[Balancing drug regulation and health democracy: The role of patient and healthcare professional advisors at the ANSM]. / Concilier régulation du médicament et démocratie sanitaire : rôle des conseillers patient ou professionnel de santé à l'ANSM.

The French National Agency for Health Products (ANSM) is a regulatory and public health agency. Its regulatory, health policing and public health protection activities require a perfect fit with the field and the various people involved in the use of health products. Since 2019, the ANSM has adapted its organisation, procedures and processes to encourage and improve interaction with its stakeholders, as part of its policy of openness towards civil society. To accompany this ambitious change and to support its staff, the Agency has recruited advisors corresponding to the main users of health products: prescribers (doctor's hospital and outpatient), pharmacists and patients. Working as a group or individually, they provide a "lived" user perspective on health products at each stage of the evaluation process. They may be involved in the assessment of dossiers, signals or applications received by the Agency, in the internal validation of reports or in discussions with stakeholders. They are particularly involved when the analysis requires expertise that goes beyond the technical, scientific or regulatory aspects. They may also work with ANSM staff to explain certain processes and difficulties in the field. Advisors help to ensure that regulatory and/or scientific expertise is clear and consistent with user experience. In addition to their scientific and therapeutic aspects, medicines are also economic, social and political issues. Their regulation is therefore particularly affected by the need for health democracy. This requires the active participation of health professionals, patients and, more broadly, civil society in the decision-making process. Civil society is a space occupied by a wide range of actors who exert pressure from different ideological positions to influence the regulation of health products. In this context, taking into account a plurality of viewpoints in the regulation of health products is necessary and complex, but its operation can be facilitated by the collective efforts of the actors and the adaptation of organisations, such as the integration of advisors.

Prevention and management of health products shortages by the French national agency (ANSM), 10 years of experience.

Shortages of drugs and medical devices have tended to increase in France and worldwide, with consequences for patients and healthcare professionals. Preventing shortages of health products has become a priority for regulatory authorities, including the French National Agency for Medicines and Health Products Safety (ANSM). To highlight perspectives for a better prevention, we described and analyzed the management of shortages in the availability of health products in France over the last 10 years. The supply chain was mapped to identify the main causes of shortages and stakeholders involved in managing shortages throughout the supply chain. National and European initiatives and regulatory measures were reviewed. A retrospective nationwide data analysis from the French reporting system of health product shortage reports was conducted over 10 years for drugs (2013-2022) and over an 18-month period for medical devices, from 1st March 2022 to 31st August 2023. An increase in drug shortage reports was observed, rising from 404 in 2013 to 3,761 in 2022 for drugs, with a relatively constant distribution of affected therapeutic classes. In 2022, the main reported causes of drug shortage risk were insufficient production capacity (27.1%), increased sales volume (21.5%), or lack of supply (13.6%). Over half of the reports on medical devices (55.4%) were objectified as indispensable, and their causes were mainly due to a lack of supply (48.2%), discontinuation of marketing (14.9%), increased sales volume (13.2%), and regulatory reasons (9.6%). ANSM and French authorities have engaged a public health policy for prevention and management of health product shortages including financial penalties, minimum safety stocks for Major Therapeutic Interest drugs, and a shortage management plan. Based on 10 years of experience, four priority measures have been identified to anticipate the risk of heath products shortages based: the importance of a national coordination from raw materials to local market, the implementation of new prevention and management actions in the supply chain, strengthening European cooperation and regulation including the establishment of a list of critical drugs, and promoting transparency and information.

Estimation of the influenza-associated respiratory hospitalization burden using sentinel surveillance data, Lebanon, 2015-2020.

