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For any therapeutic intervention in an individual, there is a balance between the potential benefits and the possible harms. The extent to which the benefits are desirable in a given condition depends on the efficacy of the intervention, the chance of obtaining it and the seriousness and intensity of the condition. The extent to which the harms are undesirable depends on the nature of the hazard that can lead to harm, the chance that the harm will occur and its seriousness and intensity. Rational therapeutic decisions require clinicians to consider competing courses of action, with potential benefits of different desirability and potential harms of different undesirability. They also have a duty to explain to the patient, for the contemplated interventions, both the possible benefits and the potential harms that the patient may consider significant. In an individual patient, it is necessary to consider (a) the probabilities of benefit from both intervention and non-intervention and (b) the probabilities of harm from both intervention and non-intervention. However, there are several potential problems. Here, we consider how failure to distinguish maximum benefits from probable benefits, or hazards (potential harms) from probable harms, and failure to consider all the competing probabilities may lead to imperfect therapeutic decisions. We also briefly discuss methods to assess the benefit to harm balance. [ABSTRACT FROM AUTHOR]

Background: Coroners, who hold inquests to determine the causes of unnatural deaths in England and Wales, having recognised factors that could cause other deaths, are legally obliged to signal concerns by sending 'Reports to Prevent Future Deaths' (PFDs) to interested persons. We aimed to establish whether Coroners' concerns about medications are widely recognised. Methods: We searched MEDLINE, Embase and Web of Science up to 30 November, 2022 for publications linking PFDs and medications using a combination of search terms "coroner*", "inquest*", "medicine*", "medication*" and "prevent*". We also searched the BMJ, a UK journal that carries news items; and the databases Nexis Advance and News On the Web for reports in national newspapers between 2013 and 2022, using the search terms ("regulation 28" OR "prevent future deaths" OR "prevention of future deaths") AND "coroner". We recorded the number of publications, as well as their citations in Google Scholar at 23 May, 2023. Results: Only 11 published papers on medicines referenced UK PFDs, nine of which were from our group. The BMJ carried 23 articles mentioning PFDs, five related to medicines. Of 139 PFDs (out of over 4000) mentioned in national newspapers, only nine related to medicines. Conclusions: The PFDs related to medicines are not widely referred to in medical journals or UK national newspapers. By contrast, the Australian and New Zealand National Coronial Information System has contributed cases to 206 publications cited in PubMed, of which 139 are related to medicines. Our search suggests that information from English and Welsh Coroners' PFDs is under-recognised, even though it should inform public health. The results of inquiries by Coroners and medical examiners worldwide into potentially preventable deaths involving medicines should be used to strengthen the safety of medicines. [ABSTRACT FROM AUTHOR]

Introduction: Medicines cause over 1700 preventable deaths annually in England. Coroners' Prevention of Future Death reports (PFDs) are produced in response to preventable deaths to facilitate change. The information in PFDs may help reduce medicine-related preventable deaths. Objectives: We aimed to identify medicine-related deaths in coroners' reports and to explore concerns to prevent future deaths. Methods: We carried out a retrospective case series of PFDs across England and Wales, dated between 1 July, 2013 and 23 February, 2022, collected from the UK's Courts and Tribunals Judiciary website using web scraping, generating an openly available database: https://preventabledeathstracker.net/. We used descriptive techniques and content analysis to assess the main outcome criteria: the proportion of PFDs in which coroners reported that a therapeutic medicine or drug of abuse had caused or contributed to a death; the characteristics of included PFDs; coroners' concerns; the recipients of PFDs; and the timeliness of their responses. Results: There were 704 PFDs (18%; 716 deaths) that involved medicines, representing an estimated 19,740 years of life lost (average of 50 years lost per death). Opioids (22%), antidepressants (9.7%), and hypnotics (9.2%) were the most common drugs involved. Coroners expressed 1249 concerns, primarily around the major themes of patient safety (29%) and communication (26%), including minor themes of failures of monitoring (10%) and poor communication between organizations (7.5%). Most expected responses to PFDs (51%; 630/1245) were not reported on the UK's Courts and Tribunals Judiciary website. Conclusions: One in five coroner-reported preventable deaths involved medicines. Addressing coroners' concerns, including problems with patient safety and communication, should reduce harms from medicines. Despite concerns being raised repeatedly, half of the PFD recipients failed to respond, suggesting that lessons are not generally learned. The rich information in PFDs should be used to foster a learning environment in clinical practice that may help reduce preventable deaths. Clinical Trial Registration: https://doi.org/10.17605/OSF.IO/TX3CS. [ABSTRACT FROM AUTHOR]

