Nivolumab Safety in Renal Cell Carcinoma: A Case Report.

Nivolumab is used to treat several different types of cancers. Although it is generally considered to be effective and well-tolerated, it has been associated with adverse effects requiring discontinuation of treatment, like many other drugs used for cancer. A 70-year-old male was switched from sunitinib to nivolumab for renal cell carcinoma. The patient developed persistent hypothyroidism, onycholysis, and pneumonitis at nivolumab cycle 6, 10, and 11, respectively. Using the Naranjo causality method, the likelihood of causality was deemed "probable" for pneumonitis and hypothyroidism and "possible" for onycholysis. Nivolumab was eventually discontinued due to disease progression, rather than safety concerns. Eudravigilance, the European pharmacovigilance database, was searched for all nivolumab-related individual case safety reports from Malta, up to September 4, 2023. Six reports were identified in Malta, although the 3 events identified in this case report were not reported, suggesting under-reporting in Malta. This case report identified an uncommon nivolumab adverse drug reaction (ADR), onycholysis and showed how, despite the occurrence of 3 ADRs, it was its lack of efficacy rather than its safety which led to its discontinuation in this particular patient.

An exploratory study of knowledge, attitudes, practice and barriers towards adverse drug reaction reporting among healthcare professionals in Malta.

BACKGROUND: Understanding knowledge and attitudes of health care professionals (HCPs) towards adverse drug reaction (ADR) reporting can inform educational interventions promoting ADR reporting. OBJECTIVE: To explore knowledge, attitudes, practice, and barriers of local HCPs towards ADR reporting. METHODS: Focus groups involving HCPs from different settings were organized to help develop a questionnaire. The questionnaire was validated and disseminated to pharmacists, physicians, dentists and nurses practicing in Malta. A review of ADR reports reported in Malta from 2004 to 2021 was carried out to contextualise questionnaire findings. RESULTS: Overall, HCPs (n = 374) had good knowledge on pharmacovigilance and a positive attitude towards ADR reporting however nurses were found to be less knowledgeable than physicians, dentists, and pharmacists. The main barrier for not reporting ADRs was difficulty to understand whether an adverse event occurred (n = 187). A total of 2581 ADR reports were reported in Malta. Among HCPs, physicians and dentists reported most ADRs (1060 reports), followed by pharmacists (307 reports) and nurses (257 reports). CONCLUSION: Further ADR educational and promotional efforts are needed to increase awareness on the importance of quality ADR reporting and increase the number of ADR reports reported by local HCPs.

Alzheimer's disease and neuroinflammation: will new drugs in clinical trials pave the way to a multi-target therapy?

Despite extensive research, no disease-modifying therapeutic option, able to prevent, cure or halt the progression of Alzheimer's disease [AD], is currently available. AD, a devastating neurodegenerative pathology leading to dementia and death, is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aß) and the intraneuronal deposits of neurofibrillary tangles (NFTs) consisting of altered hyperphosphorylated tau protein. Both have been widely studied and pharmacologically targeted for many years, without significant therapeutic results. In 2022, positive data on two monoclonal antibodies targeting Aß, donanemab and lecanemab, followed by the 2023 FDA accelerated approval of lecanemab and the publication of the final results of the phase III Clarity AD study, have strengthened the hypothesis of a causal role of Aß in the pathogenesis of AD. However, the magnitude of the clinical effect elicited by the two drugs is limited, suggesting that additional pathological mechanisms may contribute to the disease. Cumulative studies have shown inflammation as one of the main contributors to the pathogenesis of AD, leading to the recognition of a specific role of neuroinflammation synergic with the Aß and NFTs cascades. The present review provides an overview of the investigational drugs targeting neuroinflammation that are currently in clinical trials. Moreover, their mechanisms of action, their positioning in the pathological cascade of events that occur in the brain throughout AD disease and their potential benefit/limitation in the therapeutic strategy in AD are discussed and highlighted as well. In addition, the latest patent requests for inflammation-targeting therapeutics to be developed in AD will also be discussed.

An Exploratory Study of the Impact of COVID-19 Vaccine Spontaneous Reporting on Masking Signal Detection in EudraVigilance.

