High Rate of Non-Eligibility: Methodological Factors Impacting on Recruitment for a Multicentre, Double-Blind Study of Paediatric Patients with Major Depressive Disorder

Abstract

Introduction: This report describes difficulties encountered when attempting to recruit children and adolescents with major depression for a recent international double-blind, placebo-controlled trial (www.clinicaltrials.gov Nr. NCT00849901). Methods: Over a 14-month period, children and adolescents with depressive symptoms were pre-screened for their eligibility for inclusion. Results: 85 patients (age 7?17 years) were considered. Of these, only one was enrolled. The main reasons for non-eligibility were: failure to meet the baseline severity criterion on the primary outcome scale (Clinical Global Impression ? Severity; 32.1% of the patients); requirement for immediate hospitalisation (15.4%); or the presence of an exclusionary comorbid psychiatric disorder (19.1%). Discussion: The recruitment of paediatric patients with major depression was primarily limited by various inclusion and exclusion criteria. Slow recruitment of small patient samples may impact strongly on the representativeness and generalisability of research findings, and thus on analyses in evidence-based medicine and on the development and recommendations of treatment guidelines. This may impact in turn on the feasibility of the clinical development and registration process of new compounds in paediatric psychopharmacology and beyond.

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“…Drug development is a costly and time consuming process (Ciociola, Cohen, & Kulkarni, 2014). Recruiting paediatric patients with psychiatric disorders into interventional trials is particularly challenging (Bliznak, Berg, Häge, & Dittmann, 2013).…”

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“…Furthermore, the inclusion and exclusion criteria of pediatric clinical trials -which are necessary in order to meet requirements for regulatory approval/marketing authorization -are often so stringent that many patients fail the screening step (see Bliznak, Berg, Häge, & Dittmann, 2013). The principal investigator at a given site may also find it difficult to garner the interest of other senior colleagues in the recruitment process if they perceive no direct benefit to their patients and receive no form of reward for the extra work involved.…”

“…Second, recruitment often proves difficult because of the stringent inclusion and exclusion criteria applied in many pediatric clinical trials (see Bliznak et al, 2013). For example, a trial investigating treatment for depression may exclude patients with frequent suicidal thoughts or comorbid substance misuse.…”

“…Although randomized placebo-controlled trials and meta-analyses have long been considered the gold standard for high-quality clinical research and as the evidence base for guideline development, skepticism as to their generalizability to a naturalistic practice setting is increasing (Bliznak et al, 2013;Parker, Anderson, & Haddad, 2003). The conditions imposed during these trials, such as narrow inclusion and exclusion criteria and complex study protocols, mean that everyday reality and routine clinical care are not reflected.…”

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“…Unfortunately, the planned registration of all screened patients was incomplete, resulting in that no valid data on the distribution of eligible patients on various reasons for non-randomisation were available. Besides potentially reducing the power of a trial, non-randomisation of eligible patients, whether due to patients' or due to clinicians' resistance will most likely lead to limitations in generalisability of the study results [22]. Future studies should take the issues outlined above into consideration by allowing co-medication after randomisation.…”