Medicines And Healthcare Products Regulatory Agency Research Articles

The association between GLP-1 receptor agonist and diabetic ketoacidosis in the FDA adverse event reporting system

Background and aimsIn 2019, the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom (UK) and food and drug administration (FDA) of the United States of America (US) suggested that the relationship between glucagon-like peptide-1 receptor agonists (GLP-1RA) and diabetic ketoacidosis (DKA) deserved attention. This study is aiming to assess the association between GLP-1RA and DKA/ketosis in the FDA Adverse Event Reporting System (FAERS) database. Methods and resultsUsing FAERS database, we firstly extract the number of DKA reports from the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019 and calculate proportional reporting ratios (PRRs). We then mined each FAERS file from 2004 Q1 to 2020 Q4 and obtained detailed information on DKA reports. From the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019, there are 1382 DKA cases (1491 ketosis cases) associated with GLP-1RA in the FAERS database. There was a slight disproportionate reporting of DKA associated with overall GLP-1RA (PRR 1.49, 95%CI 1.24–1.79, p < 0.001) after excluding the impact of SGLT2i, T1D and insulin. Any disproportionality disappeared after selecting the GLP-1RA combined with insulin for comparison. ConclusionsWhen GLP-1RA not combined with insulin, the disproportionality of DKA reports associated with GLP-1RA was observed. Our analysis mined the FAERS database to provide evidence and highlight the potential association between DKA adverse events and GLP-1RA therapy that clinicians tend to overlook.

Evaluation of estimated glomerular function (eGFR) versus creatinine clearance (CrCl) to predict acute kidney injury when using zoledronate for the treatment of osteoporosis.

Zoledronate is widely used for the treatment of osteoporosis. A potential side effect is acute kidney injury (AKI). Advice from the UK Medicines and Healthcare products Regulatory Agency (MHRA) in 2019 stated that CrCl and not estimated glomerular filtration rate (eGFR) should be used and that treatment should not be given if CrCl < 35ml/min. The objective of this study was to compare our current method of assessing renal function (eGFR) with the method proposed by the MHRA (CrCl) for predicting AKI after zoledronate infusions. The evaluation was performed at the Metabolic Bone Centre in Sheffield Teaching Hospitals, UK. Data on all the patients who had zoledronate from 1/09/2015 to 1/10/2020 were included. Data on 4405 patients were retrieved (total number of infusions 7660). Creatinine in the 14days post-infusion was available for a total of 969 infusions and AKI was observed within 14days following 45 infusions (4.6%). One patient died due to pneumonia. One patient needed continued haemodialysis. Severe AKI (threefold in creatinine and/or eGFR < 15ml/min/173 m2) was observed within 1year following 24 infusions. If the MHRA recommendations had been followed, 996 infusions with baseline CrCl < 35ml/min would not have been given. Of these, follow-up data on serum creatinine within 14days were available for 142 infusions, showing AKI in only four (2.8%). Logistic regression showed that both CrCl and eGFR were significant factors in predicting AKI within 14days, but that the current recommended cut-off of CrCl 35ml/min had poor sensitivity. Since eGFR is at least as good a predictor of AKI as CrCl, and permits the treatment of more patients at high fracture risk, we recommend that eGFR is used to determine renal function for zoledronate treatment. We suggest that the infusion is given over 30min in patients with eGFR < 50ml/min/1.73 m2.

UK general practice: Continuing to fail in the care of people with epilepsy?

PurposeTo review the standard of clinical care of people with epilepsy (PWE) attending UK general practice after epilepsy was removed from the Quality and Outcomes Framework (QOF) in 2014. MethodThe case notes of 324 people were reviewed against standards based on National Institute for Health and Care Excellence (NICE), Drug Safety Unit (DSU), and Medicines and Healthcare products Regulatory Agency (MHRA) guidelines. ResultsAnnual face-to-face review fell significantly (p = 0.021) after the removal of epilepsy from QOF in 2014. Clinical Commissioning Group (CCG) downloaded review rates fell significantly from 95% in 2010 to only 14% in 2016. One hundred and twenty seven (39%) people had seen their GP, and108 (33%) had not seen any doctor, in the past year. One hundred and seventy three (53%) were under specialist care. Forty nine percent not under specialist care had poor control. Two hundred and fifty four (78%) people were on ASM (Anti-Seizure Medication) associated with poor bone health, of these 41 (16%) were prescribed vitamin D. Fourteen women of childbearing age were taking sodium valproate, of whom only 5 (36%) had written confirmation of being counseled of the associated risks. Fifty six (17%) people were non-complaint with prescription collection, of which 66% had documented poor control. There was a discrepancy between actual face-to-face review rates and the review rates the CCG collected. ConclusionThis study reveals poor annual review rates for PWE in UK primary care, which have fallen further since the removal of epilepsy from QOF. Unmet needs persist for people with poorly controlled epilepsy not under specialist care, bone health, and the care of women of child bearing age. This study, along with previous work, brings into question the concept of shared care for PWE. Clinical Commissioning Groups should consider investing in the training and employment of GPwSIe (GP with Special Interest in epilepsy) and ENS (Epilepsy Nurse Specialists) to work in the community. The Government should examine re-introducing epilepsy back into QOF with measurable clinical targets and adequate remuneration.

