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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]

Aims: Pharmacogenomic testing has the potential to target medicines more effectively towards those who will benefit and avoid use in individuals at risk of harm. Health economies are actively considering how pharmacogenomic tests can be integrated into health care systems to improve use of medicines. However, one of the barriers to effective implementation is evaluation of the evidence including clinical usefulness, cost‐effectiveness, and operational requirements. We sought to develop a framework that could aid the implementation of pharmacogenomic testing. We take the view from the National Health Service (NHS) in England. Methods: We used a literature review using EMBASE and Medline databases to identify prospective studies of pharmacogenomic testing, focusing on clinical outcomes and implementation of pharmacogenomics. Using this search, we identified key themes relating to the implementation of pharmacogenomic tests. We used a clinical advisory group with expertise in pharmacology, pharmacogenomics, formulary evaluation, and policy implementation to review data from our literature review and the interpretation of these data. With the clinical advisory group, we prioritized themes and developed a framework to evaluate proposals to implement pharmacogenomics tests. Results: Themes that emerged from review of the literature and subsequent discussion were distilled into a 10‐point checklist that is proposed as a tool to aid evidence‐based implementation of pharmacogenomic testing into routine clinical care within the NHS. Conclusion: Our 10‐point checklist outlines a standardized approach that could be used to evaluate proposals to implement pharmacogenomic tests. We propose a national approach, taking the view of the NHS in England. Using this approach could centralize commissioning of appropriate pharmacogenomic tests, reduce inequity and duplication using regional approaches, and provide a robust and evidence‐based framework for adoption. Such an approach could also be applied to other health systems. [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]

Background: Insulin poisoning, as opposed to hypoglycaemia induced by therapeutic doses of insulin, is rare, and guidelines on management differ. We have reviewed the evidence on treatment of insulin poisoning. Methods: We searched PubMed, EMBASE and J‐Stage with no restrictions of date or language for controlled studies on treatment of insulin poisoning, collected published cases of insulin poisoning from 1923, and used data from the UK National Poisons Information Service. Results: We identified no controlled trials of treatment in insulin poisoning and few relevant experimental studies. Case reports described 315 admissions (301 patients) with insulin poisoning between 1923 and 2022. The insulin with the longest duration of action was long‐acting in 83 cases, medium‐acting in 116, short‐acting in 36 and a rapid‐acting analogue in 16. Decontamination by surgical excision of the injection site was reported in six cases. To restore and maintain euglycaemia, almost all cases were treated with glucose, infused for a median 51 hours, interquartile range 16–96 h in 179 cases; 14 patients received glucagon and nine octreotide; adrenaline was tried occasionally. Both corticosteroids and mannitol were occasionally given to mitigate hypoglycaemic brain damage. There were 29 deaths reported, 22/156 (86% survival) up to 1999 and 7/159 (96% survival) between 2000 and 2022 (p = 0.003). Conclusions: There is no randomized controlled trial to guide treatment of insulin poisoning. Treatment with glucose infusion, sometimes supplemented with glucagon, is almost always effective in restoring euglycaemia, but optimum treatments to maintain euglycaemia and restore cerebral function remain uncertain. [ABSTRACT FROM AUTHOR]

The initial purposes of regulation of medicines in England, and latterly in the United Kingdom, were principally to raise government revenue, to discourage murder by poisoning and to regulate the activities of pharmacists. It was only much later that regulators sought to ensure that medicines were of good quality, reasonably safe, and at least somewhat effective, and to curtail misuse of drugs. Here we survey the history of the regulation of medicines and poisons in England from the perspective of clinicians with an interest in therapeutics. [ABSTRACT FROM AUTHOR]

Introduction: Free‐of‐charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning. Methods: We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available Medicines and Healthcare products Regulatory Agency Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised. Results: Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company‐FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes, 37% had phase 2 data and 19% were supported only by phase 1 data, retrospective observational studies or preclinical data. Utilisation of company‐FoC schemes increased on average by 50% per year, while MHRA EAMS schemes showed little growth. Conclusion: Company‐FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co‐ordinate schemes. Motivations for company‐FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or to allow generation of further evidence. [ABSTRACT FROM AUTHOR]

