基于真实世界数据的药物利用研究综述

近年来,医学信息技术突飞猛进,基于真实环境分析大规模的诊疗数据并挖掘其中规律,已经成为国内外药械上市评价及监管决策的重要手段。真实世界研究作为药物利用研究领域一种新的药物临床评价方法,为观察性研究在实际疗效或效果方面的评价带来了机遇和挑战。然而,作为药物利用研究领域广大学者关注的热门方法学手段,当前真实世界研究关于人群用药特征分析还存在一些局限和不足,尚未形成系统性的评估研究方法,还不能很好的生成真实世界证据。该研究旨在综述基于真实世界数据的药物利用研究的研究设计、方法路径、评价指标、混杂因素及偏倚处理等进展,以便为药物利用研究深入开展提供参考。     

真实世界数据和证据在我国临床决策中的应用现状

传统上,循证医学理念下的临床决策通常以随机对照试验作为最佳临床证据。快速发展的真实世界数据和真实世界证据领域结合了真实临床环境的复杂性,为临床医生提供了补充性证据,并丰富了证据类别,以辅助临床医生做出更好的循证临床决策。本研究旨在梳理我国用于循证临床决策的真实世界数据和证据的范围和适用性,并总结潜在障碍和可行建议,以期进一步推进高质量真实世界数据和证据在循证临床决策中的可接受性。     

真实世界数据存在的问题与质量提升对策研究

传统的随机对照临床试验在长期使用过程中暴露出一些不足,这促使越来越多的研究者将目光投向真实世界证据(RWE).真实世界数据(RWD)作为真实世界研究(RWS)的重要基础,决定了RWS是否能为监管和审评机构提供可靠的RWE.目前RWD在使用过程中存在一些问题,表现为数据非结构化和零碎化、可及性差、数据的标准化处理缺乏数据...     

真实世界数据合规探讨

真实世界数据的获取方式包括前瞻性收集和回顾性收集,分别需要进行数据管理和数据治理.真实世界数据管理和数据治理涉及数据安全、网络安全、生物安全、人类遗传资源、个人信息保护、人口健康信息、健康医疗大数据等方面的法律法规.本文将梳理真实世界数据相关概念,介绍真实世界数据监管法律体系,探讨真实世界数据应用的合规难题.     

真实世界数据在医疗器械上市后监测中的应用进展

目的 梳理总结真实世界数据在医疗器械上市后监测中的应用进展,为医疗器械监督管理部门提供监管依据.方法 从中国、美国和欧盟监管机构官网检索相关政策法规文件,同时检索国内外相关文献.结果 各国监管机构相继发布并一定程度更新了真实世界数据相关指南,唯一器械标识、通用数据模型、分布式健康数据网络等技术的发展有助于将多个数据源链...     

真实世界数据在药物警戒工作中的应用

随着医疗健康数据的快速增长,真实世界数据（real world data,RWD）分析为药物警戒工作带来了新的机遇,成为传统药品不良反应监测模式的有益补充。本文通过介绍几种主要的RWD类型,包括电子健康档案数据、医疗保险数据、注册登记数据、社交媒体数据和多源整合数据的定义和常见数据库举例,并对各种类型数据应用于相关药品安全性监测和评价的案例进行分析,总结了RWD在药物警戒中的应用范畴、优势和局限性,以期为我国利用RWD开展药物警戒活动相关研究的探索和实践提供参考。     

真实世界证据与随机对照试验：RCT DUPLICATE项目概述

摘 要近年来,利用真实世界数据（real world data, RWD）通过恰当的设计和分析产生真实世界证据（real world evidence, RWE）,已经成为学术界、工业界和监管机构共同关注的话题。但RWE能否代替来自严格受控的随机对照试验（RCT）产生的证据仍不确定。为此,2018年美国启动了RCT DUPLICATE项目,旨在利用真实世界证据,通过非随机的观察性研究来重复RCT的结果。本文回顾了RCT DUPLICATE产生的背景,重点介绍了该项目的研究团队、研究目的、研究内容及项目意义,以期促进国内学者更好地理解RWE的适用范围和应用价值。     

利用补充真实世界数据研究获得更深层次的认识

摘 要随着患者、医护人员、药品注册人员和政策决定者对现实世界中各种诊疗手段的安全性和有效性相关证据的迫切需求,我们需要新的研究设计来高效有效地对此类问题进行评估。与此同时,越来越多的二手数据可以用来提供此种相关证据,常用的二手数据包括电子医疗档案和医疗保险数据等。补充真实世界数据研究同时利用了现有二手数据和通过医生/患者收集的一手数据,并将两者进行结合。在现有数据的基础上,补充真实世界数据研究可以集中精力收集缺失的重要信息来满足研究目的。本文将对补充真实世界数据研究进行介绍,包括研究设计要素,研究的优点和局限性,实施要点以及应用实例等。     

