Industry sponsorship bias in research findings: a network meta-analysis of LDL cholesterol reduction in randomised trials of statins

Abstract

Objective: To explore the risk of industry sponsorship bias in a systematically identified set of placebo controlled and active comparator trials of statins.

Design: Systematic review and network meta-analysis.

Eligibility: Open label and double blind randomised controlled trials comparing one statin with another at any dose or with control (placebo, diet, or usual care) for adults with, or at risk of developing, cardiovascular disease. Only trials that lasted longer than four weeks with more than 50 participants per trial arm were included. Two investigators assessed study eligibility.

Data sources: Bibliographic databases and reference lists of relevant articles published between 1 January 1985 and 10 March 2013.

Data extraction: One investigator extracted data and another confirmed accuracy.

Main outcome measure: Mean absolute change from baseline concentration of low density lipoprotein (LDL) cholesterol.

Data synthesis: Study level outcomes from randomised trials were combined using random effects network meta-analyses.

Results: We included 183 randomised controlled trials of statins, 103 of which were two-armed or multi-armed active comparator trials. When all of the existing randomised evidence was synthesised in network meta-analyses, there were clear differences in the LDL cholesterol lowering effects of individual statins at different doses. In general, higher doses resulted in higher reductions in baseline LDL cholesterol levels. Of a total of 146 industry sponsored trials, 64 were placebo controlled (43.8%). The corresponding number for the non-industry sponsored trials was 16 (43.2%). Of the 35 unique comparisons available in 37 non-industry sponsored trials, 31 were also available in industry sponsored trials. There were no systematic differences in magnitude between the LDL cholesterol lowering effects of individual statins observed in industry sponsored versus non-industry sponsored trials. In industry sponsored trials, the mean change from baseline LDL cholesterol level was on average 1.77 mg/dL (95% credible interval -11.12 to 7.66) lower than the change observed in non-industry sponsored trials. There was no detectable inconsistency in the evidence network.

Conclusions: Our analysis shows that the findings obtained from industry sponsored statin trials seem similar in magnitude as those in non-industry sources. There are actual differences in the effectiveness of individual statins at various doses that explain previously observed discrepancies between industry and non-industry sponsored trials.

Fig 1 Flow diagram of study identification and selection

Fig 2 Network of available comparisons. Size of node is proportional to number of trial participants, and thickness of line connecting nodes is proportional to number of participants randomised in trials directly comparing the two treatments

Fig 3 Network of available comparisons between individual statins and control. Size of node is proportional to number of trial participants, and thickness of line connecting nodes is proportional to number of participants randomised in trials directly comparing the two treatments

Fig 4 Sensitivity of network meta-analysis findings to methodological quality attributes of randomised controlled trials of statins. In addition to the findings of the base case analysis (blue circles), findings of separate sensitivity analyses are shown. These excluded trials with low quality on the following methodological quality attributes: blinding (white circles), random sequence generation (blue squares), allocation concealment (white squares), blinding of outcome assessment (blue triangles), incomplete outcome data (white triangles), and selective reporting (blue diamonds). Figure shows mean (95% credible interval) change from baseline low density lipoprotein (LDL) cholesterol concentration with different statins and doses compared with control; lower (more negative) values favour statin treatment

Fig 5 Dose comparative effects of statins on serum low density lipoprotein (LDL) cholesterol concentration in industry sponsored clinical trials versus non-industry sponsored trials. Findings from industry sponsored trials are shown in white and findings from non-industry sponsored trials are shown in blue. Estimates shown are mean (95% credible interval) change from baseline serum LDL cholesterol concentration compared with control

Fig 6 Meta-regression analysis results: evaluation of industry sponsorship bias in the randomised controlled trials of statins. In scenario 1 a pharmaceutical sponsor would favour its own drug in placebo controlled or active comparator trials of statins or the highest dose of its own drug; in scenario 2 a sponsor would favour its own drug in placebo controlled or active comparator trials of statins, but it would not differentiate between different doses of its own drug in dose comparator trials. Figure shows the extent to which mean (95% credible interval) change from baseline low density lipoprotein (LDL) cholesterol concentration was exaggerated in trials with industry favoured statins; lower (more negative) values suggest greater bias.