Novel therapies, high-risk pediatric research, and the prospect of benefit: learning from the ethical disagreements.
Novel therapies, high-risk pediatric research, and the prospect of benefit: learning from the ethical disagreements.
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新疗法、高风险儿科研究以及获益前景：从伦理分歧中学习。
DOI：
10.1038/mt.2012.90
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Crystal,RonaldG
中科院分区：
文献类型：
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作者：
deMelo-Martín,Inmaculada;Sondhi,Dolan;Crystal,RonaldG
尽管美国食品和药物管理局 (FDA) 最近努力提高临床研究数据的质量和数量，1 目前给儿童开出的药物中，有三分之二尚未在儿科人群中进行安全性和有效性研究，也没有系统地收集和分析有关儿童药物有效性和安全性的信息。 2 根据一些研究，大多数为儿童开出的儿科药物都涉及所有药物类别的未经许可的药物或标签外处方。 3 有证据表明，儿童超说明书或未经许可使用药物会增加发生严重药物不良反应的风险。 4 获得儿科治疗的安全性和有效性信息需要系统的数据收集和临床研究试验。与人类一起进行研究需要平衡两个重要的、有时甚至是相互冲突的目标：确保获得科学研究可以提供的潜在好处，并保护人类受试者免受研究风险和伤害。这种紧张在儿科研究中尤为突出。儿童的认知、心理和社交不成熟限制了他们理解研究试验所涉及内容以及就参与做出正确决定的能力。由于儿童的脆弱性，联邦法规要求机构审查委员会 (IRB) 在批准儿科研究之前应用额外的保护措施；这些规定允许IRB仅批准那些为参与的个别儿童提供直接利益的前景或涉及最小风险或在最小风险之上略有增加的研究。涉及最小风险的研究类别和涉及最小风险的小幅增加的研究类别都受到了大量关注。 5-8 然而，除了一些例外情况 9、10，涉及具有直接受益前景的高风险儿科研究的类别受到的审查较少。此外，尽管对于 I 期试验是否可以提供“直接受益的前景”存在重大分歧，11-17 大部分讨论都是在涉及有能力的成年人而不是儿童的试验背景下进行的，其中大部分集中在肿瘤学试验上。我们在此重点关注具有直接受益前景的高风险儿科研究，并指出一些引起重大争论的方面。我们特别提请注意与此类研究的两个基本方面相关的分歧：(i) 确定涉及基因转移技术的 I 期试验中“直接受益前景”的构成因素；(ii) 评估这些试验中的风险是否因参与者儿童的预期受益而合理。尽管我们的大部分讨论也适用于其他类型的高风险
Despite recent efforts by the US Food and Drug Administration (FDA) to improve the quality and quantity of clinical research data, 1 two-thirds of drugs prescribed currently to children have not been studied for safety and efficacy in pediatric populations, and information on the efficacy and safety of drugs in children is not methodically collected and analyzed. 2 According to some studies, the majority of pediatric drugs prescribed for children involve unlicensed drugs or off-label prescribing across all medication categories. 3 There is evidence of a greater risk of a severe adverse drug reaction occurring in association with the off-label or unlicensed use of drugs in children. 4 Obtaining safety and efficacy information on pediatric therapies requires systematic data collection and clinical research trials. Conducting research with human beings requires the balancing of two important, and sometimes conflicting, aims: ensuring access to the potential benefits that scientific research can offer and protecting human subjects from research risks and harms. This tension is all the more salient in pediatric research. Children’s cognitive, psychological, and social immaturity limits their ability to understand what is involved in a research trial and to make sound decisions about participation. Because of children’s vulnerability, federal regulations mandate that institutional review boards (IRBs) apply additional protections before they can approve pediatric research; such regulations allow IRBs to approve only research that either offers the prospect of direct benefit to the individual children participating or involves minimal risk or a minor increase over minimal risk. Both the category of research that involves minimal risk and the one involving a minor increase over minimal risk have received a significant amount of attention. 5–8 With some exceptions, 9, 10 however, the category that concerns high-risk pediatric research with the prospect of direct benefit has been subjected to less scrutiny. Moreover, although there are significant disagreements over whether phase I trials can be said to offer a “prospect of direct benefit,” 11–17 much of that discussion has taken place in the context of trials involving competent adults rather than children, and much of it centers on oncology trials.We focus here on high-risk pediatric research with the prospect of direct benefit and point out some aspects that have raised significant debate. In particular, we call attention to disagreements related to two essential aspects of this type of research:(i) determining what constitutes a “prospect of direct benefit” in phase I trials that involve gene transfer technologies and (ii) assessing when in these trials the risk is justified by the anticipated benefit to the participant children. Although much of our discussion is applicable to other types of high-risk