INTRODUCTION: During the signal detection process, statistical methods are used to identify drug-event combinations (DECs) which are disproportionately reported when compared with other drugs and events in the entire database. We hypothesise that the high volume of COVID-19 vaccine adverse drug reaction (ADR) reports transmitted to EudraVigilance may have affected the performance of disproportionality statistics used in routine signal detection, potentially resulting in signals either being masked, or false associations being flagged as potential signals. OBJECTIVE: Our aim was to study the impact of COVID-19 vaccine spontaneous reporting on statistical signal detection in EudraVigilance. METHODS: We recalculated the reporting odds ratio (ROR) for signals that were previously discussed at the level of the Pharmacovigilance Risk Assessment Committee, or signals that were retrieved from EudraVigilance, by omitting COVID-19 vaccine reports from the standard ROR calculation and then comparing the lower confidence interval (LCI) of the recalculated ROR to the LCI of the actual ROR in EudraVigilance. RESULTS: In total, 52 signals for 38 active substances were reviewed. For 35 signals, the LCI of the recalculated ROR value was lower than the LCI of the actual ROR (suggesting that COVID-19 vaccine ADR reporting had a positive effect on the strength of the signal) while for 15 signals the LCI of the recalculated ROR value was higher than the LCI of the actual ROR (suggesting that COVID-19 vaccine ADR reporting had an attenuating effect on the strength of the signal). For two signals, no change in the ROR was observed. In our analysis, six significant results were found. Five DECs were found to be masked: bleomycin and immune thrombocytopenia (actual ROR LCI = 0.94, recalculated ROR LCI = 1.02), vortioxetine and heavy menstrual bleeding (actual ROR LCI = 0.3, recalculated ROR LCI = 1.06), caplacizumab and heavy menstrual bleeding (actual ROR LCI = 0.98, recalculated ROR LCI = 3.47), ziprasidone and amenorrhoea (actual ROR LCI = 0.84, recalculated ROR LCI = 1.67), and azacitidine and pericarditis (actual ROR LCI = 0.81, recalculated ROR LCI = 2.01). For the DEC of adalimumab and immune reconstitution inflammatory syndrome, the LCI of the actual ROR value was 1.14 and removing COVID-19 vaccine reporting resulted in an LCI of the recalculated ROR value of 0.94 (below threshold). CONCLUSIONS: We demonstrated five cases of masking and one case of false-positive association due to the influence of COVID-19 vaccine spontaneous reporting on the ROR. This suggests that the high number of adverse drug reaction reports for COVID-19 vaccines in EudraVigilance has the potential to affect routine statistical signal detection activities. The impact of COVID-19 vaccine ADR reports on current signal detection practices requires further evaluation and solutions to tackle masking issues in EudraVigilance may need to be developed.

QT shortening: a proarrhythmic safety surrogate measure or an inappropriate indicator of it?

OBJECTIVE: To examine whether QT interval shortening is an overlooked adverse event as compared to QT prolongation through a review of preclinical, clinical and post-marketing adverse event data available to the regulator for centrally and nationally authorized medicinal products. METHODS: Potential safety signals of QT shortening related to authorized medicinal products were detected from Eudravigilance using proportional reporting ratios. Active substances identified as having unexpected signals of QT shortening were assessed in depth using the Bradford-Hill criteria for causation. Preclinical, clinical and adverse event data related to each active substance was used in the assessments. Post marketing adverse event cases were reviewed for imputability using the French method. RESULTS: 80 adverse event cases of electrocardiogram QT shortening were detected from 13 different active substances which included antipsychotics and antiepileptics (Clozapine, Ziprasidone, Quetiapine, Olanzapine, Carbamazepine), cardiovascular drugs (Atenolol, Digoxin, Ramipril, Simvastatin), anti-inflammatories and analgesics (Ibuprofen, Paracetamol) and other substances Calcium Carbonate (Mineral Supplement/Antacid) and Fingolimod (Immunosuppressant). By comparison 404 active substances were found have a potential safety signal of Electrocardiogram QT prolongation. Following in depth review none of the 13 active substances identified were found to be clearly associated with QT shortening using the minimum level of evidence for regulatory action. In the preclinical data reviewed we observed cases of morphological changes to the action potential (AP) where the Action Potential Duration at 90% (APD90) was not affected. CONCLUSIONS: From a regulatory perspective one cannot refute the possibility of a clinically relevant risk from QT shortening through the current testing requirements. Lack of further investigations into any potential morphological changes to the AP, or APD90 shortening beyond a specified threshold in our opinion does not fully exclude the possibility of proarrhythmic effects of active substances.

Improving the data quality of spontaneous ADR reports: a practical example from Malta.

BACKGROUND: Adverse drug reaction (ADR) reporting rates and high-quality data within case summary reports are crucial to detect emerging safety concerns and implement regulatory action. In this study we aimed to improve the data quality and reporting rates of ADR reports in Malta through a series of national activities. RESEARCH DESIGN AND METHODS: Between April 2018 and July 2019, we carried out the following activities: i) a review of wholesale dealers ADR reporting forms; ii) a series of educational workshops targeting physicians and pharmacists; iii) a quality system audit of the Authority's ADR management process. RESULTS: Twelve wholesaler dealer forms were reviewed, and 155 improvements were identified. Incident reporting forms modified to capture ADRs had the most opportunities for improvement. Five workshops were organized and in total 62 physicians and 22 pharmacists attended. Although feedback from participants was positive, in our case, an increase in reporting was not observed following the workshops. The quality system audit resulted in the introduction of the 'four-eye principle' to the Authority's ADR management process. CONCLUSIONS: The implementation of such activities is expected to contribute to the overall pharmacovigilance systems in Malta and our experience could benefit other entities involved in spontaneous ADR reporting.

The changing landscape of treatment options in childhood acute lymphoblastic leukaemia.

