Communicating post-market safety risks of medicines with regulatory safety advisories: an international comparison of policy and perceptions

Background Information about the safety of medicines often emerges after approval. Medicines’ regulators use post-market safety advisories to communicate potential new harms. Advisories can influence medicines use, helping users to weigh benefits and harms. This thesis compared regulatory policy and outcomes for post-market safety communication in Australia, Canada, the United Kingdom (as part of the European Union) and the United States (US). Methods The four regulators were compared using: • A regulatory policy analysis. • An in-depth case study of safety communications for SGLT2 inhibitors (2012-2018). • A content analysis of safety advisories issued for new drugs approved in Australia 2010-2016. • Qualitative interviews exploring prescriber awareness and use of medicines safety information (Boston and Australia). Results Differences in regulatory policy among the European Medicines Agency, the US Food and Drug Administration, Health Canada, and the Therapeutic Goods Administration (TGA) included: their legislated authority for safety advisories, transparency, and interactions with pharmaceutical industry. SGLT2 inhibitor safety advice differed among regulators in number, timing, and strength. TGA advisories were issued for 20.5% of 73 safety concerns communicated by other regulators, for new drugs approved in Australia (2010-2016). Differences were not explained by the seriousness of safety concerns. Prescribers’ awareness of regulatory safety advisories was relatively low, particularly in Australia. While respecting regulators’ institutional authority, regulatory warnings may lack clinical authority. Conclusions There are considerable differences amongst the EMA, FDA, Health Canada and the TGA in policy and use of post-market safety advisories. Recommendations for improving safety and policy are discussed

Media coverage of drug regulatory agencies' safety advisories: a case study of citalopram and denosumab

AIMS: Drug regulators issue safety advisories to warn clinicians and the public about new evidence of harmful effects of medicines. It is unclear how often these messages are covered by the media. Our aim was to analyse the extent of media coverage of two medicines that were subject to safety advisories from 2007 to 2016 in Australia, Canada, the United Kingdom and the United States. METHODS: Two medicines widely used to treat mental health or physical conditions were selected: citalopram and denosumab. Media reports were identified by searching LexisNexis and Factiva. Reports were included if they stated at least one health benefit or harm. A content analysis of the reports was conducted. RESULTS: In total, 195 media reports on citalopram and 239 on denosumab were included. For citalopram, 43.1% (84/195) of the reports mentioned benefits, 85.6% (167/195) mentioned harms and 9.7% (19/195) mentioned the harm described in the advisories (cardiac arrhythmia). For denosumab, 94.1% (225/239) of the reports mentioned benefits and 39.7% (95/239) mentioned harms. The harms described in the advisories were rarely mentioned: 10.9% (26/239) of the reports mentioned osteonecrosis and ≤5% mentioned any of the other harms (atypical fractures, hypocalcaemia, serious infections and dermatologic reactions). CONCLUSIONS: We found limited media coverage of the harms highlighted in safety advisories. Almost two‐thirds of the media stories on denosumab did not include any information about harms, despite the many advisories during this time frame. Citalopram coverage covered harms more often but rarely mentioned cardiac arrhythmias. These findings raise questions about how to better ensure that regulatory risk communications reach the general public

Mix of methods is needed to identify adverse events in general practice: A prospective observational study

Contains fulltext : 69425.pdf ( ) (Open Access)BACKGROUND: The validity and usefulness of incident reporting and other methods for identifying adverse events remains unclear. This study aimed to compare five methods in general practice. METHODS: In a prospective observational study, with five general practitioners, five methods were applied and compared. The five methods were physician reported adverse events, pharmacist reported adverse events, patients' experiences of adverse events, assessment of a random sample of medical records, and assessment of all deceased patients. RESULTS: A total of 68 events were identified using these methods. The patient survey accounted for the highest number of events and the pharmacist reports for the lowest number. No overlap between the methods was detected. The patient survey accounted for the highest number of events and the pharmacist reports for the lowest number. CONCLUSION: A mix of methods is needed to identify adverse events in general practice

Classification of patient-safety incidents in primary care

Primary care lags behind secondary care in the reporting of, and learning from, incidents that put patient safety at risk. In primary care, there is no universally agreed approach to classifying the severity of harm arising from such patient-safety incidents. This lack of an agreed approach limits learning that could lead to the prevention of injury to patients. In a review of research on patient safety in primary care, we identified 21 existing approaches to the classification of harm severity. Using the World Health Organization's (WHO's) International Classification for Patient Safety as a reference, we undertook a framework analysis of these approaches. We then developed a new system for the classification of harm severity. To assess and classify harm, most existing approaches use measures of symptom duration (11/21), symptom severity (11/21) and/or the level of intervention required to manage the harm (14/21). However, few of these approaches account for the deleterious effects of hospitalization or the psychological stress that may be experienced by patients and/or their relatives. The new classification system we developed builds on WHO's International Classification for Patient Safety and takes account not only of hospitalization and psychological stress but also of so-called near misses and uncertain outcomes. The constructs we have outlined have the potential to be applied internationally, across primary-care settings, to improve both the detection and prevention of incidents that cause the most severe harm to patients

