Impact of European Union label changes to avoid inadvertent use of medicinal products containing methotrexate for once-weekly administration: A survey amongst prescribers, pharmacists and patients on awareness, knowledge, and behaviour.

PURPOSE: To determine the effectiveness of risk minimisation measures (RMM) to avoid inadvertent daily instead of weekly methotrexate (MTX) use, introduced by the European Medicines Agency (EMA) from 2019 onwards. METHODS: Using a cross-sectional online survey in France, Greece, Germany, Poland, and Sweden in 2022, we assessed awareness, knowledge, and self-declared behaviour for respondents who prescribed, dispensed, or used once-weekly MTX in the last 3 months. Respondents' answers were considered as 'successful' with regards to RMM effectiveness (vs. unsuccessful) if they provided correct ('desirable') responses to 100% of questions regarding awareness and self-declared behaviour and correct responses to ≥80% of questions about knowledge. Per target population, an outcome was considered successful if achieved by ≥80% of respondents. Effectiveness of RMM was defined by ≥80% being successful on all outcomes. RESULTS: One-hundred-fifty-one prescribers, 150 pharmacists, and 150 patients completed the survey. Success rates were 56% (95% CI 48.0%-64.3%) for awareness, 42% (95% CI 34.4%-50.7%) for knowledge, and 31% (95% CI 23.8%-39.2%) for self-declared behaviour among prescribers, 18% (95% CI 12.8%-25.8%) for awareness, 7% (95% CI 3.7%-12.7%) for knowledge, and 50% (95% CI 41.7%-58.3%) for self-declared behaviour among pharmacists, and 29% (95% CI 21.6%-36.6%) for awareness, and 3% (95% CI 1.1%-7.6%) for knowledge among patients. Overall success was not attained by any target population. CONCLUSIONS: RMM were evaluated as not effective across outcomes of awareness, knowledge, and self-declared behaviour in prescribers, pharmacists, and patients. Findings suggested we need continued efforts for RMM across all target populations and across all outcomes.

Uncertainty management in regulatory and health technology assessment decision-making on drugs: guidance of the HTAi-DIA Working Group.

OBJECTIVES: Uncertainty is a fundamental component of decision making regarding access to and pricing and reimbursement of drugs. The context-specific interpretation and mitigation of uncertainty remain major challenges for decision makers. Following the 2021 HTAi Global Policy Forum, a cross-sectoral, interdisciplinary HTAi-DIA Working Group (WG) was initiated to develop guidance to support stakeholder deliberation on the systematic identification and mitigation of uncertainties in the regulatory-HTA interface. METHODS: Six online discussions among WG members (Dec 2021-Sep 2022) who examined the output of a scoping review, two literature-based case studies and a survey; application of the initial guidance to a real-world case study; and two international conference panel discussions. RESULTS: The WG identified key concepts, clustered into twelve building blocks that were collectively perceived to define uncertainty: "unavailable," "inaccurate," "conflicting," "not understandable," "random variation," "information," "prediction," "impact," "risk," "relevance," "context," and "judgment." These were converted into a checklist to explain and define whether any issue constitutes a decision-relevant uncertainty. A taxonomy of domains in which uncertainty may exist within the regulatory-HTA interface was developed to facilitate categorization. The real-world case study was used to demonstrate how the guidance may facilitate deliberation between stakeholders and where additional guidance development may be needed. CONCLUSIONS: The systematic approach taken for the identification of uncertainties in this guidance has the potential to facilitate understanding of uncertainty and its management across different stakeholders involved in drug development and evaluation. This can improve consistency and transparency throughout decision processes. To further support uncertainty management, linkage to suitable mitigation strategies is necessary.

A drug utilization study of thiocolchicoside-containing medicinal products for systemic use in France and Italy: A cross-sectional electronic medical records database study.

