Age representation in antiepileptic drug trials: A systematic review and meta-analysis

Highlights

• Older patients are underrepresented in clinical trials of antiepileptic drugs.

• Upper age limit for enrollment in antiepileptic drug trials is prevalent.

• Exclusion of common conditions affect preponderantly recruitment of older patients.

Abstract

Objectives

To analyze age representation trends over time in antiepileptic drug (AED) trials and to assess trial design elements as possible barriers to enrollment of elderly patients.

Materials and methods

We searched MEDLINE, EMBASE, and PsycINFO, and meta-analyzed demographic data of cohorts enrolled in randomized controlled trials (RCTs) of AEDs published since 1991. Data analysis included trends of age representation over time and trial design elements associated with average age of enrolled cohorts.

Results

We identified 187 studies (n = 48,077); 184 studies were included in the meta-analysis. The mean age of participants enrolled increased steadily from a mean age of 27.0 years (SD 5.7, range 21.0–38.4) in 1991–1992, to a mean age of 41.9 years (SD 11.4, range 28.8–71.4) in 2015–2016 (r = 0.868, p < 0.0001). Maximum age limit for inclusion of participants was present in 83 trials (44%). There was no significant decrease in the use of upper age limit over time (r = 0.072, p = 0.8161). Among the eligibility criteria assessed, only the exclusion of neurological conditions other than epilepsy was associated with a significant reduction of the average age of enrolled cohorts (−2.1 years, 95% CI −4.1 to −0.1).

Conclusions

Despite a progressive increase in the average age of participants enrolled in AED trials over time, elderly patients are still largely underrepresented. Successful strategies to increase representation of elderly patients in these trials will likely need to involve more than minimal protocol modifications of eligibility criteria.

Introduction

Epilepsy is one of the most prevalent neurological conditions with an estimated 50 million people affected worldwide (WHO, 2005). It is a significant cause of disability and mortality, as well as being associated with a lower quality of life and high economic costs (Ngugi et al., 2011). It affects people of both sexes, coming from all socioeconomic, racial, and age groups, with a predilection age of onset in childhood and advanced age. However, the incidence and prevalence of epilepsy are highest in patients over the age of 65, with nearly 25% of new onset seizures occurring after this age (Faught et al., 2012; Sander et al., 1990; Wallace et al., 1998).

Despite increasing occurrence of epilepsy with age and a rapidly ageing world population, the pharmacological treatment of epilepsy in geriatric populations has not been frequently studied in randomized controlled trials (RCTs) of antiepileptic drugs (AEDs) (Glauser et al., 2013; Sillanpaa et al., 2016; Tanaka et al., 2013). Moreover, elderly have been found to be systematically underrepresented in clinical trials compared to their younger counterparts (Banzi et al., 2016; Bugeja et al., 1997; Heiat et al., 2002; Talarico et al., 2004; Van Spall et al., 2007; Zulman et al., 2011). Thus, evidence-based pharmacological interventions for epilepsy are scarce in the elderly and clinicians must routinely extrapolate findings from trials carried out in young and middle-aged patients with epilepsy. Participants in clinical trials should be representative of the patients typically receiving the therapy in daily practice. Recently, international and national working groups have recommended increasing the number of participants above the age of 65 in clinical trials (International Conference on Harmonisation Report, 2008) as well as to increase the age window of certain adult trials (Fertig et al., 2014), in hope of closing the age-gap in clinical research.

Although these working groups have acknowledged age representation in drug trials as a focus of concern and have drafted recommendations to that effect, it is still unclear what are the current limitations in representativeness in AED trials. Furthermore, if there is indeed an age gap, the possible obstacles to enrollment of elderly patients in AED trials should be characterized. We conducted a systematic review of the literature to describe and analyze the demographic characteristics of populations enrolled in RCTs over the past 26 years, to identify possible trends in age representation over time, and to analyze the effects of protocol elements on the average age of enrolled cohorts.