Assessing the potential fire risk of laundered fabrics after contamination with emollients using ATR-FTIR spectroscopy and chemometrics

Since 2010, more than 50 UK fire deaths, have been reported as linked with emollients. This prompted the Medicines and Healthcare products Regulatory Agency (MHRA) to issue advice on their safer use in 2018. The advice was in response to concerns raised by the National Fire Chiefs Council, coroners’ reports, and flammability tests. The test results show a significant reduction in ignition time of fabrics contaminated with paraffin-based and paraffin-free skin care product residues. The MHRA report also included advice on washing clothing and bedding at high temperatures but warned this may not remove all emollient residues. This paper reports on new research on the removal of skin care products from clothing investigated by laundering contaminated 100% cotton fabric at 30, 40 and 60 °C using both biological and non-biological based detergents. As part of the experiment, non-contaminated (blank) napkin samples were included in the wash experiments to assess the possible transfer from fabrics contaminated with emollients to uncontaminated clean fabrics during washing. Washed and dried fabrics were analysed using Attenuated Total Reflectance, Fourier Transform Infrared (ATR-FTIR) spectroscopy and further interpreted via principal component analysis (PCA) and network analysis. Results suggest that the majority of the 6% white soft paraffin-based lotion and paraffin-free cream were removed at all temperatures. Residues of 21% paraffin-based cream (6% light paraffin/15% white soft paraffin) remain, and more residues persist of the 100% paraffin-based ointment (5% light paraffin/95% white soft paraffin) after washing at 30, 40 and 60 °C. The wash experiments show unequivocal transfer of the 100% ointment from the contaminated napkins to clean control napkins placed within washes at 30 °C. Furthermore, residues of the ointment were observed within the machine drum, and washing machine door seal, though this did not cause secondary transfer to subsequent wash experiments. There were no differences observed when using biological versus non-biological detergents, nor when employing a pre-wash treatment in the removal of residues of the 21% cream and 100% ointment. These results suggest that a single application of an emollient when soaked and dried into a fabric is not removed by a single wash at 30, 40 or 60 °C. Instead, the residue remains a persistent potential fire risk and, its high paraffin content presents an additional fire risk via contamination of other fabrics.

The UK’s emerging regulatory framework for point-of-care manufacture: insights from a workshop on advanced therapies

Point-of-care (POC) manufacture can be defined as the production of therapies in clinical settings or units close to hospitals and patients. This approach is becoming increasingly viable due to the emergence of flexible manufacturing technologies. Expecting an increase in this kind of production, the UK’s regulatory agency, the Medicines and Healthcare products Regulatory Agency (MHRA) is proposing a regulatory framework specifically designed for POC manufacture. To discuss the challenges of POC manufacture and the MHRA’s proposal, the EPSRC Future Targeted Healthcare Manufacturing Hub (FTHMH) organized a workshop drawing insights from specialists in cell and gene therapy manufacture. Through presentations and discussion roundtables, the workshop highlighted the challenges for the UK and other countries implementing POC manufacture. The workshop attendees stressed four main issues: quality control; standardization and equipment use; availability of qualified personnel; and the challenges to be met by hospitals participating in POC manufacture systems. This commentary provides a summary of the points discussed in this workshop.

Identification of different side effects between PARP inhibitors and their polypharmacological multi-target rationale.

