Can requests for real-world evidence by the French HTA body be planned? An exhaustive retrospective case-control study of medicinal products appraisals from 2016 to 2021.

OBJECTIVES: In France, decisions for pricing and reimbursement for medicinal products are based on appraisals performed by the National authority for health (Haute Autorité de Santé (HAS)). During the appraisal process, additional real-world evidence can be requested as "Post-Registration Studies" (PRS) when there are uncertainties in evidence that could be resolved by additional data collection. To facilitate PRS planning, a retrospective exploratory analysis was conducted to identify the characteristics of medicinal products associated with a PRS request. METHODS: This analysis encompassed all appraisals finalized between January 1, 2016 and December 31, 2021 and compared products for which the appraisal led to a PRS request with those that did not. RESULTS: Six hundred positive opinions for reimbursement were identified, with a PRS request present in 17 percent (n = 103) of cases. The independent characteristics associated with a PRS request were a mild or moderate clinical benefit score, a major to moderate or minor clinical added value score, previous availability under an early access program, and certain therapeutic areas (neurology, pulmonology, and endocrinology). These findings suggest two different profiles of PRS requests: (i) products for which there is uncertainty in the size of the clinical benefit and (ii) innovative products for which a substantial benefit is expected but uncertainties persist. CONCLUSIONS: These results will assist health technology developers to better anticipate data generation to promptly address uncertainties identified by HAS. It may also help HAS and other assessment agencies to work together to improve postlaunch evidence generation according to the characteristics of the medicinal products.

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.

Added Therapeutic Value of Medicinal Products for French and German Health Technology Assessment Organizations: A Systematic Comparison.

OBJECTIVES: Determining the price and reimbursement of a new medicine is a national competence within the Member States of the European Union that is carried out by health technology authorities and is based mainly on the added therapeutic value (ATV). The primary objective of this study was to compare the ATVs granted by the French (Haute Autorité de Santé, HAS) and the German (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWIG) authorities. The secondary objective was to analyze the reasons for the discrepancies observed. METHODS: Retrospective cohort of all ATVs assigned by HAS and IQWIG for the period 2011 to 2017. ATV assessments were classified as major, considerable, minor, no benefit, or not quantifiable. The concordance between the authorities was evaluated, and a qualitative analysis of highly discordant assessments was performed. RESULTS: One hundred and ninety-one drugs were evaluated by both agencies. The overall percentage of agreement was 50.3%. It was 73.1% for no benefit of ATVs, 37.5% for minor ATVs, 31.2% for considerable ATVs, and 5% for major ATVs. Highly conflicting assessments (n = 35) mainly concerned antineoplastic drugs (n = 14) and anti-infectives (n = 14). The main reasons for inconsistency concerned the following: a different appreciation of the subgroup analysis of efficacy data (n = 15), the appropriateness of comparators (n = 15), the surrogate endpoints (n = 10), methodological differences (n = 8), and the benefit/risk criteria that were used (n = 6). CONCLUSION: In the context of the common assessment of ATVs promoted by the European Commission, the harmonization between member states regarding the way evaluation criteria are assessed deserves to be addressed.

Misuse of benzodiazepines: Prevalence and impact in an inpatient population with psychiatric disorders.

AIMS: Use and misuse of benzodiazepine might be very prevalent in patients with acute psychiatric symptoms, whereas they might be associated with specific adverse events in this population. The study investigated their prevalence in these patients. Secondary objectives were to identify risk factors for misuse of benzodiazepines, and its impact. METHODS: A cohort study was based on the hospital's electronic patient records and conducted in patients aged 18 years and over and admitted to a psychiatric hospital. They were followed up for 84 days or until the end of hospitalisation. Four variables of misuse were built: excessive duration of treatment, type of product, excessive dosage and concomitant benzodiazepines. Backward stepwise multivariate logistic regression analysis was used to assess risk factors for each misuse criterion, on the 1 hand, and impact of benzodiazepine misuse, on the other. RESULTS: In total, 511 psychiatric inpatients were included with 89.0% of them exposed to benzodiazepine. Discharge prescription included no benzodiazepine or a dosage lower than the maximum dosage prescribed during hospitalisation for 78.2% of patients exposed to benzodiazepine during their stay. Of benzodiazepine treatments, 31.4% were associated with at least 1 misuse criterion. Excessive dosage was associated with age ≥65 years (OR 11.57; 95% confidence interval 4.92-27.17), substance/alcohol use disorders (3.35; 95% confidence interval 1.70-6.62) and parenthood (0.49; 0.25-0.97). Some criteria of benzodiazepine misuse were associated with a higher frequency of adverse events occurring after treatment initiation. CONCLUSIONS: Misuse of benzodiazepines is very common in inpatients with psychiatric disorders. These findings should alert clinicians to comply with clinical recommendations.

