The Reporting of a Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Development and Statement.

BACKGROUND AND AIM: Disproportionality analyses using reports of suspected adverse drug reactions are the most commonly used quantitative methods for detecting safety signals in pharmacovigilance. However, their methods and results are generally poorly reported in published articles and existing guidelines do not capture the specific features of disproportionality analyses. We here describe the development of a guideline (REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance [READUS-PV]) for reporting the results of disproportionality analyses in articles and abstracts. METHODS: We established a group of 34 international experts from universities, the pharmaceutical industry, and regulatory agencies, with expertise in pharmacovigilance, disproportionality analyses, and assessment of safety signals. We followed a three-step process to develop the checklist: (1) an open-text survey to generate a first list of items; (2) an online Delphi method to select and rephrase the most important items; (3) a final online consensus meeting. RESULTS: Among the panel members, 33 experts responded to round 1 and 30 to round 2 of the Delphi and 25 participated to the consensus meeting. Overall, 60 recommendations for the main body of the manuscript and 13 recommendations for the abstracts were retained by participants after the Delphi method. After merging of some items together and the online consensus meeting, the READUS-PV guidelines comprise a checklist of 32 recommendations, in 14 items, for the reporting of disproportionality analyses in the main body text and four items, comprising 12 recommendations, for abstracts. CONCLUSIONS: The READUS-PV guidelines will support authors, editors, peer-reviewers, and users of disproportionality analyses using individual case safety report databases. Adopting these guidelines will lead to more transparent, comprehensive, and accurate reporting and interpretation of disproportionality analyses, facilitating the integration with other sources of evidence.

The REporting of A Disproportionality Analysis for DrUg Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Explanation and Elaboration.

In pharmacovigilance, disproportionality analyses based on individual case safety reports are widely used to detect safety signals. Unfortunately, publishing disproportionality analyses lacks specific guidelines, often leading to incomplete and ambiguous reporting, and carries the risk of incorrect conclusions when data are not placed in the correct context. The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV) statement was developed to address this issue by promoting transparent and comprehensive reporting of disproportionality studies. While the statement paper explains in greater detail the procedure followed to develop these guidelines, with this explanation paper we present the 14 items retained for READUS-PV guidelines, together with an in-depth explanation of their rationale and bullet points to illustrate their practical implementation. Our primary objective is to foster the adoption of the READUS-PV guidelines among authors, editors, peer reviewers, and readers of disproportionality analyses. Enhancing transparency, completeness, and accuracy of reporting, as well as proper interpretation of their results, READUS-PV guidelines will ultimately facilitate evidence-based decision making in pharmacovigilance.

What should be done to combat misinformation about health products?

The increasing role of digital technology, social media, the wide range of channels and the volume of information, the role of medicine as a societal subject, public information that is insufficient and poorly suited to situations of uncertainty are all observations which led to the theme of this round table. After discussing the definition of disinformation, which is not limited to fake news, and talking about contributors who misinform, whether intentionally or not, the participants of this round table made nine recommendations (R) to combat disinformation about health products: create a collaborative platform, information/training on health products, a platform with five major characteristics, namely accessibility, flexibility, objectivity, transparency and independence, as well as media suited to the different targets (R1); promote basic knowledge on health products: education/training to restore the particularly poor image of medication, and teach the public how to use basic concepts appropriately (R2); improve communication to the public based on the observation that information is the main weapon against misinformation and entails, in particular, coordinating communication from the different institutions to make public information more audible, making institutional messages clearer, ensuring they are more factual and prioritising them (R3); know how to communicate using the correct codes and tools (R4), because, to be understood, the substance and the form are inseparable; develop research on communication in the field of health products (R5); acquire tools to identify and regulate as soon as possible (R6); keep check of content by developing critical thinking (R7); define quality criteria for information sources (R8); identify, assess and reference initiatives for the public that could be placed on the platform (R9).

Trajectories of Benzodiazepine Use among Older Adults from a Concordance-with-Guidelines Perspective: A Nationwide Cohort Study.

