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Rearrangements in the anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) genes characterise two distinct molecular subsets of non-small cell lung cancer (NSCLC) tumours. Lorlatinib is a third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) shown to have systemic and intracranial activity in treatment-naive patients and in those who progressed on first- and second-generation TKIs. Despite being generally well tolerated, lorlatinib has a unique and challenging safety profile that includes hyperlipidaemia and central and peripheral nervous system adverse events (AEs). This article summarises a set of strategies designed to monitor and manage lorlatinib-related AEs that were agreed upon by a multidisciplinary panel of specialists in a meeting held in July 2020. Among the recommendations hereby described, special emphasis was placed on communication: prescribing physicians should inform patients and their families/caregivers about the likelihood and nature of lorlatinib AEs, encouraging them to report any symptoms, while at the same time reassuring them that most events are manageable and resolve spontaneously and have little to no interference with cancer treatment. Importantly, all patients should undergo a set of baseline assessments, including biochemical analysis, evaluation of cardiovascular risk, electrocardiogram (ECG), neurological evaluation and contrast-enhanced magnetic resonance imaging of the brain, which should be repeated regularly during lorlatinib treatment. Supportive medications to treat or relieve lorlatinib AEs were also discussed, as were the conditions requiring specialist consultations and/or adjustments in lorlatinib therapy. The overall goal of this article is to serve as a practical guide for oncologists to systematically and effectively approach lorlatinib AEs. [ABSTRACT FROM AUTHOR]

Background: Underreporting is the major limitation of a voluntary adverse drug reaction (ADR) reporting system. Many studies have assessed the effectiveness of different interventions designed to reduce underreporting. Objective: We aimed to conduct a critical review of papers that assessed the effectiveness of different strategies to increase ADR reporting, regardless of the health professionals or patients included. Data Sources: Scientific papers were selected after a search of the MEDLINE-PubMed and EMBASE scientific databases up to 7 December 2010. Study Selection: We included papers in English, French or Spanish that analysed an intervention aimed at increasing the number of reported ADRs, and quantify the results of the intervention in terms of number of reports. Data Extraction: The abstracts retrieved in both computerized searches were reviewed independently by two of the authors. Initially selected papers were thoroughly read to evaluate if they met inclusion and exclusion criteria. Data in finally selected papers were independently extracted by both authors and set in pre-designed tables. A third author took the final decision in case of disagreement. For each study, we analysed study design, type of intervention, assessment period, and results of the intervention. Results: Of the 4,221 papers located that fulfilled the search criteria, 43 met the selection criteria. With the exception of one study, the interventions assessed were deemed to be effective. The vast majority of papers displayed methodological and formal limitations that lowered the grade of evidence. Multiple interventions seem to have had more impact than did single interventions. There were very few cases in which interventions were designed on the basis of inappropriate attitudes and mistaken beliefs about ADRs. Conclusions: In general, there is a need for studies of better methodological quality in this topic, so that more evidence of the effectiveness of the respective strategies can be collected for the purpose of improving ADR reporting by health professionals. It is probable that multiple interventions cause greater increases in the ADR reporting rates than single. [ABSTRACT FROM AUTHOR]

Additional risk minimization strategies may be required to assure a positive benefit–risk balance for some therapeutic products associated with serious adverse drug reactions/risks of use, without which these products may be otherwise unavailable to patients. The goals of risk minimization strategies are often fundamentally to influence the behavior of healthcare professionals (HCPs) and/or patients and can include appropriate patient selection, provision of education and counselling, appropriate medication use, adverse drug reaction monitoring, and adoption of other elements to assure safe use, such as pregnancy prevention. Current approaches to additional risk minimization strategy development rely heavily on information provision, without full consideration of the contextual factors and multi-level influences on patient and HCP behaviors that impact adoption and long-term adherence to these interventions. Application of evidence-based behavioral science methods are urgently needed to improve the quality and effectiveness of these strategies. Evidence from the fields of adherence, health promotion, and drug utilization research underscores the value and necessity for using established behavioral science frameworks and methods if we are to achieve clinical safety goals for patients. The current paper aims to enhance additional risk minimization strategy development and effectiveness by considering how a behavioral science approach can be applied, drawing from evidence in understanding of engagement with pharmaceutical medicines as well as wider public health interventions for patients and HCPs. [ABSTRACT FROM AUTHOR]

The long-term and potential rare side effects of new immunomodulating drugs for the treatment of multiple sclerosis (MS) are often not well known. Spontaneous case report systems of adverse drug effects are a valuable source in pharmacovigilance, but have several limitations. Primary data collections within registries allow a comprehensive analysis of potential side effects, but face several challenges. This article will outline the chances and challenges of registry-based adverse event reporting, using the example of the German immunotherapeutic registry REGIMS. REGIMS is an observational, clinical multicenter registry that aims to assess the incidence, type, and consequences of side effects of MS immunotherapies. Patients treated with an approved MS medication are recruited by their physicians during routine visits in hospitals, outpatient clinics, and MS-specialized practices. REGIMS incorporates an electronic physician-based documentation in each center and a paper-based patient documentation, both at baseline and regular follow-up visits. By the end of 2019, 43 REGIMS centers were actively recruiting patients and performing follow-up documentations. The majority of the first 1000 REGIMS patients were female (69.3%), had relapse-remitting MS (89.8%), and were treated with a second-line therapy. During the implementation of REGIMS, several logistic and procedural challenges had to be overcome, which are outlined in this paper. Pharmacovigilance registries such as REGIMS provide high-quality primary data from a specific patient population in a real-world care setting and enable pharmacovigilance research that cannot be carried out using secondary data. Despite the logistic and procedural challenges in establishing a multicenter pharmacovigilance registry in Germany, the advantages outweigh the drawbacks. [ABSTRACT FROM AUTHOR]

Introduction: Underreporting is a major limitation of the voluntary reporting system of adverse drug reactions (ADRs). A 2009 systematic review showed the knowledge and attitudes of health professionals were strongly related with underreporting of ADRs. Objective: Our aim was to update our previous systematic review to determine factors (sociodemographic, knowledge and attitudes) associated with the underreporting of ADRs by healthcare professionals. Methods: We searched the MEDLINE and EMBASE databases for studies published between 2007 and 2021 that met the following inclusion criteria: (1) published in English, French, Portuguese or Spanish; (2) involving health professionals; and (3) the goal was to evaluate factors associated with underreporting of ADRs through spontaneous reporting. Results: Overall, 65 papers were included. While health professional sociodemographic characteristics did not influence underreporting, knowledge and attitudes continue to show a significant effect: (1) ignorance (only serious ADRs need to be reported) in 86.2%; (2) lethargy (procrastination, lack of interest, and other excuses) in 84.6%; (3) complacency (the belief that only well tolerated drugs are allowed on the market) in 46.2%; (4) diffidence (fear of appearing ridiculous for reporting merely suspected ADRs) in 44.6%; and (5) insecurity (it is nearly impossible to determine whether or not a drug is responsible for a specific adverse reaction) in 33.8%, and the absence of feedback in 9.2%. In this review, the non-obligation to reporting and confidentiality emerge as new reasons for underreporting. Conclusions: Attitudes regarding the reporting of adverse reactions continue to be the main determinants of underreporting. Even though these are potentially modifiable factors through educational interventions, minimal changes have been observed since 2009. Clinical Trials Registration: PROSPERO registration number CRD42021227944. [ABSTRACT FROM AUTHOR]

9276413 8 Norén GN, Sundberg R, Bate A. A statistical methodology for drug-drug interaction surveillance. Dear Editor, Thank you for the opportunity to respond to the comment by Dr. Yoshiro Noguchi [[1]] concerning our paper entitled " I A Disproportionality Analysis of Drug-Drug Interactions of Tizanidine and CYP1A2 Inhibitors from the FDA Adverse Event Reporting System (FAERS i )" [[2]]. 10.1007/s40264-022-01240-w. 36223038 2 Villa-Zapata L, Gómez-Lumbreras A, Horn J. A Disproportionality analysis of drug-drug interactions of tizanidine and CYP1A2 inhibitors from the fda adverse event reporting system (FAERS). [Extracted from the article]

Therefore, the validity of the drug-drug interaction signal between tizanidine and CYP1A2 inhibitors using the ROR score is not fully clear. 2014250 5 Noguchi Y, Tachi T, Teramachi H. Review of statistical methodologies for detecting drug-drug interactions using spontaneous reporting systems. To explore the drug-drug interaction signals of tizanidine and CYP1A2 inhibitors, Villa-Zapata et al. calculated the reporting odds ratios (RORs) [[2]] and 95% confidence intervals (CIs) of the concomitant use group [[1]]. [Extracted from the article]

