舌下特异性免疫疗法治疗变应性鼻炎和/或过敏性哮喘的安全性研究

目的探讨舌下特异性免疫疗法治疗变应性鼻炎和过敏性哮喘的安全性。方法对182名过敏性鼻炎和/或过敏性哮喘患者,采用舌下特异性免疫疗法和对症用药相结合的方式进行免疫治疗;跟踪并统计在免疫治疗过程中患者产生的不良反应及其严重程度。结果没有患者出现全身性的不良反应,轻中度不良反应的总发生率为8.24%;14岁以下的患者出现不良反应的比例高于14岁以上的患者。结论舌下特异性免疫治疗引起的不良反应都只是轻中度的,它是一种高安全性的免疫治疗方法。     

New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors

Introduction: Tumor development results from a cancer-induced immunosuppression (immune-editing). Immunotherapy has revolutionized the treatment paradigm for many malignancies, putting clinicians before novel toxicities, of immune-mediated etiology (immune-related adverse events).

Areas covered: Immune-mediated toxicity depends on both innate and adaptive immunity mechanisms. Healthy tissue damage depends on an aspecific T-cell hyperactivation response causing cross-reaction with normal tissues, which leads to an overproduction of CD4 T-helper cell cytokines and an abnormal migration of cytolytic CD8 T-cells. By stimulating a diffuse T-cell repertoire expansion, immune-checkpoint inhibitors counteract tumor growth but reduce the self-tolerance, damaging healthy organs. In this review, we summarize the toxicity profile of the novel immune-checkpoint inhibitors and their clinical implications, we are convinced that a deep understanding and a prompt resolution of the paradigmatic toxicities of these drugs will result in clinical benefits to patients and an enhanced antitumor effect.

Expert opinion: A focus on immunotoxicity is important in the education of clinicians and will improve patient safety. There is a willingness to tailor specific immune-therapies to each cancer patient, and to stimulate researchers through understanding of the physiopathogenesis, using the hypothesis that immune-mediated toxicities can be used as predictors of response or a prognostic sign of survival, thereby guiding therapeutic decisions.     

Safety considerations for new vaccine development

Vaccines are highly effective and extremely safe. Although most known vaccine reactions are minor (e.g. fever, injection site pain or swelling), rare but serious reactions such as vaccine‐associated paralytic polio do occur. When large populations are vaccinated, some adverse health events may occur by chance shortly after vaccination. It is difficult to determine whether these are truly coincidental or attributable to the vaccine. The most reliable way to assess causality is in a controlled study, but clinical trials of new vaccines are typically too small to detect rare but serious effects. If the size of these trials were increased, much more could be learned about the safety of a vaccine prior to its exposure to entire populations. This information would increase confidence in the safety of vaccines, would be a valuable resource for assessing spontaneous reports of adverse events after licensure, and would reduce the risk of licensing a new vaccine that had the potential to cause severe injury to a small proportion of vaccinees. Published in 2001 by John Wiley & Sons, Ltd.     

Safety of intravenous immunoglobulin treatment

Importance of the field: Intravenous immunoglobulin (IVIg) is a biologic pharmaceutical that is widely used to treat immunodeficiency conditions and a variety of autoimmune conditions. It is under-recognized that IVIg can be associated with severe complications including death.

Areas covered in this review: This review will address common mild side effects and extensively discuss the uncommon but serious complications of IVIg. Mild constitutional reactions include headache, fever and rash and severe complications include anaphylaxis, acute renal failure, stroke and myocardial infarction. IVIg has been used to treat autoimmune illnesses for ～ 30 years and the literature since then is reviewed with special attention to reports in the last 10 years that detail the serious adverse events.

What the reader will gain: The reader will understand that mild side effects are common and that these can be ameliorated with pre-treatment medications. They will also become familiar with the risk factors for serious complications so that careful patient and IVIg product selection will result in fewer poor outcomes.

Take home message: IVIg is quite safe across age groups although serious adverse reactions occur particularly in elderly individuals with multiple cardiovascular risk factors and those with preexisting renal failure.     

