史赛克（北京）医疗器械有限公司报告，由于包装标签上的产品信息和实物不一致，生产商瑞士史赛克有限公司 Stryker GmbH对其生产的髓内钉系统T2 Nailing Systems（国械注进20163132780）主动召回。召回级别为三级召回。本次召回涉及的产品未进口至中国，具体型号、规格及批次等详细信息见《医疗器械召回事件报告表》。　　附件：医疗器械召回事件报告表2025年6月11日

登士柏西诺德牙科产品（上海）有限公司报告，由于部分产品泡罩存在密封不良问题（泡罩U形对应侧未密封），生产商迈菲牙科器械控股公司MAILLEFER INSTRUMENTS HOLDING SARL对其生产的牙科机用根管锉Protaper Next（国械注进20152171646）主动召回。召回级别为三级召回。本次召回涉及的产品未进口至中国，具体型号、规格及批次等详细信息见《医疗器械召回事件报告表》。　　附件：医疗器械召回事件报告表2025年6月11日

迈柯唯（上海）医疗设备有限公司报告，由于呼吸机在新生儿模式下联合使用第三方品牌的主动式湿化器执行使用前测试时，在没有泄漏的情况下仍无法通过泄露测试，生产商迈柯唯重症监护有限公司Maquet Critical Care AB对其生产的呼吸机（国食药监械(进)字2014第3543624号、国食药监械(进)字2014第3543625号）、呼吸机Critical Care Ventilator（国械注进20193082109、国械注进20193082113）主动召回。召回级别为二级召回。本次召回涉及的产品未进口至中国，具体型号、规格及批次等详细信息见《医疗器械召回事件报告表》。　　附件：医疗器械召回事件报告表2025年6月11日

赛默飞世尔科技（中国）有限公司报告，由于受影响批次产品可能会出现一种非典型的深色，这可能导致药敏板无法被自动读取或最低抑菌浓度结果超出规格，生产商睿酶公司 Remel, Inc 对其生产的药敏接种培养液（国械备20140220）主动召回。召回级别为三级召回。本次召回涉及的产品未进口至中国，具体型号、规格及批次等详细信息见《医疗器械召回事件报告表》。附件：医疗器械召回事件报告表2025年6月11日

行政相对人名称安徽中祥义齿有限公司行政相对人类别法人及非法人组织行政相对人代码_1(统一社会信用代码)91340100MA2RPY0N25行政相对人代码_2(工商注册号)行政相对人代码_3(组织机构代码)行政相对人代码_4(税务登记号)行政相对人代码_5(事业单位证书号)行政相对人代码_6(社会组织登记证号)法定代表人丁娜法定代表人证件类型法定代表人身份证号证件类型证件号码行政处罚决定书文号皖药监械处罚〔2025〕1-10号违法行为类型《医疗器械监督管理条例》第三十五条第一款违法事实当事人生产定制式义齿使用的3D打印纯钛大钢托、3D打印纯钛小钢托的原材料及生产工艺均发生实质性改变，质量管理体系存在风险，影响产品安全、有效。当事人销售涉案产品金额合计136058元，货值金额136058元。暂扣或吊销证照名称及编号处罚依据《医疗器械监督管理条例》第八十六条第（二）项处罚类别罚款处罚名称安徽中祥义齿有限公司未按照经注册产品技术要求组织生产定制式义齿，影响产品安全、有效案处罚内容处货值金额2.5倍罚款340145元。罚款金额(万元)34.0145没收违法所得、没收非法财物的金额(万元)0处罚决定日期2025年06月10日处罚有效期2099年12月31日公示截止期2028年06月10日处罚行政机关安徽省药品监督管理局处罚机关统一社会信用代码11340000MB19570665数据来源单位安徽省药品监督管理局数据来源单位统一社会信用代码11340000MB19570665地方编码340000处罚状态有效备注

为加强医疗器械生产环节监督管理，保障医疗器械产品质量安全有效，省药品监督管理局组织对省内部分医疗器械生产企业进行了产品质量监督抽检，涉及气动吸脂仪、一次性使用输液器（带针）、造牙树脂、一次性使用负压封闭引流及管路系统、妇科凝胶（敷料）类等9个品种。经检验，有2批（台）产品不符合标准规定，详细信息见附件。对抽检发现的不合格产品，省药品监督管理局已将抽检结果通报生产企业所在地检查分局，要求依法依规开展调查处置。并督促企业对抽检不符合标准规定产品进行风险评估，主动召回产品并公开召回信息，尽快查明原因，制定整改措施并及时整改到位。特此通告。 附件:抽检不符合标准规定产品名单 山西省药品监督管理局   2025年6月9日 （主动公开） 附件 抽检不符合标准规定产品名单序号标示产品名称被抽查单位标示注册人、代理人规格型号生产日期/批号/出厂编号不符合标准规定项目1卡波姆妇科敷料　临汾市侯马经济开发区赛凌医药科技有限公司临汾市侯马经济开发区赛凌医药科技有限公司2.9g/支　2024070620240706pH值2气动吸脂仪　山西阳光中天医疗器械有限公司山西阳光中天医疗器械有限公司JNZB-A　2023-06-192023010071.输入功率；2.阻抗和载流能力；3.手柄负压调节范围　

Delivery Method:Via EmailProduct:DrugsRecipient:Kimberly Moody, Co-OwnerBridget Conzemius, Co-OwnerBio Wellness 444 LLC9003 Palm Key AveOldsmar,FL34677United Statessupport@biowellness444.comIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWARNING LETTERMay 30, 2025RE: 709333Dear Ms. Moody and Ms. Conzemius:This letter is to advise you that on March 10th, 2025 the U.S. Food and Drug Administration (FDA) reviewed your product labeling, including on your website, biowellness444.com, where your “Silver Bullet elite douche” and “Silver D elite douche” drug products are available for purchase in the United States without a prescription. We also reviewed your social media on Instagram at “biowellness444,” which directs consumers to your website to purchase your products.“Silver Bullet elite douche” and “Silver D elite douche” drug products are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of sections 505(a) and 301(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act,) 21 U.S.C. 355(a), 331(d). These violations are described in more detail below.Unapproved New Drug Violations“Silver Bullet elite douche” and “Silver D elite douche” are “drugs” as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body.Examples from the “Silver Bullet elite douche” and “Silver D elite douche” product labeling, including your website listed above, that provide evidence of the intended uses (as defined in 21 CFR 201.128) of the products as drugs include, but may not be limited to, the following:“Silver Bullet elite douche”“Why Silver Bullet Elite Douche?Colloidal silver has been used for over 2,000 years to relieve the symptoms of various health condition including the effects of viruses and bacterial infections. Silver Bullet incorporates colloidal silver containing 0.8 nanometers with 99% bioactive silver ions… [from product label]“Silver Bullet elite douche” and “Silver D elite douche”“…Biowellness 444 stands out-largely due to our proprietary blend of powerful, all-natural with only 2-ingredients: ·Colloidal Silver: Known for its potent antibacterial effects…” [from your product website]“Check out my douche, the elite douche, it’s a formula of colloidal silver, which has been used for thousands of years to combat all strands of