The aim of this study was to determine the differences and potential mechanistic rationale for observed adverse drug reactions (ADRs) between four approved PARP inhibitors (PARPi). The Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card drug analysis profiles and NHS secondary care medicines database enabled the identification of suspected ADRs associated with the PARPi in the UK from launch to 2020. The polypharmacology of the PARPi were data-mined from several public data sources. The overall ADRs per 100 000 Rx identified across the four PARPi are statistically significant (χ2 test, P < .001). Rucaparib has the greatest relative suspected ADRs, which can be explained by its least clean kinome and physicochemical properties. The suspected gastrointestinal ADRs of rucaparib and niraparib can be ascribed to their kinase polypharmacology. Suspected blood and lymphatic system ADRs of PARPi can be linked to their high volume of distribution (Vd ). The thrombocytopenia rate of niraparib > rucaparib > olaparib tracked with the Vd trend. Hypertension is only associated with niraparib and could be explained by the therapeutically achievable inhibition of DYRK1A and/or transporters. Arrhythmia cases are potentially linked to the structural features of hERG ion-channel inhibition found in rucaparib and niraparib. Enhanced psychiatric/nervous disorders associated with niraparib can be interpreted from the diverse neurotransporter off-targets reported. Despite their similar mode of action, the differential polypharmacology of PARP inhibitors influences their ADR profile.

Vaccine‐induced Immune Thrombocytopenia and Thrombosis (VITT)

Vaccine‐induced Immune Thrombocytopenia and Thrombosis (VITT)

Renal Vein Thrombosis and Pulmonary Embolism Secondary to Vaccine-induced Thrombotic Thrombocytopenia (VITT).

The Medicines and Healthcare products Regulatory Agency (MHRA) of the UK has approved the use of three vaccines to combat COVID-19 (SARS-CoV-2). There have been rare reports of thrombosis after vaccination with the AstraZeneca vaccine. We present three cases of vaccine-induced thrombotic thrombocytopenia (VITT) in one UK district general hospital following administration of this vaccine. Two of the patients had asymptomatic pulmonary emboli, while the other is the first known case of both renal vein thrombosis and pulmonary embolism.LEARNING POINTSVaccine-induced thrombotic thrombocytopenia (VITT) can be associated with unusual and multiple sites of thrombosis.Clinicians should have a low threshold for requesting anti-PF4 antibody tests and imaging (especially pulmonary imaging) in thrombocytopenic patients after administration of the AstraZeneca vaccine.We describe a localised cluster of VITT despite its rarity according to current statistics, highlighting the need for an efficient data collection system to ensure the incidence of VITT is accurately reported.

Research on Beers Criteria and STOPP/START Criteria based on the FDA FAERS database.

Inappropriate medication criteria for the elderly have played an important role in ensuring the safety of medications for the elderly. Too few drugs included in the criteria cannot guarantee the safety of medication for the elderly. Too many drugs included in the criteria will result in less selective medication for the elderly. This paper uses real-world data to evaluate the relationship between antihypertensive drugs and falls, so as to provide references for experts and scholars to revise the criteria of potentially inappropriate medications for the elderly and clinical safe medication. We use the US Food and Drug Administration Adverse Event Reporting System (FDA FAERS) to evaluate the association between specific antihypertensive drugs in six categories (alpha-1 receptor blockers (α-1 blockers), calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-receptor blockers (β-blockers), and diuretics) and falls by data mining algorithms, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), Medicines and Healthcare Products Regulatory Agency (MHRA), and the empirical Bayes geometric mean (EBGM) and compared with the relevant drugs included in the Beers Criteria and STOPP/START Criteria. There are a total of 5,157,172 co-occurrences found in 973,447 reports aged 65years or older from 2016 to 2019 in the FDA FAERS database, and the number of co-occurrences of falls is 5917 for the six categories of 51 antihypertensive drugs. Four kinds of mining methods overlap detection of 12 kinds of positive signal drugs, none of which are not included in the Beers Criteria and 7 drugs are included in the STOPP/START Criteria; 1-3 kinds of mining methods overlap detection of positive signal drugs, a total of 12 kinds, and one drug is included in the Beers Criteria and 5 drugs are included in the STOPP/START Criteria; 22 drugs have fall adverse events, but no positive signal is detected, and 13 drugs are included in STOPP/START Criteria; and 5 drugs have no fall adverse events and 3 drugs are included in the STOPP/START Criteria. The FAERS database was used to confirm the potential connection between some antihypertensive drugs and fall adverse events through data mining algorithms. The Beers Criteria did not clearly indicate the antihypertensive drugs that caused falls, and the antihypertensive drugs included in the STOPP/START Criteria were too extensive and did not include β-blockers and diuretics. It is recommended that experts and scholars use real-world data (such as FAERS, EudraVigilance, WHO VigiBase, and so on) to further explore the relationship between specific antihypertensive drugs and falls in the elderly, so as to revise and improve the criteria for inappropriate medications for the elderly.

