Medicines And Healthcare Products Regulatory Agency Research Articles

Comparing the Differences in Adverse Events among Chimeric Antigen Receptor T-Cell Therapies: A Real-World Pharmacovigilance Study

In this study, we compared the similarities and differences in adverse events (AEs) among CAR T-cell products through signal mining via the FDA Adverse Event Reporting System (FAERS) and identified unknown AEs to provide a reference for safe clinical medication. Data from the FAERS database spanning from the fourth quarter of 2017 to the first quarter of 2024 were extracted. Signals were identified using the reporting odds ratio (ROR) method and the Medicines and Healthcare Products Regulatory Agency (MHRA) method. A total of 11,386 AE reports related to six CAR T-cell products were selected. The top three categories of AEs reported were nervous system disorders, immune system disorders, and general disorders and administration site conditions. However, there were variations in the AE spectra among the different CAR T-cell products. The BCMA-targeting drugs idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel) were found to be associated with parkinsonism, which were not observed in CD19-targeting drugs. Tisagenlecleucel (Tisa-cel) and axicabtagene ciloleucel (Axi-cel) exhibited cerebrovascular accident-related AEs, graft versus host disease, and abnormal coagulation indices. Cilta-cel was associated with cerebral hemorrhage, intracranial hemorrhage, cranial nerve disorder, and facial nerve disorder. Cardiopulmonary toxicity, including hypoxia, tachypnoea, cardiorenal syndrome, and hypotension, exhibited strong signal intensities and considerable overlap with CRS. The number of positive signals for cardiopulmonary toxicity associated with drugs targeting CD-19 is greater. Clinicians should assess patients prior to medication and closely monitor their vital signs, mental status, and laboratory parameters during treatment.

Clinical benefit, reimbursement outcomes, and prices of FDA-approved cancer drugs reviewed through Project Orbis in the USA, Canada, England, and Scotland: a retrospective, comparative analysis

Project Orbis is a global initiative that aims to streamline regulatory review processes across international regulators in the USA, Canada, Australia, UK, Israel, Brazil, Singapore, and Switzerland to bring promising cancer drugs to patients earlier. We explored the clinical benefit, time to regulatory approval and health technology assessment recommendations, reimbursement outcomes, and monthly treatment prices of cancer drugs reviewed through this initiative. For this retrospective, comparative analysis, we identified cancer drug approvals reviewed through Project Orbis in the USA, Canada, and the UK between May 1, 2019, and Nov 1, 2023. Approvals of cancer drugs reviewed Project Orbis were extracted from the Food and Drug Administration (FDA) Oncology Centre of Excellence and all other FDA approvals from the Drugs@FDA database. The co-primary outcomes were time of regulatory review, time from regulatory approval to health technology assessment recommendation (England, Scotland, and Canada), reimbursement outcomes, clinical benefit (defined as median gains in progression-free survival and overall survival) between cancer drug approvals reviewed by Project Orbis and other FDA approval processes, and monthly treatment prices. The Wilcoxon rank-sum and Fisher's Exact tests were used to examine statistical significance between approvals reviewed through Project Orbis and other FDA approvals during the same period. Between May 1, 2019 and Nov 1, 2023, 81 (33%) of 244 cancer drugs approved by the FDA were reviewed through Project Orbis. The median overall survival gains were 4·1 months (IQR 3·3-5·1) compared with 2·7 months (2·1-3·9) for other FDA approvals. Similarly, progression-free survival gains were 2·6 months (IQR 1·7-4·9) for Project Orbis compared with 2·6 months (0·6-5·1) for other FDA approvals. Neither overall survival (p=0·11) nor progression-free survival (p=0·44) gains were significantly different between the two cohorts of approvals. Of the 14 UK Medicines and Healthcare products Regulatory Agency (MHRA) approvals reviewed by the Scottish Medicines Consortium (SMC), the agency gave positive recommendations for all 14 (100%). Of the 15 MHRA approvals reviewed by the National Institute for Health and Care Excellence (NICE), the agency gave positive recommendations for six (40%). Of the 49 approvals reviewed by the Canadian Agency for Drugs and Technologies in Health (CADTH), the agency conditionally recommended 44 (90%). The time between regulatory approval to NICE recommendation increased from a median of 137 days (IQR 102-172) in 2021 to 302 days (184-483) in 2023, SMC recommendation increased from 185 days (in 2021 for one drug only) to 368 days (IQR 313-476) in 2023, and CADTH decision increased from 97 days (in 2020 for one drug only) to 202 days (IQR 153-304) in 2023. The median monthly price of approvals reviewed through Project Orbis was US$20 000 per month (IQR 13 000-37 000). Clinical outcomes of Project Orbis were no different than other FDA approvals during the same time, and access, after a successful health technology assessment, was considerably delayed or absent, raising questions about whether Project Orbis participation translates into faster patient access to medicines with high clinical benefit and sustainable costs. Although future challenges might benefit from regulatory harmonisation, the advantages are currently unclear. None.

