Healthy Skepticism Library item: 10551

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Publication type: news

Nainggolan L.
Comparator Statin Trials Suffer Massive Sponsorship Bias
Heartwire 2007 Jun 11
http://www.theheart.org/article/795913.do

Full text:

A group of scientists has published a damning indictment of head-to-head statin trials, finding that company-sponsored studies were much more likely to report conclusions favoring their own product than the comparator agent. Dr Lisa Bero (Professor of Clinical Pharmacy, University of California, San Francisco) and colleagues report the results of their cross-sectional study of 192 published randomized clinical trials in PLoS Medicine [1].

Bero told heartwire that most of the studies they included were small and done for marketing purposes, and that they almost all used surrogate end points, such as lipid levels, rather than hard outcomes. She said she was not surprised that bias was identified but “was amazed by the size of the effect.” Because the trials seem to be so biased, “they don’t help you to decide between drugs,” she says, adding that “the bottom line is that a lot of these trials don’t need to be done; they are performed purely for marketing purposes. We need to be much more selective in the trials that we do.”

Bero says that people who make decisions about which statins to use, such as those deciding on formularies for managed-care organizations, should try to identify an unbiased source, such as the Cochrane Collaboration or some of the systematic review programs employed by certain US states, such as Oregon. “A systematic review will critique the trial and will weed out the poor ones,” she points out.

Company-Sponsored Trials Overwhelmingly Favor Own Drug

In the study, Bero and colleagues extracted data from 192 studies that were found by searching PubMed for RCTs of statins between January 1999 and May 2005. Only studies that compared one statin with another statin or one statin with another type of drug were included—95 studies declared industry sponsorship, 23 had government or other nonprofit funding, and 74 did not disclose any funding source.

The researchers examined data for concealment of allocation, selection bias, blinding, sample size, disclosed funding source, financial ties of authors, results for primary outcomes, and author conclusions.

They found that research sponsorship was the main factor associated with the results and conclusions of industry-sponsored research to compare statin drugs with other products.

In a multivariate analysis of industry-sponsored RCTs, funding from the test-drug company was associated with results (odds ratio, 20.16; p < 0.001) and conclusions (odds ratio, 34.55; p < 0.001) that overwhelmingly favored the test drug when other factors were controlled for.

The researchers said they identified a number of weaknesses common to the trials “that bring into question their clinical relevance.”

The most important weakness was the lack of patient-related clinical-outcome measures, they note. Almost all studies
(98%) used only surrogate outcome measures. Also, inadequate blinding, lack of concealment of allocation, poor follow-up, and lack of intention-to-treat analyses were common. Studies with adequate blinding were less likely to report statistically significant results favoring the test drug.

These weaknesses suggest that those making regulatory and purchasing decisions use these types of studies with great caution, Bero et al say. “The market for statins is competitive. Our findings suggest that available data on . . .
statins based on head-to-head comparisons might . . . be influenced by financial conflicts of interest.”

Those Making Policy Decisions Should Take Note

“This bias in drug-drug comparison trials should be considered when making health-policy decisions regarding drug choice, such as drug formulary decisions,” the researchers continue.

They point out, for example, that eight of the nine members of the US National Cholesterol Education Program (NCEP) panel, which updated adult treatment guidelines, had financial ties with pharmaceutical companies that manufactured statin drugs.

And reviewers of published reports that disclose funding by the makers of the product being tested “should be more critical of the methods than if the reports are not industry sponsored,” they add.

“It’s the company that makes the difference,” Bero told heartwire. “We controlled for a lot of other factors and I was surprised by the magnitude of the effect that remained and its consistency across trials.”

Several Reasons for “Substantial” Bias

The researchers say there are several possible explanations for their findings. First, “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,” Bero et al note.

Second, “others have suggested that trials that produce unfavorable results are not published, or that unfavorable outcomes are suppressed,”—so-called publication bias. In addition, “selective reporting of outcomes can also contribute to biased results and conclusions,” they say, and industry sponsorship might be associated with multiple reporting of studies with favorable findings, “emphasizing the imbalance toward statistically significant results in the published literature.”

Finally, more than one third of the studies in the sample had no disclosed sponsorship. “It is possible that industry funders or industry-supported authors fail to disclose the sponsorship of a published study if the findings do not support the sponsor’s product.” However, they point out that this “would have to be very prevalent to explain by itself the results concerning sponsorship.”

“Whatever the reasons for these findings, the implications are important and suggest that the evidence base relating to statins is substantially biased,” they conclude, adding that their findings are likely generalizable to other classes of drugs with competitive markets.

1. Bero L, Oostvogel F, Bacchetti P, Lee K. Factors associated with findings of published trials of drug-drug comparisons: Why some statins appear more efficacious than others. PLoS Med 2007;4(6):e184.

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Lisa Nainggolan is a journalist for Medscape. She joined theheart.org, part of the WebMD Professional Network, in 2000.
She was previously science editor of Scrip World Pharmaceutical News, covering news about research and development in the pharmaceutical industry, and a consultant editor of Scrip Magazine. Graduating in physiology from Sheffield University, UK, she began her career as a poisons information specialist at Guy’s Hospital before becoming a medical journalist in 1995. She can be reached at LNainggolan@webmd.net.