Publication bias and clinical trial outcomes reporting
Last month, the world’s leading funders of medical research and international non-governmental organizations agreed to set forth new standards that will require all clinical trials they fund or support to be registered, and the results disclosed publicly within mandatory timeframes. The aim is to dramatically improve both the quality of therapies available to patients, as well as the quality of research that leads to new breakthrough. But the question remains: Will it be enough?
Today, roughly half of clinical trials go unreported, often because results are negative. Failure to report trial outcomes paints a distorted picture of the risks and benefits of drugs, vaccines, medical devices and even diagnostics. It’s what scientists refer to as publication bias. The collective knowledge we have about healthcare interventions is skewed by the information shared, instead of being improved by the totality of information learned.
Publication bias is a controversial issue in clinical research that many argue has plagued the profession for decades. Physicians rely on data to make informed treatment decisions for their patients. When published evidence overestimates efficacy, or underestimates safety risks, as it tends to do, physicians’ ability to do their job is undermined. The ugly truth is that the impact of underreporting trial results has a long term systemic effect of wasting resources, inappropriately influencing policy decisions and misguiding future research.
There is no shortage of examples of how researchers and companies have withheld information for competitive reasons. Researchers of cancer vaccines, for example, have been asked to hold, in confidence, information that might have prevented patients from receiving ineffective or even harmful doses of a new agent.
A review of over 2,000 oncology trials registered in ClinicalTrials.gov revealed fewer than 20% were available in PubMed. Trials sponsored by clinical trial networks published roughly 60% of the time, with half of the outcomes being positive. By contrast, trials sponsored by industry only published 6% of the time, with positive outcomes reported three quarters of the time.
Publication bias has also been identified in a number of trials investigating prospective HIV medications. Over a dozen trials of six antiviral agents that included thousands of patients had remained unpublished for more than three years after the investigations had been concluded. Most of the trials had negative results.
The industry is so consumed with controlling information that they have gone to great lengths to protect negative results from being published. In one instance, a manufacturer of a vaccine filed a claim to prevent publication of data that showed no difference between the vaccine and placebo. When a judge dismissed their claim, they sued the study’s lead investigators and their universities demanding millions in damages.
The worst part is that discovery of results previously withheld by manufacturers often happens after regulators have already approved the drug. In 1997, for example, an atypical antipsychotic that had shown high rates of discontinuation and significant weight increases was approved after the manufacturer presented a subset of evidence that argued the product had weight loss advantages.
The problem of publishing bias is not new. The industry has a history of selectively reporting on outcomes that favorably represent their interventions. A well-known controversy surrounding unpublished data had to do with efficacy and safety data from SSRI trials. Of the five trials the company had conducted, only one was published, which showed mixed results for efficacy. The results of the other trials, which showed no efficacy but did show a possible increased suicide risk, were not published.
In a clinical trial conducted in the1980s, some 20% of participants died, compared to 1% of the placebo group. Investigators first stated that this was due to “chance.” The trial results went unpublished for over a decade, and the investigators later suggested that if the results had been published earlier, problems with similar drugs in the same class may have been avoided. In the book Deadly Medicine, the death toll related to this class of drugs during the 1980s was compared with combat losses in the Vietnam War.
In 2009, the journal Nature reported on two studies that identified this as an ongoing problem. In spite of the NIH establishment of the trials registry ClinicalTrials.gov, and direction from the International Committee of Medical Journal Editors to deposit data in such registries prior to publication, fewer than half of registered trials were ever published in peer-reviewed journals.
The clinical research profession has an ethical obligation to publish research findings. Patients participate in clinical trials in part because they are led to believe that they are contributing to a greater body of knowledge. Deliberately concealing outcomes from the public tarnishes the profession and inhibits the collective mission of improving lives.
The latest effort to force reporting of clinical trial outcomes is certainly a step in the right direction. But one has to wonder, what is the impact of non-compliance? And how long will it take to change what appears to be an inherent, systemic problem?
Matthew Howes is executive vice president, Strategy & Growth for PALIO, an inVentiv Health company. A leader in digital strategy, he has provided the fuel for digital businesses visited by more than 100 million people every month. Email firstname.lastname@example.org.
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