Kinetics of T-Cell Subset Reconstitution Following Bendamustine-Containing Therapy for Low-Grade Lymphoproliferative Disease; A Population Based Analysis

BackgroundThe efficacy of Bendamustine and Rituximab (BR) for indolent NHL (iNHL) has been demonstrated in 2 randomised studies (StiL NHL1 and BRIGHT), although combination therapy with monoclonal antibodies remains an off-label use. Increased toxicity was apparent in both bendamustine cohorts of the GALLIUM study, with 5% treatment-related mortality (TRM) versus 1.8% in the CHOP/CVP arms. Recently, the UK MHRA (Medicines and Healthcare products Regulatory Agency) issued notification of increased infection risks in the context of bendamustine combination therapy. Given these concerns we undertook an observational analysis of T-cell reconstitution and mortality following Bendamustine-based therapy within a large University hospital.MethodsPatients who received bendamustine for CLL or lymphoma between April 2012-Jan 2017 were identified from our electronic prescribing database. We evaluated clinical outcomes following treatment, and assessed absolute lymphocyte count (ALC), CD4, CD8, NK-cells and immunoglobulin levels over time.Results173 patients were identified, 171 (99%) received bendamustine combination therapy, 2 (1%) received monotherapy. The median age was 68 years (range 34-93). 71% had iNHL (follicular n=63, marginal zone n=34, LPL n=25), 22% had CLL whilst mantle, DLBCL and Hodgkin lymphoma accounted for 7% (n=13). The median number of previous therapy lines was 1 (0-7). Excluding CLL and overt leukaemic disease (32% of the cohort), the median ALC pre-bendamustine was 1.3x109/l (0.2-3.9x109/l) with a median nadir at 1 month post treatment of 0.5x109/l. After 12 months, 77% of this cohort had an ALC of ≥ 0.5 x109/l and 28% an ALC of ≥ 1.0 x109/l . 82 patients (47%) had immunoglobulin levels assessed within 3-12 months of bendamustine with a median IgG level of 5.2g/l (range 2-14.3). Of these 38 (46%) were <5g/l, and 15 (18%) were <3g/l.Given the potential unreliability of ALC in the context of iNHL and CLL and to better inform duration of antimicrobial prophylaxis, we evaluated T- lymphocyte recovery in more detail. Of the whole cohort, 27% (n=47) had undergone a full lymphocyte subset analysis by flow cytometry at least once following bendamustine-based treatment. The median number of lymphocyte subset analyses evaluated per patient was two (range 1-5) at time-points ranging from 1-40 months post-bendamustine.The median CD4 count in the first 6 months post bendamustine was 0.117 x109/L. 30 patients (65%) had at least one CD4 count <0.200 x109/L (200/ul), and these patients had an initial median CD4 count of 0.085 x109/L. We observed a marked delay in CD4 recovery for the whole cohort and those with initial post treatment CD4 count <0.200 x109/L, with median CD4 counts at 24 months of 0.198 x109/L and 0.124 x109/L respectively (table 1). NK-cell numbers on the same follow-up samples were also depleted, with 21% initially below the lower limit of normal, and although less profound reductions in absolute numbers were seen, recovery followed similar kinetics to CD4 cells. Interestingly, median CD8 counts were within normal range in the first 6 months post bendamustine treatment, with no clear change in absolute numbers over time (figure 1).For the whole cohort, 31 deaths were observed (18%), 11 due to progressive disease. Of the 20 non-lymphoma-related deaths, 10 were due to infection but only 4 (13%) occurred within 6 months of bendamustine. Of the remaining 6 deaths, all had received at least 1 subsequent line of treatment (including stem cell transplant in 3 cases). Of the remaining 10, 4 occurred within 12 months of bendamustine and were attributed to lung fibrosis, glioblastoma, gastric cancer and pulmonary embolism.ConclusionAmongst a population-based cohort of bendamustine-treated patients, we have demonstrated slow kinetics of T-cell reconstitution. The majority of patients experienced marked CD4 lymphopenia, with most failing to reconstitute >0.200 x109/L by 24 months post therapy. Similar but less profound reductions were seen in NK-cell numbers in addition to clinically significant reductions in IgG levels. Importantly, ALC did not correlate with the CD4 numbers and is unlikely to be a reliable indicator of T-cell recovery. These data may, at least in part, explain the TRM of bendamustine-based therapy and supports extended duration of antimicrobial prophylaxis against opportunistic infection, informed by CD4 recovery. [Display omitted] DisclosuresMcMillan:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel sponsorship. Bishton:Roche: Other: Travel Sponsorship. Fox:AbbVie: Consultancy, Honoraria, Other: Travel Sponsorship, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Sponsorship, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Sponsorship, Speakers Bureau.