Introduction: The UK Medicines and Healthcare products Regulatory Agency (MHRA) has published frequent summaries of spontaneous reports of suspected adverse drug reactions (ADRs) (Yellow Cards) to vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The EudraVigilance database has provided similar data for the European Economic Area. Objective: Our objective was to characterize the evolution over time of spontaneous reports of suspected ADRs to coronavirus disease 2019 (COVID-19) vaccines and to observe the effect of a publicized reaction (cerebral venous and sinus thrombosis [CVST]) on reporting rates. Methods: We used publicly available data on reports of suspected ADRs and doses of vaccine administered, published by the MHRA, EudraVigilance, and the European Centre for Disease Prevention and Control to calculate reporting rates. Results: Approximately 4814 Yellow Card reports (23 fatal) per million doses of ChAdOx1 nCoV-19 (AstraZeneca) and 2890 (13 fatal) per million doses of tozinameran (Pfizer/BioNTech) have been lodged. Between 15 March and 31 October 2021, cumulative European reports of CVST rose from 0 to 443 (183 with thrombocytopenia, 72 fatal) with ChAdOx1 nCoV-19 and from 2 to 315 (9 with thrombocytopenia, 28 fatal) with tozinameran. European cases of retinal vein occlusion and thrombosis rose from 0 to 168 with ChAdOx1 nCoV-19 and from 1 to 220 with tozinameran; four of the ChAdOx1 nCoV-19 cases were associated with thrombocytopenia. Conclusion: Reports of fatal adverse reactions to coronavirus vaccines are very rare. Reports of CVST have been made in relation to both vaccines. Most were submitted after the reaction had been publicized. Thrombocytopenia occurred in a minority of cases. Reports linked both vaccines to cases of retinal vein thrombosis, just four cases with thrombocytopenia. This suggests two different mechanisms of thrombosis associated with the vaccines. [ABSTRACT FROM AUTHOR]

Introduction: Harms from medical devices are important, but have been much less well studied than adverse drug reactions. Information provided to device users is of variable quality.Objective: Our aim was to define "medical device fault" and "adverse effect of a medical device"; to establish whether medical device faults arise in design, manufacture, or use; and to consider ways of mitigating the adverse effects of medical devices.Methods: We analysed 100 consecutive faults reported by the US Food and Drug Administration (FDA) and 50 faults reported by the UK Medicines and Healthcare products Regulatory Agency (MHRA), and classified faults according to the point at which they occurred.Results: Nearly 70% of reported faults related to devices that entered the body. Over 70% arose at the design stage, a quarter of the faults were associated with manufacture, and less than 5% were primarily caused by faulty use.Conclusion: We defined a medical device fault as an unintended failure in the design, manufacture, or use of a medical device that leads to, or has the potential to lead to, harm to the patient, and an adverse effect of a medical device as an unintended and appreciably harmful effect, caused by a medical device, which demonstrates a hazard of the device and may warrant preventive measures, or a change in the mode of use, or withdrawal of the device. Most faults that generate warnings arise from problems at the design stage, some arise at the manufacturing stage, and a few in usage. Careful assessment of the design of safety-critical devices in the light of previous problems may help to prevent repetition of errors. It would be helpful if, in addition to user manuals, manufacturers were required to produce Summaries of Device Characteristics (SDCs, "labels") that contained a systematically presented set of information about a product. [ABSTRACT FROM AUTHOR]

