Level of therapeutic innovation from the registration studies of the new drugs for the prophylaxis of migraine.

WHAT IS KNOWN AND OBJECTIVE: Migraine is one of the most prevalent and disabling medical illnesses. Preventive drugs are used to reduce the frequency, severity, and duration of attacks. Most patients were no longer on their medication due to contraindications or poor clinical response. Therefore, there is need for novel prophylactic agents for migraine. New preventive treatments are those of the class of calcitonin gene related peptide (CGRP)-targeting therapies. We aimed to assess the real level of therapeutic innovation of these new drugs. METHODS: The information on the new drugs was collected from several documents, including the European public assessment reports. The level of therapeutic innovation was assessed with the algorithm published by some of us in 2006. RESULTS: All new approved drugs (eptinezumab, galcanezumab, fremanezumab, erenumab) are indicated for the prophylaxis of migraine in adults who have at least four migraine days for month. All these drugs have been tested only in comparison to placebo. Their level of therapeutic innovation was only modest, that is, the lowest value of our algorithm. DISCUSSION: The new monoclonal antibodies of the class of CGRP targeting therapies have been authorized with efficacy data only against placebo. They do not offer additional clinical benefits compared to available therapies for the prevention of migraine attacks, with the exception of a lower frequency of administration and a more rapid effect. All this assigns to these drugs only a modest role in therapy according to our algorithm for therapeutic innovation with a significantly higher cost than similar therapies.

Human papilloma virus vaccination in males: A pharmacovigilance study on the Vaccine Adverse Event Reporting System.

AIMS: Human papilloma virus (HPV) is 1 of the most common sexually transmitted infection responsible for different types of cancer: cervical, penile, vulvar, anal and oropharyngeal. It can affect both males and females. Our aim was to enrich the knowledge on the safety profiles of HPV vaccines in the male population. METHODS: We reviewed all the reports of adverse events following immunization (AEFI) present in the US Vaccine Adverse Event Reporting System from 1 January 2006 to 30 September 2018. Statistical data mining was performed using the reporting odds ratio with 95% confidence interval in order to detect disproportionality in reporting. RESULTS: A total of 5493 reports of AEFI were retrieved. The events most reported and that proportionally occurred more frequently with HPV vaccines than with others in males were: syncope (n = 701, reporting odds ratio = 2.85, 95% confidence interval [1.41-5.76p), loss of consciousness (n = 425, 2.79 [1.36-5.72]) and fall (n = 272, 3.54 [2.00-6.26]). CONCLUSION: Most of the AEFIs were already reported in premarketing clinical trials and acknowledged for the corresponding vaccines. A disproportionate reporting was found for some of these events including syncope. The HPV vaccines are generally well tolerated in males, although limitations own of spontaneous reporting should be considered.

Removal of the EMA orphan designation upon request of the sponsor: cui prodest?

PURPOSE: Various incentives are provided by the European Medicines Agency (EMA) to facilitate the development and marketing of orphan drugs. A 10-year period of market exclusivity is reserved to an orphan medicinal product. Sometimes, the sponsor renounces the designation before the expiration of that standard period. Our aim was to focus on these premature withdrawals. METHODS: We retrieved all the molecules included in the Community Register of Orphan Medicinal Products for Human Use from 2000 to November 2020. We considered the active substance, therapeutic indication, sponsor, year of designation, year of approval of the corresponding medicinal product, and that of the withdrawal of the orphan designation, if occurred. RESULTS: Overall, 2350 orphan designations were approved from 2000 to November 2020. Of these, 141 have been marketed. Premature withdrawal of orphan designation concerned 23 drugs (20 being antineoplastic agents), corresponding to 16 medicinal products. These withdrawals occurred after almost 2 years (range <1-7 years). CONCLUSIONS: A not negligible fraction of marketed orphan medicinal products underwent premature removal of their orphan designation. No motivation is requested by the EMA for this renouncement, although the peculiarity of the orphan medicinal products would need a greater transparency. We can only speculate about possible compensations in support of this decision, for instance in terms of commercial agreements between pharmaceutical companies, giving way to alternative products, as a couple of examples suggest. An open debate on this topic among members of academia, regulatory bodies, price and reimbursements committees, and pharmaceutical industry representatives will be welcome.

Safety profile of chimeric antigen receptor T-cell immunotherapies (CAR-T) in clinical practice.

