Abstract：
BACKGROUND: Tivozanib (Fotivda) is an anti-angiogenic tyrosine kinase inhibitor that was denied access to the US market by the Food and Drug Administration (FDA). In contrast, it was granted approval by the European Medicines Agency (EMA) for the treatment of Renal Cell Carcinoma in adults. Given the conflicting decisions from these regulatory agencies, the objectives of the following study are (i) to critically review the evidence supporting the approval of tivozanib; (ii) to analyse the dissemination of this evidence in the literature by way of a citation analysis.
METHODS: Pivotal trials were searched by two independent reviewers using Medline, Cochrane Library, ClinicalTrials.gov and the European Public Assessment Report. The risk of bias for each trial was then inductively assessed. Articles citing any of these trials were identified using Web of Sciences. Finally, the quality of the citations was evaluated by two independent reviewers according to standard data extraction methods.
RESULTS: The search for primary evidence identified two pivotal studies: TIVO-1 upon which the FDA and the EMA decisions were based, and TIVO-3 which was conducted after the agencies\' decisions had been issued. The TIVO-1 trial presented several limitations that compromised causal inference, in relation to (i) design (absence of blinding, inappropriate comparator, and one-way crossover), (ii) poor internal consistency in the results for the primary endpoint, (iii) a discrepancy between a benefit observed for progression-free survival (HR: 0.80, 95% CI [0.64-0.99]) and the absence of difference for overall survival (HR: 1.25, 95% CI [0.95 - 1.62]). Our citation search protocol identified 229 articles that cited TIVO-1 in the 7 years following its publication, among which 151 (65.9%) citing articles discussing efficacy. Presence of spin was identified in 64 (42.4%) of these 151 citing articles, and 39 (25.8%) additional articles citing results without providing enough elements to interpret the TIVO-1 results.
CONCLUSIONS: EMA\'s approval was based on a single pivotal trial presenting critical limitations, rendering the results from the trial potentially inconclusive. The broad dissemination of TIVO-1 results in the scientific literature may have been affected by spin or results were presented in an inadequate critical manner.
METHODS: Pivotal trials were searched by two independent reviewers using Medline, Cochrane Library, ClinicalTrials.gov and the European Public Assessment Report. The risk of bias for each trial was then inductively assessed. Articles citing any of these trials were identified using Web of Sciences. Finally, the quality of the citations was evaluated by two independent reviewers according to standard data extraction methods.
RESULTS: The search for primary evidence identified two pivotal studies: TIVO-1 upon which the FDA and the EMA decisions were based, and TIVO-3 which was conducted after the agencies\' decisions had been issued. The TIVO-1 trial presented several limitations that compromised causal inference, in relation to (i) design (absence of blinding, inappropriate comparator, and one-way crossover), (ii) poor internal consistency in the results for the primary endpoint, (iii) a discrepancy between a benefit observed for progression-free survival (HR: 0.80, 95% CI [0.64-0.99]) and the absence of difference for overall survival (HR: 1.25, 95% CI [0.95 - 1.62]). Our citation search protocol identified 229 articles that cited TIVO-1 in the 7 years following its publication, among which 151 (65.9%) citing articles discussing efficacy. Presence of spin was identified in 64 (42.4%) of these 151 citing articles, and 39 (25.8%) additional articles citing results without providing enough elements to interpret the TIVO-1 results.
CONCLUSIONS: EMA\'s approval was based on a single pivotal trial presenting critical limitations, rendering the results from the trial potentially inconclusive. The broad dissemination of TIVO-1 results in the scientific literature may have been affected by spin or results were presented in an inadequate critical manner.
摘要：
背景：Tivozanib（Fotivda）是一种抗血管生成酪氨酸激酶抑制剂，被食品和药物管理局（FDA）拒绝进入美国市场。相比之下,它被欧洲药品管理局(EMA)批准用于治疗成人肾细胞癌.鉴于这些监管机构的决定相互矛盾，以下研究的目的是(i)批判性地审查支持tivozanib批准的证据;(ii)通过引文分析来分析这些证据在文献中的传播.
方法：Pivotal试验由两名独立的评论者使用Medline进行搜索，科克伦图书馆,ClinicalTrials.gov和欧洲公共评估报告。然后对每个试验的偏倚风险进行归纳评估。引用这些试验的文章是使用WebofSciences鉴定的。最后,引文的质量由两名独立评审员根据标准数据提取方法进行评估.
结果：对主要证据的搜索确定了两项关键研究：FDA和EMA决定所基于的TIVO-1，TIVO-3是在机构的决定发布后进行的。TIVO-1试验提出了几个限制，损害了因果推断，关于(I)设计(没有盲化，不合适的比较器，和单向交叉)，（ii）主要终点结果的内部一致性差，(iii)观察到的无进展生存期的获益(HR:0.80,95%CI[0.64-0.99])与总生存期无差异(HR:1.25,95%CI[0.95-1.62])之间存在差异。我们的引文搜索协议确定了在TIVO-1发表后的7年内引用了229篇文章，其中151篇(65.9%)引用讨论疗效的文章。在这151篇引用的文章中，有64篇(42.4%)发现了自旋的存在，39篇(25.8%)额外文章引用了结果，但没有提供足够的元素来解释TIVO-1结果。
结论：EMA的批准是基于一项具有关键局限性的关键试验，使试验结果可能不确定。TIVO-1结果在科学文献中的广泛传播可能受到自旋的影响，或者结果以不充分的批评方式呈现。
方法：Pivotal试验由两名独立的评论者使用Medline进行搜索，科克伦图书馆,ClinicalTrials.gov和欧洲公共评估报告。然后对每个试验的偏倚风险进行归纳评估。引用这些试验的文章是使用WebofSciences鉴定的。最后,引文的质量由两名独立评审员根据标准数据提取方法进行评估.
结果：对主要证据的搜索确定了两项关键研究：FDA和EMA决定所基于的TIVO-1，TIVO-3是在机构的决定发布后进行的。TIVO-1试验提出了几个限制，损害了因果推断，关于(I)设计(没有盲化，不合适的比较器，和单向交叉)，（ii）主要终点结果的内部一致性差，(iii)观察到的无进展生存期的获益(HR:0.80,95%CI[0.64-0.99])与总生存期无差异(HR:1.25,95%CI[0.95-1.62])之间存在差异。我们的引文搜索协议确定了在TIVO-1发表后的7年内引用了229篇文章，其中151篇(65.9%)引用讨论疗效的文章。在这151篇引用的文章中，有64篇(42.4%)发现了自旋的存在，39篇(25.8%)额外文章引用了结果，但没有提供足够的元素来解释TIVO-1结果。
结论：EMA的批准是基于一项具有关键局限性的关键试验，使试验结果可能不确定。TIVO-1结果在科学文献中的广泛传播可能受到自旋的影响，或者结果以不充分的批评方式呈现。