Introduction: Influenza epidemics cause around 3 to 5 million cases of severe illness worldwide every year. Estimates are needed for a better understanding of the burden of disease especially in low- and middle-income countries. The objective of this study is to estimate the number and rate of influenza-associated respiratory hospitalizations in Lebanon during five influenza seasons (2015-2016 to 2019-2020) by age and province of residence in addition to estimating the influenza burden by level of severity. Methods: The severe acute respiratory infection sentinel surveillance system was used to compute influenza positivity from the influenza laboratory confirmed cases. The total of respiratory hospitalizations under the influenza and pneumonia diagnosis was retrieved from the Ministry of Public Health hospital billing database. Age-specific and province-specific frequencies and rates were estimated for each season. Rates per 100 000 population were calculated with 95% confidence levels. Results: The estimated seasonal average of influenza-associated hospital admission was 2866 for a rate of 48.1 (95% CI: 46.4-49.9) per 100 000. As for the distribution by age group, the highest rates were seen in the two age groups ≥65 years and 0-4 years whereas the lowest rate was for the age group 15-49 years. For the distribution by province of residence, the highest influenza-associated hospitalization rates were reported from the Bekaa-Baalback/Hermel provinces. Conclusion: This study shows the substantial burden of influenza in Lebanon mainly on high-risk groups (≥65 years and <5 years). It is crucial to translate these findings into policies and practices to reduce the burden and estimate the illness-related expenditure and indirect costs.

Regulatory assessment of nano-enabled health products in public health interest. Position of the scientific advisory board of the French National Agency for the Safety of Medicines and Health Products.

Nanomaterials are present in a wide variety of health products, drugs and medical devices and their use is constantly increasing, varying in terms of diversity and quantity. The topic is vast because it covers nanodrugs, but also excipients (that includes varying proportions of NMs) and medical devices (with intended or not-intended (by-products of wear) nanoparticles). Although researchers in the field of nanomedicines in clinical research and industry push for clearer definitions and relevant regulations, the endeavor is challenging due to the enormous diversity of NMs in use and their specific properties. In addition, regulatory hurdles and discrepancies are often cited as obstacles to the clinical development of these innovative products. The scientific council of the Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM) undertook a multidisciplinary analysis encompassing fundamental, environmental and societal dimensions with the aim of identifying topics of interest for regulatory assessment and surveillance. This analysis allowed for proposing some recommendations for approximation and harmonization of international regulatory practices for the assessment of the risk/benefit balance of these products, considering as well the public expectations as regards efficacy and safety of nanomaterials used in Health products, in terms of human and environmental health.

Clinical Trial Authorisation: A Final Look Back to Better Appraise the New European Regulation.

The implementation of the new European Clinical Trial Regulation on 31 January 2022, is a major step to promote clinical research in Europe. The French National Agency for Medicines and Health Products Safety (ANSM) proposes to share some key aspects of the preparation for the application of the Regulation initiated in 2017 and to discuss shared indicators that should be considered to monitor clinical trials opportunities on a territory with regards to access to innovation for patients and attractiveness for sponsors. New criteria based on the time from the first request for authorisation to the first inclusion could be of particular interest to appraise the implementation of the European Clinical Trial Regulation.

Prevalence of medication administration errors in hospitalized adults: A systematic review and meta-analysis up to 2017 to explore sources of heterogeneity.

Previous estimates to meta-analyze administration error rates were limited by the high statistical heterogeneity, restricting their use. This study aimed to investigate sources of heterogeneity in pooled administration error rates in hospitalized adults. We systematically searched scientific databases up to November 2017 for studies presenting error rates/relevant numerical data in hospitalized adults. We conducted separate meta-analyses for the numerators: One Medication Error (OME) (each dose can be correct or incorrect) and Total Number of Errors (TNE) (more than one error per dose could be counted), using the generic inverse variance with a 95% confidence interval. Heterogeneity was assessed using the I2 and Cochran's Q test. We meta-analyzed 33 studies. The global pooled analyses based on the OME and TNE numerators showed very high heterogeneity (I2  = 100%; p < 0.00001). For each meta-analysis, subgroup analyses based on study characteristics (countries, wards, population, routes of administration, error detection methods, and medications) yielded results with consistently elevated heterogeneity. Beyond these characteristics, we stratified the studies according to the mean error prevalence level as the threshold. Based on the OME numerator, we identified two subgroups of low (0.15[0.13-0.17]; I2  = 0%; p = 0.43) and high (0.26[0.24-0.27]; I2  = 38%; p = 0.17) pooled prevalence rates, with controlled heterogeneity. Similarly, for the TNE numerator, we identified two subgroups of low (0.10[0.09-0.10]; I2  = 0%; p = 0.76) and high (0.28[0.27-0.29]; I2  = 0%; p = 0.89) pooled prevalence rates, with controlled heterogeneity. These subgroups differed regarding the denominators used: Total opportunities for errors versus others (doses, observations, administrations). Calculation methods, specifically the denominator, seem a primary factor in explaining heterogeneity in error rates. Standardizing numerators, denominators, and definitions is necessary.

