Medicines And Healthcare Products Regulatory Agency Research Articles

The regulatory, evaluation, pricing and reimbursement pathway for medicines in the UK: combining innovation and access

The United Kingdom has universal healthcare systems, the National Health System (NHS), in its four nations, with healthcare services provided free of charge at the point of delivery. Approximately 10.5% of the UK population has voluntary supplementary private health insurance. While the provision of inpatient medicines is free of charge, medicines provided in the outpatient setting have a dispensing fee in some of the nations, such as the case of England (co-payment). The UK marketing authorisation process is called product licensing and is overseen by the Medicines and Healthcare Products Regulatory Agency (MHRA). There are different licensing routes based on the intended market for launch. MHRA also offers early access schemes and pathways for products targeting unmet medical needs and promising technologies, that aim to accelerate and facilitate market and patient access to products in the UK. These schemes include the option for companies to engage early with regulators and other system partners such as health technology assessment (HTA) agencies. As soon as the technology is authorised, it is available at a list price. Prices for medicines are regulated in legislation and in schemes agreed between the industry association and the Department of Health and Social Care (DHSC). The prices for the NHS are negotiated between the government and the companies. Routine funding decisions in the NHS are guided by HTA evaluations informed by agencies such as the National Institute for Health and Care Excellence (NICE) in England, the Scottish Medicines Consortium (SMC) in Scotland, and the All Wales Medicines Strategy Group (AWMSG) in Wales. Many medicines and other technologies are subject to price negotiations in the NHS, sometimes with confidential price agreements. The NHS in England is legally mandated to routinely fund technologies recommended by NICE that have been evaluated by some of its programmes. The other UK nations have similar arrangements or recognise decisions made in England. The role and contribution of NICE and other HTA agencies in ensuring value for money and evidence-based decision making is well recognised worldwide.

Angiotensin II receptor blockers (ARBs) and manufacturing contamination: A retrospective National Register Study into suspected associated adverse drug reactions.

The aim of this study was to determine if any suspected adverse drug reactions (ADRs) observed with the use of angiotensin II receptor blockers (ARBs) could be linked to either (a) their unique respective physicochemical and pharmacological profiles and (b) the recently disclosed suspected carcinogenic manufacturing contaminants found in certain sartan drug class batches. The pharmacology profiles of ARBs were data-mined from the Chemical Database of bioactive molecules with drug-like properties, European Molecular Biology Laboratory (ChEMBL). Suspected ADR data (from 01/2016-10/2022, inclusive) and prescribing rates of ARBs over a 5-year prescribing window (from 09/2016 to 08/2021, inclusive) were obtained via analysis of the United Kingdom Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card drug analysis profile and Open prescribing databases, respectively. The overall suspected ADRs and fatalities per 100 000 prescriptions identified across the ARBs studied were found to be different between the sartan drug class members (chi-squared test, P < .05). There is a greater relative rate of reports for valsartan across all investigated organ classes of ADRs, than other ARBs, despite valsartan's more limited pharmacological profile and similar physicochemical properties to other sartans. The disparity in ADR reporting rates with valsartan vs other ARBs could be due to the dissimilarity in formulation excipients, patient factors and publicity surrounding batch contaminations, amongst others. Cancer-related ADRs and fatalities per 100 000 prescriptions identified across the ARBs studied are not statistically significant (chi-squared test, P > .05) based on the datasets used over the 5-year period. No connection between ARB pharmacology and their suspected ADRs could be found. No conclusion between sartan batch contaminations and increased suspected cancer-related ADRs was found.

PREVENT: Assessing and Improving Knowledge of the Sodium Valproate Pregnancy Prevention Programme in Psychiatric Prescribing

