We have previously described how a series of trials sponsored by Pfizer of its antifungal drug, fluconazole, in cancer patients with neutropenia handicapped the control drug, amphotericin B, by flaws in design and analysis. We describe similar problems in two pivotal trials of Pfizer's new antifungal agent, voriconazole, published in a prestigious journal. In a non-inferiority trial, voriconazole was significantly inferior to liposomal amphothericin B, but the authors concluded that voriconazole was a suitable alternative. The second trial used amphothericin B deoxycholate as comparator, but handicapped the drug by not requiring pre-medication to reduce infusion-related toxicity or substitution with electrolytes and fluid to reduce nephrotoxicity, although the planned duration of treatment was 84 days. Voriconazole was given for 77 days on average, but the comparator for only 10 days, which precludes a meaningful comparison. In a random sample of 50 references to these trials, we found that the unwarranted conclusions were mostly uncritically propagated. It was particularly surprising that relevant criticism raised by the FDA related to the first trial was only quoted once, and that none of the articles noted the obvious flaws in the design of the second trial. We suggest that editors ensure that the abstract reflects fairly on the remainder of the paper, and that journals do not impose any time limit for accepting letters that point out serious weaknesses in a study that have not been noted before.

译文

我们之前已经描述了由辉瑞公司赞助的抗真菌药物氟康唑在患有中性粒细胞减少症的癌症患者中的一系列试验如何通过设计和分析中的缺陷来限制对照药物两性霉素b。我们在辉瑞新型抗真菌剂伏立康唑的两项关键试验中描述了类似的问题,该试验发表在著名杂志上。在一项非劣效性试验中,伏立康唑明显低于两性霉素b脂质体,但作者得出结论,伏立康唑是合适的替代品。第二项试验使用了两性霉素b脱氧胆酸盐作为比较剂,但由于不需要预先用药以减少与输注相关的毒性或用电解质和液体替代以减少肾毒性,从而限制了药物的使用,尽管计划的治疗时间为84天。伏立康唑平均给药77天,但比较药仅给药10天,因此无法进行有意义的比较。在对这些试验的50个参考文献的随机样本中,我们发现不必要的结论大多是不加批判地传播的。尤其令人惊讶的是,FDA提出的与第一项试验有关的相关批评只被引用了一次,而且没有一篇文章注意到第二项试验设计中的明显缺陷。我们建议编辑确保摘要公平地反映在论文的其余部分上,并且期刊不要对接受指出研究中严重弱点的信件施加任何时间限制,这些信件指出了以前没有注意到的问题。

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