BACKGROUND AND OBJECTIVE: Benzodiazepines (including zolpidem and zopiclone) are often associated with higher-than-recommended intake and durations of use, especially in older adults. The objective of this study was to characterize trajectories of benzodiazepine use according to recommended patterns in older adults, and to assess predictors of the risk of developing each of these trajectories. METHODS: Using the French Health Insurance database, we constituted a cohort of adults aged ≥ 65 years who initiated benzodiazepines in 2007 and were followed for up to 8 years. Concordance with benzodiazepine use guidelines was assessed on a quarterly basis according to a "concordance-with-guideline score" with values 1-5. Group-based trajectory modeling was then applied as implemented in the Proc Traj procedure in SAS to define guideline-concordant trajectories based on seven baseline patient-centered characteristics: sex, complementary health insurance coverage, treated alcohol and tobacco use disorder, polypharmacy, hospital stay, and registered chronic diseases. RESULTS: Among 5080 new users (64.1% women, median age 74 years), six trajectories of benzodiazepine use were identified. Three, representing 70% of users, were concordant with guidelines, whereas three implied non-concordant benzodiazepine use for part or all of the benzodiazepine use follow-up. Polymedicated patients were more prone to develop chronic non-guideline-concordant initially guideline-concordant use, whereas those with a history of long-term disease and hospitalization were more likely to develop chronic non-guideline-concordant use. The number of prescribers during the first quarter, number of daily defined doses, use of loperamide, and use of psychostimulants were associated with a higher risk of developing an initial and persistent non-guideline-concordant use. Treatment initiation by a psychiatrist, initial use of World Health Organization (WHO) step-2 opioids and non-benzodiazepine anxiolytics or sedatives were associated with a higher risk of late non-guideline-concordant use. CONCLUSIONS: Concordance with guidelines varied over time during benzodiazepine use in older adults. A third of these adults will hypothetically follow one of the identified non-guideline-concordant trajectories, consisting of initial and/or late non-guideline concordance. This was associated with modifiable and nonmodifiable factors that clinicians should be aware of for tailoring the monitoring of patients.

Drugs and the elderly: A complex interaction.

Although it can be difficult to define who should be considered an elderly person, the population aged 65 and over is experiencing the fastest demographic expansion and will represent almost one billion inhabitants of the 2030 World. Drug use increases dramatically with age and the elderly population is, by far, the highest consumer of medicines, up to 10 times more than younger adults. This consumption is in many aspects inappropriate, unjustified or sub-optimal and associated with a huge number of adverse reactions, admissions in emergency units and attributable deaths. A good part of which could be prevented if basic rules of good prescription and ad-hoc guidelines were systematically used. Even if older adults are more likely to present an adverse drug reaction, available data tend to support that the main risk factor of iatrogenesis in the elderly is the number of drugs used. Moreover, it is often irrelevant to transpose to this population the conclusions concerning the benefit-risk balance of drugs assessed in younger adults; similarly, approaches and programs classically used in pharmacovigilance and pharmacoepidemiology should be tailored to this specific population.

Neurocognitive Disorders Associated with PCSK9 Inhibitors: a Pharmacovigilance Disproportionality Analysis.

