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Abstract：
BACKGROUND: Real-world evidence (RWE) generated using real-world data (RWD) presents the potential to contextualize and/or supplement traditional clinical trials for regulatory approval of rare diseases (RDs). This systematic review evaluated the use of RWD for non-oncologic RD therapies with orphan drug designation (ODD) to support efficacy outcomes in regulatory application packages to the US Food and Drug Administration (FDA). New drug applications (NDAs) and biologic license applications (BLAs) submitted between January 2017 and October 2022 were obtained from publicly available FDA drug approval websites. NDAs and BLAs of non-oncologic RD therapies were screened, and manually reviewed using RWE-related keywords. Quantitative summary of number/proportion of study types was provided, whereas qualitative synthesis focused on key categories of output assessing the use of RWD in overall drug approval process, including agency\'s feedback on its strengths and key challenges.
RESULTS: A total of 868 NDAs and BLAs were identified, of which 243 were screened for non-oncologic RDs with ODD, and 151 were subsequently reviewed for the RWD used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications met the review inclusion criteria. Most (19; 95%) applications used only retrospective RWD, while one (5%) collected RWD both retrospectively and prospectively. RWD studies included natural history including registry-based/retrospective historical controls (14; 70%), retrospective medical chart-reviews (4; 20%), and external RWD controls from other studies (2; 10%). The FDA generally accepted RWD studies demonstrating a large effect size despite the noted concerns and criticisms. However, the agency expressed concerns about overall quality and comparability of RWD with trial data for some applications, including RWD study designs with respect to differences in patients\' baseline characteristics, missing information, and potential bias and measurement errors.
CONCLUSIONS: This systematic review highlights potential benefits of appropriately conducted RWE studies in RD, which can strengthen the clinical evidence for efficacy comparison and contextualization to support product approval efforts, particularly when a large magnitude of effect is observed for the new intervention. Nonetheless, quality and completeness of RWD and its comparability with trial data remain areas of concern that can serve as valuable learnings for advancing future science and regulatory approvals.
RESULTS: A total of 868 NDAs and BLAs were identified, of which 243 were screened for non-oncologic RDs with ODD, and 151 were subsequently reviewed for the RWD used to support efficacy outcomes. Twenty (12 NDAs, 8 BLAs) applications met the review inclusion criteria. Most (19; 95%) applications used only retrospective RWD, while one (5%) collected RWD both retrospectively and prospectively. RWD studies included natural history including registry-based/retrospective historical controls (14; 70%), retrospective medical chart-reviews (4; 20%), and external RWD controls from other studies (2; 10%). The FDA generally accepted RWD studies demonstrating a large effect size despite the noted concerns and criticisms. However, the agency expressed concerns about overall quality and comparability of RWD with trial data for some applications, including RWD study designs with respect to differences in patients\' baseline characteristics, missing information, and potential bias and measurement errors.
CONCLUSIONS: This systematic review highlights potential benefits of appropriately conducted RWE studies in RD, which can strengthen the clinical evidence for efficacy comparison and contextualization to support product approval efforts, particularly when a large magnitude of effect is observed for the new intervention. Nonetheless, quality and completeness of RWD and its comparability with trial data remain areas of concern that can serve as valuable learnings for advancing future science and regulatory approvals.
摘要：
背景：使用现实世界数据（RWD）生成的现实世界证据（RWE）提供了情境化和/或补充传统临床试验以获得罕见疾病（RD）的监管批准的潜力。本系统评价评估了RWD在具有孤儿药名称（ODD）的非肿瘤学RD治疗中的使用，以支持美国食品和药物管理局（FDA）的监管应用包中的疗效结果。2017年1月至2022年10月提交的新药申请（NDA）和生物许可申请（BLAs）均从公开的FDA药品批准网站获得。筛选非肿瘤性RD疗法的NDA和BLA，并使用与RWE相关的关键字手动审核。提供了研究类型数量/比例的定量总结，而定性综合侧重于评估RWD在整个药物批准过程中使用的关键产出类别，包括机构对其优势和关键挑战的反馈。
结果：总共确定了868个NDA和BLAs，其中243例进行了ODD非肿瘤性RD筛查，随后对151例用于支持疗效结局的RWD进行了回顾.二十个(12个NDA，8个BLAs)申请符合审查纳入标准。大多数(19；95%)应用程序仅使用回顾性RWD，其中1人(5%)回顾性和前瞻性地收集了RWD。RWD研究包括自然史，包括基于注册/回顾性历史控制（14;70％），回顾性医学图表评论(4；20%)，和其他研究的外部RWD对照（2；10%）。尽管存在关注和批评，但FDA普遍接受RWD研究表明其效果较大。然而,该机构对RWD的整体质量和与某些应用的试验数据的可比性表示担忧，包括关于患者基线特征差异的RWD研究设计，缺少信息,以及潜在的偏差和测量误差。
结论：本系统综述强调了在RD中适当进行RWE研究的潜在益处，这可以加强疗效比较和情境化的临床证据，以支持产品批准工作，特别是当观察到新干预措施的效果很大时。尽管如此，RWD的质量和完整性及其与试验数据的可比性仍然是值得关注的领域,可以作为推进未来科学和监管批准的宝贵经验.
结果：总共确定了868个NDA和BLAs，其中243例进行了ODD非肿瘤性RD筛查，随后对151例用于支持疗效结局的RWD进行了回顾.二十个(12个NDA，8个BLAs)申请符合审查纳入标准。大多数(19；95%)应用程序仅使用回顾性RWD，其中1人(5%)回顾性和前瞻性地收集了RWD。RWD研究包括自然史，包括基于注册/回顾性历史控制（14;70％），回顾性医学图表评论(4；20%)，和其他研究的外部RWD对照（2；10%）。尽管存在关注和批评，但FDA普遍接受RWD研究表明其效果较大。然而,该机构对RWD的整体质量和与某些应用的试验数据的可比性表示担忧，包括关于患者基线特征差异的RWD研究设计，缺少信息,以及潜在的偏差和测量误差。
结论：本系统综述强调了在RD中适当进行RWE研究的潜在益处，这可以加强疗效比较和情境化的临床证据，以支持产品批准工作，特别是当观察到新干预措施的效果很大时。尽管如此，RWD的质量和完整性及其与试验数据的可比性仍然是值得关注的领域,可以作为推进未来科学和监管批准的宝贵经验.
