Impact analysis of signals detected from spontaneous adverse drug reaction reporting data.

This paper describes a new method of prioritising signals of potential adverse drug reactions (ADRs) detected from spontaneous reports that is called impact analysis. This is an interim step between signal detection and detailed signal evaluation. Using mathematical screening tools, large numbers of signals may now be detected from spontaneous ADR databases. Regulatory authorities need to rapidly prioritise them and focus on those that are most likely to require significant action. Using two scores ranging from one to 100, each with three input variables, signals may be categorised in terms of the strength of evidence (E) and the potential public health impact (P). In a two-by-two figure with empirically derived cut-off points of ten (the logarithmic mean) for each score, signals are placed in one of four categories (A-D) that are ranked according to their priority (A being the highest and D the lowest). A sensitivity analysis is then performed that tests the robustness of the categorisation in relation to each of the six input variables. A computer program has been written to facilitate the process and reduce error. Further work is required to test the feasibility and value of impact analysis in practice.     

A model for decision support in signal triage

Spontaneous reporting of suspected adverse drug reactions (ADRs) has long been a cornerstone of pharmacovigilance. With the increasingly large volume of ADRs, regulatory agencies, scientific/academic organizations and marketing authorization holders have applied statistical tools to assist in signal detection by identifying disproportionate reporting relationships in spontaneous reporting databases. These tools have generated large numbers of signals defined as drug-ADR reporting associations that meet specified statistical criteria.The challenge is to identify which signals are most likely to be medically important and therefore warrant priority for further investigation. Decisions related to signal triage are often complex and are based on a combination of clinical, epidemiological, pharmacological and regulatory criteria. There are no specific regulations, guidelines or standards that provide an objective basis for these decisions.This paper describes preliminary work to identify and quantify the specific factors that contribute to a decision to prioritize a specific drug-ADR combination for further in-depth review. We applied a tool from the discipline of decision analysis to systematically assess the important attributes of spontaneously reported ADRs. A model was created that integrates these assessments and produces rankings for the signals generated from quantitative signalling methods. Although more research is necessary to evaluate the performance of this model fully, preliminary results suggest that the use of formal decision analysis approaches to support signal triage can provide potential benefit and will help meet an important need.     

Development and reliability testing of the clinical pharmacist recommendation taxonomy

STUDY OBJECTIVE: To evaluate the reliability of a newly developed taxonomy--the Clinical Pharmacist Recommendation (CPR) taxonomy--to classify clinical pharmacy interventions. DESIGN: The CPR taxonomy was developed and refined in three phases. In each phase, reviewers independently reviewed recommendations made by a clinical pharmacist-physician team and categorized them into mutually exclusive categories: priority, problem, and response. Interrater reliability was assessed for all categories during each development phase. SETTING: Primary care clinics of a Veterans Affairs Medical Center. PATIENTS: Fifty-three patients enrolled in the Veterans Affairs Enhanced Pharmacy Outpatient Clinic (EPOC) trial. MEASUREMENTS AND MAIN RESULTS: Interrater reliability was assessed using the kappa statistic. A total of 423 recommendations were evaluated during the three testing phases. In the final testing phase, agreement was moderate for pharmacotherapy problem subcategories (kappa = 0.57), substantial for pharmacotherapy problem primary categories (kappa = 0.64), and almost perfect for response categories (kappa = 0.85). Taxonomy completion time/patient averaged 4.6 minutes (range 1-11 min). CONCLUSION: The CPR taxonomy provides a reliable method to systematically evaluate clinical pharmacy recommendations based on the therapeutic problem identified and specific action recommended to resolve the problem.     

熵权法在药品不良反应信号筛选及综合风险评价中的应用

目的：在运用经典方法对药品不良反应信号进行检测后,对信号进行再筛选并评价药品的综合风险。方法：以江苏省药品不良反应监测网络数据库为资料来源,SQLserver为后台数据库,Matlab为算法主要实现工具,运用熵权法结合专家评分,对BCPNN方法检测出的信号进行再调整和评级。结果：运用综合权重进行调整后,发现不同药品不良反应信号的强弱发生了一定的变化。其中,氟喹诺酮类药品中的加替沙星导致低血糖、呼吸困难等药品不良反应的风险较信号评级之前有所增加,需要专家在评审时更为留意。结论：将熵权法运用在药品不良反应信号的监测中,可使信号更接近客观筛选和主观判断的平衡值,部分罕发但严重的药品不良反应信号得到发现和重视,并能方便地研究药物引起的多种药品不良反应的综合风险。     