PURPOSE: PCSK9 might affect central nervous system development, neuronal apoptosis, and differentiation. We investigate the neurocognitive adverse events associated with the use of PCSK9 inhibitors (alirocumab and evolocumab) using pharmacovigilance reports. METHODS: We used the World Health Organization pharmacovigilance database (VigiBase) to perform a disproportionality analysis comparing the proportion of neurocognitive adverse events reported with PCSK9 inhibitors versus the proportion of these effects reported since August 14, 2015 (date of first post-marketing report suspecting a PCSK9 inhibitor), for all drugs in the database. Associations between PCSK9 inhibitor use and neurocognitive adverse events were assessed using both proportional reporting ratio (PRR) and information component (IC). Complementary analyses were performed on other neurologic events, and different sensitivity analyses were conducted to evaluate the robustness of results. RESULTS: Among the 81,108 reports involving at least one PCSK9 inhibitor, 1,941 concerned the occurrence of neurocognitive disorders. Most of patients (52.3%) were aged 45-74 years, and 58.0% were women. Signals of disproportionate reporting were found for PCSK9 inhibitors (PRR 1.22, 95% CI 1.17; 1.28; IC 0.28, IC025 0.21) and for each drug individually. No signal of disproportionality was found for any of the other neurologic events investigated. Signals of disproportionate reporting were found for the positive control (benzodiazepines), but not for the negative control (aspirin). The results of the main analysis were confirmed by sensitivity analyses. CONCLUSIONS: This study identified a signal of neurocognitive disorders associated with PCSK9 inhibitors and encourages paying attention to at-risk populations.

Decongestant use and the risk of myocardial infarction and stroke: a case-crossover study.

Pharmacovigilance reports of cerebral and cardiovascular events in those who use decongestants have triggered alerts related to their use. We aimed to assess the risk of stroke and myocardial infarction (MI) associated with the use of decongestants. We conducted a nested case-crossover study of patients with incident stroke and MI identified in France between 2013 and 2016 in two systematic disease registries. Decongestant use in the three weeks preceding the event was assessed using a structured telephone interview. Conditional logistic multivariable models were used to estimate the odds of incident MI and stroke, also accounting for transient risk factors and comparing week 1 (index at-risk time window, immediately preceding the event) to week 3 (reference). Time-invariant risk factors were controlled by design. In total, 1394 patients with MI and 1403 patients with stroke, mainly 70 years old or younger, were interviewed, including 3.2% who used decongestants during the three weeks prior to the event (1.0% definite exposure in the index at-risk time window, 1.1% in the referent time window; adjusted odds ratio (aOR), 0.78; 95%CI, 0.43-1.42). Secondary analysis yielded similar results for individual events (MI/stroke). We observed no increased risk of MI or stroke for patients 70 years of age and younger without previous MI or stroke who used decongestants.

Anticholinergic Activity of Psychotropic Drugs and Cognitive Impairment Among Participants Aged 45 and Over: The CONSTANCES Study.

INTRODUCTION: Psychotropic drugs such as anxiolytics, antidepressants and antipsychotics may have anticholinergic properties that could directly affect patients' cognition. OBJECTIVES: Our objective was to assess the relationship between exposure to anticholinergic-positive (AC+) psychotropic drugs and cognitive impairment compared with psychotropic drugs without anticholinergic activity (AC-). METHODS: This analysis included participants (aged 45-70 years) enrolled between January 2012 and October 2017 in the CONSTANCES cohort treated with psychotropic drugs (antidepressants n = 2602, anxiolytics n = 1195, antipsychotics n = 197) in the 3 years preceding cognitive assessment. Within each drug class, the Anticholinergic Cognitive Burden scale was used to classify drugs as either AC+ or AC-. Cognitive impairment was defined as a score below - 1 standard deviation from the standardized mean of the neuropsychological score. We used multiple logistic regression models and matching on propensity score to estimate the relationship between anticholinergic activity and cognitive impairment. RESULTS: Our analyses did not show any increased risk of cognitive impairment for AC+ antidepressants and anxiolytics, with the exception of a slight increase for AC+ antidepressants in episodic memory (odds ratio [OR] 1.19; 95% confidence interval [CI] 1.05-1.36). Conversely, we found a more marked increase in risk with AC+ antipsychotics on executive function (Trail Making Test-A [TMT-A], OR 4.49 [95% CI 2.59-7.97] and TMT-B, OR 3.62 [95% CI 2.25-5.89]). CONCLUSION: Our results suggest there is no clinically relevant association between the anticholinergic activity of antidepressant and anxiolytic drugs and cognitive impairment in middle-aged adults. An association could exist between AC+ antipsychotics and executive function.

Medicine misuse: A systematic review and proposed hierarchical terminology.