Introduction: Adverse drug reactions (ADRs) are an important public health challenge worldwide; however, pharmacovigilance systems are plagued by under-reporting. Mobile technologies, including mobile applications such as Med Safety, could strengthen ADR reporting. We explored the acceptability, and factors that could influence uptake of, Med Safety for ADR reporting by health workers in Uganda. Methods: The study took place between July and September 2020 in 12 HIV clinics in Uganda and employed a qualitative exploratory research design. We conducted 22 in-depth interviews and 3 mixed-gender focus group discussions (49 participants) with a diverse range of health workers. We analysed the data using a thematic approach. Results: There was goodwill among the health workers to adopt Med Safety for ADR reporting and the majority would recommend the app to other health workers. Training with practice increased acceptability of the app. Uptake of the app was favoured by the younger, technology proficient, health worker demographic; the app's offline and two-way risk communication functionalities; availability of free internet hotspots at some health facilities; goodwill and willingness of health workers to report ADRs; and the cumbersome nature of conventional ADR reporting tools. Potential barriers to the uptake of Med Safety were the perceived lengthy processes of initial app registration and completion of multiple screens during ADR reporting; challenges with health workers' smartphones (incompatibility with application, no space for more applications, low battery charge); high cost of internet data; poor internet connectivity; difficulty in recognising ADRs, language barrier and poor feedback to ADR reporters. Conclusion: There was goodwill among the health workers to adopt Med Safety for ADR reporting and the majority would recommend the app to other health workers. Training with practice increased acceptability of the app and should be integral in all future app roll-out campaigns. The identified facilitators and barriers could be used to appropriately guide future research and implementation to promote the uptake of Med Safety for pharmacovigilance in low- and middle-income countries. [ABSTRACT FROM AUTHOR]

This paper reviews the main tools for communicating benefit-risk medicines information to patients that are used, or could be used, by pharmaceutical regulators. One highly successful tool from the food safety sector (front-of-package traffic-light labelling) and the mental models approach (which provides a framework for developing new tools) are also reviewed as they show great promise for being usefully adapted to the pharmaceutical context. The evolution of benefit-risk medicines communication is first contextualised within the broader risk communication literature. Three distinct goals are then made explicit before critically examining the evidence for and against tools developed in the US (e.g. at the Food and Drug Administration [FDA]) and Europe (e.g. at the European Medicines Agency [EMA]). These goals are (i) sharing information (e.g. publishing clinical trial and adverse event data online); (ii) changing patients' beliefs by conveying factual knowledge (e.g. patient information leaflets and the drugs facts box); and (iii) changing behaviour (e.g. patient alert cards and warning labels). The mental models approach and traffic-light labelling, developed outside the pharmaceutical context, are then examined. Ultimately, the paper provides a helicopter view of the variety of benefit-risk communication tools that are used, or could be used, by pharmaceutical regulators in the US and Europe. [ABSTRACT FROM AUTHOR]

Introduction: Due to the complexity of biologics and the inherent challenges for manufacturing, it is important to know the specific brand name and batch number of suspected biologics in adverse drug reaction (ADR) reports. Objective: The aim of this study was to assess the extent to which biologics are traceable by brand name and batch number in UK hospital practice and in ADRs reported by patients and healthcare professionals. Methods: We performed an online hospital pharmacist survey to capture information on how specific product details are recorded during the processes of prescribing, dispensing and administration of biologics in routine UK hospital practice. We also assessed the proportion of ADR reports specifying brand name and batch number from electronic ADR reports submitted to the UK national spontaneous reporting database, the Yellow Card Scheme, between 1 January 2009 and 30 September 2017. Results: Brand name recording in routine hospital processes ranged from 79 to 91%, whereas batch numbers were less routinely recorded, ranging from 38 to 58%. Paper-based recording of product details was more commonly used for recording information. A total of 6108 electronic ADR reports were submitted to the Yellow Card Scheme for recombinant biologics, of which 38% and 15%, respectively, had an identifiable brand name and batch numbers. Whereas batch number traceability in electronic ADR reports improved slightly after the implementation of the European Union pharmacovigilance legislation in 2012, no improvement of brand name traceability was observed. Conclusion: Brand name and batch number traceability for biologics in UK ADR reports are generally low. Shortcomings in the systematic recording of product details in UK clinical practice may contribute to the limited traceability. [ABSTRACT FROM AUTHOR]

Vigabatrin has been an important anticonvulsant drug for over 10 years with a reputation for high efficacy and excellent tolerability. However, since 1997, there have been over 25 reports in the literature of visual field defects attributable to the use of this agent. Most are case reports and many have only been reported as abstracts or posters or as letters or short communications. Only a small number of papers give details of patient characteristics. Typically, case reports detail ophthalmological tests such as visual acuity, funduscopic examination, integrity of colour vision, and the nature of the field cut. Many also include various electrophysiological tests which were performed in an attempt to further describe the nature of the visual changes. In order to shed light on the mechanism underlying these visual field changes, many investigators also tested various electrophysiological parameters. However, because electrophysiological testing requires considerable expertise on the part of the technician, this could be a source of variability in results and may also pose a challenge with data interpretation. The magnitude of the problem is difficult to assess. The manufacturer's estimate of incidence of visual field defects with vigabatrin was approximately 0.1%, but incidences estimated in the literature range from 6 to 30%. Since the majority of the published data are in case report form, proof of causation is also very difficult. Two papers that used proper scientific methodology to investigate this condition suggest that vigabatrin causes these changes; however, there needs to be further studies with larger populations to answer this question definitively. There is a lack of data on the dose-response characteristics of vigabatrin and the development of visual field defects. The only available data are reports of trends that implicate duration of therapy or cumulative dose. Perhaps the most important area to elucidate is whether or not the visual field defects are reversible. Data are scare on this subject, but we can hope that data will emerge as follow-up periods become more substantial. There is a need for more complete information regarding several aspects of the mechanistic basis of visual field defects associated with vigabatrin that will allow rational clinical decision making. The treatment choices, both pharmacological and nonpharmacological, for patients with refractory epilepsy have grown substantially in the last few years. Thus, it is doubtful that the clinical positioning of vigabatrin is likely to change in the future from that of a very valuable ‘niche drug’, with emphasis on paediatric usage. [ABSTRACT FROM AUTHOR]

Since the introduction of the interferons in the 1990s, a multitude of different immunomodulatory and immunosuppressant disease-modifying therapies for multiple sclerosis (MS) have been developed. They have all shown positive effects on clinical endpoints such as relapse rate and disease progression and are a heterogeneous group of therapeutics comprising recombinant pegylated and non-pegylated interferon-β variants, peptide combinations, monoclonal antibodies, and small molecules. However, they have relevant side effect profiles, which necessitate thorough monitoring and straightforward patient education. In individual cases, side effects can be severe and potentially life-threatening, which is why knowledge about (neurological and non-neurological) adverse drug reactions is essential for prescribing neurologists as well as general practitioners. This paper aims to provide an overview of currently available MS therapies, their modes of action and safety profiles, and the necessary therapy monitoring. [ABSTRACT FROM AUTHOR]

Introduction: Adverse drug event (ADE) detection is a vital step towards effective pharmacovigilance and prevention of future incidents caused by potentially harmful ADEs. The electronic health records (EHRs) of patients in hospitals contain valuable information regarding ADEs and hence are an important source for detecting ADE signals. However, EHR texts tend to be noisy. Yet applying off-the-shelf tools for EHR text preprocessing jeopardizes the subsequent ADE detection performance, which depends on a well tokenized text input.Objective: In this paper, we report our experience with the NLP Challenges for Detecting Medication and Adverse Drug Events from Electronic Health Records (MADE1.0), which aims to promote deep innovations on this subject. In particular, we have developed rule-based sentence and word tokenization techniques to deal with the noise in the EHR text.Methods: We propose a detection methodology by adapting a three-layered, deep learning architecture of (1) recurrent neural network [bi-directional long short-term memory (Bi-LSTM)] for character-level word representation to encode the morphological features of the medical terminology, (2) Bi-LSTM for capturing the contextual information of each word within a sentence, and (3) conditional random fields for the final label prediction by also considering the surrounding words. We experiment with different word embedding methods commonly used in word-level classification tasks and demonstrate the impact of an integrated usage of both domain-specific and general-purpose pre-trained word embedding for detecting ADEs from EHRs.Results: Our system was ranked first for the named entity recognition task in the MADE1.0 challenge, with a micro-averaged F1-score of 0.8290 (official score).Conclusion: Our results indicate that the integration of two widely used sequence labeling techniques that complement each other along with dual-level embedding (character level and word level) to represent words in the input layer results in a deep learning architecture that achieves excellent information extraction accuracy for EHR notes. [ABSTRACT FROM AUTHOR]

