[Perception of medication risk by the public and role of the media]. / Rapport 22-09. Perception du risque médicamenteux par le public et rôle des médias.

Opinion polls regularly show that the vast majority of French people have a positive perception of the efficacy and safety of using medicines, including vaccines. Distrust or hostility towards them is only the fact of a small minority of the population, but active and noisy on social networks and overvalued by the media and public authorities. However, the pandemic due to Covid 19 (SARS-CoV-2) has confirmed to what extent the perception of drug risk by the public is unstable, sometimes irrational, how many and complex the determinants of this perception are and what role as a public resonance, fears play out in the media. We can even implicitly see the general underlying tendency of our society, which is to grant primacy to risk to the detriment of profit in the assessment of a technological innovation. The risk tree often masking the forest of efficiency. This polarization of minds on risks, associated with an overestimation of low probabilities, testifies to the impregnation of our mores by the ideology of precaution. To which are added distorting factors such as naturalistic prejudice, cultural relativism and the planetary extension of social networks which instantly spread false information that is more viral and better remembered than the true ones, hampering communication based on science data. Promoting the correct perception of drug risk requires recalling both the benefits and the risks linked to action but also those linked to inaction; to clarify institutional messages by making them as factual as possible; to limit the number of public broadcasters to achieve greater consistency in their messages; to have the frankness to sometimes say that we do not know, medicine by nature being practiced in a context of uncertainty. The Academy calls for an ambitious educational policy for young people: training in critical thinking and the acquisition of the basics of drug risk should be introduced from middle school. The Academy also believes that the public is entitled to expect quality-controlled information from the media, away from rumors, by calling on indisputable experts and by favoring objective data over subjective testimonies based on personal experiences.

[Interfering RNA and antisense oligonucleotide treatments currently available in France: An update]. / Les traitements par ARN interférents et par oligonucléotides antisens actuellement disponibles en France : une mise au point.

The arrival of anti-Covid-19 RNA vaccines in 2020 should not obscure the fact that for several years we have already had treatments based on interfering RNA or antisense oligonucleotides in a number of rare diseases with a very poor prognosis such as transthyretin amyloidosis, acute hepatic porphyria, primary hyperoxaluria, spinal muscular atrophy or familial hyperchylomicronemia. If their performance, unlike that of vaccines, is for the moment only qualified as moderate therapeutic progress (moderate clinical added value) in the therapeutic strategies against these diseases, it should be taken into account that their initial evaluation was penalized by a certain number of unfavorable factors: trials of small numbers, therapeutic modalities to be refined, the lack of hindsight on their long-term effects but especially the choice of the moment of the initiation of the treatment in the natural evolution of the sickness. This choice is not trivial because it is hard to imagine that the products used could, beyond a simple stabilization of the disease installed, allow its regression as soon as certain lesions formed are irreversible. This is why their very early implementation, possibly based on genetic screening, is an avenue to be seized in the interest of patients. But, in the competitive context of innovations in the field, interfering RNAs and antisense oligonucleotides will have to reckon with gene therapy and genome editing using the CRISPR-Cas 9 technique.

[Potentially inappropriate prescriptions for the elderly: a study of health insurance reimbursements in Southeastern France]. / Prescriptions médicamenteuses potentiellement inadaptées chez les personnes âgées : une étude en Provence-Alpes-Côte d'Azur à partir des données de remboursements de l'Assurance maladie.

