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FDA警告信22/11/22--临床试验研究未进行IND(中英文)

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临床试验研究未进行IND,FDA发出警告信。
WARNING LETTER
"David M. Lubeck, M.D./Arbor Centers for EyeCare
MARCS-CMS 643531 — NOVEMBER 18, 2022
FDA Reference Number: 22-HFD-45-11-02
Dear Dr. Lubeck:
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 April 12 and April 20, 2022. Investigator Yuanyuan Li, representing FDA, reviewed your conduct as the sponsor-investigator of the following clinical investigations:
本警告信告知企业在2022年4月12日至4月20日期间,美国食品和药物管理局(FDA)在企业的临床场所进行检查期间观察到的不良情况。代表FDA的研究员李媛媛(yuyuan Li)审查了贵公司作为以下临床研究的赞助研究者的行为:
Protocol (b)(4) , “(b)(4),” of an investigational combination product consisting of the investigational (b)(4) and (b)(4) in combination with (b)(4)
由(b)(4)和(b)(4)与(b)(4)合成的研究性组合产品的(b)(4)、“(b)(4)”协议
Protocol (b)(4), “(b)(4),” of an investigational combination product consisting of the investigational drugs (b)(4) and (b)(4) in combination with (b)(4)
由试验药物(b)(4)和(b)(4)与(b)(4)合成的试验组合产品的(b)(4)、“(b)(4)”协议
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生物研究监控计划的一部分,该计划包括旨在评估研究行为的检查,并帮助确保人类受试者的权利、安全和健康得到保护。
At the conclusion of the inspection, Investigator Li presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your May 10, 2022, written response to the Form FDA 483.
在检查结束时,李研究员向企业提交并讨论了FDA 483表格“检查观察”。我们确认收到了企业2022年5月10日对FDA 483表格的书面回复。
From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your May 10, 2022, written response to the Form FDA 483, 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:
从我们对FDA机构检查报告、与该报告一起提交的文件以及企业于2022年5月10日对FDA 483表格的书面回复来看,企业似乎没有遵守《联邦食品、药物和化妆品法》(FD&C法)中的适用法定要求,以及《联邦法规法典》第312部分(21 CFR 312)第21篇中关于开展临床研究和保护人体受试者的适用法规。我们愿强调以下几点:
You failed to submit an Investigational New Drug application (IND) for the conduct of a clinical investigation with investigational new drugs that is subject to 21 CFR 312.2(a) [21 CFR 312.20(a), 312.20(b), and 312.40(a)].
企业未能提交符合21 CFR 312.2(a) [21 CFR 312.20(a), 312.20(b)和312.40(a)]的临床试验新药临床试验申请(IND)。
FDA regulations require a sponsor to submit, and to have in effect, an IND before initiating a clinical investigation of a drug that is subject to 21 CFR 312.2(a) (see 21 CFR 312.20 and 312.40(a)) in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2. You failed to comply with these requirements. You initiated and conducted a clinical investigation of investigational drugs subject to section 505 of the FD&C Act (21 U.S.C. 355) without submitting and having in effect an IND1. Specifically, you initiated and conducted a clinical investigation of a combination product consisting of the investigational drugs (b)(4) and (b)(4) in combination with (b)(4), conducted under Protocol (b)(4), without submitting and having in effect an IND. There are no FDA records to indicate that you submitted an IND before initiating and conducting this clinical investigation, in which five human subjects were enrolled.
FDA法规要求,在对符合21 CFR 312.2(a)(见21 CFR 312.20和312.40(a))的药物进行人体试验临床研究之前,除非临床研究符合21 CFR 312.2规定的IND豁免,否则发起者必须提交并拥有有效的IND。企业没有遵守这些要求。根据FD&C法案(21 U.S.C. 355)第505条发起并进行了试验用药物的临床研究,但未提交并具有有效的IND1。具体来说,企业发起并进行了一项由试验药物(xx)和(xx)与(xx)联合组成的组合产品的临床研究,根据方案(b)(4)进行,但没有提交和有效的IND。没有FDA记录表明企业在发起和进行该临床研究(该临床研究招募了5名受试者)之前提交了IND。
In your May 10, 2022, written response to the Form FDA 483, you stated that you and an institutional review board (IRB) considered Protocol (b)(4) to be a nonsignificant risk (NSR) device study, with the use of (b)(4) as a generally recognized as safe (GRAS) substance and as “(b)(4).” You further explained that you and the IRB determined that an investigational device exemption (IDE) was not required.
