The effect of funding sources on donepezil randomised controlled trial outcome: a meta-analysis

Abstract

Objective: To investigate whether there is a difference in the treatment effect of donepezil on cognition in Alzheimer disease between industry-funded and independent randomised controlled trials.

Design: Fixed effects meta-analysis of standardised effects of donepezil on cognition as measured by the Mini Mental State Examination and the Alzheimer's Disease Assessment Scale-cognitive subscale.

Data sources: Studies included in the meta-analyses reported in the National Institute for Health and Care Excellence (NICE) technical appraisal 217 updated with new studies through a PubMed search.

Eligibility criteria: Inclusion criteria were double-blind, placebo-controlled trials of any length comparing patients diagnosed with probable Alzheimer disease (according to the NINCDS-ADRDA/DSM-III/IV criteria) taking any dosage of donepezil. Studies of combination therapies (eg, donepezil and memantine) were excluded, as were studies that enrolled patients with a diagnosis of Alzheimer disease associated with other disorders (eg, Parkinson's disease and Down's syndrome).

Results: Our search strategy identified 14 relevant trials (4 independent) with suitable data. Trials sponsored by pharmaceutical companies reported a larger effect of donepezil on standardised cognitive tests than trials published by independent research groups (standardised mean difference (SMD)=0.46, 95% CI 0.37 to 0.55 vs SMD=0.33, 95% CI 0.18 to 0.48, respectively). This difference remained when only data representing change up to 12 weeks from baseline were analysed (industry SMD=0.44, 95% CI 0.34 to 0.53 vs independent SMD=0.35, 95% CI 0.18 to 0.52). Analysis revealed that the effect of funding as a moderator variable of study heterogeneity was not statistically significant at either time point.

Conclusions: The effect size of donepezil on cognition is larger in industry-funded than independent trials and this is not explained by the longer duration of industry-funded trials. The lack of a statistically significant moderator effect may indicate that the differences are due to chance, but may also result from lack of power.

Keywords: CLINICAL PHARMACOLOGY; STATISTICS & RESEARCH METHODS.

Figure 1

Flow chart of included and excluded studies selected for this meta-analysis. AD, Alzheimer disease; RCT, randomised controlled trial; NICE, National Institute for Health and Care Excellence.

Figure 2

Forest plot of individual independent and industry-funded studies’ reported effect (standardised mean difference) of donepezil compared with placebo on cognitive scales observed at study endpoint (95% CIs).

Figure 3

Forest plot of individual independent and industry-funded studies’ reported effect (standardised mean difference) of donepezil compared with placebo on cognitive scales observed up to 12 weeks from baseline (95% CIs).