PURPOSE: The risk minimization measures (RMM) for systemic use of thiocolchicoside (TCC) was implemented across Europe during 2014-2016. RMM included restriction of use in age <16 years, maximum dose and duration, chronic conditions, contraindication in pregnancy, lactation or in women of childbearing potential [WOCBP] without appropriate contraception. The current Drug Utilization Study was aimed to describe the prescribing practices of TCC in France and Italy. METHOD: The study analyzed data (demographic, prescription, diagnosis, and concomitant treatment) from electronic medical record databases. It compares drug utilization during pre-implementation (baseline: year 2013) and post-implementation (years 1, 2, and 3) of RMM. This study included panels of general practitioners (FGP) and rheumatologists (FRH) in France and Italy (IGP). RESULTS: TCC was largely prescribed as adjuvant therapy in both pre-implementation (FGP: 93.5%, FRH: 88.8%, IGP: 86.6%) and post-implementation (FGP: 92.3%, FRH: 89.5%, IGP: 89.0%) periods. Prescribing patterns were different in France and Italy, with FGP and FRH mainly prescribing oral formulation (>95% and >80%, respectively), while IGP prescribing intramuscular formulation (>70%). Prescriptions to patients aged ≥16 years were >99% in all panels during both periods. An improvement was observed in compliance with treatment duration for oral formulation in the FGP panel post-implementation versus pre-implementation (66.2% vs. 46.7%; p < 0.001). There was no change in prescription rate post RMM implementation in pregnant (FGP: 0.5%, IGP: 4.7%) and in WOCBP without appropriate contraception (FGP: 89.3%, IGP: 93.4%). CONCLUSION: These results highlighted changes in prescribing practices of TCC after RMM implementation, which varied across panels and measures.

HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: A good practices report of a joint ISPE/ISPOR task force.

PROBLEM: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias. WHAT WE DID: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The overarching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility. STRATEGIES TO DISSEMINATE AND FACILITATE USE: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years. CONCLUSION: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions.

HARmonized Protocol Template to Enhance Reproducibility of Hypothesis Evaluating Real-World Evidence Studies on Treatment Effects: A Good Practices Report of a Joint ISPE/ISPOR Task Force.

OBJECTIVES: Ambiguity in communication of key study parameters limits the utility of real-world evidence (RWE) studies in healthcare decision-making. Clear communication about data provenance, design, analysis, and implementation is needed. This would facilitate reproducibility, replication in independent data, and assessment of potential sources of bias. METHODS: The International Society for Pharmacoepidemiology (ISPE) and ISPOR-The Professional Society for Health Economics and Outcomes Research (ISPOR) convened a joint task force, including representation from key international stakeholders, to create a harmonized protocol template for RWE studies that evaluate a treatment effect and are intended to inform decision-making. The template builds on existing efforts to improve transparency and incorporates recent insights regarding the level of detail needed to enable RWE study reproducibility. The over-arching principle was to reach for sufficient clarity regarding data, design, analysis, and implementation to achieve 3 main goals. One, to help investigators thoroughly consider, then document their choices and rationale for key study parameters that define the causal question (e.g., target estimand), two, to facilitate decision-making by enabling reviewers to readily assess potential for biases related to these choices, and three, to facilitate reproducibility. STRATEGIES TO DISSEMINATE AND FACILITATE USE: Recognizing that the impact of this harmonized template relies on uptake, we have outlined a plan to introduce and pilot the template with key international stakeholders over the next 2 years. CONCLUSION: The HARmonized Protocol Template to Enhance Reproducibility (HARPER) helps to create a shared understanding of intended scientific decisions through a common text, tabular and visual structure. The template provides a set of core recommendations for clear and reproducible RWE study protocols and is intended to be used as a backbone throughout the research process from developing a valid study protocol, to registration, through implementation and reporting on those implementation decisions.

A cross-sectional survey to evaluate prescribers' knowledge and understanding of safety messages following Dengvaxia® product information update.

