Ⅰ期临床试验健康受试者管理出现的问题及对策探讨

标准化的受试者管理是确保受试者安全和试验结果科学可信的基础。本文从Ⅰ期临床试验过程中健康受试者管理出现的一些问题出发,结合具体工作经验,探讨健康受试者管理的措施,提高受试者管理效率以及Ⅰ期药物临床试验质量。     

Ⅰ期临床试验受试者用药的关键步骤探讨

Ⅰ期临床试验是初步的临床药理学及人体安全性评价试验。因其以健康受试者为主,且受试者人数较少,所以对数据准确性的要求更高。如果受试者用药不够准确,将影响整个试验结果,无法对Ⅱ、Ⅲ期临床试验提供参考。因此,受试者用药是Ⅰ期临床试验的关键步骤之一。本文总结并探讨了口服、注射、吸入、透皮给药等不同给药方式的关键步骤,以期保证试验结果的科学性、准确性与客观性,进而保证后期临床试验的顺利开展。     

Ⅰ期临床试验过程中受试者的管理体会

目的:促进Ⅰ期临床试验过程中受试者的规范化管理。方法:总结我院Ⅰ期临床试验过程中受试者的管理体会,探讨有效的管理模式。结果与结论:通过设立专人管理受试者,在知情同意环节坚持完全告知等原则,选择依从性好的受试者,与其建立相互尊重、理解及合作的关系,为其营造舒适的受试环境等规范受试者的管理,从而提高受试者的依从性,提升临床试验的质量。     

药物Ⅰ期临床试验受试者全流程规范管理

受试者管理是影响Ⅰ期临床试验质量的关键环节之一,该文就如何加强Ⅰ期临床试验受试者全流程的细节管理,从受试者的招募、筛选入筛、样本采集、临床安全性观察等环节的全流程管理谈管理工作体会,以期提高Ⅰ期临床试验受试者的管理水平、临床试验质量和受试者的权益与安全保障能力。     

新药Ⅰ期临床试验中健康受试者的管理

Ⅰ期临床试验之目的是研究人体对药物的耐受程度,并通过药物代谢动力学研究,了解药物在人体内的吸收、分布、代谢和消除的规律,为制定给药方案提供依据.Ⅰ期临床试验必须全过程高度重视受试者的安全.因此,加强试验中健康受试者的管理是非常必要的.主要包括受试者的招募、培训、筛选、食宿、用药等环节的管理.     

Ⅰ期药物临床试验健康受试者参与体验的质性研究

目的:了解Ⅰ期药物临床试验健康受试者参与试验的体验,为促进国内Ⅰ期药物临床试验受试者参与试验的有效开展提供理论依据.方法:采用质性研究法,对符合纳入标准的12例Ⅰ期药物临床试验健康受试者参与试验的体验进行半结构化访谈,采用Colaizzi分析法进行资料分析、总结、归纳.结果:提炼出Ⅰ期药物临床试验健康受试者参与试验体验...     

Ⅰ期临床试验受试者肺结核筛查的必要性及防控分析

我国是肺结核病高发病率的国家之一.因此有必要在筛选期开展受试者肺结核筛查,并在临床试验长周期随访中做好受试者及研究人员结核防控也尤为重要.本文根据专病特点和Ⅰ期临床实践情况进行经验分享,供行业人员参考.     

国内Ⅰ期药物临床试验受试者权益相关文献分析

目的 分析国内Ⅰ期临床试验受试者权益相关研究的发展情况,为后续研究提供参考。方法 通过计算机检索中国知网和万方医学网数据库1996—2021年国内发表的关于Ⅰ期临床试验受试者权益相关研究的文献,通过文献管理软件和可视化分析软件,分析发文量、载文期刊、机构及地区分布、相关作者、关键词、获基金支持情况、研究方向等。结果 符合纳入标准的文献266篇,发文量逐年增加,涉及期刊97种;《中国新药杂志》载文量25篇,位居第1位;发文量最多的机构是四川大学华西医院,发文量为7篇;发文量排名前5位的地区为北京、江苏、湖北、广东、四川;出现频次较高的词分别是受试者(28次)和依从性(9次)、管理(9次)、健康受试者(7次)、受试者管理(6次)等;涉及研究基金资助11种,对研究资助最多的地区是北京。结论 通过对国内Ⅰ期临床试验研究受试者权益相关文献的分析,可了解该研究领域现状和存在的不足,为后续研究、合作、交流提供参考价值。     

常态化抗疫期间Ⅰ期临床试验受试者保护

新型冠状病毒肺炎的发生,给我国各行业都造成了巨大的影响,对临床试验的顺利开展也带来了很多的困难.目前来看,长期抗疫已经不可避免,疫情期间开展临床试验已经成为常态.临床试验中,应该将保护受试者的安全放在首位.本文介绍中国医学科学院皮肤病医院Ⅰ期临床在2020年5月至2020年12月开展的5个临床试验项目,通过试验前期、筛...     