BACKGROUND: This study conducted in the region of Provence-Alpes-Côte d'Azur (PACA) sought to assess the feasibility of constructing and using indicators of potentially inappropriate prescriptions for the elderly from health insurance reimbursement data. We present and discuss different indicators of inappropriate prescriptions for people aged 70 years or older (at-risk prescriptions, dangerous or at-risk coprescriptions, absence of necessary coprescriptions) and reports their prevalence in PACA. METHODS: The indicators were constructed from the French list of inappropriate prescriptions, national agency guidelines, and the advice of experts in the field. The indicators selected were applied to the databases of the PACA Salaried Workers' Health Insurance Fund for 2008 for all recipients aged 70 years or older and compared according to age, sex, chronic disease status, and, after standardization for age and sex, according to district of residence. RESULTS: In January 2009, 500,904 recipients aged 70 years or older were identified in the data base of the Salaried Workers' Health Insurance Fund, 60.8% of whom were women and 52.1% of whom had approved coverage for a chronic disease. The potentially inappropriate prescriptions most frequently observed here, in decreasing order, were: prescription of an NSAID without the coprescription of gastric protection (28.1%); long-term benzodiazepine treatment (21.5%); prescription of long half-life benzodiazepine (14.9%), and long-term treatment with NSAIDs (11.6%). Overall, the prevalence of each increased significantly with age and was higher among women and people with chronic diseases. Significant variations were also observed between the different districts of PACA. CONCLUSION: Our results confirm that a substantial proportion of elderly people receive potentially inappropriate prescriptions. They also suggest that health insurance reimbursement data could be used in some prescription domains for monitoring trends in the potentially inappropriate prescriptions in the populations of various territories, provided that specific limitations are considered.

Feedback and lessons from the prescription of rimonabant, a drug to be used under strict guidelines, in southeastern France, March 2007 through June 2008.

BACKGROUND: To provide feedback on the initial market authorization of rimonabant, a drug to be used under strict guidelines, we conducted a study with information from the National health insurance reimbursements database for southeastern France. The aims of this study were to: (1) describe the characteristics of subjects who have had one rimonabant prescription reimbursed; (2) study the frequency of prescriptions that did not comply with reimbursement criteria; (3) study the frequency of prescriptions for patients simultaneously treated with antidepressants; and (4) analyse the factors associated with both types of prescription (patient and prescriber characteristics). METHODS: Using the database of drug reimbursements maintained by the southeastern France general health insurance fund, we studied the characteristics of outpatients with at least one reimbursement for rimonabant, compared them to the rest of the population, and analysed compliance with the indications, contraindications, and regulations for rimonabant prescription with multivariate logistic regressions. RESULTS: A total of 10,510 beneficiaries (0.28%) had at least one rimonabant reimbursement. Among them, 55.7% were treated for diabetes. For at least 62.4% of rimonabant beneficiaries, the reimbursement regulations were not respected: this was significantly more frequent among women less than 57 years old, subjects with no chronic diseases, and when the prescriber was not an endocrinologist; 11.4% of rimonabant beneficiaries also received an antidepressant treatment. CONCLUSION: Despite the specific status of rimonabant regarding its reimbursement modalities, these results suggest that some prescribers get around reimbursement instructions and that a significant percentage of prescriptions did not respect an important contraindication. Tools to follow up the prescriptions of new drugs with strict guidelines for use should be developed and physicians should be better informed and trained regarding specific prescription regulations.

Adherence to treatment of osteoporosis: a need for study.

UNLABELLED: Adherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis. INTRODUCTION: Several medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients. METHODS: An extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting. RESULTS: The impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence. CONCLUSION: Adherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement.

Antiplatelet therapy for primary prevention in diabetes.

Aspirin is currently recommended by ADA (American Diabetes Association) for the diabetic patients over 40 years of age and without cardiovascular disease. This recommendation is at odds with drug approval for aspirin. The main explanation is the absence of appropriate trials assessing the usefulness of aspirin in such patients. Two assumptions, central to these guidelines are that diabetes is a coronary risk equivalent, and that aspirin benefit/risk ratio is similar in diabetic patients than in coronary disease patients. Unfortunately, vascular risk level is variable in diabetic patients. Patients with new onset diabetes have lower cardiovascular risk than patients with established cardiovascular disease. Smoking habits markedly increase the risk. Benefits may be lower in diabetic patients since aspirin resistance is common in these patients. Haemorrhagic risk may be higher since diabetes is a risk factor for haemorrhagic stroke. Awaiting trial evidence, aspirin therapy should be considered in diabetic patients with a very high risk, such as smokers, patients with long diabetes duration, or atherosclerotic plaques at echography.