PURPOSE: Two chimeric antigen receptor T-cell (CAR-T) therapies have been approved in the United States (USA) in 2017 and Europe (EU) in 2018: axicabtagene ciloleucel and tisagenlecleucel. They contain the patient's own T cells, which are extracted, genetically modified, and reinfused. Alongside the good efficacy results, the assessment of safety profile of these new therapies represents a great challenge. Our aim was to analyze the reports of the adverse drug reactions (ADR) after CAR-T administration as occurred in the real clinical setting. METHODS: We performed a retrospective observational study, collecting all the reports in EU (EudraVigilance, EV) and US (FAERS) databases of ADRs regarding axicabtagene ciloleucel and tisagenlecleucel. Both descriptive and statistical analyses were performed, the latter by using Reporting Odds Ratio (ROR). RESULTS: A total number of 1426 reports of suspected ADRs were retrieved in EudraVigilance and FAERS. Patients' reported age reflected the age range for which the drugs are approved (18-64 years for axicabtagene ciloleucel and patients aged under 25 years for tisagenlecleucel). The most reported event was cytokine release syndrome (CRS), 185 events for tisagenlecleucel and 462 for axicabtagene ciloleucel in FAERS and 137 and 498, respectively, in EudraVigilance. A disproportionality was found comparing axicabtagene ciloleucel with tisagenlecleucel for the above-mentioned event: EV ROR 2.47, 95% CI 2.22-2.74, FAERS 1.89, 1.70-2.10. CONCLUSION: CRS represents the major problem with the administration of CAR-T therapies. Our analysis has not revealed new ADRs; however, it supports the safety profile of CAR-T with new data from real clinical setting.

Direct-acting oral anticoagulants and alopecia: The valuable support of postmarketing data.

Little is known about the administration of direct-acting oral anticoagulants (DOACs) and the occurrence of alopecia. Our aim was to analyse the reports of alopecia following DOAC administration received until 2 May 2018 from VigiBase, the World Health Organization database. A descriptive analysis of age, sex, seriousness and dechallenge/rechallenge outcome was carried out. For each report, the time-to-onset was evaluated and the causality was assessed by using Naranjo algorithm. Overall, 1316 reports were retrieved, most concerning rivaroxaban (58.8%); 80% of the reports were related to females, in particular to those aged ≥65 years (23.1%). The median value of the time-to-onset was 28 days, with an interquartile range of 63 days. In 54.3% of the reports the causality was assessed as possible. In conclusion, a possible association could exist between DOACs administration and alopecia, but further observational studies are needed to confirm these findings.

Drug-induced disseminated intravascular coagulation: a pharmacovigilance study on World Health Organization's database.

BACKGROUND: Disseminated intravascular coagulation (DIC) occurs in several clinical conditions, including drug therapy. We aim to investigate the association between the administration of several drug classes and the onset of DIC by using the reports of Adverse Drug Reactions (ADR) collected in Vigibase, the World Health Organization (WHO) database of ADR. METHODS: We collected reports of drug-related DIC from 1968 to September 2015, classified in Vigibase according to the MedDRA (Medical Dictionary for Regulatory Activities) term "Disseminated intravascular coagulation". A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI95%) was performed. RESULTS: Overall, 4653 reports of drug-associated DIC were retrieved and the 75.9% of them was serious according to WHO seriousness criteria. DIC was significantly (ROR > 1, lower limit of CI95% > 1) associated with 88 drugs, mainly antineoplastic agents, antithrombotic agents and antibacterials for systemic use. Among of the most frequently reported individual drugs we found dabigatran (94 reports) ROR = 1.34 (CI95% 1.08-1.67), oxaliplatin and bevacizumab both with 75 reports and ROR = 1.77 (1.38-2.27) and 2.02 (1.57-2.61), respectively. CONCLUSION: A substantial number of drugs, widely used in the clinical practice, may be associated with the potential occurrence of DIC. For many of these drugs, the ADR is not acknowledged in the corresponding Summary of Product Characteristics. The high number of drugs involved underlines the importance of evaluate this condition such as an ADR that might occur during drug therapy.

Antibacterial prescription in Italian preschool children: analysis of 7 years of data from the Emilia-Romagna region reimbursement database.

OBJECTIVES: To describe antibacterial prescribing patterns in outpatients aged 0-5 years from 2007 to 2013 in the Emilia-Romagna region, assessing sex- and age-specific consumption over time. METHODS: All children aged 0-5 years resident in the Emilia-Romagna region who received at least one prescription of a systemic antibacterial in the period 2007-13 were enrolled. The prescriptions of systemic antibacterials to children were collected from the regional prescription database. Data were stratified by year, sex and age, and analysed in terms of periodic prevalence and of annual prescription rate per 1000 person-years. RESULTS: The prevalence of children receiving at least one prescription per year varied from 68.0% in 2007 to 59.0% in 2013, while the average prevalence of children receiving five or more prescriptions per year was 6.96%. The annual prescription rate varied from 1621.26 in 2007 to 1372.27 in 2013. Penicillins + ß-lactamase inhibitors accounted for 35.3% of total prescriptions, followed by extended-spectrum penicillins (28.6%), macrolides (17.0%) and third-generation cephalosporins (13.9%). CONCLUSIONS: Despite recommendations, a significant overprescription of antibacterials to children still exists, showing no satisfactory improvements over the years. In contrast to Northern European countries, adherence to evidence-based guidelines was poor, with frequent prescribing of broad-spectrum agents for the treatment of mostly viral childhood infectious disease.

