疫情防控新常态下人体生物等效性试验受试者管理探讨

摘要：目的:为保证新型冠状病毒肺炎（COVID-19）疫情防控常态化下,仿制药人体生物等效性试验的有序开展和试验质量,最大限度的保护受试者和研究者的安全,针对新常态下影响受试者管理的因素进行探讨。方法:以生物等效性试验流程中受试者管理关键环节为切入点,分别对COVID-19疫情防控新常态下受试者的招募、筛选、入住、出院、随访等阶段进行深入探讨。结果与结论:在保障受试者权益与安全的前提下,对COVID-19疫情后开展生物等效性试验受试者的管理流程和细节作出相应调整,从而有效的保证了受试者安全和试验质量,提高了特殊公共卫生事件下生物等效性试验受试者管理的水平。     

对盐酸特拉唑嗪口服制剂人体生物等效性试验几个关键问题的探讨

我国的药品研究开发以仿制药为主,仿制药上市前通常需要进行人体生物等效性试验。人体生物等效性试验的质量直接关系到众多药品的质量,进而影响到广大人民群众的用药安全和疗效。作者在完成盐酸特拉唑嗪口服制剂人体生物等效性试验中总结了一些做法和体会,通过探讨试验设计、受试制剂和参比制剂、受试者选择和例数、临床监护、生物样品采集、处理和检测等几个关键问题,旨在为今后人体生物等效性试验的规范化和质量提高提供一些建设性意见。     

以健康受试者为研究对象的仿制药生物等效性 试验不良事件分级标准

药物临床试验不良事件严重程度评估有多种不同的评价标准,但目前尚无专门针对以健康受试者参与为主的仿制药生物等效性试验不良事件分级评价标准。仿制药生物等效性试验有其特殊性,可参考相关最新研究进展的成果,设计适用于以健康受试者为研究对象的仿制药生物等效性试验不良事件分级评价标准,以利于仿制药生物等效性试验安全性数据的评价。     

《以药动学参数为终点评价指标的化学药物仿制药人体生物等效性研究技术指导原则》解读

等效性评价是我国仿制药评审的重要环节,目前等效性评价均以2005年颁布的《化学药物制剂人体生物利用度和生物等效性研究技术指导原则》为依据。2016年3月,国家食品药品监督管理总局发布《以药动学参数为终点评价指标的化学药物仿制药人体生物等效性研究技术指导原则》,本文从分析方法、试验设计、受试者和试验例数、参比制剂等几个方面解读两者的差别。     

浅析生物等效性试验风险管理策略

仿制药一致性评价推动着生物等效性试验的开展,生物等效性试验的风险日益突出。本文基于临床试验管理者的视角,对生物等效性试验实施过程中的机构组织管理、受试者管理、试验药物和生物样品管理风险现状及存在问题进行剖析,提出加强对机构管理者及研究者生物等效性试验专业知识和法规的培训、关注受试者招募合规性及试验期间管理的合理性、规范试验药物和生物样品的管理流程和记录等相应的风险管控措施和策略。     

美国FDA《特定药物的生物等效性指导原则》 高变异性药物生物等效性指导原则调研

目的：研究美国食品药品管理局（FDA）《特定药物的生物等效性指导原则》对高变异性药物生物等效性研究相关规定,为我国仿制药质量和疗效一致性评价工作提供借鉴和帮助。方法：从剂型、给药方式、试验设计、受试者选择、给药条件、检测物质选择、豁免条件、体外溶出试验等多个方面对美国FDA公布的高变异性药物《特定药物的生物等效性指导原则》进行详细分析,并特别指出涉及我国仿制药质量与疗效一致性评价首批品种的高变异性药物。结果：美国FDA公布的涉及高变异性药物《特定药物的生物等效性指导原则》对具体化学仿制药的生物等效性评价从多个方面进行较为详细的规范,是对美国FDA相关生物等效性总则的补充和解读,对仿制药的发展有重要的推动作用。结论：在我国国家食品药品监督管理总局（CFDA）尚未颁布针对具体高变异性药物相关生物等效性指导原则的背景下,美国FDA《特定药物的生物等效性指导原则》中对高变异性药物相关规范对我国正在进行的仿制药质量和疗效一致性评价具有一定指导和借鉴意义。     

国内奥美拉唑(盐)口服制剂人体生物等效性试验的问题和对策

奥美拉唑是质子泵抑制剂类代表药物,临床上应用广泛.文中通过对国内26篇奥美拉唑(盐)12服制剂人体生物等效性试验文献进行分析,探讨了试验内容、参比制剂、受试者、生物样品采集及分析、药动学参数、上市后生物等效性再评价或监测等方面的问题和对策,以期为奥美拉唑(盐)口服制剂人体生物等效性研究和临床应用提供参考信息,并基于现有...     

