LAUSR

Adjunctive randomized placebo-controlled trials are the gold standard for determining whether new antiseizure drugs (ASDs) are effective for patients with treatmentresistant epilepsy. In these studies, patients receiving the novel ASD as an add-on are compared with patients for whom a placebo has been added. These studies have been quite robust overall. In general, drugs that have succeeded in standard animal models of epilepsy (maximal electroshock, pentylenetetrazol) have also succeeded in randomized controlled trials, suggesting that the trial design is effective for its purpose. Moreover, until recently the two “adequate and well-controlled trials” that are required by regulatory bodies in order for a drug to be approved have shown consistent results. This is perhaps surprising, considering that these trials depend on patient seizure report, which is notoriously poor. Many epilepsy patients also have significant memory difficulties. Moreover, seizures are counted by means of a paper diary, which is shockingly low-tech in the era of seizure detection devices, or at the very least electronic diaries. This low-tech mechanism for seizure counting should fail for a number of reasons, including failure of patients to be aware that a seizure has occurred, retrograde amnesia for the seizure after the fact, and failure to write down a seizure in a timely fashion, with subsequent forgetting of its occurrence. In this interesting exercise by Goldenholz et al., a dataset of 10 patients who had intracranial electrodes implanted chronically are used to model patients enrolled in randomized controlled add-on studies. These patients all had the Seizure Advisory System in place, which differed from other chronically implanted systems (such as the Responsive Neurostimulator) in that it incorporated not only an electrographic seizure detector but also an audio recorder that could capture sounds occurring at the time of detections. This allowed the researchers to sort out “true clinical seizures” (those with electroencephalogram and audio confirmation) and determine which “true seizures” were identified by patients in their diaries. The authors compare study results (1) when diary data are used exclusively (reproducing the conditions under which all trials of ASDs have been performed to date); (2) when all clinically verified seizures were counted, whether reported or not (and diary-reported seizures without electroencephalogram were discarded); and (3) when all electrographic seizures, whether clinically verified or not, were counted. The authors conclude that if the drug does not have a strong effect, counting all seizures, whether clinical or not, resulted in a higher chance of a “successful trial” (defined as a statistically significant outcome with a level of p < 0.05, consistent with regulatory requirements) than counting clinical seizures, verified or not. Is this a “win” for the high-tech solution? Actually (and surprisingly), perhaps not, because the only improvement in trial efficiency was seen when subclinical (electrographic) seizures were counted in addition to clinical ones. So, what is wrong with counting electrographic seizures if this is what would improve trial efficiency? This might work for a phase II or proof-of-concept study and should definitely be considered for this purpose. However, likely issues would preclude the use of this type of seizure counting for a regulatory phase III trial. In the eyes of regulatory Accepted December 31, 2016. NYU Langone School of Medicine, New York, New York, U.S.A. Address correspondence to Jacqueline A. French, NYU Langone School of Medicine, New York, NY 10016, U.S.A. E-mail: [email protected]