Total joint replacement of hip or knee as an outcome measure for structure modifying trials in osteoarthritis.

OBJECTIVE: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working group to assess the value of time to joint surgery as a potential therapeutic failure outcome criterion for osteoarthritis (OA) of the hip or knee in the assessment of potential structure modifying agents. METHODS: PubMed was searched for manuscripts from 1976 to 2004. Relevant studies were discussed at a 1-day meeting. RESULTS: There are no accepted guidelines for 'time to' and 'indications for' joint replacement surgery. A limited number of trials have examined joint replacement surgery within the study population. Several parameters, particularly joint space narrowing (interbone distance), correlate with surgical intervention. However, at the level of the knee, none of the parameters have positive predictive value for joint replacement surgery better than 30%. In contrast, lack of significant joint space narrowing has a strong negative predictive value for joint replacement surgery (>90%), that remains after controlling for OA pain severity. CONCLUSION: At this time, GREES cannot recommend time to joint surgery as a primary endpoint of failure for structure modifying trials of hip or knee OA-as the parameter has sensitivity but lacks specificity. In contrast, in existing trials, a lack of progression of joint space narrowing has predictive value of >90% for not having surgery. GREES suggests utilizing joint space narrowing (e.g., >0.3-0.7 mm) combined with a lack of clinically relevant improvement in symptoms (e.g., >/=20-25%) for 'failure' of a secondary outcome in structure modifying trials of the hip and knee.

Delivering generics without regulatory incentives? Empirical evidence from French general practitioners about willingness to prescribe international non-proprietary names.

France presents a unique situation in which the take-off of a generic drug market depends, out of regulatory incentives, on whether physicians choose a prescription method (international non-proprietary names, INN) that can lead to the delivery of these drugs and on whether patients accept them. This paper is aimed at pointing out factors explaining general practitioners' (GPs') willingness to prescribe in INN through data collected from a South-Eastern France representative sample of 600 GPs in March 2002. The main results shed light on the key-role played by GPs' information about drugs and the source which they take it from, by GPs' volume of services and caseloads, and slightly by socio-economic characteristics of patients.

Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach.

OBJECTIVES: To provide an updated document assessing the global, NSAID-specific, and time dependent risk of gastrointestinal (GI) complications through meta-analyses of high quality studies. METHODS: An exhaustive systematic search was performed. Inclusion criteria were: RCT or controlled study, duration of 5 days at least, inactive control, assessment of minor or major NSAID adverse effects, publication range January 1985 to January 2003. The publications retrieved were assessed during a specifically dedicated WHO meeting including leading experts in all related fields. Statistics were performed conservatively. Meta-regression was performed by regressing NSAID adjusted estimates against study duration categories. RESULTS: Among RCT data, indolic derivates provided a significantly higher risk of GI complications related to NSAID use than for non-users: RR = 2.25 (1.00; 5.08) than did other compounds: naproxen: RR = 1.83 (1.25; 2.68); diclofenac: RR = 1.73 (1.21; 2.46); piroxicam: RR = 1.66 (1.14; 2.44); tenoxicam: RR = 1.43 (0.40; 5.14); meloxicam: RR = 1.24 (0.98; 1.56), and ibuprofen: RR = 1.19 (0.93; 1.54). Indometacin users had a maximum relative risk for complication at 14 days. The other compounds presented a better profile, with a maximum risk at 50 days. Significant additional risk factors included age, dose, and underlying disease. The controlled cohort studies provided higher estimates: RR = 2.22 (1.7; 2.9). Publication bias testing was significant, towards a selective publication of deleterious effects of NSAIDs from small sized studies. CONCLUSION: This meta-analysis characterised the "compound" and "time" aspects of the GI toxicity of non-selective NSAIDs. The risk/benefit ratio of such compounds should thus be carefully and individually evaluated at the start of long term treatment.

[Survey on the treatment of hospitalised community-acquired lower respiratory tract infections]. / Enquête sur la prise en charge thérapeutique des malades hospitalisés pour infection respiratoire basse communautaire.

