Internal industry documents show that in numerous clinical trials of gabapentin for off-label uses, the reporting of results was biased to make the drug appear more effective than it actually is, according to a report in the Nov. 12 issue of the New England Journal of Medicine.
The documents were made available as part of litigation involving Pfizer Inc. and Parke-Davis, manufacturers of the anticonvulsant gabapentin. The lawsuits involved industry-funded trials of the drug’s effectiveness for off-label use in migraine, bipolar disorders, neuropathic pain, and nociceptive pain.
“We are concerned that the reporting practices observed in our analysis do not meet the ethical standards for clinical research or maintain the integrity of scientific knowledge,” said Dr. S. Swaroop Vedula of Johns Hopkins University, Baltimore, and associates.
“Fair and honest treatment of patients enrolled in clinical trials of any kind requires full, open, and unbiased reporting. Journal publication, a formalized platform for scientific discourse and dissemination of knowledge, should not be used as a marketing tool for off-label drug use,” they noted.
Dr. Vedula and colleagues compared trial outcomes as they were reported in published reports against the outcomes that had been specified in the original protocols of the 20 clinical trials.
The results of eight of these trials were never reported at all in publications.
In 8 of the 12 trials that were reported, the primary outcome measures in the original protocol were changed in some way by the time the report was published. Prespecified primary outcomes were eliminated, altered, or changed into secondary outcomes, or new primary outcomes were added, to cast the study findings in a more favorable light.
In some cases in which the findings for a given primary outcome measure proved to be not significant, they were not reported in full.
In addition, only one of the published trials included all the secondary outcomes that had been specified in the original study protocols. “Of the 180 secondary outcomes described in the protocols of the 12 published trials, 122 were never reported in the main publication,” the investigators said (N. Engl. J. Med. 2009;361:1963-71).
All of these alterations “led to a more favorable presentation in the medical literature of gabapentin’s efficacy for unapproved indications. Of particular concern is our finding that the prespecified primary outcome – the most important measure of efficacy – was often reported inaccurately,” they noted.
Such reporting biases “increase the likelihood that interventions will appear to be effective when they are not,” and can lead to the omission of negative findings in systematic reviews and evidence-based guidelines, the researchers added.
Dr. Vedula reported receiving fees from plaintiffs’ lawyers in litigation concerning Neurontin, the Pfizer brand of gabapentin. Funds from the litigation were donated to support academic scholarship in the area of reporting biases.
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据11月12日刊《新英格兰医学杂志》上的一项报告，行业内部文件显示，在多项针对加巴喷丁标签外应用的临床试验中，结果报道存在偏倚，往往使该药的疗效超过其实际效果。
作为对加巴喷丁(一种抗惊厥药物)制造商辉瑞公司和Parke-Davis进行诉讼的一部分，这些文件现已供读者参阅。这些诉讼涉及制造商资助的针对药物标签外应用(包括偏头痛、双相性情感障碍、神经性疼痛和伤害性疼痛)效果的一系列临床试验。
美国巴尔的摩约翰霍普金斯大学的S. Swaroop Vedula博士及其同事说：“我们担心本分析中所观察的报告操作无法满足临床研究的伦理标准，或者无法保持科学知识的完整性。”
研究者指出：“在任何临床试验中，对入选患者进行公正而诚实地治疗需要进行充分、开放和无偏倚地报道。杂志出版、知识传播和科学声明的正式平台不应被用作药物标签外应用的市场推广工具。”
Vedula博士及其同事对20项临床试验结果的杂志报道与其原试验方案中详述的结果进行了比较。
其中8项试验的结果从未在杂志上发表过。
在12项已发表试验中，8项试验在发表时，其原试验方案中的主要结果指标均被以某种方式加以改变。预先设定的主要结果被删除、改动或被更改为次要结果，或者增加了新的主要结果，以使研究结果更为完美。
某些情况下，若既定主要结果指标的结果被证实无意义，则其研究发现常不会被完整地报道。
另外，已发表的临床试验中仅1项包括了原研究方案中详述的所有次要结果。“12项已发表临床试验的原研究方案中描述了180项次要结果，其中122项在主要发表论文中从未被报道，”研究者说(N. Engl. J. Med. 2009;361:1963-71)。
研究者指出，所有这些改动“都为有关加巴喷丁治疗其未获准适应证疗效的医学文献带来更有利的结果。值得特别关注的是，我们发现预先设定的主要结果(最重要的疗效评价指标)常不能被准确报道”。
研究者补充道，这些报告偏倚“增加了原本无效治疗变为有效治疗的可能性”，并可导致阴性结果无法被系统评价和循证指南采纳。
Vedula博士承认接受了关于Neurontin(辉瑞公司上市的加巴喷丁)诉讼原告律师给予的资助。来自诉讼的基金被用于资助报道偏倚研究领域的学术奖学金。
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