Statistical Signal Detection Algorithm in Safety Data: A Proprietary Method Compared to Industry Standard Methods.

Several quantitative methods have been established, in pharmacovigilance, to detect signals of disproportionate reporting (SDRs) from databases containing reports of adverse drug reactions (ADRs). The signal detection algorithms (SDAs) and the source of the reporting per product vary, but it is unclear whether any algorithm can provide satisfactory performance using data with such large variance factors. Determine the appropriate SDA for Biogen's internal Global Safety Database (GSD) given the characteristics of the database including frequencies of events, data skewness, outliers, and missing information. Compare performance of standard approaches (EBGM, EB05, PRR, and ROR), well accepted by industry, to a Biogen-developed Machine Learning (ML) Regression Decision Tree (RDT) model, across several Biogen products, to determine a champion SDA. All data associated with seven marketed Biogen products were chosen and a historical subset of reported ADRs were considered. Six SDAs (five common industry disproportionality methods) and RDT were evaluated. The SDRs were calculated on training and test data composed of quarterly reporting intervals from 2004-2019. The performance measures used were sensitivity, precision, time to detect new events, and frequency of detected cases for each algorithm for each product. Outcomes in the test data are known a priori and easily compared to predicted outcomes. Validation was performed via rates of misclassification. This work solely represents Biogen's internal information, intentionally chosen to serve the performance review of its signal detection systems, and results will not necessarily be generalizable to other external sources. Several algorithms performed differently among products, but no one method dominated any other. Performance was dependent on the thresholds used to define a signal according to different criteria. However, those different statistics subtly influenced the achievable performance. The relative performance of RDT and Medicines and Healthcare products Regulatory Agency (MHRA) algorithms were superior and paired across products. A reduction in precision for all methods spanning the products was present. Hence, companies evaluating signal detection approaches, search for innovative methods to minimize this effect. In designing signal detection systems, careful consideration should be given to the criteria that are used to define SDRs. The choice of disproportionality statistics does not affect the achievable range of signal detection performance. These choices should consider mainly ease of implementation and interpretation. The implementation of a method is specific to its accuracy. The RDT attempted to take advantage of known methods and compare results on a per-product basis. Many factors influencing ADRs may improve RDT in future efforts. In this experiment, RDT demonstrated superiority in terms of quickest time to detect and capturing of the highest number of ADRs. Next steps include expansion of data for products representing other indications and testing models in external databases to investigate generalizability of estimates when comparing SDAs.

Dossier submission in the UK after Brexit

The withdrawal of the United Kingdom (UK) from the European Union (EU), commonly known as Brexit, occurred on January 31, 2020, triggering a transition period until December 31, 2020, during which the UK and EU negotiated their future relationship. Brexit has brought significant changes to regulatory frameworks, particularly in the pharmaceutical sector. This article examines the transition of dossier submission procedures in the UK following Brexit, focusing on the implications for marketing authorizations (MAs) and pharmacovigilance. The Medicines and Healthcare Products Regulatory Agency (MHRA) transitioned to an independent regulatory body, establishing new guidelines for pharmaceutical companies seeking MAs in the UK. Key changes in marketing authorization routes include the conversion of centrally authorized products (CAPs) to UK MAs, the introduction of the Decentralized and Mutual Recognition Reliance Procedure (MRDCRP), and the implementation of a 150-day assessment timeline for national procedures. This article compares dossier requirements before and after Brexit in the UK and highlights pharmacovigilance requirements post-Brexit, emphasizing adjustments to reporting obligations, Qualified Person for Pharmacovigilance (QPPV) responsibilities, and the establishment of UK-specific Pharmacovigilance System Master Files (PSMFs). Additionally, it addresses the dossier Module 1 administrative information requirements to provide a comprehensive overview of the changes in regulatory procedures in the UK pharmaceutical sector following Brexit. Overall, the article aims to serve as a valuable resource for industry professionals, regulatory experts, and other stakeholders seeking clarity on the regulatory changes and their implications for pharmaceutical products in the UK following Brexit.

Survey of Scottish Dermatology Society members on thenew MHRA isotretinoin recommendations.

Recent Medicines and Healthcare products Regulatory Agency (MHRA) isotretinoin legislation includes significant changes that will affect clinical practice for dermatologists across the UK. We obtained opinions from members of the Scottish Dermatological Society on these recommendations. The survey yielded an adequate number of responses with significant results and free-text comments of interest to practising UK dermatologists. Overall responses from SDS members highlighted many concerns with the MHRA guidance and its impact on patient care. The results of this survey question the credibility of the MHRA. We propose the creation of an objective working group, with no conflicts of interest.

