Published pharmaceutical industry–sponsored trials are more likely than non-industry-sponsored trials to report results and conclusions that favor drug over placebo. Little is known about potential biases in drug–drug comparisons. This study examined associations between research funding source, study design characteristics aimed at reducing bias, and other factors that potentially influence results and conclusions in randomized controlled trials (RCTs) of statin–drug comparisons.
Methods and Findings
This is a cross-sectional study of 192 published RCTs comparing a statin drug to another statin drug or non-statin drug. Data on concealment of allocation, selection bias, blinding, sample size, disclosed funding source, financial ties of authors, results for primary outcomes, and author conclusions were extracted by two coders (weighted kappa 0.80 to 0.97). Univariate and multivariate logistic regression identified associations between independent variables and favorable results and conclusions. Of the RCTs, 50% (95/192) were funded by industry, and 37% (70/192) did not disclose any funding source. Looking at the totality of available evidence, we found that almost all studies (98%, 189/192) used only surrogate outcome measures. Moreover, study design weaknesses common to published statin–drug comparisons included inadequate blinding, lack of concealment of allocation, poor follow-up, and lack of intention-to-treat analyses. In multivariate analysis of the full sample, trials with adequate blinding were less likely to report results favoring the test drug, and sample size was associated with favorable conclusions when controlling for other factors. In multivariate analysis of industry-funded RCTs, funding from the test drug company was associated with results (odds ratio = 20.16 [95% confidence interval 4.37–92.98], p < 0.001) and conclusions (odds ratio = 34.55 [95% confidence interval 7.09–168.4], p < 0.001) that favor the test drug when controlling for other factors. Studies with adequate blinding were less likely to report statistically significant results favoring the test drug.
RCTs of head-to-head comparisons of statins with other drugs are more likely to report results and conclusions favoring the sponsor's product compared to the comparator drug. This bias in drug–drug comparison trials should be considered when making decisions regarding drug choice.
Lisa Bero and colleagues found published trials comparing one statin with another were more likely to report results and conclusions favoring the sponsor's product than the comparison drug.
Randomized controlled trials are generally considered to be the most reliable type of experimental study for evaluating the effectiveness of different treatments. Randomization involves the assignment of participants in the trial to different treatment groups by the play of chance. Properly done, this procedure means that the different groups are comparable at outset, reducing the chance that outside factors could be responsible for treatment effects seen in the trial. When done properly, randomization also ensures that the clinicians recruiting participants into the trial cannot know the treatment group to which a patient will end up being assigned. However, despite these advantages, a large number of factors can still result in bias creeping in. Bias comes about when the findings of research appear to differ in some systematic way from the true result. Other research studies have suggested that funding is a source of bias; studies sponsored by drug companies seem to more often favor the sponsor's drug than trials not sponsored by drug companies
Why Was This Study Done?
The researchers wanted to more precisely understand the impact of different possible sources of bias in the findings of randomized controlled trials. In particular, they wanted to study the outcomes of “head-to-head” drug comparison studies for one particular class of drugs, the statins. Drugs in this class are commonly prescribed to reduce the levels of cholesterol in blood amongst people who are at risk of heart and other types of disease. This drug class is a good example for studying the role of bias in drug–drug comparison trials, because these trials are extensively used in decision making by health-policy makers.
What Did the Researchers Do and Find?
This research study was based on searching PubMed, a biomedical literature database, with the aim of finding all randomized controlled trials of statins carried out between January 1999 and May 2005 (reference lists also were searched). Only trials which compared one statin to another statin or one statin to another type of drug were included. The researchers extracted the following information from each article: the study's source of funding, aspects of study design, the overall results, and the authors' conclusions. The results were categorized to show whether the findings were favorable to the test drug (the newer statin), inconclusive, or not favorable to the test drug. Aspects of each study's design were also categorized in relation to various features, such as how well the randomization was done (in particular, the degree to which the processes used would have prevented physicians from knowing which treatment a patient was likely to receive on enrollment); whether all participants enrolled in the trial were eventually analyzed; and whether investigators or participants knew what treatment an individual was receiving.
One hundred and ninety-two trials were included in this study, and of these, 95 declared drug company funding; 23 declared government or other nonprofit funding while 74 did not declare funding or were not funded. Trials that were properly blinded (where participants and investigators did not know what treatment an individual received) were less likely to have conclusions favoring the test drug. However, large trials were more likely to favor the test drug than smaller trials. When looking specifically at the trials funded by drug companies, the researchers found various factors that predicted whether a result or conclusion favored the test drug. These included the impact of the journal publishing the results; the size of the trial; and whether funding came from the maker of the test drug. However, properly blinded trials were less likely to produce results favoring the test drug. Even once all other factors were accounted for, the funding source for the study was still linked with results and conclusions that favored the maker of the test drug.
What Do These Findings Mean?
This study shows that the type of sponsorship available for randomized controlled trials of statins was strongly linked to the results and conclusions of those studies, even when other factors were taken into account. However, it is not clear from this study why sponsorship has such a strong link to the overall findings. There are many possible reasons why this might be. Some people have suggested that drug companies may deliberately choose lower dosages for the comparison drug when they carry out “head-to-head” trials; this tactic is likely to result in the company's product doing better in the trial. Others have suggested that trials which produce unfavorable results are not published, or that unfavorable outcomes are suppressed. Whatever the reasons for these findings, the implications are important, and suggest that the evidence base relating to statins may be substantially biased.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040184.
The James Lind Library has been created to help people understand fair tests of treatments in health care by illustrating how fair tests have developed over the centuries
The International Committee of Medical Journal Editors has provided guidance regarding sponsorship, authorship, and accountability
The CONSORT statement is a research tool that provides an evidence-based approach for reporting the results of randomized controlled trials
Good Publication Practice guidelines provide standards for responsible publication of research sponsored by pharmaceutical companies
Information from Wikipedia on Statins. Wikipedia is an internet encyclopedia anyone can edit