New study finds publication bias among trials submitted to FDA

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Public release date: 24-Nov-2008

http://www.eurekalert.org/pub_releases/2008-11/plos-nsf112008.php

Contact: Hyde

press@...

44-

Public Library of Science

New study finds publication bias among trials submitted to FDA

A quarter of drug trials submitted in support of new drug applications

to the US Food and Drug Administration (FDA) remain unpublished five

years after the fact, says new research published in the open access

journal PLoS Medicine. Among those trials published, unexplained

discrepancies between the FDA submissions and their corresponding

publications—the addition or deletion of outcomes, changes in the

statistical significance of reported outcomes, and changes in overall

trial conclusions—tended to lead to more favorable presentations of the

drugs in the medical literature available to health care professionals.

Bero and colleagues from the University of California San Francisco

reviewed the publication status of all 164 efficacy trials carried out

in support of the 33 new drug applications (NDA) for new molecular

entities approved by the FDA in 2001�, and compared information from the

FDA reviews with published journal articles. Seventy-eight percent of

the trials were published. Trials with favorable outcomes for the drugs

were more likely to be published as those without favorable outcomes. Of

a total of 179 primary outcomes included in the NDAs, 41 were omitted

from the papers. The papers included 138 outcomes that were also in the

NDAs (77%), plus 15 additional outcomes that favored the test drug, and

two other neutral or unknown additional outcomes. Thus, the papers

included more outcomes favoring the test drug than did the NDAs, report

the authors.

The research also found additional discrepancies between the FDA reviews

and the published papers. Of the 43 primary outcomes reported in the

NDAs that showed no statistically significant benefit for the test drug,

only half were included in the papers; for five of the reported primary

outcomes, the statistical significance differed between the NDA and the

paper and generally favored the test drug in the papers. Nine out of 99

conclusions differed between the NDAs and the papers; each time, the

published conclusion favored the test drug. The authors did not

investigate why the discrepancies existed, nor whether the changes were

prompted by the drug sponsor, authors, or journals.

Because of their findings of publication bias and selective reporting,

the authors conclude that " the information that is readily available in

the scientific literature to health care professionals is incomplete and

potentially biased. "

In a commentary on the research, An-Wen Chan from the Mayo Clinic in

Rochester (uninvolved in the study) says this new research makes an

important contribution to the growing body of evidence that the trial

literature is skewed towards reporting favorable results. " Biased

reporting of results from NDA trials is particularly concerning because

these journal articles are the only peer reviewed source of information

on recently approved drugs for health care providers, who will have had

limited clinical experience with these new treatments, " Dr Chan says.

" There are also substantial cost implications if the efficacy is

overestimated and the drugs overused. "

Before a new drug is approved for the treatment of a specific disease in

the United States and becomes available for doctors to prescribe, the

drug's sponsors must submit a " New Drug Application " (NDA) to the FDA,

which provides details of the drug's development from laboratory and

animal studies through to clinical trials. FDA reviewers use this

evidence to decide whether to approve a drug.

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Citation: Rising K, Bacchetti P, Bero L (2008) Reporting bias in drug

trials submitted to the Food and Drug Administration: A review of

publication and presentation. PLoS Med 5(10): e217.

doi:10.1371/journal.pmed.0050217

http://medicine.plosjournals.org/perlserv/?request=get-document & doi=10.1371/jour\

nal.pmed.0050217

CONTACT:

Bero

University of California, San Francisco

Clinical Pharmacy

3333 California Street, Suite 420

Box 0613

San Francisco, CA 94143

United States of America

+1

+1 (fax)

berol@...

PLEASE NOTE that there is a correction to the results section that we've

been made aware of since the full manuscript was accepted for

publication. Under the heading 'Discrepancies in Primary Outcome

Reporting' on page 5 of the PDF, the 155/179 outcomes that were also

found in the NDAs should read 138/179. On page 7, under the heading

'Discrepancies in Conclusions', " 35 of 36 " including unknowns should

read " 34 of 36. " A note of clarification will be made available on

publication and a formal correction is forthcoming.

Related PLoS Medicine Perspective

Citation: Chan A-W (2008) Bias, spin, and misreporting: Time for full

access to trial protocols and results. PLoS Med 5(11): e230.

doi:10.1371/journal.pmed.0050230

http://medicine.plosjournals.org/perlserv/?request=get-document & doi=10.1371/jour\

nal.pmed.0050230

CONTACT:

An-Wen Chan

Mayo Clinic

Rochester

United States of America

chan.anwen@...

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