浅谈Ⅰ期临床试验受试者招募筛选信息管理系统的使用

目的：介绍上海市徐汇区中心医院临床试验研究中心的Ⅰ期临床试验受试者招募筛选信息管理系统的功能和实际应用。方法：该系统利用人体的重要生物特征指纹,并配合身份证的验证和近照的比对,能快速、准确地发现不符合试验要求的受试者。结果和结论：目前已经建立405例健康受试者的信息记录。受试者信息电子化提高了筛选的效率,节约人力资源和时间,方便研究者对受试者进行管理,保证临床试验的质量。     

Clinical trial with muzolimine in healthy and hypertensive subjects: new vistas on the drug action

The mechanism of muzolimine (3-amino-1-[3,4-dichloro-alpha-methyl-benzyl]-2 pyrazolin-5-one) action is still not completely defined. The identified site of action is the Henle loop, similarly to furosemide which acts also by mediating renal prostaglandin synthesis. The aim of the present study was to evaluate the early effects of muzolimine (30 mg per os) on renal function and prostaglandin urinary excretion in healthy controls and hypertensive subjects. Urinary flow reached the peak values by the third hour after the drug and a diuretic effect not directly dependent on glomerular filtration was observed, especially in hypertensive patients. In these cases the diuresis increased also due to a low glomerular filtration rate and tubular phenomena were more evident than in controls: an increasing Na+ tubular excretion and a parallel decreasing % Na+ reabsorption. Blood pressure was not significantly influenced by muzolimine in healthy subjects, while it returned to normal values in the hypertensive group. A cyclooxigenase inhibitor, lysine acetylsalicylate (1 g i.m.) administered 10 minutes after muzolimine, was not able to modify the parameters under consideration. Therefore a mediation by prostaglandins on the diuretic and antihypertensive effects of the drug under study may probably be excluded.     

Monitoring of proteinuria in phase I studies in healthy male subjects

Objective: The quantitative measurement of urinary marker proteins may improve the sensitivity of monitoring renal function in healthy male subjects in phase I studies. Little is known about the variability of physiological proteinuria in young, healthy male subjects. Thus, the biological and analytical variability of three marker proteins, i.e. albumin, α₁-microglobulin and N-acetyl-β-d-glucosaminidase (NAG), were investigated in this population. Methods: Seven young, healthy male subjects participated in a prospective two-way cross-over study, and 139 in a retrospective study. Albumin and α₁-microglobulin were determined by immunological methods (radial immunodiffusion and/or kinetic nephelometry), and NAG by enzyme activity in a colorimetric assay. Results: The inter-assay precision of NAG, albumin and α₁-microglobulin is good (<15%) if automated kinetic nephelometry is applied for albumin and α₁-microglobulin determination, but less impressive (<25%) with radial immunodiffusion. The highest frequency of detectable proteinuria and highest creatinine-adjusted protein levels are found in the second morning urine voided after a night's rest. The intra-individual biological variability of NAG excretion from day to day is low (CV: 15–25%), irrespective of outpatient or inpatient settings. By contrast, albumin and α₁-microglobulin excretion can differ by a factor of 2–3 from day to day, and higher levels are predominantly found in outpatient settings. The reference ranges for young, healthy male subjects are generally lower than published in cross-sectional studies in the total healthy population. Conclusion: These findings and established reference ranges for young, healthy male subjects may assist in the evaluation of proteinuria in clinical pharmacological phase I trials.     

Subjective symptoms and quality of life in healthy subjects during a phase I study

