Research Article: Reporting Bias in Drug Trials Submitted to the Food and Drug Administration: Review of Publication and Presentation

Date Published: November 25, 2008

Publisher: Public Library of Science

Author(s): Kristin Rising, Peter Bacchetti, Lisa Bero, John Ioannidis

Abstract: BackgroundPrevious studies of drug trials submitted to regulatory authorities have documented
selective reporting of both entire trials and favorable results. The objective of this
study is to determine the publication rate of efficacy trials submitted to the Food and
Drug Administration (FDA) in approved New Drug Applications (NDAs) and to compare the
trial characteristics as reported by the FDA with those reported in publications.Methods and FindingsThis is an observational study of all efficacy trials found in approved NDAs for New
Molecular Entities (NMEs) from 2001 to 2002 inclusive and all published clinical trials
corresponding to the trials within the NDAs. For each trial included in the NDA, we
assessed its publication status, primary outcome(s) reported and their statistical
significance, and conclusions. Seventy-eight percent (128/164) of efficacy trials
contained in FDA reviews of NDAs were published. In a multivariate model, trials with
favorable primary outcomes (OR = 4.7, 95% confidence interval
[CI] 1.33–17.1, p = 0.018) and
active controls (OR = 3.4, 95% CI 1.02–11.2,
p = 0.047) were more likely to be published. Forty-one
primary outcomes from the NDAs were omitted from the papers. Papers included 155
outcomes that were in the NDAs, 15 additional outcomes that favored the test drug, and
two other neutral or unknown additional outcomes. Excluding outcomes with unknown
significance, there were 43 outcomes in the NDAs that did not favor the NDA drug. Of
these, 20 (47%) were not included in the papers. The statistical significance
of five of the remaining 23 outcomes (22%) changed between the NDA and the
paper, with four changing to favor the test drug in the paper (p
= 0.38). Excluding unknowns, 99 conclusions were provided in both NDAs and
papers, nine conclusions (9%) changed from the FDA review of the NDA to the
paper, and all nine did so to favor the test drug (100%, 95% CI
72%–100%, p = 0.0039).ConclusionsMany trials were still not published 5 y after FDA approval. Discrepancies between the
trial information reviewed by the FDA and information found in published trials tended
to lead to more favorable presentations of the NDA drugs in the publications. Thus, the
information that is readily available in the scientific literature to health care
professionals is incomplete and potentially biased.

Partial Text: Evidence-based clinical medicine relies on the publication of high-quality data to
determine standards of patient care. Publication bias occurs when some types of results
(e.g., those that are statistically significant) are reported more frequently or more
quickly than others [1–4].
Publication bias favors the dissemination of information about clinical interventions
showing statistically significant benefit. Publication bias, therefore, may lead to
preferential prescribing of newer and more expensive treatment choices and may underestimate
the harms of drugs that have been in use for only a limited time, and clinical decisions may
be based on erroneous information [5]. The objective of this study is to assess the extent and nature of
publication bias among newly approved drugs by determining the publication rate of efficacy
trials submitted to the United States Food and Drug Administration (FDA) in approved New
Drug Applications (NDAs) for NMEs (New Molecular Entities) and comparing the trial
characteristics as reported by the FDA with those reported in publications.

We conducted a study of all efficacy trials found in approved NDAs for new molecular
entities (NMEs) from 2001 to 2002 inclusive and all published clinical trials corresponding
to the trials within the NDAs. NMEs are a subset of NDAs that represent novel active
ingredients rather than, for example, “me-too” drugs, which are very
similar to existing drugs, or combinations of previously approved drugs. Thus, NMEs are
clinically important drugs about which new information is needed.

Publication bias can occur in several ways, including not publishing data at all,
selectively reporting data, or framing data. We found evidence of both lack of publication
and selective reporting of data. Seventy-eight percent of the trials submitted to the FDA
were published, and trials with active controls or statistically significant outcomes
favoring the test drug were more likely to be published. In a multivariate model, trials
with favorable primary outcomes (OR = 4.7, 95% CI 1.33 to 17.1, p
= 0.018) and active controls (OR = 3.4, 95% CI 1.02 to
11.2, p = 0.047) were more likely to be published. In addition, reporting
sometimes differed between trials as they were described in FDA reviews and their
corresponding publications. These changes included the addition or deletion of outcomes,
changes in statistical significance of reported outcomes, and changes in overall trial
conclusions. Papers included 155 outcomes that were also in the NDAs, 15 additional outcomes
that favored the test drug, and two other neutral or unknown additional outcomes. Excluding
outcomes with unknown significance, there were 43 outcomes in the NDAs that did not favor
the NDA drug. Of these, 20 (47%) were not included in the papers. The statistical
significance of five of the remaining 23 outcomes (22%) changed between the NDA
and the paper, with four changing to favor the test drug in the paper (p
= 0.38). Excluding unknowns, 99 conclusions were provided in both NDAs and
papers, nine conclusions (9%) changed from the FDA review of the NDA to the
paper, and all nine did so to favor the test drug (100%, 95% CI
72% to 100%, p = 0.0039). All of these
changes in reporting led to more favorable presentations of the NDA drug in the published
articles.

Source:

http://doi.org/10.1371/journal.pmed.0050217

 

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