[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.

[Comparative study of production and control processes of parenteral nutritional admixtures in neonatology]. / Étude comparative des processus de production et de contrôle analytique des préparations magistrales de mélanges nutritifs parentéraux en néonatalogie.

OBJECTIVES: To assess the impact of disparities in production and analytical control processes on the quality of parenteral nutrition (PN) preparations produced in the Auvergne-Rhône-Alpes region. METHODS: This study was carried out in four hospital pharmacies of the Auvergne-Rhône-Alpes region. To assess the impact of production processes, each centre produced ten PN preparations from the same prescription. Analytical controls (sodium, potassium and calcium dosage) were carried out on all the preparations. To assess the impact of the control processes, a batch of ten preparations was produced from the same prescription. Samples were sent to the four hospital pharmacies for analytical control (sodium, potassium and calcium dosage). RESULTS: Measurements of relative production bias show that there is a significant difference between the preparations from the four centres in terms of sodium and potassium content. Each centre had at least one production bias for one of the three electrolytes measured. Concerning analytical controls, there was a significant difference between the four centres in the sodium and potassium levels measured. With the exception of calcium, all the centres reported measurements within the usual specifications of±10% of the target value. The results obtained have no clinically significant impact. CONCLUSION: The diversity of NP practices has a real impact on the quality of the preparations made. A regional collaboration should be envisaged to standardise patient care.

Comparison of three automated compounding devices for parenteral nutrition according to four key technical tests.

OBJECTIVES: Automation of parenteral nutrition (PN) preparation is nowadays a recommended practice in order to reduce human errors and thus improve the safety and accuracy of the finished product. Other benefits of automation may include full documentation of preparation and a reduction in personnel requirements or staff injuries. The market of automation compounding presents different automated compounding devices (ACDs). The aim of this study is to compare the technical characteristics of ACDs by carrying out four specific challenges. METHODS: Three ACDs: Two piston pumps with ACD 1: MediMix Multi 4120R (Impromediform) and ACD 2: Mibmix Compounder C12 (Hemedis), and one peristaltic pump ACD 3: ExactaMix Compounder EM2400 (Baxter) were assessed in a pharmaceutical manufacturing unit within a controlled atmosphere area, under horizontal laminar flow hood (LFH) according to four tests: volumetric accuracy, flush volume, smoke test, and a production test with three configurations of PN bags. For this test, a PN bag was considered accepted when all quality controls (weight, molar concentration of sodium, potassium and calcium) were fulfilled. RESULTS: The maximum relative biases found for the different ACDs were heterogeneous. ACD 1 had the best volumetric accuracy with respect to supplier specifications and for extreme volumes (0.2 mL). Evaluation of the flushing volume allowed the validation of 50 mL volumes for ACD 1 and ACD 3. The smoke test was only conclusive for ACD 1 under a horizontal LFH. The percentage of PN bags accepted were 98.8% for ACD 1, 70% for ACD 2%, and 95.5% for ACD 3. CONCLUSION: This study compared three ACDs according to four relevant and specific tests. Based on the data acquired, we conclude that ACD 1 is the most accurate, has the lowest flushing volume, is suitable for use in a LFH, and achieves the best results in the production test.

Place of magistral preparations to continue the treatment if the drug is commercially stopped worldwide? A case report of a 10-year-old child with subacute sclerosing panencephalitis (SSPE) requiring inosiplex.

Subacute sclerosing panencephalitis (SSPE) is a late-onset and fatal viral disease caused by persistent infection of the central nervous system by measles virus (MeV). We present the case of a 10-year-old child from South Asia affected by SSPE, stabilized with a combination of intrathecal interferon-α2b (INF-α2b) injections and oral inosiplex and how we continued the treatment when inosiplex was commercially stopped worldwide.

A quality by design approach for the qualification of automating compounding device for parenteral nutrition.