New paediatric acute lymphoblastic leukaemia (ALL) treatments have been developed and innovative products are in the pipeline. However, despite many active clinical trials, bridging bench science to clinical development to authorised medicines remains challenging. Research in first-line treatment continues to focus on multidrug chemotherapy with the potential addition of new targeted molecules being studied. Research in second- and third-line treatment represents a shift from cytotoxic intensification to an area of precision medicine through emergent innovative and immuno-oncology products. The collaborative research model in ALL involving different stakeholders should intensify to facilitate bench-to-bedside clinical translation for the benefit of patients.

Outcomes and endpoints in clinical trials supporting the marketing authorisation of treatments in paediatric acute lymphoblastic leukaemia.

The improvement in acute lymphoblastic leukaemia (ALL) treatment has led research efforts to focus on the unmet medical needs of an increasingly smaller patient cohort with resistant leukaemia and to develop more-targeted agents. Survival and response rates remain the most-prevalent endpoints in paediatric ALL research, but other intermediate clinical endpoints and molecular biomarkers for efficacy and mid- and long-term safety endpoints are also being investigated. The success of current ALL treatment appears to be driving new paradigms to optimise clinical drug development, while at the same time, regulatory tools in place are supporting meaningful drug development in the area.

Regulatory experience of handling Risk Management Plans (RMPs) for medicinal products in the EU.

Introduction: Risk Management Plans (RMPs) aim to optimize a medicinal product's benefit/risk balance for the individual patient and the target population. Despite differences in regulatory RMP requirements between jurisdictions worldwide, their ultimate aim is to protect public health.Areas covered: The review presents findings of different RMP requirements by different regulatory authorities and additional risk minimization measures (issued between January 2010 and December 2018) indicate how RMPs and additional risk minimization measures translate into actions to protect public health within the European Union (EU) member states and worldwide. Areas covered also include the different International Council for Harmonization (ICH) regional requirements of RMPs by the different regulatory authorities as well as data regarding the number of RMP assessments carried out by the EMA, FDA and Japan, and number of safety communications issued in Malta (taken as an example of a typical small EU member state) and in the United States of America (USA).Expert opinion: The EU legislation adopted in 2010 required RMPs to be included in all new applications for medicinal products in the EU, both for EU centrally authorized and nationally authorized medicinal products. Lessons learnt by EU regulators during this process are discussed in this review.

Regulatory sciences and translational pharmacogenetics: amitriptyline as a case in point.

Regulatory developments and clinical implementation, or the lack thereof, are primary clinchers, in the enduring endeavors to realize the translational quality of pharmacogenetics. Here, we present the case of amitriptyline, an established drug with pharmacogenetic implications. The integration of pharmacogenetic information in the official product literature and throughout the evaluation of safety concerns is considered. In our opinion, apart from emboldening genomic research in drug development and the valid pursuit towards global harmonization in the field, it is rational to look into the applicability of the data we have today.

A review of the National pharmacovigilance system in Malta - implementing and operating a pharmacovigilance management system.

INTRODUCTION: Regulatory authorities have a legal mandate to implement and maintain a Pharmacovigilance System designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance. Areas covered: This review maps the implementation of pharmacovigilance activities in Malta since accession in the EU in mid 2004 and discusses the challenges the Maltese Regulator encountered while setting up adequate and effective systems to fulfil its legal mandate. Areas reviewed are those around ADR reporting, promotion and safety communications including rapid alerts and recalls, direct healthcare professional communications, risk minimisation measures and safety circulars and quality systems. Expert opinion: Within a ten year period, 3 EU directives on pharmacovigilance were implemented by our agency. Despite limitations to resources, based on a prioritised implementation, the legislation provisions are now fully operational with a good level of sustainability. Lessons learnt from this process are discussed in this review. The coming years will involve strengthening and consolidation of existing processes.

Opinions of Maltese doctors and pharmacists on medication errors.

BACKGROUND: Pharmacovigilance directive 2010/84/EU focused attention on medication errors and encouraged regulators to identify causing and contributing factors. OBJECTIVES: (1) To study opinions of doctors/pharmacists on factors bearing a causal link to MEs as well as ways to minimise MEs (2) to test whether differences in opinion exist between subgroups of doctors and pharmacists working in community, hospital or office settings. METHODS: Different questionnaires were circulated to doctors and pharmacists. Respondents were subdivided according to their primary practice. RESULTS: 320 responses were received (204 doctors/116 pharmacists). Differences in opinion reaching statistical significance were observed on distractions from staff, overwork and fatigue, availability of technical resources and having more than 1 doctor on duty. For pharmacists', differences on issues of generic medicine availability and interruptions were found. CONCLUSION: Distractions and interruptions while executing tasks was flagged as an area requiring attention. Issues of overwork and fatigue affect especially doctors in hospital the majority of which are of the opinion that regulatory control on patient numbers could minimize errors. Increasing technical resources and keeping knowledge up-to-date, addressing overwork and high patient workloads have been identified as important areas when looking to reduce MEs.