Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
Yale School of Medicine, New Haven, Connecticut, USA.
BMJ Open. 2024 Oct 26;14(10):e090376. doi: 10.1136/bmjopen-2024-090376.
To compare the premarket and postmarket evidence of safety and efficacy of direct oral anticoagulants approved for stroke prevention in atrial fibrillation patients across four major regulatory agencies.
Cross-sectional.
European Medicines Association (EMA), US Food and Drug Administration (FDA), Health Canada and Australian Therapeutic Goods Administration (TGA).
Apixaban, dabigatran, edoxaban and rivaroxaban marketing authorisations.
Concordance among regulatory agencies with respect to (1) premarket evidence used to establish efficacy and safety and (2) postmarket safety boxed warnings and postmarketing study requirements.
Apixaban, dabigatran and rivaroxaban were approved by each of the four regulatory agencies; edoxaban was only not approved by TGA. For premarket efficacy evidence, there was concordance across all agencies in terms of phase 3 trials for three (75%) drugs, sample size for three (75%) drugs, primary endpoints for four (100%) drugs, numerical results for three (75%) drugs, agency interpretation of results for four (100%) drugs and number of phase 2 trials for three (75%) drugs. For the premarket safety evidence, there was concordance across all agencies in terms of phase 3 trials for three (75%) drugs, sample size for two (50%) drugs, primary endpoints for four (100%) drugs, numerical results for three (75%) drugs, agency interpretation of results for three (75%) drugs and number of phase 2 trials for zero (0%) drugs. For postmarket safety information, FDA was the only agency that issued boxed warnings (for three (75%) drugs). Additionally, EMA and TGA required postmarketing studies (for four (100%) and two (50%) drugs, respectively), while FDA and Health Canada did not have any postmarketing requirements.
There was a high degree of concordance in the phase 3 trial premarket evidence used to establish efficacy and safety of direct oral anticoagulant approvals across four major regulatory agencies, but discordance in the phase 2 trial premarket evidence used, as well as in postmarket safety boxed warnings and postmarketing study requirements. These discrepancies highlight opportunities for further harmonisation in the evaluation and regulation of medical products globally.
比较四个主要监管机构批准用于预防心房颤动患者中风的直接口服抗凝剂的上市前和上市后安全性和疗效证据。
横断面研究。
欧洲药品管理局（EMA）、美国食品和药物管理局（FDA）、加拿大卫生部和澳大利亚治疗商品管理局（TGA）。
阿哌沙班、达比加群、依度沙班和利伐沙班的营销许可。
阿哌沙班、达比加群和利伐沙班获得了四个监管机构的批准；依度沙班仅未获得 TGA 的批准。对于上市前的疗效证据，四个机构在三个（75%）药物的三期临床试验、三个（75%）药物的样本量、四个（100%）药物的主要终点、三个（75%）药物的数值结果、四个（100%）药物的机构结果解释以及三个（75%）药物的二期临床试验数量方面均达成一致。对于上市前的安全性证据，四个机构在三个（75%）药物的三期临床试验、两个（50%）药物的样本量、四个（100%）药物的主要终点、三个（75%）药物的数值结果、三个（75%）药物的机构结果解释以及零（0%）药物的二期临床试验数量方面均达成一致。在上市后安全性信息方面，FDA 是唯一发布黑框警告（适用于三个（75%）药物）的机构。此外，EMA 和 TGA 要求进行上市后研究（适用于四个（100%）和两个（50%）药物），而 FDA 和加拿大卫生部没有任何上市后要求。
在四个主要监管机构中，用于建立直接口服抗凝剂批准的疗效和安全性的三期临床试验上市前证据具有高度一致性，但用于建立上市前证据的二期临床试验以及上市后安全性黑框警告和上市后研究要求存在差异。这些差异突出了在全球范围内进一步协调评估和监管医疗产品的机会。