Bridging the gap from medical to psychological safety assessment: consensus study in a digital mental health context.

Digital Mental Health Interventions (DMHIs) that meet the definition of a medical device are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. The MHRA uses procedures that were originally developed for pharmaceuticals to assess the safety of DMHIs. There is recognition that this may not be ideal, as is evident by an ongoing consultation for reform led by the MHRA and the National Institute for Health and Care Excellence. The aim of this study was to generate an experts' consensus on how the medical regulatory method used for assessing safety could best be adapted for DMHIs. An online Delphi study containing three rounds was conducted with an international panel of 20 experts with experience/knowledge in the field of UK digital mental health. Sixty-four items were generated, of which 41 achieved consensus (64%). Consensus emerged around ten recommendations, falling into five main themes: Enhancing the quality of adverse events data in DMHIs; Re-defining serious adverse events for DMHIs; Reassessing short-term symptom deterioration in psychological interventions as a therapeutic risk; Maximising the benefit of the Yellow Card Scheme; and Developing a harmonised approach for assessing the safety of psychological interventions in general. The implementation of the recommendations provided by this consensus could improve the assessment of safety of DMHIs, making them more effective in detecting and mitigating risk.

Philosophical Interpretation of Article 24 of the Medicines Act: Drug Safety, Efficacy, and Quality Control

Article 24 of the Medicines Act serves as a cornerstone in the regulatory framework governing pharmaceuticals in the United Kingdom. This article emphasizes the rigorous evaluation of drug safety, efficacy, and quality through a structured, multi-phase process involving pre-clinical studies, clinical trials, and post-marketing surveillance. This paper explores the philosophical underpinnings of Article 24, delving into its ethical, epistemological, and regulatory dimensions. The ethical analysis focuses on balancing public health and individual rights, the principle of informed consent, and equitable access to high-quality medicines. The epistemological discussion highlights the commitment to evidence-based medicine, scientific rationalism, and the critical role of regulatory bodies like the Medicines and Healthcare products Regulatory Agency (MHRA). The regulatory perspective examines the comprehensive and precautionary approach to drug approval and quality control, emphasizing global harmonization and collaboration. By integrating these perspectives, the paper underscores the significance of Article 24 in ensuring that only safe, effective, and high-quality medicinal products are available in the UK, thereby setting a model for global regulatory practices.

An observational study on the safety of teprotumumab based on FAERS database.

Teprotumumab plays an important role in thyroid eye disease pathogenesis and progression. We intend to mine the adverse event (AE) signals from a relevant database, thereby contributing to the safe use of teprotumumab. The data obtained from the ASCII data packages in the FAERS database from January 2020 to the second quarter of 2023 were imported into the SAS software (version 9.4) for data cleaning and analysis. Disproportionality analysis was performed using the reporting odds ratio (ROR) in conjunction with the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) omnibus standard method to detect positive signals. This retrospective observational study relied on adverse drug reactions reported to the FDA through FAERS, which is a standard public system for spontaneous reporting. Collectively, 2171 AE reports for teprotumumab were collected, among which 108 significant signals were identified involving 17 system organ classes. The SOC of ear and labyrinth disorders included the most AE signals and reports. Muscle spasms, fatigue, headache, nausea, diarrhea, alopecia, blood glucose increased, hypoacusis, tinnitus, and diabetes mellitus were the top ten PTs ranked by the frequency of reporting, meanwhile, the two high-strength signals of thyroid-stimulating immunoglobulin increase (ROR 662.89, 95% CI 182.40-2409.19) and gingival recession (ROR 125.13, 95% CI 79.70-196.45) were not documented in the drug instruction. Meanwhile, we found a higher risk of increased blood glucose, deafness, and decreased appetite for male patients, and headache for female patients. Clinical application of teprotumumab should be closely monitored for ototoxicity, nail abnormalities, and menstrual changes, as well as for AEs not mentioned in the drug instruction, including gingival recession, thyroid-stimulating immunoglobulin increase, and so on.