基于AERS的丙戊酸不良反应信号挖掘与数据分析

目的：检测美国不良事件报告系统（AERS）中丙戊酸致各系统不良反应（ADR）的信号并分析其影响因素,为临床合理用药提供参考。方法：采用报告比值比法（ROR）对AERS数据库中2017年第1季度-2017年第4季度收集的报告进行提取分析,挖掘丙戊酸致血液、代谢、消化、皮肤系统不良反应的相关信号,并使用SPSS20.0分析年龄、性别、用药剂量及联合用药对血液系统不良反应的影响。结果：纳入以丙戊酸为首要怀疑药物的不良反应报告110份,其中血液系统不良反应报告数和信号数均为最多。统计学分析显示血液系统ADR相对于其他系统ADR,在年龄（P=0.002）、性别（P=0.003）中分布有统计学意义,在用药剂量（P=0.778）、联合用药（P=0.847）中分布无统计学意义。儿童特别是女性患者对血液系统不良反应较敏感。结论：通过对丙戊酸安全信号和影响因素的检测和分析发现,应重视年龄和性别对血液系统不良反应的影响,并有必要进行进一步信号评价和验证,为临床安全用药提供依据。     

基于VAERS的轮状病毒疫苗不良反应信号挖掘和数据分析

目的:挖掘、评价轮状病毒疫苗上市后药物不良反应信号,为临床安全用药提供参考.方法:采用报告比值比法、比例报告比值比法、贝叶斯法对美国疫苗不良反应报告系统中的轮状病毒疫苗不良反应信号进行挖掘和分析.结果:纳入以轮状病毒疫苗为首要怀疑药品的不良反应(adverse drug reaction,ADR)报告15 417例,经...     

Signal generation in a non-EU country

One of the most important objects of post-marketing surveillance is the early detection of serious, unknown and unexpected adverse events. As spontaneous reported adverse events vary considerably in their signal-generating value the Swiss Drug Monitoring Center SANZ implemented an early signal detection system in 1991. With a set of screening criteria the individual case reports are automatically checked by the system and read into a signal file. Subsequently these potential signals are processed to quantify the signal generating value of the particular case. According to the screening criteria 2072 (53%) of the reported cases were considered as potential signals. After validating and quantifying their signal value 27% (565) were drug-related and unlabelled, 8% (173) were also rated as serious. On the basis of these cases 114 labelling changes were made. Some of the most interesting cases are discussed. This computer-assisted early signal generation model in a small country with 7 million inhabitants has a high detectability of new, rare, serious and quality of life affecting adverse drug reactions (ADRs). These newly detected ADRs must be interpreted in cognizance of the limitations and restrictions of spontaneous reporting and do not allow pharmacoepidemiologic conclusions.     

替格瑞洛上市后出血不良反应信号检测与分析

目的:检测替格瑞洛上市后出血不良反应信号,并分析其影响因素,为临床合理用药提供参考。方法:采用报告比值比法(ROR)对美国食品药品监督管理局不良事件报告系统(AERS)数据库进行替格瑞洛不良反应信号检测,应用标准MedDRA分析查询(SMQ)检索其中的出血信号,并利用SPSS 17.0分析年龄、性别、用药时长对出血信号的影响。结果:总的药物不良反应报告6806330份,以替格瑞洛为首要怀疑药物的不良反应报告5279份,经ROR法检测,共得到158个替格瑞洛不良反应信号,其中出血信号42个。统计学分析结果显示:维持剂量时,与其他ADR相比,出血ADR在年龄(P=0.003)、用药时长(P=0.026)分布中差异有统计学意义,在性别(P=0.417)分布中差异无统计学意义;负荷剂量时,与其他ADR相比,出血ADR在年龄(P=0.000)分布中差异有统计学意义,在性别(P=0.846)分布中差异无统计学意义。其中,年龄大于75岁负荷剂量时,维持剂量用药半年内,发生出血ADR风险更大。结论:检测到的替格瑞洛不良反应信号和影响因素,有必要进行进一步信号评价和验证,为临床安全用药提供依据。     

