WARNING LETTER

FDA Ref. No.: 24-HFD-45-12-01

尊敬的Shah博士：

這封警告信通知您，在2022年12月5日至12月16日期間，美國(guó)食品藥品監(jiān)督管理局（FDA）對(duì)您的臨床中心進(jìn)行審查時(shí)發(fā)現(xiàn)了不合規(guī)情況。代表FDA的檢查員Kristin M. Abaonza審查了您進(jìn)行的一項(xiàng)臨床研究（方案（b）（4），“(b)（4）”）的研究新藥（b）（4），屬于（b）（4）的范疇。

此次檢查是作為FDA的生物研究監(jiān)管計(jì)劃的一部分進(jìn)行的，其中包括旨在評(píng)估研究行為以及確保保護(hù)人類受試者的權(quán)利、安全和福利的檢查。

檢查結(jié)束時(shí)，檢查員Abaonza向您呈交并討論了FDA檢查觀察表。我們已收到您于2023年1月9日的書面回復(fù)FDA觀察表，以及您于2023年2月9日之后的通訊。

經(jīng)過我們對(duì)FDA機(jī)構(gòu)檢查報(bào)告、提交此報(bào)告的文件以及您于2023年1月9日和2月9日的書面回復(fù)的評(píng)估，似乎您沒有遵守聯(lián)邦食品、藥品和化妝品法案（FD＆C法案）中適用的法定要求和21 CFR第312部分中包含的適用法規(guī)，這些法規(guī)規(guī)定了臨床研究的進(jìn)行方式。我們希望強(qiáng)調(diào)以下幾點(diǎn)：

您未能確保研究按照21 CFR 第312.60條的要求進(jìn)行。

作為臨床研究者，您有責(zé)任確保您的臨床研究按照研究計(jì)劃進(jìn)行。方案(b)(4)的研究計(jì)劃要求，與研究定義的療效終點(diǎn)相關(guān)的醫(yī)生評(píng)定評(píng)估應(yīng)由對(duì)安全評(píng)估（例如臨床實(shí)驗(yàn)室評(píng)估、生命體征、體格檢查和不良事件評(píng)估）進(jìn)行盲態(tài)評(píng)估的評(píng)估員完成。盲態(tài)評(píng)估員負(fù)責(zé)進(jìn)行方案要求的療效評(píng)估，包括蒙哥馬利-阿斯伯格抑郁評(píng)定量表（MADRS）評(píng)估，在第2次訪視至第8次訪視或提前終止期間，所有訪視都需要完成。方案(b)(4)還指定盲態(tài)評(píng)估員不得使用ClinTrak電子數(shù)據(jù)采集系統(tǒng)，并且不得接觸可能泄露受試者治療分組信息的受試者基礎(chǔ)數(shù)據(jù)（包括化驗(yàn)結(jié)果、心電圖、不良事件、伴隨用藥、患者自述結(jié)果和臨床醫(yī)生報(bào)告的安全評(píng)估）。您未能遵守此要求。

具體而言，作為指定的盲態(tài)評(píng)估員，您為貴單位招募的三位受試者共進(jìn)行了16次MADRS評(píng)估（受試者(b)(6)進(jìn)行了5次MADRS評(píng)估，受試者(b)(6)進(jìn)行了6次MADRS評(píng)估，受試者(b)(6)進(jìn)行了5次MADRS評(píng)估）。然而，您對(duì)某些安全評(píng)估并未保持盲態(tài)。例如，對(duì)于受試者(b)(6)，您評(píng)估了生命體征測(cè)量，包括血壓、心率和體溫。此外，對(duì)于受試者(b)(6)，您還評(píng)估了臨床化驗(yàn)報(bào)告并進(jìn)行了體格檢查。