bacteria…so if you have any issues with bacterial vaginosis or yeast infections use my douche you’ll see immediate results…” [transcription from your Instagram social media page video]“Hey ladies, if you have any issues down there such as bacterial vaginosis or yeast infections check out my product, the elite douche. That’s the three-day cleanser, the one-day cleanser and it will give you immediate relief…” [transcription from your Instagram social media page video]“Frequently Asked Questions (FAQs)…What makes your product so different from the other products on the market?We are the only Douche Product on the market that contains the combination of Colloidal Silver and Tea Tree Oil...” [from your product website]“Testimonials… ‘This product is amazing!I had the onset of a yeast infection and tried this product for instant relief. I’m very prone to UTI’s and yeast infections.I’ve never felt relief as quickly as I did after first use…” [from your product website]“Tea tree oil and colloidal silver are better together…Combining these two, natural antibiotics has proven to be make them [sic] more effective at killing microorganisms...” [from your product website]Based on the above labeling evidence “Silver Bullet elite douche” and “Silver D elite douche” are over-the-counter (OTC) colloidal silver-containing drug products intended for use in the treatment of vaginal infections. The Agency has determined that any OTC drug product containing colloidal silver ingredients or silver salts that is labeled, represented, or promoted for the treatment and/or prevention of any disease is regarded as a new drug within the meaning of section 201(p) of the FD&C Act, and that all such products are deemed to be new drugs and require an approved new drug application or abbreviated new drug application under section 505 of the FD&C Act to be lawfully marketed according to 21 CFR 310.548(b).No FDA-approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355 are in effect for these products. Thus, “Silver Bullet elite douche” and “Silver D elite douche” are unapproved new drugs marketed in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of these products into interstate commerce violates section 301(d) of the FD&C Act, 21 U.S.C. 331(d).ConclusionThe violations cited in this letter are not intended to be an all-inclusive list of violations that may exist in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations.This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address this matter may result in legal action including, without limitation, seizure, and injunction.Please notify FDA in writing, within 15 working days of receipt of this letter, of the specific steps you have taken to correct any violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration. If you cannot complete corrective action within 15 working days, state the reason for the delay and the time within which you will complete the correction. Your response should be sent to U.S. Food and Drug Administration, CDER/OC/Office of Unapproved Drugs and Labeling Compliance by email to FDAAdvisory@fda.hhs.gov and include your firm name in the subject line of your email.Sincerely,/S/CAPT Tina SmithOffice DirectorOffice of Unapproved Drugs and Labeling ComplianceOffice of ComplianceCenter for Drug Evaluation and ResearchFood and Drug Administration

Delivery Method:VIA EMAIL WITH READ RECEIPTReference #:320-25-76Product:DrugsRecipient:Ms. Manon PilonPresidentLaboratoire Druide Inc.154 Oneida Ave.Pointe-ClaireQCH9R 1A8CanadaIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWarning Letter320-25-76May 29, 2025Dear Ms. Pilon:The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Laboratoires Druide Inc., FEI 3008226137, at 154 Oneida Avenue, Pointe-Claire, Quebec, Canada, from February 10 to 14, 2025.This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).We reviewed your March 6, 2025 response to our Form FDA 483 in detail.During our inspection, our investigator observed specific violations including, but not limited to, the following.1. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).Your firm manufactures over-the-counter (OTC) drug products, such as(b)(4), sunscreens, skin protectants,(b)(4), and hand sanitizer. You failed to conduct adequate identity testing on incoming components, such as inactive ingredients, used in the manufacture of your OTC drug products. Furthermore, you relied on your suppliers’ certificates of analysis (COAs) without establishing the reliability of each of your component suppliers’ analyses at appropriate intervals.You failed to adequately test each shipment of each lot of glycerin at high risk of diethylene glycol (DEG) and ethylene glycol (EG) contamination. Identity testing for glycerin and certain other high-risk drug components includes a limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for levels of DEG or EG. Because you did not perform adequate identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in manufacture of your drug product.The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance documentTesting of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycolto help you meet the CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.In your response, you state that you source your excipients from producers holding GMP or(b)(4)certification and that the glycerin manufacturer conducts the DEG/EG testing.Your response is inadequate. You do not commit to performing at least one identity test for each lot of incoming raw materials nor do you provide sufficient details on how you will establish the reliability of your component suppliers’ COAs at appropriate intervals. Furthermore, you do not address how you will assess the quality of your components used in previously distributed drug products that are within expiry.In response to this letter, provide:A commitment to provide DEG and EG test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a retain of a component lot is unavailable, perform retain sample testing of all implicated finished drug product lots for the presence of DEG and EG.A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG or EG contamination (including, but not limited to, glycerin). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain DEG or EG, including customer notifications and product recalls for any contaminated lots. Identify additional appropriate corrective action and preventive action (CAPA) that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of glycerin and certain additional high-risk components we note that this includes the performance of parts A, B, and C of the USP monograph.The chemical and microbiology quality control specifications you use to test each incoming shipment of each incoming lot of components, including, high-risk drug components to determine acceptability for use in manufacturing.A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.2. Your firm failed to establish adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess (21 CFR 211.100(a)).Inadequate(b)(4)ValidationYou failed to adequately qualify your(b)(4)to ensure it produces(b)(4)that meets appropriate chemical and microbial attributes for use in your OTC drug product manufacturing and equipment cleaning. You failed to test for total organic carbon (TOC), and your conductivity limit is inappropriate as it exceeds the(b)(4)USP monograph specifications. Furthermore, you did not monitor your(b)(4)for absence of biofilm forming microbes, such asBurkholderia cepaciacomplex (BCC). Additionally, you lacked documentation showing that you investigated out-of-specification microbiological test results obtained during validation of your(b)(4)that indicated your(b)(4)may not be in a state of control.In your response, you state that you have established a procedure for sampling the(b)(4)prior to use in production and added TOC testing. You also state that you revised the procedure for(b)(4)and added alert and action limits.Your response is inadequate because you do not provide supporting documentation and do not include a risk assessment of the drug products manufactured and released using the unsuitable(b)(4).Lack of Process ValidationYou lacked process validation data for your OTC drug products, such as(b)(4), sunscreens, skin protectants,(b)(4), and hand sanitizer. During the inspection, you were unable to provide the bulk hold time study for your(b)(4), which may be held in(b)(4). You had no data to demonstrate that your hold time did not adversely affect the quality of your drugs, including bioburden of the bulk formulation.In your response, you state that you test all finished products prior to release to ensure they meet the quality attributes.Your response is inadequate as you do not provide a timeframe for completion of process validation activities for each of your drug products, and your interim plan for any drugs distributed before validation activities are completed to ensure you produce drug products of acceptable quality.Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to determine whether an initial state of control has been established.Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.See FDA’s guidance documentProcess Validation: General Principles and Practicesfor general principles and approaches that FDA considers appropriate elements of process validation, at https://www.fda.gov/media/71021/download.In response to this letter, provide:A comprehensive, independent assessment of your(b)(4)design, control, and maintenance.A thorough remediation plan to install and operate a suitable(b)(4). Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design consistently produces(b)(4)adhering to(b)(4), USP monograph specifications, and appropriate microbial limits.Regarding the latter, ensure that your total microbial count limit and specified objectionable microorganisms for(b)(4)is appropriate in view of the intended use of the products produced by your firm.A detailed risk assessment addressing the potential effects of the observed(b)(4)failures on the quality of all drug product lots currently in U.S. distribution. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.A process validation protocol which evaluates the impact of process variability (i.e., excipient and API quality, hold times,(b)(4), etc.) and determines appropriate control limits to ensure the quality of your finished drug products.An equipment qualification protocol as well as a calibration and maintenance program, as applicable, for each piece of major production equipment (i.e.,(b)(4)and motors, filling equipment, etc.) to ensure physical and mechanical capabilities meet the needs of established operating parameters and that each is of appropriate design and construction for its intended use.A timeline for performing appropriate process performance qualification (PPQ) studies for each of your marketed drug products. Also include an explanation how you will ensure proper satisfactory PPQ studies are performed prior to future distribution of any drug products.3. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).You have not demonstrated that your cleaning practices are adequate to remove contaminants from the shared equipment used to manufacture your OTC drug products. During the inspection, you stated that cleaning validation studies have not been conducted to demonstrate that residues are reduced to an acceptable level, nor could you provide any cleaning logs.In your response, you state that you have developed a cleaning validation procedure and will initiate the study, and that you implemented a cleaning record that is now included in your batch records.Your response is inadequate because you do not provide evidence that your cleaning methods are appropriate and effective, nor do you assess the impact of your unvalidated cleaning processes on drug product that is currently on the market and within expiry.In response to this letter, provide the following:Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst-case in your drug manufacturing operation. This should include, but not be limited to, identification and evaluation of all worst-case:o Drugs with higher toxicitieso Drugs with higher drug potencieso Drugs of lower solubility in their cleaning solventso Drugs with characteristics that make them difficult to cleano Swabbing locations for areas that are most difficult to cleano Maximum hold times before cleaningIn addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.A summary of updated standard operating procedures that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.Quality SystemsYour firm’s quality systems are inadequate. See FDA’s guidance documentQuality Systems Approach to Pharmaceutical CGMP Regulationsfor help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.CGMP Consultant RecommendedBased upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPAs before you pursue resolution of your firm’s compliance status with FDA.Cosmetics Manufactured for Distribution in the United StatesIn addition, some of the products you manufacture may be regulated as cosmetics, as defined in section 201(i) of the FD&C Act [21 U.S.C. 321(i)]. Any cosmetics