We propose the following definition of a medical device: "A contrivance designed and manufactured for use in healthcare, and not solely medicinal or nutritional." Current regulatory classifications of medical devices are complex and designed primarily for regulators. We propose a simpler classification, based on (1) the site of application of the device, (2) the time scale of its use, and (3) whether it has an external power source. The regulation of medical devices is less well developed than the regulation of medicinal products, which it could follow more closely. In particular, devices that incorporate medicines should be required to meet the same regulatory standards as medicinal products. This would remove the anomaly that some delivery systems that incorporate medicines are classified as devices while other similar systems that deliver the same medicines are classified as medicinal products. Some improvements might also result from more widespread use of registries, such as those used for prosthetic joint replacements. Registries would allow both a prospective examination of the performance of high-risk devices and a retrospective analysis when signals from other sources of information suggest problems. Those who apply for a marketing authorization for a new device should have to assure regulators of its quality of manufacture, safety, and efficacy before licensing. Even the most straightforward device should be shown to be useable in practice. Trials on patients, or at least simulations of use in the real world, should be practicable for most devices. [ABSTRACT FROM AUTHOR]

Introduction: Coroners inquire into sudden, unexpected, or unnatural deaths. We have previously established 99 cases (100 deaths) in England and Wales in which medicines or part of the medication process or both were mentioned in coroners' 'Regulation 28 Reports to Prevent Future Deaths' (coroners' reports).Objective: We wished to see what responses were made by National Health Service (NHS) organizations and others to these 99 coroners' reports.Methods: Where possible, we identified the party or parties to whom these reports were addressed (names were occasionally redacted). We then sought responses, either from the UK judiciary website or by making requests to the addressee directly or, for NHS and government entities, under the Freedom of Information Act 2000. Responses were analysed by theme to indicate the steps taken to prevent future deaths.Results: We were able to analyse one or more responses to 69/99 cases from 106 organizations. We analysed 201 separate actions proposed or taken to address the 160 concerns expressed by coroners. Staff education or training was the most common form of action taken (44/201). Some organisations made changes in process (24/201) or policy (17/201), and some felt existing policies were sufficient to address some concerns (22/201).Conclusions: Coroners' concerns are often of national importance but are not currently shared nationally. Only a minority of responses to coroners' reports concerning medicines are in the public domain. Processes for auditing responses and assessing their effectiveness are opaque. Few of the responses appear to provide robust and generally applicable ways to prevent future deaths. [ABSTRACT FROM AUTHOR]

Introduction: Since legislation in 2009, coroners in England and Wales must make reports in cases where they believe it is possible to prevent future deaths. We categorised the reports and examined whether they could reveal preventable medication errors or novel adverse drug reactions.Methods: We examined 500 coroners' reports by pre-defined criteria to identify those in which medicines played a part, and to collect information on coroners' concerns.Results: We identified 99 reports (100 deaths) in which medicines or a part of the medication process or both were mentioned. Reports mentioned anticoagulants (22 reports), opioids (17), antidepressants (17), drugs of abuse excluding opioids (12 deaths) and other drugs. The most important concerns related to adverse reactions to prescribed medicines (22), omission of necessary treatment (21), failure to monitor treatment (17) and poor systems (17). These were related to defects in education or training, lack of clear guidelines or protocols and failure to implement existing guidelines, among other reasons. Most reports went either to NHS Hospital Trusts or to local trusts. The responses of addressees were rarely published. We identified four safety warnings from the Medicines and Healthcare Products Regulatory Agency that were based on coroners' warnings.Conclusion: Coroners' reports to prevent future deaths provide some information on medication errors and adverse reactions. They rarely identify new hazards. At present they are often addressed to local bodies, but this could mean that wider lessons are lost. [ABSTRACT FROM AUTHOR]