PURPOSE: We evaluated the effectiveness of additional risk minimisation measures (aRMMs; i.e., educational materials) distributed to prescribers to ensure that only individuals with evidence of prior dengue infection (PDI, i.e., dengue seropositive) would be vaccinated with the tetravalent dengue vaccine (CYD-TDV; Dengvaxia®). METHODS: A survey was conducted in 2020 among 300 CYD-TDV prescribers in Brazil and Thailand to ascertain three success criteria: prescribers' awareness of the materials (receiving and reading them); knowledge of the key messages; and whether their self-reported behaviour regarding practice-related scenarios was aligned with the updated guidance. RESULTS: The aRMMs were not generally effective as <80% of prescribers in both countries met two of the three predefined success criteria. In Brazil, 98.7% were aware of the aRMMs whereas in Thailand this criterion was fulfilled by 74.0%. Almost all prescribers knew that CYD-TDV was recommended only in individuals with PDI (98.7% and 96.7% in Brazil and Thailand, respectively). In Brazil, where vaccination was restricted to those with a documented history of PDI, 11.3% considered that confirmation should be done through a blood test. More than 75% in both countries considered additional signs of dengue, as early warning signs, and not only those regarded as such by the 2009 WHO guidelines. CONCLUSIONS: These results do not support that the aRMMs were effective as the predefined success criteria were not met. The use of reliable rapid diagnosis tests together with the revised prescribing information and educational materials will facilitate the implementation and compliance with pre-vaccination screening for CYD-TDV eligibility.

Overview of the European post-authorisation study register post-authorization studies performed in Europe from September 2010 to December 2018.

BACKGROUND: The European post-authorisation study (EU PAS) register is a repository launched in 2010 by the European Medicines Agency (EMA). All EMA-requested PAS, commonly observational studies, must be recorded in this register. Multi-database studies (MDS) leveraging secondary data have become an important strategy to conduct PAS in recent years, as reflected by the type of studies registered in the EU PAS register. OBJECTIVES: To analyse and describe PAS in the EU PAS register, with focus on MDS. METHODS: Studies in the EU PAS register from inception to 31st December 2018 were described concerning transparency, regulatory obligations, scope, study type (e.g., observational study, clinical trial, survey, systematic review/meta-analysis), study design, type of data collection and target population. MDS were defined as studies conducted through secondary use of >1 data source not linked at patient-level. Data extraction was carried out independently by 14 centres with expertise in pharmacoepidemiology, using publicly available information in the EU PAS register including study protocol, whenever available, using a standardised data collection form. For validation purposes, a second revision of key fields for a 15% random sample of studies was carried out by a different centre. The inter-rater reliability (IRR) was then calculated. Finally, to identify predictors of primary data collection-based studies/versus those based on secondary use of healthcare databases) or MDS (vs. non-MDS), odds ratios (OR) and 95% confidence intervals (CI) were calculated fitting univariate logistic regression models. RESULTS: Overall, 1426 studies were identified. Clinical trials (N = 30; 2%), systematic reviews/meta-analyses (N = 16; 1%) and miscellaneous study designs (N = 46; 3%) were much less common than observational studies (N = 1227; 86%). The protocol was available for 63% (N = 360) of 572 observational studies requested by a competent authority. Overall, 36% (N = 446) of observational studies were based fully or partially on primary data collection. Of 757 observational studies based on secondary use of data alone, 282 (37%) were MDS. Drug utilisation was significantly more common as a study scope in MDS compared to non-MDS studies. The overall percentage agreement among collaborating centres that collected the data concerning study variables was highest for study type (93.5%) and lowest for type of secondary data (67.8%). CONCLUSIONS: Observational studies were the most common type of studies in the EU PAS register, but 30% used primary data, which is more resource-intensive. Almost half of observational studies using secondary data were MDS. Data recording in the EU PAS register may be improved further, including more widespread availability of study protocols to improve transparency.

Effectiveness of risk minimization measures for valproate: a drug utilization study based on implementation of a risk minimization programme in Europe, analysis of data from the UK.

