Zou Constance X, Becker Jessica E, Phillips Adam T, Garritano James M, Krumholz Harlan M, Miller Jennifer E, Ross Joseph S
Yale School of Medicine, New Haven, CT, USA.
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Trials. 2018 Oct 23;19(1):581. doi: 10.1186/s13063-018-2957-0.
Mandatory trial registration, and later results reporting, were proposed to mitigate selective clinical trial publication and outcome reporting. The Food and Drug Administration (FDA) Amendments Act (FDAAA) was enacted by Congress on September 27, 2007, requiring the registration of all non-phase I clinical trials involving FDA-regulated medical interventions and results reporting for approved drugs. The association between FDAAA enactment and the registration, results reporting, and publication bias of neuropsychiatric trials has not been studied.
We conducted a retrospective cohort study of all efficacy trials supporting FDA new drug approvals between 2005 to 2014 for neuropsychiatric indications. Trials were categorized as pre- or post-FDAAA based on initiation and/or completion dates. The main outcomes were the proportions of trials registered and reporting results in ClinicalTrials.gov, and the degree of publication bias, estimated using the relative risks pre- and post-FDAAA of both the publication of positive vs non-positive trials, as well as of publication of positive vs non-positive trials without misleading interpretations. Registration and results reporting proportions were compared pre- and post-FDAAA using the two-tailed Fisher exact test, and the degrees of publication bias were compared by calculating the ratio of relative risks (RRR) for each period.
The FDA approved 37 new drugs for neuropsychiatric indications between 2005 and 2014 on the basis of 142 efficacy trials, of which 101 were pre-FDAAA and 41 post-FDAAA. Post-FDAAA trials were significantly more likely to be registered (100% vs 64%; p < 0.001) and report results (100% vs 10%; p < 0.001) than pre-FDAAA trials. Pre-FDAAA, positive trials were more likely to be published (relative risk [RR] = 1.52; 95% confidence interval [CI] = 1.17-1.99; p = 0.002) and published without misleading interpretations (RR = 2.47; CI = 1.57-3.73; p < 0.001) than those with non-positive results. In contrast, post-FDAAA positive trials were equally likely to have been published (RR = 1; CI = 1-1, p = NA) and published without misleading interpretations (RR = 1.20; CI = 0.84-1.72; p = 0.30). The likelihood of publication bias pre-FDAAA vs post-FDAAA was greater for positive vs non-positive trials (RRR = 1.52; CI = 1.16-1.99; p = 0.002) and for publication without misleading interpretations (RRR = 2.06, CI = 1.17-3.61, p = 0.01).
The enactment of FDAAA was followed by significantly higher proportions of trials that were registered and reporting results on ClinicalTrials.gov and significantly lower degrees of publication bias among trials supporting recent FDA approval of drugs for neuropsychiatric indications.
为减少临床试验结果的选择性发表和报告，有人提议实行强制性试验注册及随后的结果报告。美国国会于2007年9月27日颁布了《食品药品监督管理局修正案法案》（FDAAA），要求对所有涉及FDA监管的医学干预措施的非I期临床试验进行注册，并对获批药物进行结果报告。尚未对FDAAA的颁布与神经精神科试验的注册、结果报告及发表偏倚之间的关联进行研究。
我们对2005年至2014年期间支持FDA批准用于神经精神科适应症新药的所有疗效试验进行了一项回顾性队列研究。根据试验开始和/或完成日期，将试验分为FDAAA之前或之后的试验。主要结局是在ClinicalTrials.gov上注册并报告结果的试验比例，以及发表偏倚程度，通过比较FDAAA之前和之后阳性试验与非阳性试验发表的相对风险，以及无误导性解释的阳性试验与非阳性试验发表的相对风险来估计。使用双侧Fisher精确检验比较FDAAA之前和之后的注册及结果报告比例，并通过计算各时期相对风险比（RRR）来比较发表偏倚程度。
2005年至2014年期间，FDA基于142项疗效试验批准了37种用于神经精神科适应症的新药，其中101项试验在FDAAA之前，41项试验在FDAAA之后。与FDAAA之前的试验相比，FDAAA之后的试验更有可能进行注册（100%对64%；p<0.001）和报告结果（100%对10%；p<0.001）。在FDAAA之前，阳性试验比非阳性试验更有可能发表（相对风险[RR]=1.52；95%置信区间[CI]=1.17-1.99；p=0.002）且发表时无误导性解释（RR=2.47；CI=1.57-3.73；p<0.001）。相比之下，FDAAA之后的阳性试验发表的可能性相同（RR=1；CI=1-1，p=无意义）且发表时无误导性解释（RR=1.20；CI=0.84-1.72；p=0.30）。对于阳性试验与非阳性试验，以及无误导性解释的发表情况，FDAAA之前与之后的发表偏倚可能性在阳性试验与非阳性试验之间更大（RRR=1.52；CI=1.16-1.99；p=0.002），在无误导性解释的发表情况中（RRR=2.06，CI=1.17-3.61，p=0.01）。
FDAAA颁布后，在ClinicalTrials.gov上注册并报告结果的试验比例显著更高，且在支持FDA近期批准用于神经精神科适应症药物的试验中，发表偏倚程度显著更低。