Introduction: Pharmacovigilance includes analysis of large databases of information on drugs and events using algorithms that detect disproportional frequencies of associations. In order to test such algorithms, attempts have been made to provide canonical reference lists of so-called 'positive controls' and 'negative controls'. Reference sets with even modest levels of misclassification may result in under- or overstatement of the performance of algorithms.Aim: We sought to determine the extent to which 'negative control' drug-event pairs in the Observational Medical Outcomes Partnership (OMOP) database are misclassifiedMethods: We searched the medical literature for evidence of associations between drugs and events listed by OMOP as negative controls.Results: The criteria used in OMOP to classify positive and negative controls are asymmetric; drug-event associations published only as case series or case reports are classified as positive controls if they are cited in Drug-Induced Diseases by Tisdale and Miller, but as negative controls if case series or case reports exist but are not cited in Tisdale and Miller. Of 233 drug-event pairs classified in the 2013 version of OMOP as negative controls, 21 failed to meet pre-specified OMOP adjudication criteria; in another 19 cases we found case reports, case series, or observational evidence that the drug and event are associated. Overall, OMOP misclassified, or may have misclassified, 40 (17 %) of all 'negative controls.'Conclusions: Results from studies of the performance of signal-detection algorithms based on the OMOP gold standard should be viewed with circumspection, because imperfect gold standards may lead to under/overstatement of absolute and relative signal detection algorithm performance. Improvements to OMOP would include omitting misclassified drug-event pairs, assigning more specific event labels, and using more extensive sources of information. [ABSTRACT FROM AUTHOR]

Background: Life-threatening adverse drug reactions (ADRs) such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) continue to affect patients' lives long after the event. Survivors and their relatives rely heavily on Internet sources for support and advice, but narratives of their experiences posted on patient websites have not been explored previously.Objectives: The aim of the study was to illuminate patient experience by analysing Internet narratives of drug-induced SJS and TEN and considering the reasons for postings on patient websites, and the concerns they reflect. We also aimed to compare these experiences with a previous study of survivors of SJS and TEN conducted by face-to-face interview.Methods: We searched for unsolicited personal narratives or descriptions of drug-induced SJS and TEN posted on the Internet between February 2009 and June 2010, and analysed them using a thematic qualitative approach.Results: We analysed 208 Internet descriptions. Motivation for posting on the Internet included a desire to share experiences and to seek advice from others. Patients and their relatives expressed concern that the ADR may be hereditary, worries about effects on fertility and a fear of recurrence. They also wished to increase awareness of the potential harms from medicines and to inform others of the suspected cause of the ADR.Conclusion: Individuals experiencing SJS or TEN had many unanswered questions and concerns long after the event. Our findings could guide health professionals in the management of survivors of the ADR, and in communicating more effectively with patients and their relatives. Internet forum postings of patient experiences of ADRs provide insight into patient concerns and supplement findings from detailed face-to-face interviews. [ABSTRACT FROM AUTHOR]

Background: The omission of charted (prescribed) doses for hospitalized patients is an important problem in the UK. Inappropriate drug omission can clearly lead to harm from lack of therapeutic effect. However, healthcare professionals administering medicines may decide that omission of a dose is appropriate in certain circumstances, e.g. when patients show signs of a possible adverse drug reaction (ADR).Objective: The aim of this study was to characterize dose omissions to understand the factors that influence non-administration of therapy and to determine the proportion of doses that are appropriately omitted due to ADRs.Methods: We used data from a bespoke hospital-wide electronic prescribing and administration system at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. We extracted data on 6.01 million drug administrations during 2010 and then randomly selected four 7-day periods, concentrating on doses that were charted but not given. Omitted medicines were counted if either there was a charted 'non-administration' (i.e. an active acknowledgement of the omitted dose) or there was no charting of that dose (i.e. no record of either administration or omission). Paused medicines were not counted. When a dose was omitted, staff indicated the reasons for non-administration using codes ('hard coded') or free text in the electronic system. We used both to compare the contribution of different factors, including ADRs, to the total rates of dose omissions.Results: In the four 7-day periods analysed, 60 763 (12.4%) of the 491 894 charted doses were omitted. The most common code was 'patient refused drug' (45.4%). Only 1.6% of doses were omitted for reasons of patient safety, of which 4 in 1000 omissions were coded as directly due to an ADR.Conclusions: Measures to improve the quality of care should seek to reduce dose omissions, but in some cases omission may be rational. Electronic medication administration records allow for detailed analysis of decisions made by healthcare professionals at the point of administration. While dose omissions related to ADRs are uncommon, they are important both for patient safety and for therapeutic decision making. [ABSTRACT FROM AUTHOR]