COVID-19 Infection and Subsequent Psychiatric Morbidity, Sleep Problems and Fatigue: Analysis of an English Primary Care Cohort of 226,521 Positive Patients

Background: While some people who have had COVID-19 experience fatigue and sleep problems long after the acute phase of the illness, the proportion affected and the length of time symptoms persist remains uncertain. There are also concerns of an increase in psychiatric illness following COVID-19 infection; however evidence of a direct effect is inconclusive.Methods: This was a retrospective cohort study using a UK primary care registry. Adults with a positive PCR COVID-19 test between 1st February and 8th December 2020 were matched to controls based on gender, general practice and year of birth. Separate matched cohorts were assembled for those with and without prior recorded mental illness, fatigue and sleep problems. Cox proportional hazard models estimated the association between a COVID-19 positive test and subsequent psychiatric morbidity (depression, anxiety, psychosis, or self-harm), sleep problems, fatigue or psychotropic prescribing, adjusted for comorbidities, ethnicity, smoking status and BMI. Interaction with age and area-level deprivation were tested for. Additional cohorts examined those with a negative COVID-19 test and those with influenza symptoms (and a negative COVID-19 test).Results: After adjusting for observed confounders, there was an association between testing positive for COVID-19 (n=232,780) and almost all markers of psychiatric morbidity, psychotropic prescribing, fatigue and sleep problems. The adjusted hazard ratio for any indicator of incident psychiatric morbidity was 1.75 (95% CI: 1.56-1.96) and for new psychotropic prescribing 2.17 (95% CI: 2.00-2.35). However, there was an increased risk of incident psychiatric morbidity for those with a negative COVID-19 test of similar magnitude and a larger increase associated with having influenza.Interpretation: Whilst COVID-19 infection appears to be causing sleep problems and fatigue, there is less clear evidence of an effect on subsequent psychiatric morbidity.Funding Information: This work was funded by the NIHR Greater Manchester Patient Safety Translational Research Centre.Declaration of Interests: TC received ad hoc payments for conducting workshops on evidence-based treatments for persistent physical symptoms. TC has received grants from NIHR programme grants, HTA, RfPB, Guy’s and St Thomas Charity, King’s Challenge Fund. Personal financial interests: TC is the author of several self-help books on chronic fatigue and received royalties in the past. TC received expenses for workshops on evidence-based treatments for persistent physical symptoms for BABCP and IAPT services (travel and accommodation). None of the other authors have any conflicts of interest.Ethics Approval Statement: This study was conducted using data from the CPRD obtained under licence from the UK Medicines and Healthcare products Regulatory Agency (MHRA). The data are provided by patients and collected by the NHS as part of their care and support. The study was approved by the Independent Scientific Advisory Committee for CPRD research (20_094R2).

Compliance to completion of sodium valproate annual risk acknowledgement form among women of child-bearing age prescribed sodium valproate in the intellectual disability (ID) services of an NHS trust

AimsTo determine the proportion of women of child-bearing age prescribed SV who have the SV ARF filled.BackgroundIn 2018, the Medicines and Healthcare products Regulatory Agency (MHRA) gave guidance regarding Sodium Valproate (SV) prescription. It acknowledged the significant risk of birth defects and developmental disorders in women of child-bearing age prescribed SV.Consequently, the MHRA recommendation is that SV must not be used in females of child-bearing age unless: conditions of pregnancy prevention programme are met; other treatments are ineffective or not tolerated; and evidence of discussion of risks with patient or carer and annual review of the risks are documented. The evidences of the above criteria are expected to be documented in an Annual Risk Acknowledgement Form (ARF).MethodRetrospective study involving systematic search of Trust database to identify women with ID, aged 16–50 years prescribed SV from 2018 to 2019.Result18 of 28 patients had ARF filled, a 64% compliance.The main indications for SV prescription were epilepsy; challenging behaviour; and mood stabilization.The distribution showed neurology and psychiatrist led prescription initiation equally distributed at 50%.The ARF compliance was higher in the neurology group (93%) compared to 36% in psychiatrist group.A review across the 5 ID teams (A,B,C,D and E) of the trust shows variable compliance to ARF compliance (17%,81%,100%,60%,0% respectively) with teams having higher proportion of neurology led SV prescription initiation also having higher proportion of ARF completion compliance (0%,55%,80%,80%,0% respectively).ConclusionConclusion / RecommendationARF compliance is below standard at 64%.Despite the SV prescription being equally distributed between neurology led and psychiatry led, patients whose prescription of SV is neurology led (prescription indication as epilepsy) had better ARF compliance outcome (93%) compared with patients whose prescription is psychiatry led (prescription indication as challenging behaviour or mood stabilization) with 36% ARF compliance.Organizational difference with dedicated epilepsy nurse in the ID service means patients with epilepsy had reviews of medication and compliance to MHRA guidance in completing the ARF.There is need to increase doctors’ awareness to review ARF status during patients’ appointment. Information Technology design to flag up out of date ARF may be helpful.The review of ARF may also flag up consideration of other alternatives: behavioural, psychological, functional and environmental interventions as well as alternative medications like Risperidone for challenging behaviours and other mood stabilizing options. This will minimize SV prescription, which is the original goal of the MHRA guidance.