OBJECTIVES: The assessment of treatment habits regarding community-acquired lower respiratory tract infections and comparison with current national recommendations. METHOD: Prospective survey of treatment habits. Patients hospitalised for community-acquired pneumonia in the department of internal medicine, the department of neurology and the department of respiratory diseases (127 beds) at the Sainte-Marguerite Hospital in Marseilles were included. We studied the socio-economical context, the presence of severity factors, the analysis of risk factors, the antibiotic treatments prescribed (type, route of administration, duration) and the outcome of the patients. RESULTS: From November 2001 to February 2002, 98 patients with community-acquired pulmonary infections were included (61 men with a mean age of 72.5 years). The treatment of these patients conformed to guidelines in 79 cases. In 19 cases, the prescription did not conform (unjustified bi-therapy in 8 patients; absence of bi-therapy in suspected cases of intra-cellular bacteria in 4 patients; insufficient dose in 2 patients; and non-adapted antibiotherapy in 5 patients). CONCLUSION: In the study conditions, the management of community-acquired pneumonia in the hospital most often conformed to current guidelines. Nevertheless, efforts made for initial and continued medical training together with the wide circulation of the guidelines must be continued.

[Willingness to prescribe by international non proprietary names: general practitioners attitudes in South East France in 2002]. / Disposition à prescrire en dénomination commune internationale. Attitudes des médecins libéraux en PACA en 2002.

OBJECTIVES: To evaluate the willingness, reasons and perceived obstacles to prescription by international non-proprietary name (INN) among general practitioners (GPs) in private practice. Method A panel of private GPs practicing in South-eastern France was surveyed twice, 2 months before and 5 months after a new contract between the National Health Insurance system and GP associations (5 June 2002). The panel was constructed with a random sampling approach stratified according to age, sex, and size of the urban unit. RESULTS: Between March-April and November-December 2002, the percentage of GPs willing to prescribe according to INN rose from 76.2% to 89.7%. These physicians reported that their principal reasons for such prescription were the June agreement and concern about the finances of the Health Insurance system. The principal obstacles they mentioned were the complexity of prescription by INN (66%), lack of appropriate information and tools (47%), and patient reticence (41%). CONCLUSION: More effort must be devoted to providing adequate information to patients and GPs. GPs need better training, information, and tools to help transform their willingness into action.

Guidelines for clinical studies assessing the efficacy of drugs for the management of acute low back pain.

In this paper we propose guidelines for clinical trials aimed at assessing the efficacy of drugs for acute non-specific low back pain (LBP) with or without radicular pain, preliminary to their approval and registration. To this end, consensus statements were obtained from a group of experts in the fields of rheumatology, clinical medicine, public health and epidemiology. EBM resources were systematically used as references. Four diagnostic categories were defined: type 1--LBP with no radiation; type 2--LBP radiating no further than the knee; type 3--LBP radiating beyond the knee, but with no neurologic signs; and type 4--LBP radiating to a specific and entire leg dermatome, with or without neurologic signs. Studies should be designed on the basis of the claimed indications for the drug, but must be double-blinded whatever the indication. The duration of the study may be shorter for LBP type 1 or 2 (one week) than for LBP types 3 and 4 (up to one month), depending on the aim of the study and the indications for the drug. The comparator may be inactive (placebo) or active (for a superiority trial, e.g., versus paracetamol). Specific inclusion and exclusion criteria have been defined here for each category. An appropriate wash-out period for any drugs that could affect the pain status should be planned. Paracetamol may be allowed as rescue medication. The primary endpoint should be based on a validated pain assessment tool that may be either generic (type 1 or 2) or oriented (back and knee for types 3 and 4). Secondary endpoints could include the assessment of functional performance; the duration of any period of bed-rest; work limitation; a global assessment comprising pain at rest, standing and walking; the time elapsed before epidural injection, the prescription of other therapeutic agents, or surgery; and the use of rescue medication. Adverse events (AE) should be monitored systematically using a methodology that reflects the mode of action of the tested drug. With the application of these guidelines, LBP could serve as an appropriate disease for testing analgesic drugs. Rigorous evaluation may also help to improve the management of acute LBP.

