《肿瘤临床试验运用核心患者报告结局行业指南(草案)》解读

以患者为中心的药物研发理念愈发受到国内外研究者的重视,患者报告结局(patient-reported outcome, PRO)已逐渐成为临床试验的终点观察指标之一。PRO提供直接来自患者的健康信息,在医生的临床决策中起到重要作用。但肿瘤临床试验中PRO评估方法的运用和数据解释还有待改进。核心PRO指标的选用对PRO评估标准的一致性至关重要。2021年美国FDA发布的《肿瘤临床试验运用核心患者报告结局行业指南(草案)》针对肿瘤临床试验的药物研发,为申办方核心PRO收集、PRO评估工具选择和规范化试验设计提供指导意见。本文对该指南核心PRO的系统评估及运用进行解读,帮助新药临床试验从业者进一步了解PRO,对PRO在新药临床试验中的运用起到良好的促进作用。     

患者报告结局及其在胃肠疾病领域的应用

在临床研究中，准确、可靠、完整地测量结局至关重要。临床结局通常采用客观测量指标，但现患者报告结局（patient-reported outcomes, PRO）、临床医师报告结局和观察者报告结局这些主观测量方法已越来越多地被应用于临床研究。不同的结局测量方法各有特点，它们拟解决的关键问题不同，具有相辅相成的作用。从患者角度看，客观测量指标常常不能反映自己对身体、心理、社会功能和总体幸福感的主观感知。临床医师报告结局容易产生较大的主观评价偏倚风险；观察者报告结局可能存在代理人偏倚。PRO直接来自于患者关于自己健康状况的报告，很多时候能更敏感、更快捷地反映患者对自身疾病或治疗结局的主观感知，而且PRO测量通常较客观指标测量快，数据采集成本低。本文概要介绍PRO的定义、工具及其在胃肠疾病领域的应用。     

美国患者报告结局测量工具在药物研发与注册中的应用

对患者报告结局测量工具在美国药物研发与注册中的应用进行研究,通过阐述患者报告结局测量工具定义、分类、资格认定、法规及指南要求,分析美国FDA根据患者报告结局工具为临床终点批准药物,为我国提供参考和借鉴.     

药物治疗相关的患者报告结局量表研究进展

药物治疗是治愈疾病和缓解症状的常用方法,患者报告结局在评价药物治疗效果中的价值逐渐得到重视。患者报告结局量表是一种标准化的问卷,能从患者的角度出发科学评估药物治疗的体验及其主观效果,有助于患者和临床医师做出更合理的用药决策。通过查阅并整理国内外相关文献,发现药物治疗相关的患者报告结局量表在内容上集中于“用药满意度”“用药依从性”“药物治疗负担”“用药相关生活质量”以及“药品不良反应”5个领域。本研究从上述内容中分别阐述近年来常用量表的基本信息、测量学特性和应用情况,总结该领域量表研制存在的问题与启示,旨在为量表的选择、应用与开发提供参考。     

电子化患者报告结局在新药临床试验疗效评价中的应用

患者报告结局（PRO）作为临床结局疗效评价最重要的指标之一,被广泛用于新药临床试验。在新药临床试验电子化的趋势下,电子化患者报告结局（ePRO）数据采集系统基于其种种可以推进新药临床评价的优势,迎来了快速发展。然而,ePRO在中国仍然处在初期发展阶段,因此将对ePRO的基本概念、功能、国内外临床应用情况及其在新药临床试验疗效评价中的价值等进行介绍;同时总结概括了目前ePRO在我国临床试验应用中存在的问题,最后对ePRO在中国的发展前景进行了探讨。     

患者报告结局在药品不良反应报告中的应用和思考

目的探索患者报告结局在药品不良反应报告中的应用。方法通过文献回顾的方法,对国外药品安全性研究中纳入患者报告结局的背景、驱动因素、当前监管情况进行了全面综述。结果目前数据收集的局限性、患者和医务人员间的不一致、通过患者能获取更丰富的信息等多个因素的驱动,且美国、英国等国家对此制定了监管措施,有效推动了患者报告结局在药品安全性研究中的应用。结论患者报告结局以患者为中心,为药品使用的效益、风险和结局的全面分析提供了丰富而宝贵的信息,可用作目前药物警戒和上市后研究的补充内容,为我国将患者报告结局的方法纳入药品安全性研究提供重要参考。     