Safety profile of human papilloma virus vaccines: an analysis of the US Vaccine Adverse Event Reporting System from 2007 to 2017.

AIMS: Human papilloma virus (HPV) is the cause of different types of carcinoma. Despite the remarkable effectiveness of the HPV vaccines, there have been many complaints about their risk-benefit profile due to adverse events following immunization (AEFI). The purpose of this study is to analyse the safety profile of the HPV vaccine basing on real-life data derived from reports of suspected AEFIs collected in the US Vaccine Adverse Events Reporting System (VAERS) and assess if the searches on Google overlap with spontaneous reporting. METHODS: We collected all the reports in VAERS between January 2007 to December 2017 related to the HPV vaccines. A disproportionality analysis using reporting odds ratio (ROR) with 95% confidence interval was performed. RESULTS: Over the 10-year period, 55 356 reports of AEFI related to HPV vaccines were retrieved in VAERS, corresponding to 224 863 vaccine-event pairs. The highest number of reports was related to Gardasil (n = 42 244). The two events more frequently reported and statistically significant for HPV vaccines were dizziness (n = 6259; ROR = 2.60; 95% confidence interval 2.53-2.66) and syncope (n = 6004; ROR = 6.28; 95% confidence interval 6.12-6.44). The trends of spontaneous reporting and Google searches overlap. CONCLUSION: The AEFI analysis showed that the events most frequently reported were non-serious and listed in the corresponding summary of product characteristics. Potential safety signals arose regarding less frequent AEFIs that would deserve further investigation. It is extremely important to disseminate correct and evidence-based scientific information.

Non-commercial trials on medicines submitted to the Ethics Committee of the University Hospital of Bologna (Italy) along 8 years of activity: time to update rules and recommendations.

PURPOSE: In Italy, the non-commercial trials on medicines are regulated by the Ministry Decree 17 December, 2004. Its intent is of encouraging the independent research for the improvement of clinical practice. We aimed to analyze the main features of the proposals of non-commercial clinical trials on medicines submitted to the Independent Ethics Committee (IEC) of the University Hospital of Bologna in the period 2010-2017. METHODS: Data were extracted from IEC registry and were organized with an ad hoc database. The relationships between the variables were examined using contingency tables. When appropriate, we applied the chi-square statistical test for the comparison of the categorical variables. RESULTS: Over the 8-year period, the IEC evaluated 2931 studies, of which 1156 (39.4%) related to clinical trials on medicines; 245 (21.2%) out of the latter were non-commercial ones. A percentage of 49.8 of the trials were of phase II; 137 trials (55.9%) were promoted by hospitals, medical schools or institutes for research, hospitalization and health care. Non-profit organizations and scientific societies were promoters of 88 trials (35.9%). Most phase I and phase II trials received additional support from pharmaceutical companies. CONCLUSIONS: Our results show a not negligible industrial influence on non-commercial trials through additional support, mostly to those of phase II. An update of the present legislation on this matter is desirable, adopting clearer rules on the relations sponsor-industry.

Cardiovascular safety of macrolide and fluoroquinolone antibiotics: An analysis of the WHO database of adverse drug reactions.

INTRODUCTION: The cardiovascular safety profile of macrolides and fluoroquinolones has been widely discussed. The aim of the present study is to provide the contribution of real-world data onto the ongoing discussion about cardiovascular toxicity of both macrolides and fluoroquinolones. METHODS: Reports of adverse drug reactions (ADRs) were retrieved from VigiBase. Macrolides and fluoroquinolones were compared with amoxicillin by using the reporting odds ratio (ROR) as a measure of disproportionality. Macrolides were then compared with fluoroquinolones. RESULTS: Overall, 6810 reports of ADRs were retrieved: 62% of them were serious and 35% concerned female. Macrolides were more frequently associated with "atrial fibrillation" (ROR = 1.26, CI 1.02-1.57) and "ventricular fibrillation" ROR = 2.60, CI 1.92-3.54) than fluoroquinolones. Antimicrobials more frequently reported for "cardiac disorder" were azithromycin (375 reports) and clarithromycin (302) for macrolides and levofloxacin (470) and moxifloxacin (391) for fluoroquinolones. CONCLUSION: Our data highlighted that macrolides and fluoroquinolones may influence cardiac rhythm and suggest caution in the prescribing of these drugs to patients with hidden cardiovascular risk factors. Although these ADRs seem to be not common, they have a notable impact in clinical practice because of the huge number of the exposed subjects.