Appropriateness of psychotropic drug prescriptions in the elderly: structuring tools based on data extracted from the hospital information system to understand physician practices.

BACKGROUND: The appropriateness of psychotropic prescriptions in the elderly is a major quality-of-care challenge at hospital. Quality indicators have been developed to prevent inappropriate psychotropic prescriptions. We aimed to select and automatically calculate such indicators, from the Bordeaux University Hospital information system, and to analyze the appropriateness of psychotropic prescription practices, in an observational study. METHODS: Experts selected indicators of the appropriateness of psychotropic prescriptions in hospitalized elderly patients, according to guidelines from the French High Authority for Health. The indicators were reformulated to focus on psychotropic administrations. The automated calculation of indicators was analyzed by comparing their measure to data collected from a clinical audit. In elderly patients hospitalized between 2014 and 2015, we then analyzed the evolution of the appropriateness of psychotropic prescription practices during hospital stay, using methods of visualization, and described practices by considering patients' characteristics. RESULTS: Two indicators were automated to detect overuse and misuse of psychotropic drugs. Indicators identified frequent inappropriate drug administrations, but practices tended to become more appropriate after quality-of-care improvement actions. In the majority of patients (85%), there was no inappropriate administration of psychotropic drugs during hospital stay; for the remaining 15% with at least one inappropriate administration, physicians tended to limit overuse or misuse during hospital stay. Inappropriate administrations were more frequent in patients suffering from psychiatric disorders, dependence and associated complications or morbidities. CONCLUSIONS: The automated indicators are structuring tools for the development of a drug prescription monitoring system. Inappropriate psychotropic administrations were limited by physicians during hospital stay; some inappropriate prescriptions might be explained by clinical characteristics of patients.

Requests for post-registration studies (PRS), patients follow-up in actual practice: Changes in the role of databases.

Early market access of health products is associated with a larger number of requests for information by the health authorities. Compared with these expectations, the growing expansion of health databases represents an opportunity for responding to questions raised by the authorities. The computerised nature of the health system provides numerous sources of data, and first and foremost medical/administrative databases such as the French National Inter-Scheme Health Insurance Information System (SNIIRAM) database. These databases, although developed for other purposes, have already been used for many years with regard to post-registration studies (PRS). The use thereof will continue to increase with the recent creation of the French National Health Data System (SNDS [2016 health system reform law]). At the same time, other databases are available in France, offering an illustration of "product use under actual practice conditions" by patients and health professionals (cohorts, specific registries, data warehouses, etc.). Based on a preliminary analysis of requests for PRS, approximately two-thirds appeared to have found at least a partial response in existing databases. Using these databases has a number of disadvantages, but also numerous advantages, which are listed. In order to facilitate access and optimise their use, it seemed important to draw up recommendations aiming to facilitate these developments and guarantee the conditions for their technical validity. The recommendations drawn up notably include the need for measures aiming to promote the visibility of research conducted on databases in the field of PRS. Moreover, it seemed worthwhile to promote the interoperability of health data warehouses, to make it possible to match information originating from field studies with information originating from databases, and to develop and share algorithms aiming to identify criteria of interest (proxies). Methodological documents, such as the French National Authority for Health (HAS) recommendations on "Les études post-inscription sur les technologies de santé (médicaments, dispositifs médicaux et actes). Principes et méthodes" [Post-registration studies on health technologies (medicinal products, medical devices and procedures). Principles and methods] should be updated to incorporate these developments.

Off-label prescriptions: how to identify them, frame them, announce them and monitor them in practice?