Implementation of a computer-assisted monitoring system for the detection of adverse drug reactions in gastroenterology

AIM: To investigate the effectiveness of a computer monitoring system that detects adverse drug reactions (ADRs) by laboratory signals in gastroenterology. METHODS: A prospective, 6-month, pharmaco-epidemiological survey was carried out on a gastroenterological ward at the University Hospital Erlangen-Nuremberg. Two methods were used to identify ADRs. (i) All charts were reviewed daily by physicians and clinical pharmacists. (ii) A computer monitoring system generated a daily list of automatic laboratory signals and alerts of ADRs, including patient data and dates of events. RESULTS: One hundred and nine ADRs were detected in 474 admissions (377 patients). The computer monitoring system generated 4454 automatic laboratory signals from 39 819 laboratory parameters tested, and issued 2328 alerts, 914 (39%) of which were associated with ADRs; 574 (25%) were associated with ADR-positive admissions. Of all the alerts generated, signals of hepatotoxicity (1255), followed by coagulation disorders (407) and haematological toxicity (207), were prevalent. Correspondingly, the prevailing ADRs were concerned with the metabolic and hepato-gastrointestinal system (61). The sensitivity was 91%: 69 of 76 ADR-positive patients were indicated by an alert. The specificity of alerts was increased from 23% to 76% after implementation of an automatic laboratory signal trend monitoring algorithm. CONCLUSION: This study shows that a computer monitoring system is a useful tool for the systematic and automated detection of ADRs in gastroenterological patients.     

伊布替尼致不良反应文献分析

目的：分析伊布替尼所致不良反应（ADRs）的发生情况及临床特点，为临床安全用药提供参考。方法：检索PubMed、Web of Science、中国知网数据库、维普中文科技期刊数据库、万方数据库、中国医院知识总库关于伊布替尼不良反应的文献并进行分析。结果：伊布替尼致ADRs的个案共41例，多发生在用药30d内（13例，31.7%）；伊布替尼致ADRs累及系统-器官以呼吸系统损害（13例，28.9%）、皮肤及附件损害为主（10例，22.2%）为主。结论：临床医师或药师应了解伊布替尼ADRs的发生规律和特点，尽量将ADRs的影响及危害降至最低，最大程度保障用药安全。     

Results of forty years Yellow Card reporting for commonly used perioperative analgesic drugs

BACKGROUND: A variety of analgesics are used perioperatively and associated adverse drug reactions (ADRs) may complicate anaesthesia and recovery. METHODS: We aimed to measure the demographics of reported suspected ADRs to alfentanil, fentanyl, ketorolac, morphine, nalbuphine, papaveretum, pethidine and remifentanil. We report a retrospective analysis of Yellow Card reports of suspected ADRs from 1965-2004 as classified in the Adverse Drug Reaction On-line Tracking database (ADROIT) of the Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: In total, 1312 reactions were retrieved. A single drug was reported in 908, 39 were fatal and 219 categorised as 'allergic'. Allergic phenomenon varied from 2/33 (6%) for remifentanil to 11/53 (21%) for alfentanil. 'Cardiovascular' reactions were reported frequently with remifentanil (18/33, 55%) and alfentanil (19/53, 36%) and these generated a signal for possible hazards from proportional reporting ratios (PRRs). The opioid fentanyl was associated with similar hazard signals for muscular and psychiatric ADRs. CONCLUSIONS: Perioperative vigilance may reduce morbidity and mortality from preventable ADRs to analgesic drugs. Denominator and diagnostic data are essential for prospective studies.     

Evaluation of adverse drug reactions in medical intensive care units

Purpose

Patterns of adverse drug reactions (ADRs) in the medical intensive care unit (MICU) were analysed, and signals for detecting ADRs were developed from the analysis.

Method

A retrospective study was conducted in MICU wards at a tertiary care teaching hospital in Seoul, Korea. The areas included one general MICU and one cancer centre MICU. Two pharmacists evaluated ADRs in terms of length of stay, causality, severity, preventability, types, related organs, and incidence. Differences in ADR perception rates between physicians and pharmacists were also evaluated. ADR cases detected through the evaluation were reviewed to develop specific alerting signals for ICU ADRs.