you manufacture must comply with applicable statutory and regulatory requirements, including the FD&C Act. We note that under section 301(a) of the FD&C Act [21 U.S.C. 331(a)], it is a prohibited act to introduce or deliver for introduction into interstate commerce a cosmetic that is adulterated or misbranded.We also note that the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) provides new requirements with which facilities that manufacture cosmetic products must comply. You may find the FD&C Act, MoCRA, and FDA’s regulations through links on FDA’s website at www.fda.gov.ConclusionThe violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Laboratoires Druide Inc., 154 Oneida Avenue, Pointe-Claire, Quebec, Canada, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3008226137 and ATTN: Christopher Leach.Sincerely,/S/Francis GodwinDirectorOffice of Manufacturing QualityOffice of ComplianceCenter for Drug Evaluation and Research

Delivery Method:VIA UNITED PARCEL SERVICE AND VIA E-MAILReference #:25-HFD-45-04-02Product:DrugsRecipient:Timea CilibertiExecutive Chair and CEOAmerican Behavioral Research Institute, LLC2255 Glades Road, Suite 324aBoca Raton,FL33431-8571United StatesIssuing Office:Center for Drug Evaluation and Research (CDER)United StatesWARNING LETTERFDA Ref. No.: 25-HFD-45-04-02Dear Timea Ciliberti:This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted between April 17 and May 3, 2024. Investigator Sheri L. Stephenson, representing FDA, reviewed the role of American Behavioral Research Institute, LLC (ABRI) as the sponsor of a clinical investigation (Protocol ABRI-002, “A Study to Evaluate the Effects of Relaxium in Subjects with Sleep Disorder”) of the investigational drug Relaxium® Sleep.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 Stephenson presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your May 24, 2024, written response to the Form FDA 483.From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your May 24, 2024, written response, 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:You failed to submit an Investigational New Drug application (IND) for the conduct of a clinical investigation with an investigational new drug that is subject to 21 CFR 312.2(a) [21 CFR 312.20(a), 312.20(b), and 312.40(a)].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 312.21. ABRI failed to comply with these requirements. Specifically, ABRI initiated and conducted Protocol ABRI-002, a clinical investigation of the investigational drug Relaxium® Sleep (Relaxium) subject to section 505 of the FD&C Act [21 U.S.C. 355], without submitting and having in effect an IND.We acknowledge that this finding was not included on the Form FDA 483 you received, and therefore your written response does not directly address this violation as discussed in this letter.In ABRI’s May 24, 2024, written response to the Form FDA 483, your authorized representative stated, “As is obvious from the formulation, labeling, marketing, and advertising of Relaxium, the article is and is intended to be a dietary supplement, and not a drug.” ABRI’s authorized representative also stated that “whether Relaxium has any effect on subjects with sleep disorders is not evidence that the article is a drug as defined by 21 USC 321(g). Subjects with sleep disorders (as with any medical condition) may also take dietary supplements – and doing so does not cause the supplements to be drugs. Even determining the effect of a dietary supplement on persons with a particular condition does not amount to an intended use of that supplement to treat that condition.” Additionally, ABRI’s authorized representative stated that at no time was Relaxium intended to treat, cure, mitigate, or diagnose a disease, whether as a commercially available finished product or as a supplement, in study ABRI-002.For the reasons described below, we conclude that the evidence collected during the inspection shows that Relaxium was intended for use as a drug, not as a dietary supplement, for the clinical investigation conducted under Protocol ABRI-002. Therefore, ABRI was required to submit an IND before conducting the clinical investigation.Section 201(g)(1) of the FD&C Act [21 U.S.C. 321(g)(1)] defines drug, in part, as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease….” ABRI studied the efficacy of Relaxium to mitigate and treat insomnia. As shown by