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WARNING LETTER FDA Ref. No.: 24-HFD-45-12-01 尊敬的Shah博士： 这封警告信通知您，在2022年12月5日至12月16日期间，美国食品药品监督管理局（FDA）对您的临床中心进行审查时发现了不合规情况。代表FDA的检查员Kristin M. Abaonza审查了您进行的一项临床研究（方案（b）（4），“(b)（4）”）的研究新药（b）（4），属于（b）（4）的范畴。 此次检查是作为FDA的生物研究监管计划的一部分进行的，其中包括旨在评估研究行为以及确保保护人类受试者的权利、安全和福利的检查。 检查结束时，检查员Abaonza向您呈交并讨论了FDA检查观察表。我们已收到您于2023年1月9日的书面回复FDA观察表，以及您于2023年2月9日之后的通讯。 经过我们对FDA机构检查报告、提交此报告的文件以及您于2023年1月9日和2月9日的书面回复的评估，似乎您没有遵守联邦食品、药品和化妆品法案（FD＆C法案）中适用的法定要求和21 CFR第312部分中包含的适用法规，这些法规规定了临床研究的进行方式。我们希望强调以下几点： 您未能确保研究按照21 CFR 第312.60条的要求进行。 作为临床研究者，您有责任确保您的临床研究按照研究计划进行。方案(b)(4)的研究计划要求，与研究定义的疗效终点相关的医生评定评估应由对安全评估（例如临床实验室评估、生命体征、体格检查和不良事件评估）进行盲态评估的评估员完成。盲态评估员负责进行方案要求的疗效评估，包括蒙哥马利-阿斯伯格抑郁评定量表（MADRS）评估，在第2次访视至第8次访视或提前终止期间，所有访视都需要完成。方案(b)(4)还指定盲态评估员不得使用ClinTrak电子数据采集系统，并且不得接触可能泄露受试者治疗分组信息的受试者基础数据（包括化验结果、心电图、不良事件、伴随用药、患者自述结果和临床医生报告的安全评估）。您未能遵守此要求。 具体而言，作为指定的盲态评估员，您为贵单位招募的三位受试者共进行了16次MADRS评估（受试者(b)(6)进行了5次MADRS评估，受试者(b)(6)进行了6次MADRS评估，受试者(b)(6)进行了5次MADRS评估）。然而，您对某些安全评估并未保持盲态。例如，对于受试者(b)(6)，您评估了生命体征测量，包括血压、心率和体温。此外，对于受试者(b)(6)，您还评估了临床化验报告并进行了体格检查。 在检查过程中，您承认不仅查阅了研究记录、征得了受试者的同意并进行了与研究相关的评估，还为所有三位受试者进行了16个MADRS评估。您表示，当您意识到这些评估应由对安全评估不知情的评估员进行时，随后您提交了一个方案偏离，并没有进行任何额外的MADRS评估。 此外，在2023年1月9日对FDA 483表格的书面回复中，您再次承认为所有三位受试者进行了16个MADRS评估。您还详细说明了您所在研究机构计划采取的纠正和预防措施，包括：（1）明确标识与盲态有关的方案要求，并在源记录表上注明盲态的评估；（2）咨询申办方和第三方质量咨询团队，以明确理解方案中的任何模糊之处，在填写授权报或归档源文件时也是如此；（3）临床研究负责人和研究机构人员参加各种临床研究合规培训，例如GCP 培训，您在2023年2月9日的后续书面回复中提供了培训证书。 虽然我们承认您所在研究机构已经采取和计划采取的行动，但是您的回复是不充分的，因为您没有提供关于纠正措施计划的足够详细信息。例如，您没有提供足够详细的信息，说明在进行未来的临床研究时，您所在研究机构实施的建议做法以确保符合研究方案，包括盲态程序的方案要求。没有这些信息，我们无法确定您的纠正措施是否足够，能够帮助防止类似违规事件的再次发生。 我们强调，作为临床研究者，您有责任确保研究按照研究计划进行，并确保研究数据的完整性。方案（b）（4）的主要目的是评估研究药物与安慰剂在改善（b）（4）的患者中的疗效，评估指标是从基线到第4周（第29天）的MADRS评分变化。您以非盲评估员的身份对每位入组受试者进行了至少五次七次必需的MADRS评估，并未保证按照方案要求的盲态程序进行，这引起了对在您的研究中收集到的数据可靠性和完整性的重大关注。 此信函并非您进行研究药物的临床研究中存在的所有缺陷的全面清单。您有责任确保遵守法律和相关FDA规定的每个要求。您应解决任何缺陷，并建立程序以确保任何正在进行或将来进行的研究符合FDA规定。 本信函通知您我们的发现，并为您提供解决上述缺陷的机会。在收到本信函后的15个工作日内，您应书面通知本办公室您已采取的措施，以防止类似的违规行为。不采取足够措施解决此事可能会导致监管行动。如果您认为您已遵守FD＆C法案和相关法规，请附上您的理由和任何支持信息供我们考虑。 Note: 以上中文翻译由 ChatGPT3.5进行，仅供参考。 WARNING LETTER FDA Ref. No.: 24-HFD-45-12-01 Dear Dr. Shah: This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site between December 5 and December 16, 2022. Investigator Kristin M. Abaonza, representing FDA, reviewed your conduct of a clinical investigation (Protocol(b)(4), “(b)(4)”) of the investigational drug (b)(4), performed for (b)(4). This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected. At the conclusion of the inspection, Investigator Abaonza presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your January 9, 2023, written response to the Form FDA 483, and your subsequent correspondence dated February 9, 2023. From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses dated January 9 and February 9, 2023, it appears that you did not adhere to the applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in Title 21 of the Code of Federal Regulations, part 312 [21 CFR 312] governing the conduct of clinical investigations. We wish to emphasize the following: You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60]. As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan. The investigational plan for Protocol(b)(4), required the clinician-administered assessments related to study-defined efficacy endpoints to be completed by a rater who was blinded to the safety assessments (for example, clinical laboratory evaluations, vital signs, physical examinations, and adverse event assessments). The blinded assessor was responsible for administering protocol required efficacy assessments, including the Montgomery-Asberg Depression Rating Scale (MADRS) assessments, that were required to be completed during all study visits from Visit 2 until Visit 8 or early termination. Protocol (b)(4), also specified that the blinded assessor would not have access to the ClinTrak Electronic Data Capture system and should not have access to subject source data (including laboratory results, electrocardiograms, adverse events, concomitant medications, patient-reported outcomes, and clinician-reported outcomes