OBJECTIVE: Since 2014, valproate has not been recommended for use in girls and women of childbearing potential unless other treatments are ineffective or not tolerated. Risk minimization measures (RMMs) of valproate were implemented to reduce the potential risks of developmental disorders among pregnant women. A drug utilization study was carried out to assess the effectiveness of RMMs. METHODS: This was a multinational, non-interventional cohort study. For the UK, existing data from the Clinical Practice Research Datalink database were used. The primary study endpoint was a change in the proportion of valproate initiations preceded by other medications relevant for valproate indications before and after implementation of RMMs. RESULTS: The proportion of valproate initiations preceded by medications related to valproate indications increased after RMM implementation in incident female users in the UK from 66.4% to 72.4%. The proportion of incident prescriptions for epilepsy and bipolar disorder with prior medication related to valproate indications increased, from 36.2% to 44.1% and 72.9% to 77.8%, respectively. The incidence rate of valproate-exposed pregnancies decreased from 16.9 to 10.9 per 1000 person-years in the pre- and post-implementation periods, respectively. CONCLUSIONS: Results from this study indicated some improvement in physician prescribing and a potential reduction in valproate-exposed pregnancies in the UK. Given only modest improvement has been achieved, additional RMMs were implemented in 2018.

Safety and Persistence of Nalmefene Treatment for Alcohol Dependence. Results from Two Post-authorisation Safety Studies.

AIMS: Two post-authorisation studies assessed the safety and persistence of patients' use of nalmefene. METHODS: The START study (EUPAS5678) was a non-interventional, multi-country, prospective, 18-month (8 follow-up visits) cohort study including outpatients initiating nalmefene for the first time. The multi-database retrospective cohort study (MDRC, EUPAS14083) included baseline and follow-up data from German, Swedish and UK healthcare databases. Both studies permitted 'all comers' without explicit exclusion criteria; predefined subgroups of interest included the elderly (≥65 years) as well as patients with significant psychiatric and/or somatic comorbidities. RESULTS: START study: Overall, the mean duration of nalmefene treatment was 10.3 ± 7.3 months (N = 1348), with 49.0% of patients treated for ≥1 year; frequent reasons for treatment discontinuation were 'goal reached' and 'drug cost'. The most frequently reported adverse drug reactions (ADRs) were nausea (4.7%), dizziness (3.2%) and insomnia (2.0%). ADR rates appeared higher in the elderly subpopulation (18.6% reported ≥1 ADR vs. 12.0% in the total population) but were not higher in the other predefined subgroups.MDRC study: The database follow-up analysis followed 2892 patients over 18 months for whom the duration of nalmefene treatment was between 2 and 3 months and <5% of patients used nalmefene for ≥1 year. CONCLUSIONS: Despite the inclusion of a wider patient population (e.g. elderly patients and those with relevant co-morbidities), the safety and tolerability profile of nalmefene given in routine practice was consistent with previous clinical studies. The differing rates of persistence beyond 1 year likely reflect the different methodologies and highlight the relevance of psychosocial support at follow-up visits.

Assessment of Healthcare Professionals' Knowledge and Understanding of the Risk of Blood Typing Interference with Daratumumab: A Survey of 12 European Countries.

INTRODUCTION: Daratumumab, a monoclonal antibody targeting CD38, is approved to treat multiple myeloma. Red blood cells express low levels of CD38, which can result in a false-positive antibody screen in daratumumab-treated patients. Educational materials were developed to inform healthcare professionals (HCPs) and blood transfusion management department personnel (BTMDP) about this risk and recommended measures to mitigate that risk. Materials were distributed in European countries where daratumumab was commercially available. This post-authorization safety study was designed to evaluate whether HCPs and BTMDP understood the materials. METHODS: An anonymous, cross-sectional, non-interventional, web-based survey was distributed in 12 European countries. Four key questions were identified, for which a correct answer from at least 80% of respondents was considered indicative of satisfactory effectiveness. RESULTS: A total of 408 participants completed the questionnaires (62.3% (n = 254) HCPs and 37.7% (n = 154) BTMDP). Responses were consistent between groups. All respondents were aware of the educational materials (the first key question) and at least 80% correctly answered three of the four key questions. A key question regarding which blood typing test(s) daratumumab interferes with did not achieve satisfactory effectiveness (60% correct responses). In a weighted analysis, 79% of respondents correctly identified the recommended measures for daratumumab-treated patients requiring transfusion. This was attributed to an error in the survey's German translation; in a sensitivity analysis, 90% of participants correctly responded to this question. CONCLUSIONS: Results suggest that participants were aware of the educational materials, the risk of daratumumab interference with blood testing, and recommended measures to mitigate that risk.