E-cigarette knowledge of undergraduate pharmacy students

Abstract Introduction The use of e-cigarettes (known as vaping) is creating public health opportunities and challenges. E-cigarettes are effective as a smoking cessation tool. However, they are not without risk. E-cigarettes are relevant to pharmacists as they can provide advice about smoking cessation and they are well placed to provide more generic support and information about e-cigarettes, including side effects. Notifications about any issues with e-cigarettes can be done through the United Kingdom’s (UK’s) Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card Scheme. Vaping products can be considered as licensed, but not yet prescribed within the UK National Health Service (NHS). There are benefits in pharmacists being knowledgeable about the legal and regulatory status of e-cigarettes. It is currently unclear whether pharmacy students are knowledgeable about e-cigarettes and their role in smoking cessation. It is also unclear whether they are aware of the relevance to the Yellow Card scheme. Aim To examine e-cigarette knowledge of undergraduate pharmacy students studying at a large university in the northwest of England, some of which may be concurrently working within retail pharmacy. Methods A link to an online quantitative survey was distributed to all students (approximately 500) studying on the four-year undergraduate pharmacy (MPharm) programme by the programme leader. This was done by email in April 2023. The research was carried out as part of a public health student’s dissertation with a questionnaire designed and piloted by the student. Results were mainly descriptive and χ2 tests were carried out using SPSS where appropriate. Results A convenience sample of 55 students (approximately 10%) was achieved. Just over half the respondents stated they did not know if e-cigarettes were available on prescription or from the NHS. Only 12% of respondents knew that e-cigarettes were regulated for safety and quality in the UK, with 50% of all respondents stating that they were not. Just over half (58%, n=32) did not know whether medically licensed e-cigarettes were available. Less than 10% of all respondents (n=5) were aware that e-cigarettes users can report via Yellow Card Scheme if suspecting a side effect from using e-cigarettes. Interestingly, 46% of those currently working in retail pharmacy (n=11) wrongly stated “no” when asked about the Yellow Card Scheme. This compared to 19% (n=6) of those not currently working in retail settings (χ2=4.44, df=1, p=0.035), indicating that those with current retail experience were less knowledgeable about the Yellow Card Scheme in relation to e-cigarettes. All respondents agreed that pharmacists should be providing health-related advice on vaping to their clients/patients. Conclusion There may be merit in including relevant material on e-cigarettes, including the licensing and Yellow Card scheme, along with more general information on the benefits of switching from cigarettes to vaping and the need to stop vaping, within undergraduate programmes. A strength of this study was that it was one of the first that looked at knowledge of the Yellow Card scheme among pharmacy students, but a main weakness was that it was a small, self-selecting sample of students.

P081 Out-patient management of gout in secondary care: Results from the North West regional audit

Abstract Background/Aims Recommendations for gout management have significantly evolved as outlined by the latest National Institute for Health and Care Excellence (NICE), European League Against Rheumatism (EULAR), British Society for Rheumatology (BSR) and the Medicines and Healthcare products Regulatory Agency (MHRA) guidelines, with increased emphasis being placed on optimising cardiovascular risk. This regional audit aimed to assess concordance with these guidelines within rheumatology outpatient settings in the North West region of England. Methods New or follow-up patients with gout, presenting to a rheumatology outpatient setting within the Greater Manchester and Lancashire area over a five-week period between 1/3/23 and 7/4/23 were included. We collated data on demographics, co-morbidity assessment including cardiovascular risk, prescribing of febuxostat in major cardiovascular disease, diuretic use and advice, setting of treat-to-target levels, use of cardiovascular risk prediction tools and subsequent follow up arrangements. For new patients, collected data also included referral reason, and prescription recommendations for first-line urate-lowering therapy (ULT) and co-prescriptions for flare prophylaxis. Results Ninety-two patients (mean age 60 years, 80% male) were included from 13 rheumatology departments. Twenty-three patients were new referrals. Sixty-seven patients (73%) had ≥ 1 relevant comorbidity; hypertension being the most common (55%). Twenty (22%) patients were on diuretics. Twelve (55%) of these patients had a diagnosis of hypertension without heart failure; none received recommendations to reduce or stop diuretics. In line with current guidelines, no patient with major cardiovascular disease was treated with febuxostat. Treat-to-target levels were agreed in 49 (57%) applicable patients. Cardiovascular prediction tools were only calculated or known in three (3%) patients. However, clinic data collected would have allowed a risk assessment calculation in 13 (14%) patients. Sixteen (17%) patients audited had no planned follow-up. Compared to NICE guidelines, 18 (78%) new patients reviewed in clinic were referred appropriately to rheumatology services. Twenty-two (96%) new patients referred were eligible to start ULT, of which 15 (75%) were started on a NICE/ EULAR recommended first-line ULT treatment (14 patients on allopurinol including 11 patients with no major cardiovascular disease, one patient on febuxostat). Eleven (79%) patients started on allopurinol were initiated on a low dose (50-100mg), as recommended by NICE and the BSR. Ten (67%) patients of those initiated on ULT were also prescribed prophylactic colchicine. Two additional patients were prescribed NSAIDs with PPI cover and one patient was prescribed oral steroids without PPI cover. Conclusion Most new patients were referred and prescribed first-line ULT treatment appropriately, often with colchicine prophylaxis. Uptake of febuxostat as first-line therapy was limited. Cardiovascular risk assessment was rarely done; further work exploring barriers to undertaking these assessments in rheumatology clinics is likely to improve both patient care and guideline compliance. Disclosure L. Gould: Other; L.G. has received conference fees from Eli Lilly. A. Richards: None. L. Gray: Other; L.G. has received travel and conference fees from Eli Lilly. M. Badarulla: Other; M.B. has received conference fees from Eli Lilly. L. Mercer: Other; L.M. has received conference fees from Nordic Pharma and UCB. R. Farid: None. R. Heaton: Consultancies; R.H. has received consultancy fees from Galapagos. Honoraria; R.H. has received speaker honorarium from Abbvie and Nordic. Other; R.H. has received conference fees from UCB. M. Al-Attar: None. M. Whitehead: None. S. Kamath: None. L. Teh: None. A. Odekunle: None. C.A. Sharp: None. A. Babiker: None. S. Hopping: None. A. Oldroyd: None. K. Lazarewicz: None. C. Saleh: None. S. Horton: None. D. Roy: Honoraria; D.R. has an honorary University of Manchester research assistant contract. A. Opeseyitan: None. D. Das: None. S. Varughese: None. D. Yidana: None. S. Wig: None. J. Bluett: Grants/research support; J.B. has received a research grant award from Pfizer. Other; J.B. has received travel/conference fees from UCB, Fresenius Kabi, Pfizer and Eli Lilly.