临床试验中不良事件数据的可视化评价

目的:探讨可视化方法在临床试验不良事件数据分析中的应用。方法:基于临床试验中的真实不良事件数据,结合发现安全信号的目的和国际协调会议(International Conference on Harmonization,ICH)有关药物安全性评价指南要求,使用SAS v9.2和JMP/clinical3进行可视化绘图,比较不良事件发生的组间差异,突出需重点关注的不良事件。结果:文中共绘制6幅图,分别是森林图、树图、火山图、韦恩图、生存函数图和风险函数图。结论:不良事件数据的可视化评价不仅能描述不良事件特征,还能突出显示应引起重视的不良事件,在临床试验不良事件数据分析中应当优先考虑使用。     

Safety evaluation of the drugs available to prevent malaria

All drugs used for malaria prophylaxis have common adverse effects, in addition to rare and/or severe adverse effects. For many of the drugs in current use, the common adverse effects include neuropsychiatric harms. This property makes these drugs unpopular with tourists and business travellers, most of whom will be well at the start of chemoprophylaxis. Drugs available to prevent malaria have not been rigorously researched in terms of the phenomenology of their unwanted effects. Consequently, prescribers are not well placed to give useful information to travellers on the incidence, natural history and avoidability of the harms they may experience from malaria chemoprophylaxis. There is some evidence that the adverse effects of mefloquine may be a post-hepatic syndrome caused by drug-induced liver damage with, in some users, symptomatic thyroid disturbance. However, confusion in the interpretation of the scientific evidence has led to conflicting messages regarding the safety of mefloquine and other antimalaria drugs, and to incorrect self-therapy by individual travellers, sometimes with fatal outcomes. In this review, the existing knowledge base for the safety of drugs currently used to prevent malaria is described along with present designs for future studies that would allow a rigorous safety assessment of candidate chemoprophylactic agents and of new drugs introduced to prevent malaria. There is an urgent need for internationally-agreed, evidence-based malaria prevention guidelines. These guidelines should be explicitly linked to the best available research evidence (normally systematic reviews of trials and individual randomised trials) and should highlight gaps in the knowledge base as priority areas for research.     

免疫接种的安全性及不良事件

免疫接种是预防和控制传染病的重要手段之一,随着免疫接种覆盖率的提高,疑似免疫接种不良事件（AEFI）也日益增多。中国疾病预防控制中心将AEFI分为7类,包括疫苗本身的不良反应（一般反应和异常反应）、疫苗质量、实施差错、非疫苗引起的偶合反应、心因性反应和不明原因的反应。本文概述了乙型肝炎疫苗、卡介苗、口服脊髓灰质炎疫苗、麻疹/麻疹-腮腺炎-风疹疫苗、百白破疫苗、乙型脑炎疫苗、B型流感嗜血杆菌偶联疫苗、狂犬病疫苗和甲型H1N1流感疫苗等9种疫苗不良事件的发生情况,以及AEFI的监测和管理措施,旨在为增强免疫接种的安全性提供参考。     

药物临床试验机构对临床试验中不良事件的监控

不良事件的监控是临床试验的关键环节之一,也是新药临床试验相关部门所关注的重点。目前国际上高水平的临床试验已经建立了较为完善的多方位的监控机制,国内还存在着较大的差距。由于药物临床试验机构对临床试验中不良事件的监控直接关系着受试者的安全和临床试验的质量,因此加强临床试验机构对不良事件的监控,才能最大限度地保障受试者的权益。本文结合作者所在单位的具体经验和体会,就如何加强临床试验中不良事件的监控力度提出了建议。     

The Vaccine Safety Datalink project

The Vaccine Safety Datalink (VSD) is a collaborative project between the National Immunization Program of the Centers for Disease Control and Prevention (CDC) and several large health maintenance organizations (HMOs) in the United States. The project began in 1990 with the primary purpose of rigorously evaluating concerns about the safety of vaccines. Computerized data on vaccination, medical outcome (e.g. hospital discharge, outpatient visits, emergency room visits, and deaths), and covariate data (e.g. birth certificates and census) are prospectively collected at multiple HMOs (initially four) and linked under joint protocol for analyses. Approximately 6 million people (2% of the US population) are members of HMOs participating in the VSD. The VSD has proven to be a valuable resource that has provided important information on a number of vaccine safety issues. The databases and infrastructure created for the VSD have also provided opportunities to address other immunization questions including vaccination coverage and cost‐effectiveness. In a recent investigation of intussusception following rotavirus vaccination, the VSD methodology was expanded to include 10 managed care organizations. A cohort study was conducted that allowed estimation of incidence rates of intussusception and attributable risks associated with rotavirus vaccine. Published in 2001 by John Wiley & Sons, Ltd.     

Safety and pharmacological profile of tiotropium bromide

Background: Chronic obstructive pulmonary disease (COPD) is associated with progressive airflow obstruction and is characterized by a high risk of morbidity and mortality. With early detection and treatment, the natural history of this disease may be improved. So far, bronchodilator therapy is the most important treatment for COPD. Tiotropium is a bronchodilator of recent introduction. Objective: To discuss the clinical data on the safety and efficacy of tiotropium, a very long-acting antimuscarinic drug, available at present. Methods: The Cochrane trial database, Medline, Embase, were searched systematically, and ～ 20 respiratory journals and conference abstracts were searched manually. Language of publication was limited to English. included tiotropium, COPD, anticholinergic, safety and adverse events. Conclusion: A large body of evidence is available at present on the safety and efficacy of tiotropium in COPD, with dry mouth being the most common adverse event. Reviews of serious adverse event data in the literature have reported that tiotropium is safe and that the incidence of these events is the same as with placebo. Tiotropium is a convenient treatment for COPD with a good clinical efficacy and safety profile.     