Real world utilization of 91 day extended levonorgestrel-containing combined oral contraceptives in Europe: a multinational database study.

OBJECTIVE: As part of the risk management plan in Europe, this study was conducted to characterize drug utilization patterns of Seasonique, a 91 day extended levonorgestrel-containing combined oral contraceptive (COCLNG). METHODS: A retrospective observational study was conducted in France, Italy and Belgium using electronic medical record databases obtained from general practitioners (GPs) in all participating countries and gynecologists in France from 2015 to 2018. The study population included women receiving ≥1 prescription of 91 day COCLNG during the study period. Prescribing patterns of 91 day COCLNG were examined including: (1) treatment duration; (2) indication; (3) use of combined oral contraceptive (COC) before 91 day COCLNG initiation; and (4) switch from and to combined hormonal contraceptives (CHCs) or other contraceptives. RESULTS: Totals of 235, 220, 207 and 659 women using 91 day COCLNG were identified in French, Italian and Belgian GP, and French gynecologist databases, respectively. Across databases, 46-76% of women were prescribed a single 91 day COCLNG prescription and median treatment duration ranged from 3 to 6 months. The most common indication was contraception (42-81%), followed by menstrual migraines (2-14%). Use of COC during the 6 months prior to 91 day COCLNG initiation was 14% across GP databases, but was lower (8%) in the French gynecologist database. The frequency of switching from 91 day COCLNG to CHCs or other contraceptives was generally low (5-12%), with the highest proportion being among patients of French gynecologists. CONCLUSIONS: Findings indicate that 91 day COCLNG was prescribed for relatively short durations and predominantly as indicated for contraception. Most results were comparable across all participating countries. KEY POINTSFindings from this drug utilization study in European databases across general practitioners and French gynecologists confirmed that 91 day extended levonorgestrel-containing combined oral contraceptive (COCLNG) was prescribed for relatively short durations (median 3-6 months); predominantly for the intended indication of contraception.Combined oral contraceptive use during the 6 months prior to 91 day COCLNG initiation, and switching from 91 day COCLNG to combined hormonal contraceptives or other contraceptives, were generally low (14% or less).These findings were mostly consistent across participating countries.

Effectiveness of risk minimisation measures for valproate: A cross-sectional survey among physicians in Europe.

PURPOSE: This study evaluated the effectiveness of risk minimisation measures (RMMs) implemented following the 2014 referral for valproate in Europe. METHODS: Cross-sectional survey was conducted over 2-month period in 2016 among physicians who prescribed valproate in France, Germany, the United Kingdom, Spain and Sweden. The web-based questionnaire included five endpoints to evaluate physicians' knowledge on (a) prescribing valproate only for epilepsy and bipolar disorder in women if other treatments were ineffective or not tolerated; (b) ensuring supervision by experienced physicians while treating these conditions; (c) considering alternative treatments for women planning pregnancy, regular review of treatment needs and re-assessing the benefit-risk balance in women and girls reaching puberty; (d) informing patients about the risks of taking valproate during pregnancy and (e) advising women on effective contraception during their treatment. RESULTS: Among 1153 physicians, 95.5% responded prescribing valproate for epilepsy and bipolar disorder in women only if other treatments are ineffective/not tolerated; 66.5% supervised while treatment; 76.6% considered alternative treatments for women planning pregnancy; 92.1% informed patients about the risks of taking valproate during pregnancy and 94.4% advised patients on the use of effective contraception during its treatment. Overall, 25.8% physicians recalled receiving both educational material (EM) and Dear Healthcare Professional Communication (DHPC). All endpoint rates were higher for physicians who acknowledged receipt of both DHPC and EM compared to physicians who did not receive them. CONCLUSIONS: Although results varied across geography and physician speciality, majority of physicians had good knowledge about the indication and safety aspects of prescribing and using valproate.

Effectiveness of risk minimisation measures for valproate: A drug utilisation study in Europe.