Following the Mediator crisis and the passage of the Health and Safety Law of December 2011, off-label prescriptions are a real concern shared by all those involved in healthcare system. Off-label, in the strictest sense of the term, is defined as all prescriptions that do not correspond to the summary of product characteristics (SPC), particularly those that fail to comply with the indications and dosage regimens defined by the marketing authorization (MA) for clear safety reasons. There are various rasons for off-label prescriptions, both conscious and unconscious. They are intended to respond to unmet medical needs, the needs of poorly studied populations or not studied at all in trials, but in relation to whom it is reasonable to extrapolate that MA would be given (common-sense prescriptions) and, additionally, to urgent public health needs (such as baclofen, pregnant women, and HIV drugs). All these prescriptions would deserve to be studied for a potential MA. However, there are off-label prescriptions that need to be restricted or even penalized in the case of compassionate prescriptions or unjustified prescriptions or prescriptions not based on any scientific grounds. Off-label prescriptions are not easy to track down because if the prescriber has to write "off-label" on his prescription, then clearly, in practice, he will only do so in exceptional cases. Neither the pharmacists who dispense the drug nor the Social Security that reimburses it, have access to the diagnosis (or targeted indication). Thus, in order to identify the off-label prescription, we must be able to cross reference the available databases (such as pharmacovigilance database, medicalized information system program [programme de médicalisation des systèmes d'information, PMSI], hospital drug formularies, general sample of beneficiaries [échantillon généraliste de bénéficiaires, EGB] or national inter-regional Health Insurance Information System [système national d'informations inter-régions d'Assurance maladie, SNIIRAM], sales data, and data from market surveys). The shared computerized patient file may resolve this problem. The temporary use recommendation (TUR) proposed by the Drug Safety Law will only partially deal with this problem for recently marketed molecules. This temporary and exceptional mechanism will authorize a recognized off-label prescription, which may be reimbursed and monitored for 3 years. These TURs will only concern a small portion of "off-label" drugs having yet a positive risk/benefit ratio (conditional MA) but this is far from matching with majority of off-label prescriptions. As such, and in order to improve the use of drugs, it is important to propose a control system for all "off-label" prescriptions with a dedicated committee: the "off-label" committee which would determine the frame of the "off-label" prescriptions.

Pharmacoepidemiology for oncology clinical practice: Foundations, state of the art and perspectives.

Since the early 2000s, the arrival of the so-called targeted therapies and immunotherapies have prolonged survival rates in many cancers. In parallel, post-marketing surveillance of anticancer drugs through pharmacoepidemiology has gradually developed. This paper provides (i) a detailed argumentation of the foundations for pharmacoepidemiology of anticancer drugs, (ii) an overview of pharmacoepidemiological studies currently available in this field, and (iii) some perspectives to improve pharmacoepidemiology for oncology practice. First of all, according to the existing literature, the development of pharmacoepidemiological studies for the clinical evaluation of anticancer drugs appears particularly justified based on common limitations of clinical trials in oncology regarding essential methodological principles such as adequate control groups, randomisation or double blinding. Many descriptive field cohort studies have investigated together treatment patterns, effectiveness, and safety to compare results from clinical trials with those of everyday practice. The utilisation of anticancer drugs has also been extensively described through cross-sectional or cohort studies by often using medico-administrative or medical databases. Such studies are useful to quantify and characterise use over time in the population, including clinically unvalidated use, and to evaluate adherence and persistence to increasingly available oral anticancer drugs. Despite their importance to increase knowledge, comparative effectiveness or safety studies remain uncommon. In a context of rapidly emerging therapies and personalised treatments, this may be due to methodological challenges especially related to the choice of a comparator or the consideration of confounding by indication. In the future, efforts must be pursued to provide real-time access to high-quality, large-scale clinical, biological and treatment data, and to improve record-linkage between hospital and outpatient databases. More research is also needed to better evaluate all medications, not only anticancer, as part of an overall cancer care pathway and to bring the evaluation of anticancer drugs closer to patients and society (social pharmacology).

The Multidimensional Nature of Research Ethics: Letters Issued by a French Research Ethics Committee Included Similar Proportions of Ethical and Scientific Queries.

Debate is ongoing concerning the activities and functioning of Research Ethics Committees (REC), especially a possible science-or-ethics dichotomy in research ethics review. We retrospectively analyzed 145 letters issued by a French REC over 18 months. All queries were classified in three levels: qualification (definition of the problem), category (aggregation of broader topics) and finally fields (ethical, scientific, or administrative). Overall, 971 queries were identified, of which 407 (42%), 379 (39%), and 135 (14%) were deemed ethical, scientific, and administrative queries, respectively. The most frequent concern was about participants' information. The main influencing factor was the profession of the reporting readers-scientific queries were more frequently raised by a methodologist, whereas ethical queries were more frequently raised by an ethicist. These results indicate that research ethics review is a multidimensional task that should be considered a collaborative effort.

Adverse drug reactions induced by cotrimoxazole: Still a lot of preventable harm.

