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

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.

How Silencing of Dissent in Science Impacts Woman. The Gardasil® Story

“…Unfortunately, even when opposing researchers point out glaring faults such as if population selection differed or alternate statistical methods were used even from the same dataset, that wildly different results could be the result they are routinely dismissed [27]. Accusations by vaccine researchers and vaccine manufacturers of data manipulation and selective data shopping by vaccine opposition groups are somewhat ironic, when data manipulation in an effort to obtain favorable outcomes is a technique that the pharmaceutical industry has been shown to use in obtaining FDA approval of various medications [28]. It should come as no surprise that distrust of both government [29] as well as pharmaceutical manufacturers is extremely high [30].…”

Reporting of Conflicts of Interest in Meta-Analyses of Trials of Pharmacological Treatments

“…4,5 Results from positive trials and from favorable analyses are more likely to be published than results unfavorable to sponsors. [6][7][8] Compared with nonindustry-funded trials, pharmaceutical industry-funded studies more often yield results or conclusions in support of the sponsor's drug, [9][10][11][12][13][14][15][16] and authors' relationships with drug manufacturers have been linked to favorable assessments of drug efficacy and safety. [17][18][19][20] As a result, increased emphasis has been placed on the transparent disclosure of COI.…”

Disclosure of Clinical Trial Results When Product Development Is Abandoned

“…In recent years, there has been increasing recognition that publication bias-the selective reporting of only clinical trials with positive results-may degrade the base of publicly available information on approved drugs (9,10). Pharmaceutical company sponsors o en do not submit the results of negative drug trials for publication (11)(12)(13) and may downplay adverse events (14,15).…”