PURPOSE: The purpose of this study was to evaluate the effectiveness of the risk minimisation measures (RMMs) implemented in Europe in 2014 for valproate-containing products to mitigate their risk during pregnancy and to characterise valproate prescribing patterns in women of childbearing potential (WCBP) before and after implementation of RMMs. METHODS: A multinational cohort study based on existing data sources using a pre-/post- design was performed in five European countries (France, Germany, Spain, Sweden, UK) in an outpatient setting. Effectiveness of RMMs was assessed by comparing the proportion of valproate initiations as second (or subsequent) line therapy before and after implementation of RMMs (primary outcome) with an increase in this proportion indicating success of RMMs. Overall use of valproate and incidence of pregnancies in WCBP were also examined. RESULTS: The proportion of valproate initiations as second line therapy increased after implementation of RMMs in incident female users in Sweden (from 81.1%, 95% CI 79.9%-82.3% to 84.5%, 95% CI 83.5%-85.5%) and the UK (from 66.4%, 95% CI 64.5%-68.3% to 72.4%, 95% CI 70.0%-74.9%), it remained the same in Germany and Spain and decreased in France from 48.7% (95% CI 45.6%-51.9%) to 40.6% (95% CI 37.6%-43.7%). In Sweden and the UK, the incidence of pregnancies exposed to valproate decreased in the post-implementation period: 8.0 vs 9.5 and 10.9 vs 16.9 per 1000 person-years, respectively. CONCLUSION: The results on primary outcome of this study suggest limited effectiveness of the RMMs. Additional RMMs were implemented in 2018.

A drug utilization study to evaluate effectiveness of risk minimization measures for trimetazidine in France, Hungary, Romania and Spain.

WHAT IS KNOWN AND OBJECTIVE: The approved indication for trimetazidine (TMZ) was restricted to "add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies" in 2012 by the Committee for Medicinal Products for Human Use (CHMP). TMZ was no longer indicated for ophthalmology and otolaryngology (ENT) indications. This drug utilization study analysed actual utilization of TMZ before and after the restriction on its indications to evaluate the effectiveness of risk minimization measures (RMM). METHODS: This was a multi-national, cross-sectional, non-interventional drug utilization study using European databases: IMS Prescribing Insights (PI) for France and Spain, National Diagnostic Index (NDI) for Romania and National Prescription Audit (NPA) for Hungary. TMZ prescriptions issued by Ear-Nose-Throat (ENT) specialists, ophthalmologists, cardiologists and General Physicians (GPs)/others were analysed during the 24-month period before (reference period) and after RMM implementation (assessment period). RESULTS AND DISCUSSION: During the assessment period, most of the TMZ prescriptions for ENT and ophthalmology indications (un-authorized indications) were made by GPs/others followed by ENT specialists, ophthalmologists and cardiologists in most of the countries. The proportion of TMZ prescriptions for ENT or ophthalmological indications after the restrictions on indication was reduced in Hungary (by 0.4%) and Spain (by 11.8%), remained the same in Romania and increased in France (by 3.7%). WHAT IS NEW AND CONCLUSION: This study showed that a significant proportion of TMZ prescriptions was off-label for ENT or ophthalmological indications following the RMM implementation. More effective RMM strategies are required to reduce off-label prescriptions of TMZ.

Evaluation of the Reported Rates of Severe Hypersensitivity Reactions Associated with Ferric Carboxymaltose and Iron (III) Isomaltoside 1000 in Europe Based on Data from EudraVigilance and VigiBase™ between 2014 and 2017.

