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.

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.

Risk management of medication errors: a novel conceptual framework.

BACKGROUND: Medication error is a common cause of patient harm. The study aims to propose a way to manage the risk of medication errors in a novel way, by identifying practice areas where mitigating patient harm should be prioritized using a risk management approach. METHODS: Suspected Adverse Drug Reactions (sADRs) in Eudravigilance database over three years were reviewed to identify preventable medication errors. These were classified using a new method based upon the root cause underlying pharmacotherapeutic failure. The correlation between severity of harm and type of medication error, and other clinical parameters was investigated. RESULTS: Overall, 2294 medication errors were identified from Eudravigilance, of which 1300 (57%) were due to pharmacotherapeutic failure. Most cases of preventable medication error involved prescribing (41%) and administration (39%). The variables which significantly predicted severity of medication errors were pharmacological group, patient age, number of drugs prescribed, and route of administration. The drug classes most strongly associated with harm included cardiac drugs, opioids, hypoglycaemics, antipsychotics, sedatives, and antithrombotic agents. CONCLUSION: The findings of this study highlight the feasibility of using a novel conceptual framework to identify areas of practice at risk of pharmacotherapeutic failure where Interventions by healthcare professionals in these areas are most likely to improve medication safety.

HPLC-UV Method Development and Validation to Monitor Difluprednate Synthesis.

During the synthesis of active pharmaceutical ingredients (APIs) there is a need for the development and validation of a simple and rapid high performance liquid chromatography (HPLC) method for the determination and quantification of the synthesized product and related by-products. An HPLC method gives a better understanding of how a synthesis is proceeding. A rapid and easy to use HPLC-UV (ultraviolet) method for the determination of difluprednate and monitoring of impurities generated during synthesis was developed and validated. A Shimadzu VP Series HPLC equipped with a LabSolutions software and UV detector set at 240 nm was used for analysis. The mobile phase consisted of phosphate buffer (pH 6) and acetonitrile 50:50 (v/v) and was eluted at a flow rate of 1.2 mL/min. Separation took place on a reversed-phase Kinetex C18 column (150 × 4.60 mm; 5 µm i.d.). Column temperature was set at 40°C. The developed method was found to have good linearity and acceptable accuracy and precision. The developed method may be effectively applied to determine products and by-products formed during synthetic reactions of steroids and to calculate the yield of the products obtained during each step of the synthesis.

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.

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.

Pharmacist and physician perception of pharmacogenetic testing.

OBJECTIVES: To assess the perception of pharmacists and physicians towards pharmacogenetic testing. METHODS: A self-administered questionnaire was developed, validated, tested for reliability and disseminated to pharmacists and physicians in Malta. KEY FINDINGS: The study population consisted of 292 participants; 61% pharmacists (64% female, 38% practicing >10 years) and 39% physicians (50% female, 54% practicing >10 years). Pharmacists and physicians felt they lack sufficient competence in the area (95.0% and 97.4%, respectively; P > 0.05) and agreed that further training is required (92.7% and 91.2%, respectively; P > 0.05). CONCLUSIONS: The need for further training was identified by the participants to support competency development and sustain confidence on the topic, hence facilitating the clinical implementation of pharmacogenetic testing.

The interplay between pharmacogenetics, concomitant drugs and blood levels of amitriptyline and its main metabolites.

Background: The research considers the impact of genotype-inferred variability on blood levels of amitriptyline and its main metabolites, as may be moderated by phenocopying. Patients & methods:CYP2D6 and CYP2C19 genotypes, and serum concentrations of amitriptyline, nortriptyline and hydroxymetabolites, were determined in 33 outpatients. Co-medications were reviewed to identify CYP inhibition risk. Results: CYP2C19 metabolizer status explained interpatient variation in nortriptyline to amitriptyline concentration ratios. The hydroxymetabolite to parent ratios increased with higher CYP2D6 activity scores and lower CYP2D6 inhibition risk. In patients at high CYP2D6 inhibition risk, the amitriptyline + nortriptyline concentration was, on average, 52% above the higher end of expected ranges. Conclusion: Practical construal of pharmacogenetics and drug interactions tantamount to aberrant metabolism can facilitate patient-tailored use of the established drug.

Amitriptyline is an established drug in managing depression and neuropathic pain. Body exposure to amitriptyline and its by-products is influenced by enzymes activities, which are subject to genetic variation, whereas other medications in a patient's treatment regimen may alter drug breakdown. To study these implications, genetic testing was conducted in 33 outpatients on amitriptyline therapy, alongside measurement of drug concentrations in blood and consideration of any co-administered medications. Breakdown of amitriptyline to nortriptyline was associated with the genetically determined status of patients. Subjects at high risk of having their rate for further breakdown delayed by other drugs had higher blood levels than expected in normal cases. A proportion of variation observed in blood drug concentrations across individuals with same genetic results could be explained by actions of drugs received concurrently. Supportive evidence is provided on the integration of drug interaction information with insights from genetic testing for patient-tailored pharmacotherapy that attempts to mitigate the possibility of missing an intended benefit or the risk of adverse events due to altered blood levels.

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.

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.

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.