A primary aim in pharmacovigilance is the timely detection of either new adverse drug reactions (ADRs) or a relevant change of the frequency of ADRs that are already known to be associated with the drugs involved, i.e. signal detection. Adequate signal detection solely based on the human intellect (case-by-case analysis or qualitative signal detection) has proven its value. However, it is becoming increasingly time consuming given the growing volume of data, as well as less effective, especially in more complex associations, such as drug-drug interactions, syndromes and when various covariates are involved. In quantitative signal detection, measures that express the extent in which combinations of drug(s) and clinical event(s) are disproportionately present in the database of reported suspected ADRs are used to reveal associations of interest. Although the rationale and the methodology of the various quantitative approaches differ, they all share the characteristic in that they express to what extent the number of observed cases differs from the number of expected cases. Recent years have shown that the use of quantitative measures in addition to qualitative analysis is a step forward in signal detection in pharmacovigilance. This paper uses historical, classic examples and studies to illustrate the principles, pros and cons of especially quantitative methods in signal detection and adds a flavour of future perspective. [ABSTRACT FROM AUTHOR]

Pharmacovogilance policy, methods and practice require transformation at all levels to create an integrated, comprehensive, continuously improving system, fulfilling the broader remit of overall healthcare vigilance. In pursuit of this vision, energetic measures, including active engagement with patients, are needed to reduce our ignorance about many aspects of patients' experience of medical therapies and their outcomes, including the benefits, but especially the extensive harm known to be caused by medical interventions. More information and communication in this domain will help set more accurate and realistic public expectations about the benefits and harm of therapy. All aspects of medicines development, regulation and use must be characterized by openness, transparency, ethical practice and a primary focus on the benefit and self-determined choices of patients. Notwithstanding, progress has been made in medicines safety information and communication but significant gaps and deficiencies remain. Promotion of the most beneficial use of medicines and the prevention of harm have not advanced sufficiently. This paper is a report from a group of experts, following previous similar decade reviews: the Erice Declaration (1996) and the Erice Manifesto (2006). [ABSTRACT FROM AUTHOR]

Drug safety profiles are dynamic and established over time using multiple, complimentary datasets and tools. The principal concern of pharmacovigilance is the detection of adverse drug reactions that are novel by virtue of their clinical nature, severity and/or frequency as soon as possible with minimum patient exposure. A key step in the process is the detection of ‘signals’ that direct safety reviewers to associations that might be worthy of further investigation. Although the ‘prepared mind’ remains the cornerstone of signal detection safety reviewers seeking potential signals by scrutinising very large, sparse databases may find themselves ‘drowning in data but thirsty for knowledge’. Understandably, health authorities, pharmaceutical companies and academic centres are developing, testing and/or deploying computer-assisted database screening tools (also known as data-mining algorithms [DMAs]) to assist human reviewers. The most commonly used DMAs involve disproportionality analysis that project high-dimensional data onto two-dimensional (2 × 2) contingency tables in the context of an independence model. The objective of this paper is to extend the discussion of the evaluation, potential utility and limitations of the commonly used DMAs by providing a ‘holistic’ perspective on their use as one component of a comprehensive suite of signal detection strategies incorporating clinical and statistical approaches to signal detection – a marriage of technology and the ‘prepared mind’. Data-mining exercises involving spontaneous reports submitted to the US FDA will be used for illustration. Potential pitfalls and obstacles to the acceptance and implementation of data mining will be considered and suggestions for future research will be offered. [ABSTRACT FROM AUTHOR]

Background: The WHO Foundation Collaborating Centre for International Drug Monitoring (Uppsala Monitoring Centre [UMC]) has received many individual case safety reports (ICSRs) associating HMG-CoA reductase inhibitor drug (statin) use with the occurrence of muscle damage, including rhabdomyolysis, and also peripheral neuropathy. A new signal has now appeared of disproportionally high reporting of upper motor neurone lesions.Aim and Scope: The aim of this paper is to present the upper motor neurone lesion cases, with other evidence, as a signal of a relationship between statins and an amyotrophic lateral sclerosis (ALS)-like syndrome. The paper also presents some arguments for considering that a spectrum of severe neuromuscular damage may be associated with statin use, albeit rarely. The paper does not do more than raise the signal for further work and analysis of what must be regarded as a potentially very serious and perhaps avoidable or reversible adverse reaction, though it also suggests action to be taken if an ALS-like syndrome should occur in a patient using statins.Methods: The 43 reports accounting for the disproportional reports in Vigibase (the database of the WHO Programme for International Drug Monitoring) are summarised and analysed for the diagnosis of an ALS-like syndrome. The issues of data quality and potential reporting bias are considered.Results: 'Upper motor neurone lesion' is a rare adverse event reported in relationship to drugs in Vigibase (a database containing nearly 4 million ICSRs). Of the total of 172 ICSRs on this reported term, 43 were related to statins, of which 40 were considered further: all but one case was reported as ALS. In 34/40 reports a statin was the sole reported suspected drug. The diagnostic criteria were variable, and seven of the statin cases also had features of peripheral neuropathy. Of a total of 5534 ICSRs of peripheral neuropathy related to any drug in Vigibase, 547 were on statins. The disproportional reporting of statins and upper motor neurone lesion persisted after age stratification, and such disproportionality was not seen for statins and Parkinson's disease, Alzheimer's disease, extrapyramidal disorders, or multiple sclerosis-like syndromes.Discussion: Because the cases were sometimes atypical we propose the use of the term 'ALS-like syndrome' and speculate whether this is part of a spectrum of rare neuromuscular damage. The diagnosis of ALS is often problematic, and the insidiousness and chronicity of the disease make causality with a drug difficult to assess. The disproportionally high reporting makes this an important signal nevertheless, since ALS is serious clinically and statins are so widely used. Wide use of the statins also makes a chance finding more probable, but is unlikely to cause disproportional reporting when there are no obvious biases identified.Conclusion: We emphasise the rarity of this possible association, and also the need for further study to establish whether a causal relationship exists. We do advocate that trial discontinuation of a statin should be considered in patients with serious neuromuscular disease such as the ALS-like syndrome, given the poor prognosis and a possibility that progression of the disease may be halted or even reversed. [ABSTRACT FROM AUTHOR]

Introduction: The ability to detect safety concerns from spontaneous adverse drug reaction reports in a timely and efficient manner remains important in public health.Objective: This paper explores the behaviour of the Sequential Probability Ratio Test (SPRT) and ability to detect signals of disproportionate reporting (SDRs) in the Singapore context.Methods: We used SPRT with a combination of two hypothesised relative risks (hRRs) of 2 and 4.1 to detect signals of both common and rare adverse events in our small database. We compared SPRT with other methods in terms of number of signals detected and whether labelled adverse drug reactions were detected or the reaction terms were considered serious. The other methods used were reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN) and Gamma Poisson Shrinker (GPS).Results: The SPRT produced 2187 signals in common with all methods, 268 unique signals, and 70 signals in common with at least one other method, and did not produce signals in 178 cases where two other methods detected them, and there were 403 signals unique to one of the other methods. In terms of sensitivity, ROR performed better than other methods, but the SPRT method found more new signals. The performances of the methods were similar for negative predictive value and specificity.Conclusions: Using a combination of hRRs for SPRT could be a useful screening tool for regulatory agencies, and more detailed investigation of the medical utility of the system is merited. [ABSTRACT FROM AUTHOR]

Evidence on drug safety obtained from randomised clinical trials is very limited due to, among other reasons, their relatively small sample size. Hence, combining the results of available studies can prove particularly useful. This paper reviews the different data sources for summarising drug safety outcomes, according to study design, publication of data, and origin of the information. It then discusses the various types of overviews that can be used in the study of treatment harms, focusing on meta-analyses of aggregate data and meta-analyses of individual patient data, with their advantages and drawbacks, such as publication bias and heterogeneity. Although the different approaches available for combining the results are of great utility in assessing treatment harms, none of them is free from limitations. Therefore, it might be appropriate to perform an analysis of sensitivity to assess whether the results are sensitive to the technique that has been used. [ABSTRACT FROM AUTHOR]