Audit on clozapine dose and plasma level correlation for patients with chronic treatment-resistant psychosis

AimsClozapine is associated with a risk of severe adverse events for which there are current monitoring systems are in place; however, there are no established regimens for monitoring of clozapine plasma levels. Recent Medicines and Healthcare products Regulatory Agency (MHRA) guidance advises clozapine levels should be monitored in certain clinical situations where toxicity may be suspected. This audit aimed to evaluate current practice of clozapine level monitoring within one Local Mental Health Team (LMHT).MethodElectronic (RiO) records of 41 patients (33 male, 8 female; aged from 27 to 76 years; mean age 45 years) registered to the ZTAS system within the Nottingham City Central LMHT were reviewed. 46% had been on clozapine for over 16 years. 73.3% of patients were within clusters 12 and 13; 25.4% of patients were in cluster 11, with one patient in cluster 8. Dates of clozapine plasma level tests for each patient between 2006 and 2020 were found on the electronic NoTIS system, along with clozapine, norclozapine and total clozapine levels. Concurrent clozapine dose and regimens were obtained from pharmacy records from 2018 onwards.Result273 clozapine plasma levels were conducted between 2006 and 2020. The average interval between levels taken was 10 months, 2 weeks but had a wide range, the shortest interval being 2 days, the longest being 13 years. 88 levels taken were &gt;600 ug/L, suggesting increased toxicity risk. 108 levels were &lt;350 ug/L, suggesting possible sub-optimal dosing or non-compliance. Statistical tests on correlation coefficient, although statistically non-significant (R = 0.37), showed a positive trend between total clozapine dose and the plasma level between all 3 parameters (i.e. clozapine, norclozapine and total clozapine).ConclusionThere does not appear to be any routine plasma clozapine level monitoring throughout the LMHT with an average interval between tests of 10 months. There was a non-significant but positive trend between total daily dose of clozapine and clozapine level. 32% of clozapine levels returned were higher than the recommended level. We would recommend as suggested in the guidelines from MHRA, clozapine plasma levels should be monitored in certain clinical situations with increased toxicity risk. Trough levels should be taken with records of time of previous dose taken. Limitations of this study included a small sample size (41 patients) with data collection reliant on electronic systems. It was unclear if these results represent trough levels, making values difficult to interpret. Multifactorial impact on clozapine metabolism causes wide patient variability in plasma levels.

Orofacial adverse effects of COVID-19 vaccines exist but are rare.

Data sources The US Food and Drug Administration (FDA), Health Canada, European Medicines Agency (EMA)/European Commission and UK's Medicines and Healthcare products Regulatory Agency (MHRA).Study selection Product monographs, product information and consumer medicine information for the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines.Data extraction and synthesis Reported side/adverse/undesirable effects concerning the orofacial region were extracted and tabulated.Results There were rare reports of adverse events affecting the orofacial region for both vaccines in their pertaining documents, including acute peripheral facial paralysis (Bell's palsy), facial swelling and swelling of the lips, face or tongue associated with anaphylaxis. There was heterogeneity in the acknowledgement of vaccine-related adverse events in North America compared with Europe.Conclusions There are rare reports of orofacial adverse effects of two mRNA-based COVID-19 vaccines in their documents; however, there are inconsistencies in the description of these adverse effects in different countries.