Real-world safety of Levetiracetam: Mining and analysis of its adverse drug reactions based on FAERS database

Levetiracetam is a relatively new and widely utilized anti-seizure medication; however, limited information is available regarding its adverse effects. This study aims to thoroughly investigate, evaluate, and present evidence on the safety profile of Levetiracetam, relying on data from the FDA Adverse Event Reporting System (FAERS) database to facilitate informed clinical decision-making. We employed various statistical measures, including Reporting Odds Ratio (ROR), Proportionate Reporting Ratio (PRR), and analysis by the Medicines and Healthcare Products Regulatory Agency (MHRA), to identify signals of adverse reactions associated with Levetiracetam. Positive signals consistent with Designated Medical Event (DME) were singled out for focused comparison and discussion. The analysis of 26,182 adverse events linked to Levetiracetam as the primary suspected drug revealed 692 positive signals spanning 22 System Organ Classes (SOCs). Nervous system disorders were the most frequently reported, followed by psychiatric disorders, and general disorders and administration site conditions. 11 positive signals consistent with Preferred Terms (PTs) in DME were identified, predominantly concentrated in 6 SOCs. Among these, rhabdomyolysis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) exhibited relatively large values of A, ROR, and Chi-squared. Additionally, PTs related to spontaneous abortion, drug interaction, urethral atresia, ventricular septal defect, and atrial septal defect showed significant strength. The study indicates that Levetiracetam carries a potential risk of causing rhabdomyolysis, SJS, TEN, DRESS as well as spontaneous abortion. Signals related to drug interaction, urethral atresia, ventricular septal defect, and atrial septal defect warrant heightened attention in clinical use.

An innovative mobile app for the provision of medical information and collection of safety data on exposure to medicines during pregnancy or breastfeeding: An IHI ConcePTION contribution

AbstractObjectiveTo increase the volume, quality, and comprehensiveness of pregnancy and breastfeeding reports related to medication exposure.MethodsInnovative Health Initiative (IHI) ConcePTION, in collaboration with the Medicines and Healthcare products Regulatory Agency (MHRA), has developed a mobile application designed for exchange of safety information for pregnancy and breastfeeding. The users will also be able to report medication exposure during pregnancy and breastfeeding, regardless of the outcome, by answering simple questions, tailored for their level of medical knowledge.ResultsThrough the first version of the app, the users will receive trusted safety information on their medication of interest, from the Health Authority (RSS feeds, tagged for ‘pregnancy’ and ‘breastfeeding’). By using the app, women and healthcare providers will also be able to help future mothers, by reporting the events they experienced following the utilization of medications during pregnancy and breastfeeding. These will be analyzed by MHRA to further characterize the safety profiles of the medications required to be used in these situations.ConclusionCollection of pregnancy outcomes after exposure to medications during pregnancy is limited by under‐reporting and focused on reporting of harms. By developing the app, ConcePTION brings reliable safety information closer to healthcare professionals and pregnant and breastfeeding women and proposes an easy‐to‐use, general data protection regulation‐compliant, secure tool tailored for safety in pregnancy and breastfeeding.