AimsThe sodium valproate PREVENT programme was introduced by the Medicines and Healthcare products Regulatory Agency (MHRA) in March 2018, and is now a legal requirement due to valproate's risks in pregnancy. This project had two main aims: 1) To assess clinician knowledge of PREVENT, and identify deficiencies in current education. 2) To assess the barriers psychiatrists face in achieving compliance with PREVENT.MethodsKnowledge and awareness of PREVENT was assessed through an online survey sent to local consultants and specialty doctors in February 2021. The survey included ten questions, four were Likert style to assess attitudes, two assessed local arrangements and four were knowledge based. A free-text section allowed respondents to describe challenges faced implementing PREVENT. Results were analysed, an educational presentation given at local teaching and a poster was created and distributed - both targeting areas of weakest knowledge. A repeat survey was sent out in June 2021, and results collected to reassess.ResultsThe pre-teaching survey received twelve responses, the post teaching survey received eleven. In both, 75% of respondents represented general adult services, and 25% represented intellectual disability services.There was an improvement in confidence of knowledge with all respondents being either “somewhat” (55%) or “very confident” (45%) post-teaching compared to 75% being “somewhat” confident, 10% “unsure” and 17% “very confident” prior to intervention. Pre-teaching, 10% of respondents were unaware that a risk acknowledgement form must be signed annually, while post-teaching 100% correctly identified this should be annual.Respondents correctly identifying “highly effective” forms of contraception rose from 83% to 100% following teaching. Post-teaching there was an increase of 31% in the number of respondents correctly identifying the necessary documentation where a patient declines the PREVENT programme.Pre-teaching, half of respondents were unsure if their team had a reminder system for risk acknowledgement forms, and 42% reported having no system. Post-teaching, 27% of respondents reported now having a reminder system in place, and 27% had plans to implement one.ConclusionInitial results showed variable knowledge of the PREVENT programme, and a lack of awareness of the administrative requirements including risk acknowledgement forms. Results demonstrated an improvement in knowledge and organisation to help support compliance with the PREVENT programme. Respondents highlighted that knowledge of the PREVENT programme quickly deteriorates given how rarely it is used. Further work includes a full audit of compliance with PREVENT across the health board, as well as considering “refresher” sessions to prevent atrophy of knowledge.

136 New valproate guidelines and adherence to the pregnancy prevention programme: experience in a tertiary clinic

Objectives: To establish the proportion of women of childbearing age on Sodium Valproate (VPA) for epilepsy who met the requirements of the Pregnancy Prevention Programme (PPP) in accordance with the Medicines and Healthcare products Regulatory Agency (MHRA) guidelines, with a view to identifying rates of compliance and the reasons for non-adherence.Methods128 female participants of childbearing age currently on VPA, who had completed an annual risk assessment from Greater Manchester, were included in the study. Patient data was gathered review of Electronic Patient Records.ResultsThe majority of women (n=86, 67%) did not meet the conditions of the PPP: 59 (69%) were on no contraception, and 27 (31%) were on inadequate contraception such as OCP, Depo injection, and condoms. Non adherence to PPP was due to 11 different reasons, the most common (n=27) being learning disability, followed by, no intention of becoming pregnant (n=7), not sexually active (n=13), and patient choice (n=9)ConclusionsPPP does not appear to be relevant to the majority of women of child bearing age pre- scribed VPA. Further patient education about rates of unplanned pregnancies and risks of VPA might help improve adherence to PPP.asmithaa.prabhakaran@student.manchester.ac.uk

AB0412 CYCLING OF JAK-INHIBITORS IN PATIENTS WITH RHEUMATOID ARTHRITIS: A SINGLE-CENTRE EXPERIENCE

BackgroundDespite the availability of multiple effective disease-modifying antirheumatic drugs (DMARDs), discontinuation/switching of treatment is common for many patients with rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors or JAKi, are the latest class of DMARDs approved for RA. Data on the outcomes of cycling JAKi in RA patients is still limited to this day.ObjectivesTo assess the outcomes of switching between JAKi baricitinib, tofacitinib and upadacitinib in a real-world cohort of RA patients.MethodsThis was a hospital-based, retrospective observational study of all RA patients treated in a single-centre. Data was collected between 2016 and 2021 for all patients who failed JAKi and were treated with another JAKi. Demographic data, antibody status, history of DMARD use and clinical outcomes were assessed according to change in disease activity scores, time to JAKi discontinuation and reason for switching based on DAS 28-CRP scores.ResultsWe identified 26 RA patients, 23 (88%) of which were RhF and/or anti-CCP positive, that failed JAKi and were cycled to another JAKi. 23 (88%) patients had failed treatment with one or more biological therapies prior to initiating JAKi. 13 (50%) patients were prescribed baricitinib and the other 13 patients Tofacitinib as their initial JAKi. During their RA treatment pathway, 9 (35%) of the patients on tofacitinib switched to baricitinib, and 4 (15%) switched to upadacitinib. 7 (27%) patients who started on baricitinib were switched to upadacitinib, and 6 (23%) were switched to tofacitinib. 3 (12%) patients cycled between all 3 JAKi. Reasons for switching first JAKi included primary treatment failure at initial 3-month rescore due to lack of efficacy (7/26; 27%), secondary failure (9/26; 35%), adverse drug reactions (ADR) (2/26; 8%) and others (1/26; 4%). Additionally, 7 (27%) patients on tofacitinib were switched following a drug safety update published by the Medicines and Healthcare products Regulatory Agency (MHRA), in an effort to minimize risk of major adverse cardiovascular events and malignancies. The median time to switching first JAKi was 11.5 months (range 3-23 months). After switching JAKi, 17 (65%) patients were found to have improved DAS 28-CRPs at their 3-month rescore and continued treatment with their second JAKi. Following their switch, a total of 8 (31%) patients stopped their second JAKi due to inefficacy, 3 (12%) due to ADRs and 2 (8%) for other reasons. Of the 3 patients that went on to receive treatment with a 3rd JAKi (2/3 for primary failure; 1/3 for secondary failure), 2 patients were found to improve at their 3-month rescore.ConclusionCycling through JAKi is an appropriate and safe treatment strategy in RA patients that discontinue first JAKi therapy due to lack of efficacy or ADR.ReferencesNADisclosure of InterestsNone declared