that are completed by investigators responsible for the assessment of subject safety) that could potentially unblind the assessor to a subject’s treatment assignment. You failed to adhere to this requirement. Specifically, as a designated blinded rater, you conducted a total of 16 MADRS assessments for all three subjects enrolled at your site (five MADRS assessments for Subject(b)(6), six MADRS assessments for Subject (b)(6), and five MADRS assessments for Subject (b)(6)). However, you were not blinded to certain safety assessments. For example, for Subject (b)(6), you evaluated safety assessments such as vital-sign measurements, including blood pressure, heart rate, and body temperature. Additionally, for Subject (b)(6), you assessed a clinical laboratory report and performed a physical examination. During the inspection, you acknowledged that you not only reviewed study records, consented subjects, and performed study-related assessments, but you also conducted 16 MADRS assessments for all three subjects. You stated that when you realized that the assessments should be conducted by a rater blinded to the safety assessments, you subsequently filed a protocol deviation and did not conduct any additional MADRS assessments. Further, in your January 9, 2023, written response to the Form FDA 483, you again acknowledged that you conducted 16 MADRS assessments for all three subjects. You also detailed the corrective and preventive actions your site planned to take, including: (1) clearly identifying protocol requirements that concern blinding, and annotating the source worksheets to clearly identify blinded assessments; (2) consulting with both the sponsor and a third-party quality consulting group to provide clarity in understanding any ambiguities in the protocol, in completing the Delegation of Authority log, or in filing source documents; and (3) clinical investigator and site personnel participation in various clinical research compliance trainings, such as Good Clinical Practice training, for which you provided the training certificates in your February 9, 2023, follow-up written response. While we acknowledge the actions that your site has taken and plans to take, your response is inadequate because you did not include sufficient details about your corrective action plan. For example, you did not provide sufficient details about the implementation of the proposed practices being instituted at your site to ensure compliance with study protocols, including protocol requirements for blinding procedures, when conducting future clinical investigations. Without this information, we are unable to determine whether your corrective actions appear adequate to help prevent similar violations in the future. We emphasize that as the clinical investigator, it is your responsibility to ensure that the study is conducted in accordance with the investigational plan and to ensure the integrity of the study data. The primary objective of Protocol(b)(4), was to assess the efficacy of the investigational drug compared to placebo in improving (b)(4) in subjects with (b)(4), as assessed by the change in the MADRS score from Baseline to Week 4 (Day 29). Your administration of at least five of the seven required MADRS assessments for each enrolled subject as an unblinded assessor, as well as your failure to ensure that protocol-required blinding procedures were followed, raises significant concerns about the reliability and integrity of the data collected at your site. This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address any deficiencies and establish procedures to ensure that any ongoing or future studies comply with FDA regulations. This letter notifies you of our findings and provides you with an opportunity to address the above deficiencies. Within 15 business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to address this matter adequately may lead to regulatory action. If you believe you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration. Note: 以上中文翻译由 ChatGPT3.5进行，仅供参考。 |
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来自： rodneyzhang > 《临床研究》