Owing to a broad spectrum and low cost antimicrobial, cotrimoxazole is largely prescribed. However, its use is associated with various adverse drug reactions (ADRs) that warrant to ensure rational prescribing. This study aimed to describe spontaneous reports of cotrimoxazole ADRs and to evaluate the quality of prescription in patients who had ADRs. Suspected cotrimoxazole-induced ADRs cases reported to the Bordeaux regional pharmacovigilance center (France) during a 5-year period were described. Seriousness was assessed according to international criteria. Quality of prescription was assessed by compliance with the Summary of Product Characteristics (SPC) and relevance of cotrimoxazole indication. Then, an ADR was considered as preventable if the cotrimoxazole indication was not relevant, or potentially preventable if indication was relevant but the prescription was not compliant with the SPC. A total of 96 cases were analyzed: median age was 60.5 years (range: 4-94); 59.4% of patients were male. ADRs were mostly cutaneous disorders (n = 46) and hematological disorders (n = 25). A total of 60 serious ADRs occurred in 55 patients. Prescribers complied with all SPC recommendations in 21.9% of cases. Indication of cotrimoxazole was relevant or highly relevant in 41 cases. In 58% of cases, the occurrence of a cotrimoxazole-induced ADR would have been preventable or potentially preventable. In a context of increasing interest for this antibiotic to treat infections due to resistant bacteria, physicians should be more aware of the potential consequences of inappropriate prescribing cotrimoxazole and reserve its use when there is no alternative and under suitable monitoring.

Ambulatory drug changes in the elderly after hospital discharge: A cohort study.

AIM: To describe the ambulatory changes in drug prescriptions 3 months after hospital discharge among elderly patients aged 75 and over, and to identify the reasons for these changes. METHODS: A prospective cohort study was conducted on subjects, discharged between 09/2016 and 01/2017 from the Bordeaux University Hospital. Prescription forms were collected from patients' pharmacists. The main outcome was the occurrence of at least one significant change (SC) defined as an initiation, a discontinuation, a switch or change in drug daily dosage as regards the drugs prescribed upon hospital discharge and those prescribed 3 months after. Whenever drug SC occurred, general practitioners were requested to elicit reasons for such changes. RESULTS: Among the 126 patients included in our study, 73 underwent a 3-month follow-up period, without death or being re-hospitalised. 87.7% of them had at least one SC 3 months after discharge, with an average of 3.1±2.5 SC per patient. Main changes involved: discontinuation or dose decrease of anxiolytics, hypnotics, antalgics, betablockers and calcium channel blockers; start or dose increase of diuretics, ACE inhibitors and angiotensin receptor blockers. In patients with a 3-month follow-up period, 27.4% underwent at least one ADR-induced SC. CONCLUSION: Most elderly patients experience drug prescription changes after discharge. Some, according to drug iatrogenic, could be avoided through better cooperation between hospital and ambulatory prescribers.

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.

Comparators (medicinal and non medicinal) for marketing authorization, for public health, for payers and at the European level.

Drug evaluation is based on comparison. Thus, the choice of the comparator for any new treatment becomes a key issue, especially when there are great differences in medical practice and of use conditions of the comparators depending on the geographical zones and their evolution with time. The choice of the comparators must satisfy sometimes different expectations from the registration authorities and for insurance coverage. The universal comparator that allows answering all the clinical assessment questions does not exist. Placebo, when it can be used, remains a reference for the MA (marketing authorisation) application, but does not exclude the use of the reference drug available on the market and prescribed under optimal efficacy conditions. The reference treatment is sometimes a difficult choice due to the absence of validated therapeutic recommendations or if the recommendations vary depending on the countries. The expansion and international harmonization of prescription guidelines (clinical practice guidelines) would reinforce the robustness and efficiency of clinical research efforts with respect to the relevance of the comparison to reference treatments. This principle also applies to the use of a non-drug comparator when it has been recognized as the reference comparator in the treatment of the pathology in question. In as much as possible, the search for a consensus must also aim at defining in the clinical development recommendations significant thresholds for the size of evaluated effects. Optimization of the information made available after clinical trials could also be helped by the development of use of methodologies that allow assessing superiority on secondary criteria during a non-inferiority study on the main criterion. Finally, the development of early scientific consultations by the Haute Autorité de Santé (HAS, French Health Authority) would contribute to adapt phase III clinical trials better to questions concerning the assessment of the clinical added value of the medicinal products evaluated.