Good Statistical Practice—development of tailored Good Clinical Practice training for statisticians

BackgroundStatisticians are fundamental in ensuring clinical research, including clinical trials, are conducted with quality, transparency, reproducibility and integrity. Good Clinical Practice (GCP) is an international quality standard for the conduct of clinical trials research. Statisticians are required to undertake training on GCP but existing training is generic and, crucially, does not cover statistical activities. This results in statisticians undertaking training mostly unrelated to their role and variation in awareness and implementation of relevant regulatory requirements with regards to statistical conduct. The need for role-relevant training is recognised by the UK NHS Health Research Authority and the Medicines and Healthcare products Regulatory Agency (MHRA).MethodsThe Good Statistical Practice (GCP for Statisticians) project was instigated by the UK Clinical Research Collaboration (UKCRC) Registered Clinical Trials Unit (CTU) Statisticians Operational Group and funded by the National Institute for Health and Care Research (NIHR), to develop materials to enable role-specific GCP training tailored to statisticians. Review of current GCP training was undertaken by survey. Development of training materials were based on MHRA GCP. Critical review and piloting was conducted with UKCRC CTU and NIHR researchers with comment from MHRA. Final review was conducted through the UKCRC CTU Statistics group.ResultsThe survey confirmed the need and desire for the development of dedicated GCP training for statisticians. An accessible, comprehensive, piloted training package was developed tailored to statisticians working in clinical research, particularly the clinical trials arena. The training materials cover legislation and guidance for best practice across all clinical trial processes with statistical involvement, including exercises and real-life scenarios to bridge the gap between theory and practice. Comprehensive feedback was incorporated. The training materials are freely available for national and international adoption.ConclusionAll research staff should have training in GCP yet the training undertaken by most academic statisticians does not cover activities related to their role. The Good Statistical Practice (GCP for Statisticians) project has developed and extensively piloted new, role-specific, comprehensive, accessible GCP training tailored to statisticians working in clinical research, particularly the clinical trials arena. This role-specific training will encourage best practice, leading to transparent and reproducible statistical activity, as required by regulatory authorities and funders.

Enhancing Patient-Centric Approaches and Regulatory Measures in Valproate Use

Valproate is an effective treatment for bipolar disorder, migraine, and seizures. It is a flexible medication for neurological illnesses. In addition to its immediate benefits, the neuroprotective capabilities of this substance, which may be attributed to its antioxidant and anti-inflammatory properties, contribute to its complexity. Nevertheless, the presence of significant negative consequences such as pancreatitis, liver failure, teratogenicity, and an elevated risk of suicide present considerable difficulties. Significantly, its capacity to block histone deacetylase motivates investigation into possible epigenetic impacts for the treatment of AIDS and cancer. The article discusses the issue surrounding the use of valproate in neurology. It agrees with the guidelines set by the MHRA (Medicines and Healthcare products Regulatory Agency), but also emphasises the need for further considerations in patient care and regulatory enhancements. The statement emphasises the need of providing clear guidance to patients and carers, while highlighting the need for comprehensive education of neurologists worldwide, with the backing of government. The paper advocates for allocating funding to support in-depth understanding through preclinical and clinical investigations, emphasising the importance of a well-rounded approach that prioritises the needs of patients. The aim is to create a flexible framework that can respond to changing medical knowledge by incorporating risk assessment, patient education, and thorough monitoring after regulatory changes. The objective of this strategy is to achieve a balance between ensuring reproductive safety and promoting the well-being of those who are reliant on valproate. This involves taking into account both the practical and emotional aspects of patient care.

Real-world Data and Evidence to support a switch in status from Prescription drug to Over the Counter drug as applied by the EMA, the US FDA, the MHRA, and the BfArM

PurposeWe studied under which circumstances and to what extent Real-World Data (RWD) and Real-World Evidence (RWE) were used in regulatory decisions when switching products from Prescription-only (Rx) to Over-the-Counter (OTC) status with the aim of extracting learnings that could be applied in future switches. MethodsSanofi commissioned Clarivate Analytics to identify switches from Rx to OTC in the European Union (centrally by the European Medicines Agency [EMA] and in Germany by the Bundesinstitut für Arzneimittel und Medizinprodukte [BfArM]), in the United States by the Food and Drug Administration (FDA), and in the United Kingdom by the Medicines and Healthcare products Regulatory Agency (MHRA) as far back as data were available in the public domain, mainly Health Authority webpages. They covered the period from and including 2022 and went as far back as they could find data in their proprietary database or in the public domain; for the EMA back to 2008, the US FDA back to 2001, the UK MHRA back to 1991, and the German BfArM for the period 2013–2022. We also asked Clarivate to investigate the nature of acceptance of RWD and RWE, and to what extent they are accepted by the different regulators in their decision-making and approval processes. FindingsWe found that the number of drugs available in the OTC segment is higher in regulatory jurisdictions where OTC policies are clear and supplemented by guidelines and transparent decision-making processes at the regulator level. A wide range of different data sources, many of which can be regarded as RWD/RWE in their broadest definitions, have been used to support switches. The data required by regulators to support a switch from Rx-only to OTC availability primarily centers on drug safety—both the drug's intrinsic safety and the safety associated with consumer usage. ImplicationsClear and transparent regulatory switch frameworks are conducive to growing the number of medicines available to consumers willing to self-manage their conditions. Transparent disclosure of the RWD and RWE data sets that regulators have found acceptable in historic switch applications is desirable because it would help sponsors to facilitate and increase prospective switches, thereby benefiting patients and society.