Pharmaceuticals and the environment.

The marked progress and increase in the number of medications available for the treatment of conditions and diseases left a footprint on the surrounding environment. The consumption of medications for human and veterinarian use impact the terrestrial and marine environment and affects the ecosystem. The increase in environmental awareness regarding pharmaceutical related activities led to the development of principles and measures to mitigate a negative environmental impact. Various measures were introduced to promote green manufacturing and practices which led to the development of alternative techniques and processes, which are of benefit to both the environment and the industry. Distributors and pharmacists can contribute through the efficient management of everyday operations which include better stock taking and rotation, grouping deliveries and reducing unused medications. The incorporation of green practices in the pharmacy curriculum empowers future pharmacists with skills and competences required at the place of work to decrease the impact of processes and medicines on the environment. The presence of a pharmacist workforce which is more conscientious about the environment leads to the needed ripple effect to embrace and implement green principles in different pharmacy related settings. Patients should also be educated to avoid hoarding of medications and dispose of medication in a safe and appropriate manner. The implementation of green practices results in a decrease in the use of chemicals and production of waste which in turn leads to a decrease in pollutants which have an impact on climate change.

A three-year post-graduate Doctorate in Pharmacy course incorporating professional, experiential and research activities: A collaborative innovative approach.

This article was migrated. The article was marked as recommended. Background A three-year post-graduate international Doctorate in Pharmacy collaborative course, was launched by the Department of Pharmacy, University of Malta in collaboration with the College of Pharmacy, University of Illinois at Chicago. Aim and rationale To demonstrate that the professional Doctorate in Pharmacy (i) fits the requirements of a Level 8 degree according to the Bologna process, (ii) helps graduates develop competencies and attributes in proficiency in clinical and professional aspects, (iii) has a research component that provides the right level of abilities to participate in research initiatives and to interpret research outcomes, (iv) enables graduates to obtain leadership characteristics. Approach The unique characteristics of the course were evaluated through an outcomes result-oriented measurement. Leadership aspects were measured through policies and strategies presented by students and graduates. Outcomes i) course is in line with the Bologna declaration, ii) research work shown in the dissertation satisfied competencies required iii) research abilities have been examined through a third party and found to be compliant with acquiring of concepts in the design, carrying out, assessment of outcomes and interpretation of results of the research study carried out by each student, and iv) leadership characteristics were shown by the positions taken up by the graduates and early outcomes from these positions. Conclusion Learning activities enable development of professionals able to merge scientific and practice aspects in the evaluation of innovative therapies, the use of medicines and patient monitoring, and in pharmaceutical policy development and regulation. Leadership positions taken up by graduates point to the acquisition of leadership skills by graduates. Next Steps The authors are happy to extend collaboration for this model to be adapted by other institutions for the curricular development entailed in this programme to enhance and improve an innovative aspect in the evolvement of the pharmacy profession on the international scenario.

A multi-technique analytical approach for impurity profiling during synthesis: The case of difluprednate.

A methodology for the qualitative analysis of a mixture of compounds obtained during the synthesis of difluprednate is described herein for the first time. For this scope a multi-technique analytical approach was developed, combining Liquid Chromatography/Mass Spectrometry (LC/MS), Nuclear Magnetic Resonance (NMR) and computational chemistry. Separation of isomers is frequently required for the identification of impurities in active pharmaceutical ingredients (APIs) to assess the impact they may exhibit on public health. During the final step of the difluprednate synthesis apart from the desired product, various by-products may be obtained. Structural analysis of the products using LC/MS and NMR indicated that the steroid difluprednate was obtained along with its acetyl/butyryl regional isomers, whereas the results were further supported by semi-empirical calculations of the MS-derived data. Following the proposed approach, we managed to elucidate the structures of the challenging 11-acetate, 17-butyrate from the 17-acetate, 21-butyrate, 6α,9α-difluoro prednisolone isomers. The approach utilized may be of general applicability for the analysis of impurities in active pharmaceutical ingredients obtained during chemical synthesis.

Treatment of Leber's hereditary optic neuropathy: An overview of recent developments.

Leber's hereditary optic neuropathy (LHON) is a rare, maternally-inherited optic neuropathy caused by mitochondrial DNA point mutations and which can cause blindness. Currently, Raxone (idebenone) is the only available medicinal product authorised to treat LHON within the European Union and LHON remains an unmet medical need. The aim of this article was to summarise interventional clinical trials published over the past 5 years (between 2014 and 2019) with the primary purpose of treating LHON. Therapeutic approaches discussed include modulating agents of the mitochondrial electron transport chain such as Raxone, cysteamine bitartrate and KH176, inhibitors of apoptosis such as elamipretide, gene therapy medicinal products such as GS010 and scAAV2P1ND4 and retinal tissue regeneration medicinal products such as bone marrow-derived stem cells.

Practical liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of amitriptyline, nortriptyline and their hydroxy metabolites in human serum.

