Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
Innovative and Clinical Research Promotion Center, Graduate School of Medicine, Gifu University, Gifu, Japan.
Clin Ther. 2020 Feb;42(2):305-320.e0. doi: 10.1016/j.clinthera.2020.01.002. Epub 2020 Jan 31.
The present study aimed to examine the differences between enrolled subject populations and use of combination therapies as defined by the pivotal clinical trial protocols and the approved indications of anticancer drugs as determined by 3 major regulatory agencies.
Thirty-eight approvals were collected that received market authorization from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) between January 2010 and September 2018 for initial approval of an anticancer drug or for an expanded therapeutic indication for a previously approved anticancer drug, based on the same pivotal clinical trial(s). The subject eligibility criteria of the pivotal clinical trials and the approved indications as established by these agencies were compared, and the differences were categorized according to patient biomarkers status, prior treatment status, and the use of combination therapies.
In 20 (53%) approvals, there was a discrepancy between biomarker status of enrolled subjects in the pivotal trial and the therapeutic indication. In 7 of these cases, the biomarkers were used to diagnose the target cancer or to stratify the study subjects in the pivotal trial. In 9 cases, the biomarker discrepancies were related to minor histologic subtypes of the target cancer. Regarding prior treatment status, the FDA and the EMA generally approved indications for the same treatment line as the pivotal trials, whereas the PMDA did not restrict approval to untreated patients when the pivotal trial included only treatment-naive subjects. In 14 approvals, the FDA and the EMA designated the same co-administered drugs as part of the approved indications in line with the pivotal trials. However, the PMDA did not specify the co-administered drugs in 2 approvals and did not require combination therapy in 1 case.
In principle, the approved therapeutic indications should be determined by the characteristics of the pivotal trial subjects and combination therapies. The use of biomarkers can be essential for identifying those patients who are most likely to benefit from a drug. Unfortunately, biomarker-defined subgroups are often insufficient in size to allow meaningful interpretation of results. Consequently, regulatory agencies may deviate from one another and from the pivotal trial protocol when interpreting study results and attempting to define the optimal treatment population. The PMDA-approved indications deviated more liberally from the pivotal trial protocols regarding specification of prior treatment status and the use of co-administered drugs.
本研究旨在考察纳入研究人群的差异，以及根据关键临床试验方案和三大监管机构批准的抗癌药物适应证来确定的联合治疗方案的使用情况。
本研究共纳入 38 项批准，这些批准均于 2010 年 1 月至 2018 年 9 月间获得美国食品药品监督管理局（FDA）、欧洲药品管理局（EMA）和日本药品和医疗器械管理局（PMDA）的市场授权，适应证为首次批准的抗癌药物或先前批准的抗癌药物的治疗适应证扩展，这些适应证均基于相同的关键临床试验。比较了关键临床试验的受试者入选标准和这些机构确定的批准适应证，并根据患者生物标志物状态、既往治疗情况和联合治疗方案对差异进行分类。
在 20 项（53%）批准中，关键性试验中纳入的研究人群的生物标志物状态与治疗适应证存在差异。在这 7 种情况下，生物标志物用于诊断目标癌症或对关键性试验中的研究对象进行分层。在 9 种情况下，生物标志物差异与目标癌症的次要组织学亚型有关。关于既往治疗情况，FDA 和 EMA 通常批准与关键性试验相同的治疗线适应证，而 PMDA 在关键性试验仅纳入未经治疗的患者时，并未限制批准用于未经治疗的患者。在 14 项批准中，FDA 和 EMA 指定了与关键性试验一致的联合用药作为批准适应证的一部分。然而，PMDA 在 2 项批准中未指定联合用药，在 1 项批准中未要求联合治疗。
原则上，批准的治疗适应证应由关键性试验受试者和联合治疗方案的特点决定。生物标志物的使用对于确定最有可能从药物中获益的患者至关重要。不幸的是，生物标志物定义的亚组通常规模太小，无法对结果进行有意义的解释。因此，监管机构在解释研究结果并试图确定最佳治疗人群时，可能会彼此之间以及与关键性试验方案产生分歧。PMDA 的批准适应证在既往治疗情况和联合用药的规定方面比关键性试验方案更加宽松。
