关注|FDA 给Dr. Daswani的一封警告信

WARNING LETTER

FDA Ref. No.: 22-HFD-45-12-01

Dear Dr. Daswani:

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 October 18 and October 29, 2021. Investigators Dustin R. Abaonza and Yuanyuan Li, representing FDA, reviewed your conduct of a clinical investigation [Protocol (b)(4), “(b)(4)”] of the investigational drug (b)(4), performed for (b)(4).

本警告函告知您，在美国食品和药物管理局（FDA）于2021 10月18日至29日在您的临床中心进行检查期间，发现了不利的情况。代表FDA的检查人员Dustin R.Abaonza和Yuanyuan Li审查了您对试验药物(b)(4) 进行的临床研究[方案(b)(4) ]，该药物是针对(b)(4) 进行的。

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.

该检查是作为FDA生物研究监测计划的一部分进行的，该计划包括旨在评估研究行为并帮助确保受试者的权利、安全和福利得到保护的检查。

At the conclusion of the inspection, Investigators Abaonza and Li presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your November 18, 2021, written response to the Form FDA 483.

在检查结束时，检查人员Abonza和Li向您提交并讨论了FDA 483表格，检查观察结果。我们确认收到您2021年11月18日对FDA 483表的书面回复。

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated November 18, 2021, 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 and the protection of human subjects. We wish to emphasize the following:

根据我们对FDA机构检查报告、随报告提交的文件以及您2021年11月18日的书面回复的审查，您没有严格遵守《联邦食品、药品和化妆品法案》（FD&C Act）中的适用法定要求以及《联邦法规法典》第21款中的适用规定，第312部分[21 CFR 312]管理临床研究的进行和人体受试者的保护。我们希望强调以下几点：

You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].

您未能确保根据研究计划进行研究[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 you to ensure that randomized treatment was administered, randomized treatment dose adjustments were made by the Interactive Response Technology (IRT) system, and protocol-specified procedures were followed when hemoglobin concentration (Hgb) measured by HemoCue was ≥12 g/dL. You failed to adhere to these requirements. Examples of this failure include, but are not limited to, the following:

作为一名临床研究者，您必须确保临床研究按照研究计划进行。方案(b)(4) 的研究计划要求您正确进行随机治疗，通过交互反应技术（IRT）系统进行随机治疗剂量调整，并且当HemoCue测量的血红蛋白浓度（Hgb）≥12 g/dL时，遵循方案规定的程序。您未能遵守这些要求。此类问题的示例包括但不限于以下内容：

a. From Study Day 1 until end of treatment, the protocol required subjects randomized (b)(4).

a. 从研究第1天到治疗结束，方案要求受试者随机接受(b)(4) 治疗。

You failed to adhere to these requirements. Specifically, (b)(4) doses were not administered to the following subjects randomized to receive (b)(4) and on (b)(4):

您未能遵守这些要求。具体而言，下列随机接受(b)(4) 治疗的受试者未使用 (b)(4) 治疗。

i. For Subject (b)(6), thirty-four (b)(4) doses were not administered, including fourteen consecutive doses.

对于受试者(b)(6)，34次(b)(4) 给药未进行，包括14次连续给药。

ii. For Subject (b)(6), forty-three (b)(4) doses were not administered, including twelve consecutive doses from (b)(6). On (b)(6), this subject had severe (b)(4) and was hospitalized to receive 1 unit of packed red blood cells.

对于受试者(b)(6)，43次（(b)(4) )给药未进行，包括从(b)(6)开始中的12次连续给药。在(b)(6)中，该受试者患有严重(b)(4) ，并住院接受1单位的填充红细胞。

iii. For Subject (b)(6), fifteen (b)(4) doses were not administered.

对于受试者(b)(6)，15次(b)(4) 给药未进行。

b. The protocol required randomized treatment dose adjustments to be made programmatically by the IRT system, based on the HemoCue Hgb value measured at least every 12 weeks from Week 52 through end of treatment.

b. 该方案要求从第52周到治疗结束至少每12周测量一次的HemoCue Hgb值，通过IRT系统进行随机治疗剂量调整。

You failed to adhere to this requirement. Specifically, IRT transactions were not conducted to obtain the randomized treatment dose for the following subjects:

您没有遵守这一要求。具体而言，未进行IRT操作以获得以下受试者的随机治疗剂量：

i. Subject (b)(6) did not have IRT transactions performed at Week 76 ((b)(6)), Week 88 ((b)(6)), or Week 124 ((b)(6)). Of note, Week 76 and Week 88 were consecutive protocol-required study visits.