Authorization of COVID-19 clinical trials: lessons from 2 years of experience of a national competent authority.

The COVID-19 pandemic was immediately marked by strong clinical research activity. The French national competent authority presents the data on request for authorization during the first 2 years of COVID-19 pandemic to inform discussions on future clinical research issues. Applications for authorization of interventional COVID-19 trials submitted between March 2020 and February 2022 were analysed. Trials on medicinal products were classified according to market authorization status, mechanism of action of the investigational product, target population and clinical context. In 2 years, 208 clinical trials were submitted. 75% were authorized, 3% refused, 22% withdrawn by the sponsor. Among medicinal products trials, 6% were adaptative, 28% included outpatients and 2% were focused on post COVID-19 symptoms. Vaccines were evaluated in 9% of trials, antivirals in 38% and immunomodulators in 35%; 63% of antiviral and 60% of immunomodulation trials included a drug with a marketing authorization in another indication. The dynamics of authorization prove the involvement of stakeholders but also illustrates the risk of dispersion of research efforts and the risk of decorrelation between trials and the epidemic evolution. The high rate of withdrawal of applications could be explained by changes in the sanitary context and by the dropping of some therapeutic approaches. Most of clinical trials evaluate drugs authorized in another indication and assessment procedures by authorities have to mitigate between the knowledge of safety profile of those drugs and the uncertainty in a new clinical context with rapidly evolving knowledge. COVID-19 experience should now support future evolution in clinical research practices.

Feasibility study and evaluation of expert opinion on the semi-automated meta-analysis and the conventional meta-analysis.

PURPOSE: To assess the feasibility and acceptance of the semi-automated meta-analysis (SAMA). The objectives are twofold, namely (1) to compare expert opinion on the quality of protocols, methods, and results of one conventional meta-analysis (CMA) and one SAMA and (2) to compare the time to execute the CMA and the SAMA. METHODS: Experts evaluated the protocols and manuscripts/reports of the CMA and SAMA conducted independently on the safety of metronidazole in pregnancy. Expert opinion was collected using AMSTAR 2 checklist. Time spent was recorded using case report forms. RESULTS: The overall scores of the opinion of all experts for protocols, methods, and results for SAMA (6.75) and CMA (6.87) were not statistically different (p = 0.88). The experts' confidence in the results of each MA was 7.89 ± 1.17 and 8.11 ± 0.92, respectively. The time to completion was 14 working days for SAMA and 24.7 for CMA. MA tasks such as calculation of effect estimates, subgroup/sensitivity analysis, and publication bias investigation required no investment in time for SAMA. CONCLUSION: In conclusion, our study demonstrated the feasibility of SAMA and suggests acceptance for risk assessment by an expert committee. Our results suggest that SAMA reduces the time required for a MA without altering expert confidence in the methodological and scientific rigor. As our study was limited to one example, the generalization of our results requires confirmation by other studies.

Patterns of Medication Errors Involving Older Adults Reported to the French Medication Error Guichet.

OBJECTIVES: The aims of the study were to describe medication errors (MEs) involving older adults reported to the French Medication Error Guichet and to compare them with MEs in younger adults, in each of the hospital and community settings. METHODS: Retrospective secondary data analysis of MEs reported throughout 2013 to 2017 was performed. Descriptive and multivariate analyses were performed to compare actual and potential ME reports between older adults (aged ≥60 y) and younger adults (aged ≥18, <60 y). RESULTS: We analyzed 4979 reports. In older adults, both in hospital (n = 1329) and community (n = 1264) settings, antithrombotic agents were frequently reported in MEs and were significantly more likely to be associated with reported MEs in older adults compared with younger adults. In hospital setting, antibacterials for systemic use (adjusted odds ratio [aOR] = 1.87, 95% confidence interval [CI] = 1.19-2.93) and antineoplastic agents (aOR = 2.22, 95% CI = 1.34-3.69), whereas in community setting, psycholeptics (aOR = 1.43, 95% CI = 1.04-1.98) and drugs used in diabetes (aOR = 6.01, 95% CI = 3.21-11.2) were more likely to be associated with reported MEs in older adults. In both settings, wrong dose and wrong drug were the most frequently reported error types in older adults; however, wrong technique error type (aOR = 2.06, 95% CI = 1.30-3.28) in hospital setting and wrong patient (aOR = 2.17, 95% CI = 1.30-3.60) in community setting were more likely to be associated with reported MEs in older adults. CONCLUSIONS: We identified specific ME patterns for older adults, including antithrombotic agents in both settings; antibacterials for systemic use, antineoplastic agents, and wrong technique in hospital setting; and psycholeptics, drugs used in diabetes, and wrong patient in community setting. These findings inform future studies investigating population-specific medication safety strategies.