Results

The study group included 346 patients admitted to the ICU over 4 months. The overall incidence of ADRs was 32%. ICU length of stay is closely related to ADRs (p?=?0.014). Most ADR cases were mild, temporary, and harmful to the patient. Twenty percent of ADRs were preventable, and 74% were type A. Of the ADRs, 70% were noted by physicians; 80% required intervention. The most commonly implicated drug was amphotericin B, and the clinical presentation was a haematologic reaction. Data on the time required for pharmacists to identify ADRs indicated that they were not slower than physicians. Six signals for early detection of the ADRs were developed.

Conclusions

The overall ADR incidence in the MICU was about one-third, and the length of stay of the ADR group was longer than that of those without this experience. Automated signal generation was developed. It seemed to be a valuable tool for faster and more efficient patient management, and possibly prevention of ADRs. A future study should scientifically evaluate the clinical relevance of this tool.     

Identification of adverse drug reactions in geriatric inpatients using a computerised drug database

INTRODUCTION AND OBJECTIVE: Geriatric patients with multiple comorbidities are at high risk of experiencing an adverse drug reaction (ADR) during hospitalisation. The aim of the study was to compare the rate of ADRs as predicted by a computerised pharmacological database to the actual rate determined by direct observation in a sample of geriatric patients. STUDY DESIGN: During a 4-month period, geriatric patients were monitored using prospective observation. Patients were intensively screened for ADRs by a pharmacoepidemiological team (PET), consisting of two pharmacists and a physician. Actual ADRs detected by the PET were compared with those predicted by a computerised drug database. Furthermore, the set of actual ADRs, which resulted from drug-drug interactions (DDIs), were contrasted with potential DDIs signalled by the database. The main outcome measures were the incidence of actual ADRs. For the detection rate of the database we focused on frequent ADRs (>1% according to product information and database) and all DDIs indicated automatically by the database. RESULTS: 163 patients (121 female), mean age 79.8 +/- 7.1 years (range 60-98), were included in the study which was conducted on a geriatric rehabilitation hospital ward. The mean duration of hospitalisation was 24.3 +/- 8.4 days. Elderly patients received an average of 14.0 drugs (range 2-35) during their hospital stay.Of all patients, 60.7% experienced at least one ADR. The PET detected a total of 153 ADRs, with a mean of 0.9 ADRs per patient (range 0-5). The computerised drug database predicted an average of 309 potential ADRs for each patient; however, only 21 ADRs per patient were of high frequency. In 48% of ADR-positive patients (defined by PET) at least one of these frequent ADRs occurred.DDIs were detected by the PET in 14.7% of patients. Our database indicated a mean of 12 potential DDIs per patient. In 14 out of 24 DDI-positive patients, at least one signal indicated a real DDI. The database sensitivity was consequently 58.3%. CONCLUSION: In geriatric patients the incidence of ADRs is high. Computerised drug databases are a useful tool for detecting and avoiding ADRs. Our software, however, also produced a large number of signals that did not relate to actual ADRs found by the PET. The sheer number of these 'false' signals shows the need for refinement and optimisation of databases for daily clinical use.     

An intensive drug monitoring study suggesting possible clinical irrelevance of impaired drug disposition in liver disease

1 Liver disease can alter the disposition and clinical effects of drugs. However, even though altered drug disposition occurs, there is no clinical evidence relating it to an increased susceptibility to adverse drug reactions (ADRs). 2 An intensive prospective drug monitoring study of 2,582 hospitalized patients was conducted. The adverse drug reactions probability scale (APS) was used to assess ADRs. Only non-mild, definite or probable ADRs (APS greater than or equal to 5) were included. Severity of liver dysfunction was assessed by a composite clinical and laboratory index (CCLI). 3 The frequency of ADRs was higher in 402 patients with cirrhosis (27.4%) than in 661 with renal dysfunction (22.8%) and in 249 with other parenchymatous liver diseases (13.7%) or in 1,270 patients with neither liver diseases nor renal dysfunction (10.9%) (chi 2 3 = 85.53, P less than 0.001). The frequency of ADRs in cirrhotics was highly correlated with the severity of the liver dysfunction measured by CCLI (r = 0.82, P less than 0.001). 4 Drugs predominantly eliminated by liver metabolism were not among those most commonly inducing ADRs or those causing severe reactions in cirrhotics. Thus, frusemide caused the most common and the most severe ADRs, whereas reactions induced by sedatives were uncommon. Drug-induced hepatic encephalopathy was more common in cirrhotics receiving diuretics (13.3%) than in those receiving sedatives (1.8%) (chi 2 y.c. = 5.29, P less than 0.025). Patients with alcoholic liver disease had more drug-induced hepatic encephalopathy (7.7%) than those with non-alcoholic liver disease (1.2%) (chi 2 y.c. = 11.86, P less than 0.001). 5 These results indicate that susceptibility to ADRs is increased only in severe cirrhosis and that the most common and severe ADRs seem more likely related to enhanced pharmacodynamic action than to impaired drug disposition.     