A review of significant events analysed in general practice: implications for the quality and safety of patient care

<p>Abstract</p> <p>Background</p> <p>Significant event analysis (SEA) is promoted as a team-based approach to enhancing patient safety through reflective learning. Evidence of SEA participation is required for appraisal and contractual purposes in UK general practice. A voluntary educational model in the west of Scotland enables general practitioners (GPs) and doctors-in-training to submit SEA reports for feedback from trained peers. We reviewed reports to identify the range of safety issues analysed, learning needs raised and actions taken by GP teams.</p> <p>Method</p> <p>Content analysis of SEA reports submitted in an 18 month period between 2005 and 2007.</p> <p>Results</p> <p>191 SEA reports were reviewed. 48 described patient harm (25.1%). A further 109 reports (57.1%) outlined circumstances that had the potential to cause patient harm. Individual 'error' was cited as the most common reason for event occurrence (32.5%). Learning opportunities were identified in 182 reports (95.3%) but were often non-specific professional issues not shared with the wider practice team. 154 SEA reports (80.1%) described actions taken to improve practice systems or professional behaviour. However, non-medical staff were less likely to be involved in the changes resulting from event analyses describing patient harm (p < 0.05)</p> <p>Conclusion</p> <p>The study provides some evidence of the potential of SEA to improve healthcare quality and safety. If applied rigorously, GP teams and doctors in training can use the technique to investigate and learn from a wide variety of quality issues including those resulting in patient harm. This leads to reported change but it is unclear if such improvement is sustained.</p

What do family physicians consider an error? A comparison of definitions and physician perception

BACKGROUND: Physicians are being asked to report errors from primary care, but little is known about how they apply the term "error." This study qualitatively assesses the relationship between the variety of error definitions found in the medical literature and physicians' assessments of whether an error occurred in a series of clinical scenarios. METHODS: A systematic literature review and pilot survey results were analyzed qualitatively to search for insights into what may affect the use of the term error. The National Library of Medicine was systematically searched for medical error definitions. Survey participants were a random sample of active members of the American Academy of Family Physicians (AAFP) and a selected sample of family physician patient safety "experts." A survey consisting of 5 clinical scenarios with problems (wrong test performed, abnormal result not followed-up, abnormal result overlooked, blood tube broken and missing scan results) was sent by mail to AAFP members and by e-mail to the experts. Physicians were asked to judge if an error occurred. A qualitative analysis was performed via "immersion and crystallization" of emergent insights from the collected data. RESULTS: While one definition, that originated by James Reason, predominated the literature search, we found 25 different definitions for error in the medical literature. Surveys were returned by 28.5% of 1000 AAFP members and 92% of 25 experts. Of the 5 scenarios, 100% felt overlooking an abnormal result was an error. For other scenarios there was less agreement (experts and AAFP members, respectively agreeing an error occurred): 100 and 87% when the wrong test was performed, 96 and 87% when an abnormal test was not followed up, 74 and 62% when scan results were not available during a patient visit, and 57 and 47% when a blood tube was broken. Through qualitative analysis, we found that three areas may affect how physicians make decisions about error: the process that occurred vs. the outcome that occurred, rare vs. common occurrences and system vs. individual responsibility CONCLUSION: There is a lack of consensus about what constitutes an error both in the medical literature and in decision making by family physicians. These potential areas of confusion need further study

Comparison of glucosamine sulfate and a polyherbal supplement for the relief of osteoarthritis of the knee: a randomized controlled trial [ISRCTN25438351]

<p>Abstract</p> <p>Background</p> <p>The efficacy and safety of a dietary supplement derived from South American botanicals was compared to glucosamine sulfate in osteoarthritis subjects in a Mumbai-based multi-center, randomized, double-blind study.</p> <p>Methods</p> <p>Subjects (n = 95) were screened and randomized to receive glucosamine sulfate (n = 47, 1500 mg/day) or reparagen (n = 48, 1800 mg/day), a polyherbal consisting of 300 mg of vincaria (<it>Uncaria guianensis</it>) and 1500 mg of RNI 249 (<it>Lepidium meyenii</it>) administered orally, twice daily. Primary efficacy variable was response rate based on a 20% improvement in WOMAC pain scores. Additional outcomes were WOMAC scores for pain, stiffness and function, visual analog score (VAS) for pain, with assessments at 1, 2, 4, 6 and 8 weeks. Tolerability, investigator and subject global assessments and rescue medication consumption (paracetamol) were measured together with safety assessments including vital signs and laboratory based assays.</p> <p>Results</p> <p>Subject randomization was effective: age, gender and disease status distribution was similar in both groups. The response rates (20% reduction in WOMAC pain) were substantial for both glucosamine (89%) and reparagen (94%) and supported by investigator and subject assessments. Using related criteria response rates to reparagen were favorable when compared to glucosamine. Compared to baseline both treatments showed significant benefits in WOMAC and VAS outcomes within one week (P < 0.05), with a similar, progressive improvement over the course of the 8 week treatment protocol (45–62% reduction in WOMAC or VAS scores). Tolerability was excellent, no serious adverse events were noted and safety parameters were unchanged. Rescue medication use was significantly lower in the reparagen group (p < 0.01) at each assessment period. Serum IGF-1 levels were unaltered by treatments.</p> <p>Conclusion</p> <p>Both reparagen and glucosamine sulfate produced substantial improvements in pain, stiffness and function in subjects with osteoarthritis. Response rates were high and the safety profile was excellent, with significantly less rescue medication use with reparagen. Reparagen represents a new natural productive alternative in the management of joint health.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN25438351.</p