Oesophageal protection during AF ablation: real world registry data and mechanisms behind the therapeutic effect of tissue cooling

Abstract Funding Acknowledgements Type of funding sources: None. Background Oesophageal protection using a dedicated device to provide controlled active thermal protection of the oesophagus during atrial fibrillation ablation has been shown to be effective at reducing endoscopically detected oesophageal lesions. Real world registry data of this device and established evidence on the effect of cooling on localized tissue after thermal injury have been under review. Purpose To determine the safety of an oesophageal temperature control device by a review of real-world registry data on its clinical use during catheter ablation procedures and to clarify basic mechanisms of its therapeutic action by a literature review of scientific studies on cooling in the context of thermal injury. Methods 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) databases were reviewed for any device-related adverse events. A systematic literature review was conducted to clarify the findings from studies investigating the physiological processes behind the therapeutic effect of cooling after tissue thermal injury. Results Of over 20,000 oesophageal temperature control devices clinically used, 7976 were recorded as having been used for the purpose of oesophageal protection during left atrial catheter ablations. No adverse events occurred related to its use during left atrial catheter ablations. No case of clinically significant oesophageal injury was reported in a patient who had been protected by the oesophageal temperature control device. 208 research articles retrieved from PubMed and MEDLINE that met the search criteria were reviewed. The common finding in all the studies was that cooling had an anti-inflammatory and restorative effect via modulation of several immune-mediated pathways, local cellular function and genetic expression. Conclusions There have been no adverse events reported to date in real world clinical use of an oesophageal temperature control device during left atrial catheter ablations, for the purpose of active thermal protection. Literature review data suggests that there are complex biophysical and cellular effects from cooling that leads to its therapeutic effect but further work is required to define the mechanisms of action of thermal protection in this specific context.

CA-528-03 A REGISTRY REVIEW UPDATE OF 7120 CATHETER ABLATIONS FOR ATRIAL FIBRILLATION USING A DEDICATED ESOPHAGEAL TEMPERATURE CONTROL DEVICE FOR PROTECTION

Esophageal protection using a dedicated device to provide controlled active thermal protection of the esophagus during atrial fibrillation ablation has been shown to be effective. Randomized evidence from the IMPACT trial showed an 83.4% reduction in endoscopically detected esophageal lesions compared to standard care. Real world registry data of this device has been under review. To determine the safety of an esophageal temperature control device by an updated review of real-world registry data on its clinical use and any reported device-related adverse events. The following databases were reviewed for any reported esophageal 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 underwent an updated review including any instances of device-related adverse events when used during catheter ablations. Of the 20,000 oesophageal temperature control devices used, 7120 were recorded as having been used for the purpose of esophageal protection during left atrial catheter ablations. 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 during left atrial catheter ablations. No case of clinically significant esophageal injury was reported in a patient who had been protected by the esophageal temperature control device. Real world registry data has shown no adverse events reported to date in 7120 uses of an esophageal temperature control device during left atrial catheter ablations, for the purpose of active thermal protection.