A registry review of 2532 catheter ablations for atrial fibrillation using active thermal protection

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Dr Leung has received research support from Attune Medical (Chicago, IL). Dr Gallagher has received research funding from Attune Medical (Chicago, IL). Background Thermal injury to the oesophagus causes a spectrum of adverse effects after ablation for atrial fibrillation (AF); at the most severe end, atrio-oesophageal fistula carries a high mortality rate. Controlled active thermal protection in the oesophagus during ablation is the most promising method of oesophageal protection. Randomized evidence from the IMPACT trial (NCT03819946) showed an 83.4% reduction in endoscopically detected oesophageal lesions compared to standard care when an oesophageal temperature control device was used to control the local temperature. The IMPACT patients who were randomized to the use of the device had no adverse event related to its use. Real world registry data on applications of this device have not previously been available. Purpose To determine the safety of an oesophageal temperature control device by review of real-world registry data on its clinical use and any reported device-related adverse events. Methods We reviewed the following databases for any reported oesophageal temperature control device-related complications: The United States Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE), FDA Medical and Radiation Emitting Device Recalls, the Medicines and Healthcare products Regulatory Agency (MHRA) Medical Device Alerts and SwissMedic records of Field Safety Corrective Actions (FSCA). An internal registry (post-marketing follow up) database maintained by the manufacturer of the device was used to quantify the number used for each indication. Reported events were reviewed and catalogued for description and identification of any events related to its use in the cardiac electrophysiology lab. The IMPACT study patients were reviewed for any device-related events. Results Of the 13, 284 oesophageal temperature control devices used, 2532 were recorded as having been used for the purpose of oesophageal protection during catheter ablation for AF. A total of 5 events associated with the device were identified, all from the MAUDE database. Three were from 2017, one from 2018, and one from 2019. All involved its use in critical care or trauma patients and were related to user error or contraindicated patient selection; none resulted in serious harm to the patient. No adverse events occurred related to its use in the cardiac electrophysiology lab. No case of clinically significant oesophageal injury was reported in a patient who had been protected by the oesophageal temperature control device. Conclusions Real world registry data has shown no adverse events reported to date in over 2500 uses of an oesophageal temperature control device in the cardiac electrophysiology lab, for the purpose of active thermal protection. This data supports the randomized trial evidence of its clinical effectiveness. Abstract Figure. Oesophageal active thermal protection

A Novel Fluorescent c-Met Targeted Imaging Agent for Intra-Operative Colonic Tumour Mapping: Translation from the Laboratory into a Clinical Trial

Background: Curative resection of colon cancer requires accurate intraoperative identification of tumour margins and lymph node (LN) burden. The c-Met protein is important for cell differentiation and migration and is overexpressed in many gastrointestinal cancers. We explored EMI-137, a novel c-Met targeting fluorescent probe, for application in fluorescence-guided colon surgery, in HT-29 colorectal cancer (CRC) cell line and an in vivo murine model. This informed a first-in-man clinical trial of EMI-137. Methods: HT-29 cells were used as a representative CRC model. SiRNA was used to demonstrate the specificity of EMI-137 for c-Met. A HT-29 CRC xenograft model was developed in female BALB/c mice. Tumours were cultured for 14 days to 10mm diameter. EMI-137 (0.18mg/kg) was injected into tail veins and biodistribution analysed through in vivo fluorescent imaging. Nine patients, aged 67-77 years, received a single intravenous dose of EMI-137 (0.13mg/kg), 1-3 hours before laparoscopic-assisted colon cancer resection surgery (NCT03360461). Tumour and LN fluorescence was assessed with a modified Karl Storz® laparoscope. Immunohistochemistry with a monoclonal antibody analysed c-Met expression in eight resected samples. Findings: c-Met expression in HT-29 cells was effectively silenced and imaged with EMI-137. Strong EMI-137 uptake in tumour xenografts was observed for up to 6 hours post-administration. At clinical trial, no serious adverse events related to EMI-137 were reported. Marked background fluorescence was observed in all trial participants, 4/9 showed an increase in tumour fluorescence over background; 5/9 had histological LN metastases; no fluorescent LN were detected intraoperatively. All primary tumours (8/8) and malignant LN (15/15) exhibited moderate to high c-Met protein expression. Interpretation: EMI-137, binds specifically to the human c-Met transmembrane protein, is safe in patients and with further refinement, shows potential for long-term application in fluorescence-guided colon surgery. Trial Registration: The trial was registered with ClinicalTrials.gov identifier NCT03360461. Funding: Research was supported by internal University of Leeds funding. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: Ethical approval was granted by the Yorkshire and Humber Leeds West Research and Ethics Committee (Ref 17/YH/0263), on 19th October 2017 and Regulatory approval was granted by the Medicines and Healthcare products Regulatory Agency (MHRA), under The Medicines for Human Use (Clinical Trials) regulations on 29th August 2017.

Severe allergic reactions after COVID-19 vaccination with the Pfizer/BioNTech vaccine in Great Britain and USA: Position statement of the German Allergy Societies: Medical Association of German Allergologists (AeDA), German Society for Allergology and Clinical Immunology (DGAKI) and Society for Pediatric Allergology and Environmental Medicine (GPA).

