Public Health Strategy and Analysis Staff, Office of the Commissioner Food and Drug Administration, Silver Spring, Maryland.
Office of New Drugs, Center for Drug Evaluation and Research Food and Drug Administration, Silver Spring, Maryland.
JAMA Intern Med. 2021 Apr 1;181(4):522-529. doi: 10.1001/jamainternmed.2020.8866.
Before reviewing drug applications, the US Food and Drug Administration (FDA) conducts "filing reviews" to assess whether they are complete enough for full review. If the applications are incomplete, the FDA issues refuse-to-file (RTF) letters identifying deficiencies. The FDA does not make these RTF letters public at the time of issuance. Why the FDA issues RTF letters and how often the letters and their contents are made publicly available are unknown.
To quantitatively analyze the FDA's reasons for issuing RTF letters and assess the public transparency of RTF letters and their contents.
This cross-sectional study analyzes RTF letters issued in response to new drug applications and efficacy supplements (applications for new indications or patient populations for already approved drugs) submitted to the FDA between January 1, 2008, and December 31, 2017. Statistical analysis was conducted in July 2019.
Two types of information were extracted and cataloged from RTF letters: (1) the reasons why the FDA refused to file applications and (2) the FDA comments that, while not a basis for RTF letters, conveyed important information to applicants. The extent to which applicants publicly disclosed the FDA's refusal reasons were also assessed.
The study included 103 RTF letters containing a total of 644 identified FDA refusal reasons. Among the 2475 applications that the FDA received during the study time frame, 98 (4.0%) received RTF letters. Overall, 84.5% (544 of 644) of the refusal reasons were for scientific deficiencies; most reasons were related to drug efficacy and safety (196 [30.4%]) and drug quality (125 [19.4%]). The remaining 15.5% of refusal reasons (100 of 644) were for application organization deficiencies or legal issues. A total of 26.2% of the RTF letters (27 of 103) identified presubmission advice from the FDA that applicants did not follow; the most frequently ignored advice was related to clinical trial design (33.3% [9 of 27]), followed by product chemistry and manufacturing (25.9% [7 of 27]). Applicants publicly disclosed the existence of 16 of 103 RTF letters (15.5%); however, only 5.4% of applicant-disclosed reasons (35 of 644) matched the refusal reasons that the FDA had provided in the RTF letters.
This cross-sectional study found that the FDA refused to file applications for substantive reasons related to quality, safety, and efficacy, and applicants' disclosure of those reasons was incomplete. This work sheds light on the FDA's regulatory decision-making processes and the RTF reasons that could delay availability of therapies to patients.
在美国食品和药物管理局（FDA）进行“申报审查”以评估其是否足以进行全面审查之前，会先对药品申请进行审查。如果申请不完整，FDA 将发出拒绝受理（RTF）信函，指出缺陷。FDA 在发出信函时不会将这些 RTF 信函公开。FDA 发出 RTF 信函的原因以及这些信函及其内容多久会公开，目前尚不清楚。
定量分析 FDA 发出 RTF 信函的原因，并评估 RTF 信函及其内容的公开透明度。
本横断面研究分析了 2008 年 1 月 1 日至 2017 年 12 月 31 日期间向 FDA 提交的新药申请和疗效补充申请（针对已批准药物的新适应症或患者人群的申请）中发出的 RTF 信函。统计分析于 2019 年 7 月进行。
从 RTF 信函中提取并编目了两类信息：（1）FDA 拒绝受理申请的原因；（2）FDA 的意见，虽然不是 RTF 信函的依据，但向申请人传达了重要信息。还评估了申请人公开披露 FDA 拒绝理由的程度。
该研究纳入了 103 封 RTF 信函，共包含 644 项确定的 FDA 拒绝理由。在研究期间 FDA 收到的 2475 份申请中，有 98 份（4.0%）收到了 RTF 信函。总体而言，84.5%（544/644）的拒绝理由是由于科学缺陷；大多数原因与药物疗效和安全性（196 [30.4%]）和药物质量（125 [19.4%]）有关。其余 15.5%（100/644）的拒绝理由是申请组织缺陷或法律问题。共有 26.2%（27/103）的 RTF 信函确定了 FDA 提供的申请人未遵循的预先提交建议；最常被忽视的建议与临床试验设计有关（33.3%[27 封中的 9 封]），其次是产品化学和制造（25.9%[27 封中的 7 封]）。申请人公开披露了 103 封 RTF 信函中的 16 封（15.5%）；然而，只有 5.4%（35/644）的申请人披露的理由与 FDA 在 RTF 信函中提供的拒绝理由相匹配。
这项横断面研究发现，FDA 拒绝受理与质量、安全性和疗效相关的实质性申请，且申请人对这些理由的披露并不完整。这项工作阐明了 FDA 的监管决策过程以及可能延迟患者获得治疗的 RTF 理由。