Biases associated with epidermal necrolysis reporting in pharmacovigilance: An exploratory analysis using World Health Organization VigiBase.

BACKGROUND: Possible biases in pharmacovigilance reporting may impact epidermal necrolysis (EN) and drugs associations. OBJECTIVES: To assess biases associated with EN-reporting. METHODS: Using VigiBase, the World Health Organization-pharmacovigilance database, among drugs associated with EN between 2016 and 2020, we used an unsupervised clustering including reports characteristics, that is, reporter quality, time from drug intake to EN onset, and only one suspected drug in the report. RESULTS: Among 152 drugs, three clusters were identified. Cluster 1 (n = 41) exhibited drugs frequently reported within a time from intake to onset longer than 4 days, in 57 ± 13% of reports. It corresponded to well-reported drugs and was composed mainly of antivirals and antiepileptics. Cluster 2 (n = 42) exhibited drugs frequently reported within a time from drug intake to onset shorter than 4 days, in 31 ± 12% of reports. It corresponded to drugs with a high risk of protopathic bias and was composed of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, and antibiotics. Cluster 3 (n = 69) exhibited drugs frequently reported with an unavailable time from drug intake to reaction, in 66 ± 11% of reports, and reported by a high frequency of consumers (9 ± 9%). It corresponded to drugs reported with a high risk of classification bias, and was composed of anticancer therapies and cardiovascular drugs. CONCLUSION: Protopathic and classification biases impact EN-reporting and should be considered regarding associations with antibiotics, NSAIDs, analgesics, anticancer therapies, and cardiovascular drugs.

An evaluation of prophylactic and therapeutic antibiotic prescribing in Lebanese dental practice.

OBJECTIVES: To evaluate antibiotic prescribing patterns and correlates among Lebanese dentists. METHODS: A descriptive observational study was conducted, from the first of April to the end of May 2017. Dentists who specialized in oral dental surgery or general dental practitioners were eligible to participate in this study. All patients who sought consultation with the selected dentists over a 1 month period were included. KEY FINDINGS: A total of 2323 oral and dental procedures were performed by 60 dentists; 553 antibiotic prescriptions were prescribed, representing 23.8% (52.35% for prophylactic purposes and 47.65% for curative purposes). Prophylactic indications were mainly for implant surgery (36.3%) with only 1% appropriate. Curative use was mainly for periodontal abscesses/abscesses (indeterminate) (22.8%), followed by pulpal diseases and periradicular complications (20.5%); it was appropriate in only 1.7 and 1.9% of cases respectively. Amoxicillin-clavulanic acid was the antibiotic that was mostly prescribed for both curative and prophylactic uses (57.6 and 55.9%, respectively), followed by amoxicillin for prophylactic purposes and a combination of spiramycin plus metronidazole for curative purposes. Adherence to guidelines was low for both curative and prophylactic purposes (17.4 and 21.8%, respectively), but was better in patients who were younger [adjusted odds ratio(aOR) = 0.96], male (aOR = 0.40), or had cardiac disease with moderate or high infective endocarditis risk (aOR = 21.72), and when prescribed by oral surgeons (aOR = 0.15). CONCLUSIONS: This study showed evidence of the overuse of antibiotics among Lebanese dentists. It can serve as a basis for future studies to optimize antibiotic use among dentists in Lebanon.

Trend of antibiotic consumption and its association with influenza-like illnesses in France between 2004 and 2018.