Automated compounding device (ACD) are increasingly used for parenteral nutrition (PN) bag production, and their acquisition must be sufficiently thought. The law requires the qualification of these ACD, but did not specify the tests to be performed. The quality by design (QbD) risk based approach allowed to define the quality target product profile in order to acquire the best ACD for each unit, and thanks a risk analysis permitted to define the critical quality attributes (CQA). These CQA will allowed to define tests performed during qualification. The ACD qualified was a 12 pump volumetric system. The CQA for PN bags consisted in sterile, precisely and accurately production with enough stability. During operational qualification volumetric accuracy test was performed, and during the performance qualification: flush volume, media fill, microbiological integrity of environment, sterility of control bag and production test were performed. At the end, all tests were conclusive (excepted for some results mostly due to analytical bias) and the ACD was considered to produce sterile bags in a control environment, precisely (relative standard deviation < 4%) and accurately (mean bias < 1% for weight and < 7% for other controls) with a sufficient stability. The QbD risk based approach allowed to acquire the best ACD for our need, and qualify relevant elements regarding the production process.

Clinical evaluation of pharmacists' interventions on multidisciplinary lung transplant outpatients' management: results of a 7-year observational study.

OBJECTIVES: Lung transplant (LT) recipients require multidisciplinary care because of the complexity of therapeutic management. Pharmacists are able to detect drug-related problems and provide recommendations to physicians through pharmacists' interventions (PIs). We aimed at assessing the clinical impact of PIs on therapeutic management in LT outpatients. DESIGN: Data were collected prospectively from an LT recipients cohort during 7 years. A multidisciplinary committee assessed retrospectively the clinical impact of accepted PIs. SETTING: French University Hospital. PARTICIPANTS: LT outpatients followed from 2009 to 2015. PRIMARY OUTCOME MEASURES: Clinical impact of PIs performed by pharmacists using the CLEO tool and the Pareto chart. RESULTS: 1449 PIs led to a change in patient therapeutic management and were mainly related to wrong dosage (39.6%) and untreated indication (19.6%). The clinical impact of PIs was 'avoids fatality', 'major' and 'moderate', in 0.1%, 7.0% and 57.9%, respectively. Immunosuppressants, antimycotics for systemic use and antithrombotic agents had the greatest clinical impact according to the Pareto chart. PIs related to drug-drug interactions (10%) mainly had a moderate and major clinical impact (82.3%, p<0.0001). CONCLUSION: Clinical pharmacists play a key role for detecting drug-related problems mostly leading to a change in therapeutic management among LT outpatients. Our study provides a new insight to analyse the clinical impact of PIs in order to target PIs which have most value and contribute to patient care through interdisciplinary approach.

Biopharmaceutical Assessment of Dexamethasone Acetate-Based Hydrogels Combining Hydroxypropyl Cyclodextrins and Polysaccharides for Ocular Delivery.

We previously developed two optimized formulations of dexamethasone acetate (DXMa) hydrogels by means of special cubic mixture designs for topical ocular administration. These gels were elaborated with hydroxypropyl-ß-CD (HPßCD) and hydroxypropyl-γ-CD (HPγCD) and commercial hydrogels in order to enhance DXMa water solubility and finally DXMa's ocular bioavailability and transcorneal penetration. The main objective of this study was to characterize them and to evaluate in vitro, ex vivo, and in vivo their safety, biopermanence, and transcorneal permeation. Gels A and B are Newtonian fluids and display a viscosity of 13.2 mPa.s and 18.6 mPa.s, respectively, which increases their ocular retention, according to the in vivo biopermanence study by PET/CT. These hydrogels could act as corneal absorption promoters as they allow a higher transcorneal permeation of DXMa through porcine excised cornea, compared to DEXAFREE® and MAXIDEX®. Cytotoxicity assays showed no cytotoxic effects on human primary corneal epithelial cells (HCE). Furthermore, Gel B is clearly safe for the eye, but the effect of Gel A on the human eye cannot be predicted. Both gels were also stable 12 months at 25 °C after sterilization by filtration. These results demonstrate that the developed formulations present a high potential for the topical ocular administration of dexamethasone acetate.