生物等效性研究中的若干问题

生物等效性研究对于保证受试药品（仿制药品）与参比药品（原创新药品）生物等效，具有相同的有效性和安全性，保证受试药品的质量是极其重要的。在新药开发和新药评价过程中发挥着非常重要的作用。但目前的生物等效笥试验中还存在着不少问题，这些问题直接影响对生物等效性结果的判断以及将生物等效性研究结果作为替换使用相关产品依据的参考价值。本文将概要介绍当前生物等效性研究在管理要求方面和具体实践中的一些尚未解决的问题，这些问题包括研究设计、受试者选择、用于研究的药品选择、替代的药代动力学参数等实验方法中的问题，以及生物等效性研究中药物代谢物、立体异构、高变异性药物的研究问题、食物效应问题，体外溶出试验在生物等效性评估中的作用，新药获批准后的生物等效性研究，个体和群体生物等效性评价问题。     

仿制药人体生物等效性试验的若干问题

对于仿制药的人体生物等效性试验虽然已有相关指导原则对其加以指导和规范,但随着国内仿制药研究和评价实践的不断拓展和深入,仍然有一些问题需要进一步探讨和明确,例如立体异构体问题、代谢物问题、高变异药物、长半衰期药物等。本文旨在对这些问题进行初步汇总和探讨。     

药物制剂人体生物利用度研究的若干问题

为获得较为理想、可靠的人体试验研究结果介绍药物制剂人体生物利用度研究中涉及到的一些具体实际问题，包括受试者的选择、试验条件均衡性的控制、药物动力学分析、生物利用度计算和生物等效性评价等．     

Bioequivalence Approaches for Highly Variable Drugs and Drug Products

Over the past decade, concerns have been expressed increasingly regarding the difficulty for highly variable drugs and drug products (%CV greater than 30) to meet the standard bioequivalence (BE) criteria using a reasonable number of study subjects. The topic has been discussed on numerous occasions at national and international meetings. Despite the lack of a universally accepted solution for the issue, regulatory agencies generally agree that an adjustment of the traditional BE limits for these drugs or products may be warranted to alleviate the resource burden of studying relatively large numbers of subjects in bioequivalence trials. This report summarizes a careful examination of all the statistical methods available and extensive simulations for BE assessment of highly variable drugs/products. Herein, the authors present an approach of scaling an average BE criterion to the within-subject variability of the reference product in a crossover BE study, together with a point-estimate constraint imposed on the geometric mean ratio between the test and reference products. The use of a reference-scaling approach involves the determination of variability of the reference product, which requires replication of the reference treatment in each individual. A partial replicated-treatment design with this new data analysis methodology will thus provide a more efficient design for BE studies with highly variable drugs and drug products. The opinions expressed in this report by the authors do not necessarily reflect the views or policies of the Food and Drug Administration (FDA).     

Scientific drug safety information for patients' consent

One of the important roles of pharmacists is to continue their contributions to new drug discovery and development. However, it seems to be very difficult to obtain patient satisfaction with new drugs. Because new medicines have both benefit and risk, there should be many systems to maximize the safety and efficacy of the drugs. In clinical trials, the rights, safety and welfare of human subjects under the investigator's care must be protected. Good Clinical Practice is a harmonized ICH-guideline, and the safety information of an investigational product is explained to patients who voluntarily enter the clinical trials. Since safety information about investigational products is still limited, subjects are informed about the results of animal experiments and those of finished clinical trials. The sponsor of clinical trials should be responsible for the on-going safety evaluation of the investigational products. When additional safety information is collected in the clinical trials, the written informed consent form should be appropriately revised. During the review process, quality, safety and efficacy of new drugs are evaluated and judged based on the scientific risk-benefit balance. The safety information collected in clinical trials is reflected in the decision-making process written in the review reports. All-case investigation should be also performed until data from a certain number of patients has been accumulated in order to collect early safety and efficacy data. Important messages written in review reports for drug safety and patient consent are explained. Risk communication will improve the application of patients' consent for new drugs.     