Growing evidence indicates that many drugs have the ability to cause a potentially lethal cardiac arrhythmia, torsades de pointes (TdP). This necessitates the development of a compilation of drugs that have this potential toxicity. Such a list is helpful in identifying the etiology of TdP in patients taking multiple drugs and assists decision making by those caring for patients at high risk of TdP. The Arizona Center for Education and Research on Therapeutics (AZCERT) has developed a process to standardize the identification of drugs and place them in risk categories for their clinical ability to cause TdP and QT prolongation. AZCERT's Adverse Drug Event Causality Analysis (ADECA) utilizes 16 types of data drawn from four sources to compile an open-source knowledge base, QTdrugs, which is maintained on the CredibleMeds.org website. Because the evidence for most drugs is incomplete, the ADECA process is used to place drugs into one of three categories that represent different levels of certainty: known TdP risk, possible TdP risk, and conditional TdP risk. Each category has strict evidentiary requirements for clinical evidence of TdP and/or QT prolongation. These are described in this paper. Because evidence can evolve over time, the ADECA process includes the continuous gathering and analysis of newly emerging evidence to revise the lists. The QTdrugs lists have proven to be a valued, readily available, commercial influence-free resource for healthcare providers, patients, researchers, and authors of consensus guidelines for the safe use of medicines. [ABSTRACT FROM AUTHOR]

Introduction: An important goal in drug regulation is understanding serious safety issues with new drugs as soon as possible. Achieving this goal requires us to understand whether information provided during the Food and Drug Administration (FDA) drug review can predict serious safety issues that are usually identified after the product is approved. However, research on this topic remains understudied. In this paper, we examine whether any pre-marketing drug characteristics are associated with serious post-marketing safety actions.Methods: We study this question using an internal FDA database containing every new small molecule drug submitted to the FDA's Center for Drug Evaluation and Research (CDER) on or after November 21, 1997, and approved and commercially launched before December 31, 2009. Serious post-marketing safety actions include whether these drugs ever experienced either a post-marketing boxed warning or a withdrawal from the market due to safety concerns. A random effects logistic regression model was used to test whether any pre-marketing characteristics were associated with either post-marketing safety action.Results: A total of 219 new molecular entities were analyzed. Among these drugs, 11 experienced a safety withdrawal and 30 received boxed warnings by July 31, 2016. Contrary to prevailing hypotheses, we find that neither clinical trial sample sizes nor review time windows are associated with the addition of a post-marketing boxed warning or safety withdrawal. However, we do find that new drugs approved with either a boxed warning or priority review are more likely to experience post-marketing boxed warnings. Furthermore, drugs approved with boxed warnings tend to receive post-marketing boxed warnings resulting from new safety information that are unrelated to the original warning. Drugs approved with a boxed warning are 3.88 times more likely to receive a post-marketing boxed warning, while drugs approved with a priority review are 3.51 times more likely to receive a post-marketing boxed warning.Conclusion: Although drugs approved with a boxed warning or priority review are more likely to experience serious post-marketing safety events, other information provided during the FDA drug review that is easy to quantify is generally not associated with post-marketing safety events. It appears that these post-marketing events are not discernible during a pre-marketing review and therefore might not be avoidable using current review data. [ABSTRACT FROM AUTHOR]

It has been more than 25 years since an adverse drug reaction (ADR) monitoring agency was first established in China. In the past few years, the National ADR Monitoring System (NADRMS) has developed rapidly in the country. However, this system has not been reviewed in detail in the literature. Our aim was to demonstrate how individual case safety reports (ICSRs) are reported and evaluated and how data quality control is achieved in China. We also aimed to discuss the present status and future of NADRMS. We reviewed the relevant regulations and literature around ADR reporting in China. ADR report collection tools in China have gone through three phases, namely paper-based reporting, software-based reporting using standalone computers, and online reporting. Nowadays the online reporting system plays an important role in China and the number of ADR reports has rapidly increased. NADRMS is similar to most of the ADR reporting systems around the world, but also has its own unique characteristics such as four levels of monitoring agencies. In summary, there is still a long way to go for China to establish a high-level ADR monitoring system to ensure drug safety. [ABSTRACT FROM AUTHOR]

Introduction and Objective: Regulatory authorities often receive poorly structured safety reports requiring considerable effort to investigate potential adverse events post hoc. Automated question-and-answer systems may help to improve the overall quality of safety information transmitted to pharmacovigilance agencies. This paper explores the use of the VACC-Tool (ViVI Automated Case Classification Tool) 2.0, a mobile application enabling physicians to classify clinical cases according to 14 pre-defined case definitions for neuroinflammatory adverse events (NIAE) and in full compliance with data standards issued by the Clinical Data Interchange Standards Consortium.Methods: The validation of the VACC-Tool 2.0 (beta-version) was conducted in the context of a unique quality management program for children with suspected NIAE in collaboration with the Robert Koch Institute in Berlin, Germany. The VACC-Tool was used for instant case classification and for longitudinal follow-up throughout the course of hospitalization. Results were compared to International Classification of Diseases , Tenth Revision (ICD-10) codes assigned in the emergency department (ED).Results: From 07/2013 to 10/2014, a total of 34,368 patients were seen in the ED, and 5243 patients were hospitalized; 243 of these were admitted for suspected NIAE (mean age: 8.5 years), thus participating in the quality management program. Using the VACC-Tool in the ED, 209 cases were classified successfully, 69 % of which had been missed or miscoded in the ED reports. Longitudinal follow-up with the VACC-Tool identified additional NIAE.Conclusion: Mobile applications are taking data standards to the point of care, enabling clinicians to ascertain potential adverse events in the ED setting and during inpatient follow-up. Compliance with Clinical Data Interchange Standards Consortium (CDISC) data standards facilitates data interoperability according to regulatory requirements. [ABSTRACT FROM AUTHOR]

Health professionals from different countries are known to differ considerably in their use of medical terminology, including the terminology used for adverse drug reactions (ADRs) and in the exact meanings attributed to terms. To remedy this situation, the Council for International Organizations of Medical Sciences (CIOMS) has attempted to provide definitions and basic requirements for proper use of ADR terms. The work has concentrated on terms liable to be misinterpreted and those used for serious and frequently reported ADRs. For every selected term a short monograph has been prepared. It consists of a preamble, definition, basic requirements for use of the term and additional comments, if any. In cooperation with medical experts, drug regulators and the pharmaceutical industry, 13 papers have been published so far. Approximately 160 terms have been defined and work on another 50 terms continues. The full collection of monographs will eventually appear in the form of a book and CD-ROM intended to help doctors fill in case reports, and regulatory agencies and the pharmaceutical industry assess reports. Pharmaceutical companies receive numerous reports of suspected ADRs from medical practitioners and other prescribing professionals. Each company is required to transmit these reports to the drug regulatory agency of the country, or countries, in which the drug is used. Therefore, in addition to receiving the correct name of the ADR, collecting and evaluating centres, regardless of whether they are part of a regulatory agency or a pharmaceutical company, need to be provided with sufficient supporting data to be convinced that what is reported was what was actually observed, and that the ADR term used represents the observed event. [ABSTRACT FROM AUTHOR]

Introduction: Post-marketing safety surveillance primarily relies on data from spontaneous adverse event reports, medical literature, and observational databases. Limitations of these data sources include potential under-reporting, lack of geographic diversity, and time lag between event occurrence and discovery. There is growing interest in exploring the use of social media ('social listening') to supplement established approaches for pharmacovigilance. Although social listening is commonly used for commercial purposes, there are only anecdotal reports of its use in pharmacovigilance. Health information posted online by patients is often publicly available, representing an untapped source of post-marketing safety data that could supplement data from existing sources.Objectives: The objective of this paper is to describe one methodology that could help unlock the potential of social media for safety surveillance.Methods: A third-party vendor acquired 24 months of publicly available Facebook and Twitter data, then processed the data by standardizing drug names and vernacular symptoms, removing duplicates and noise, masking personally identifiable information, and adding supplemental data to facilitate the review process. The resulting dataset was analyzed for safety and benefit information.Results: In Twitter, a total of 6,441,679 Medical Dictionary for Regulatory Activities (MedDRA(®)) Preferred Terms (PTs) representing 702 individual PTs were discussed in the same post as a drug compared with 15,650,108 total PTs representing 946 individual PTs in Facebook. Further analysis revealed that 26 % of posts also contained benefit information.Conclusion: Social media listening is an important tool to augment post-marketing safety surveillance. Much work remains to determine best practices for using this rapidly evolving data source. [ABSTRACT FROM AUTHOR]