Amitriptyline (AMI) has been in use for decades in treating depression and more recently for the management of neuropathic pain. A highly sensitive and specific LC-tandem mass spectrometry method was developed for simultaneous determination of AMI, its active metabolite nortriptyline (NOR) and their hydroxy-metabolites in human serum, using deuterated AMI and NOR as internal standards. The isobaric E-10-hydroxyamitriptyline (E-OH AMI), Z-10-hydroxyamitriptyline (Z-OH AMI), E-10-hydroxynortriptyline (E-OH NOR) and Z-10-hydroxynortriptyline (Z-OH NOR), together with their parent compounds, were separated on an ACE C18 column using a simple protein precipitation method, followed by dilution and analysis using positive electrospray ionisation with multiple reaction monitoring. The total run time was 6 min with elution of E-OH AMI, E-OH NOR, Z-OH AMI, Z-OH NOR, AMI (+ deuterated AMI) and NOR (+ deuterated NOR) at 1.21, 1.28, 1.66, 1.71, 2.50 and 2.59 min, respectively. The method was validated in human serum with a lower limit of quantitation of 0.5 ng/mL for all analytes. A linear response function was established for the range of concentrations 0.5-400 ng/mL (r2 > .999). The practical assay was applied on samples from patients on AMI, genotyped for CYP2C19 and CYP2D6, to understand the influence of metaboliser status and concomitant medication on therapeutic drug monitoring.

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.

Pharmacist-led medicine use review in community pharmacy for patients on warfarin.

Background Medicine use review by pharmacists has the potential to improve anticoagulation therapy management in patients on warfarin. Objective To develop, implement and evaluate a pharmacist-led medication use review service for patients on warfarin. Setting Six community pharmacies in Malta. Method Patients (N = 100) aged 18 or older and on warfarin were recruited through pre-selected community-pharmacies. These patients were then invited to attend two sessions: a review session (t1) and a follow-up session after 2 months (t2). During the medication use review session, medication reconciliation was performed (a) to detect drug-related problems using the DOCUMENT classification system, (b) to develop an individualised care plan for each patient and (c) to recommend an action for each identified problem for physician, pharmacist or patient consideration. At t2, the degree of acceptance of the recommendations was determined by assessing the number of drug-related problems for which action was taken to address the problem. International normalisation ration (INR) control was evaluated by calculating the percentage Time in Therapeutic Range (TTR) at t1 and t2 using the Rosendaal linear interpolation method. Main outcome measures Frequency and type of drug-related problems detected; percentage of accepted recommendations; and INR control. Results A total of 481 drug-related problems were identified; 40% (n = 190) were related to warfarin treatment. Need for monitoring (30%; n = 145), lack of compliance (20%; n = 97) and need for patient education (19%; n = 90) were the top three problems identified. There was a significant correlation between frequency of the problems and number of chronic medications (Spearman Correlation 0.583, p < 0.001), number of comorbidities (Spearman Correlation 0.327, p = 0.001) and older age (Spearman Correlation 0.285, p = 0.04). A total of 475 recommendations were followed-up; 49% (n = 234) were referred for consideration by the physician. The percentage of recommendations accepted (84%; n = 397) was significantly higher than the percentage of recommendations not accepted (16%; n = 78) (p < 0.001). The time in therapeutic range improved significantly from 68.7% at t1 to 79.8% at t2 (p = 0.01). Conclusions The high percentage of accepted recommendations and the improvement in INR control indicate that a pharmacist-led medication use review service in community pharmacy contributes to improving anticoagulation therapy management in patients on warfarin.

Clinical pharmacist implementation of a medication assessment tool for long-term management of atrial fibrillation in older persons.

BACKGROUND: Optimisation of drug therapy is important in the older population and may be facilitated by medication assessment tools (MATs). OBJECTIVE: The purpose of the study was to evaluate whether appropriateness of drug therapy and clinical pharmacist intervention documentation improved following implementation of a previously developed MAT for the long-term management of atrial fibrillation (MAT-AF). METHODS: Adherence to MAT-AF review criteria and clinical pharmacist intervention documentation was assessed by the researcher pre-MAT implementation in 150 patients aged ≥60 years admitted to a rehabilitation hospital with a diagnosis of atrial fibrillation. MAT-AF was introduced as a clinical tool in the hospital for identification of pharmaceutical care issues in atrial fibrillation patients. Adherence to MAT-AF and pharmacist intervention documentation were assessed by the researcher post-MAT implementation for a further 150 patients with the same inclusion criteria. Logistic regression analysis and measurement of odds ratio was used to identify differences in adherence to MAT-AF pre- and post-MAT implementation. The differences between two population proportions z-test was used to compare pharmacist intervention documentation pre- and post-MAT implementation. RESULTS: Adherence to MAT-AF criteria increased from 70.9% pre-implementation to 89.6% post-implementation. MAT-AF implementation resulted in a significant improvement in prescription of anticoagulant therapy (OR 4.07, p<0.001) and monitoring of laboratory parameters for digoxin (OR 10.40, p<0.001). Clinical pharmacist intervention documentation improved significantly post-implementation of MAT-AF (z-score 20.249, p<0.001). CONCLUSIONS: Implementation of MAT-AF within an interdisciplinary health care team significantly improved the appropriateness of drug therapy and pharmacist intervention documentation in older patients with atrial fibrillation.