Reflections on using non-inferiority randomised placebo controlled trials in assessing cardiovascular safety of new agents for treatment of type 2 diabetes.

Evidence-Based Medicine Pub Date : 2017-04-01 Epub Date: 2017-03-08 DOI:10.1136/ebmed-2017-110685
Denise Campbell-Scherer
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引用次数: 1

Abstract

The 2008 Food and Drug Administration (FDA) guidance to industry requires experimental evidence that new agents to treat type 2 diabetes do not have an unacceptable increase in cardiovascular risk. They specify this unacceptable increase to be a risk ratio of 1.3 in non-inferiority trials which may use placebo control. Clinically, this means that if a new agent achieves this threshold of not being 30% worse than placebo it is declared 'non-inferior'. This guidance was in response to safety concerns raised about medications approved on their basis of reducing glycated haemoglobin alone. There was concern that this FDA guidance would stifle new drugs coming to market. On the contrary, there have been a number of exciting new classes of agents approved with improved confidence that they reduce glycated haemoglobin, and that they also do not excessively increase cardiovascular risk. Cardiovascular safety trials have been conducted for a number of novel medications using a non-inferiority approach. However, clinicians need to recognise that the results of non-inferiority trials are not as credible as superiority trials. It is important to closely review the trials before accepting claims of 'non-inferiority' or 'cardiac neutrality' especially when these studies are often compared with placebo, and may be accepting estimates of effect which span potentially clinically meaningful harm. There are compelling reasons to further investigate agents showing promise in non-inferiority trials with superiority trials, which include prespecified subgroups, and with sufficient power and duration to provide robust estimates of harms and benefits to inform clinical decision-making.

使用非劣效性随机安慰剂对照试验评估治疗2型糖尿病新药心血管安全性的思考
2008年美国食品和药物管理局(FDA)的工业指南要求实验证据证明治疗2型糖尿病的新药不会增加心血管风险。他们指出,在可能使用安慰剂对照的非劣效性试验中,这种不可接受的增加风险比为1.3。在临床上,这意味着如果一种新药达到不比安慰剂差30%的阈值,它就被宣布为“非劣效”。本指南是针对仅以降低糖化血红蛋白为基础而被批准的药物所引起的安全性担忧作出的回应。有人担心FDA的指导方针会阻碍新药进入市场。相反,已经有许多令人兴奋的新型药物被批准,它们可以降低糖化血红蛋白,也不会过度增加心血管风险。使用非劣效性方法对许多新型药物进行了心血管安全性试验。然而,临床医生需要认识到,非劣效性试验的结果不像优效性试验那样可信。在接受“非劣效性”或“心脏中性”的声明之前,仔细审查试验是很重要的,特别是当这些研究经常与安慰剂进行比较时,并且可能接受的效果估计跨越了潜在的临床有意义的伤害。有令人信服的理由进一步研究在非劣效性试验中显示出希望的药物与优势试验,包括预先指定的亚组,有足够的功效和持续时间来提供可靠的危害和益处估计,以告知临床决策。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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