In response to the COVID‐19 pandemic, Health Education England (HEE) and the University of Birmingham provided National Health Service (NHS) staff free access to SCRIPT, a national eLearning programme for safer prescribing and therapeutics. The eLearning was particularly for those returning to work or being redeployed. In the year March 2020‐21, 3412 users registered to access portfolios and opened an aggregate of 17 198 modules. Each user completed a median of 2 (range 1‐50, interquartile range [IQR] 1‐7) assessed learning modules. Marks improved from pre‐test to post‐test by a median of 2 (IQR 0‐3) marks out of 10. The most frequently selected modules were Adherence and Concordance (1109 users), Fluids (981 users) and Diabetic Emergencies (818 users). A total of 878 users accessed the unassessed COVID‐19 module. The SCRIPT modules provided standardised education in core principles relating to prescribing and therapeutics, and were used by professionals from many healthcare disciplines. [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]

The article discusses the successful national Prescribing Safety Assessment (PSA) in United Kingdom (UK) medical education as of 2023. Topics covered include its push for medical schools to ensure students' capability in prescription, the UK Medical Licensing Assessment (MLA), and the dilemma in its relation to the PSA. Also noted is the PSA's possible other purpose that the MLA cannot cover.

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]

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]

Context:Some authors have proposed that post-mortem drug concentrations in bile are useful in estimating concentrations in blood. Both The International Association of Forensic Toxicologists (TIAFT) and the US Federal Aviation Administration recommend that samples of bile should be obtained in some circumstances. Furthermore, standard toxicological texts compare blood and bile concentrations, implying that concentrations in bile are of forensic value. Aim:To review the evidence on simultaneous measurements of blood and bile drug concentrations reported in the medical literature. Methods:We made a systematic search of EMBASE 1980–2016 using the search terms (“bile/” OR “exp drug bile level/concentration/”) AND “drug blood level/concentration/”, PubMed 1975–2017 for (“bile[tw]” OR “biliary[tw]”) AND (“concentration[tw]” OR “concentrations[tw]” OR “level[tw]” OR “levels[tw]”) AND “post-mortem[tw]” and also MEDLINE 1990–2016 for information on drugs whose biliary concentrations were mentioned in standard textbooks. The search was limited to human studies without language restrictions. We also examined recent reviews, indexes of relevant journals and citations in Web of Science and Google Scholar. We calculated the bile:blood concentration ratio. The searches together yielded 1031 titles with abstracts. We scanned titles and abstracts for relevance and retrieved 230, of which 161 were considered further. We excluded 49 papers because: the paper reported only one case (30 references); the data referred only to a metabolite (1); the work was published before 1980 (3); the information concerned only samples taken during life (10); or the paper referred to a toxin or unusual recreational drug (5). The remaining 112 papers provided data for analysis, with at least two observations for each of 58 drugs. Bile:blood concentration ratios:Median bile:blood concentration ratios varied from 0.18 (range 0.058–0.32) for dextromoramide to 520 (range 0.62–43,000) for buprenorphine. Median bile concentrations exceeded blood concentrations by one order of magnitude for several drugs, including dihydrocodeine, quetiapine and sildenafil; and by two orders of magnitude of for buprenorphine, colchicine and 3,4-methylenedioxy-methamphetamine (MDMA), among others. The minimum and maximum values for the ratio differed by a factor of three or more in three-quarters of the cases where data were available and by a factor of 10 or more for over half of the analytes. Limitations:The data were difficult to find. Medline does not explicitly index the term “drug bile concentration”. It may well be that other reports exist, although they would not alter our major conclusion. Many of the papers that contributed data failed to specify the source of the blood samples or the post-mortem interval, so that no judgment was possible regarding post-mortem redistribution in whole blood or bile. Conclusions:For most drugs, there are wide ranges of bile:blood concentration ratios, which means that bile and blood concentrations are generally poorly correlated. Bile concentration measurements cannot readily be used to establish post-mortem blood concentrations; nor can they be extrapolated to ante-mortem concentrations. However, because drug concentrations in bile often exceed those in blood, bile may allow qualitative identification of drugs present, even when the blood concentration is below the limit of detection. [ABSTRACT FROM PUBLISHER]