Comparison of three algorithms used to evaluate adverse drug reactions

The consistency of three algorithms in evaluating adverse drug reactions (ADRs) was studied. As part of a hospital's ADR protocol, doctor of pharmacy students were required to collect and summarize all ADR data. Algorithms by Kramer, Naranjo, and Jones were used to evaluate all ADRs between January and May 1984. Kramer's algorithm was used for every reported ADR; Naranjo's and Jones' algorithms were used to check consistency in scoring among ADRs already scored with the Kramer algorithm. The two numerical scales (Kramer and Naranjo) were compared using linear regression. The results of all three algorithms were translated into categories of suspicion (A = definite or probable; B = probable; C = possible; and D = unlikely, doubtful, or remote) and evaluated for consistency with a weighted kappa (kw) statistical test. A total of 28 ADRs were evaluated, and the correlation (r = 0.87) between the total numerical scores of the Kramer and Naranjo algorithms was significant. Comparison of the Kramer and Naranjo algorithms showed 67% agreement with a kw value of 0.43 (-1 = perfect disagreement and +1 = perfect agreement). Similarly, there was 67% agreement (kw = 0.48) between Kramer's algorithm and Jones' algorithm. Agreement between Naranjo's and Jones's algorithms was 64%, but the kw value was only 0.28. The simpler and less time-consuming Naranjo algorithm compared favorably with the Kramer algorithm in scoring ADRs; more data are needed to support the use of the Jones algorithm.     

Improving medication safety in oncology care: impact of clinical pharmacy interventions on optimizing patient safety

Background Adverse drug reactions (ADRs) monitoring in cancer patients is important to ensure early detection, effective management and possible prevention subsequently. Objectives This study was conducted to detect and monitor ADRs to anti-cancer agents, and to assess impact of clinical pharmacists (CPs)’ interventions in minimizing ADRs to anti-cancer agents. Setting Private, specialty oncology care hospital in South India. Methods CPs prospectively followed cancer patients admitted to inpatient wards and treated at ambulatory care in order to identify ADRs, for a period of 3 years. Identified/reported ADRs were discussed with concerned oncologists and/or nurses, documented electronically and assessed further for their causality, severity, preventability and grading. Based on study findings during year 1, interventions (educational, therapeutic and system based) were developed by CPs and implemented in order to minimize preventable ADRs. Impact of CPs’ interventions was studied during year 2 and year 3. Main outcome measure(s) Preventable factors contributing to ADRs and percentage of preventable ADRs before and after CPs’ interventions. Results A total of 1279 ADRs were reported in 1133 patients from a cohort of 1328 patients. Vomiting (23.22%), alopecia (9.53%), diarrhoea (8.67%) and myelosuppression (7.42%) were the common ADRs reported. Inappropriate administration frequency and regimen of anti-emetics (22%), lack of/suboptimal supportive care (18%) and administration errors (16%) were identified as common contributing (preventable) factors for ADRs in year 1. Percentage of preventable ADRs was 81% during year 1 (pre-intervention), and 45% and 34% in year 2 and year 3 respectively (post-interventions). Conclusion Interventions by CPs helped to minimize preventable ADRs to anti-cancer agents.