Introduction: Following the start of the World Health Organization (WHO) Programme for International Drug Monitoring (PIDM) by 10 member countries in 1968, it took another 24 years for the first two African countries to join in 1992, by which time the number of member countries in the PIDM had grown to 33. Whilst pharmacovigilance (PV), including the submission of individual case safety reports (ICSR) to VigiBase(®), the WHO global ICSR database, is growing in Africa, no data have been published on the growth of ICSR reporting from Africa and how the features of ICSRs from Africa compare with the rest of the world (RoW).Objective: The objective of this paper was to provide an overview of the growth of national PV centres in Africa, the reporting of ICSRs by African countries, and the features of ICSRs from Africa, and to compare ICSRs from Africa with the RoW.Methods: The search and analysis interface of VigiBase(®)--VigiLyze(®)--was used to characterise ICSRs submitted by African countries and the RoW. The distribution of ICSRs by African countries was listed and characterised by anatomic therapeutic chemical (ATC) code, Medical Dictionary for Regulatory Activities (MedDRA(®)) system organ class (SOC) classification, and patient age and sex. The case-defining features of ICSRs between Africa and the RoW were also compared.Results: The number of African countries in the PIDM increased from 2 in 1992 to 35 at the end of September 2015, and African PIDM members have cumulatively submitted 103,499 ICSRs (0.88 % of global ICSRs) to VigiBase(®). The main class of products in African ICSRs are nucleoside and nucleotide reverse transcriptase inhibitors (14.04 %), non-nucleoside reverse transcriptase inhibitors (9.09 %), antivirals for the treatment of HIV infections (5.50 %), combinations of sulfonamides and trimethoprim (2.98 %) and angiotensin-converting enzyme (ACE) inhibitors (2.42 %). The main product classes implicated in ICSRs from the RoW are tumour necrosis factor-α (TNFα) inhibitors (5.29 %), topical nonsteroidal anti-inflammatory preparations (2.26 %), selective immunosuppressants (2.08 %), selective serotonin reuptake inhibitors (2.04 %) and HMG CoA reductase inhibitors (1.85 %). The main SOCs reported from Africa versus the RoW include skin and subcutaneous tissue disorders (31.14 % vs. 19.58 %), general disorders and administration site conditions (20.91 % vs. 30.49 %) and nervous system disorders (17.48 % vs. 19.13 %). The 18-44 years age group dominated ICSRs from Africa, while the 45-64 years age group dominated the RoW. Identical proportions of females (57 % Africa and the RoW) and males (37 % Africa and the RoW) were represented.Conclusions: As at the end of September 2015, 35 of 54 African countries were Full Member countries of the PIDM. Although the number of ICSRs from Africa has increased substantially, ICSRs from Africa still make up <1 % of the global total in VigiBase(®). The features of ICSRs from Africa differ to those from the RoW in relation to the classes of products as well as age group of patients affected. The gender of patients represented in these ICSRs are identical. [ABSTRACT FROM AUTHOR]

The comparative evaluation of benefits and risks is one of the most important tasks during the development, market authorization and post-approval pharmacovigilance of medicinal products. Multi-criteria decision analysis (MCDA) has been recommended to support decision making in the benefit-risk assessment (BRA) of medicines. This paper identifies challenges associated with bias or variability that practitioners may encounter in this field and presents solutions to overcome them. The inclusion of overlapping or preference-complementary criteria, which are frequent violations to the assumptions of this model, should be avoided. For each criterion, a value function translates the original outcomes into preference-related scores. Applying non-linear value functions to criteria defined as the risk of suffering a certain event during the study introduces specific risk behaviours in this prescriptive, rather than descriptive, model and is therefore a questionable practice. MCDA uses weights to compare the importance of the model criteria with each other; during their elicitation a frequent situation where (generally favourable) mild effects are directly traded off against low probabilities of suffering (generally unfavourable) severe effects during the study is known to lead to biased and variable weights and ought to be prevented. The way the outcomes are framed during the elicitation process, positively versus negatively for instance, may also lead to differences in the preference weights, warranting an appropriate justification during each implementation. Finally, extending the weighted-sum MCDA model into a fully inferential tool through a probabilistic sensitivity analysis is desirable. However, this task is troublesome and should not ignore that clinical trial endpoints generally are positively correlated. [ABSTRACT FROM AUTHOR]

Introduction: Observational healthcare data contain information useful for hastening detection of adverse drug reactions (ADRs) that may be missed by using data in spontaneous reporting systems (SRSs) alone. There are only several papers describing methods that integrate evidence from healthcare databases and SRSs. We propose a methodology that combines ADR signals from these two sources.Objectives: The aim of this study was to investigate whether the proposed method would result in more accurate ADR detection than methods using SRSs or healthcare data alone.Research Design: We applied the method to four clinically serious ADRs, and evaluated it using three experiments that involve combining an SRS with a single facility small-scale electronic health record (EHR), a larger scale network-based EHR, and a much larger scale healthcare claims database. The evaluation used a reference standard comprising 165 positive and 234 negative drug-ADR pairs.Measures: Area under the receiver operator characteristics curve (AUC) was computed to measure performance.Results: There was no improvement in the AUC when the SRS and small-scale HER were combined. The AUC of the combined SRS and large-scale EHR was 0.82 whereas it was 0.76 for each of the individual systems. Similarly, the AUC of the combined SRS and claims system was 0.82 whereas it was 0.76 and 0.78, respectively, for the individual systems.Conclusions: The proposed method resulted in a significant improvement in the accuracy of ADR detection when the resources used for combining had sufficient amounts of data, demonstrating that the method could integrate evidence from multiple sources and serve as a tool in actual pharmacovigilance practice. [ABSTRACT FROM AUTHOR]

Prescription-event monitoring (PEM) is a non-interventional intensive method for post-marketing drug safety monitoring of newly licensed medicines. PEM studies are cohort studies where exposure is obtained from a centralised service and outcomes from simple questionnaires completed by general practitioners. Follow-up forms are sent for selected events.Because PEM captures all events and not only the suspected adverse drug reactions, PEM cohorts potentially differ in respect to the distribution of number of events per person depending on the nature of the drug under study. This variance can be related either with the condition for which the drug is prescribed (e.g. a condition causing high morbidity will have, in average, a higher number of events per person compared with a condition with lower morbidity) or with the drug effect itself.This paper describes an exploratory investigation of the distortion caused by product-related variations of the number of events to the interpretation of the proportional reporting ratio (PRR) values (“the higher the PRR, the greater the strength of the signal”) computed using drug-cohort data.We studied this effect by assessing the agreement between the PRR based on events (event of interest vs all other events) and PRR based on cases (cases with the event of interest vs cases with any other events). PRR were calculated for all combinations reported to ten selected drugs against a comparator of 81 other drugs. Three of the ten drugs had a cohort with an apparent higher proportion of patients with lower number of events. The PRRs based on events were systematically higher than the PRR based on cases for the combinations reported to these three drugs. Additionally, when applying the threshold criteria for signal screening (n ≥3, PRR ≥1.5 and Chi-squared ≥4), the binary agreement was generally high but apparently lower for these three drugs.In conclusion, the distribution of events per patient in drug cohorts shall be examined when comparing the ‘strength of the signals’ across drugs using PRR values. Further research will be required to address the sensitivity and specificity of the two ways of calculating PRR using data derived from drug cohorts. [ABSTRACT FROM AUTHOR]

Post-marketing pharmacovigilance involves the review and management of safety information from many sources. Among these sources, spontaneous adverse event reporting systems are among the most challenging and resource-intensive to manage. Traditionally, efforts to monitor spontaneous adverse event reporting systems have focused on review of individual case reports. The science of pharmacovigilance could be enhanced with the availability of systems-based tools that facilitate analysis of aggregate data for purposes of signal detection, signal evaluation and knowledge management. GlaxoSmithKline (GSK) recently implemented Online Signal Management (OSM) as a data-driven framework for managing the pharmacovigilance of marketed products. This pioneering work builds upon the strong history GSK has of innovation in this area. OSM is a software application co-developed by GSK and Lincoln Technologies that integrates traditional pharmacovigilance methods with modern quantitative statistical methods and data visualisation tools. OSM enables the rapid identification of trends from the individual adverse event reports received by GSK. OSM also provides knowledge-management tools to ensure the successful tracking of emerging safety issues. GSK has developed standard procedures and 'best practices' around the use of OSM to ensure the systematic evaluation of complex safety datasets. In summary, the implementation of OSM provides new tools and efficient processes to advance the science of pharmacovigilance. [ABSTRACT FROM AUTHOR]

The safety profile of a drug evolves over its lifetime on the market; there are bound to be changes in the circumstances of a drug's clinical use which may give rise to previously unobserved adverse effects, hence necessitating surveillance postmarketing. Postmarketing surveillance has traditionally been carried out by systematic manual review of spontaneous reports of adverse drug reactions. Vast improvements in computing capabilities have provided opportunities to automate signal detection, and several worldwide initiatives are exploring new approaches to facilitate earlier detection, primarily through mining of routinely-collected data from electronic healthcare records (EHR). This paper provides an overview of ongoing initiatives exploring data from EHR for signal detection vis-à-vis established spontaneous reporting systems (SRS). We describe the role SRS has played in regulatory decision making with respect to safety issues, and evaluate the potential added value of EHR-based signal detection systems to the current practice of drug surveillance. Safety signal detection is both an iterative and dynamic process. It is in the best interest of public health to integrate and understand evidence from all possibly relevant information sources on drug safety. Proper evaluation and communication of potential signals identified remains an imperative and should accompany any signal detection activity. [ABSTRACT FROM AUTHOR]