BACKGROUND: Antibiotic consumption has been reported to be driven by the treatment of respiratory tract infections. Our objectives were to describe the trend of antibiotic consumption in France compared with that of other European countries; to describe the evolution of each antibiotic class in France; and to explore the relationship between antibiotic consumption and incidence of influenza-like illnesses. METHODS: In this observational study, antibiotic consumption was reported as defined daily doses per 1000 inhabitants per day in the community and hospital sectors in descriptive and graphical formats, using data from the European Surveillance of Antimicrobial Consumption Network database. The total consumption and the consumption of different classes of antibiotics in France according to time and influenza-like illnesses were studied using multiple linear regression models. RESULTS: The total consumption of antibiotics in France was constant over the 15 years. It was driven by the community sector (92.8%) and was higher than the consumption of other European Union countries (P-value < 0.001). The beta-lactam penicillins were the most consumed antibiotic class and the only class that increased with time. The multiple linear regression models showed a positive correlation between antibiotic consumption in the community sector and incidence of influenza-like illnesses [B = 0.170, 95% CI (0.088-0.252)]. Similar significant results were shown between other antibiotic classes used in the management of influenza-like illnesses (other beta-lactams, and macrolides, lincosamides and streptogramins) and influenza-like illnesses. CONCLUSION: Our results suggest that antibiotics used in the management of respiratory tract infections might be involved in the irrational use of antibiotics.

Patterns of medication errors involving pediatric population reported to the French Medication Error Guichet.

BACKGROUND: Medication error is a global threat to patient safety, particularly in pediatrics. Yet, this issue remains understudied in this population, in both hospital and community settings. OBJECTIVES: To characterize medication errors involving pediatrics reported to the French Medication Error Guichet, and compare them with medication errors in adults, in each of the hospital and community settings. METHODS: This was a retrospective secondary data analysis of medication errors reported throughout 2013-2017. Descriptive and multivariate analyses were performed to compare actual and potential medication error reports between pediatrics (aged <18 years) and adults (aged >18 and <60 years). Two subanalyses of actual medication errors with adverse drug reaction (ADR), and serious ADR were conducted. RESULTS: We analyzed 4,718 medication error reports. In pediatrics, both in hospital (n=791) and community (n=1,541) settings, antibacterials for systemic use (n=121, 15.7%; n=157, 10.4%, respectively) and wrong dose error type (n=391, 49.6%; n=549, 35.7%, respectively) were frequently reported in medication errors. These characteristics were also significantly more likely to be associated with reported errors in pediatrics compared with adults. In the hospital setting, analgesics (adjusted odds ratio (aOR)=1.59; 95% confidence interval (CI) 1.03:2.45), and blood substitutes and perfusion solutions (aOR=3.74; 95%CI 2.24:6.25) were more likely to be associated with reported medication errors in pediatrics; the latter drug class (aOR=3.02; 95%CI 1.59:5.72) along with wrong technique (aOR=2.28; 95%CI 1.01:5.19) and wrong route (aOR=2.74; 95%CI 1.22:6.15) error types related more to reported medication errors with serious ADR in pediatrics. In the community setting, the most frequently reported pediatric medication errors involved vaccines (n=389, 25.7%). Psycholeptics (aOR=2.42; 95%CI 1.36:4.31) were more likely to be associated with reported medication errors with serious ADR in pediatrics. Wrong technique error type (aOR=2.71; 95%CI 1.47:5.00) related more to reported medication errors with ADR in pediatrics. CONCLUSIONS: We identified pediatric-specific medication error patterns in the hospital and community settings. Our findings inform focused error prevention measures, and pave the way for interventional research targeting the needs of this population.

Investigating the efficacy and safety of metronidazole during pregnancy; A systematic review and meta-analysis.