Review and Comparison of Food Drug Administration (FDA) and Medicines and Healthcare products Regulatory Agency (MHRA) on Good Manufacturing Practice (GMP) Implementation

A government is responsible for ensuring public health and safety. One of the approaches is to establish a regulatory body that governs health-related items such as pharmaceuticals and other human health-related products. These regulatory bodies exist to ensure that goods satisfy high standards of quality, safety, and efficacy. This article investigates several aspects of regulatory bodies' regulation and Good Manufacturing Practice (GMP) standards controlled by two regulatory organizations, the Food and Drug Administration (FDA) and the Medicines and Healthcare products Regulatory Agency (MHRA). Both regulatory agencies appear to have some items controlled and fairly specific product authorization guidelines. It is apparent that both regulatory authorities have some comparable notions in common when it comes to GMP implementation, product registration, mutual recognition agreements, and MoU implementation.

Examining the effect of evaluation sample size on the sensitivity and specificity of COVID-19 diagnostic tests in practice: a simulation study

BackgroundIn response to the global COVID-19 pandemic, many in vitro diagnostic (IVD) tests for SARS-CoV-2 have been developed. Given the urgent clinical demand, researchers must balance the desire for precise estimates of sensitivity and specificity against the need for rapid implementation. To complement estimates of precision used for sample size calculations, we aimed to estimate the probability that an IVD will fail to perform to expected standards after implementation, following clinical studies with varying sample sizes.MethodsWe assumed that clinical validation study estimates met the ‘desirable’ performance (sensitivity 97%, specificity 99%) in the target product profile (TPP) published by the Medicines and Healthcare products Regulatory Agency (MHRA). To estimate the real-world impact of imprecision imposed by sample size we used Bayesian posterior calculations along with Monte Carlo simulations with 10,000 independent iterations of 5,000 participants. We varied the prevalence between 1 and 15% and the sample size between 30 and 2,000. For each sample size, we estimated the probability that diagnostic accuracy would fail to meet the TPP criteria after implementation.ResultsFor a validation study that demonstrates ‘desirable’ sensitivity within a sample of 30 participants who test positive for COVID-19 using the reference standard, the probability that real-world performance will fail to meet the ‘desirable’ criteria is 10.7–13.5%, depending on prevalence. Theoretically, demonstrating the 'desirable' performance in 90 positive participants would reduce that probability to below 5%. A marked reduction in the probability of failure to hit ‘desirable’ specificity occurred between samples of 100 (19.1–21.5%) and 160 (4.3–4.8%) negative participants. There was little further improvement above sample sizes of 160 negative participants.ConclusionBased on imprecision alone, small evaluation studies can lead to the acceptance of diagnostic tests which are likely to fail to meet performance targets when deployed. There is diminished return on uncertainty surrounding an accuracy estimate above a total sample size of 250 (90 positive and 160 negative).

P030 Quality improvement project on awareness in patients to stop teratogenic disease-modifying anti-rheumatic drugs (DMARDs) while planning pregnancy and need for highly effective contraception

Abstract Background/Aims The MHRA (Medicines and Healthcare Products Regulatory Agency) published guidelines in February 2018 on highly effective contraception (injectable/IUCD/partner vasectomy) for women of childbearing age consuming potentially teratogenic DMARDs (disease-modifying anti-rheumatic drugs) which might result in increased risk of birth defects. Objective: A quality improvement project was carried out in the rheumatology department at James Cook University Hospital, Middlesbrough to assess patient awareness of the potential teratogenicity of the DMARDS like methotrexate, leflunomide and mycophenolate mofetil and need for highly effective contraception to avoid foetal complications. Methods A spot audit was carried out from June to September 2019, through patient questionnaires to assess awareness in women of childbearing age (15- 45 years) about the potential teratogenic effects of these DMARDs and the need for highly effective contraception. Following this audit more tailored consent forms were introduced in February 2020 to increase awareness of potential teratogenicity at initiation of DMARDs with robust counselling. Subsequent to this we carried out quality improvement project to accumulate similar data between June and September 2021. Results Data were collected from 43 patients during the spot and 27 patients during the second cycle. 88% patients were on methotrexate, 9% on MMF, 2% on leflunomide and 2% on multiple DMARDS during the first audit compared to 66.6% on methotrexate, 16.6% on leflunomide and 6% on MMF during the second cycle. It was very positive to see 74% of patients reporting increased awareness about potential teratogenicity of the DMARDS gained through counselling compared to the 37% previously. 90% of the patients were aware to stop these DMARDs when planning pregnancy compared to the 88% previously. We achieved 100% awareness that the medication should be stopped in pregnancy compared to 90% previously. Rates of contraception use were comparable across cycles - 54% during the first cycle and 56.7% during the second. Of patients using contraception, 33.3% were using highly effective contraception the first cycle which improved to 37% during the second cycle. Nearly 44.4% patients were not on any contraception. Reasons why contraception was not used was not explored which was beyond remit of this project. Since this is a significant proportion there is certainly a need for further assessment and analysis. Conclusion Overall this quality improvement project has highlighted the need for robust counselling as well as structured and informative consent forms to improve the awareness of teratogenicity with certain DMARDs therapy in woman of childbearing age. In spite of increased awareness of the teratogenicity of these DMARD 44.4% patients were not on any form of contraception. There is definitely room for improvement in effectively disseminating information regarding highly effective form of contraception to prevent inadvertent exposure during pregnancy which may result in foetal birth defects. Disclosure F.A. Khan: None.