AIMS: Although medicine misuse is a public health issue, it has multiple meanings in the medical literature. This study aimed to characterize, classify and identify the most appropriate definitions of medicine misuse. METHODS: A systematic review was performed in Medline, ISI Web of Science, SocINDEX, PsycInfo, PsycArticles and Psychological and Behavioral Sciences Collection, using keywords related to "misuse", "appropriateness" and "medicine" between 1 November 2008 and 25 August 2020. Additional searches were conducted in websites of regulatory agencies and public health institutions. Two authors independently selected studies providing both definitions and examples of misuse, while a third resolved disagreements. Definitions were used to propose a hierarchical classification based on initiator, intent, purpose and context of medicine misuse. The study is registered on PROSPERO: CRD42018115789. RESULTS: Of 3404 identified records, 51 were included. A total of 71 definitions and 74 examples of misuse were retrieved. When the prescriber is initiator and according to intent, potential medicine misuse referred to "intentional or unintentional prescribing not in line with clinical evidence". Based on context, they could prescribe medicines not clinically justified, i.e. overprescribing, or prescribe indicated medicines incorrectly, i.e. misprescribing. Among other groups of definitions, those overlapping with drug abuse or medication use errors were considered out-of-scope. CONCLUSION: This systematic review provides a comprehensive overview of the terms and definitions used to characterize medicine misuse and could serve as a basis for a terminology that makes clear distinctions between misuse, abuse and errors.

Patterns of Benzodiazepine Use and Excess Risk of All-Cause Mortality in the Elderly: A Nationwide Cohort Study.

INTRODUCTION: Despite the risks associated with their use, benzodiazepines remain used more widely than wisely. In this context, a better understanding of how their patterns of use can be associated with an increased risk of death appears essential. Indeed, the studies that investigated this association so far are inconsistent and question the influence of potential biases. OBJECTIVE: The objective of this study was to investigate the association of various patterns of benzodiazepine use with all-cause mortality. METHODS: A nationwide cohort of non-prevalent benzodiazepine users aged ≥ 65 years was identified using French healthcare insurance system claims databases. Exposure to benzodiazepines considered short-term, chronic (defined as a cumulated ≥ 6-month period over the previous 12 months), ongoing, and discontinued use. Using a Cox model, adjusted hazard ratios for all-cause mortality were estimated according to benzodiazepine patterns of use; exposure and confounders were treated as time-dependent variables. RESULTS: In the cohort of 54,958 individuals aged ≥ 65 years, adjusted hazard ratios for all-cause mortality and benzodiazepines were 2.26 (95% confidence interval 1.96-2.61) for short-term use, 3.86 (3.04-4.90) for chronic use-discontinued, and 3.05 (2.17-4.29) for chronic use-ongoing. At age 80 years, these were 1.62 (1.48-1.79), 2.00 (1.82-2.19) and 1.13 (1.02-1.26), respectively. Adjusted hazard ratios show similar decreases with age for all patterns of benzodiazepine use. CONCLUSIONS: These findings confirm the existence of an excess risk of mortality associated with benzodiazepine use and provide pattern- and age-specific estimates. Higher risks were observed for patients aged < 80 years, short-term use, or chronic use recently interrupted. If the two latter can relate to an indication bias, the associations found for ongoing chronic use and short-term use conversely support a potential causal hypothesis.

Overview of French databases available for studying anticancer drugs in real-life setting.

Considering their novelty and cost, post-marketing evaluation is highly relevant for new anticancer drugs. Identify and characterize available and potentially useful databases for post-marketing evaluation of these specific drugs is necessary. A review was conducted to identify available and accessible databases to study the post-marketing evaluation of drugs in real-life care setting. Databases identified have been classified into medico-administrative databases, medical record databases, and databases resulting from ad hoc collections. Taking as examples databases available in France, each type was described as well as its strengths and limits for a potential use in the oncology field. Record linkage of medico-administrative databases could cover almost the whole population and is now used to evaluate anticancer drugs (e.g., Système National des Données de Santé). Large medical record databases are still lacking, but efforts are currently made to give access to hospital data warehouses for research purposes. Finally, databases resulting from ad hoc collections are also available for some cancer localizations and allow to obtain highly valuable clinical and biological data. A range of important and valuable databases exist but, individually, none is enough to answer to all questions from health authorities, healthcare professionals, and patients. In order to obtain a complete overview on utilization, associated health outcomes and costs of these drugs, it seems necessary to better interlink available databases.