氩离子凝固术联合药物治疗Barrett食管疗效分析

目的APC联合埃索美拉唑治疗BE的临床疗效及安全性。方法将92例BE随机分为A、B治疗组和对照组,A组服用埃索美拉唑及莫沙必利;B组行APC加服与A组相同的药物;而对照组未予特殊治疗。比较3组患者治疗后的临床症状、内镜表现及组织学改变情况。结果A、B治疗组临床症状均明显改善,与对照组相比差异有统计学意义（P〈0．05）;A组与对照组内镜表现和组织学改变无明显改善（P〉0．05）;B组31例（100％）患者BE食管黏膜内镜表现和组织学恢复正常,与另外两组相比改善有统计学差异（P〈0．05）。结论APC联合埃索美拉唑、莫沙必利方案可明显改善BE患者的临床症状和内镜表现,是一种安全、有效治疗BE的综合治疗方法。     

Review on 505(b)(2) Drug Products Approved by USFDA from 2010 to 2020 Emphasizing Intellectual Property and Regulatory Considerations for Reformulations and New Combinations

Repurposing is considered an attractive approach for developing new drug products. However, it consists of challenges relating to intellectual property (IP) protection, and regulatory approvals. This study aimed to analyze the recent trends in repurposed drugs approved by USFDA from 2010 to 2020 and to assess the challenges connected with bridging study requirements, patent protection, and exclusivities. Out of 1001 NDAs, 570 were approved via 505(b)(2) pathway. Of 570 NDAs, the highest number of approvals are allied to type 5-new formulations (42.4%), followed by type 3-new dosage forms (26.4%) and type 4-new combinations (13.1%). Of 570 NDAs, 470 are considered to examine the patent and exclusivity protection of which 341 have patent and/or exclusivity. A total of 97 type-3 and type-5 and 14 type-4 drugs have been approved based on human bioavailability/bioequivalence (BA/BE) data. For 131 type-3 and type-5 and 34 type-4 drugs, the applicants conducted new clinical (efficacy and/or safety) studies along with BA/BE (100 drugs) or without BA/BE (65 drugs) studies. In this review, mechanistic reasons for conducting new clinical investigations, IP and regulatory considerations along with broader perspective on new pharmaceutical approaches employed in 505(b)(2) drugs are illustrated that provide guidance for development of reformulations and combinations.     

美欧关于透皮贴剂临床研究要求的探究与思考

目的：为我国透皮贴剂的研发提供参考。方法：通过查阅美国和欧盟药监机构官网,就欧美关于透皮贴剂临床研究的要求及已上市透皮贴剂产品案例进行讨论和分析。结果与结论：结合欧美经验及我国法规现状,对我国透皮贴剂创新药、改良型透皮贴剂和透皮贴剂仿制药的临床研究要求分别提出了相应的思考建议：透皮贴剂创新药需开展充分的体内外研究以揭示其安全性和有效性;改良型透皮贴剂应与对照药开展桥接试验,并侧重于揭示经皮给药的临床特点和特有的不良反应;透皮贴剂仿制药可开展生物等效性试验、黏附性、皮肤刺激性和致敏性研究。     

内源性药物尿药生物等效性的试验设计和分析方法

目的以枸橼酸钾为例,介绍内源性药物的尿药生物等效性试验(BE)的设计和分析方法。方法根据FDA关于内源性药物BE研究相关指南及相关文献,以枸橼酸钾尿药BE研究为实例,探讨其研究流程、质量监控、剂量选择、样本采集以及数据分析等关键问题。结果在枸橼酸钾BE研究中,用单剂量、双交叉设计,对试验期间的饮食和活动进行标准化控制,用同一周期的给药前的内源性物质作为基线,校正尿药排泄量,最后用24 h尿药累积排泄量(Ae0-24h)、最大尿药排泄速率(Rmax)进行生物等效性分析。结论内源性药物BE研究,在设计上更为复杂,饮食和生理因素对结果影响大,需要基线校正,数据波动明显。尿药参数以Ae0-t和Rmax为主,而Tmax和T1/2没有实际意义。     

The importance of sample size,log-mean ratios,and intrasubject variability in the acceptance criteria of 108 bioequivalence studies

