WARNING LETTER

　　Ref.: 20-HFD-45-02-01

　　Dear Dr. Corbett:

　　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 June 26 and July 8, 2019. Ms. Andrace Deyampert, representing FDA, reviewed your conduct of a clinical investigation (Protocol (b)(4), “(b)(4)”) of the investigational drug (b)(4), which you performed as a sponsor-investigator.

　　本警告信告知您在2019年6月26日至7月8日期间在您的临床研究中心进行的美国食品药品监督管理局(FDA)检查期间观察到的不良状况。FDA代表Andrace Deyampert女士对您的临床研究进行了审查(您作为申办者-研究者执行的研究药物(b)(4)的方案编号(b)(4)，“(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.

　　该检查是FDA生物研究监测计划的一部分，该检查旨在评估研究行为并帮助确保人类受试者的权利，安全和福祉得到保护。

　　At the conclusion of the inspection, Ms. Deyampert presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your July 26, 2019, written response to the Form FDA 483.

　　在检查结束时，Deyampert女士向您提交并讨论了FDA 483表“现场检查观察”。我们确认收到了您对FDA 483表格的书面答复(2019年7月26日)。

　　From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated July 26, 2019, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:

　　根据我们对FDA机构检查报告的审查，与该报告一起提交的文件以及您在2019年7月26日的书面答复中，我们得出结论，您未遵守适用的法定要求和FDA法规来管理临床研究和保护人类受试者。我们重点强调以下几点：

　　1. You failed to maintain an effective IND with respect to the investigations (21 CFR 312.50). 对于您进行的临床研究，未维持有效的IND (21 CFR 312.50)

　　FDA terminated IND (b)(4) on June 1, 2014, because FDA did not receive an annual report for your investigation for at least 2 years. As the sponsor-investigator for IND (b)(4) (Protocol (b)(4)), you were required to maintain an effective IND throughout the course of the clinical investigation. You failed to do so, and you continued to conduct the investigation even after FDA terminated the study. According to FDA’s Termination Letter, you were required to submit a new IND if the study drug was subsequently subjected to a clinical investigation.

　　FDA在2014年6月1日终止了IND(b)(4)，因为FDA至少有两年未收到您的临床研究的年度报告。作为IND(b)(4)(协议(b)(4))的申办者-研究者，您需要在整个临床研究过程中保持有效的IND。您没有这样做，即使在FDA终止研究后，您仍继续进行该项研究。根据FDA的终止通知书，如果随后对该研究药物进行了临床调查，则您必须提交新的IND。

　　Specifically, you continued to enroll subjects and administer study drug to 18 subjects after IND termination on June 1, 2014. Subjects were administered study drug until at least January 9, 2018. Thus, subject safety and rights were compromised for a period of more than 3 years.

　　具体来说，您在2014年6月1日IND终止后继续入组受试者并向18名受试者给药研究药物。受试者一直服用研究药物，直到2018年1月9日。因此，受试者的安全和权利受到的损害超过 3年。

　　In your July 26, 2019, written response, you stated that you did not fully understand that an IND was necessary for a study using an FDA-approved drug as a “stressor” in a normal healthy subject population. You stated that you further did not understand your responsibilities as a sponsor-investigator to maintain the IND throughout the conduct of this study. We acknowledge that your written response indicated that you will discontinue conduct of all FDA-regulated research as either a sponsor or clinical investigator, effective immediately. However, your response is inadequate because you failed to explain how you would conduct clinical investigations if you should undertake research in the future.

　　在您2019年7月26日的书面答复中，您表示您不完全了解在正常健康受试者人群中使用FDA批准的药物作为“应激物”进行研究的必要条件。您说您还不理解您作为申办者-研究者在整个研究过程中维护IND的责任。我们承认您的书面回复表明您将终止所有以FDA监管的临床研究，无论是以申办者还是以研究者的身份，并立即生效。但是，您的回答不充分，因为您未解释如果将来进行研究时，将如何进行临床研究。

　　We wish to emphasize that, as the sponsor-investigator, you are responsible for ensuring that an investigational new drug be used in a clinical investigation only if you have submitted an IND to FDA and the IND remains in effect throughout the course of the investigation. Your enrollment of subjects and your administration of study drug after IND termination raise significant concerns about the adequacy of your protection of study subjects.