Benefit-Risk Assessment of Vaccines. Part II: Proposal Towards Consolidated Standards of Reporting Quantitative Benefit-Risk Models Applied to Vaccines (BRIVAC).

INTRODUCTION: Quantitative benefit-risk models (qBRm) applied to vaccines are increasingly used by public health authorities and pharmaceutical companies as an important tool to help decision makers with supporting benefit-risk assessment (BRA). However, many publications on vaccine qBRm provide insufficient details on the methodological approaches used. Incomplete and/or inadequate qBRm reporting may affect result interpretation and confidence in BRA, highlighting a need for the development of standard reporting guidance. OBJECTIVES: Our objective was to provide an operational checklist for improved reporting of vaccine qBRm. METHODS: The consolidated standards of reporting quantitative Benefit-RIsk models applied to VACcines (BRIVAC) were designed as a checklist of key information to report in qBRm scientific publications regarding the assessed vaccines, the methodological considerations and the results and their interpretation. RESULTS: In total, 22 items and accompanying definitions, recommendations, explanations and examples were provided and divided into six main sections corresponding to the classic subdivisions of a scientific publication: title and abstract (items 1-2), introduction (items 3-4), methods (items 5-15), results (items 16-17), discussion (items 18-20) and other (items 21-22). CONCLUSIONS: The BRIVAC checklist is the first initiative providing an operational checklist for improved reporting of qBRm applied to vaccines in scientific articles. It is intended to assist authors, peer-reviewers, editors and readers in their critical appraisal. Future initiatives are needed to provide methodological guidance to perform qBRm while taking into account the vaccine specificities.

Benefit-Risk Assessment of Vaccines. Part I: A Systematic Review to Identify and Describe Studies About Quantitative Benefit-Risk Models Applied to Vaccines.

INTRODUCTION: Understanding the balance between the benefits and risks of vaccination is essential to ensure informed and adequate public health decision making. Quantitative benefit-risk models (qBRm) represent useful tools to help decision makers with supporting benefit-risk assessment throughout the lifecycle of a medical product. However, few initiatives have been launched to harmonise qBRm approaches, specifically for vaccines. OBJECTIVES: The aim of this paper was to identify publications about qBRm applied to vaccines through a systematic literature review, and to describe their characteristics. METHODS: Medline, Scopus and Institute for Scientific Information Web of Knowledge databases were searched to identify articles in English, published from database inceptions up to December 2019. The search strategy included the combination of three key concepts: 'benefit-risk', 'modelling' and 'vaccines'. Data extracted included the modelling context and the methodological approaches used. RESULTS: Of 3172 publications screened, 48 original publications were included. Most of the selected studies were published over the past decade and focused on rotavirus (15), dengue (10) and influenza (6) vaccines. The majority (30) of studies reported analyses related to high-income countries. The methodology of the studies differed, particularly in modelling techniques, benefit-risk measures, and sensitivity analyses. The present work also pointed out a high level of variability in the quality of reporting across studies, with particular regard to input parameters and methodological approaches. CONCLUSIONS: This review provides an extensive list of qBRm applied to vaccines. Discrepancies across studies were identified during our review. While the number of published qBRm studies is increasing, no reporting guidance for qBRm applied to vaccines is currently available. This may affect decision makers' confidence in the results and their benefit-risk assessment(s); therefore, the development of such reporting guidance is highly needed.

Using Discretely Integrated Condition Event Simulation To Construct Quantitative Benefit-Risk Models: The Example of Rotavirus Vaccination in France.

