Department of Clinical Pharmacology, Tokai University School of Medicine Isehara, Kanagawa, 259-1193, Japan.
Department of Medical Informatics, Kagawa University Hospital, Miki-cho, Kagawa, 761-0793, Japan.
Br J Clin Pharmacol. 2021 Oct;87(10):3938-3948. doi: 10.1111/bcp.14814. Epub 2021 Mar 31.
In 2008, the US Food and Drug Administration (FDA) issued a guidance requiring that cardiovascular outcome trials (CVOTs) be conducted for newer hypoglycaemic drugs for type 2 diabetes (T2D). We aimed to examine the decisions by 3 regulatory authorities in response to identical CVOT data.
We surveyed ClinicalTrials.gov to identify CVOTs and examined the revision histories of drug labels in databases from the FDA, the European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan.
We selected 14 drugs and corresponding CVOTs, 12 of which were conducted as postmarketing trials. In the USA and the EU, the pre-CVOT indication on all 14 labels was "improvement in glycaemic control". Six drugs showed significant cardiovascular risk reduction, which led to an additional indication regarding reduction of cardiovascular adverse events in the USA, and a change to the EU indication to specify treatment of adults with T2D. The initial indication in Japan, T2D, remained unchanged. Regarding safety, significant increases in heart failure were observed only in the saxagliptin trial. A warning was added to the saxagliptin labels in the EU and Japan, whereas the FDA required a class effect warning to be added to the labels of all 4 dipeptidyl peptidase-4 inhibitors.
Regulatory authorities using identical trial data made substantially different decisions regarding both safety and efficacy of hypoglycaemic drugs. The differences in initial indication wording between Japan and the other authorities suggest that trial data and T2D are interpreted differently in these regions.
2008 年，美国食品和药物管理局（FDA）发布了一项指导意见，要求对 2 型糖尿病（T2D）的新型降糖药物进行心血管结局试验（CVOT）。我们旨在研究 3 个监管机构对相同 CVOT 数据的决策。
我们在 ClinicalTrials.gov 上进行了调查，以确定 CVOT，并在 FDA、欧洲药品管理局和日本药品和医疗器械管理局的数据库中检查了药物标签的修订历史。
我们选择了 14 种药物及其对应的 CVOT，其中 12 种是作为上市后试验进行的。在美国和欧盟，所有 14 个标签的 CVOT 前适应症都是“改善血糖控制”。6 种药物显示出显著的心血管风险降低，这导致在美国增加了减少心血管不良事件的适应症，并将欧盟的适应症更改为专门治疗 T2D 的成年人。日本的初始适应症 T2D 保持不变。关于安全性，只有在沙格列汀试验中观察到心力衰竭显著增加。在欧盟和日本，沙格列汀标签上添加了警告，而 FDA 要求在所有 4 种二肽基肽酶-4 抑制剂的标签上添加类效应警告。
使用相同试验数据的监管机构在降糖药物的安全性和疗效方面做出了截然不同的决定。日本和其他当局之间初始适应症措辞的差异表明，这些地区对试验数据和 T2D 的解释不同。