An audit to determine how teratogenic risks of carbimazole are considered for patients of child-bearing potential in an acute hospital setting

Abstract Introduction Carbimazole is associated with an increased risk of congenital malformations when used in pregnancy. In 2019, the Medicines and Healthcare products Regulatory Agency (MHRA) strengthened its advice on risk minimisation (1). The valproate national campaign raised awareness of risks amongst healthcare professionals and the public (2). However, within our organisation it was perceived that awareness of teratogenic effects of carbimazole was potentially less well-known. Aim The aim was to determine if teratogenic risks associated with carbimazole were considered in patients of child-bearing potential. Objectives were to measure the percentage of patients that had a documented: acknowledgement of risk (audit standard 70%); pregnancy or contraception status (audit standard 80%); record of provision of patient information (audit standard 70%) and make recommendations to improve practice. Methods An audit approach was used with standards derived from national guidance (1). The setting was an acute NHS organisation comprising two main sites. The prescribing, health record (HR) and pharmacy dispensing systems were electronic. A cluster sample of female patients aged ≤45 years that had carbimazole dispensed between November 2018 and November 2019 were included. A data collection tool was developed and piloted prior to use. A trainee pharmacist reviewed patient HRs and extracted details of prescription, risk conversations, contraception and pregnancy status onto the data collection tool. Patients without a consultation record were excluded. No patient or staff identifiable data were recorded. Data were collated using Microsoft Excel and analysed descriptively. Results Seventy-nine of 81 patients aged 11-45 years were included; two patients were excluded because their consultation records were unavailable. Of 79 patients, 35 (44%) had either pregnancy status, contraception, teratogenic risk consideration or discussion documented. For 44 (56%) patients, there was no documented acknowledgement of risk. Twenty-nine (36%) patients had their pregnancy or contraception status documented. For six pregnant patients, provision of advice was unclear. Only fifteen (19%) had specific documentation about risk consideration and six of documented risk conversations with patients. There was no evidence pharmacists had checked risk considerations made by prescribing clinicians or actively provided information to patients. Conclusion Findings suggest that consideration of teratogenic risk of carbimazole is inconsistent. Where pregnancy and contraception status were documented in the absence of further information, it was unclear if patients were informed of risks or involved in treatment discussions. Findings have limited generalisability due to the small sample. Although HR were thoroughly reviewed, findings were based on documentation that was potentially incomplete or not representative of detailed discussions during patient consultations. Further research should use methods to explore clinician and patient awareness of teratogenic risk of carbimazole and patient involvement in their treatment decisions. Recommendations are to: upskill pharmacists so they more actively provide risk information; better utilise electronic prescribing to mandate inclusion of contraception status and facilitate standardised risk consideration. National bodies should implement formal risk minimisation strategies for all teratogenic drugs. References (1) Medicines and Healthcare products Regulatory Agency. Carbimazole: increased risk of congenital malformations strengthened advice on contraception [internet]. London: MHRA; 2019 [cited February 2019]. Available from: https://www.gov.uk/drug-safety-update/carbimazole-increased-risk-of-congenital-malformations-strengthened-advice-on-contraception (2) NHS England and NHS Improvement. Patient Safety Alert Resources to support the safety of girls and women who are being treated with valproate [internet]. London: NHSEI; 2017 [updated 2019 December 6]. Available from https://www.england.nhs.uk/wp-content/uploads/2019/12/Patient_Safety_Alert_-_Resources_to_support_safe_use_of_valproate.pdf

Impact of regulatory safety notices on valproate prescribing and pregnancy outcome among women of child-bearing potential in Scotland: a population-based cohort study

ObjectiveTo examine the impact of Medicines and Healthcare products Regulatory Agency (MHRA) safety alerts on valproate prescribing among women aged 14–45 years in Scotland and examine trends in pregnancies exposed...