Recent Advances in the Design of Topical Ophthalmic Delivery Systems in the Treatment of Ocular Surface Inflammation and Their Biopharmaceutical Evaluation.

Ocular inflammation is one of the most common symptom of eye disorders and diseases. The therapeutic management of this inflammation must be rapid and effective in order to avoid deleterious effects for the eye and the vision. Steroidal (SAID) and non-steroidal (NSAID) anti-inflammatory drugs and immunosuppressive agents have been shown to be effective in treating inflammation of the ocular surface of the eye by topical administration. However, it is well established that the anatomical and physiological ocular barriers are limiting factors for drug penetration. In addition, such drugs are generally characterized by a very low aqueous solubility, resulting in low bioavailability as only 1% to 5% of the applied drug permeates the cornea. The present review gives an updated insight on the conventional formulations used in the treatment of ocular inflammation, i.e., ointments, eye drops, solutions, suspensions, gels, and emulsions, based on the commercial products available on the US, European, and French markets. Additionally, sophisticated formulations and innovative ocular drug delivery systems will be discussed. Promising results are presented with micro- and nanoparticulated systems, or combined strategies with polymers and colloidal systems, which offer a synergy in bioavailability and sustained release. Finally, different tools allowing the physical characterization of all these delivery systems, as well as in vitro, ex vivo, and in vivo evaluations, will be considered with regards to the safety, the tolerance, and the efficiency of the drug products.

Treprostinil Hydrogel Iontophoresis in Systemic Sclerosis-Related Digital Skin Ulcers: A Safety Study.

Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC0-4 h at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC0-3 h at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer.

Pharmacokinetic study of intravenously administered artemisinin-loaded surface-decorated amphiphilic γ-cyclodextrin nanoparticles.

Artemisinin and its derivatives are currently recommended by World Health Organization for the treatment of malaria. Severe malaria requires a parenteral administration of artemisinin-based formulations. However, the effective use of artemisinin is limited by the pharmacokinetic characteristics of the drug (low water solubility, poor bioavailability and short half-life). To overcome some of these drawbacks, artemisinin-loaded surface-decorated nanoparticles were prepared by co-nanoprecipitation of γ-cyclodextrin bioesterified with C10 alkyl chains and polyethylene glycol (PEG) derivatives (polysorbate 80 and DMPE-mPEG2000). Using a single dose (1.5 mg kg-1 or 2 mg kg-1) by intravenous administration, we investigated the in vivo pharmacokinetic properties in healthy rats of two types of artemisinin-loaded nanoparticle formulations, namely, nanosphere and nanoreservoir systems versus an ethanolic-aqueous solution of artemisinin as reference. Significantly enhanced pharmacokinetic parameters were obtained with artemisinin-loaded nanoparticles. In comparison to reference formulation, the geometric mean exposures in plasma (AUC0-t) exhibited 2.35 and 3.26-fold increases when artemisinin was loaded in nanoreservoir and nanosphere systems, respectively. Its plasma half-life increased 4.00 and 6.25-fold and its clearance decreased up to 2.5 and 4.72-fold. Artemisinin was successfully administered intravenously by means of surface-decorated amphiphilic γ-cyclodextrin nanostructures and showed a longer elimination half-life with respect to an artemisinin solution in ethanol. Therefore, these systems are likely to provide significant advantages for the intravenous treatment of severe malaria.

Nebulized hypertonic saline 3% for 1 versus 3 days in hospitalized bronchiolitis: a blinded non-inferiority randomized controlled trial.

