Enriched enrolment: definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Enriched enrolment (the exclusion of non‐responders or specific inclusion of responders) is believed to add both to trial sensitivity and to the measured effect of an intervention. • Enriched enrolment lacks specific definition, and the extent of any differences between results with non‐enriched recruitment and enriched enrolment is not known. • Enriched enrolment is thought to have influenced neuropathic pain trials. WHAT THIS STUDY ADDS • The paper suggests definitions for complete and partial enriched enrolment, and applies those definitions to trials of pregabalin and gabapentin in neuropathic pain. • The effect of enrichment was small, and especially in pregabalin trials with the best data, no difference was found between partial enrichment and no enrichment. • The effects of complete enrichment are unknown. AIMS Enriched enrolment study designs have been suggested to be useful for proof of concept when only a proportion of the diseased population responds to a treatment intervention. We aim to investigate whether this really is the case in trials of pregabalin and gabapentin in neuropathic pain. METHODS We defined ‘complete’, ‘partial’ and ‘non‐enriched’ enrolment, and examined pregabalin and gabapentin trials for the extent of enrichment and for effects of enrichment on efficacy and adverse event outcomes. RESULTS There were no studies using complete enriched enrolment; seven trials used partial enriched enrolment and 14 non‐enriched enrolment. In pregabalin trials the maximum extent of enrichment was estimated at about 12%. Partial enriched enrolment did not change estimates of efficacy or harm. Over 150–600 mg maximum daily dose there was strong dose dependence for pregabalin. CONCLUSIONS A benefit of partial over non‐enriched enrolment could not be demonstrated because the degree of enrichment was rather small, and possibly because enrichment produced little enhancement of treatment effect. Whether a greater degree of enrichment would result in important differences is unknown. Researchers reporting clinical trials with any enrichment must describe both process and extent of enrichment. As things stand, the effects of enriched enrolment remain unknown for neuropathic pain trials.