真实世界数据在上市后药品安全性研究中的伦理风险

目的 为更好地利用符合伦理要求的真实世界数据(real-world data,RWD)开展上市后药品安全性监测和评价.方法 从患者安全和数据安全的维度出发,探讨RWD在研究方案中的伦理要求、研究注册和发表的伦理要求、以及数据归属和数据使用权限的伦理考虑.结果 与结论建议对真实世界研究(real-world study,...     

基于真实世界数据研究万古霉素治疗重症感染患儿的血药浓度变化

目的 探讨真实世界万古霉素在初始给药剂量达稳态后,血药浓度与重症感染患儿疗效、年龄、性别之间的关系.方法 选择我院2013年1月-2019年12月依据适应证使用万古霉素的住院患儿,采用药品说明书推荐剂量,在不干预临床治疗情况下,监测万古霉素血药峰浓度及谷浓度,评价抗菌疗效及安全性.结果 215例患儿中,有效率73.95...     

Real-world Evidence of the Herb-drug Interactions

Herbal medicine (HM) is a type of medicine that uses active ingredients made from plants to treat diseases and maintain health and wellbeing. Due to its increasing worldwide usage, the possibility of HMs and conventional drugs being concurrently used is high, potentially leading to adverse events resulting from herb-drug interactions. Despite the safety concerns regarding such interactions, few studies have been conducted for assessing clinical consequences of using HMs with conventional drugs in real-world settings. As clinical trials are not forthcoming rapidly enough to provide the evidence for herb-drug interactions, observational studies are considered as an alternative approach. The present review focuses on evaluating the utility of analyzing real-world data in observational research to study the clinical consequences of herb-drug interactions between HMs and conventional drugs. The data sources and study designs of each highlighted literature are examined based on its strengths and limitations in analyzing herb-drug interactions. Finally, future observational studies involving novel and rigorous methodologies that may be effective in studying herb-drug interactions are discussed.     

Real world evidence of use of anti-VEGF therapy in Denmark

Objective: This study evaluates real-world evidence regarding the frequency of anti-vascular-endothelial-growth-factor (VEGF) injections during the first year of therapy of treatment-naïve patients with neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME) and retinal vein occlusion (RVO) from the Danish National Patient Registry. There was a switch in anti-VEGF treatment for naïve nAMD patients during the study period, following the introduction of aflibercept, which was expected to reduce the injection frequency relative to ranibizumab due to a perception of prolonged treatment duration of aflibercept.

Methods: All treatment-naïve nAMD, DME or RVO patients who received an intravitreal injection in Denmark from 1 January 2012 to 31 July 2015 were eligible for inclusion. Patients were required to have been treated for at least one year and, for nAMD, to have received at least three injections during the first four months of treatment. Patients were allocated to half-year groupings (2012/1 to 2014/1) based on registration of their first intravitreal injection. Injection frequency during the first year of treatment was calculated for each group and t-tests investigated whether injection frequencies changed over time.

Results: In treatment naïve nAMD patients (n?=?500), the mean (SD) number of anti-VEGF injections increased significantly from 6.04 (1.71) in 2012/1 to 6.73 (1.62) in 2014/1 (p?=?.001; 2012/1 and 2012/2 vs. 2014/1) across all treatments. A similar trend was found for DME patients (n?=?76) from 2012/1 to 2014/1 and RVO patients (n?=?82) from 2012/2 to 2014/1, with mean injection frequencies increasing significantly from 5.14 (2.29) to 5.93 (1.98) (p?=?.007), and from 4.83 (1.21) to 6.08 (1.55) (p?=?.024), respectively. Post hoc sensitivity analysis also found a significant increase in injection frequency in nAMD patients who did not receive a loading phase (4.55 in 2012/1 and 5.05 in 2014/1; p?=?.006; n?=?616).

Conclusions: In contrast to the decrease in injection frequency predicted with a switch to aflibercept treatment for nAMD, our study showed that injection frequencies increased significantly from 2012 to 2014 in patients initiating therapy across the three diseases.     