BACKGROUND: The use and optimal duration of treatment with nebulized hypertonic saline (HS) in infants hospitalized for acute bronchiolitis is unclear. The objective was to compare the efficacy of 1 versus 3 days of nebulized 3% HS at 72 h of treatment. We conducted a blinded non-inferiority randomized controlled trial including infants aged less than 12 months old, hospitalized for a moderate bronchiolitis. METHODS: Nebulisations of 3% HS for 1 day were followed by either the continuation of 3% HS (HS3d group) or switched to 0.9% normal isotonic saline (HS1d group) for 2 days Randomization was performed according to a predefined list with a 1:1 ratio, obtained with a random generator number with blocks.. Main outcome was mean Wang clinical severity score (CSS) after 72 h of treatment. RESULTS: One hundred sixteen infants (HS1d n = 59 and HS3d n = 57), were included over two epidemic seasons from 2014 to 2016, but recruitement did not reach the planned sample size. The difference for the Wang CSS score in the HS3d vs HS1d group was 0.71 [IC 90% 0.1; 1.3], above the precluded value of 0.4 set in the protocol defining the non-inferiority of shorter treatment duration. Clinical remission was more rapidly obtained in the HS3d than in HS1d (2.3 ± 1.6 vs 2.9 ± 1.4 days, p = 0.04), with a non-significant tendency for less need of nutritional support and supplemental oxygen in HS3d group. Clinical worsening and treatment intolerance were similar in the 2 groups. CONCLUSIONS: Despite being underpowered, results seem not to be in favour of reducing the duration of nebulised HS treatment from 3 to 1 day in acute moderate bronchiolitis. TRIAL REGISTRATION: Clinical trials NCT02538458, October 2014.

Investigation of Combined Cyclodextrin and Hydrogel Formulation for Ocular Delivery of Dexamethasone Acetate by Means of Experimental Designs.

Dexamethasone acetate (DXMa) has proven its efficiency to treat corneal inflammation, without a great propensity to increase intraocular pressure. Unfortunately, its poor aqueous solubility, associated with a rapid precorneal elimination, results in a low drug bioavailability and a low penetration after topical ocular administration. The main objective of this study was to improve the apparent aqueous solubility of DXMa using cyclodextrins. First, hydroxypropyl-ß-CD (HPßCD) and hydroxypropyl-γ-CD (HPγCD) were used to enhance DXMa concentration in aqueous solution. The ß and γ HPCD derivatives allowed the increase of the DXMa amount in solution at 25 °C by a factor of 500 and 1500, respectively. Second, with the aim of improving the persistence of the complex solution after instillation in the eye, the formulations of DXMa-based CD solutions with marketed ophthalmic gels (CELLUVISC®, GEL-LARMES®, and VISMED®) were investigated and optimized by means of special cubic mixture designs, allowing the defining of mixed gels loaded with 0.7% (HPßCD) and 2% (HPγCD) DXMa with osmolality within acceptable physiological range. Finally, in vitro drug release assays from the mixed gels were performed and compared with reference eye drops. Similarly to MAXIDEX® and DEXAFREE®, in the case of mixed gel containing HPßCD, more than 90% of the drug was released within 2 h, while in mixed gel containing HPγCD, the release of DXMa was partial, reaching ≈60% in 2 h. This difference will have to be further addressed with ex vivo and in vivo ocular delivery experiments.

Self-assembled biotransesterified cyclodextrins as potential Artemisinin nanocarriers. II: In vitro behavior toward the immune system and in vivo biodistribution assessment of unloaded nanoparticles.