Introduction: : Electronic decision support can reduce medication errors, and dose-range checking is one element of that support.Objective: : The aim of this study was to design an approach to setting upper dose warning limits in electronic prescribing systems where there are historical data on dosing.Method: : We used historical data on 56 drug-form combinations for which over 100 prescriptions had been issued between 1 June 2009 and 31 May 2010 in a bespoke electronic prescribing system at University Hospital Birmingham, UK. First, two experts derived dose limits for each drug-form combination, then the drugs were randomly divided into a training set and a test set. A variation of the 'Nearest Rank' approach to estimate statistical limits was used to derive the percentile with the optimal sensitivity and specificity.Results: : For the 28 drug-form combinations in the test set, the 86th percentile of dose gave a mean sensitivity of 95.3% and a mean specificity of 97.9% for warning limits, representing the highest reasonable dose; the 96th percentile gave a mean sensitivity of 90.2% and mean specificity of 99.5% for disallow limits, beyond which no dose should be prescribed.Conclusions: : Dosing decision support within electronic prescribing systems can be derived by statistical analysis of historical prescription data. We advocate a combined theoretical and statistical derivation of dose checking rules in order to ensure that prescribers are alerted appropriately to potentially toxic doses. [ABSTRACT FROM AUTHOR]

Biochemical monitoring of patients treated with antihypertensive therapy is recommended in order to identify potential adverse reactions to treatment. We aimed to review the literature investigating the nature of biochemical monitoring in adults treated in primary care with antihypertensive drugs. Specifically, we wished to establish (i) the proportion of patients with biochemical baseline testing prior to the initiation of antihypertensive therapy; (ii) the proportion of patients with biochemical monitoring after initiation of antihypertensive therapy; (iii) the patient characteristics associated with biochemical monitoring; (iv) the frequency of biochemical monitoring after the initiation of antihypertensive therapy; and (v) the relationship, if any, between biochemical monitoring and adverse patient outcomes. We searched MEDLINE, EMBASE and Google Scholar from 1948 to 31 December 2010 using a combination of text words and search terms. Retrospective and prospective cohort studies, cross-sectional studies, randomized controlled trials or quasi-randomized controlled trials, and audits of current clinical practice were included. Clinical trials, case reports and case series were excluded. Studies were included if they provided data on the proportion of patients treated with antihypertensive therapy in primary care who had any biochemical monitoring before or after the initiation of therapy. In total, 15 studies were included in our review, which used a wide variety of definitions of monitoring prior to and after the initiation of antihypertensive therapy. From 17% to 81% of patients treated with antihypertensive drugs had a baseline biochemical test and from 20% to 79% had any follow-up monitoring. In only 7 of the 12 studies that examined follow-up monitoring did more than half of the patients have any monitoring. Overall, this systematic review provides evidence that monitoring as recommended by published guidelines is not commonly undertaken. Only two studies were identified that examined patients with both baseline testing and follow-up monitoring. Omission of one or the other limits the ability to analyse the effect of treatment on electrolyte concentrations or renal function. There is limited research on the patient factors associated with monitoring and further work is required to determine the impact of monitoring on adverse patient outcomes. Important barriers to effective monitoring exist and this review emphasizes that these have not yet been overcome. [ABSTRACT FROM AUTHOR]