Patient and caregiver outcomes after 6 ± 1.5-months of rivastigmine therapy for mild-to-moderate Alzheimer's disease:the Belgian FExT study

ABSTRACT

Objective: Despite response variability, cholinesterase inhibitors are recommended in mild to moderate Alzheimer's disease. Dose titration is common; however randomized controlled trials (RCTs) have mainly investigated fixed-dose regimens. We examined practice patterns and outcomes of 6 ± 1.5-month rivastigmine therapy.

Methods: Prospective, pharmacoepidemiologic, naturalistic study of 175 evaluable patients with mild to moderate Alzheimer's disease (+ 151 caregivers) from 52 centers in Belgium on 6 ± 1.5 month (titrated) rivastigmine treatment.

Main outcome measures: Measured at baseline (enrollment) and follow-up (6 ± 1.5 months). For patients: Mini-Mental State Exam (MMSE), Activities of Daily Living (ADL), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS) scores; treatment response (improvement, maintenance, or decline less than normative slope). For caregivers: hours/week spent caring; Zarit Caregiver Burden Scale (ZCBS), 12‐item version of General Health Questionnaire (GHQ‐12), Instrumental Activities of Daily Living (IADL) scores.

Results: Patients’ MMSE and NPI scores (?p < 0.001) improved from baseline to follow-up, but not ADL and GDS scores. Treatment response was 89.1% of patients for MMSE (including 60.6% with improvement) and 77.7% for NPI (including 57.1% with improvement). Quadratic curves were fitted for the average daily dose and the MMSE and NPI scores; with a trend towards average daily dose of 6.0 ± 3.0?mg/day. Caregivers’ ZCBS (?p = 0.036) and GHQ‐12 (?p = 0.029) scores improved, but not IADL scores and time spent caring.

Conclusions: Patients’ MMSE and ADL scores confirmed the meta-analyses of rivastigmine efficacy trials, while NPI scores exceeded efficacy results. Proportionately more patients responded to (titrated) treatment than in fixed-dose RCTs. Caregivers reported less burden (similar to meta-analysis) and better general health over the study period. Where efficacy and effectiveness results diverge, the benefit is in ‘real-world’ effectiveness. Large sample, multi-country replications, less sensitive to censoring secondary to missing data and powered to permit advanced modeling, as well as RCTs with adaptive designs to accommodate titration, are needed. The profile of patients most likely to benefit from treatment or most vulnerable to treatment outcome must be studied, as must the impact of physician- and center-related variables on outcomes.     

The incremental costs of recommended therapy versus real world therapy in type 2 diabetes patients

ABSTRACT

Background: The goals of diabetes management have evolved over the past decade to become the attainment of near-normal glucose and cardiovascular risk factor levels. Improved metabolic control is achieved through optimized medication regimens, but costs specifically associated with such optimization have not been examined.

Objective: To estimate the incremental medication cost of providing optimal therapy to reach recommended goals versus actual therapy in patients with type 2 diabetes.

Methods: We randomly selected the charts of 601 type 2 diabetes patients receiving care from the outpatient clinics of Massachusetts General Hospital March 1, 1996–August 31, 1997 and abstracted clinical and medication data. We applied treatment algorithms based on 2004 clinical practice guidelines for hyperglycemia, hyperlipidemia, and hypertension to patients’ current medication therapy to determine how current medication regimens could be improved to attain recommended treatment goals. Four clinicians and three pharmacists independently applied the algorithms and reached consensus on recommended therapies. Mean incremental medication costs, the cost differences between current and recommended therapies, per patient (expressed in 2004 dollars) were calculated with 95% bootstrap confidence intervals (CIs).

Results: Mean patient age was 65 years old, mean duration of diabetes was 7.7 years, 32% had ideal glucose control, 25% had ideal systolic blood pressure, and 24% had ideal low-density lipoprotein cholesterol. Care for these diabetes patients was similar to that observed in recent national studies. If treatment algorithm recommendations were applied, the average annual medication cost/patient would increase from $1525 to $2164. Annual incremental costs/patient increased by $168 (95% CI $133–$206) for antihyperglycemic medications, $75 ($57–$93) for antihypertensive medications, $392 ($354–$434) for antihyperlipidemic medications, and $3 ($3–$4) for aspirin prophylaxis. Yearly incremental cost of recommended laboratory testing ranged from $77–$189/patient.

Limitations: Although baseline data come from the clinics of a single academic institution, collected in 1997, the care of these diabetes patients was remarkably similar to care recently observed nationally. In addition, the data are dependent on the medical record and may not accurately reflect patients’ actual experiences.