Typically, ethnobotanical/ethnopharmacological (EB/EP) surveys are used to describe uses, doses/dosages, sources and methods of preparation of traditional herbal medicines; their application to date in examining the adverse effects, contraindications and other safety aspects of these preparations is limited. From a pharmacovigilance perspective, numerous challenges exist in applying its existing methods to studying the safety profile of herbal medicines, particularly where used by indigenous cultures. This paper aims to contribute to the methodological aspects of EB/EP field work, and to extend the reach of pharmacovigilance, by proposing a tool comprising a list of questions that could be applied during interview and observational studies. The questions focus on the collection of information on the safety profile of traditional herbal medicines as it is embedded in traditional knowledge, as well as on identifying personal experiences (spontaneous reports) of adverse or undesirable effects associated with the use of traditional herbal medicines. Questions on the precise composition of traditional prescriptions or 'recipes', their preparation, storage, administration and dosing are also included. Strengths and limitations of the tool are discussed. From this interweaving of EB/ EP and pharmacovigilance arises a concept of ethnopharmacovigilance for traditional herbal medicines: the scope of EB/EP is extended to include exploration of the potential harmful effects of medicinal plants, and the incorporation of pharmacovigilance questions into EB/EP studies provides a new opportunity for collection of 'general' traditional knowledge on the safety of traditional herbal medicines and, importantly, a conduit for collection of spontaneous reports of suspected adverse effects. Whether the proposed tool can yield data sufficiently rich and of an appropriate quality for application of EB/EP (e.g. data verification and quantitative analysis tools) and pharmacovigilance techniques (e.g. causality assessment and data mining) requires field testing. [ABSTRACT FROM AUTHOR]

Adverse drug reactions, including those resulting from interactions between herbal medicines and conventional drugs, are a public health problem worldwide. The need for pharmacovigilance for herb-drug interactions (HDIs) is essential for the identification and assessment of risks of using herbal products (questionable safety, efficacy and quality), which are not always tested with rigor, or often not subject to approval by regulatory agencies. Spontaneous and active surveillance conducted by national pharmacovigilance centres permits a rapid detection of potentially harmful combinations of products. The incidence and prevalence of HDIs are difficult to predict because of the underreporting of adverse effects. It is important for health professionals, consumers, regulatory authorities and suppliers of herbal medicines to be aware of the possible adverse effects and drug interactions caused when herbal medicines are co-administered with conventional drugs. National pharmacovigilance centres continue to play a significant role in increasing awareness of drug safety, in this case with HDIs. The authors' objective for this paper is to provide awareness among policy makers responsible for the design of appropriate pharmacovigilance practices and therefore to highlight the importance of pharmacovigilance in the safety monitoring of HDIs. [ABSTRACT FROM AUTHOR]

Background: There has been discussion about the acceptance of adverse drug reactions (ADRs) reported by patients to spontaneous reporting systems. Lack of experience with patient reporting in real life was one of the main drawbacks in this debate. This study covers 3 years of experience with patient reporting in daily practice. We compared patient reports with reports from healthcare professionals. Although patients have the opportunity to report ADRs in several countries, little is published in the literature about the contribution that patient reports have in practice. To our knowledge, this paper is the first to describe long-term experiences with patient reporting as part of a spontaneous reporting system.Methods: The number of reports received, age and sex of the reporters, characteristics of the most frequently reported drugs and characteristics of the ADRs (most frequently reported ADRs, seriousness, outcome) in a 3-year period (April 2004-April 2007) were compared between patient reports and reports from healthcare professionals.Findings: During this 3-year period, the Netherlands Pharmacovigilance Centre Lareb received 2522 reports directly from patients, concerning 5401 ADRs. In the same period, healthcare professionals submitted 10 635 reports, concerning 16 722 ADRs. Differences were found in the categories of seriousness and outcome of the reported ADRs between patients and healthcare professionals. Conversely, similarities between patient reports and reports from healthcare professionals were found in age, sex, most frequently reported ADRs and most frequently reported drugs.Interpretation: Our study highlights clearly that valuable differences between ADR reports from patients and reports from healthcare professionals exist. Differences in interpretation by patients and healthcare professionals may cause the observed disparities in seriousness and outcome of reported ADRs. However, the similarities between patient reports and reports from healthcare professionals in most frequently reported ADRs and most frequently reported drugs are striking. After 3 years of experience with patient reporting, we conclude that patient reporting in spontaneous reporting systems is feasible and that it contributes significantly to a reliable pharmacovigilance. [ABSTRACT FROM AUTHOR]

Objective: Using a patient targeted survey, we sought to assess patient representations of how physicians responded when patients presented with possible adverse drug reactions (ADRs). As a demonstration case, we took one widely prescribed drug class, the HMG-CoA reductase inhibitors ('statins'). This information was used to assess whether a patient-targeted ADR surveillance approach may complement provider reporting, potentially fostering identification of additional patients with possible or probable ADRs.Methods: A total of 650 adult patients taking statins with self-reported ADRs completed a survey. Depending on the problems reported, some patients completed additional surveys specific to the most commonly cited statin ADRs: muscle, cognitive or neuropathy related. Patients were asked to report drug, dose, ADR character, time course of onset with drug, recovery with discontinuation, recurrence with rechallenge, quality-of-life impact, and interactions with their physician in relation to the perceived ADR. This paper focuses on patients' representation of the doctor-patient interaction and physicians' attribution, when patients report perceived ADRs.Results: Eighty-seven percent of patients reportedly spoke to their physician about the possible connection between statin use and their symptom. Patients reported that they and not the doctor most commonly initiated the discussion regarding the possible connection of drug to symptom (98% vs 2% cognition survey, 96% vs 4% neuropathy survey, 86% vs 14% muscle survey; p < 10(-8) for each). Physicians were reportedly more likely to deny than affirm the possibility of a connection. Rejection of a possible connection was reported to occur even for symptoms with strong literature support for a drug connection, and even in patients for whom the symptom met presumptive literature-based criteria for probable or definite drug-adverse effect causality. Assuming that physicians would not likely report ADRs in these instances, these patient-submitted ADR reports suggest that targeting patients may boost the yield of ADR reporting systems.Conclusions: Since low reporting rates are considered to contribute to delays in identification of ADRs, findings from this study suggest that additional putative cases may be identified by targeting patients as reporters, potentially speeding recognition of ADRs. [ABSTRACT FROM AUTHOR]

Drug use during pregnancy is sometimes unavoidable, especially in chronic inflammatory diseases such as rheumatoid arthritis (RA). The use of disease-modifying antirheumatic drugs (DMARDs) often starts in the early stage of RA; therefore, women of reproductive age are at risk for exposure to a DMARD at time of conception as well as during pregnancy. The aim of this paper was to review recent literature about DMARDs used for rheumatic diseases in pregnancy and to describe the type of study designs and results reported. Twenty-nine studies; eight on hydroxychloroquine/chloroquine, thirteen on methotrexate, three on sulfasalazine and six on azathioprine were identified. With respect to hydroxychloroquine, most studies concluded that it could be safely used in systemic lupus erythematosus or RA. The same conclusions were drawn from the azathioprine studies, but the available evidence is scarce. Although the evidence regarding the safety of methotrexate during pregnancy is conflicting, a high rate of pregnancy losses indicates a risk to the fetus. For each individual case it must be decided whether the benefits outweigh the potential risks. No major teratogenic effects of sulfasalazine were seen although teratogenic effects still can not be excluded. For all other DMARDs, the information on their use in pregnancy was limited. This review underscores the gross absence of data on safety and risks of DMARD use during conception and pregnancy. While young women use these drugs in pregnancy, this review stresses the importance of good monitoring and further research. [ABSTRACT FROM AUTHOR]

