From clinical trials of antiepileptic drugs to treatment

Abstract

SummaryRational prescribing should be based on the assessment of high‐quality evidence about the benefits and risks of available treatment options. Because clinical trials, particularly randomized controlled trials (RCTs), provide the best source of evidence, their design and results need to be carefully scrutinized. The majority of RCTs of antiepileptic drugs (AEDs) have been designed to address regulatory requirements, and generally they involve restrictive eligibility criteria, rigid dosing schemes, short duration of follow‐up, and comparison with placebo rather than standard treatments. Although these studies have high internal validity, they are conducted in a setting that is distant from routine clinical practice and therefore their usefulness in guiding treatment decisions is limited. Information more directly applicable to clinical practice can be derived from a relatively small number of comparative effectiveness monotherapy RCTs, although the design of some of these studies was probably biased in favor of the sponsor's product. Alarmingly, there is a paucity of well‐designed trials in epilepsy syndromes other than focal epilepsies, and no RCTs at all in most of the less common epileptic syndromes of infancy and childhood. In the light of these shortcomings, there is scope for re‐assessing regulatory requirements to facilitate generation of data more directly applicable to the routine clinical setting. Likewise, research‐funding organizations should be sensitized about the lack of adequate evidence to guide therapeutic practice in epilepsy, and the need to promote high‐quality comparative effectiveness trials. Future prospective pragmatic trials may benefit from the increasingly widespread availability of electronic health records.

Understanding the challenge of comparative effectiveness research in focal epilepsy: A review of network meta‐analyses and real‐world evidence on antiepileptic drugs

“…For example, placebo response tends to be higher in studies conducted more recently 10 and can vary across different regions 26 . Furthermore, the use of last‐observation‐carried‐forward (LOCF), which is common in RCTs for focal epilepsy, is expected to artificially inflate seizure reduction and freedom rates 6 . Heterogeneity in study design between NMA RCTs could, therefore, mask true treatment effect differences or produce artificial ones.…”

“…There are different approaches to generating comparative evidence, resulting in different levels of evidence; randomized controlled trials (RCTs) designed for registration purposes are often considered the gold standard. However, head‐to‐head RCTs directly comparing antiepileptic drugs (AEDs) as adjunctive treatment of focal (partial onset) epilepsy are not mandated by regulatory bodies, and given the expense and uncertainty over whether statistically significant differences can be demonstrated against an active comparator, few of these study types have been conducted in this setting 5,6 . Additionally, RCTs, which have high internal validity, may incorrectly estimate the benefits of treatment in clinical practice, 7 due to a lack of external validity, which often arises from strict eligibility criteria resulting in unrepresentative patient samples 6,8 …”

Antiepileptic drugs: evolution of our knowledge and changes in drug trials

“…Regulatory requirements to obtain monotherapy indications have traditionally shown a transatlantic divide. The US Food and Drug Administration (FDA) has required demonstration of superiority over a comparator, whereas EMA guidelines require demonstration that the investigational AED is at least as effective as an already established treatment used at optimized doses in patients with newly diagnosed epilepsy followed for at least one year (Perucca, 2008(Perucca, , 2018. FDA requirements have been traditionally met by a variety of trial designs which have in common a comparison with a suboptimal control (often referred to as 'pseudoplacebo'), but over the years this approach faced increasing ethical concerns.…”

“…The possibility of extrapolation from the addon to the monotherapy setting is also mentioned in the latest EMA draft guidelines, which state that 'on a case by case basis, it may be justified that a monotherapy trial is not necessary to support a monotherapy indication' (European Medicines Agency, 2018). The principle of extrapolation is also accepted by regulatory authorities to extend the indication of an AED from adults to children, at least for focal seizures, based on the concept of similarity of disease (Pellock et al, 2017;Perucca, 2018). Of course, when extrapolation of an indication is made from adults to children, the recommended dose regimen takes into account age-related pharmacokinetic differences.…”

<p>Predicted Efficacy of Once-Daily Extended-Release Oxcarbazepine (Oxtellar XR®) Monotherapy in Adults and Children with Partial-Onset Seizures: Exposure-Response Modeling and Simulation</p>

“…13 The FDA took a similar position with regard to extrapolating AED efficacy as adjunctive therapy to monotherapy use. 8,14 Beginning in the 1980s, adjunctive therapy and monotherapy had been separate indications for AEDs, requiring that each indication be supported by RCT(s) demonstrating a statistically significant difference favoring study drug over a control. 15 Because epilepsy is a potentially life-threatening disorder, placebo monotherapy is generally considered unethical.…”