informants’ role and their influence on the final report.