In a previous study, we reported on the formulation of Artemisinin-loaded surface-decorated nanoparticles (nanospheres and nanoreservoirs) by co-nanoprecipitation of PEG derivatives (PEG1500 and PEG4000-stearate, polysorbate 80) and biosynthesized γ-CD fatty esters. In the present study, the co-nanoprecipitation was extended to the use of a PEGylated phospholipid, namely DMPE-PEG2000. As our goal was to prepare long-circulating nanocarriers for further systemic delivery of Artemisinin (ART), here, we have investigated, on the one hand, the in vitro behavior of these surface-modified γ-CD-C10 particles toward the immune system (complement activation and macrophage uptake assays) and, on the other hand, their biodistribution features in mice. These experiments showed that the in vitro plasma protein adsorption and phagocytosis by macrophage cells triggered by γ-CD-C10 nanoparticles were significantly reduced when their surface was decorated with amphiphilic PEGylated molecules, in particular PEG1500-stearate, DMPE-mPEG2000 or polysorbate 80. The prolonged blood circulation time assessed by fluorescence imaging was demonstrated for unloaded γ-CD-C10-based nanospheres and nanoreservoir particles containing DMPE-PEG2000 and polysorbate80, respectively. These nanoparticles also proved to be non-hemolytic at the concentration range used in vivo. Within the limits of the conducted experiments, the co-nanoprecipitation technique may be considered as an alternative for surface modification of amphiphilic CD-based drug delivery systems and may be applied to the systemic delivery of ART.

Radioiodine therapy in benign thyroid disorders. Evaluation of French nuclear medicine practices.

OBJECTIVES: Radioiodine is currently used routinely in the treatment of hyperthyroidism including Graves' disease (GD), toxic multinodular goitre (TMNG) and toxic solitary nodule (TSN) but no consensus exists on the most appropriate way to prescribe iodine--fixed dose or calculated doses based on the gland size or turnover of (131)I. We carried out the first nationwide French survey assessing the current practices in radioiodine treatment of hyperthyroidism. MATERIAL AND METHODS: A questionnaire was sent to French nuclear medicine hospital units and cancer treatment centres (n=69) about their practices in 2012. RESULTS: Euthyroidism was considered the successful outcome for 33% of respondents, whereas hypothyroidism was the aim in 26% of cases. Fixed activities were the commonest therapeutic approach (60.0% of GD prescribed doses and 72.5% for TMNG and TSN), followed by calculated activities from Marinelli's formula (based on a single uptake value and thyroid volume). The fixed administered dose was chosen from between 1 to 3 levels of standard doses, depending on the patient characteristics. Factors influencing this choice were disease, with a median of 370 MBq for GD and 555 MBq for TSN and TMNG, thyroid volume (59%) and uptake (52%) with (131)I or (99m)Tc. Even physicians using fixed doses performed pretherapeutic thyroid scan (98%). CONCLUSION: This study shows that practices concerning the prescription of (131)I therapeutic doses are heterogeneous. But the current trend in France, as in Europe, is the administration of fixed doses. The study provides the baseline data for exploring the evolution of French clinical practices.

Comparison between two generic questionnaires to assess satisfaction with medication in chronic diseases.

OBJECTIVE: The objective of this work was to compare two generic questionnaires assessing patients' satisfaction with medication. In addition we tested whether satisfaction can predict adherence to medication regimens in patients with chronic diseases, and which dimensions of satisfaction are most involved. METHODS: This prospective, observational study was conducted over one year in a heterogeneous population of patients with various chronic diseases. Satisfaction with medication was assessed by using the TSQM® vII and the SatMed-Q® questionnaires, and adherence to treatment was assessed with the Morisky-Green questionnaire. Clinical pharmacists interviewed patients to collect clinical, demographic and therapeutic data. RESULTS: 190 patients were enrolled. Both questionnaires showed excellent reliability and correlation was high (R=0.70; p<0.001). Adherence was correlated with satisfaction with medication whether assessed with the SatMed-Q® (R=0.23; p=0.002) or the TSQM® (R=0.17; p=0.02). Among different dimensions of satisfaction, convenience of use and side effects are prominent predictors of adherence. CONCLUSION: Adherence is related to the patient's satisfaction with medication whether assessed with the TSQM® vII or the SatMed-Q®. Therefore, these simple questionnaires could be used as predictive tools to identify patients whos' adherence needs to be improved.