慢性心力衰竭患者报告结局量表的信度 效度和可行性评价

目的对慢性心力衰竭患者报告结局(PRO)量表进行信度、效度和可行性的评价。方法参考国外的慢性心血管疾病评价工具,编制慢性心力衰竭PRO量表。用该量表对太原不同区的8所医院进行大规模调查,利用大规模调查的信息数据再一次进行条目筛选,形成终量表,并对终量表的信度、效度、可行性进行分析。结果慢性心力衰竭PRO量表共57个条目,对360例患者和100名健康人有效数据进行分析。结果显示:该心力衰竭PRO量表具有较好的信度、效度及临床可行性。总量表的克朗巴赫系数为0.913,生理领域0.903,心理领域0.941,社会领域0.827,治疗领域0.839;内容效度、维度相关性、构念效度、反应度结果显示该表具有良好的效度;此次调查的回收率为98.9%,有效率为98.9%。结论我们研制出的基于慢性心力衰竭患者报告的临床结局评价量表具有较好的信度、效度和可行性,可以作为慢性心力衰竭疾病临床疗效评价研究的工具。     

神经源性膀胱特异性患者报告结局评估工具的研究进展

神经源性膀胱功能障碍是持续动态进展的,其症状长期存在并持续干扰患者的生活及心理,严重影响患者的生活质量。患者报告结局的评估逐渐成为临床实践中收集患者健康信息的重要组成部分。本文就目前已研发出的神经源性膀胱患者报告结局特异性评估工具进行介绍,为促进我国开展神经源性膀胱患者报告结局相关研究提供参考。     

禁忌药物在行冠心病介入手术的透析患者中的风险分析

背景及目的：美国FDA通过药品说明书警示临床医生在特殊患者群体中某些药物是禁忌的或不推荐使用的。但是这些药物会对临床结局产生什么影响却并不清楚。本研究探讨了禁忌或不推荐使用的依诺肝素（enoxaparin）和依替巴肽（eptifibatide）在行冠心病介入手术（PCI）的透析患者中的应用,及其与不良临床结局的关系。     

哮喘患者报告临床结局量表的研制和条目筛选

目的研制具有良好信度、效度与反应度,适用于新药临床试验或临床疗效评价的哮喘患者报告临床结局(PRO)量表。方法遵照美国食品药品管理局(FDA)PRO量表研制的程序化方法,建立量表的理论框架,建立条目池,并通过专家咨询、患者访谈等修改量表,得到含有72个条目的初量表。现场调查共收集108例样本,使用离散趋势法、因子分析法、相关系数法、克朗巴赫α系数法及修正条目的总相关系数法和项目反应理论5种方法对初量表进行条目筛选。结果经过条目筛选,调整量表的框架结构,共保留67个条目,分为生理、心理、社会、治疗4个领域及13个方面。结论哮喘PRO量表严格按照国际量表的操作原则和方法进行,科学性强、结论可信,有利于临床研究中推广使用。     

Utility analysis and calibration of QOL assessment in disease management

In clinical trials, the assessment of health-related quality of life (QOL) (or patient-reported outcome [PRO] measure) has become very popular especially for clinical studies conducted for evaluating clinical benefits of patients with chronic, severe, and/or life threatening diseases. Health-related QOL information and PRO measures are useful for disease management for achieving best clinical practice. In this article, we will focus on health-related QOL assessment. The concept, design, and analysis of health-related QOL in clinical trials are reviewed. Validation of the use of health-related QOL instrument in terms of some key performance characteristics such as accuracy, reliability, sensitivity, and responsibility for assuring quality, integrity, and validity of collected QOL data are discussed. The concept of utility analysis and calibration (e.g., with respect to life events) for achieving the optimization of disease management are proposed. The change of the QOL could be translated into different life events for effective disease management. These translations could evaluate the treatment effect by more directly displaying the change of the QOL.     

Patient-reported outcome measurement in drug discovery: a tool to improve accuracy and completeness of efficacy and safety data

ABSTRACT

Introduction: Patient-reported outcomes (PROs) reflect how patients feel and function as conveyed directly by patients themselves, for example symptoms and physical functioning. PRO measures can be included in any phase of product development as primary, secondary, or exploratory endpoints to understand the impact of treatment on the patient experience.

Areas covered: In this review, the authors describe approaches commonly used to assess PROs in drug development programs, including how to select or develop outcomes and measures, implement these in trials, and analyze data. Barriers and facilitators for effectively including PROs in clinical trials are discussed, and strategies for making labeling claims based on PRO data are noted.