The terms 'licensed', 'unlicensed', and 'off-label', often used in relation to marketing and prescribing medicinal products, may confuse UK prescribers. To market a medicinal product in the UK requires a Marketing Authorization ('product licence') for specified indications under specified conditions, regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The Marketing Authorization includes the product's agreed terms of use (the 'label'), described in the Summary of Product Characteristics (SmPC). Prescribing a licensed product outside those terms is called 'off-label' prescribing. Products for which no-one holds a UK Marketing Authorization are unlicensed. Prescribers can prescribe authorized products according to the conditions described in the SmPC ('on-label') or outside those conditions ('off-label'). They can also prescribe unauthorized products, even if they are unlicensed in the UK, if they are licensed elsewhere or if they have been manufactured in the UK by a licensed manufacturer as a 'special'. The complexities of this system can be understood by considering the status of the manufacturer of the product, the company that markets it (which may or may not be the same), the product itself, and its modes of use, and by emphasizing the word 'authorized'. If a Marketing Authorization is granted to the supplier of a product, it will specify the authorized modes of use; the product will be prescribable as authorized (i.e. 'on-label') or in other modes of use, which will all be off-label. Unlicensed products with no authorized modes of use can be regarded as 'unauthorized products'. All 'specials' can be regarded as authorized products lacking authorized modes of use. [ABSTRACT FROM AUTHOR]

Objective:To review the evidence for “the Mellanby effect”, that is, whether the response to a given blood alcohol concentration (BAC) is more marked when BAC is rising than at the same concentration when BAC is falling. Methods:We systematically searched the databases EMBASE, Medline, and Scopus up to and including December 2016 using text words “tolerance”, “ascending”, “descending” or “Mellanby” with Medline term “exp *alcohol/” or “exp *drinking behavior/” or equivalent. Articles were identified for further examination by title or abstract; full text articles were retained for analysis if they dealt with acute (within dose) alcohol tolerance in human subjects and provided quantitative data on both the ascending and descending parts of the BAC–time curve. Reference lists of identified works were scanned for other potentially relevant material. We extracted and analyzed data on the subjective and objective assessment of alcohol effects. Results:We identified and screened 386 unique articles, of which 127 full-text articles were assessed; one provided no qualitative results, 62 involved no human study, 25 did not consider acute tolerance within dose, and 13 failed to provide data on both ascending and descending BAC. We extracted data from the 26 remaining articles. The studies were highly heterogeneous. Most were small, examining a total of 770 subjects, of whom 564 received alcohol and were analyzed in groups of median size 10 (range 5–38), sometimes subdivided on the basis of drinking or family history. Subjects were often young white men. Doses of alcohol and rates of administration differed. Performance was assessed by at least 26 different methods, some of which measured many variables. We examined only results of studies which compared results for a given alcohol concentration (C) measured on the ascending limb (Cup) and the descending limb (Cdown) of the BAC-time curve, whether in paired or parallel-group studies. When subjects were given alcohol in more than one session, we considered results from the first session only. Rating at Cdownwas better than at Cupfor some measures, as expected if the Mellanby effect were operating. For example, subjects rated themselves less intoxicated on the descending limb than at the same concentration on the ascending limb in 12/13 trials including 229 subjects that gave statistically significant results. In 9 trials with a total of 139 subjects, mean difference could be calculated; weighted for study size, it was 29% [range 24–74%]. Willingness to drive was significantly greater in 4 of 6 studies including a total of 105 subjects; weighted mean difference increased by 207% [range 79–300%]. By contrast, measure of driving ability in three groups of a total of 200 trials in 57 subjects showed worse performance by a weighted mean of 96% [range 3–566%]. In three trials that tested inhibitory control (cued go or no-go response times), weighted mean performance was 30% [range 14–65%] worse on the descending limb. Conclusions:The “Mellanby effect” has been demonstrated for subjective intoxication and willingness to drive, both of which are more affected at a stated ethanol concentration when BAC is rising than at the same concentration when BAC is falling. By contrast, objective measures of skills necessary for safe driving, such as response to inhibitory cues and skills measured on driving simulators, were generally worse on the descending part of the BAC-time curve for the same BAC. [ABSTRACT FROM PUBLISHER]