P616 Prescribing practices of tofacitinib and preferences amongst high-risk patients in the UK

Abstract Background Tofacitinib was licensed for use in patients with ulcerative colitis in August 2018. Because it is administered orally, has a rapid onset of action and is relatively inexpensive, it was quickly adopted in real-world practice. Safety warnings linking high-dose tofacitinib use to venous thromboembolic events (VTE) and death followed. Further warnings were issued linking its use to an increased risk of malignancy and adverse cardiovascular events in patients: over 65 years, with a history of diabetes, current or past smokers, and those with a history of coronary vascular disease. The most recent Medicines and Healthcare products Regulatory Agency (MHRA) statement advised against the use of all commercially available JAKi in this high-risk cohort unless a suitable alternative is unavailable (MHRA 2023). We sought to define the number of patients who had, or were, being treated with tofacitinib who were in this high-risk group and the proportion who opted to switch therapy once we had outlined their risk-status and the MHRA advice to them. Methods We conducted a retrospective observational cohort study of 131 patients with UC and IBD-U (61% male [80/131]; median age 43 years [range 16-85]; 46% [60/131] patients had previously had at least one biologic agent) treated with tofacitinib from October 2018 to December 2022 in our centre with at least 3 months follow-up. Patients were categorised as high-risk according to the MHRA statement if they had at least one of the criteria above. Results Overall, about one-third, 31.3% [41/131] patients that we had treated with tofacitinib were classified in the MHRA high-risk group. Rates of treatment discontinuation were similar in the high-risk versus no risk group. In the high-risk group ten patients (24.4% [10/41]) had discontinued treatment due to lack of response (4) or an adverse event (6). The most common adverse events were herpes zoster infections (14.6%), malignancy (3.3%) and infections requiring hospitalisation (3.3%). Two patients died while on treatment (one due to complications following cervical spinal surgery and the other due to ischaemic heart disease). There were no incidences of VTE. We clinically reviewed 29 high risk patients who were being treated with tofacitinib after a median of 2.4 years (range 0.6-4.56) of treatment. 25/29 high-risk patients decided on continuing their treatment in spite of the health care warnings and alternative therapies being available. Conclusion About one-third of our tofacitinib-treated patients were classified as at high-risk. The majority of high-risk patients opted to continue therapy even though alternative therapies were available.

Identifying new safety risk of human serum albumin: a retrospective study of real-world data.

Objective: To mine and analyze the adverse reaction signals of human serum albumin (HSA) using the FDA adverse event reporting system (FAERS) database for the safe clinical use of this drug. Methods: Data cleaning and analysis of adverse event reports in the FAERS database for a total of 76 quarters from Q1 2004 to Q4 2022 were performed using the reporting odds ratio (ROR), Medicines and Healthcare Products Regulatory Agency (MHRA), and Bayesian confidence propagation neural network (BCPNN). Gender-differentiated signal detection was used to investigate the gender differences in the occurrence of HSA adverse events. Results: Through a combination of three methods, a total of 535 adverse event reports were identified. These reports involved 1,885 cases of adverse reactions, with respiratory, thoracic, and mediastinal disorders, as well as general disorders and administration site conditions, as the most common. One noteworthy new signal was the occurrence of transfusion-related acute lung injury. Additionally, gender-differentiated signals were present, with females experiencing paraesthesia, hypertension, pulmonary oedema, loss of consciousness, and vomiting. Conclusion: This study has revealed that HSA poses a risk of causing transfusion-related acute lung injury. It has also been observed that adverse reactions, including paraesthesia, hypertension, pulmonary oedema, loss of consciousness, and vomiting, are more prevalent in females. These findings should be taken into account when using HSA in a clinical setting.

Enhancing Data Security Resilience in AI-Driven Digital Transformation: Exploring Industry Challenges and Solutions Through ALCOA+ Principles.