　　我们希望强调，作为申办者-研究者，您有责任确保仅在将IND提交给FDA且IND在整个调查过程中仍然有效的情况下，才能将研究的新药物用于临床研究。在IND终止后，您的受试者入组和研究药物的给药引起了对您保护研究受试者的充分性的重大担忧。

　　2. You failed to promptly report all changes in research activity to the Institutional Review Board (IRB) [21 CFR 312.66]. 您没有及时向研究机构审查委员会(IRB)报告所有研究活动的变化。[21 CFR 312.66]

　　As a sponsor-investigator, you are required to promptly report to the IRB all changes in research activity. You failed to promptly report to the IRB all changes in research activity.

　　作为申办者-研究者，您需要立即向IRB报告研究活动的所有变化。您没有及时向IRB报告研究活动的所有变化。

　　Specifically, you did not promptly report to the IRB FDA’s February 5, 2014, Pre-termination Letter or FDA’s June 1, 2014, Termination Letter.

　　具体来说，您没有立即向IRB 报告FDA的2014年2月5日终止通知书或FDA的2014年6月1日终止书报告。

　　Your failure to promptly report all changes in research activity to the IRB prevented the IRB from completing a full review of your application to conduct the clinical investigation, because the IRB was not given FDA’s Pre-termination Letter and Termination Letter. As a result, the IRB was unable to make an informed determination regarding the continued safety of the subjects enrolled in your clinical investigation.

　　您未及时向IRB报告研究活动的所有变化，从而使IRB无法完成对您进行临床研究的申请的完整审查，因为IRB没有收到FDA的终止前通知书和终止报告。结果，IRB无法就参与您的临床研究的受试者的持续安全性做出知情决定。

　　We wish to emphasize that, as the sponsor-investigator, you are responsible for promptly reporting to the IRB all changes in research activity. Your failure to promptly report to the IRB all changes in research activity raises significant concerns about your protection of study subjects enrolled in the study mentioned above.

　　我们希望强调，作为申办者-研究者，您有责任及时向IRB报告研究活动的所有变化。您未能及时向IRB报告所有研究活动的变化，这使您对保护参加上述研究的受试者产生了极大的担忧。

　　3. You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].您无法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 requires that you exclude subjects with cardiac atrioventricular conduction abnormalities. You failed to adhere to these requirements. Specifically, Subject (b)(6) had first-degree atrioventricular block.

　　作为临床研究人员，您需要确保根据研究计划进行临床研究。研究计划要求您排除心脏房室传导异常的受试者。您没有遵守这些要求。具体而言，受试者(b)(6)具有一级房室传导阻滞。

　　We acknowledge that your July 26, 2019, written response indicated that you will discontinue conduct of all FDA-regulated research as either a sponsor or clinical investigator, effective immediately. However, your response is inadequate because you failed to explain how you would conduct clinical investigations if you should undertake research in the future. As a clinical investigator, you are responsible for ensuring that all enrolled subjects meet eligibility criteria. Enrollment of subjects who do not meet eligibility criteria jeopardizes subject safety and welfare.

　　我们确认您在2019年7月26日的书面回复中指出，您将以申办者或临床研究人员的身份终止所有FDA监管的研究，该研究立即生效。但是，您的回答不充分，因为您无法解释如果将来应该进行研究将如何进行临床研究。作为临床研究人员，您有责任确保所有已入组的受试者均符合资格标准。不符合资格标准的受试者的入学会危害受试者的安全和福祉。

　　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 these deficiencies and establish procedures to ensure that any ongoing or future studies comply with FDA regulations.

　　这封信未将您的研究药物临床研究中的所有缺陷都包括在内。您有责任确保遵守法律和FDA相关法规的每一项要求。您应解决这些缺陷并建立流程，以确保任何正在进行的或将来的研究均符合FDA法规。

　　Within fifteen (15) working 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 the violations noted above adequately and promptly may result in regulatory action without further notice. If you believe you have complied with FDA regulations, include your reasoning and any supporting information for our consideration.

　　在收到此函后的十五(15)个工作日内，您应将为防止将来再次发生类似违规行为而采取的行动以书面形式通知本办公室。如果未能充分及时地解决上述违规行为，可能会导致监管行动，恕不另行通知。如果您认为自己已遵守FDA法规，请提供您的理由和任何支持信息，以供我们考虑。

　　以下略。。

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