PURPOSE: Although quantitative benefit-risk models (qBRms) are indisputably valuable tools for gaining comprehensive assessments of health care interventions, they are not systematically used, probably because they lack an integrated framework that provides methodologic structure and harmonization. An alternative that allows all stakeholders to design operational models starting from a standardized framework was recently developed: the discretely integrated condition event (DICE) simulation. The aim of the present work was to assess the feasibility of implementing a qBRm in DICE, using the example of rotavirus vaccination. METHODS: A model of rotavirus vaccination was designed using DICE and implemented in spreadsheet software with 3 worksheets: Conditions, Events, and Outputs. Conditions held the information in the model; this information changed at Events, and Outputs were special Conditions that stored the results collected during the analysis. A hypothetical French birth cohort was simulated for the assessment of rotavirus vaccination over time. The benefits were estimated for up to 5 years, and the risks in the 7 days following rotavirus vaccination versus no vaccination were assessed, with the results expressed as benefit-risk ratios. FINDINGS: This qBRm model required 8 Events, 38 Conditions, and 9 Outputs. Two Events cyclically updated the rates of rotavirus gastroenteritis (RVGE) and intussusception (IS) according to age. Vaccination occurred at 2 additional Events, according to the vaccination scheme applied in France, and affected the occurrence of the other Events. Outputs were the numbers of hospitalizations related to RVGE and to IS, and related deaths. The entire model was specified in a small set of tables contained in a 445-KB electronic workbook. Analyses showed that for each IS-related hospitalization or death caused, 1613 (95% credible interval, 1001-2800) RVGE-related hospitalizations and 787 (95% credible interval, 246-2691) RVGE-related deaths would be prevented by vaccination. These results are consistent with those from a published French study using similar inputs but a very different modeling approach. IMPLICATIONS: A limitation of the DICE approach was the extended run time needed for completing the sensitivity analyses when implemented in the electronic worksheets. DICE provided a user-friendly integrated framework for developing qBRms and should be considered in the development of structured approaches to facilitate benefit-risk assessment.

DPP-4 Inhibitors in Combination with Lipid-Lowering Agents and Risk of Serious Muscular Injury: A Nested Case-Control Study in a Nationwide Cohort of Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: After a safety warning was issued for a risk of muscular injury associated with dipeptidyl peptidase-4 (DPP-4) inhibitor use, especially when co-prescribed with statins, spontaneous reporting analyses provided conflicting results. OBJECTIVE: The aim of this study was to investigate the association between DPP-4 inhibitor use and the risk of muscular injury in individuals with type 2 diabetes mellitus using statins or fibrates. METHODS: We conducted a nested case-control study amongst a cohort of individuals with type 2 diabetes using statins or fibrates, identified from a nationwide French health insurance database (2009-2014). Cases of serious muscular injury were defined as subjects hospitalized for rhabdomyolysis or myopathy, or for whom testing for myoglobin or creatine phosphokinase followed by a change in statin or fibrate prescription (dose decrease, treatment switch, or stop) was identified. Up to ten controls were matched to each case according to sex, age, and type of lipid-lowering agent. Associations between DPP-4 inhibitor use and serious muscular injury were estimated using a multivariate conditional logistic regression model, providing odds ratios (ORs) adjusted for alcoholism, chronic renal failure, hypothyroidism, and number of concomitant drugs. RESULTS: Within the 35,117 individuals with type 2 diabetes mellitus constituting the source cohort, 437 statin-user cases were identified who were matched to 4358 statin-user controls. Similarly, 54 fibrate-user cases were identified who were matched to 540 fibrate-user controls. The adjusted OR for DPP-4 inhibitor use and serious muscular injury was estimated at 1.0 (95% confidence interval [CI] 0.7-1.2) in statin users and 0.8 (95% CI 0.4-1.9) in fibrate users. CONCLUSION: In this study, DPP-4 inhibitor use was not associated with an increased risk of serious muscular injury among patients with type 2 diabetes mellitus using statins or fibrates.