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日期間在您的臨床研究中心進行的美國食品藥品監督管理局（FDA）檢查期間觀察到的不良狀況。FDA代表Andrace Deyampert女士對您的臨床研究進行了審查（您作為申辦者-研究者執行的研究藥物（b）（4）的方案編號（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.
該檢查是FDA生物研究監測計劃的一部分，該檢查旨在評估研究行為並幫助確保人類受試者的權利，安全和福祉得到保護。
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.
在檢查結束時，Deyampert女士向您提交並討論了FDA 483表「現場檢查觀察」。我們確認收到了您對FDA 483表格的書面答覆（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:
根據我們對FDA機構檢查報告的審查，與該報告一起提交的文件以及您在2019年7月26日的書面答覆中，我們得出結論，您未遵守適用的法定要求和FDA法規來管理臨床研究和保護人類受試者。我們重點強調以下幾點：
1. You failed to maintain an effective IND with respect to the investigations (21 CFR 312.50). 對於您進行的臨床研究，未維持有效的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日終止了IND（b）（4），因為FDA至少有兩年未收到您的臨床研究的年度報告。作為IND（b）（4）（協議（b）（4））的申辦者-研究者，您需要在整個臨床研究過程中保持有效的IND。您沒有這樣做，即使在FDA終止研究後，您仍繼續進行該項研究。根據FDA的終止通知書，如果隨後對該研究藥物進行了臨床調查，則您必須提交新的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.
具體來說，您在2014年6月1日IND終止後繼續入組受試者並向18名受試者給藥研究藥物。受試者一直服用研究藥物，直到2018年1月9日。因此，受試者的安全和權利受到的損害超過 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日的書面答覆中，您表示您不完全了解在正常健康受試者人群中使用FDA批准的藥物作為「應激物」進行研究的必要條件。您說您還不理解您作為申辦者-研究者在整個研究過程中維護IND的責任。我們承認您的書面回復表明您將終止所有以FDA監管的臨床研究，無論是以申辦者還是以研究者的身份，並立即生效。但是，您的回答不充分，因為您未解釋如果將來進行研究時，將如何進行臨床研究。
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.
我們希望強調，作為申辦者-研究者，您有責任確保僅在將IND提交給FDA且IND在整個調查過程中仍然有效的情況下，才能將研究的新藥物用於臨床研究。在IND終止後，您的受試者入組和研究藥物的給藥引起了對您保護研究受試者的充分性的重大擔憂。
2. You failed to promptly report all changes in research activity to the Institutional Review Board (IRB) [21 CFR 312.66]. 您沒有及時向研究機構審查委員會（IRB）報告所有研究活動的變化。[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.
作為申辦者-研究者，您需要立即向IRB報告研究活動的所有變化。您沒有及時向IRB報告研究活動的所有變化。
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.
具體來說，您沒有立即向IRB 報告FDA的2014年2月5日終止通知書或FDA的2014年6月1日終止書報告。
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.
您未及時向IRB報告研究活動的所有變化，從而使IRB無法完成對您進行臨床研究的申請的完整審查，因為IRB沒有收到FDA的終止前通知書和終止報告。結果，IRB無法就參與您的臨床研究的受試者的持續安全性做出知情決定。
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.
我們希望強調，作為申辦者-研究者，您有責任及時向IRB報告研究活動的所有變化。您未能及時向IRB報告所有研究活動的變化，這使您對保護參加上述研究的受試者產生了極大的擔憂。
3. You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].您無法確保根據研究計劃進行研究。[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.
作為臨床研究人員，您需要確保根據研究計劃進行臨床研究。研究計劃要求您排除心臟房室傳導異常的受試者。您沒有遵守這些要求。具體而言，受試者（b）（6）具有一級房室傳導阻滯。
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.
我們確認您在2019年7月26日的書面回覆中指出，您將以申辦者或臨床研究人員的身份終止所有FDA監管的研究，該研究立即生效。但是，您的回答不充分，因為您無法解釋如果將來應該進行研究將如何進行臨床研究。作為臨床研究人員，您有責任確保所有已入組的受試者均符合資格標準。不符合資格標準的受試者的入學會危害受試者的安全和福祉。
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.
這封信未將您的研究藥物臨床研究中的所有缺陷都包括在內。您有責任確保遵守法律和FDA相關法規的每一項要求。您應解決這些缺陷並建立流程，以確保任何正在進行的或將來的研究均符合FDA法規。
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.
在收到此函後的十五（15）個工作日內，您應將為防止將來再次發生類似違規行為而採取的行動以書面形式通知本辦公室。如果未能充分及時地解決上述違規行為，可能會導致監管行動，恕不另行通知。如果您認為自己已遵守FDA法規，請提供您的理由和任何支持信息，以供我們考慮。
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