在企业2022年5月10日对FDA 483表格的书面回复中表示,企业和一个机构审查委员会(IRB)认为xx方案是一项非显著风险(NSR)器械研究,将xx作为一种普遍公认的安全(GRAS)物质使用,并作为“xx”。企业进一步解释说,和IRB确定不需要试验器械豁免(IDE)。
However, the investigational product used in Protocol (b)(4) and (b)(4) in combination with (b)(4) comprises both drug and device components and is therefore a combination product within the meaning of section 503(g) of the FD&C Act (21 U.S.C. 353(g)). Because the primary mode of action2 of the investigational combination product is attributable to (b)(4), and because (b)(4) meets the definition of a drug under section 201(g) of the FD&C Act3, an IND is required for any clinical investigation of the investigational combination product used in Protocol (b)(4). In addition, Section 10.3.1 of Protocol (b)(4) noted that “CDER [Center for Drug Evaluation and Research] has primary jurisdiction for the regulation of this product.”
然而,在(b)(4)和(b)(4)方案中使用的试验产品与(b)(4)联合使用,包括药物和器械成分,因此属于FD&C法案(21 U.S.C. 353(g))第503(g)条所指的联合产品。由于研究联合产品的主要作用方式2可归因于(b)(4),并且由于(b)(4)符合FD&C Act3第201(g)条对药物的定义,因此对方案(b)(4)中使用的研究联合产品的任何临床研究都需要IND。此外,协议(b)(4)第10.3.1条指出,“CDER[药物评估和研究中心]对本产品的监管具有主要管辖权。”
You further stated that subject enrollment commenced after IRB approval. However, on October 29, 2019, the IRB notified you that an IND was required. Subsequently, enrollment was immediately halted, the study was paused, and an IND was submitted to FDA. You then stated that you recommenced enrollment in this study only after FDA received the IND on (b)(4), and the IRB gave approval.
企业进一步说明在IRB批准后开始受试者登记。然而,在2019年10月29日,IRB通知企业需要IND。随后,登记立即停止,研究暂停,IND提交给FDA。企业随后声明,只有在FDA收到xx的IND并获得IRB批准后,才重新开始本研究的登记。
Your written response is inadequate for several reasons, including that neither the IRB approval itself nor your enrollment of subjects after receiving IRB approval met your obligation to have an IND in effect before beginning enrollment and treatment of subjects. Also, while we acknowledge that you halted enrollment and ceased study activities upon learning from the IRB that an IND was required to be submitted to the FDA, the IND you submitted to the FDA and referenced in your written response did not contain Protocol (b)(4). Rather, the IND contained a similar but substantively unique clinical protocol, Protocol (b)(4). Protocol (b)(4) clinical investigation of (b)(4) and (b)(4) in combination with (b)(4), whereas Protocol (b)(4) is a (b)(4), (b)(4) and (b)(4) in combination with (b)(4). Therefore, the IND you submitted containing Protocol (b)(4) did not cover the study you initiated under Protocol (b)(4).
企业的书面回复是不充分的,有几个原因,包括IRB的批准本身和企业获得IRB批准后的受试者注册都没有满足企业在开始注册和治疗受试者之前有IND生效的义务。此外,虽然我们承认企业在从IRB获悉需要向FDA提交IND后停止了注册和研究活动,但企业提交给FDA并在书面回复中引用的IND不包含方案b(4)。相反,IND包含了一个类似但实质上独特的临床方案,即方案(b)(4)。(b)(4)方案与(b)(4)结合在一起进行(b)(4)和(b)(4)的临床研究,而(b)(4)方案是a (b)(4)、(b)(4)和(b)(4)与(b)(4)结合在一起。因此,企业提交的包含xx方案的IND不包括企业根据xx方案发起的研究。
Consequently, you initiated a clinical investigation under (b)(4) without submitting an IND, and you administered the study drug to all enrolled subjects. Also, we note that an IND does not go into effect upon FDA’s receipt of the IND submission4; rather, an IND generally goes into effect 30 days after FDA receives the application, or on earlier notification by FDA that the clinical investigation in the IND may begin (21 CFR 312.40(b)). We emphasize that FDA regulations require a sponsor to submit, and to have in effect, an IND before initiating a clinical investigation that must be conducted under an IND in accordance with 21 CFR 312.40.