Background Adverse drug reactions are sometimes described as being 'non-dose-related' because no relationship has been found between increasing doses and either the intensity of the response or the proportion of individuals in whom the response occurs; furthermore, hypersensitivity reactions are often regarded as being non-dose-related, even if different doses have not been studied. However, the law of mass action implies that all pharmacological effects are concentration related and should increase in intensity with increasing dose. We set out to explain this paradox. Methods We searched for published adverse drug reactions that have been described as non-dose-related and analysed them. Results We identified four categories of explanations that resolve the paradox: (i) the reaction is not real; it may have occurred by chance or there may be methodological problems, such as bias or confounding factors; (ii) the dose-response curve for the adverse effect reaches a maximum at doses lower than were studied (i.e. a hypersusceptibility reaction); this underpins the use of test doses to predict the possibility of an adverse reaction at therapeutic doses; (iii) susceptibility to the adverse reaction differs widely among individuals; and (iv) imprecision or inaccuracy in the measurement of either dose or effect obscures dose responsiveness. This last explanation encompasses: (a) reactions related to cumulative dose; (b) dissociation between dose and concentration through saturable pharmacokinetics; and (c) variability in the measurement of the effect. Conclusions and implications If an adverse drug reaction appears to be non-dose-related, the reasons should be sought, having these mechanisms in mind. [ABSTRACT FROM AUTHOR]

We have traced the historical link between the Law of Mass Action and clinical pharmacology. The Law evolved from the work of the French chemist Claude Louis Berthollet, was first formulated by Cato Guldberg and Peter Waage in 1864 and later clarified by the Dutch chemist Jacobus van 't Hoff in 1877. It has profoundly influenced our qualitative and quantitative understanding of a number of physiological and pharmacological phenomena. According to the Law of Mass Action, the velocity of a chemical reaction depends on the concentrations of the reactants. At equilibrium the concentrations of the chemicals involved bear a constant relation to each other, described by the equilibrium constant, K. The Law of Mass Action is relevant to various physiological and pharmacological concepts, including concentration-effect curves, dose-response curves, and ligand-receptor binding curves, all of which are important in describing the pharmacological actions of medications, the Langmuir adsorption isotherm, which describes the binding of medications to proteins, activation curves for transmembrane ion transport, enzyme inhibition and the Henderson-Hasselbalch equation, which describes the relation between pH, as a measure of acidity and the concentrations of the contributory acids and bases. Guldberg and Waage recognized the importance of dynamic equilibrium, while others failed to do so. Their ideas, over 150 years old, are embedded in and still relevant to clinical pharmacology. Here we explain the ideas and in a subsequent paper show how they are relevant to understanding adverse drug reactions. [ABSTRACT FROM AUTHOR]

Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations. In the first part of this review we proposed an operational definition that incorporates the processes by which products are manufactured, the causes of shortages and stock‐outs (local shortages), and the contributory factors. Here we discuss causes and possible solutions. Drug shortages have complex causes, and a single cause cannot always be identified. Reasons include lack or shortage of raw materials, manufacturing difficulties, regulatory and political actions, voluntary recalls, just‐in‐time inventory systems, halts in production for financial or other business reasons, low demand (eg, orphan products, reduced usage), mergers, market shifts (eg, diversion to home markets) and unexpected increases in demand (eg, improved diagnosis, new trial information, epidemics and pandemics, inappropriate use, off‐label use). Potential solutions are as diverse as the potential causes. Prevention is hard, because shortages are not easily predicted. Everyone in the supply chain is involved in anticipating and managing shortages, with responsibilities for preventing them or at least trying to mitigate their effects. This includes manufacturers and suppliers, particularly of generic formulations, pharmacists, prescribers, patients and governments. Solutions can therefore be linked to the causes and classified according to where the responsibility for implementing them lies. [ABSTRACT FROM AUTHOR]

Drug shortages are repeatedly in the news. The earliest drug shortages were reported during the First World War, but the numbers of shortages have increased in recent years. In the first part of this two‐part review, we discuss definitions of drug shortages and so‐called stockouts, which are localized shortages, and the harms that they can cause. Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations, but we lack an adequate definition. The problems are too complicated to be encompassed in a brief intensional dictionary‐style definition, and that is reflected in the many different attempts at definition that have been proposed. We therefore propose an extensional operational definition that incorporates the processes by which products are manufactured, the causes of shortages and the contributory factors. A definition of this sort allows one to identify the main causes of a particular drug shortage and therefore the remedies that might prevent, mitigate or manage it. In the second part of the review we discuss the causes and solutions in more detail. Adverse drug reactions and medication errors attributable to shortages occur but are not often reported. Adverse reactions to substitute medicines are possible, and errors can occur because of unfamiliarity or unnecessary treatment with replacement medicines. Other harmful outcomes include withdrawal reactions, undertreatment, treatment delays and cancellations, failure of alternatives and disruption of clinical trials. [ABSTRACT FROM AUTHOR]

Health systems encourage switching from originators to biosimilars as biosimilars are more cost‐effective. The speed and completeness of biosimilar adoption is a measure of efficiency. We describe the approach to biosimilar adoption at a single hospital Trust and compare its efficiency against the English average. We additionally follow up patients who reverted to a previously used biologic, having switched to a biosimilar, to establish whether they benefitted from re‐establishing prior treatment. The approach we describe resulted in a faster and more complete switch to biosimilars, which saved an additional £380 000 on drug costs in 2021/2022. Of patients who reverted to their original biologic, 87% improved short‐term, and a time on treatment analysis showed the benefit was retained long term. Our approach to biosimilar adoption outperformed the English average and permits patients to revert to their original biosimilar post‐switch if appropriate. [ABSTRACT FROM AUTHOR]

Rational therapeutics requires a balance between benefits and harms. (i) Harm may be inevitable. Some adverse drug reactions cannot be predicted or prevented. (ii) Some harm occurs in error when a medicine is wrongly formulated, prescribed, dispensed or administered. Adverse drug reactions that might have been prevented, for example, by monitoring, fall into this category. (iii) Rarely, harm is inflicted deliberately, for example, in murder by poisoning. Here I consider adverse drug reactions, errors and deliberate drug-induced harm from the perspective of a clinical pharmacologist. [ABSTRACT FROM AUTHOR]

Medication errors cause substantial harm to patients. We need good methods for counting errors, and we need to know how errors defined in different ways and ascertained by different methods are related to the harm that patients suffer. As errors arise within the complex and poorly designed systems of hospital and primary care, analysis of the factors that lead to error, for example by failure mode and effects analysis, may encourage better designs and reduce harms. There is almost no information on the best ways to train prescribers to be safe or to design effective computerized decision support to help them, although both are important in reducing medication errors and should be investigated. We also need to know how best to provide patients with the data they need to be part of initiatives for safer prescribing. [ABSTRACT FROM AUTHOR]

The article mentions that poisoning caused due to intake of paracetamol could be fatal and talks about several other side effects that are associated with it such as acute liver failure and liver injury. It discusses the metabolism of paracetamol in the body, the damage caused by it to the liver and several factors that could aggravate the impact of the damage such as malnourishment and alcoholism. It mentions several symptoms associated with paracetamol poisoning which are visible within a few hours of its intake. It informs about the diagnostic methods which should adopted to determine the level of the poisoning and the type of subsequent and supportive courses of treatment that should be prescribed. It also mentions situations where the patient succumbs to the poisoning.