Use of benzodiazepines non-compliant with guidelines in patients with psychiatric and non-psychiatric chronic disorders.

OBJECTIVE: To quantify benzodiazepine use non-compliant with guidelines in patients with psychiatric and non-psychiatric chronic diseases and assess the risk of non-recommended use associated with these diseases. METHOD: A cohort study was conducted in the French health insurance databases, including 254,488 new benzodiazepine users between 2007 and 2014. Psychiatric, cardiovascular, cancer, diabetes and inflammatory diseases were identified. Patients were followed for 2 years. Non-recommended use was defined as excessive treatment duration, use of long half-life drugs in older patients and concomitant use of several benzodiazepines. Cox models identified the factors associated with non-recommended use. RESULTS: Non-recommended use was frequent, ranging from 44.9% to 68.1%. It was independently associated with each chronic disease, with a slight increase in patients with chronic inflammatory disease (HR = 1.07; 95%CI 1.03-1.13) or diabetes (HR = 1.09; 1.06-1.12), a higher risk in those with chronic cardiovascular disease (HR = 1.34; 1.31-1.37) or cancer (HR = 1.30; 1.25-1.35) and the highest risk in those with psychiatric disease (HR = 2.04; 2.00-2.09). CONCLUSION: Patients with chronic disease have a high risk of benzodiazepine use leading to a higher exposure than recommended. Prescribers should be aware of the need to comply with the recommendations, especially in these patients who are the most frail and vulnerable to adverse events.

Discontinuing statins or not in the elderly? Study protocol for a randomized controlled trial.

BACKGROUND: The risk/benefit ratio of using statins for primary prevention of cardiovascular (CV) events in elderly people has not been established. The main objectives of the present study are to assess the cost-effectiveness of statin cessation and to examine the non-inferiority of statin cessation in terms of mortality in patients aged 75 years and over, treated with statins for primary prevention of CV events. METHODS: The "Statins in the elderly" (SITE) study is an ongoing 3-year follow-up, open-label comparative multi-centre, randomized clinical trial that is being conducted in two parallel groups in outpatient primary care offices. Participants meeting the following criteria are included: people aged 75 years and older being treated with statins as primary prevention for CV events, who provide informed consent. After randomization, patients in the statin-cessation strategy are instructed to withdraw their treatment. In the comparison strategy, patients continue their statin treatment at the usual dosage. The cost-effectiveness of the statin-cessation strategy compared to continuing statins will be estimated through the incremental cost per quality-adjusted life years (QALYs) gained at 36 months, from the perspective of the French healthcare system. Overall mortality will be the primary clinical endpoint. We assumed that the mortality rate at 3 years will be 15%. The sample size was computed to achieve 90% power in showing the non-inferiority of statin cessation, assuming a non-inferiority margin of 5% of the between-group difference in overall mortality. In total, the SITE study will include 2430 individuals. DISCUSSION: There is some debate on the value of statins in people over 75 years old, especially for primary prevention of CV events, due to a lack of evidence of their efficacy in this population, potential compliance-related events, drug-drug interactions and side effects that could impair quality of life. Data from clinical trials guide the initiation of medication therapy for primary or secondary prevention of CV disease but do not define the timing, safety, or risks of discontinuing the agents. The SITE study is one of the first to examine whether treatment cessation is a cost-effective and a safe strategy in people of 75 years and over, formerly treated with statins. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02547883. Registered on 11 September 2015.

Pharmacovigilance - The next chapter.

The discovery and quantification of adverse drug reactions has long relied on the careful analysis of spontaneously reported cases. Causality assessment (imputation) was a fundamental feature of individual case report analysis. This was complemented by analysis of aggregated cases, and of disproportionality analyses in spontaneous reports databases. In the absence of more specific information sources, these have resulted in the discovery of many new adverse reactions, altering drug information. It has led to the withdrawal from the market of many drugs, but its use for risk quantification remains fraught with uncertainty. The recent access to population-wide claims or electronic health records databases have confirmed for spontaneous reporting a predominant role in hypothesis generation for serious adverse drug reactions, notably those that result in hospital admission or death. In these cases, the events are identifiable at the population level, and can be quantified precisely using the tools of modern pharmacoepidemiology, to generate specific benefit-risk analyses. Spontaneous reporting remains irreplaceable in signal and alert generation in drug safety, despite its inherent limitations. For signal strengthening and assessment, more systematic and quantitative methods should be sought, such as claims databases for reactions resulting in hospital admissions.