Covid-19 Vaccines: Is the Seriousness Criterion ''Medically Important'' Applied Correctly in Reports and Are There Differences between HCPs and Non-HCPs?

Introduction: During the Covid-19 vaccination campaign, Swissmedic received approximately 50% of the spontaneous reports from health care professionals (HCP) and 50% directly from patients/consumers. The rate of adverse drug reactions (ADRs) following Covid-19 vaccination categorized as ''serious'' by the reporters is approximately 35% in Switzerland and thus significantly higher than e.g. in the US (6.6%), while rates of reports with fatal outcome are comparable (1.4% vs. 1.3%) (1). A high proportion of the cases labelled as ''serious'' in Switzerland was classified based on the category ''medically important''. Since this criterion is used very commonly but is less distinct than the other seriousness criteria, we aimed to analyze whether it is used correctly by the reporters and whether differences between healthcare professionals and patients/consumer can be identified. Objective(s): To evaluate the appropriate usage of the seriousness criterion ''medically important'' in spontaneous ADR reports submitted by health care professionals compared to non-health care professionals following immunization with a Covid-19 vaccine. Method(s): All serious ADR reports received between the 1st of January 2021 and 31st of December 2021 following immunization with a Covid-19 vaccine were extracted from the Swiss database. Cases categorized as ''medically important'' were further analyzed. We extracted the preferred terms (PT) according to the medical dictionary for regulatory activities (MedDRA) (2) of the reported ADRs and matched them with the important medical event terms list (IME list) (3). Result(s): From a total of 11,115 ADR reports, 4,125 (37.1%) were classified as ''serious''. 2,773 (67.2%) of the serious cases were reported by HCPs and 1,352 (32.8%) by non-HCPs. In 2,260 (55%) reports, the seriousness was based solely on the criterion ''medically important''. 755 (33.4%) of these reports would also be classified as ''serious'' according to the IME List. 498 (39%) reports by HCP and 257 (26%) by non-HCP match with the IME list. The proportion of correctly categorized ADRs is significantly higher (p<0.0001) in reports from HCPs compared to non-HCPs. Conclusion(s): Only approximately one third of the cases, which were classified as ''medically important'' and thus reported as ''serious'', would also be classified as such according to the IME list. The proportion of correctly categorized ADRs is significantly higher in reports from HCPs. Additional information and training for HCPs appears necessary to achieve a higher rate of appropriate seriousness categorization in ADR reports. The usage of the category ''medically important'' in reports by patients/consumers requires general revision.

Spontaneous Reports of Delayed Urticaria Following Booster Vaccination with Spikevax in Switzerland

Introduction: The post-marketing surveillance of COVID-19 mRNA vaccines revealed that urticarial reactions could occur with a delayed time course following both primary vaccinations [1-4] and the booster vaccinations [5,6]. While delayed urticarial reactions following COVID-19 primary vaccinations resolve in general with a median of 2-4 days, delayed urticaria after booster vaccination can show a prolonged and intermittent clinical course requiring treatment for several weeks [5,6]. Shortly after the booster vaccination campaign began in Switzerland in December 2021, an increasing number of delayed urticarial reactions in association with Spikevax was reported to Swissmedic, whereby a safety signal was opened. Objective(s): To characterize cases of delayed urticarial reactions reported in Switzerland following booster vaccination with Spikevax. Method(s): Case-by-case assessment of spontaneously reported delayed urticarial reactions following booster vaccination with Spikevax recorded in the Swiss national pharmacovigilance database up to February 8th, 2022. Result(s): There were 107 cases of delayed urticaria following booster vaccination with Spikevax. Of these, 79 (73.8%) were reported by consumers/non-health professionals. Women were more frequently affected (55, 51.4%) and median age was 38 years (interquartile range, IQR, 34-44 years). Urticaria developed a median of 10 days after booster vaccination (IQR 9-11.5 days). In 55 (51.4%) cases, urticaria was the solely reported adverse event, whilst 52 (48.6%) cases reported urticaria with additional adverse events, including pruritus (n = 27) and angioedema (n = 7). In 81 (75.7%) cases, delayed urticaria had not serious consequences (i.e. did not require/ prolonged hospitalisation, was not disabling/incapacitating, did not determine other clinically relevant conditions). In 69 (64.5%) cases the outcome of urticaria was not recovered at the time of reporting, which occurred a median of 14 days after booster administration (IQR 6-21 days). Conclusion(s): To our knowledge, this is the first case series to date of delayed urticaria following booster vaccination with Spikevax, showing that these reactions were more frequently not self-limiting and with a prolonged course in contrast to delayed urticaria developed after COVID-19 mRNA primary vaccinations. Although these reactions should not discourage from subsequent COVID-19 mRNA vaccinations, further investigations with regard to additional booster vaccinations seem necessary.