在檢查過程中，您承認(rèn)不僅查閱了研究記錄、征得了受試者的同意并進(jìn)行了與研究相關(guān)的評(píng)估，還為所有三位受試者進(jìn)行了16個(gè)MADRS評(píng)估。您表示，當(dāng)您意識(shí)到這些評(píng)估應(yīng)由對(duì)安全評(píng)估不知情的評(píng)估員進(jìn)行時(shí)，隨后您提交了一個(gè)方案偏離，并沒有進(jìn)行任何額外的MADRS評(píng)估。

此外，在2023年1月9日對(duì)FDA 483表格的書面回復(fù)中，您再次承認(rèn)為所有三位受試者進(jìn)行了16個(gè)MADRS評(píng)估。您還詳細(xì)說明了您所在研究機(jī)構(gòu)計(jì)劃采取的糾正和預(yù)防措施，包括：（1）明確標(biāo)識(shí)與盲態(tài)有關(guān)的方案要求，并在源記錄表上注明盲態(tài)的評(píng)估；（2）咨詢申辦方和第三方質(zhì)量咨詢團(tuán)隊(duì)，以明確理解方案中的任何模糊之處，在填寫授權(quán)報(bào)或歸檔源文件時(shí)也是如此；（3）臨床研究負(fù)責(zé)人和研究機(jī)構(gòu)人員參加各種臨床研究合規(guī)培訓(xùn)，例如GCP 培訓(xùn)，您在2023年2月9日的后續(xù)書面回復(fù)中提供了培訓(xùn)證書。

雖然我們承認(rèn)您所在研究機(jī)構(gòu)已經(jīng)采取和計(jì)劃采取的行動(dòng)，但是您的回復(fù)是不充分的，因?yàn)槟鷽]有提供關(guān)于糾正措施計(jì)劃的足夠詳細(xì)信息。例如，您沒有提供足夠詳細(xì)的信息，說明在進(jìn)行未來的臨床研究時(shí)，您所在研究機(jī)構(gòu)實(shí)施的建議做法以確保符合研究方案，包括盲態(tài)程序的方案要求。沒有這些信息，我們無法確定您的糾正措施是否足夠，能夠幫助防止類似違規(guī)事件的再次發(fā)生。

我們強(qiáng)調(diào)，作為臨床研究者，您有責(zé)任確保研究按照研究計(jì)劃進(jìn)行，并確保研究數(shù)據(jù)的完整性。方案（b）（4）的主要目的是評(píng)估研究藥物與安慰劑在改善（b）（4）的患者中的療效，評(píng)估指標(biāo)是從基線到第4周（第29天）的MADRS評(píng)分變化。您以非盲評(píng)估員的身份對(duì)每位入組受試者進(jìn)行了至少五次七次必需的MADRS評(píng)估，并未保證按照方案要求的盲態(tài)程序進(jìn)行，這引起了對(duì)在您的研究中收集到的數(shù)據(jù)可靠性和完整性的重大關(guān)注。

此信函并非您進(jìn)行研究藥物的臨床研究中存在的所有缺陷的全面清單。您有責(zé)任確保遵守法律和相關(guān)FDA規(guī)定的每個(gè)要求。您應(yīng)解決任何缺陷，并建立程序以確保任何正在進(jìn)行或?qū)磉M(jìn)行的研究符合FDA規(guī)定。

本信函通知您我們的發(fā)現(xiàn)，并為您提供解決上述缺陷的機(jī)會(huì)。在收到本信函后的15個(gè)工作日內(nèi)，您應(yīng)書面通知本辦公室您已采取的措施，以防止類似的違規(guī)行為。不采取足夠措施解決此事可能會(huì)導(dǎo)致監(jiān)管行動(dòng)。如果您認(rèn)為您已遵守FD＆C法案和相關(guān)法規(guī)，請(qǐng)附上您的理由和任何支持信息供我們考慮。

Note: 以上中文翻譯由 ChatGPT3.5進(jìn)行，僅供參考。

WARNING LETTER

FDA Ref. No.: 24-HFD-45-12-01

Dear Dr. Shah:

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 December 5 and December 16, 2022. Investigator Kristin M. Abaonza, representing FDA, reviewed your conduct of a clinical investigation (Protocol(b)(4), “(b)(4)”) of the investigational drug (b)(4), performed for (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.