某院药物临床试验不良事件监控质量调查

目的:分析及评价某院药物临床试验不良事件监控质量.方法:对照不良事件监控的质量评分标准,调查2007-2013年结题的Ⅱ~Ⅲ期项目中不良事件监控的质量得分及各要素的年均得分率.并对2007-2013年发生的15例严重不良事件(SAE)监控情况进行分析.结果:总体上,某院药物临床试验不良事件监控质量得分及各要素得分率均呈现逐年增长的趋势.2011年某院针对不良事件的监控实施展开全面整改工作,整改前存在的问题主要集中在:启动会培训缺失或不完整、实验检查类不良事件收集的遗漏、SAE获知的滞后性、SAE报告表原件的遗失、不良事件源文件记录的缺失或不完整.通过完善规章制度、建立应急预案、强化伦理审查力度、强化试验前不良事件的预防措施、加强机构办公室及科室的监控力度等措施,某院不良事件的监控质量显著提高.结论:加强临床试验机构对不良事件的监控作用,依靠临床试验各部门的共同努力,不断完善安全性监控体系,才能提高临床试验的质量和水平.     

Development and evaluation of a standardized questionnaire for identifying adverse events in vaccine clinical trials

In vaccine trials, diary questionnaires or vaccination report cards (VRCs) are used extensively to collect complaints reported by subjects or guardians following vaccination. These have not been evaluated for accuracy or standardized to facilitate tolerability comparisons among vaccines. Objectives —(1) Develop standardized, age‐specific VRCs for collecting self‐reported adverse events (AEs) in trials; (2) Evaluate whether complaints elicited by nurse examinations or telephone interviews were missed by VRCs. Methods —Vaccine‐trial databases, focus groups, experts and experienced nurses were used to develop paediatric and adolescent/adult VRCs. VRCs were evaluated at four sites. The primary outcome was subjects with AEs missed on the VRC and reported in nurse examinations (for injection‐site reactions) or telephone interviews (for systemic complaints). Results —Of 855 subjects, 96.5% completed VRCs. For systemic complaints, 1.5% (12/812) reported both no complaint on VRCs and at least one complaint in telephone interviews. For injection‐site reactions, 5.1% (53/1030) of injection sites had both no reaction reported on VRCs and had reactions noted by nurse examination. No missed AEs were rated as severe. Conclusion —The data suggest VRCs provide a practical and reasonably complete method of eliciting complaints following vaccination. Copyright © 2000 John Wiley & Sons, Ltd.     

Safety review in 10,008 users of lansoprazole in daily practice

Purpose —Soon after the introduction of the proton pump inhibitor, lansoprazole, a 4‐year observational follow‐up study was started to evaluate the safety of this drug in naturally‐occurring groups of patients in The Netherlands. Results of this study were compared with clinical trial data and the limited published data from observational studies. Methods — prospective, observational study in which patients with a new episode of lansoprazole use were followed during the medication period for a maximum of 2 years. All (adverse) events during use were documented by the prescriber, irrespective of possible association with lansoprazole therapy. Results — total of 805 general practitioners (GPs) and 266 specialists provided a total of 10,008 lansoprazole users with a broad range of diagnoses. Of all patients, 17.4% reported one or more adverse events. The profile and frequency of reported adverse events was consistent with results from clinical trials and other observational studies. The most frequently reported adverse events were diarrhoea, headache, nausea, skin disorders, dizziness and generalized abdominal pain/cramps. There was no new evidence of rare adverse events. Furthermore, no lansoprazole‐related unlabelled adverse events of clinical significance were recorded. Conclusions — Although the patterns of use of lansoprazole in daily practice deviated to some extent from the diagnoses in the information leaflet, lansoprazole was found to have a highly acceptable safety profile in this large naturally‐occurring group of users. Reporting rates were higher soon after introduction of lansoprazole before falling to a lower stable level. Copyright © 2000 John Wiley & Sons, Ltd.     