Signal Detection by Disproportionality Analysis in the Monitoring of COVID-19 Vaccine Safety in Switzerland

Introduction: Initial knowledge on the COVID-19 vaccines' safety from randomised clinical trials was limited and concerned mostly common adverse events related to vaccine immunogenicity occurring rapidly after vaccination [1,2]. Since these vaccines have been approved and used in large scale, the Swiss Agency for Therapeutic Products Swissmedic has been conducting an intensive surveillance activity on their safety, based on the collection and analysis of spontaneous reports from healthcare professionals and patients. Objective(s): Signal detection in spontaneous reports associated with COVID-19 vaccines first relies on a case-by-case analysis by clinically qualified assessors who take into account detailed information provided by reporters. However, with the number of reports increasing, the clinical review could benefit from the use of statistical methods for signal detection, such as disproportionality analysis [3]. Method(s): In light of this, the Institute of Pharmacological Sciences of Southern Switzerland, in close collaboration with Swissmedic, set up and routinely perform a signal detection activity by disproportionality analysis in VigiBase, the global database of the World Health Organization (WHO) Programme for International Drug Monitoring, using spontaneous reports originating from Switzerland and concerning adverse events following immunization (AEFIs) associated with the Moderna (Spikevax) and Pfizer/BioNTech (Comirnaty) COVID-19 vaccines. These included the measurement of the reporting odds ratios (RORs) for COVID-19 vaccine/AEFI combinations meeting two predefined statistical signal detection criteria, namely a minimum of 5 reports concerning a COVID-19 vaccine/AEFI combination and a ROR lower limit of the 95% confidence interval>1. Excluding AEFIs either already labelled in the Swiss information for healthcare professionals, or already debated internationally, a panel of pharmacovigilance and clinical pharmacology experts are examining and discussing findings on novel and unexpected COVID-19 vaccine/ AEFI combinations, in order to promptly detect potential safety signals that could warrant further investigation. Result(s): Since the start of the signal detection activity in August 2021, an early signal of disproportionate reporting in VigiBase for paraesthesia with the Moderna (Spikevax) vaccine was detected in Switzerland. This occurred a few months before the same signal was assessed and validated by the European Medicines Agency, which ultimately added paraesthesia to the European summary of product characteristics for the Moderna (Spikevax) vaccine [4]. Conclusion(s): Disproportionality analysis has some limitations such as lack of information about incidence rate of the adverse event in the population, and the existence of reporting biases. Nevertheless, continued research on newly identified safety signals can provide valuable information to support public health, guide regulatory decisions and design specific follow-up confirmatory studies.

Covid-19 Vaccines: Is the Seriousness Criterion "Medically Important" Applied Correctly in Reports and Are There Differences between HCPs and Non-HCPs?: An International Journal of Medical Toxicology and Drug Experience

Introduction: During the Covid-19 vaccination campaign, Swissmedic received approximately 50% of the spontaneous reports from health care professionals (HCP) and 50% directly from patients/consumers. The rate of adverse drug reactions (ADRs) following Covid-19 vaccination categorized as "serious" by the reporters is approximately 35% in Switzerland and thus significantly higher than e.g. in the US (6.6%), while rates of reports with fatal outcome are comparable (1.4% vs. 1.3%) (1). A high proportion of the cases labelled as "serious" in Switzerland was classified based on the category "medically important". Since this criterion is used very commonly but is less distinct than the other seriousness criteria, we aimed to analyze whether it is used correctly by the reporters and whether differences between healthcare professionals and patients/consumer can be identified. Objective: To evaluate the appropriate usage of the seriousness criterion "medically important" in spontaneous ADR reports submitted by health care professionals compared to non-health care professionals following immunization with a Covid-19 vaccine. Methods: All serious ADR reports received between the 1st of January 2021 and 31st of December 2021 following immunization with a Covid-19 vaccine were extracted from the Swiss database. Cases categorized as "medically important" were further analyzed. We extracted the preferred terms (PT) according to the medical dictionary for regulatory activities (MedDRA) (2) of the reported ADRs and matched them with the important medical event terms list (IME list) (3). Results: From a total of 11,115 ADR reports, 4,125 (37.1%) were classified as "serious". 2,773 (67.2%) of the serious cases were reported by HCPs and 1,352 (32.8%) by non-HCPs. In 2,260 (55%) reports, the seriousness was based solely on the criterion "medically important". 755 (33.4%) of these reports would also be classified as "serious" according to the IME List. 498 (39%) reports by HCP and 257 (26%) by non-HCP match with the IME list. The proportion of correctly categorized ADRs is significantly higher (p < 0.0001) in reports from HCPs compared to non-HCPs. Conclusion: Only approximately one third of the cases, which were classified as "medically important" and thus reported as "serious", would also be classified as such according to the IME list. The proportion of correctly categorized ADRs is significantly higher in reports from HCPs. Additional information and training for HCPs appears necessary to achieve a higher rate of appropriate seriousness categorization in ADR reports. The usage of the category "medically important" in reports by patients/consumers requires general revision.

