Navigating the Regulatory Landscape to Develop Pediatric Oncology Drugs: Expert Opinion Recommendations.
Navigating the Regulatory Landscape to Develop Pediatric Oncology Drugs: Expert Opinion Recommendations.
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DOI：
10.1007/s40272-021-00455-1
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Jacobs IA
中科院分区：
文献类型：
--
作者：
Barry E;Walsh JA;Weinrich SL;Beaupre D;Blasi E;Arenson DR;Jacobs IA
美国（US）和欧盟（EU）已经颁布了监管改革，以鼓励开发新的儿科癌症治疗方法。在这里，我们回顾了一些阻碍儿童癌症治疗发展的因素，并提供了美国和欧盟为满足这一临床需求而实施的法规的比较。然后，我们为肿瘤药物开发途径的每个阶段提供一些建议，以帮助研究人员在遵守法规的同时最大限度地提高药物开发成功的机会。一项重要建议是在药物开发过程的早期让监管机构、儿科肿瘤学家、学术研究人员、患者倡导团体和儿科专家组等关键利益攸关方参与。在药物靶点选择过程中，鼓励申办者咨询美国食品和药物管理局（FDA）、欧洲药品管理局（EMA）和FDA靶点清单，以及已经建立的相关美国和欧洲联盟，以确定肿瘤药物靶点的特征和优先级。申办者还需要仔细考虑临床前试验的资源要求，包括确保适当访问最相关的数据库、临床样本和临床前模型（细胞系和动物模型）。在临床开发期间，申办者可以通过开发儿科配方、选择合适的PD终点、采用稀疏的PK抽样或在适当的情况下对药物暴露进行建模/模拟，来考虑针对儿科人群的药效学(PD)/药代动力学（PK）考虑。其他临床考虑因素包括临床试验的具体设计、在成人试验中纳入儿童的可能性以及合作组试验的价值。在过去的几十年里，在开发成人癌症的新疗法方面取得了很大的进展。然而，儿童癌症新疗法的发展却要慢得多。为了鼓励制药公司（赞助商）开发有效的儿童癌症治疗方法，美国和欧洲当局制定了药物开发的新规则。在这些新规定下，开发针对成人特定癌症的药物的赞助商必须考虑该药物的靶点是否也会导致儿童癌症。如果是这种情况，赞助商必须在患有由相同药物靶点引起的癌症的儿童中进行药物临床研究。在这篇文章中，我们描述了儿童癌症药物开发缓慢的一些原因，以及美国和欧洲为解决这一问题而制定的规则。我们分享了一些建议，以帮助赞助商在满足新规定的同时，最大限度地提高开发儿童有效药物的机会。具体来说，赞助者需要了解在成人和儿童身上研究药物的差异，以及这些差异如何影响药物测试的方式。我们对发展过程的每个阶段提出了几项建议，从甚至在人体研究开始之前就需要什么开始。最后，我们强调了在药物开发过程中，从临床前阶段（在细胞和动物中测试药物）到成人和儿童癌症患者的临床测试，赞助商需要考虑的一些问题。
Regulatory changes have been enacted in the United States (US) and European Union (EU) to encourage the development of new treatments for pediatric cancer. Here, we review some of the factors that have hampered the development of pediatric cancer treatments and provide a comparison of the US and EU regulations implemented to address this clinical need. We then provide some recommendations for each stage of the oncology drug development pathway to help researchers maximize their chance of successful drug development while complying with regulations. A key recommendation is the engagement of key stakeholders such as regulatory authorities, pediatric oncologists, academic researchers, patient advocacy groups, and a Pediatric Expert Group early in the drug development process. During drug target selection, sponsors are encouraged to consult the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the FDA target list, in addition to relevant US and European consortia that have been established to characterize and prioritize oncology drug targets. Sponsors also need to carefully consider the resourcing requirements for preclinical testing, which include ensuring appropriate access to the most relevant databases, clinical samples, and preclinical models (cell lines and animal models). During clinical development, sponsors can account for the pharmacodynamic (PD)/pharmacokinetic (PK) considerations specific to a pediatric population by developing pediatric formulations, selecting suitable PD endpoints, and employing sparse PK sampling or modeling/simulation of drug exposures where appropriate. Additional clinical considerations include the specific design of the clinical trial, the potential inclusion of children in adult trials, and the value of cooperative group trials. In the last few decades, great progress has been made in developing new treatments for adult cancers. However, development of new treatments for childhood cancers has been much slower. To encourage drug companies (sponsors) to develop effective treatments for childhood cancer, authorities in the United States (US) and Europe have made new rules for drug development. Under these new rules, sponsors developing drugs for specific cancers in adults have to consider whether the target of that drug also causes cancers in children. If this is the case, sponsors have to carry out clinical studies of their drug in children who have cancer that is caused by the same drug target. In this article, we describe some reasons for why drug development for childhood cancers has been slow and the rules created to address this problem in the US and Europe. We share some recommendations to help sponsors maximize their chances of developing an effective drug in children while satisfying the new rules. Specifically, sponsors need to be aware of the differences between studying drugs in adults versus children and how these influence the way the drug is tested. We make several recommendations for each stage of the development process, beginning with what is needed even before human studies begin. Finally, we highlight some issues that sponsors need to think about during drug development, from the preclinical stage (testing drugs in cells and animals) through to clinical testing in adults and pediatric patients with cancer.
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