INTRODUCTION: Hypersensitivity reactions (HSRs) are among the known adverse events of intravenous (i.v.) iron products. Of these, particularly severe HSRs such as anaphylaxis are of great clinical concern due to their life-threatening potential. METHODS: This was a retrospective pharmacoepidemiological study with a case-population design evaluating the number of reported severe HSRs following administration of the two i.v. iron products-ferric carboxymaltose and iron (III) isomaltoside 1000-in relation to exposure in European countries from January 2014 to December 2017. Exposure to both products was estimated using IQVIA MIDAS sales data in European countries. Information on spontaneously reported severe HSRs was obtained from and analysed separately for the two established safety surveillance databases EudraVigilance and VigiBase™ using the MedDRA® Preferred Terms anaphylactic reaction, anaphylactic shock, anaphylactoid reaction and anaphylactoid shock associated with administration of either product. RESULTS: Between 2014 and 2017, the reporting rate of severe HSRs per 100,000 defined daily doses (100 mg dose equivalents of iron) varied from 0.3 to 0.5 for ferric carboxymaltose and from 2.4 to 5.0 for iron (III) isomaltoside 1000. The reporting rate ratio for iron (III) isomaltoside 1000 versus ferric carboxymaltose was between 5.6 (95% CI 3.5-9.0) and 16.2 (95% CI 9.4-27.8). CONCLUSIONS: Findings suggest that iron (III) isomaltoside 1000 is associated with a higher reporting rate of severe HSRs related to estimated exposure than ferric carboxymaltose in European countries. Future research investigating the occurrence of severe HSRs associated with i.v. ferric carboxymaltose and iron (III) isomaltoside 1000 is needed to broaden the evidence for benefit-risk assessment.

Evaluation of the effectiveness of risk minimization measures for trimetazidine: A cross sectional joint PASS survey among physicians in selected European countries.

PURPOSE: In 2012, the Committee for Medicinal Products for Human Use (CHMP) restricted prescription of trimetazidine (TMZ) to "add-on therapy for patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line therapies." TMZ was no longer indicated for ophthalmology and otolaryngology. Risk minimization measure (RMM) was communicated to physicians. The survey presented here evaluated effectiveness of the RMM and assessed physicians knowledge and compliance with RMM. It also analyzed actual prescribing pattern of TMZ. METHODS: A cross sectional, web-based survey was developed and conducted among prescribing physicians of TMZ across 12 European countries. Physicians' samples were weighted to account for the actual proportion of specialties within and across countries. RESULTS: Using weighted samples, data from 1123 physicians and 8332 prescriptions were analyzed. Most (74.0%) of the physicians assumed stable angina pectoris to be an indication for TMZ. Three quarter of (75.7%) of these physicians were aware of the approved indication. Vertigo (62.1%), tinnitus (42.5%), declined visual acuity, and visual field disturbances (45.1%) were also presumed to be approved indications for TMZ, and physicians actually prescribed for these indications. Only 29.8% of the physicians remembered receiving RMM communications regarding TMZ. Most (90.5%) of the physicians expressed their interest to know and comply with the safety communications. Of all prescriptions, 33.9% were issued for add-on therapy for patients with stable angina pectoris. CONCLUSIONS: RMM for TMZ prescription have been moderately effective. Improvement in physician's compliance with safety information of TMZ is necessary for patient's safety.

Microvascular Outcomes in Patients with Type 2 Diabetes Treated with Vildagliptin vs. Sulfonylurea: A Retrospective Study Using German Electronic Medical Records.

INTRODUCTION: Preliminary data suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors may reduce microvascular events, but there is a little evidence to support this from adequate real-world studies. This study aimed to compare microvascular outcomes between patients-prescribed vildagliptin and those prescribed sulfonylurea (SU). METHODS: This retrospective cohort study was conducted on a large sample from the German electronic medical records database IMS Lifelink Disease Analyzer. We used propensity score-matched samples of patients prescribed either vildagliptin or SU. Exposure was defined as therapy (SU or vildagliptin); primary outcomes were a diagnosis of retinopathy, nephropathy, neuropathy, or diabetic foot ulcer over the observation period in patients with no previous record of these outcomes. Secondary outcome was a composite of any primary outcome occurring in the observation period. RESULTS: In total, 16,321 patients prescribed SU and 4481 prescribed vildagliptin met the inclusion criteria. After propensity score matching, each sample comprised 3015 patients. Mean age was 63.7/64.6 years for SU/vildagliptin, respectively, with mean disease duration of 3.2/3.1 years, and mean treatment duration of 2.5/2.3 years. Treatment with vildagliptin was associated with a significant lower incidence of retinopathy [odds ratio (OR) = 0.55, P = 0.0004], neuropathy (OR 0.71, P = 0.0001), and composite outcome (OR 0.70, P < 0.0001). Incidences of nephropathy and diabetic foot ulcer were lower for vildagliptin, but not significantly so (OR 0.90, P = 0.3920; OR 0.76, P = 0.0742, respectively). There were no significant differences in incident rate ratios (all P > 0.05). CONCLUSION: Treatment with vildagliptin was associated with a reduced incidence of microvascular complications, especially neuropathy and retinopathy, compared to treatment with SU in this clinical practice setting. FUNDING: Novartis Pharma AG.