Comparative risk/benefit profile of biosimilar and originator erythropoiesis-stimulating agents (ESAs): data from an Italian observational study in nephrology.

PURPOSE: The aim of this multicenter prospective study was to evaluate efficacy and safety of biosimilar erythropoiesis-stimulating agents (ESAs) vs originator, based on data from clinical practice in patients with chronic kidney disease (CKD). METHODS: We collected data of the patients with diagnosis of CKD on conservative treatment from nine Italian structures. Patients were enrolled applying different exclusion criteria, and various individual parameters were registered at the beginning for descriptive analysis. Patients were treated with epoetin alfa, beta, and darbepoetin as originator and epoetin zeta as biosimilar. Hemoglobin levels have been analyzed at baseline and after 3, 6, and 12 months. Descriptive statistics were used to analyze the results. RESULTS: At baseline, 47 patients were in the biosimilar group and 57 in the originator; the basal level of hemoglobin was similar between the groups (mean Hb 9.4 and 9.3 g/dL, respectively). Median age, weight, and comorbidities were almost comparable. After 3 months, 44 patients remained in the biosimilar group and 48 in the originator; hemoglobin increase was significantly greater in patients treated with biosimilar [absolute increase 1.6 vs 1.0 g/dL, p < 0.001]. After 6 and 12 months, number of patients fall furthermore. Hemoglobin levels increased more in the biosimilar group after 6 months (2.1 vs 1.1 g/dL, p < 0.001) and 12 months (2.0 vs 1.0 g/dL, p < 0.001). CONCLUSIONS: Biosimilar ESAs have similar risk/benefit profile compared to originators. Our data are in agreement with relevant scientific literature and, on the other hand, they are in contrast with common thought that considers biosimilar less efficacious and less safe than originators.

Real-life safety profile of mRNA vaccines for COVID-19: An analysis of VAERS database.

INTRODUCTION: Since the first COVID-19 messenger RNA vaccines became available globally for emergency or conditional use, post-marketing surveillance activities have been implemented for the monitoring of any adverse events that might arise in daily clinical practice and were not detected earlier during clinical trials. METHODS: Safety data concerning the BNT162b2 and the mRNA-1273 COVID-19 vaccines were collected from the Vaccine Adverse Event Reporting System (VAERS) for the period from December 2020 to October 15, 2021. In addition to a descriptive analysis of individuals who experienced an adverse event after vaccination, a case-non-case analysis was performed by using the Reporting Odds Ratio with 95 % confidence interval as statistical parameter for detecting differences in reporting rates between the two mRNA vaccines. RESULTS: At the cut-off date, a total of 758,040 reports were submitted to VAERS, of which 439,401 were related to the Pfizer-BioNTech (BNT162b2) vaccine and 318,639 to the Moderna vaccine (mRNA-1273). Most common adverse events following immunization for both mRNA vaccines were headache, fatigue, pyrexia, dizziness, nausea, pain, chills, and pain in extremity. A disproportionality was found for BNT162b2 as compared with mRNA-1273 for some events of special interest, such as myocarditis [ROR 2.00; 95 % confidence interval (CI), 1.93-2.06], Bell's palsy (1.34; 1.29-1.39), and anaphylactic shock (3.23; 2.96-3.53). CONCLUSION: Even if some rare adverse events were identified, our survey of post-marketing surveillance has provided further evidence of the favourable safety profile of mRNA vaccines.

Safety profile of hydroxychloroquine used off-label for the treatment of patients with COVID-19: A descriptive study based on EudraVigilance data.