1. Medication errors should be amenable to epidemiological analysis, giving insights into the causes of error and the effects of interventions to prevent them or reduce harm from them. 2. There are formidable difficulties in establishing the rates of medication errors. 3. There is no agreement on a clear operational definition of the condition. 4. The methods used to enumerate cases so far have been unreliable or incomplete or both. 5. There is disagreement about whether cases of error that do not cause harm should be included in calculations of error rates. 6. When harm occurs in association with drug therapy, it is often unclear whether the harm might have been prevented, and its occurrence should therefore be considered to result from error. 7. The denominator for calculating the rate of error is both ill-defined and inconsistently measured. Better definitions, more complete evaluation, and more thorough impact assessment may improve matters. [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]

The article discusses the question of whether the use of codeine by nursing mothers could kill their infants. A case in which a breast-fed baby died after its mother had taken paracetamol and codeine is discussed. It is said to be difficult to accurately assess fatal drug concentrations through autopsy, due to postmortem changes in the cardiovascular system. Toxic levels of codeine are unlikely to be excreted in breast milk, it is believed, except in cases of abnormal opioid metabolism by the mother. Complicating factors are also addressed, such as the health status of the infant and whether the action of a sedative drug would normally induce sleep before a lethal dose was ingested.

The authors reflect on legislative proposals which have been developed which would increase people's access to over the counter medicines. They suggest that the risks of increasing access may outweigh the benefits. They argue that given the concerns that are associated with potential problems with over the counter medications it would be wise to avoid a rush to increase their availability.

Presents an editorial on the monitoring of drug treatments. Value of monitoring treatment to anticipate or detect adverse reactions to drugs before they become inevitable or irreversible; Monitoring tests which should be safe, simple, precise and validated; Actions to take in response to positive tests; Monitoring strategy.

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]

Context of the Article: An important forensic problem is whether the presence of a drug such as morphine caused or contributed to a death or was merely incidental. The reliance that can be based on postmortem drug concentrations remains controversial. To investigate this further we obtained antemortem and postmortem samples of individuals admitted to hospital who were receiving morphine and who died in hospital. Methods: Eleven subjects were recruited. Samples were sent for analysis for free and total morphine concentrations. Results: The median difference (postmortem – antemortem) free morphine concentration was 25.5 (range 0 to +126) µg/L, p <.01; the mean difference between postmortem and antemortem total morphine concentration was 34.5 (range −225 to 342) µg/L (not significant). Discussion: Our study supports previous investigators who note that there is an inconstant and sometimes tenuous relationship between ante- and postmortem morphine concentrations. [ABSTRACT FROM AUTHOR]

The clinical doses of antithrombotics—antiplatelet and anticoagulant agents—need to balance efficacy and safety. It is not clear from the published literature how the doses currently used in clinical practice have been derived from preclinical and clinical data. There are few large randomised controlled trials (RCTs) that compare outcomes with different doses vs placebo. For newer antithrombotics, RCT doses appear to have been chosen to maximise the probability of demonstrating noninferiority when compared to established agents such as warfarin or clopidogrel. Data from RCTs show that aspirin is an effective antithrombotic at doses below 75 mg daily, and that direct oral anticoagulants reduce the risk of stroke in patients with coronary disease at doses 1/4 of those recommended in atrial fibrillation. Lower doses than those currently recommended are safer and still maintain substantial efficacy. [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]

The authors ponder on the problems surrounding orphan drugs, or the drugs developed for life threatening or chronically debilitating rare disorders. They cite the aim of the orphan drug legislation in the U.S. and Europe, along with the unintended consequences of such legislation. They explain how prescribing expensive licensed drugs, despite the availability of cheaper ones, affects medical care costs. They also emphasize the significance of incentives to drug manufacturers.