受试者(b)(6)在第76周（(b)(6)）、第88周（(b)(6)）或第124周（(b)(6)）未进行IRT操作。值得注意的是，第76周和第88周是连续的方案要求的研究访视。

ii. Subject (b)(6) did not have IRT transactions performed at Week 88 ((b)(6)), Week 100 ((b)(6)), Week 112 ((b)(6)), or Week 124 ((b)(6)). Of note, Week 88, Week 100, Week 112, and Week 124 were consecutive protocol-required study visits.

受试者(b)(6)在第88周（(b)(6)）、第100周（(b)(6)）、112周（(b)(6)）或124周（(b)(6)）未进行IRT操作。值得注意的是，第88周、第100周、第112周和第124周为连续的方案要求的研究访视。

iii. Subject (b)(6) did not have IRT transactions performed at Week 64 ((b)(6)).

受试者(b)(6)在第64周时未进行IRT操作。

c. The protocol required that, if HemoCue Hgb was ≥12 g/dL at a study visit, HemoCue Hgb was to be repeated at the same study visit and the values were to be averaged. If HemoCue Hgb was repeated and confirmed to be ≥12 g/dL, randomized treatment dose was to be temporarily held. HemoCue Hgb was to be checked at a study visit 4 weeks later. If HemoCue Hgb was <11.5 g/dL, provided it had been at least 2 weeks since the previous study visit, randomized treatment was to be restarted at one dose step lower.

c. 方案要求，如果访视时HemoCue Hgb≥12 g/dL，则在同一访视中复测HemoCue-Hgb，并取平均值。如果复测HemoCue Hgb并确认了≥12 g/dL，则应暂时中止治疗。HemoCue Hgb将在4周后的研究访问中进行检查。如果HemoCue Hgb<11.5 g/dL，并且自上次研究访视后至少2周，则应以低一个剂量重新开始随机治疗。

You failed to adhere to these requirements. Specifically, Subject (b)(6), randomized to (b)(4), had a HemoCue Hgb of 12.6 g/dL, which was repeated and confirmed to be ≥12 g/dL (12.6 g/dL) on (b)(6). However, randomized treatment dose was not held, and (b)(4) was administered on (b)(6).

您未能遵守这些要求。具体而言，随机接受(b)(4) 的受试者(b)(6)的HemoCue Hgb为12.6 g/dL，在(b)(6)重复测量并确认其≥12 g/dL（12.6 g/d L）。然而，随机治疗剂量未被暂停，在(b)(6)仍然给药(b)(4) 治疗。

Subsequently, on (b)(6), HemoCue Hgb was 12.7 g/dL, which was repeated and confirmed to be ≥12 g/dL (12.7 g/dL), and (b)(4) was held. However, on (b)(6), (b)(4) was administered, rather than reducing or holding the (b)(4) dose as required by the protocol.

随后，在(b)(6)中，HemoCue Hgb为12.7 g/dL，重复并确认其≥12 g/dL（12.7 g/dL），并且(b)(4)保持不变。然而，在(b)(6)、(b)(4)中，并未按照方案的要求减少或中止(b)(4)的剂量。

On (b)(6), HemoCue Hgb was <11.5 g/dL (10.9 g/dL). However, (b)(4) was not administered as required by the protocol, even though it had been at least 2 weeks since the previous study visit. Subsequently, on (b)(6), (b)(4) was administered without reducing the dose of (b)(4) by one dose step.

在(b)(6)中，HemoCue Hgb<11.5 g/dL（10.9 g/dL）。然而，(b)(4)未按照方案要求进行给药，即使距上次研究访问至少2周。随后，在(b)(6)中，在不将(b)(4)的剂量减少一个剂量步骤的情况下给药(b)(4)。

You stated during the inspection that nurses would periodically tell you, “We are supposed to have a dose and don’t have a dose,” and you would then text the study coordinator. You also stated that you first became aware that the study coordinators were ordering replacement kits to resupply the inventory rather than using the IRT system to generate randomized treatment doses, when the monitor emailed you in January 2020, which we note is over a year after multiple subjects missed multiple doses, as described above.

您在检查期间表示，护士会定期告诉你，“我们应该给药，但没有给药”，然后你会给研究协调员发短信。您还表示，您第一次意识到研究协调员正在订购替换药盒以补充库存，而不是使用IRT系统来生成随机治疗剂量，是在在2020年1月监查员向您发送电子邮件时。我们注意到，这个时候，多个受试者已经错过多次给药后的一年以后了。

In your November 18, 2021, written response to the violations listed above, you confirmed what you had stated during the inspection. You reiterated that, among other things, your lack of awareness of study staff’s not performing IRT transactions as required by the protocol, leading to missed and incorrect doses of randomized treatment for an extended period of time, suggests inadequate oversight. You also stated that your lack of awareness that a particular individual was performing the task of study coordinator suggests inadequate oversight.