the protocol, the primary objective of Protocol ABRI-002 was to investigate the effect of Relaxium on sleep parameters in subjects with insomnia. To assess the efficacy of Relaxium in the study, Protocol ABRI-002 used various sleep parameters, which were also identified as the study efficacy endpoints. These efficacy assessments included wrist actigraphy, to estimate wake/sleep time and to assess sleep variability; the Leads Sleep Evaluation Questionnaire (LSEQ), which measures sleep and daytime effects; and a daily sleep diary that rated the quality of the subjects’ sleep and the quality of the subjects’ day by rating their daily energy. The sleep quality information from the diaries and the LSEQ data collected was used to evaluate the baseline disease severity and to evaluate the treatment’s effect. The wrist actigraphy data were compared from the lead-in period (averaged as a baseline) to Days 8 to 15, with variables measured, including total sleep time and awake time. Therefore, Protocol ABRI-002 collected study data to assess the effect of Relaxium on insomnia, as measured by variability and quality of sleep.Whether an investigational article is a drug or a dietary supplement depends on the intent of the investigation. Based on the study design of Protocol ABRI-002, the investigational product, Relaxium, as used in the clinical investigation, was a drug as defined in section 201(g)(1) of the FD&C Act, because Relaxium was studied for use in the treatment of insomnia.Thus, before initiating the clinical investigation of Relaxium conducted under Protocol ABRI-002, under 21 CFR 312.40, ABRI was required to submit an IND to FDA and to have an IND in effect. FDA’s records indicate that ABRI failed to submit an IND before conducting Protocol ABRI-002, in which 40 human subjects were enrolled and received investigational drug.In their written response, ABRI also stated that because they are in the business of marketing and distributing dietary supplements, and not performing clinical studies, there is no risk of future violations because there is no chance of future studies. We acknowledge your statement. However, ABRI’s written response does not provide sufficient details of a corrective and preventive action plan for developing and implementing procedures to comply with IND regulations, should ABRI decide in the future to initiate another clinical investigation for which an IND is required. As a result, ABRI’s response is inadequate. Without this information, we are unable to determine whether ABRI will comply with IND regulations in the future.As a sponsor, you are responsible to comply with IND requirements, including submitting and having in effect an IND before initiating a clinical investigation, 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 Protocol ABRI-002 with an investigational drug raises significant concerns about the safety and welfare of enrolled subjects, and raises concerns about the validity and integrity of the data collected during the conduct of this clinical investigation.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 deficiencies noted above. 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 that you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.Should you have any questions or concerns regarding this letter or the inspection, please e-mail FDA at CDER-OSI-Communications@fda.hhs.gov.Your written response and any pertinent documentation should be addressed to:Brittany L. Garr-Colón, MPHBranch ChiefCompliance Enforcement BranchDivision of Enforcement and Postmarketing SafetyOffice of Scientific InvestigationsOffice of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug AdministrationBuilding 51, Room 535210903 New Hampshire AvenueSilver Spring, MD 20993Sincerely yours,/S/David C. Burrow, Pharm.D., J.D.DirectorOffice of Scientific InvestigationsOffice of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug Administration____________________1Protocol ABRI-002 does not qualify for any of the exemptions listed at 21 CFR 312.2 from the application of 21 CFR 312. To be IND-exempt under 21 CFR 312.2, the investigational product must, among other things, be lawfully marketed in the United States as a drug product. As stated in your May 24, 2024, written response, Relaxium is marketed as a dietary supplement, not as a drug product.

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