SummaryTwo employees of the National Health Service (NHS) in England developed severe allergic reactions following administration of BNT162b2 vaccine against COVID-19 (coronavirus disease 2019). The British SmPC for the BNT162b2 vaccine already includes reference to a contraindication for use in individuals who have had an allergic reaction to the vaccine or any of its components. As a precautionary measure, the Medicines and Healthcare products Regulatory Agency (MHRA) has issued interim guidance to the NHS not to vaccinate in principle in “patients with severe allergies”. Allergic reactions to vaccines are very rare, but vaccine components are known to cause allergic reactions. BNT162b2 is a vaccine based on an mRNA embedded in lipid nanoparticles and blended with other substances to enable its transport into the cells. In the pivotal phase III clinical trial, the BNT162b2 vaccine was generally well tolerated, but this large clinical trial, used to support vaccine approval by the MHRA and US Food and Drug Administration, excluded individuals with a “history of a severe adverse reaction related to the vaccine and/or a severe allergic reaction (e.g., anaphylaxis) to a component of the study medication”. Vaccines are recognized as one of the most effective public health interventions. This repeated administration of a foreign protein (antigen) necessitates a careful allergological history before each application and diagnostic clarification and a risk–benefit assessment before each injection. Severe allergic reactions to vaccines are rare but can be life-threatening, and it is prudent to raise awareness of this hazard among vaccination teams and to take adequate precautions while more experience is gained with this new vaccine.

Valproate use in women aged 15-44 years: an observational study in general practice.

BackgroundValproate is a known teratogen. In April 2018, the Medicines and Healthcare products Regulatory Agency (MHRA) restricted its use in women and banned use in pregnancy, except for epilepsy with no other effective treatment. To date, there is limited information on valproate prescribing within primary care.AimTo characterise valproate prescribing to women of childbearing age, recorded advice or GP prescribed contraception, and recorded pregnancies.Design & settingA cross-sectional study of patients from all 141 general practices across three clinical commissioning groups (CCGs) in East London.MethodWomen aged 15–44 years prescribed valproate between 1 October 2017 and 1 January 2020 were included. Exclusion criteria were early menopause, sterilisation procedures, or hysterectomy. Pseudonymised data on valproate indication, pregnancy, pre-conception, and contraception advice were retrospectively extracted from general practice consultation data. Data were analysed by quarter using univariate statistics.ResultsOf the total 1 042 463 registered patients, 344 women aged 15–44 years were prescribed valproate during the study period; 14 were excluded. There were 10 pregnancies during possible valproate exposure; one was terminated. During the study period, the number of women prescribed valproate significantly decreased (P = 0.003). The pregnancy rate decreased from 9.9/1000 on valproate before the MHRA April 2018 warning, to an average of 2.8/1000 afterwards. Recorded pre-conception and contraception advice increased by 79%, from 24% to 43%, of women prescribed valproate.ConclusionWith continued pregnancies in women aged 15–44 years prescribed valproate, patient education and foetal outcomes remain ongoing concerns. Further improvements are needed to ensure women make informed reproductive choices and safeguard future pregnancies from valproate exposure.

Regulation and validation of smartphone applications in plastic surgery: It's the Wild West out there

Background and purposeThe use of smartphone applications is ubiquitous within healthcare. Over recent years there have been multiple applications developed within the field of plastic surgery. In the UK, applications with a medical purpose should be registered with the Medicines and Healthcare products Regulatory Authority (MHRA) as a medical device. The aim of this study was to evaluate plastic surgery specific smartphone applications designed for healthcare professional usage, and determine what proportion meet the criteria of a medical device and are suitably certified. MethodsA systematic review of the Apple and Google Play App stores was carried out using search terms relevant to plastic surgery. Data was extracted from the app store listing, developer website and the contents of each application. Each application was evaluated against the criteria given by the MHRA to determine whether it constituted a medical device. Results215 applications for plastic surgery healthcare professionals were identified, of which 22 met the definition of a medical device. Only 14% (n = 3) of these applications were appropriately certified, 14% (n = 3) were validated in peer-reviewed literature and 45% (n = 10) had documented medical professional involvement. ConclusionMost applications with a medical purpose were not certified as a medical device, had not been validated in any peer-reviewed research, and did not have any documented involvement of medical professionals. The potential consequences of such applications operating incorrectly are stark and represent a risk to patient safety. Usage of multiple applications in a single patient encounter may compound error and safety of clinical care.

Key facts about the COVID-19 vaccination programme in the UK

Key facts about the COVID-19 vaccination programme in the UK