At the beginning of the COVID-19 pandemic, worldwide attempts were made to identify potential drugs effective against the COVID-19. Hydroxychloroquine was among the first receiving attention. However, following its use in therapy, it has been shown that hydroxychloroquine was not only ineffective but probably, due to its known side effects, even responsible of increased mortality of patients. The objective of this study was to review the safety profile of hydroxychloroquine used off-label for the treatment of COVID-19. We analyze the reports of suspected adverse drug reactions (ADRs) collected in EudraVigilance, the European database of ADR reports. We collected 2266 reports for 2019 and 6525 for 2020. The most reported ADRs during 2020 were those relating to cardiac, hepatic, renal toxicity such as QT prolongation with 400 cases in 2020 (of which, 345 cases-9.97%-with COVID-19 as a therapeutic indication) versus 1 case only in 2019 (0.01%), long QT syndrome: 38 cases in 2020 (36 as COVID-19 treatment) versus 0 in 2019, hepatitis: 13 cases in 2019 (0.11%) and 132 in 2020, and 32 cases (24, 0.69%) of acute kidney injury in 2020 and only 3 cases in 2019. Moreover, some important vision-related ADRs also increased significantly during 2020, such as retinal toxicity with 92 cases in 2020 versus 7 in 2019. Even though with its intrinsic limitations, our results may be added to the most recent scientific evidence to confirm the unfavorable risk profile of hydroxychloroquine in its off-label use in the treatment of COVID-19 disease.

Adverse Event Reporting with Immune Checkpoint Inhibitors in Older Patients: Age Subgroup Disproportionality Analysis in VigiBase.

Older patients represent a subpopulation of concern for immune checkpoint inhibitor (ICI) toxicity because of changes in the aging immune system and the potentially relevant clinical implications for their quality of life. Current evidence on ICI safety in older patients is conflicting. This study aimed to assess whether older patient age was a risk factor for increased reporting with ICIs as compared to other antineoplastic drugs in VigiBase, the World Health Organization database of suspected adverse drug reactions. Disproportionality analyses computing the reporting odds ratios (RORs) were performed by age subgroups (<18 years, 18-64 years, 65-74 years, 75-84 years and ≥85 years). There were not signals of disproportionate reporting with ICIs specifically detected in older patient age subgroups (≥65 years), which were not present in the disproportionality analysis over the entire dataset. A signal of disproportionate reporting with ICIs emerged for eye disorders only in the age subgroup 18-64 years (ROR 1.13, 95% confidence interval 1.05-1.23). These findings showed that adverse event reporting with ICIs in older patients was comparable to that in the overall patient cohort and prompt for the further investigation of eye disorders with ICIs to elucidating risk factors and defining management strategies.

Evaluation of the safety profile of rotavirus vaccines: a pharmacovigilance analysis on American and European data.

Rotaviruses (RVs) are the most common cause of severe diarrheal disease. To date two rotavirus oral vaccines are licensed: Rotarix and Rotateq. Our aim was to contribute to the post-marketing evaluation of these vaccines safety profile. We collected all RV vaccines-related reports of Adverse Events Following Immunization (AEFI) in US Vaccine Adverse Events Reporting System (VAERS) and VigiBase between January 2007 and December 2017. A disproportionality analysis using Reporting Odds Ratio (ROR) was performed. A total of 17,750 reports in VAERS and 6,358 in VigiBase were retrieved. In VAERS, 86.2% of the reports concerned RotaTeq, whereas in VigiBase 67.7% of them involved Rotarix. Across the databases, diarrhea (1,672 events in VAERS, 1,961 in VigiBase) and vomiting (1,746 in VAERS, 1,508 in VigiBase) were the most reported AEFIs. Noteworthy, the RV vaccines-intussusception pair showed a ROR greater than 20 in both databases. Some new potential safety signals emerged such as fontanelle bulging, hypotonic-hyporesponsive episode, livedo reticularis, and opisthotonus. Overall, our data show that most of the reported AEFIs are listed in the Summary of Product Characteristics (SPCs). However, there remains the need to investigate the potential safety signals arose from this analysis, in order to complete the description of the AEFIs.

The prescription of antimicrobials by general practitioners: the differences between north and south Italian provinces.

Background: Antimicrobials resistance (AMR) is an increasingly serious global health problem, both in terms of clinical implications and economic expenditure. In Italy, there are differences in prescribing rates between regions. We aimed to compare these differences in two Italian provinces: one of Emilia Romagna (north region) and one of Puglia (south region).Methods: The number of antibiotics prescribed packages and the relative expenditure data (year 2015) were obtained. We applied the prescription quality indicators proposed by the European Surveillance of Antimicrobial Consumption for an in-depth analysis.Results: Both consumption and expenditure were higher in the south province. In the Apulian province also the use of parenteral antibiotics was more frequent. The most prescribed antibiotics in both the provinces were: penicillins (combined or not), macrolides, and fluoroquinolones.Conclusion: We observed variability between the north and south province in terms of antibiotics prescription. Overall, our study indicates that antibacterials could be overprescribed. The choice of the right antibiotic continues to be a demanding task for practitioners and much still needs to be done in the fight against AMR, starting from a more appropriate use and interventions aimed at raising awareness of antibiotic resistance.