At the conclusion of the inspection, Investigator Abaonza presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your January 9, 2023, written response to the Form FDA 483, and your subsequent correspondence dated February 9, 2023.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses dated January 9 and February 9, 2023, 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:

You failed to ensure that the investigation was conducted according to the investigational plan [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 the clinician-administered assessments related to study-defined efficacy endpoints to be completed by a rater who was blinded to the safety assessments (for example, clinical laboratory evaluations, vital signs, physical examinations, and adverse event assessments). The blinded assessor was responsible for administering protocol required efficacy assessments, including the Montgomery-Asberg Depression Rating Scale (MADRS) assessments, that were required to be completed during all study visits from Visit 2 until Visit 8 or early termination. Protocol (b)(4), also specified that the blinded assessor would not have access to the ClinTrak Electronic Data Capture system and should not have access to subject source data (including laboratory results, electrocardiograms, adverse events, concomitant medications, patient-reported outcomes, and clinician-reported outcomes that are completed by investigators responsible for the assessment of subject safety) that could potentially unblind the assessor to a subject’s treatment assignment. You failed to adhere to this requirement.

Specifically, as a designated blinded rater, you conducted a total of 16 MADRS assessments for all three subjects enrolled at your site (five MADRS assessments for Subject(b)(6), six MADRS assessments for Subject (b)(6), and five MADRS assessments for Subject (b)(6)). However, you were not blinded to certain safety assessments. For example, for Subject (b)(6), you evaluated safety assessments such as vital-sign measurements, including blood pressure, heart rate, and body temperature. Additionally, for Subject (b)(6), you assessed a clinical laboratory report and performed a physical examination.

During the inspection, you acknowledged that you not only reviewed study records, consented subjects, and performed study-related assessments, but you also conducted 16 MADRS assessments for all three subjects. You stated that when you realized that the assessments should be conducted by a rater blinded to the safety assessments, you subsequently filed a protocol deviation and did not conduct any additional MADRS assessments.

Further, in your January 9, 2023, written response to the Form FDA 483, you again acknowledged that you conducted 16 MADRS assessments for all three subjects. You also detailed the corrective and preventive actions your site planned to take, including: (1) clearly identifying protocol requirements that concern blinding, and annotating the source worksheets to clearly identify blinded assessments; (2) consulting with both the sponsor and a third-party quality consulting group to provide clarity in understanding any ambiguities in the protocol, in completing the Delegation of Authority log, or in filing source documents; and (3) clinical investigator and site personnel participation in various clinical research compliance trainings, such as Good Clinical Practice training, for which you provided the training certificates in your February 9, 2023, follow-up written response.

While we acknowledge the actions that your site has taken and plans to take, your response is inadequate because you did not include sufficient details about your corrective action plan. For example, you did not provide sufficient details about the implementation of the proposed practices being instituted at your site to ensure compliance with study protocols, including protocol requirements for blinding procedures, when conducting future clinical investigations. Without this information, we are unable to determine whether your corrective actions appear adequate to help prevent similar violations in the future.

We emphasize that as the clinical investigator, it is your responsibility to ensure that the study is conducted in accordance with the investigational plan and to ensure the integrity of the study data. The primary objective of Protocol(b)(4), was to assess the efficacy of the investigational drug compared to placebo in improving (b)(4) in subjects with (b)(4), as assessed by the change in the MADRS score from Baseline to Week 4 (Day 29). Your administration of at least five of the seven required MADRS assessments for each enrolled subject as an unblinded assessor, as well as your failure to ensure that protocol-required blinding procedures were followed, raises significant concerns about the reliability and integrity of the data collected at your site.

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.

This letter notifies you of our findings and provides you with 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 address this matter adequately 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.

Note: 以上中文翻譯由 ChatGPT3.5進(jìn)行，僅供參考。