PURPOSE: Fulfilling bioequivalence criteria with highly variable drugs is difficult. The aim of this study was to compare the importance of sample size, intrasubject variability, and the point estimate of test and reference formulations with regard to meeting bioequivalence (BE) criteria [maximum observed plasma concentration (C(max)) and area under the concentration-time curve (AUC)]. METHODS: We compared 137 pairs of data from BE studies with a conventional number of subjects, approximately 31-32 volunteers, developed in the last 10 years. RESULTS: The third part of the studies failed to demonstrate BE, in part due to an unacceptable difference between the mean ratios (T/R) (18) but also due to high variability with small differences between formulations (17). Increasing the number of subjects is hard to justify, and expanding the confidence interval (CI) was insufficient for the most highly variable drugs. CONCLUSIONS: Therefore, for low-variable drugs, the difference between formulations was the cornerstone of the fulfillment of BE criteria, but for highly variable drugs, the intrasubject coefficient of variability (ICV) was decisive. Our proposal is that for highly variable drugs that fall outside BE 90% CI limits could result in BE in the absence of formulation effect and maximal differences between formulations below 20%.     

重组干扰素α-2b注射液Ⅱ期临床试验中常见问题及解决方法

在药物临床试验过程中,筛选失败率、受试者依从性与病例脱落率都将影响,临床试验的进展和对药物有效性与安全性客观、准确的评价,影响临床试验的可靠性,最终影响用药安全和患者的身体健康。因此,对这3方面因素的控制已成为新药研发亟待解决的重要问题。本文通过重组干扰素α-2b注射液在4个研究中心进行的Ⅱ期临床研究试验,对其筛选失败率、受试者依从性和病例脱落率这3个方面进行数据统计、处理和分析,探究其原因,期望为今后药物临床试验工作的顺利开展,相关操作的规范,数据的完整准确提供合理的依据和保证,进而提高药物临床试验的质量。     

Analysis of information submitted by clinical trial sponsors regarding the safety of investigational drugs

During performance of clinical trials in medical institutions, information regarding the safety of investigational drugs is submitted by trial sponsors according to guidelines for good clinical practice. In the present study, reports of clinical trials conducted at the University of Tokyo Hospital were examined, focusing on the safety information provided to the Institutional Review Board (IRB). Two hundred two reports (52 protocols) of safety information were submitted to the IRB by clinical trial sponsors between April 2000 and March 2001, of which 185 contained a total of 3021 cases of adverse events. Of those, 194 reports were judged by clinical investigators/physicians not to be associated with any significant problems and the trials were continued. For 157 of those 194 reports, it was considered unnecessary to inform the test subjects of the report contents, including the adverse events. The decision of whether or not the test subjects should be informed of such contents tended to depend on the causal relationship between the adverse events and drug intake, as well as the predictability of the adverse events. For 8 of those 194 reports, the IRB recommended that the clinical investigators/ physicians provide information to the test subjects and/or submit detailed information on the status of these subjects to the IRB. From these results, we suggest that establishment of a system to unify and evaluate drug safety information is necessary to provide safe and efficient clinical trials.     

In Vitro Studies are Sometimes Better than Conventional Human Pharmacokinetic In Vivo Studies in Assessing Bioequivalence of Immediate-Release Solid Oral Dosage Forms

Human pharmacokinetic in vivo studies are often presumed to serve as the "gold standard" to assess product bioequivalence (BE) of immediate-release (IR) solid oral dosage forms. However, when this general assumption is re-visited, it appears that in vitro studies are sometimes better than in vivo studies in assessing BE of IR solid oral dosage forms. Reasons for in vitro studies to sometimes serve as the better method are that in vitro studies: (a) reduce costs, (b) more directly assess product performance, and (c) offer benefits in terms of ethical considerations. Reduced costs are achieved through avoiding in vivo studies where BE is self-evident, where biopharmaceutic data anticipates BE, and where in vivo BE study type II error is high. In vitro studies more directly assess product performance than do conventional human pharmacokinetic BE studies, since in vitro studies focus on comparative drug absorption from the two products, while in vivo BE testing can suffer from complications due to its indirect approach. Regarding ethical considerations, in vitro studies better embrace the principle "No unnecessary human testing should be performed" and can result in faster development. Situations when in vitro test should be viewed as preferred include Class I drugs with rapid dissolution, Class III drugs with very rapid dissolution, and highly variable drugs with rapid dissolution and that are not bio(equivalence)problem drugs. Sponsors of potential in vivo human pharmacokinetic BE testing should be required to justify why in vitro data is insufficient, similar to proposed animal testing requires justification to not employ an in vitro approach.