Information for children and young people about reporting suspected adverse drug reactions

BackgroundWhen children and young people (CYP) report their own suspected adverse drug reactions (ADRs), different patterns of drugs and symptoms are noted. A new guide to reporting suspected ADRs using...

COVID-19 vaccine related menstrual irregularities: A cause of vaccine hesitation?

To, The Editor-in-Chief Vaccination against Coronavirus Disease of 2019 (Covid-19) has shown remarkable progress in controlling the ongoing pandemic. Currently, over nine billion doses of Covid-19 vaccines have been administered worldwide(1), and although this widespread vaccination has shown great progress in managing the pandemic, multiple side effects have been noted. Most of these side effects are mild such as pain at injection site, fever, rash, etc., but some are serious and long-lasting like myocarditis and other cardiovascular complications. Recently, there have been reports of several women experiencing menstrual irregularities after being administered Covid-19 vaccines, and that has created hesitation amongst women to get their shot.(2) Table 1. summarizes the number of menstrual disturbances recorded by Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card Scheme until 22nd December 2021. While several factors have been implicated to be the cause of these irregularities, a definitive reason still remains to be established. A recent meta-analysis by Sharifian-Dorche M et al. has shown that Covid-19 vaccines induce thrombocytopenia.(3) This can result in the loss of endometrial haemostasis, and consequently, vaccinated women might experience increased blood loss/heavy menstrual bleeding (HMB). Moreover, since body's immune system is activated by Covid-19 vaccines(4), immune cells lining the uterus can contribute to early shedding of uterine wall, and that may manifest as intermenstrual bleeding (IMB) or postmenopausal bleeding (PMB). Women who have recovered from Covid-19 infection continue to suffer from menstrual irregularities for prolonged times. Therefore, the possibility of Long Covid Syndrome causing these menstrual disturbances cannot be disregarded.(5) Additionally, the prevailing gender bias in pre-and post-covid literature has led to under-reporting of events related to female reproductive health, further limiting our understanding of this subject. In conclusion, to minimize vaccine hesitation among women, it is imperative that a better understanding of these side effects should be sought. Further research should be encouraged to investigate vaccines' short- and long-term effects on reproductive health. Questions regarding menstrual cycle should be included in clinical trials for Covid-19 vaccines, and women should be encouraged to report any unusual post-vaccination changes in menstrual cycles to their doctors. Moreover, strict pharmacovigilance should be practiced to monitor people with pre-existing coagulopathies, and those on certain medications in order to limit the possibility of life-threatening conditions such as cerebral venous sinus thrombosis (CVST) after taking the Covid-19 vaccines. ---Continue

ESHRE guideline: endometriosis.

ESHRE guideline: endometriosis.

Copper chelation in patients with hypertrophic cardiomyopathy

BackgroundDisturbances of copper (Cu) homeostasis can lead to hypertrophic cardiac phenotypes (eg, Wilson’s disease). We previously identified abnormal Cu homeostasis in patients with hypertrophic cardiomyopathy (HCM) and, therefore, hypothesised that...

Automating the final cell therapy bioprocess step for robust CMC/GMP compliance Cell &amp; Gene Therapy Insights 2021; 8(1), 61–74

Until recently, Tracy Moore worked with the Medicines and Healthcare products Regulatory Agency (MHRA) as an Expert Good Manufacturing Practice (GMP) Inspector, specializing in sterile products and data integrity. In the following article and interview, she draws on this experience to highlight:Regulatory considerations and requirements for GMP compliance when manufacturing advanced therapy medicinal products (ATMPs) How to identify specific gaps in compliance that may occurCommon areas of weakness found upon inspectionThe potential benefits and pitfalls of open versus closed processes

OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

SummaryBackgroundThe manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS).MethodsThe design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing.FindingsContinuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support.InterpretationThe mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale.FundingWork supported by Wellcome/EPSRC Centre for Medical Engineering,King’s Together Fund and Oxford University.

Spontaneous Reporting to Regulatory Authorities of Suspected Adverse Drug Reactions to COVID-19 Vaccines Over Time: The Effect of Publicity.

IntroductionThe 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.ObjectiveOur 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.MethodsWe 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.ResultsApproximately 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.ConclusionReports 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.

An interview on rare diseases and orphan medicines with Dr Daniel O’Connor, medical assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), UK

An interview on rare diseases and orphan medicines with Dr Daniel O’Connor, medical assessor at the Medicines and Healthcare products Regulatory Agency (MHRA), UK