Presents an editorial about regulating herbal medicines in England. Lack of evidence on the effectiveness of herbal medicine; Difficulty of judging whether such medicines are safe; Description of regulations in the United States for supplements, which is what herbal medicines are regarded as; Efforts of the European Union in regulating herbal products.

Discusses the medical concept of concordance, in which the physician and patient come together to make a decision regarding the prescribed medical treatment for the patient's condition. Importance of dialogue between a physician and patient in optimizing the potential benefits of medical care; Difficulty in assessing the risks and benefits in the taking of prescribed medicines; Behavioral aspects of taking prescribed medicines.

The author discusses whether the mefloquine drug should still be used for chemoprophylaxis by the British military personnel. Topics discussed include the three options for chemoprophylaxis against chloroquine resistant Plasmodium falciparum malaria, two forms of mefoquine-induced neuropsychiatric reaction, and nomination of a first-line treatment and reservation of another drug for second-line use.

The authors convey their thoughts on licensing and pricing of medicinal products in Great Britain. Topics discussed include the number of products recommended by the European Medicines Agency in 2014 for human use, supply of unlicensed medicines through special order manufacturers, and exclusion of cost, convenience, and operational needs by the Medicines and Healthcare Products Regulatory Agency as criteria of special need.

The authors discuss criminal prosecution of physicians that committed medical errors associated with patient mortality. They report increase in number of cases focusing on negligent acts of physicians from 1990 to 2005. They cite various factors which could bring change in the link between medicine and criminal law in England and Wales. Brief details about the implementation of the Corporate Manslaughter and Corporate Homicide Act of 2007 in Great Britain are also presented.

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]

A letter to the editor is presented in response to the article "How long should treatments be continued?," by J. C. Craig et al, published in the August 19, 2010 issue.

Aims: To report on a retrospective study of individual funding request (IFR) submissions from a large tertiary hospital and describe gaps in current mechanisms for funding of high‐cost medicines in England. Methods: Data on the number and outcome of IFR submissions submitted to commissioners between 2014/15 and 2018/19 was extracted from the electronic patient health record and a local high‐cost drug database. Results: In total, 230 IFRs were submitted: 112 to NHS England and 118 to a Clinical Commissioning Group (CCG). The decline rate for IFRs was 71% for NHS England and 34% for CCGs. Lack of exceptionality was the primary reason cited for declining IFRs submitted between 2016–18 (n = 42/45; 93%). Half of the patients whose IFR was declined received treatment funded through other routes, the majority (13/23; 57%) from internal hospital budget. This was governed via a local high‐cost drug panel. Positive clinical outcomes were observed in 50% (4/8) of patients who received NHS England IFR‐funded treatment, 54% (19/35) who received CCG IFR‐funded treatment and 91% (21/23) who were funded via other routes. Conclusion: The high rate of IFR decline signals inefficient use of resource expended in the IFR process. Gaps in access to high‐cost medicines remain for patients with rare and refractory disease requiring urgent treatment, largely due to the demand for exceptionality from NHS commissioners. Local mechanisms address this unmet need but have limitations. An outcomes‐based evaluation approach to commissioning and greater transparency of previous funding decisions by commissioners may improve efficiency and equity in the IFR system. [ABSTRACT FROM AUTHOR]

Direct‐acting oral anticoagulants (DOACs) are licensed for the prevention of thromboembolism in non‐valvular atrial fibrillation, amongst other indications. Prescribers use information derived from the summary of product characteristics which is based on the key trials supporting the DOAC's market authorisation. However, prescribers may not be aware of the limitations within these trials regarding underrepresentation of patient populations commonly encountered in clinical practice and how this may adversely impact them. This review highlights the gaps in the licensing evidence using four clinical vignettes that explore prescribing challenges in older adults, female patients, patients with obesity and patients from non‐Europid ethnic backgrounds. [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 nonadministration 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, 60763 (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]

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]