Pharmacovigilance science has traditionally been a discipline focussed on the postmarketing or post-authorisation period, with due attention directed towards pre-clinical safety data, clinical trials and adverse events. As the biological sciences have evolved, pharmacovigilance has slowly shifted toward earlier, proactive consideration of risks and potential benefits of drugs in the pre- and peri-approval stages of drug development, leading to a maturing of drug safety risk management. Further advances in biology, pharmacology and improvements in computational applications to medicine have led to the development of more complex medicines previously unobtainable and have also permitted a more thorough assessment of risks and potential benefits even earlier in the development process. Elevated public concern with the safety of more sophisticated medicines, combined with new science, have led pharmaceutical innovators, regulators and healthcare professionals to collaborate to develop guidelines, which drive enhanced pharmacovigilance and safety risk management earlier in drug development.In this paper, we review international guidelines on pharmacovigilance planning applicable to the pre-approval phases of medicines development and provide author opinion on these guidelines’ potential drug safety implications. We discuss the possible evolution of a pharmaceutical industry model to respond to these guidelines; a view on multidisciplinary safety management teams is provided to encourage refinement of safety-signal identification and risk assessment early in drug development and to communicate important safety concerns to internal research efforts, patients, investigators and regulators. We further describe these functions in the context of the complexities of vulnerable populations, including the example of medicines research for paediatric populations. We also discuss the special role of epidemiology in pre-approval drug development and the impact on epidemiological science of changes to the pharmacovigilance paradigm. [ABSTRACT FROM AUTHOR]

Data mining is the discovery of interesting, unexpected or valuable structures in large datasets. As such, it has two rather different aspects. One of these concerns large-scale, 'global' structures, and the aim is to model the shapes, or features of the shapes, of distributions. The other concerns small-scale, 'local' structures, and the aim is to detect these anomalies and decide if they are real or chance occurrences. In the context of signal detection in the pharmaceutical sector, most interest lies in the second of the above two aspects; however, signal detection occurs relative to an assumed background model, therefore, some discussion of the first aspect is also necessary. This paper gives a lightning overview of data mining and its relation to statistics, with particular emphasis on tools for the detection of adverse drug reactions. [ABSTRACT FROM AUTHOR]

Signals detected by measuring disproportionality of drug-event combinations are only statistical indicators of possible real safety issues, and are not per se necessarily medically important. Nevertheless, once a signal is observed, sponsors are obligated by regulations and ethical considerations to determine whether it represents a new product-associated risk by additional analysis, validation and evaluation of its clinical relevance. Signal strength does not necessarily correlate with medical significance. Strong signals most often represent known, expected and/or medically trivial adverse reactions or confounding by treatment indication, common co-morbidities or other common concomitant treatments. Conversely, any product with reasonably extensive clinical use and reporting of suspected adverse reactions is likely to manifest many weak but clinically unimportant signals, creating significant background 'noise'. Since relatively rare, medically important adverse drug reactions are often likely to manifest as weak signals, sponsors face a potentially onerous burden of evaluating multiple signals in order to distinguish true, clinically important events of concern from spurious signals. This paper discusses the regulatory, clinical and potential legal liability issues that confront industry as a consequence of signal identification activities, including: current and anticipated regulatory requirements for detection, assessment and reporting; the reliability of the data used for signal generation; assessment of clinical relevance; organisational approaches and responses to observed signals; targeted clinical and scientific responses to observed signals; and potential regulatory, legal and commercial impact. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and aim: Statistical signal detection methods such as proportional reporting ratios (PRRs) detect many drug safety signals when applied to databases of spontaneous suspected adverse drug reactions (ADRs). Impact analysis is a tool that was developed as an aid to prioritisation of such signals. This paper describes a pilot project whereby impact analysis was simultaneously introduced into practice in a regulatory setting and tested in comparison with the existing approach. Methods: Impact analysis was run on signals detected during a 26-week period from the UK Adverse Drug Reactions On-line Information Tracking (ADROIT) database of spontaneous ADRs that met minimum criteria (PRR ≥3.0, χ2 ≥4.0 and ≥3 reported cases) and related to established drugs (i.e. those that have been available for at least 2 years and no longer carry the ‘black triangle’ symbol). The current method of signal prioritisation (i.e. the collective judgement at a weekly meeting) was initially performed without knowledge of the findings of impact analysis. Subsequently, the meeting was presented with the findings and, where appropriate, given the opportunity to reconsider the judgement made. The categories arising from the two methods were compared and the ultimate action recorded. Inter-observer variation between scientists performing impact analysis was also assessed. Results: Eighty-six separate signals were analysed by impact analysis, of which 5% were categorised as high priority (A), 14% as requiring further information (B), 31% as low priority (C) and 50% as no action required (D). In general, the new method tended to give a higher level of priority to signals than the existing approach. Overall, there was 59% agreement between the impact analysis and the collective judgement at the meetings (kappa statistic = 0.30). There was slightly greater agreement between impact analysis and the final action taken (kappa statistic = 0.39), indicating that the findings of an impact analysis had an influence on the outcome. Assessment of inter-observer variation demonstrated that the method is repeatable (kappa statistic for overall category = 0.77). Almost 70% of those who participated in the pilot study believed that impact analysis represented an improvement in how signals were prioritised. Conclusions: Impact analysis is a repeatable method of signal prioritisation that tended to give a higher level of priority to signals than the standard approach and which had an influence on the ultimate outcome. [ABSTRACT FROM AUTHOR]

Nearly 50 medications have been implicated as inducing hypomagnesaemia, sometimes based on insufficient data regarding clinical significance and frequency of occurrence. In fact, clinical effects attributed to hypomagnaesemia have been reported in only 17 of these drugs. A considerable amount of literature relating to individual drugs has been published, yet a comprehensive overview of this issue is not available and the hypomagnesaemic effect of a drug could be either overemphasised or under-rated. In addition, there are neither guidelines regarding treatment, prevention and monitoring of drug-induced hypomagnesaemia nor agreement as to what serum level of magnesium may actually be defined as ‘hypomagnesaemia’. By compiling data from published papers, electronic databases, textbooks and product information leaflets, we attempted to assess the clinical significance of hypomagnesaemia induced by each drug. A practical approach for managing drug-induced hypomagnesaemia, incorporating both published literature and personal experience of the physician, is proposed. When drugs classified as inducing ‘significant’ hypomagnesaemia (cisplatin, amphotericin B, ciclosporin) are administered, routine magnesium monitoring is warranted, preventive treatment should be considered and treatment of hypomagnesaemia should be initiated with or without overt clinical manifestations. In drugs belonging to the ‘potentially significant’ category, among which are amikacin, gentamicin, laxatives, pentamidine, tobramycin, tacrolimus and carboplatin, magnesium monitoring is justified when either of the following occurs: clinical manifestations are apparent; persistent hypokalaemia, hypocalcaemia or alkalosis are present; other precipitating factors for hypomagnesaemia coexist; or treatment is with more than one potentially hypomagnesaemic drug. No preventive treatment is required and treatment should be initiated only if hypomagnesaemia is accompanied by symptoms or clinically significant relevant laboratory findings. In those drugs whose hypomagnesaemic effect is labelled as ‘questionable’, including furosemide and hydrochlorothiazide, routine monitoring and treatment are not required. [ABSTRACT FROM AUTHOR]

Although the number of clinically relevant drug-drug interactions (DDIs) is probably low, DDIs may be responsible for a substantial number of hospital admissions. In some countries, the pharmacist is responsible for preventing the use of unsafe or non-effective drug regimens. Specifically they should avoid the dispensing of combinations of drugs that may cause serious DDIs. In order to assess the determinants related to community pharmacies and associated with these dispensings, a systematic literature review was conducted. Medline and International Pharmaceutical Abstracts were searched for articles published in English between 1993 and 2003. Additional relevant articles were identified by screening the reference lists of relevant articles. Seven papers were located. The determinants described in the literature were divided into three groups. The first group focussed on the relationship between the pharmacist and the prescriber. The number of prescribers is of importance as well as the number of dispensing pharmacies. Both a high number of primary care physicians and multiple dispensing pharmacies increased the risk of DDIs. The availability, quality and sensitivity of the medication surveillance software appeared to be a second important determinant. Both too many and too few signals increased the risk of dispensing interacting drugs. The third group of determinants was related to the pharmacist and pharmacy organisation. Signals from the surveillance program are usually judged first by technicians and subsequently managed by the pharmacist. Consequently, knowledge, instructions and supervision are important determinants. A fourth group of determinants was identified in literature assessing interventions by pharmacists, including interventions for DDIs. A higher workload was associated with lower intervention rates, which indicated a higher risk of dispensing interacting drugs. The determinants identified in this review can be used to develop strategies to minimise patient harm resulting from DDIs. Further assessment of the relation between these determinants and the dispensing of DDIs and of the relation between DDI-associated dispensing and patient harm is recommended. [ABSTRACT FROM AUTHOR]