Background: Adverse drug reactions (ADRs) cause significant morbidity and mortality and account for around 6.5% of hospital admissions. Patient experiences of serious ADRs and their long-term impact on patients' lives, including their influence on current attitudes towards medicines, have not been previously explored.Objective: The aim of the study was to explore the experiences, beliefs, and attitudes of survivors of serious ADRs, using drug-induced Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) as a paradigm.Methods: A retrospective, qualitative study was undertaken using detailed semi-structured interviews. Fourteen adult survivors of SJS and TEN, admitted to two teaching hospitals in the UK, one the location of a tertiary burns centre, were interviewed. Interview transcripts were independently analysed by three different researchers and themes emerging from the text identified.Results: All 14 patients were aware that their condition was drug induced, and all but one knew the specific drug(s) implicated. Several expressed surprise at the perceived lack of awareness of the ADR amongst healthcare professionals, and described how the ADR was mistaken for another condition. Survivors believed that causes of the ADR included (i) being given too high a dose of the drug; (ii) medical staff ignoring existing allergies; and (iii) failure to monitor blood tests. Only two believed that the reaction was unavoidable. Those who believed that the condition could have been avoided had less trust in healthcare professionals. The ADR had a persisting impact on their current lives physically and psychologically. Many now avoided medicines altogether and were fearful of becoming ill enough to need them.Conclusions: Life-threatening ADRs continued to affect patients' lives long after the event. Patients' beliefs regarding the cause of the ADR differed, and may have influenced their trust in healthcare professionals and medicines. We propose that clear communication during the acute phase of a serious ADR may therefore be important. [ABSTRACT FROM AUTHOR]

Background: Contraindications to medicines define circumstances in which the medicines must not be given. Computerized prescribing systems with decision support should display alerts to warn prescribers of contraindications. However, for such systems to be effective, alerts should only be displayed when relevant.Objective: We set out to construct an algorithm that would classify contraindications according to the data available to a computerized system, and allow them to be displayed in context as far as possible.Method: We drafted an initial algorithm from first principles, refined it by classifying further datasets, and then tested it on a further set of 95 phrases for contraindications.Results: We were able to classify 94 of the 95 phrases; 13 related to age or sex and four related to allergies, but the majority depended on co-morbid conditions.Conclusions: We have constructed a practicable algorithm for classifying alerts to contraindications. The classification used will allow alerts to be displayed when relevant. However, most contraindications relate to co-morbid conditions, and prescribing systems will only be able to display these in context if they have access to relevant clinical data. [ABSTRACT FROM AUTHOR]

Background: 'Preventability' is a crucial concept in the literature on adverse drug effects. However, a systematic review of the definitions of preventability of adverse drug effects has suggested that none fits all circumstances. Furthermore, when the reliability of these definitions has been examined they have been found to be imperfect.Objective: To propose and outline a method for determining the theoretical preventability of an adverse drug effect, based on frameworks for classifying adverse drug reactions - the EIDOS and DoTS methods.Methods: EIDOS is based on the mechanism of action of the drug. It observes that a drug (an Extrinsic species) causes an adverse effect by interacting with an Intrinsic species that is its target when the two are Distributed together, and that the resulting pathophysiological Outcome (the adverse effect) causes the Sequela (the adverse reaction). DoTS observes that the Dose-relatedness of the adverse effect compared with the beneficial effect is relevant (determining toxic, collateral, or hypersusceptibility effects), that adverse effects have Time-courses (varying from immediate to delayed), and that there are individual Susceptibility factors.Results and Discussion: We have elicited many published examples that show that each of these factors in the causation of an adverse drug effect can be adduced to assess its preventability. We have constructed a flowchart that illustrates how the processes can be logically analysed.Conclusions: This approach suggests methods for devising prospective preventive strategies and for deciding retrospectively whether an adverse reaction in an individual should have been prevented. [ABSTRACT FROM AUTHOR]