[Diagnostic and therapeutic management of urinary infections. Survey in the medical services of the hospitals south of the Marseille Hospital Center]. / Prise en charge diagnostique et thérapeutique des infections urinaires. Enquête dans les services de médecine des hôpitaux sud du CHU de Marseille.

OBJECTIVE: The aim of this prospective study was to observe diagnostic and antibiotic prescribing practices in urinary tract infection disease (UTID) in comparison with available guidelines. PATIENTS AND METHODS: We included all patients hospitalized in four medical wards of the Sainte-Marguerite Hospital in Marseille France who suffered from UTID. RESULTS: During the study period, 60 cases of UTID were observed, 29 were community-acquired and 31 were nosocomially-acquired. Management of uncomplicated UTID, the most frequent type (47/60 cases), showed considerable divergence between practices and guidelines. Not in keeping with the guidelines, urinalysis reagent strips were only used for 3 of the 47 cases. Furthermore, broad-spectrum antibiotics were prescribed as the first line treatment in more than 70% of the patients whereas only half of these prescriptions were warranted according to the guidelines. For complicated UTID however (13 cases) diagnostic and antibiotic prescribing practices were globally in accordance with the guidelines. CONCLUSION: This survey points out the divergence between guidelines and real management of UTID in hospitals. Clinical practices should be revisited to be in agreement with guidelines. Drafting antibiotic prescription guides explaining UTID management would be helpful for training future physicians.

[Reflections on some methodological errors in the evaluation of drugs. Ten years experience at the National Marketing Authorization Commission]. / Réflexions sur quelques erreurs méthodologiques communes dans l'évaluation des médicaments. Dix ans d'expérience à la Commission d'autorisation de mise sur le marché.

A ten year experience at the national french marketing authorization committee has permitted to notice the most commonly methodological errors in the field of clinical research and, particularly, in the dossiers for drug approval: a frequent insufficient sample size resulting in lack of statistical power, an unsatisfactory optimal dosing research, a misuse of the so-called surrogate markers, an erroneous opinion about the meaning of the p value, an abusive claim for equivalence in non significant superiority trials, a misuse of unadjusted multiple comparisons and too much confidence in subgroup analysis results.

[Critical reflections on innovation, therapeutic progress and economics of health]. / Réflexions critiques sur l'innovation, le progrès thérapeutique et l'économie de la santé.

Innovation should not be likened to progress and cost, true innovation should be clearly distinguished from false, novelty for novelty's sake should be avoided, and medicoeconomic evaluations should be interpreted with caution as they are often too precocious and overfavourable. It seems preferable (taking into account examples of statins, anti-Cox 2 NSAIDs, antiTNFs, recombinants...) that therapeutic innovation, as concerns both the prescriber and the evaluator, should give rise to critical reflection rather than to blind enthusiasm and scientistic belief. Delayed use, focusing on real or potential dangers, can be as deleterious for our patients' health as precipitate or generalized use while only considering increased efficacy. Innovation is extremely desirable, particularly when it seems to correspond to a health requirement of prior concern. However, it should be evaluated with a cool head, without prejudice, and even with a hint of scepticism to act as a counterbalance. It should be used with discernment, without improper extrapolation to patients for whom it is not necessary. Careful assessment of the sanitary and economic consequences of therapeutic innovation--which constitute a source of expenditure or economy--should be a permanent concern of health authorities. They must be evaluated using reliable and partly independent data from firms and paying agencies.

[In vitro study of the antimutagenic activity of alphahederin]. / Etude in vitro de l'activité antimutagène de l'alphahédérine.