OBJECTIVE: We aimed to review and analyze studies focusing on the efficacy of metronidazole in reducing the risk of preterm birth and the safety of metronidazole taking into account the different doses, duration of treatment and routes of administration. STUDY DESIGNS: Embase, Cochrane Library and PubMed were searched up to 29 July 2019 to identify studies assessing metronidazole exposure during pregnancy. Additional studies were identified from reference lists of retrieved papers. Measured outcomes were preterm births (<37 weeks of gestation) and associated delivery outcomes such as spontaneous abortions (≤ 20 weeks of gestation), stillbirths (≥20 weeks of gestation) and low birth weight (<2500 g) irrespective of the period of exposure and major malformations after first-trimester exposure. Overall effect estimates for RCTs and observational studies were calculated using the random-effects model and pooled using Risk Ratios (RR) and Odds Ratios (OR) respectively. ROB-2 and ROBINS-I tool were used to assess Risk of Bias for RCTs and observational studies, respectively. RESULTS: Twenty-four studies (17 observational studies and 7 RCTs) were selected. Pooled RR was 1.10 (95 % CI 0.78-1.55; n = 7; I2 = 72 %) for preterm birth. Subgroup analysis found RR 1.67; 95 % CI 1.07-2.62; n = 3; I² = 32 %) for treatment duration of ≤3 days among women with a previous preterm delivery. Pooled OR for spontaneous abortion was 1.72 (95 % CI 1.40-2.12; n = 5; I2 = 72 %) and 1.15 (95 % CI 0.98-1.34; n = 12; I2 = 25 %) for major malformations. After exclusion of studies with critical risk of bias, pooled OR were 1.7 (1.42-2.04; n = 3; I2 = 19 %) and 1.13 (0.93-1.36; n = 9; I2 = 28 %) respectively. Among several specific malformations analyzed, only congenital hydrocephaly was significantly increased at 4.06 (95 % CI 1.75-9.42; n = 2; I² = 0%). CONCLUSIONS: Data do not confirm the efficacy of metronidazole in reducing the risk of preterm birth and associated delivery outcomes. Further research is required to confirm the effect of high dose and short duration of metronidazole treatment on preterm birth among the high-risk group. Regarding the increased odds of spontaneous abortion, RCTs are required to assess the role of the underlying infection. The need for further studies to confirm the risk of congenital hydrocephaly is paramount.

Trends in the consumption of antibiotics in the Lebanese community between 2004 and 2016.

Background Antibiotic resistance has reached an alarming rate globally especially in middle-income countries such as Lebanon. The development of antibiotic resistance is strongly linked to the increased population's injudicious consumption of antibiotics. Objective This study aims to explore the trends of antibiotics consumption in the Lebanese community, between 2004 and 2016, to inform rational use of antibiotics. Setting The study was performed using the Intercontinental Marketing Statistics (IMS) Health Lebanon database Method This is an observational longitudinal study conducted through a review of the IMS database. The annual antibiotics consumption was determined by the Defined Daily Dose (DDD)/1000 inhabitants/day (DID). The trends of antibiotics consumption were then categorized by antibiotic class and spectrum of activity. Main outcome measure The total consumption of antibiotics in Lebanon and the classes of antibiotics used by the community. Results Total community consumption of antibiotics, measured by DDD/1000 inhabitants/day (DID), significantly increased from 18.71 in 2004 to 31.26 in 2016. Penicillin combinations, quinolones, third-generation cephalosporins, tetracyclines, and carbapenems showed significant uptrends, in contrast to first-generation cephalosporins, sulfonamides and diaminopyrimidines, and beta-lactamase resistant penicillins. Broad-spectrum antibiotics showed a marked increase in their consumption from 11.50 DID in 2004 to 22.51 DID in 2016 whereas intermediate-spectrum antibiotics had only a slight increase in their consumption from 7.18 DID in 2004 to 8.51 DID in 2016, and narrow-spectrum antibiotics had a severe decline in their consumption from 0.006 DID in 2004 to 0.0003 DID in 2016. Conclusion There is an alarming increase in antibiotics consumption in Lebanon, particularly broad-spectrum antibiotics. This should be complemented with evidence on the determinants of antibiotic consumption such as prescriber and patient-related factors and drug promotional activities to minimize antibiotics overuse.

Dorsal Onlay Oral Mucosa Graft Urethroplasty: A Case Report and Review of Literature.

The use of buccal mucosa grafts in urethral reconstruction for complex anterior urethral strictures has gained popularity over the years with very good outcomes reported in literature. We report on the successful repair of a complex anterior urethral stricture in a 14-year-old boy following catheterization using this method at the Komfo Anokye Teaching Hospital. The aim is to describe the method of dorsal onlay oral mucosa graft urethroplasty and to review the literature.