Characterising the nature of primary care patient safety incident reports in the England and Wales National Reporting and Learning System: a mixed-methods agenda-setting study for general practice

Background There is an emerging interest in the inadvertent harm caused to patients by the provision of primary health-care services. To date (up to 2015), there has been limited research interest and few policy directives focused on patient safety in primary care. In 2003, a major investment was made in the National Reporting and Learning System to better understand patient safety incidents occurring in England and Wales. This is now the largest repository of patient safety incidents in the world. Over 40,000 safety incident reports have arisen from general practice. These have never been systematically analysed, and a key challenge to exploiting these data has been the largely unstructured, free-text data. Aims To characterise the nature and range of incidents reported from general practice in England and Wales (2005–13) in order to identify the most frequent and most harmful patient safety incidents, and relevant contributory issues, to inform recommendations for improving the safety of primary care provision in key strategic areas. Methods We undertook a cross-sectional mixed-methods evaluation of general practice patient safety incident reports. We developed our own classification (coding) system using an iterative approach to describe the incident, contributory factors and incident outcomes. Exploratory data analysis methods with subsequent thematic analysis was undertaken to identify the most harmful and most frequent incident types, and the underlying contributory themes. The study team discussed quantitative and qualitative analyses, and vignette examples, to propose recommendations for practice. Main findings We have identified considerable variation in reporting culture across England and Wales between organisations. Two-thirds of all reports did not describe explicit reasons about why an incident occurred. Diagnosis- and assessment-related incidents described the highest proportion of harm to patients; over three-quarters of these reports (79%) described a harmful outcome, and half of the total reports described serious harm or death (n = 366, 50%). Nine hundred and ninety-six reports described serious harm or death of a patient. Four main contributory themes underpinned serious harm- and death-related incidents: (1) communication errors in the referral and discharge of patients; (2) physician decision-making; (3) unfamiliar symptom presentation and inadequate administration delaying cancer diagnoses; and (4) delayed management or mismanagement following failures to recognise signs of clinical (medical, surgical and mental health) deterioration. Conclusions Although there are recognised limitations of safety-reporting system data, this study has generated hypotheses, through an inductive process, that now require development and testing through future research and improvement efforts in clinical practice. Cross-cutting priority recommendations include maximising opportunities to learn from patient safety incidents; building information technology infrastructure to enable details of all health-care encounters to be recorded in one system; developing and testing methods to identify and manage vulnerable patients at risk of deterioration, unscheduled hospital admission or readmission following discharge from hospital; and identifying ways patients, parents and carers can help prevent safety incidents. Further work must now involve a wider characterisation of reports contributed by the rest of the primary care disciplines (pharmacy, midwifery, health visiting, nursing and dentistry), include scoping reviews to identify interventions and improvement initiatives that address priority recommendations, and continue to advance the methods used to generate learning from safety reports

DESIGN AND TESTING OF MULTIPLIER CIRCUIT USING BIST FOR FPGA

The intricacies of IC (Integrated circuits) are increasing at a swift pace, Thus testing these ICs for erogenous faults has become very important. BIST is very popular testing mechanism which involves the design of test circuitry around a system that automatically tests the system by applying certain test stimulus and observing the system response generated due to the stimulus of the applied testing patterns. In BIST, the framework for testing the circuit is integrated in the system hardware, As a result the testing process becomes fast and cheaper than using ATE (Automatic test Equipment). Multipliers are basic building blocks of electronic design, they are extensively used in processors, microcontrollers, computers etc for signal processing. The self testing ability of a multiplier is an improvement compared to a basic multiplier design. This feature enables on-field testing of the multipliers without the use of costly ATEs. The BIST (built-in-self-test) functionality gives a brief analysis of the hardware faults that may be present in the multiplier. This paper puts forward a implementation of a multiplier with BIST functionality. Using BIST the multiplier is checked for various stuck at faults. Xilinx Vivado tool is used for modeling of this multiplier. For the design of self-test circuit, TPG (Test Pattern Generator) is used