The Medicines and Healthcare Products Regulatory Agency (MHRA) defines data integrity as the maintenance of accuracy, consistency, and completeness of data over time. Recently, "artificial intelligence" has become prevalent across industries, education, culture,and technology, denoting systems that mimic human intelligence and critical thinking using computers and related technologies. This article examines the construction of a robust artificial intelligence (AI) system and the incorporation of ALCOA+ principles for data validation, with a specific focus on enhancing data certainty and security. This study was carried out through a comprehensive review of various Scopus-indexed literature over the past decade. Results and Discussion: AI has been widely applied in Manufacturing System Optimization, involving organizing production systems, including machines, robots, conveyors, and related operations like maintenance and material handling. Moreover, it's used for Process Monitoring, Diagnostics, and Prognostics in medicine, as well as supervision and regulation in industries. Yet, it's not immune to shortcomings, which could result in system biases and jeopardize data security. This article explores the creation of a robust AI system, implementing ALCOA+ for data validation in AI-Driven Digital Transformation to improve data certainty and security in industries. It involves systematically recording AI system activities, ensuring database validity, sustaining data recording practices, regularly updating records, ensuring authenticity and completeness, and facilitating data accessibility for review and audits. As AI integration in education advances, there's a crucial need for oversight to maintain data integrity in these systems.

Gene therapy for neurotransmitter-related disorders.

Inborn errors of neurotransmitter (NT) metabolism are a group of rare, heterogenous diseases with predominant neurological features, such as movement disorders, autonomic dysfunction, and developmental delay. Clinical overlap with other disorders has led to delayed diagnosis and treatment, and some conditions are refractory to oral pharmacotherapies. Gene therapies have been developed and translated to clinics for paediatric inborn errors of metabolism, with 38 interventional clinical trials ongoing to date. Furthermore, efforts in restoring dopamine synthesis and neurotransmission through viral gene therapy have been developed for Parkinson's disease. Along with the recent European Medicines Agency (EMA)and Medicines and Healthcare Products Regulatory Agency (MHRA) approval of an AAV2 gene supplementation therapy for AADC deficiency, promising efficacy and safety profiles can be achieved in this group of diseases. In this review, we present preclinical and clinical advances to address NT-related diseases, and summarise potential challenges that require careful considerations for NT gene therapy studies.

Community pharmacists' perceptions of the POM to P reclassification of medicines for sexual and reproductive health – A survey study

Abstract Introduction In the UK, medicines reclassification is the process of changing the legal classification of a medication, such as from a prescription-only medicine (POM) to a pharmacy (P) or general sales list (GSL) medicine.1 It is overseen by the Medicines and Healthcare products Regulatory Agency (MHRA). and improves patient access to certain medications while ensuring safeguards are in place for their safe and responsible use.2 A number of the most recent POM to P reclassifications have been for medications used in sexual and reproductive healthcare. Aim To investigate community pharmacists' (CPs’) perceptions of POM to P medicine reclassifications for sexual and reproductive health: sildenafil citrate (Viagra Connect, for erectile dysfunction), desogestrel (Hana/Lovima, for contraception), and estradiol hemihydrate (Gina, for vaginal atrophy). Methods The study population was all CPs in Greater London. The survey consisted of 59-questions in five sections. The first section was for general perceptions about the reclassification of medicines, while the other sections were specific to the medicines studied. The final section was demographics. Question types included multiple-choice, 5-point Likert scale, and free text. The recommended sample size was 340 (95% CI), therefore, 398 CPs, in 210 pharmacies, were approached. Ethical approval was obtained from the university ethics committee. Participants were posted a participant information sheet (PIS) one week before distribution of the survey as a hard copy. The survey was also available on Microsoft Forms. Data were analysed in Microsoft Excel and Statistical Package for Social Sciences (SPSS). Descriptive statistics were given in numbers and percentages. Results The response rate was 37.7% (N=150/398). Most CPs (88%) perceived that medication reclassification increased their role and provided greater access to medicines for the public. However, less than half (44%) had a good understanding of the reclassification process. Sildenafil was available to purchase in all of the visited pharmacies, however, desogestrel was only sold in 50% of them, and estradiol was sold in only 28%. Reasons cited for not selling desogestrel and/or estradiol included lack of public awareness about the availability of these products, and a lack of public interest in purchasing them. While the availability of sildenafil as a P medicine was seen as a positive for improving safe access, many CPs (86%) expressed concerns about the high risk of its misuse. In terms of training, the available training for sildenafil received higher ratings compared to that for desogestrel or estradiol. Most CPs (67%) indicated that having case studies incorporated into the training for POM to P switches helped them understand which patients could safely purchase these medications. Discussion/Conclusion CPs are positive about the availability of sexual and reproductive health medications over the counter. They do have concerns, however, about the potential of some of these medications to be misused, and also feel that more awareness of the availability of these products needs to be raised. Those producing training materials for reclassified medications should incorporate case studies as these support CP decision making. A limitation of this study was that the recommended sample size was not achieved.