     

基于FDA不良事件数据库和指定医疗事件对氯喹和羟氯喹不良反应信号的检测与评价

目的： 挖掘和评价新型冠状病毒肺炎治疗方案（试行第七版）中加入的药物"磷酸氯喹"和《上海市2019冠状病毒病综合救治专家共识》中推荐加入的"硫酸羟氯喹"上市后的安全信号,为临床合理用药提供参考。方法： 检索美国FDA不良事件报告系统（FDA adverse event reporting system,FAERS）数据库2004年1月1日-2019年12月31日收录以"氯喹"及"羟氯喹"为怀疑对象的不良事件（adverse drug events,ADEs）报告,提取排名前200位药物不良反应（adverse drug reaction,ADR）报告进行指定医疗事件（designated medical event,DME）筛选,采用报告比值比法（ROR）和比例报告比值比法（PRR）检测ADR信号,重点评估和比较出现DME的系统器官分类（SOC）中的安全信号,并对DME进行分析。结果： 提取FAERS数据库得到氯喹与羟氯喹ADEs报告数量分别为1 128例和29 639例;氯喹严重不良事件（serious adverse event,SAE）占比57.89%,羟氯喹占比26.60%。经DME筛选,共涉及7种SOC,其中眼部疾病与呼吸系统相关ADR中,羟氯喹检出的信号较多;皮肤和皮下组织类疾病,2种药物信号检出数量大致相等;心脏、血液及肝胆系统相关ADR中,信号主要集中在氯喹;耳部系统相关ADR中,信号检出较少。另外,氯喹检出的7种DME中尖端扭转型室速信号值最高,羟氯喹检出的4种DME中中毒性表皮坏死松解症信号值最高。结论： 基于真实世界的ADR信号检测有助于新冠疫情中氯喹与羟氯喹的安全性评价,降低临床用药风险。     

Interrater reliability of the Antipsychotic Non-Neurological Side-Effects Rating Scale measured in patients treated with clozapine

The Antipsychotic Non-Neurological Side-Effects Rating Scale (ANNSERS) was developed to provide a comprehensive measure for rating non-neurological adverse drug reactions (ADRs) to antipsychotics. Although there were already available measures that adequately rated specific non-neurological ADRs, such as sexual side effects, a need was identified for a scale that comprehensively rated the full range of non-neurological ADRs commonly seen across the spectrum of first and second generation antipsychotic drugs, including metabolic and autonomic ADRs. This article reports on work to establish the interrater reliability of an early version and a later, more comprehensive version of the ANNSERS (versions 1 and 2, v1 and v2, respectively). The measures were administered in London centres to patients treated with clozapine. Trained clinicians rated the patients simultaneously and independently. Interrater reliability on the scores was calculated using the kappa coefficient method. The results (mean kappa coefficients of 0.77 and 0.72, respectively) indicate that substantial interrater reliability was achieved for both versions. Items for which the main basis for rating was laboratory investigations rather than patient interview were largely excluded from this study, and kappas were also not calculated for items with a low frequency (less than 10%) of endorsement. Samples of patients on other antipsychotics would be required to reliably calculate kappa coefficients for these items. In conclusion, the ANNSERS represents a clinically applicable research innovation, with good interrater reliability on clinician judged items, which is now available for the comprehensive assessment of non-neurological ADRs to antipsychotics, to aid the processes of clinical audit, research and drug discovery.     

Intensive monitoring of duloxetine: results of a web-based intensive monitoring study

Purpose

Duloxetine (Cymbalta^®) is a serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitor indicated for the treatment of depression, diabetic peripheral neuropathic pain and general anxiety disorder. The aim of this study is to gain insight in the user and safety profile of duloxetine in daily practice, reported by patients via a web-based intensive monitoring system during their first 6 months of use.

Methods

First-time users of duloxetine were identified through the first dispensing signal in the pharmacy. Patient demographics and information about drug use and adverse drug reactions, ADRs, were collected through electronic questionnaires sent 2 and 6 weeks, 3 and 6 months after the start of duloxetine administration. ADRs were quantified and signal detection was performed on a case by case basis.

Results

Three hundred and ninety-eight patients registered for the study; 69.1 % were female. Depression was the main indication. Three hundred and three patients (76.1 %) filled in at least one questionnaire and 78.9 % of these reported an ADR. Serious ADRs were reported by 4 patients. Three new signals were identified, amenorrhea, shock-like paraesthesias and micturition problems.

Conclusions

Web-based intensive monitoring is an observational prospective cohort study mirroring the use and ADRs of duloxetine in daily practice. This study indicates that duloxetine is a relatively safe drug as used by patients for six months in daily practice, but the aforementioned signals need to be evaluated in more detail.