Objective: Participants in a phase I study were interviewed in order to establish the incidence and variability of subjective symptoms and changes in quality of life during phase I trials. Methods: The healthy subjects were randomized to receive a single dose of either 0.5 mg digoxin or an equivalent amount of each of four digitaloid mixtures every 14 days. The trial involved five 24-h monitoring periods. The duration of the study was 57 days. Wellbeing, subjective symptoms and quality of life were measured before, during and after the trial using the Freiburg Symptoms List (FSL), Wellbeing Scales (WBS), and Life Satisfaction Questionnaire (LSQ). Results: Eight healthy subjects (25 years) were enrolled in the study. Their subjective symptoms were below the reference values for healthy subjects for each test but above the theoretical minimum and maximum values for total wellbeing, indicating that healthy subjects – not just patients – display subjective symptoms and impairment of wellbeing to a greater or lesser extent prior to a clinical trial. In terms of the total study population, comparison of the questionnaire scores before, during and after the study disclosed no significant changes in wellbeing or quality of life. However, some participants displayed marked intraindividual fluctuation. Conclusions: A careful exploration of the baseline symptoms is necessary even in healthy subjects to avoid observation bias. The symptom course differs greatly from individual to individual; therefore in a phase I study only group scores of wellbeing should be used to assess the possible effects of trial-related factors. A setting like the one used in our study does not impair the quality of life of healthy subjects and as such can be regarded as a fairly neutral means of measuring wellbeing. Received: 18 March 1996/Accepted in revised form: 5 July 1996     

生物等效性试验健康受试者筛选流程的优化

目的 探讨如何提高生物等效性试验健康受试者筛选期的工作效率.方法 试验甲给予受试者根据各个检查项目等待人数自由分流的筛选方法;试验乙给予对部分检查项目进行先后顺序限定,并要求研究者在发现受试者某项检查结果异常后,应及时终止其继续参加其他检查的筛选方法.比较2个试验中受试者在某项检查不合格时合并有其他项目检查的情况.结果...     

Hormonal effects of MPV-2213ad, a new selective aromatase inhibitor, in healthy male subjects. A phase I study

Aims A novel non-steroidal competitive inhibitor of the aromatase enzyme, MPV-2213ad, was entered into an open dose-escalation study. The objective of this study was to investigate the tolerability and efficiency of this new compound with assessment of the hormonal effects after study drug administration.
Methods MPV-2213ad was given to 39 healthy male volunteers. Single increasing oral doses of 0.003, 0.03, 0.3, 3, 9, 30 and 100  mg were given to three subjects at each dose level, after which ten subjects received the 300  mg dose and eight subjects the highest 600  mg dose of MPV-2213ad.
Results Serum oestradiol levels were suppressed by 58–65% when MPV-2213ad was given at doses between 0.3 and 30  mg. A reduction in serum oestradiol levels by 83% from baseline was achieved with the 300  mg dose. No additional decrease was seen with the highest dose. The suppression lasted longer with higher doses of MPV-2213ad. After the 300 and 600  mg doses serum oestradiol returned to baseline within 4 days. Marked increases in serum concentrations of testosterone, androstenedione, 17-OH-progesterone, LH and FSH were also observed at doses between 100 and 600  mg of MPV-2213ad. The drug was well-tolerated and the adverse events were mild or moderate including hot flushes, mild vertigo, nausea, acne and gastrointestinal discomfort.
Conclusions MPV-2213ad has a potent, dose-dependent inhibitory effect on serum oestradiol. It was selective for the aromatase enzyme with no signs of adreno-cortical suppression or haematological or biochemical toxicity.     

A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects

Aim:

To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root, in healthy Chinese volunteers.

Methods:

Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0 μg·kg⁻¹·min⁻¹, each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject''s heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate.

Results:

Peak concentrations (C_max) of higenamine ranged from 15.1 to 44.0 ng/mL. The half-life of higenamine was 0.133 h (range, 0.107–0.166 h), while the area under concentration-time curve (AUC), extrapolated to infinity, was 5.39 ng·h·mL⁻¹ (range, 3.2-6.8 ng·h·mL⁻¹). The volume of distribution (V) was 48 L (range, 30.8–80.6 L). The total clearance (CL) was 249 L/h (range, 199-336 L/h). Within 8 h, 9.3% (range, 4.6%–12.4%) of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The E₀, E_max, and EC₅₀ were 68 bpm, 73 bpm and 8.1 μg/L, respectively.

Conclusion:

Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important information for future clinical studies on higenamine.     

用于新药筛选的药靶的研究进展

目的讨论选择正确的药靶在新药研发过程中的重要性。方法作者以近年来发表的21篇中外文献为依据,以细胞膜G蛋白偶合受体、生长因子受体、细胞膜离子通道蛋白、细胞核受体为例,介绍药靶的筛选、确认以及在此基础上筛选出的代表性药物。结果与结论随着分子遗传学、功能基因组学、蛋白质组学和生物信息学的快速进展,越来越多的功能清楚的生物学分子正在被发现,这其中的某些基因及其产物由于被证明与疾病发生和发展相关而成为分子药靶,选择正确的药靶在新药研发过程中具有重要作用。