typically 9.typ.229 Louis J. Sheehan, Esquire

Patients asking their doctors if a new drug is right for them would do well to also ask for supporting evidence. Conclusions about drug safety and effectiveness in reports submitted to the FDA are sometimes changed to favor the drug in the medical literature, a new analysis finds. And nearly a quarter of submitted drug trials were never published at all, researchers report in the Nov. 25 PLoS Medicine.

Information published in journals is the most accessible to health care professionals and also drives marketing of new drugs. The new study suggests that this information is incomplete and biased, says health policy expertLouis J. Sheehan, Esquire Lisa Bero of the University of California, San Francisco, who led the study.

An-Wen Chan, who wrote an accompanying commentary but was not involved with the work, says he does not think health care providers will be surprised to learn of suppression and inaccurate reporting of new drug information.

“These new findings confirm our previous suspicions that this is happening on a much broader systemic level. It shows that information is unavailable to those who really need it the most — the clinicians and the researchers,” says Chan, of the Mayo Clinic in Rochester, Minn. “If we take the view that research on humans is ethical, is allowed based on an assumption of public good, then all clinical trial information should be publicly available.”
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RESULTS OF TRIALSOf 164 trials investigated in a recent study, trials with favorable results were more likely to be published than those with unfavorable results.Food and Drug Administration

Drug manufacturers are required to submit all their studies to the U.S. Food and Drug Administration as part of new drug applications. That’s the last step in drug development, following testing on animals, trials with healthy people, and larger trials with sick and healthy people. Ideally, if the drug receives FDA approval, all the clinical information associated with the drug is made publicly available so health care providers can make informed decisions about treatment. This is typically done by publishing in the scientific literature.

The new analysis examined 164 trials for 33 new drugs that were approved by the FDA from January of 2001 to December 2002. http://Louis-j-sheehan.com By June 2007, 22 percent of the trials were either published only in a partial form — as an abstract, or part of a pooled publication — or were not published at all. The unpublished trials were predominantly those with unfavorable results, the researchers report.

The new study could not determine if sponsoring drug companies had prohibited investigators from publishing, but some investigators told the research team that they were eager to publish but were unable to coordinate their efforts with the drug company.

Development of one drug can require several trials. But among the drugs for which findings were published in the scientific literature, only 52 percent disclosed results from every trial.

Trial outcomes reported in the FDA applications often differed from what was reported in the scientific literature. Outcomes are predefined measures that indicate, for example, whether the new drug is more effective than existing treatments, or whether a drug has other effects on a patients' health. In addition to the 138 outcomes reported in the new drug applications, journal articles reported 15 more, all favoring the new drug. Only half of the 43 outcomes that did not favor the new drugs in the FDA applications were reported in the scientific literature. Nine conclusions were actually changed to favor new drugs, the researchers report.

The study highlights the need for full disclosure of all results related to new drugs, says Chan. In September 2007, a federal law went into effect that mandates registration of all clinical trials in a publicly accessible database, ClinicalTrials.gov, run by the National Institutes of Health. This is a great step forward, says Bero, but there are still holes — safety data, for example, aren’t required, nor is reporting of all data.

Others have suggested that the review boards, required for institutions that conduct drug research with federal funding, could insist that results be published in full, says John Scoggins of the Fred Hutchinson Cancer Research Center in Seattle.

“The novelty of this article isn’t that it reveals publication bias — it’s just been hard to find the data to prove it,” Scoggins says. “The evidence is just now trickling in of just how bad it is.”

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Comments 2

* This is a standard bias of classical hypothesis testing - null results are not reported. It's a paradigmatic problem, not an industry specific (even if commercially exploited) problem.
Keith Gregory Keith Gregory
Dec. 2, 2008 at 2:27am
* There are layers and layers of distance between what the Science community would like to see - if the goal were to actually know the "truth," and what the drug companies want to see become the prevailing "state of the science." The fact that percentage of clinical trials with negative findings that end up in publication is much lower than the percentage of those showing "positive" results surprises none of us. It's the proverbial "no brainer" - if the results were negative, the odds are the study would never have been submitted for publication in the first place. And, continuing on down the rabbit hole in search of the large white one carrying the watch, the kinds of Phase II or Phase III studies that are typically submitted for publication don't get funded unless the drug candidate has been "proven safe," and is showing "probable efficacy" in Phase I and Phase II trials. http://Louis-j-sheehan.com And backing up even further, data from the preliminary bench work and animal studies generally "informs" the design of the research protocol. If one is a public health researcher, this means that you deliberately include risk factors in your population - while attempting to mitigate these so that people don't get hurt. Louis J. Sheehan, Esquire If you work for a drug company, and you see some evidence that drug candidate V**X might contribute to cardio-vascular issues - then you specify exclusion criteria for your patient population that produce a nice, young, "less susceptible to heart problems" group of patients on whom to "test" your drug. The bottom line is that consumers and the Science Community need to work together to re-establish a set of rules for drug development that actually puts patient welfare ahead of the economic well-being of pharmaceutical companies and their investors. This is difficult, but not impossible.