在您2021年11月18日对上述违规行为的书面回复中，您确认了您在检查期间所说的内容。您重申，除其他事项外，您对研究人员未按照方案要求进行IRT操作缺乏了解，导致长期遗漏和不正确进行随机治疗，这表明监管不足。您还表示，您没有意识到某个特定人员正在执行研究协调员的任务，这表明监督不足。

We emphasize that your failure to conduct the clinical study in accordance with the protocol raises significant concerns about your protection of the study subjects enrolled at your site, and also raises concerns about the validity and integrity of the data collected at your site. Specifically, your failure to administer doses, make protocol-required dose adjustments, and perform IRT transactions to appropriately generate randomized treatment doses as required by the protocol, jeopardizes subject safety and welfare and raises significant concerns about the validity and integrity of the data collected at your site. As the clinical investigator, you are responsible for ensuring compliance with the protocol-required IRT transaction and dosing requirements.

我们强调，您未能按照方案进行临床研究，会对您对在您入组的研究受试者的保护产生重大担忧，也会对您收集的数据的有效性和完整性产生担忧。具体而言，您未能按照方案的要求进行剂量管理、进行方案要求的剂量调整以及进行IRT操作以适当生成随机治疗剂量，这会危及受试者的安全和福利，并会对您所在地收集的数据的有效性和完整性产生重大担忧。作为临床研究者，您负责确保符合方案要求的IRT操作和给药要求。

In addition, you stated in your written response the corrective and preventive actions you have taken or plan to take, including the development of a new oversight standard operating procedure (SOP) to improve protocol compliance and communication and awareness of issues between you and your study staff, and to ensure that all staff involved in conducting and managing a research study are qualified and trained to undertake their delegated duties. You also stated that you are retaking a good clinical practice course and a course on oversight and responsibilities in clinical research; that you are requiring the site management organization to notify you whenever a study coordinator is departing or being assigned to the study; and that you are assigning a backup study coordinator to each of your studies.

此外，您在书面回复中说明了您已采取或计划采取的纠正和预防措施，包括制定新的标准操作程序（SOP），以提高方案合规性、沟通和您与研究人员之间的问题意识，并确保参与开展和管理研究的所有工作人员都具备履行其授权职责的资格和培训。您还表示，您正在重新学习GCP课程和关于临床研究监督和责任的课程；您要求SMO在研究协调员离开或被分配到研究时通知您；并且您正在为您的每个研究指派一名备用研究协调员。

While we acknowledge the actions that you and your site have taken or plan to take, we request that you specify the corrective actions that you, as a clinical investigator, have taken or plan to take to prevent similar violations in the future. For example, the SOP does not include sufficient details about the policies being instituted to ensure compliance with the protocol, particularly with respect to ensuring that similar violations having to do with IRT transactions and treatment requirements are prevented. Without these details, we are unable to determine whether your corrective actions appear adequate to help prevent similar violations in the future.

虽然我们承认您和您的研究机构已采取或计划采取的措施，但我们要求您作为临床研究人员，明确您自己已采取或打算采取的纠正措施，以防止将来发生类似违规行为。例如，SOP没有包括有关为确保遵守方案而制定的政策的足够细节，特别是在确保与IRT操作和治疗要求相关的类似违规行为得到预防方面。如果没有这些细节，我们无法确定您的纠正措施是否足以帮助防止将来发生类似的违规行为。

We emphasize that as the clinical investigator, you were ultimately responsible to ensure that your clinical study was conducted properly and in compliance with FDA regulations, both to protect the rights, safety, and welfare of study subjects and to ensure the integrity of study data. Your failure to perform the above-mentioned study procedures as required by the protocol, and your lack of oversight and supervision of the clinical study, raise significant concerns about the safety of study subjects enrolled at your site and the integrity of the data generated at your site.

我们强调，作为临床研究者，您最终有责任确保您的临床研究正确进行并符合FDA法规，以保护研究对象的权利、安全和福利，并确保研究数据的完整性。您未能按照方案要求执行上述研究程序，以及您缺乏对临床研究的监督和监督，这会对您所在研究中心入组的研究受试者的安全性以及您所在研究中心生成的数据的完整性产生重大担忧。

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.

本函并非旨在列出您对试验药物的临床研究中的所有缺陷。您有责任确保遵守法律和相关FDA法规的各项要求。您应解决任何缺陷并建立程序，以确保任何正在进行或未来的研究符合FDA法规。

This letter notifies you of our findings and provides you an opportunity to address the deficiencies specified above. 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 adequately address this matter may lead to regulatory action. If you believe that you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.

本函通知您我们的调查结果，并为您提供解决上述缺陷的机会。在收到本函后的15个工作日内，您应书面通知本办公室您为防止今后发生类似违规行为而采取的措施。未能充分解决这一问题可能会导致监管行动。如果您认为自己遵守了FD&C Act 和相关法规，请提供您的理由和任何支持信息，以供我们考虑。

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