Duration of Effectiveness Evaluation of Additional Risk Minimisation Measures for Centrally Authorised Medicinal Products in the EU Between 2012 and 2021.

INTRODUCTION: In studies evaluating the effectiveness of additional risk minimisation measures (aRMMs), the need for speed must be properly balanced with the quality of the study. We assessed the duration of aRMM effectiveness evaluations, using additional pharmacovigilance activities, for centrally authorised medicinal products in the European Union. METHODS: We established a cohort of medicinal products with aRMMs at marketing authorisation (MA) that were centrally authorised from July 2012-December 2021 using the European Public Assessment Reports. Evaluation studies were identified from the Risk Management Plans at the time of MA. Subsequently, we retrieved protocols, final study reports, Pharmacovigilance Risk Assessment Committee (PRAC) assessment reports, and PRAC minutes. We calculated the probability of completing an effectiveness evaluation within 60 months after MA using time-to-event analyses. Besides, we compared the planned final report with the actual final report date. RESULTS: We identified 134 medicinal products authorised with aRMMs, of which almost half (n = 63, 47.0%) had an effectiveness evaluation study. The probability of an evaluation for a medicinal product being completed within 60 months after MA was 20.7% (95% CI 6.8-32.6). Regarding study design, the probability of completing a study was higher for cross-sectional studies when compared to cohort studies (p = 0.002). Moreover, 81.0% of studies were delayed when compared to their planned final report date. CONCLUSION: The probability of completing an aRMM effectiveness evaluation at time for renewal of the MA was only one in five. Furthermore, estimates of the duration of studies around MA are too optimistic, with the majority being delayed.

3-Methylmethcathinone (3-MMC) Poisonings: Acute Clinical Toxicity and Time Trend Between 2013 and 2021 in the Netherlands.

STUDY OBJECTIVE: The synthetic cathinone 3-methylmethcathinone (3-MMC, or metaphedrone) has recently gained popularity. We studied the numbers of 3-MMC poisonings over time and the clinical effects following poisonings with 3-MMC. METHODS: We performed a retrospective study on the numbers of self-reported 3-MMC poisonings to the Dutch Poisons Information Center (DPIC) from 2013 to June 2021. For poisonings reporting 3-MMC only, the symptoms were extracted and the Poisoning Severity Score (PSS) was determined. From 2016 to June 2019, a prospective cohort study on poisonings reporting only 3-MMC was performed, in which details on the clinical courses were collected through telephone interviews. RESULTS: From 2013 to June 2021, the DPIC was consulted on 184 3-MMC poisonings. The number of poisonings increased from 1 in 2013 to 70 in the first half of 2021. In 84 poisonings with only 3-MMC (46%), sympathomimetic symptoms were commonly reported, including tachycardia (n=29, 35%), hypertension (n=17, 20%), and agitation (n=16, 19%). The initial PSS was usually minor (n=37, 44%) to moderate (n=39, 46%). Five patients (6%) experienced severe effects, including 3 patients experienced severe hypertension (systolic blood pressure >180 mmHg; n=3) and nonfatal cardiac arrest (n=1). Sympathomimetic symptoms (n=8) were also reported in the prospective cohort study. The percentage of moderate poisonings increased (n=6, 75%), and 1 (13%) severe poisoning was observed. Analytical confirmation of 3-MMC exposure was performed in 2 cases. CONCLUSION: The number of 3-MMC poisonings reported to the DPIC has increased over time. Most poisonings with 3-MMC resulted in moderate toxicity and involved sympathomimetic effects, while severe effects were observed in 5 cases.

Significant toxicity following an increase in poisonings with designer benzodiazepines in the Netherlands between 2010 and 2020.

BACKGROUND: Designer benzodiazepines (DBs) are an emerging class of new psychoactive substances. While structurally derived from pharmaceutical benzodiazepines, their toxicological profile is less clear. We investigated time trends in the rate of DB poisonings and their clinical toxicity. METHODS: A retrospective observational study was performed on the incidence rate of DB poisonings, relative to all recreational drug poisonings reported to the Dutch Poisons Information Center (DPIC) from 2010 to 2020. Time-trend analysis was performed using Poisson regression. A prospective cohort study was performed on toxicity of DBs, including the Poisoning Severity Score, from January 2016-June 2019. Data was collected through telephone interviews. RESULTS: Between 2010 and 2020, the DPIC was consulted on 142 DB exposures. The incidence rate of DB exposures increased from 0.1% to 4.3%, with a year effect estimate of 1.35 (95% CI [1.14;1.54]). Twenty different DBs were reported, mostly etizolam (33%), clonazolam (17%), and flunitrazolam (8%). During consultation (often shortly after exposure), poisoning was graded moderate-severe in 29% of cases (n = 146). In the prospective cohort sample with follow-up (n = 22), 86% of cases (n = 19) showed a moderate-severe poisoning. The severity of poisoning did not differ between mono- and mixed intoxications. Frequently reported symptoms in the prospective cohort sample included drowsiness (86%), confusion (59%), and agitation (55%). Coma was observed in seven cases (32%) and respiratory depression requiring mechanical ventilation in five cases (23%). CONCLUSION: The rate of DB poisonings reported to the DPIC strongly increased from 2010 to 2020, indicating increased (ab)use of DBs. Most DB exposures resulted in moderate-severe toxicity with neurological effects.