Safety of human papillomavirus vaccines: a review

Introduction: Between 2006 and 2009, two different human papillomavirus virus (HPV) vaccines were licensed for use: a quadrivalent (qHPVv) and a bivalent (bHPVv) vaccine. Since 2008, HPV vaccination programmes have been implemented in the majority of the industrialized countries. Since 2013, HPV vaccination has been part of the national programs of 66 countries including almost all countries in North America and Western Europe. Despite all the efforts made by individual countries, coverage rates are lower than expected. Vaccine safety represents one of the main concerns associated with the lack of acceptance of HPV vaccination both in the European Union/European Economic Area and elsewhere.

Areas covered: Safety data published on bivalent and quadrivalent HPV vaccines, both in pre-licensure and post-licensure phase, are reviewed.

Expert opinion: Based on the latest scientific evidence, both HPV vaccines seem to be safe. Nevertheless, public concern and rumors about adverse events (AE) represent an important barrier to overcome in order to increase vaccine coverage. Passive surveillance of AEs is an important tool for detecting safety signals, but it should be complemented by activities aimed at assessing the real cause of all suspect AEs. Improved vaccine safety surveillance is the first step for effective communication based on scientific evidence.     

The safety of vedolizumab for the treatment of ulcerative colitis

Introduction: Vedolizumab is a humanized monoclonal antibody to the α4β7-integrin that blocks lymphocyte trafficking to the gut and is approved for treatment of patients with moderate-to-severe ulcerative colitis (UC). The gut-selective mechanism of action has the potential to improve vedolizumab’s safety profile compared to other approved biologic drugs.

Areas covered: We review the mechanism of action, efficacy and safety of vedolizumab treatment for UC. The positioning of vedolizumab in management algorithms is also discussed.

Expert opinion: The highly selective mechanism of action of vedolizumab restricts immunosuppressive effects to the gut. Vedolizumab is efficacious as induction and maintenance therapy in UC patients who are naïve or refractory to tumor necrosis factor antagonists. No clinically important safety signals have been identified. Infusion reactions are reported in <5% of cases. The rates of adverse events (AE), serious AEs, and serious infections were not different between patients treated with placebo and those who received vedolizumab in a pooled analysis of six randomized controlled trials. Rates of malignancy and mortality in vedolizumab-exposed patients are similar to those of the general UC patient population. Progressive multifocal leukoencephalopathy has not been observed. Vedolizumab is a safe and effective therapy for UC with a unique mechanism of action.     

A safety review of recent advancements in the treatment of psoriasis: analysis of clinical trial safety data

Introduction: The management of psoriasis can include oral medications and injectable biologics. Safety data of these various treatment options are important to consider when choosing the right treatment for the patient.

Areas covered: This review evaluates the safety of newer treatments approved for psoriasis, including interleukin-(IL)-17 inhibitors, IL-23/p19 inhibitors, ustekinumab, certolizumab pegol and apremilast, using phases III and IV clinical trial data.

Expert opinion: Even as treatment of psoriasis becomes safer, it is important to recognize both common and uncommon adverse effects of treatment. Common adverse effects are similar across treatment options, including upper respiratory infection and injection-site reaction. Serious adverse effects occur less frequently and specific to the psoriasis treatment option, such as inflammatory bowel disease and candida infections with IL-17 inhibitors, tuberculosis with certolizumab pegol, and psychiatric events with apremilast. While IL-23/p19 inhibitors may have a slightly better safety profile than other biologics, long-term data are limited. The conclusions that can be drawn from clinical trial safety data are limited given that many clinical trials are not large enough to detect rare safety events. Data from registries provide important complementary information on long-term safety but there are limitations including a lack of randomized assignment between drug treatments.     

The FDA's Final Rule on Expedited Safety Reporting: Statistical Considerations

In March 2011 ——— (2011), Code of Federal Regulations Title 21 Food and Drugs Chapter I Food and Drug Administration Department of Health and Human Services Subchapter D Drugs for Human Use Part 312 Investigational New Drug Application. [Google Scholar], a Final Rule for expedited reporting of serious adverse events took effect in the United States for studies conducted under an Investigational New Drug (IND) application. In December 2012, the U.S. Food and Drug Administration (FDA) promulgated a final Guidance describing the operationalization of this Final Rule. The Rule and Guidance clarified that a clinical trial sponsor should have evidence suggesting causality before defining an unexpected serious adverse event as a suspected adverse reaction that would require expedited reporting to the FDA. The Rule's emphasis on the need for evidence suggestive of a causal relation should lead to fewer events being reported but, among those reported, a higher percentage actually being caused by the product being tested. This article reviews the practices that were common before the Final Rule was issued and the approach the New Rule specifies. It then discusses methods for operationalizing the Final Rule with particular focus on relevant statistical considerations. It concludes with a set of recommendations addressed to Sponsors and to the FDA in implementing the Final Rule.