Liver transplant associated with paracetamol overdose: results from the seven-country SALT study.

AIMS: Acute drug overdose, especially with paracetamol, may cause acute liver failure leading to registration for transplantation (ALFT). Population statistics and between-country differences for ALFT related to overdose have been poorly described. The aim of the present study was to evaluate overdose ALFT in the multi-country Study of Acute Liver Transplantation (SALT). METHODS: All adult overdose-related ALFT, with or without suicidal intent, in France, Greece, Ireland, Italy, the Netherlands, Portugal and the UK between 2005 and 2007 were identified from liver transplant registries and hospital records. These were compared with whole-country and per capita use of paracetamol. RESULTS: Six hundred cases of ALFT were identified in 52 of 57 eligible transplant centres, of which 114 involved overdose (72 intentional, 10 non-intentional, 32 uncertain). Overdose represented 20% of all-cause ALFT: Ireland 52%, UK 28%, France 18%, the Netherlands 8%, and Italy 1%. Overdose ALFT were mostly females (61%), mean age 33.6 ± 10.9 years. A total of 111 (97%) of the overdoses involved paracetamol. Event rates ranged from one ALFT for 20.7 tons of paracetamol in Ireland, to one for 1074 tons in Italy and one case in 60 million inhabitants over 3 years in Italy to one case in 286 000 inhabitants per year in Ireland. Per-country event rates for non-overdose ALFT exposed to paracetamol were between 2.5 and 4.0 per million treatment-years sold. CONCLUSIONS: Paracetamol overdose was found to represent one-sixth of all-cause ALFT. There was a 50-fold difference in Europe in the rates of paracetamol overdose ALFT, and a 200-fold difference per million inhabitants.

Using data mining techniques to explore physicians' therapeutic decisions when clinical guidelines do not provide recommendations: methods and example for type 2 diabetes.

BACKGROUND: Clinical guidelines carry medical evidence to the point of practice. As evidence is not always available, many guidelines do not provide recommendations for all clinical situations encountered in practice. We propose an approach for identifying knowledge gaps in guidelines and for exploring physicians' therapeutic decisions with data mining techniques to fill these knowledge gaps. We demonstrate our method by an example in the domain of type 2 diabetes. METHODS: We analyzed the French national guidelines for the management of type 2 diabetes to identify clinical conditions that are not covered or those for which the guidelines do not provide recommendations. We extracted patient records corresponding to each clinical condition from a database of type 2 diabetic patients treated at Avicenne University Hospital of Bobigny, France. We explored physicians' prescriptions for each of these profiles using C5.0 decision-tree learning algorithm. We developed decision-trees for different levels of detail of the therapeutic decision, namely the type of treatment, the pharmaco-therapeutic class, the international non proprietary name, and the dose of each medication. We compared the rules generated with those added to the guidelines in a newer version, to examine their similarity. RESULTS: We extracted 27 rules from the analysis of a database of 463 patient records. Eleven rules were about the choice of the type of treatment and thirteen rules about the choice of the pharmaco-therapeutic class of each drug. For the choice of the international non proprietary name and the dose, we could extract only a few rules because the number of patient records was too low for these factors. The extracted rules showed similarities with those added to the newer version of the guidelines. CONCLUSION: Our method showed its usefulness for completing guidelines recommendations with rules learnt automatically from physicians' prescriptions. It could be used during the development of guidelines as a complementary source from practice-based knowledge. It can also be used as an evaluation tool for comparing a physician's therapeutic decisions with those recommended by a given set of clinical guidelines. The example we described showed that physician practice was in some ways ahead of the guideline.