Expert opinion: Early planning with PRO experts is recommended to assure a successful PRO strategy in a product development program. Outcomes that are meaningful to patients should be rationally identified early in a product development program based on qualitative work, literature search and/or assumed mechanism of action. Measures corresponding to those outcomes should be selected or developed, with demonstration of robust psychometric properties in a related patient population. Ideally, these measures will be tested prior to a pivotal trial to support the design and analysis in the pivotal trial. Selection of timing and mode of assessments should be specified a priori and justified. If a labeling claim is sought, a statistical plan should be pre-specified. Strategies to minimize and handle missing data in analyses should be planned up front.     

The use of patient-reported outcomes in advanced breast cancer clinical trials: a review of the published literature

Objective: As a means to measure quantifiable signs, symptoms, and impacts of a disease or its treatment, patient-reported outcome (PRO) instruments can be applied to numerous settings, including use in drug development to support labeling claims. This research summarizes the use of PROs in trials for 16 commonly used regulatory approved treatments for advanced or metastatic breast cancer.

Methods: For each treatment (n?=?16), a literature search was conducted in MEDLINE, Embase, and PsycINFO. The primary criterion for selection was the report of studies that used PROs to evaluate treatment benefit and/or toxicity in advanced or metastatic breast cancer. From this, a sub-set of articles for each treatment were selected for full-text review where PRO-related information was extracted and summarized.

Results: The searches yielded 1727 publications. Following abstract review, 1702 were excluded because they failed to meet criteria, or were duplicates or less relevant for PRO information reported. Thus, 25 articles were reviewed in detail for this evaluation. Eleven PRO instruments were identified from these publications. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core (EORTC QLQ-C30) was utilized the most frequently (n?=?13, 52.0%). Most publications reported PROs positioned as secondary endpoints (n?=?20, 80.0%); described some of the statistical analyses applied to PRO data (n?=?21, 84.0%); and specified PRO results (n?=?23, 92.0%).

Conclusions: While several of the publications provided some information on how PROs were utilized, many did not describe details for PRO administration, scoring, analyses, and results interpretation. While it is encouraging that PROs are often used in clinical trials for patients with metastatic breast cancer, they are not commonly used to support endpoints that establish the basis for label claims. Because they yield direct insight into the patient experience of a condition, PROs may be used to provide a more comprehensive perspective of the benefits and risks from treatment.     

Association Among Outcomes in a Naturalistic Statewide Assessment of Substance User Treatment

Substance user treatment outcome measurement is important for research and policy questions, yet little literature has addressed the relationships among outcome measures of treatment success. Ideally, treatment outcomes would correlate to at least a moderate degree. The Iowa Department of Public health requires substance user treatment programs receiving public funds to provide client information. Demographic information, “substance abuse” history, current use, arrests, and hospitalizations were ascertained at admission and a 6-month follow-up for 1374 clients (from January 1999 to December 2000). Abstinence, arrests, and hospitalizations were good outcome measures of substance user treatment success. Reduction in frequency of use was negatively associated with arrests, substance use-related hospitalizations, and increased income. Full-time employment at follow-up produced different results depending on the client's sex. However, all associations among outcomes were modest. Specificity may be reasonable in some instances; however, other situations might require a broad-spectrum approach that ideally would produce a wide range of benefits.     

Development of a Brief Treatment Instrument for Routine Clinical Use with Methadone Maintenance Treatment Clients: The Methadone Treatment Index

Routine measurement of treatment outcome between clinician and client in alcohol and drug user treatment services is an important quality improvement initiative. It is particularly important for clients receiving long-term treatment such as methadone maintenance treatment, as fluctuations in substance use, functioning, and health are to be expected. Although there are a number of standardized alcohol and drug user treatment outcome instruments available for research and clinical use, a key challenge is to develop clinical instruments that will actually be used routinely in busy practice settings by a range of staff. Such instruments need to be brief, acceptable to staff and clients, easy to use, provide immediate feedback, and meet adequate psychometric requirements. This report describes development work undertaken in three studies of the Methadone Treatment Index (MTI). The MTI is a brief instrument comprising measures of recent substance use, aspects of social and behavioral functioning, and physical and psychological health. The MTI was designed in consultation with clinicians and clients for use in monitoring treatment progress with clients receiving methadone maintenance treatment. Key findings were that the MTI was acceptable to clients, produced clinically relevant information, and has satisfactory psychometric properties, although it was not used to measure change in this study. Further evaluation of the MTI on a longitudinal basis is supported.     

