Factors Associated with Results and Conclusions of Trials of Thiazolidinediones

Abstract

BackgroundWhen a sponsor funds a study of two competing drugs in a head-to-head comparison, the results and conclusions are likely to favor the sponsor’s drug. Thiazolidinediones, oral medications used for the treatment of type 2 diabetes, are one of the most costly choices of oral anti-diabetic medications, yet they do not demonstrate clinically relevant differences in achieving lower glycosylated hemoglobin levels compared to other oral antidiabetic drugs. Our aim is to examine associations between research funding source, study design characteristics aimed at reducing bias, and other factors with the results and conclusions of randomized controlled trials (RCTs) of thiazolidinediones compared to other oral hypoglycemic agents.Methods and FindingsThis is a cross-sectional study of 61 published RCTs comparing a thiazolidinedione (glitazone) to another anti-diabetic drug or placebo for treatment of type 2 diabetes. Data on study design characteristics, funding source, author’s financial ties, results for primary outcomes, and author conclusions were extracted. Univariate logistic regression identified associations between independent variables and results and conclusions that favored the glitazone. Of the RCTs, 59% (36/61) were funded by industry, 39% (24/61) did not disclose any funding. Common study design weaknesses included inadequate blinding and lack of concealment of allocation. Trials that reported favorable glycemic control results for the glitazone were more likely to have adequate blinding (OR (95% CI) = 5.42 (1.46, 21.19), p = 0.008) and have a corresponding author with financial ties to the glitazone manufacturer (OR (95% CI) = 4.12 (1.05, 19.53); p = 0.04). Trials with conclusions favoring the glitazone were less likely to be funded by a comparator drug company than a glitazone company (OR (95% CI) = 0.026 (0, 0.40), p = 0.003) and less likely to be published in journals with higher impact factors (OR (95% CI) = 0.79 (0.62, 0.97), p = 0.011). One limitation of our study is that we categorized studies as funded by industry based on each article’s disclosure which could underestimate the number of industry sponsored studies and personal ties of investigators. Additionally, our study did not include any head-to-head comparisons of one glitazone to another.ConclusionsPublished RCT comparisons of glitazones with other anti-diabetic drugs or placebo are predominantly industry supported and this support, as well as the financial ties of study authors, appears to be associated with favorable findings.

The relationship between risk of bias criteria, research outcomes, and study sponsorship in a cohort of preclinical thiazolidinedione animal studies: a meta‐analysis

“…Building upon the evidence that biases are common in human clinical drug studies, including studies of TZDs, funded by pharmaceutical companies,2, 10 this systematic review investigated bias in the design of TZD preclinical studies and examined the association between industry support and the outcomes. Assessment of the 112 included TZD animal studies showed evidence of poor reporting of risk of bias criteria regardless of sponsorship source, exaggerations in the effect size of efficacy and harms outcomes in industry‐sponsored studies, and non‐disclosure of funding sources (34.8%) or financial ties of investigators (83.0%) in a substantial number of articles.…”

“…This instrument was modelled after previous studies that followed a similar protocol10, 11, 12, 13, 14 and included a coding manual. Methodological criteria were based on a published systematic review of tools for assessing biases in animal studies 9…”

“…These oral hypoglycaemic agents were targeted because the market for these drugs is competitive and the vast majority of their safety and efficacy studies are funded by industry. Furthermore, previous research has identified the factors associated with biased results and conclusions of human trials for TZDs 10. We hypothesize that industry‐sponsored TZD animal studies will have different efficacy and/or harm estimates compared with non‐industry‐sponsored trials, regardless of their risk of bias.…”

In Silico Approach for Lead Identification and Optimization Of Antidiabetic Compounds

“…In the last decade, numerous PTP1B inhibitors have been designed as drug candidates [18]. Thiazolidinedione (TZD) compounds class exhibit properties as antidiabetic compounds [19].…”

It's time to rebuild the evidence base

“…6 In 2009 researchers demonstrated that sponsored trials of new antidiabetes drugs, and trials run by authors with financial ties to companies, tended to find more favourable results for the sponsor's product: an extremely worrying finding, given the harms associated with rosiglitazone. 7 And now, in 2011, the JAMA paper suggests that the vast majority of meta-analyses fail to report such basic facts as the funding source for the original studies.…”