van den Bogert Cornelis A, Souverein Patrick C, Brekelmans Cecile T M, Janssen Susan W J, Koëter Gerard H, Leufkens Hubert G M, Bouter Lex M
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, TB Utrecht, The Netherlands.
Central Committee on Research involving Human Subjects (CCMO), BH The Hague, the Netherlands.
PLoS One. 2016 Dec 14;11(12):e0167709. doi: 10.1371/journal.pone.0167709. eCollection 2016.
The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands.All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non-publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials.
本研究的目的是调查荷兰临床药物试验未发表的情况及其决定因素。对2007年荷兰28个机构审查委员会（IRB）审查的所有临床药物试验从批准到发表进行随访。候选决定因素包括申办者、阶段、申请者、中心、预期治疗效果、试验类型、药物批准状态、药物类型、参与者类别、肿瘤学或其他疾病领域、前瞻性注册和提前终止。主要结果是作为同行评审文章发表。已发表试验的百分比、粗比值比（OR）和调整后比值比以及95%置信区间（CI）用于量化决定因素与发表之间的关联。2007年，荷兰的IRB审查了622项临床药物试验。随访结束时，其中19项被IRB拒绝，另有19项从未开始纳入，10项仍在进行。在分析中剩余的574项试验中，334项（58%）作为同行评审文章发表。多变量逻辑回归模型确定了以下与发表有稳健、统计学显著关联的决定因素：与1期试验（35%发表）相比，2期试验（60%发表；调整后OR 2.6，95%CI 1.1 - 5.9）、3期试验（73%发表；调整后OR 4.1，95%CI 1.7 - 10.0）以及不属于1 - 4期的试验（60%发表；调整后OR 3.2，95%CI 1.5至6.5）；与以合同研究组织（CRO）为申请者的试验（50%发表；调整后OR 1.7；95%CI 1.1 - 2.8）相比，以公司或研究者为申请者的试验（63%发表）；与单中心试验（45%发表）相比，也在其他欧盟国家进行的多中心试验（68%发表；调整后OR 2.2，95%CI 1.1 - 4.4）或也在欧盟以外进行的多中心试验（72%发表；调整后OR 2.0，95%CI 1.0 - 4.0）。与前瞻性注册的试验（75%发表；调整后OR 0.5，95%CI 0.3 - 0.8）相比，未进行前瞻性注册的试验（48%发表）发表的可能性较低，与按计划完成的试验（64%发表；调整后OR 0.2，95%CI 0.1 - 0.3）相比，提前终止的试验（33%发表）也是如此。与之前的起始队列相比，临床试验的未发表率似乎有所改善，但仍远未达到最佳水平，特别是在1期、单中心、未前瞻性注册和提前终止的试验中。