Spontaneous Reports of Delayed Urticaria Following Booster Vaccination with Spikevax® in Switzerland: An International Journal of Medical Toxicology and Drug Experience

Introduction: The post-marketing surveillance of COVID-19 mRNA vaccines revealed that ürticarial reactions coüld occür with a delayed time course following both primary vaccinations [1-4] and the booster vaccinations [5,6]. While delayed urticarial reactions following COVID-19 primary vaccinations resolve in general with a median of 2-4 days, delayed urticaria after booster vaccination can show a prolonged and intermittent clinical course requiring treatment for several weeks [5,6]. Shortly after the booster vaccination campaign began in Switzerland in December 2021, an increasing number of delayed urticarial reactions in association with Spikevax® was reported to Swissmedic, whereby a safety signal was opened. Objective: To characterize cases of delayed urticarial reactions reported in Switzerland following booster vaccination with Spikevax®. Methods: Case-by-case assessment of spontaneously reported delayed urticarial reactions following booster vaccination with Spikevax® recorded in the Swiss national pharmacovigilance database up to February 8th, 2022. Results: There were 107 cases of delayed urticaria following booster vaccination with Spikevax®. Of these, 79 (73.8%) were reported by consumers/non-health professionals. Women were more frequently affected (55, 51.4%) and median age was 38 years (interquartile range, IQR, 34-44 years). Urticaria developed a median of 10 days after booster vaccination (IQR 9-11.5 days). In 55 (51.4%) cases, urticaria was the solely reported adverse event, whilst 52 (48.6%) cases reported urticaria with additional adverse events, including pruritus (n = 27) and angioedema (n = 7). In 81 (75.7%) cases, delayed urticaria had not serious consequences (i.e. did not require/ prolonged hospitalisation, was not disabling/incapacitating, did not determine other clinically relevant conditions). In 69 (64.5%) cases the outcome of urticaria was not recovered at the time of reporting, which occurred a median of 14 days after booster administration (IQR 6-21 days). Conclusion: To our knowledge, this is the first case series to date of delayed urticaria following booster vaccination with Spikevax®, showing that these reactions were more frequently not self-limiting and with a prolonged course in contrast to delayed urticaria developed after COVID-19 mRNA primary vaccinations. Although these reactions should not discourage from subsequent COVID-19 mRNA vaccinations, further investigations with regard to additional booster vaccinations seem necessary.

Signal Detection by Disproportionality Analysis in the Monitoring of COVID-19 Vaccine Safety in Switzerland: An International Journal of Medical Toxicology and Drug Experience

Introduction: Initial knowledge on the COVID-19 vaccines' safety from randomised clinical trials was limited and concerned mostly common adverse events related to vaccine immunogenicity occurring rapidly after vaccination [1,2]. Since these vaccines have been approved and used in large scale, the Swiss Agency for Therapeutic Products Swissmedic has been conducting an intensive surveillance activity on their safety, based on the collection and analysis of spontaneous reports from healthcare professionals and patients. Objective: Signal detection in spontaneous reports associated with COVID-19 vaccines first relies on a case-by-case analysis by clinically qualified assessors who take into account detailed information provided by reporters. However, with the number of reports increasing, the clinical review could benefit from the use of statistical methods for signal detection, such as disproportionality analysis [3]. Methods: In light of this, the Institute of Pharmacological Sciences of Southern Switzerland, in close collaboration with Swissmedic, set up and routinely perform a signal detection activity by disproportionality analysis in VigiBase, the global database of the World Health Organization (WHO) Programme for International Drug Monitoring, using spontaneous reports originating from Switzerland and concerning adverse events following immunization (AEFIs) associated with the Moderna (Spikevax) and Pfizer/BioNTech (Comirnaty) COVID-19 vaccines. These included the measurement of the reporting odds ratios (RORs) for COVID-19 vaccine/AEFI combinations meeting two predefined statistical signal detection criteria, namely a minimum of 5 reports concerning a COVID-19 vaccine/AEFI combination and a ROR lower limit of the 95% confidence interval[1. Excluding AEFIs either already labelled in the Swiss information for healthcare professionals, or already debated internationally, a panel of pharmacovigilance and clinical pharmacology experts are examining and discussing findings on novel and unexpected COVID-19 vaccine/AEFI combinations, in order to promptly detect potential safety signals that could warrant further investigation. Results: Since the start of the signal detection activity in August 2021, an early signal of disproportionate reporting in VigiBase for paraesthesia with the Moderna (Spikevax) vaccine was detected in Switzerland. This occurred a few months before the same signal was assessed and validated by the European Medicines Agency, which ultimately added paraesthesia to the European summary of product characteristics for the Moderna (Spikevax) vaccine [4]. Conclusion: Disproportionality analysis has some limitations such as lack of information about incidence rate of the adverse event in the population, and the existence of reporting biases. Nevertheless, continued research on newly identified safety signals can provide valuable information to support public health, guide regulatory decisions and design specific follow-up confirmatory studies.