'Preventability' is a crucial concept in the literature on adverse drug reactions (ADRs). We have carried out a systematic review in order to identify and analyse the approaches used to define 'preventability' in relation to ADRs. We have restricted this investigation to definitions of preventability and have not dealt with other aspects. We searched MEDLINE (1963-April 2009) and EMBASE (1980-April 2009), without language restriction, for papers in which preventability of ADRs was likely to be defined. We found 234 papers, of which we retrieved 231. Of these, 172 either contained original definitions of preventability or referred to other papers in which preventability was defined. Forty contained no definition, and 19 were not relevant. In the 172 papers selected, we identified eight different general approaches to defining the preventability of ADRs: (1) analysis without explicit criteria; (2) assessment by consensus; (3) preventability linked to error; (4) preventability linked to standards of care; (5) preventability linked to medication-related factors; (6) preventability linked to information technology; (7) categorization of harmful treatments in explicit lists; and (8) a combination of more than one approach. These approaches rely on two general methods: the judgement of one or more investigators or the use of pre-defined explicit criteria; neither is satisfactory. Specific problems include the weakness of consensus as a method (since experts can agree and yet be wrong), inadequacy of definition of standards of care, and circularity in several definitions of preventability. Furthermore, attempts to list all preventable effects are bound to be incomplete and will not always apply to an individual case. We conclude that an approach based on analysis of the mechanisms of adverse reactions and their clinical features could be preferable; such an approach is described in a companion paper (Part II) in this issue of Drug Safety. [ABSTRACT FROM AUTHOR]

The mechanisms of adverse drug effects have not been adequately classified. Here, we propose a comprehensive mechanistic classification of adverse drug effects that considers five elements: the Extrinsic chemical species (E) that initiates the effect; the Intrinsic chemical species (I) that it affects; the Distribution (D) of these species in the body; the (physiological or pathological) Outcome (O); and the Sequela (S), which is the adverse effect. This classification, which we have called EIDOS, describes the mechanism by which an adverse effect occurs; it complements the DoTS classification of adverse effects (based on clinical pharmacology), which takes into account Dose responsiveness, Time course, and Susceptibility factors. Together, these two classification systems, mechanistic and clinical, comprehensively delineate all the important aspects of adverse drug reactions; they should contribute to areas such as drug development and regulation, pharmacovigilance, monitoring therapy, and the prevention, diagnosis, and treatment of adverse drug effects. [ABSTRACT FROM AUTHOR]

Background: Spontaneous reports of suspected adverse drug reactions to regulatory bodies and market authorization holders are important in pharmacovigilance. Follow-up information, which can be difficult to obtain, is often required from reporters; therefore, we developed targeted follow-up letters that we hoped would make replying easier.Objective: To examine the effects of introducing targeted letters on responses to follow-up requests from a regional pharmacovigilance centre in the UK.Method: In January 2001 we redesigned our follow-up request letter to include tick-boxes targeted to obtain the appropriate information from reporters. Response rates and the requirement for a second follow-up letter were examined for the 5-year period before introduction of the targeted follow-up letter (1996-2000) and the 5 years after the change to the targeted follow-up system (2001-5). In an 18-month sub-study examining data from 2001-2, time from the production of the first targeted follow-up letter to receipt of a response from reporters was also measured.Results: The introduction of targeted follow-up letters was associated with an increase in the mean annual response rate for follow-up from 36.4% in the 5 years pre-targeted follow-up to 60.5% in the 5 years post-targeted follow-up (p < 0.0001). Fifty percent of all successful follow-up responses were obtained within 70 days.Conclusion: Targeted follow-up letters were associated with increased follow-up success rates. Results also indicate that closing cases to follow-up information at 70 days would allow collection of 78% of all follow-up that would ever arrive. [ABSTRACT FROM AUTHOR]

Regulatory agencies grant product licences (marketing authorizations) for medicinal products in the light of evidence that the balance between benefit and harm in the population is favourable. Here we consider a framework for allowing regulatory agencies to make rational decisions when reviewing product licences in the light of new information about harms that change that balance. The regulator can revoke the product licence, restrict the product's availability or change the 'label' in different ways. We examine the features of the adverse effect that may be relevant in making the decision: namely, individual differences in susceptibility; the possibility of monitoring; and the availability of protective strategies. The balance of benefit and harm, and the time-course and dose relation of the adverse effect play important roles in the decision-making process. We set out how these factors can help determine the logical response to new information on the balance between benefit and harm, and provide a series of relevant examples. We believe that when regulatory agencies have to decide how to amend the product licence of a drug when new serious adverse effects cause concern, they would find it useful to adopt a framework of this kind, using different strategies for different cases. Our proposed framework could also be useful in risk management planning during drug development. [ABSTRACT FROM AUTHOR]