因此,企业在xx项下启动了一项临床研究,而没有提交IND,并且企业给所有入选受试者使用了该研究药物。此外,我们注意到在FDA收到IND提交后不会生效;相反,IND通常在FDA收到申请后30天内生效,或在FDA提前通知IND的临床研究可能开始时生效(21 CFR 312.40(b))。我们强调,FDA法规要求发起人在启动临床研究前提交并拥有有效的IND,该临床研究必须根据21 CFR 312.40在IND下进行。
Lastly, your response is inadequate because you did not provide a corrective action plan to address how you, as a sponsor-investigator, will determine when an IND is required for clinical investigations of products regulated by FDA, and how you will comply with IND regulations in accordance with 21 CFR 312.2. Without this information, we are unable to determine whether you will comply with IND regulations in the future.
最后,企业的回复是不充分的,因为没有提供一份纠正行动计划,说明企业作为主办方-研究者,将如何确定FDA监管的产品的临床研究何时需要IND,以及企业将如何按照21 CFR 312.2遵守IND规定。如果没有这些信息,我们无法确定企业将来是否会遵守IND的规定。
As a sponsor-investigator, you are responsible for compliance with IND requirements, and it is your responsibility to be aware of and to follow all applicable FDA regulations. Your failure to submit, and to have in effect, an IND before initiating a clinical investigation with investigational drugs raises significant concerns regarding the safety and welfare of enrolled subjects, and also raises concerns about the validity and integrity of data collected at your site during the conduct of the clinical investigation.
作为赞助-研究者,企业有责任遵守IND要求,企业有责任了解并遵守所有适用的FDA法规。企业未能在启动试验用药物的临床研究之前提交并实施IND,这引发了对入选受试者安全和健康的严重担忧,也引发了对临床研究期间在企业现场收集的数据的有效性和完整性的担忧。
This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational combination product. 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.
本信没有列出企业临床研究联合产品的所有缺陷。企业有责任确保遵守法律和相关FDA法规的各项要求。企业应该解决任何不足,并建立程序,以确保任何正在进行或未来的研究符合FDA的规定。
This letter notifies you of our findings and provides you 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 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.
这封信通知企业我们的发现,并为企业提供了一个解决上述缺陷的机会。贵方应在收到本函后15个工作日内,以书面形式将贵方为防止今后发生类似违规行为而采取的措施通知本办公室。未能充分解决这一问题可能导致监管行动。如果企业认为已经遵守了FD&C法案和相关法规,请提供企业的理由和任何支持信息,以供我们考虑。
If you have any questions, please call Miah Jung, Pharm.D., M.S., at 240-402-3728. Alternatively, you may email 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 5352
10903 New Hampshire Avenue
Silver Spring, MD 20993
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/
------------------------------------------------------------
DAVID C BURROW
11/18/2022 11:49:10 AM
______________________
1 Protocol (b)(4) did not qualify for any of the exemptions listed at 21 CFR 312.2 from the application of 21 CFR 312.
1 (b)(4)号议定书不符合21 CFR 312.2中所列21 CFR 312申请的任何豁免。
2 The FD&C Act defines the term primary mode of action as “the single mode of action of a combination product expected to make the greatest contribution to the overall intended therapeutic effects of the combination product” [21 U.S.C. 353(g)(1)(C)]. See also 21 CFR 3.2(m).
2FD&C法将“主要作用方式”定义为“组合产品的单一作用方式,预计对组合产品的总体预期治疗效果做出最大贡献”[21 U.S.C. 353(g)(1)(C)]。另见21 CFR 3.2(m)。
3 In relevant part, the FD&C Act defines the term drug as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals” [21 U.S.C. 321(g)(1)].
3在相关部分中,FD&C法将“药品”一词定义为“旨在用于诊断、治愈、缓解、治疗或预防疾病的物品”和“旨在影响人或其他动物身体结构或任何功能的物品(食品除外)”[21 U.S.C. 321(g)(1)]。
4 While we recognize that you did not in fact enroll any subjects to Protocol 330019 before the IND went into effect, we note that in your May 10, 2022, response, you highlighted that enrollment in the study was “recommenced only after the IND . . . was received on 2 January 2020.”
4虽然我们认识到,在IND生效之前,企业实际上没有登记330019协议的任何受试者,但我们注意到,在企业2022年5月10日的回复中,强调了研究的登记“仅在IND生效后才重新开始……于2020年1月2日收到。”
发布于 2022-12-01 11:32:11 © 著作权归作者所有
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