Authors have studied the antimutagenic power of alphahederin (a saponin extracted from Hedera helix) versus a clastogenic agent, doxorubicin and an aneugenic agent, carbendazim. We have applied a protocol of incorporation of alphahederin (pretreatment, simultaneous treatment and post treatment) to determine a mechanism of action. According to this protocol, alphahederin induces a significant diminution of the rate of micronuclei wathever the phases of the protocol. These results demonstrate the antimutagenic activity of alphahederin with a mechanism of action, both desmutagenic and bioantimutagenic.

[Prescriptions and consumption of hypnotic and anxiolytic drugs in the South University Hospital of Marseille]. / Prescription et consommation des médicaments hypnotiques et anxiolytiques dans les services de médecine des hôpitaux sud du CHU de Marseille.

An investigation of prescription and consumption of hypnotic and anxiolytic drugs in hospital was carried out and has associated a transverse prescription study and a prospective consumption study. The prescription study was undertaken on one day in several medical departments of Sainte-Marguerite Hospital in Marseille in February 1999. Of the 91 hospitalized patients included, 42 (46 per cent) had been prescribed a hypnotic or anxiolytic. Furthermore, the quantities of drugs taken out of the pharmacy during the month of February were 1.54 time more than those prescribed. This discrepancy was even more obvious in the case of certain benzodiazepines such as bromazepam (ratio from 1 to 4) and lorazepam (ratio from 1 to 8). Self-prescription and patients being supplied without a prescription are the hypotheses advanced to explain this phenomenon.

[How to prevent drug therapy risk]. / Comment prévenir le risque thérapeutique médicamenteux.

PURPOSE: Therapeutic risk is largely foreseeable and can also largely be avoided. The art of prescription consists of favoring the beneficial effect of the medicament while taking all useful precautions to minimize undesirable effects. CURRENT KNOWLEDGE AND KEY POINTS: The appropriate method is correct use of the medicament at the collective and individual level. This is based on respect of reference systems and firstly on the particulars of the marketing license and the summary of the characteristics of the product, which provide validated knowledge concerning the medication. However, these may also be gray areas, insufficient updating, and insufficiently clear and concrete information on the expected therapeutic benefit as opposed to the pernicious effects feared. It is also based on opposing medical references, which attract attention to dangerous prescription practices. Moreover, for an individualized prescription it is necessary to take into account the actual patient, here and now, and not only the standard patient of clinical trials. Prescription priority must also be organized to favor indispensable medications only. In some cases drug monitoring based on personalized pharmacokinetics should be performed. Monitoring and informing of the patient must be strict for maximum safety; however, this is never complete. In this connection, lack of hindsight, premature enthusiasm, and falsely reassuring surveillance should be taken into account, particularly where undesirable effects not dependent on dosage are concerned. FUTURE PROSPECTS AND PROJECTS: Health education for the public, improved training of health staff as concerns iatrogenic effects and, shortly, computerized risk prevention with suitable software and data banks, systematic reviews and meta-analyses of therapeutic safety will help provide the patient with improved protection. This constitutes a major scientific, economic and ethical challenge for our societies.

[Anti-TNF-alpha monoclonal antibodies in the treatment of rheumatoid arthritis]. / Les anticorps monoclonaux anti-TNF-alpha dans le traitement de la polyarthrite rhumatoïde.

INTRODUCTION: Current slow-acting anti-rheumatic drugs available for rheumatoid arthritis can fail for certain severe cases; some are used empirically. Improvements in our knowledge of its pathogenesis and advances in molecular biology have made it possible to develop partially selective immunotherapy approaches. CURRENT KNOWLEDGE AND KEY POINTS: Tumor necrosis factor-alpha (TNF-alpha) is a critical inflammatory mediator in rheumatoid arthritis and may therefore be a useful target for specific immunotherapy. This article summarizes clinical studies using anti-TNF-alpha antibodies. It appears that there is good evidence for both safety and beneficial effects of anti-TNF-alpha antibodies in short-term treatment of rheumatoid arthritis. FUTURE PROSPECTS AND PROJECTS: It remains to be determined whether specific blockade of a single inflammatory mediator may be useful in long-term management. Therapeutic strategies aimed at concomitantly interfering with multiple pathogenic pathways are currently under investigation.