Background: Factors such as age, sex and disease state alter a patient's susceptibility to adverse drug reactions (ADRs). Ethnicity may also alter the risk of an ADR.Objective: To review the evidence for ethnic differences in susceptibility to adverse reactions to drugs used to treat psychoses and depression.Data Sources: We searched MEDLINE (from 1951), EMBASE (from 1974), and PsycINFO (from 1950) to March 2006.Study Selection: Studies were included if there was a mention of ethnicity, ethnic or racial groups and a description of a procedure to investigate ADRs specifically or a description of ADRs that were a result of drugs in therapeutic use. Studies selected by any two reviewers were retained if they referred to drugs used in the treatment of psychoses and related disorders or antidepressant drugs. Of 124 studies describing ADRs to antipsychotics or antidepressants, 51 reported data from different ethnic groups.Data Extraction: Data were extracted independently from those studies selected for inclusion by two reviewers, using a standard data extraction form. Studies were assessed for bias in order to determine the quality of the study.Data Synthesis: In a pooled analysis of patients treated with antipsychotics, the relative risk (RR) of tardive dyskinesia in Black compared with White patients was 1.03 (95% CI 0.85, 1.24); the RR of extrapyramidal symptoms in East Asian compared with non-East Asian patients was 1.38 (95% CI 1.11, 1.72); the RR of hyperglycaemia in Black compared with non-Black patients was 1.55 (95% CI 0.95, 2.53); and the RR of diabetes mellitus in non-White compared with White patients was 1.35 (95% CI 0.95, 1.92). It was impossible to perform pooled analysis of data from studies investigating antidepressants due to insufficient data.Conclusions: We found limited evidence of ethnic differences in the risk of ADRs. The clinical implications of these results remain unclear because of confounding factors. Further progress will require improved recruitment of patients from different ethnic groups and an established consensus on how to define ethnicity. [ABSTRACT FROM AUTHOR]

We have previously described and analysed some terms that are used in drug safety and have proposed definitions. Here we discuss and define terms that are used in the field of medication errors, particularly terms that are sometimes misunderstood or misused. We also discuss the classification of medication errors. A medication error is a failure in the treatment process that leads to, or has the potential to lead to, harm to the patient. Errors can be classified according to whether they are mistakes, slips, or lapses. Mistakes are errors in the planning of an action. They can be knowledge based or rule based. Slips and lapses are errors in carrying out an action - a slip through an erroneous performance and a lapse through an erroneous memory. Classification of medication errors is important because the probabilities of errors of different classes are different, as are the potential remedies. [ABSTRACT FROM AUTHOR]

Nomenclature surrounding drug safety needs to be clear and unambiguous, so that patients, prescribers, manufacturers, and regulators can all understand each other. In particular, it needs to make it clear how adverse events and drug therapy are related to one another, how they are best classified, and their frequency, intensity and seriousness. In this article, we therefore discuss and define terms used in the field of drug safety, particularly terms that are sometimes misunderstood or misused, including medicinal product, pharmaceutical formulation, excipient, adverse event (or experience) and adverse drug reaction (or effect). We also discuss terms used to define the seriousness, intensity, and risk of adverse reactions, and their classification. Instead of creating definitions from scratch, as is commonly done, we have taken the novel approach of critically examining definitions that have been proposed or widely used and have formulated new or modified definitions based on a logical appraisal of their merits and demerits. We hope that these definitions will lead to discussion that will allow a corpus of satisfactory definitions to be widely agreed. [ABSTRACT FROM AUTHOR]

Implementing mechanisms for rewarding those who introduce innovative medicinal products requires a definition of 'rewardable innovation'. Here, we propose a definition of innovation with respect to medicinal products, accompanied by a ranking of the importance of different types of innovativeness, with the aim of providing a basis for rewarding such innovation. [ABSTRACT FROM AUTHOR]