Vitex agnus castus L. (VAC) [Verbenaceae] is a deciduous shrub that is native to Mediterranean Europe and Central Asia. Traditionally, VAC fruit extract has been used in the treatment of many female conditions, including menstrual disorders (amenorrhoea, dysmenorrhoea), premenstrual syndrome (PMS), corpus luteum insufficiency, hyperprolactinaemia, infertility, acne, menopause and disrupted lactation. The German Commission E has approved the use of VAC for irregularities of the menstrual cycle, premenstrual disturbances and mastodynia. Clinical reviews are available for the efficacy of VAC in PMS, cycle disorders, hyperprolactinaemia and mastalgia, but so far no systematic review has been published on adverse events or drug interactions associated with VAC. Therefore, this review was conducted to evaluate all the available human safety data of VAC monopreparations. Literature searches were conducted in six electronic databases, in references lists of all identified papers and in departmental files. Data from spontaneous reporting schemes of the WHO and national drug safety bodies were also included. Twelve manufacturers of VAC-containing preparations and five herbalist organisations were contacted for additional information. No language restrictions were imposed. Combination preparations including VAC or homeopathic preparations of VAC were excluded. Data extraction of key data from all articles reporting adverse events or interactions was performed independently by at least two reviewers, regardless of study design. Data from clinical trials, postmarketing surveillance studies, surveys, spontaneous reporting schemes, manufacturers and herbalist organisations indicate that the adverse events following VAC treatment are mild and reversible. The most frequent adverse events are nausea, headache, gastrointestinal disturbances, menstrual disorders, acne, pruritus and erythematous rash. No drug interactions were reported. Use of VAC should be avoided during pregnancy or lactation. Theoretically, VAC might also interfere with dopaminergic antagonists. Although further rigorous studies are needed to assess the safety of VAC, the data available seem to indicate that VAC is a safe herbal medicine. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to review preclinical and clinical evidence relating to drug interactions with preparations of the medicinal herb St John's wort (Hypericum perforatum). A systematic literature search was carried out in three electronic databases up to June 2004. Information about case reports classified as St John's wort drug interactions was retrieved from the WHO Collaborating Centre for International Drug Monitoring and from the UK Medicines and Healthcare products Regulatory Agency in June 2003. Against the background of proven efficacy in mild to moderate depressive disorders and an excellent tolerability profile in monotherapy, there is sufficient evidence from interaction studies and case reports to suggest that St John's wort may induce the cytochrome P450 (CYP) 3A4 enzyme system and the P-glycoprotein drug transporter in a clinically relevant manner, thereby reducing efficacy of co-medications. Drugs most prominently affected and contraindicated for concomitant use with St John' s wort are metabolised via both CYP3A4 and P-glycoprotein pathways, including HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors (only CYP3A4), the immunosuppressants ciclosporin and tacrolimus, and the antineoplastic agents innotecan and imatinib mesylate. Efficacy of hormonal contraceptives may be impaired as reflected by case reports of irregular bleedings and unwanted pregnancies. Drugs with a narrow therapeutic index should be monitored more closely when St John' s wort is added, discontinued or the dosage is changed. The St John' s wort constituent hyperforin is probably responsible for CYP3A4 induction via activation of a nuclear steroid/pregnane and xenobiotic receptor (SXR/PXR) and hypericin may be assumed to be the P-glycoprotein inducing compound, although the available evidence is less convincing. Combinations of St John's wort with serotonergic agents and other antidepressants should be restricted to prescription-only, by experienced clinicians, due to potential central pharmacodynamic interactions. In conclusion, providing certain precautions and contraindications are followed, and adequate information is given to healthcare professionals and patients, the safe and effective use of quality-tested St John's wort products can be ensured. [ABSTRACT FROM AUTHOR]

The case-population approach aims at providing a risk estimate by comparing the incidence of the disease of interest among those exposed to the drug under study with the incidence among the non-exposed. For that purpose, the cases with the disease of interest have to be ascertained independently of the exposure status. Their rate and pattern of exposure have to be ascertained by interview with a structured questionnaire. Information on the patterns and the prevalence of drug consumption is needed in order to estimate the rate of exposure, and drug consumption statistics can be used to this end. In this paper, we review the main characteristics of studies using this approach or a similar one, and studies where series of cases exposed to the drug of interest were compared with drug consumption statistics. We looked at selected basic methodological requirements. Most of the studies reviewed suffer from incomplete case ascertainment, inaccurate definition of the disease of interest, incomplete information on exposures and other risk factors, and/or limited control of potential confounding, among other limitations. All the reviewed studies had several limitations regarding the estimation of the population at risk. The methods used in case-population studies should be clearly described, particularly with respect to the identification of the cases (numerator) and the estimation of the consumption prevalence (denominator). Case-population studies can give approximate risk estimates, but the method should be validated by comparing its results with those of case-control studies. [ABSTRACT FROM AUTHOR]

As recognition of the role of free radicals and reactive toxins in the pathogenesis of disease, poisoning, and adverse drug reactions has evolved, interest in the use of acetylcysteine as a modulator of these effects has steadily increased in recent years. Acetylcysteine is commonly thought to serve as a glutathione precursor and consequently can increase or sustain intracellular glutathione which scavenges reactive oxygen species caused by toxins or subsequent tissue injury. At least 10 additional mechanisms of action for acetylcysteine have been demonstrated in various laboratory models, but a unifying framework of its actions is still to be proposed. This paper reviews the current experimental and therapeutic status of acetylcysteine for the treatment of poisonings and adverse drug reactions. Of the 45 potential uses of acetylcysteine that were identified for the treatment of poisonings or adverse drug reactions, 14 of the toxic effects have little support for its use while promising results have been demonstrated for 27 toxicities. Currently, treatment of acute paracetamol (acetaminophen) poisoning is the only widely accepted clinical indication for acetylcysteine as a treatment for poisoning or adverse drug reactions. In many clinical situations acetylcysteine is used empirically utilising modifications of dosage regimens employed for paracetamol poisoning. Often it is difficult to determine the benefit of therapy with acetylcysteine owing to the nature of the toxicity being treated, the use of other therapies, the presence of comorbid conditions, and the small number of patients studied. The diverse and positive nature of the investigations suggest that there is considerable promise in acetylcysteine as a research tool and pharmacological agent. [ABSTRACT FROM AUTHOR]

Akathisia is a frequent and common adverse effect of treatment with antipsychotic (neuroleptic) drugs. This syndrome consists of subjective (feeling of inner restlessness and the urge to move) as well as objective components (rocking while standing or sitting, lifting feet as if marching on the spot and crossing and uncrossing the legs while sitting). Antipsychotic-induced akathisia can be classified according to the time of onset in the course of antipsychotic treatment (acute, tardive, withdrawal and chronic akathisia). Reported prevalence rates vary widely between 5 and 36.8%. Numerous risk factors for acute akathisia have been described and the exact pathophysiology of akathisia is still unknown. Since akathisia is a drug-induced adverse effect, optimal management involves its prevention rather than treatment. Standardised titration and the use of novel antipsychotics are successful measures of prevention. This paper reviews different forms of therapeutic approaches for the treatment of akathisia. Based on the available literature, propranolol or other lipophilic beta-blockers seem to be the most consistently effective treatment for acute akathisia. There is nothing in the literature to guide a clinician when treatment with beta-blockers fails. Addition of benzodiazepines would appear to be a sensible next choice, especially if subjective distress persists. If all of these drugs are unsuccessful, amantadine or clonidine can be tried. Other agents that have been investigated include ritanserin, piracetam, valproic acid (sodium valproate) and tricyclic antidepressants. Evidence on the treatment of tardive akathisia is unsatisfactory. [ABSTRACT FROM AUTHOR]

Background and Aim: Disproportionality analysis is traditionally used in spontaneous reporting systems to generate working hypotheses about potential adverse drug reactions: the so-called disproportionality signals. We aim to map the methods used by researchers to assess and increase the validity of their published disproportionality signals. Methods: From a systematic literature search of published disproportionality analyses up until 1 January 2020, we randomly selected and analyzed 100 studies. We considered five domains: (1) rationale for the study, (2) design of disproportionality analyses, (3) case-by-case assessment, (4) use of complementary data sources, and (5) contextualization of the results within existing evidence. Results: Among the articles, multiple strategies were adopted to assess and enhance the results validity. The rationale, in 95 articles, was explicitly referred to the accrued evidence, mostly observational data (n = 46) and regulatory documents (n = 45). A statistical adjustment was performed in 34 studies, and specific strategies to correct for biases were implemented in 33 studies. A case-by-case assessment was complementarily performed in 35 studies, most often by investigating temporal plausibility (n = 26). Complementary data sources were used in 25 articles. In 78 articles, results were contextualized using accrued evidence from the literature and regulatory documents, the most important sources being observational (n = 45), other disproportionalities (n = 37), and case reports (n = 36). Conclusions: This meta-research study highlighted the heterogeneity in methods and strategies used by researchers to assess the validity of disproportionality signals. Mapping these strategies is a first step towards testing their utility in different scenarios and developing guidelines for designing future disproportionality analysis. [ABSTRACT FROM AUTHOR]