The association between cocaine use and short-term outcomes for the treatment of heroin dependence: findings from the Australian Treatment Outcome Study (ATOS)

The aim of this study was to determine the prevalence of cocaine use among individuals presenting for treatment for heroin dependence, describe the clinical profile of heroin users who also use cocaine and to establish the effects of cocaine use on short term outcomes for the treatment for heroin dependence. A longitudinal follow-up of 549 heroin users recruited in Sydney for the Australian Treatment Outcome Study was conducted at 3-month post-baseline interview. At baseline, current cocaine use was common (39%) and was associated with increased drug use, needle risk taking and criminality. The 3-month prevalence of cocaine use declined significantly to 19%. Thirty-five per cent of those who had used cocaine at baseline continued to use at 3 months, while 9% of the sample had commenced cocaine use. Those who entered residential rehabilitation at baseline were less likely than other treatment entrants and the non-treatment group to have used cocaine at follow-up. Treatment retention was not affected by baseline cocaine use status; however, baseline cocaine users (CU) displayed higher levels of heroin use, polydrug use and drug-related problems. A poorer outcome was associated with the commencement or continuation of cocaine use, while cessation of cocaine use resulted in significant improvements on these measures. Cocaine use was common among individuals seeking treatment for heroin dependence and was an important moderator of treatment outcome. It appears that cocaine use has a strong negative effect on treatment outcome over and above that caused by polydrug use generally. [Williamson A, Darke S, Ross J, Teesson M. The association between cocaine use and short-term outcomes for the treatment of heroin dependence: findings from the Australian Treatment Outcome Study (ATOS). Drug Alcohol Rev 2006;25:141 - 148]     

2016—2017年焦作市第二人民医院注射用血栓通（冻干）的使用情况分析

目的 调查焦作市第二人民医院注射用血栓通（冻干）的使用情况,为临床合理用药提供参考。方法 调取焦作市第二人民医院2016年1月—2017年12月使用注射用血栓通（冻干）的患者病例1 200份,并对患者的基本情况、用药目的、用法用量、用药疗程、联合用药等信息进行统计分析,评价其临床应用的合理性。结果 使用注射用血栓通（冻干）的患者中男性明显多于女性,用药科室主要为神经内科和心脏内科,构成比分别为27.33%、22.83%。用药原因主要为脑血管疾病（36.58%）和心血管疾病（24.33%）。用药疗程主要分布于≤7、8～15 d,构成比分别为33.92%、53.58%。联合用5、6种药物的患者最多,分别占23.67%、28.08%。不合理使用例数为220例,占总例数的18.33%,以使用疗程不适宜（49.09%）为主。结论 焦作市第二人民医院注射用血栓通（冻干）的应用科室或病种广泛,且存在不合理现象,应加强规范该药的使用管理,做好对患者的用药监测,提升其临床应用的合理性。     

贝伐珠单抗应用分析与合理性评价

目的：了解贝伐珠单抗在肿瘤治疗中的临床应用现状。方法：对其院2015年1月-2016年1月期间使用过贝伐珠单抗的209例患者,897次用药情况进行回顾性分析,按原发疾病分类,参考说明书及药品信息对患者治疗情况进行统计、评价及安全性评估。结果：209例患者数据分析中显示,适应证应用基本符合中国CFDA、美国FDA审批批准的范围,说明书内适应证治疗用药比例为53.73%,超说明书用药比例为46.27%,其中包含FDA批准适应证、NCCN指南推荐及其他超说明书用药。贝伐珠单抗应用期间所出现的不良反应（ADR）基本与说明书相符。结论：贝伐珠单抗超说明书应用普遍存在,部分超说明书应用有一定的循证学依据。应加强对超说明书用药的监管规范,确保药物安全合理使用。     

The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways

The development of adverse outcome pathways (AOPs) is becoming a key component of twenty-first century toxicology. AOPs provide a conceptual framework that links the molecular initiating event to an adverse outcome through organized toxicological knowledge, bridging the gap from chemistry to toxicological effect. As nuclear receptors (NRs) play essential roles for many physiological processes within the body, they are used regularly as drug targets for therapies to treat many diseases including diabetes, cancer and neurodegenerative diseases. Due to the heightened development of NR ligands, there is increased need for the identification of related AOPs to facilitate their risk assessment. Many NR ligands have been linked specifically to steatosis. This article reviews and summarizes the role of NR and their importance with links between NR examined to identify plausible putative AOPs. The following NRs are shown to induce hepatic steatosis upon ligand binding: aryl hydrocarbon receptor, constitutive androstane receptor, oestrogen receptor, glucocorticoid receptor, farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptor, pregnane X receptor and the retinoic acid receptor. A preliminary, putative AOP was formed for NR binding linked to hepatic steatosis as the adverse outcome.