Conclusion: Average yearly incremental cost of optimizing drug regimens to achieve recommended treatment goals for type 2 diabetes was approximately $600/patient. These results provide valuable input for assessing the cost-effectiveness of improving comprehensive diabetes care.     

实施循证医疗决策探索降低癌症经济负荷的有效途径

随着我国癌症发病和死亡率的增加,因癌症而带来的疾病经济负担会越来越对社会经济发展产生不良影响。癌症已成为我国经济负担最高的慢性疾病,癌症不仅给患者心身体带来巨大的打击,诊治过程中产生的巨额费用还给家庭及社会带来沉重的经济负荷,成为严重影响社会的和谐稳定的潜在因素。在日益增加的经济负荷越来越突出情形下,迫切需要探索癌症的科学合理诊治及充分考虑成本-效益、价值和资源的有效途径。本文从癌症循证医疗决策的模式、癌症循证医疗技术信息平台、癌症诊疗过程中的成本-效益与益害比等方面提出构想与实施方案。     

基于中国医院药物警戒系统的药源性帕金森综合征真实世界研究

目的 探索利用中国医院药物警戒系统（CHPS）开发主动监测药源性帕金森综合征（DIP）的方法,并分析DIP的人群特征。方法 利用CHPS制订主动监测方案,对2019年1月至2020年12月的聊城市人民医院入院病人从病历、医嘱、体征、影像学检查中通过关键词检索出报警病例,对其临床症状、治疗药物、体征检查、既往用药等方面的资料进行分析判断后,生成最终监测结果。结果 在纳入研究的36 369病例中,实际使用研究药物的为12 021例,CHPS报警病例2 488例,经人工复核后确定阳性病例52例,CHPS阳性预警率为2.1%(52/2 488),DIP实际发生率为0.43%(52/12 021)。可疑药物有曲美他嗪、利血平、氟桂利嗪、丙戊酸盐、氟哌啶醇、奥氮平、氯氮平、阿普唑仑、多奈哌齐、利培酮。52例阳性病例的年龄为（68.36±12.98）岁,年龄>65岁者共38例（73.08%）,女性病人34例（65.38%）,既往有缺血性脑病病史者18例（34.62%）,双侧肢体阳性症状者40例（76.92%）,颅脑CT或MRI检查显示异常者37例（71.15%）,11例（21.15%）未停用可...     

Integration of Pharmacometric and Statistical Analyses Using Clinical Trial Simulations to Enhance Quantitative Decision Making in Clinical Drug Development

This article outlines a general framework in which clinical trial simulations (CTS) are employed integrating both pharmacometric and statistical analyses to support trial design and quantitative decision making in drug development. Specifically, predictive pharmacometric models are used as data-generation models to simulate data, while data-analytic models as specified in the statistical analysis plan are used to analyze the simulated data and to apply a quantitative data-analytic decision rule. Various probability metrics including probability of achieving the target value, probability of success, and probability of a correct decision are proposed to support study design recommendations and quantitative decision-making. A case study is presented to illustrate the CTS methods and procedures described in this article.     

Using semi covert research to evaluate an emergency hormonal contraception service

OBJECTIVE: The aim of our study was to evaluate whether the patient group direction protocol for supply of emergency hormonal contraception was being adhered to, that pharmacists were undertaking their professional duties appropriately and to evaluate how women researchers felt that the service was being delivered. METHOD: Semi covert research was used, two women researchers posed as clients seeking emergency contraception in a sample of participating community pharmacies. They used two rehearsed scenarios about unsafe sexual intercourse and missed doses of the oral contraceptive pill. All transactions were tape recorded and the recordings were used to produce the findings. The two women researchers posing as clients were also asked to record their feelings and experiences concerning the service on leaving the pharmacy. MAIN OUTCOME MEASURE: Adherence to the patient group direction protocol and women's perceptions of service provision. RESULTS: In both scenarios the protocol was largely adhered to and emergency contraception was supplied appropriately. The length of each consultation for both scenarios was between 10-15 min. The women reported that the pharmacists had been courteous, polite and non judgemental. The consultations were carried out in a private area or in the dispensary. The women had no concerns about confidentiality. CONCLUSION: Whilst there are clear limitations of this study in terms of the size of the sample, our results do highlight the fact that the PGD protocol was being utilised appropriately in most cases. In addition, neither woman reported any instances of judgmental or negative attitudes and commented favourably on the scope for discussion about emergency hormonal contraception and other important issues with the pharmacist.