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News & trends
April 2008 | Volume 44, Issue 4
Published clinical trials show skewed results, study says
Allison Torres Burtka, Associate Editor
The results of clinical trials appear much more positive in published
literature than they really are, according to a study in the New
England Journal of Medicine.
Drug manufacturers must register with the FDA all clinical trials
they plan to use to seek approval or a labeling change for a drug.
This study looked at 74 registered trials of 12 antidepressants, including
Prozac, Paxil, Zoloft, and Effexor, and compared the FDA’s data
with published data. It found that 94 percent of the trials appeared
to be positive in published literature, while the FDA judged only
51 percent as positive. (Erick H. Turner et al., Selective Publication
of Antidepressant Trials and Its Influence on Apparent Efficacy,
358 New Eng. J. Med. 252 (2008).)
Doctors rely on peer-reviewed medical journals for information on
drug safety. But, the researchers noted, “by altering the apparent
risk-benefit ratio of drugs, selective publication can lead doctors
to make inappropriate prescribing decisions that may not be in the
best interest of their patients and, thus, the public health.”
The study found that “the published literature conveyed an effect
size [treatment effect] nearly one-third larger than the effect size
derived from the FDA data.”
Marcia Angell, a senior lecturer at Harvard Medical School and former
editor-in-chief of the New England Journal of Medicine, said
the study was not surprising, as previous research has generated
similar findings. Still, doctors remain unaware of how biased information
in a peer-reviewed medical journal can be, she said.
“Doctors are largely educated by the pharmaceutical industry,”
Angell said, “but [medical] journals are the last place doctors
would expect to find biased information.”
Companies’ FDA-registered trial data was not always publicly
available. The ClinicalTrials.gov database was made public in 2000,
although it initially excluded most company-sponsored trials. Now,
it’s possible—but not easy—for doctors to evaluate
the data themselves, Angell said.
The study found that nearly all trials the FDA deemed positive were
presented as positive in the medical literature (37 of 38); most that
were deemed negative or questionable were either not published (22)
or the published reports conflicted with the FDA’s judgment
(11). Only three negative or questionable studies were published as
such.
The researchers noted that they could not determine why some trials
were not published but added that “to be fair to the people
who put themselves at risk to participate, a cogent public reason
should be given for failure to publish.” The studies involved
12,564 patients; data from 3,449 patients was not published.
Each drug was shown to be superior to a placebo, the study found,
but “the true magnitude of each drug’s superiority to
placebo was less than a diligent literature review would indicate.”
“Companies suppress negative trials and skew the design of
positive trials,” Angell said.
“This manipulation has gone on for a long time; physicians
have been aware of it for a while,” said Gale Pearson, a Minneapolis
lawyer. “It’s now making its way into the legal body of
knowledge.” Pearson represents the mother of a man who committed
suicide while a participant in a clinical trial of Seroquel, an antipsychotic
drug. The plaintiff sued the manufacturer for negligence and for failure
to warn patients and doctors involved in its research about the drug’s
risks. (Weiss v. Bd. of Regents for U. of Minn., No. 27 CV
07-1679 (Minn., Ramsey Co. Dist. filed Nov. 21, 2006).)
“It’s a fundamental mistake to think that companies whose
profits depend on selling these drugs can be the source of unbiased
information on them,” Angell said. In any other arena, doctors
would know better, she said—if they were shopping for a Honda
or a Toyota, they wouldn’t ask the manufacturer for advice.
But regarding pharmaceutical products, “they have suspended
their critical faculties.”
The researchers acknowledged that the study “did not account
for other factors that may distort the apparent risk-benefit ratio,
such as selective publication of safety issues, as has been reported
with rofecoxib (Vioxx, Merck) and with the use of selective-serotonin
reuptake inhibitors for depression in children.”
The lack of unbiased information on drug safety is “a real
problem, particularly with psychiatric drugs,” Angell said,
noting that many people take multiple drugs at once.
In February, a meta-analysis of published and unpublished data submitted
to the FDA for a group of antidepressants (drugs that were also part
of the New England Journal of Medicine study) found that
their overall effect is “below recommended criteria for clinical
significance.” It found that “efficacy reaches clinical
significance only in trials involving the most extremely depressed
patients, and that this pattern is due to a decrease in the response
to placebo rather than an increase in the response to medication.”
(Irving Kirsch et al., Initial Severity and Antidepressant Benefits:
A Meta-Analysis of Data Submitted to the Food and Drug Administration,
5 PLoS Med. e45 (Feb. 2008), http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050045.)
Pearson pointed out that while drug reps are not permitted to promote
off-label uses of drugs, clinical trials serve as “a way for
drug companies to sell off-label uses without violating FDA rules.”
In February, the FDA proposed guidelines that would allow makers
of drugs and medical devices to give doctors copies of medical journal
articles that outline unapproved uses.
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