Lee Kirby, Bacchetti Peter, Sim Ida
Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California, USA.
PLoS Med. 2008 Sep 23;5(9):e191. doi: 10.1371/journal.pmed.0050191.
The United States (US) Food and Drug Administration (FDA) approves new drugs based on sponsor-submitted clinical trials. The publication status of these trials in the medical literature and factors associated with publication have not been evaluated. We sought to determine the proportion of trials submitted to the FDA in support of newly approved drugs that are published in biomedical journals that a typical clinician, consumer, or policy maker living in the US would reasonably search.
We conducted a cohort study of trials supporting new drugs approved between 1998 and 2000, as described in FDA medical and statistical review documents and the FDA approved drug label. We determined publication status and time from approval to full publication in the medical literature at 2 and 5 y by searching PubMed and other databases through 01 August 2006. We then evaluated trial characteristics associated with publication. We identified 909 trials supporting 90 approved drugs in the FDA reviews, of which 43% (394/909) were published. Among the subset of trials described in the FDA-approved drug label and classified as "pivotal trials" for our analysis, 76% (257/340) were published. In multivariable logistic regression for all trials 5 y postapproval, likelihood of publication correlated with statistically significant results (odds ratio [OR] 3.03, 95% confidence interval [CI] 1.78-5.17); larger sample sizes (OR 1.33 per 2-fold increase in sample size, 95% CI 1.17-1.52); and pivotal status (OR 5.31, 95% CI 3.30-8.55). In multivariable logistic regression for only the pivotal trials 5 y postapproval, likelihood of publication correlated with statistically significant results (OR 2.96, 95% CI 1.24-7.06) and larger sample sizes (OR 1.47 per 2-fold increase in sample size, 95% CI 1.15-1.88). Statistically significant results and larger sample sizes were also predictive of publication at 2 y postapproval and in multivariable Cox proportional models for all trials and the subset of pivotal trials.
Over half of all supporting trials for FDA-approved drugs remained unpublished >/= 5 y after approval. Pivotal trials and trials with statistically significant results and larger sample sizes are more likely to be published. Selective reporting of trial results exists for commonly marketed drugs. Our data provide a baseline for evaluating publication bias as the new FDA Amendments Act comes into force mandating basic results reporting of clinical trials.
美国食品药品监督管理局（FDA）基于申办者提交的临床试验批准新药。这些试验在医学文献中的发表状况以及与发表相关的因素尚未得到评估。我们试图确定提交给FDA以支持新批准药物的试验中，在美国生活的普通临床医生、消费者或政策制定者可能合理检索的生物医学期刊上发表的试验比例。
我们对1998年至2000年间支持FDA医学和统计审评文件以及FDA批准的药品标签中所述新药的试验进行了队列研究。通过检索PubMed和其他数据库直至2006年8月1日，我们确定了在2年和5年后医学文献中从批准到完全发表的发表状况和时间。然后我们评估了与发表相关的试验特征。我们在FDA审评中识别出909项支持90种批准药物的试验，其中43%（394/909）已发表。在FDA批准的药品标签中描述并在我们的分析中归类为“关键试验”的试验子集中，76%（257/340）已发表。在批准后5年对所有试验的多变量逻辑回归分析中，发表可能性与具有统计学显著意义的结果相关（比值比[OR]3.03，95%置信区间[CI]1.78 - 5.17）；样本量越大（样本量每增加2倍，OR为1.33，95%CI 1.17 - 1.52）；以及关键状态（OR 5.31，95%CI 3.30 - 8.55）。在批准后5年仅对关键试验的多变量逻辑回归分析中，发表可能性与具有统计学显著意义的数据相关（OR 2.96，95%CI 1.24 - 7.06）以及样本量越大（样本量每增加2倍，OR为1.47，95%CI 1.15 - 1.88）。具有统计学显著意义的结果和更大的样本量在批准后2年以及对所有试验和关键试验子集的多变量Cox比例模型中也可预测发表情况。
FDA批准药物的所有支持性试验中有超过一半在批准后≥5年仍未发表。关键试验以及具有统计学显著意义的结果和更大样本量的试验更有可能发表。对于常用上市药物存在试验结果的选择性报告情况。随着新的FDA修正案法案生效，强制要求报告临床试验的基本结果，我们的数据为评估发表偏倚提供了一个基线。
