未按要求保存临床研究记录，FDA发出警告信。
WARNING LETTER
Vasyl Melnyk, M.D.
MARCS-CMS 623671 — DECEMBER 21, 2021
Ref.: 21-HFD-45-12-01
Dear Dr. Melnyk:
This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site from September 13 to September 14, 2021. Investigator Tawny L. Colling, representing FDA, reviewed your conduct of a clinical investigation (b)(4), performed for (b)(4).
本警告信告知贵公司，2021年9月13日至9月14日，美国食品和药物管理局(FDA)在贵司的临床场所进行检查期间发现了缺陷。代表FDA的检查员Tawny L. Colling审查了贵司针对xx进行的xx临床研究的执行情况。
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进行并帮助确保受试者的权利、安全和健康得到保护的检查。
At the conclusion of the inspection, Investigator Colling presented and discussed with you and your staff Form FDA 483, Inspectional Observations.
在检查结束时，调查员Colling提交了FDA 483检查观察表，并与企业人员进行了讨论。
From our review of the FDA Establishment Inspection Report and the documents submitted with that report, 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:
从FDA工厂检查报告和该报告提交的文件的审查来看，企业似乎没有遵守《联邦食品、药物和化妆品法案》(FD&C法案)中的适用法律要求，以及《联邦法规》第312部分(21 CFR 312)第21篇中有关临床调查的适用法规。FDA强调以下几点:
You failed to retain records required to be maintained under 21 CFR Part 312 for a period of two years following the date a marketing application is approved for the drug for the indication for which the drug is being investigated; or, if no application is filed or if the application is not approved for such indication, until two years after the investigation is discontinued [21 CFR 312.62(c)].
未能按照21 CFR Part 312的要求，在药品上市申请被批准后的两年时间内保留该药品正在调查的适应症的记录;或者，如果没有提交该适应症的申请或该适应症的申请未获批准，应该直到调查终止后2年[21 CFR 312.62(c)]。
As a clinical investigator, you are required to retain records of the disposition of the drug, including dates, quantity, and use by subjects, and to retain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. You are required to retain these records for a period of two years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or the application is not approved for such indication, until two years after the investigation is discontinued and FDA is notified.
作为临床研究者，需要保留药物处置的记录，包括日期、数量和受试者的使用情况，并保留充分和准确的病历记录，记录所有观察结果和与研究相关的每个受试者或研究中用作对照的其他数据。贵司需要保留这些记录在该药物的上市申请被批准之日后两年，该适应症正在被调查;或者，如果没有提交申请或该适应症的申请未获批准，则直到调查终止并通知FDA两年后。
You failed to adhere to these requirements. Specifically, for Protocol (b)(4), you failed to retain adequate and accurate case histories, including the following:
企业未能遵守这些要求。具体而言，对于(b)(4)方案，未能保留足够和准确的病例记录，包括以下内容:
Signed and dated informed consent forms for all (b)(4) randomized subjects
所有(b)(4)随机受试者签署并注明日期的知情同意书
Supporting data documenting medical history, study eligibility, adverse events, concomitant medications, progress notes, and visit assessments, including (b)(4), for 16 of the (b)(4) randomized subjects
记录病史、研究资格、不良事件、伴随用药、进展记录和访视评估的支持数据，包括对16名随机受试者的(b)(4)
Case report forms for all (b)(4) randomized subjects
所有(b)(4)随机受试者的病例报告表格
You were required to retain the study records for this protocol because a Biologics License Application had been filed for the indication under study, and the outcome of the application had not yet been determined (that is, approved or not approved) before you lost the study records.
企业需要保留本方案的研究记录，因为在企业丢失研究记录之前，已经针对研究中的适应症提交了生物制剂许可申请，而申请的结果尚未确定(即批准或未批准)。
During the inspection, you stated that all study records were stored in a locked archival room at your site, with access limited to your site personnel only. You stated that once the study was closed by the sponsor, all study records were packed into four boxes and placed into an archiving room. On August 2, 2021, the sponsor’s contract research organization arrived at your site to prepare for this FDA inspection, and noted that study records, including but not limited to the study records specified above, were missing. You explained that you searched other boxes to see if the study records had been misplaced, but you could not locate them. You also stated that the study monitor reviewed study records (subjects’ informed consent forms, medical histories, spirometry reports) during the study and at the closeout visit, and did not have any major comments regarding the documents.
在检查期间，企业声明所有研究记录都存储在现场上锁的一间档案室中，只有企业现场工作人员才能访问。且指出，一旦申办方关闭研究，所有的研究记录都被打包到四个盒子里，并放入档案室。2021年8月2日，申办方的合同研究机构到达贵地准备本次FDA检查，并指出研究记录，包括但不限于上述研究记录缺失。企业解释说找过其他盒子想看看研究记录是否被放错了地方，但企业找不到它们。还表示，研究监测人员在研究期间和结束来访时审查了研究记录(受试者的知情同意书、病史、肺量测量报告)，没有对这些文件做出任何重大评论。
You explained that your department had undergone a reorganization, which made conducting clinical studies more difficult. You suggested this may be why some study records were missing, even though your study staff were the only ones with access to the archival room. You noted that you have not been involved in clinical research since 2020, and that not being able to locate these records reinforced your decision to no longer conduct clinical research in the future.
企业解释说贵司部门进行了改组，这使得进行临床研究更加困难。企业认为这可能是一些研究记录丢失的原因，尽管只有企业的研究人员可以访问档案室。并指出，自2020年以来，企业就没有参与临床研究，由于无法找到这些记录，企业决定在未来不再进行临床研究。
While we acknowledge that you indicated that you do not plan to conduct clinical research in the future, you have not provided any details about how you personally plan to prevent similar violations from occurring if you should change your mind and decide to participate as a clinical investigator in a future clinical investigation. Your explanation, when taken into consideration with the violations described above, suggests systemic failures in your conduct of this clinical investigation.
虽然FDA承认企业表示未来不打算进行临床研究，但未提供任何详细信息。如果企业改变主意并决定以临床研究者的身份参与未来的临床研究，企业还没有提供任何关于个人计划如何防止类似违规行为的发生。考虑到上述违规行为，企业的解释表明在本次临床研究中存在系统性缺陷。
Your failure to retain study records as required by FDA regulations significantly compromises the validity and integrity of data collected at your site.
未能按照FDA法规的要求保留研究记录，严重损害了在企业收集的数据的有效性和完整性。
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.
本函并非企业临床试验药物研究缺陷的全面清单。企业有责任确保遵守法律和FDA相关法规的每一项要求。企业应该解决任何缺陷，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。
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 you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.
企业应在收到本信件后的15个工作日内，以书面形式通知本办事处已采取的措施，以防止未来再次发生类似的违规行为。未能充分解决这一问题可能会导致监管行动。如果企业认为已遵守FD&C法案和相关法规，请提供理由或任何支持信息，以供FDA参考。
If you have any questions, please call Miah Jung, Pharm.D., M.S., at 240-402-3728. Alternatively, you may e-mail FDA at CDER-OSI-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:
Miah Jung, Pharm.D., M.S.
Branch Chief
Compliance Enforcement Branch
Division of Enforcement and Postmarketing Safety
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
Building 51, Room 5219
10903 New Hampshire Avenue
Silver Spring, MD 20993
U.S.A.
Sincerely yours,
{See appended electronic signature page}
David C. Burrow, Pharm.D., J.D.
Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
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This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.
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/s/
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DAVID C BURROW
12/21/2021 10:49:32 AM
