Biosimilarity. Do not confuse biosimilar and biocopy. Example of tenecteplase.

Non-innovator biological products (NIBPs) or 'biocopies' are available in several countries at lower prices than biosimilars. These drugs, sometimes so-called 'biosimilars', may not meet all of the quality criteria expected of clinically equivalent products. NIBPs can exhibit major differences in physicochemical and pharmacological properties compared with their reference biological but may be presented to prescribers based on clinical trial data and claimed clinical equivalence. Tenecteplase (TNK-tpA) is a recombinant derivative of tissue plasminogen activator, used as a third-generation thrombolytic agent for treatment of acute myocardial infarction. A TNK-tPA presented as biosimilar to the originator (Metalyse®, Boehringer Ingelheim; TNKase®, Roche/Genentech) is now available for use in India (Elaxim®, Gennova Pharmaceuticals). Elaxim® is not approved in Europe or the USA but has been proposed in several countries as a replacement for the originator. Based on available literature, we discuss why this biocopy cannot be considered biosimilar to the originator tenecteplase. We describe clear differences in physicochemical and pharmacological properties. For example, the biocopy demonstrates clot lysis activity that is substantially lower than the originator and contains high concentrations of foreign proteins that confer potential for immunological reactions. Clinical data on the biocopy are limited; randomized trials to demonstrate the absence of difference in efficacy and safety between the biocopy and originator have not been conducted. This example demonstrates that confirmation of similarity, by close examination of pharmaceutical quality attributes, and preclinical and clinical data, is mandatory before presenting to prescribers a biological product as clinically equivalent.

Persistent swallowing disorders after extubation in mechanically ventilated patients in ICU: a two-center prospective study.

BACKGROUND: Persistent swallowing disorders (SD) are non-pulmonary complications of mechanical ventilation (MV). However, there are few clinical studies on persistent SD in critically ill patients undergoing tracheal intubation for MV. The aim of the present study was to assess the incidence and characteristics of clinical manifestations associated with persistent SD. METHODS: We prospectively evaluated in patients requiring more than 7 days of invasive MV the incidence and characteristics of clinical manifestations related to persistent SD. For this purpose, quality of swallowing was assessed within 24 h after extubation by an experienced physical therapist not directly involved in patient management. Swallowing assessment consisted in a specific standardized test combining a swallowing test and a full clinical evaluation of the cranial nerves involved in swallowing. In patients with SD on the first test, a second test was done within 48 h in order to discriminate between transient and persistent SD. RESULTS: Among the 482 patients mechanically ventilated more than 7 days, 138 were enrolled in this study. The first test performed 24 h after extubation revealed SD in 35 patients (25%). According to the second test performed 48 h later, SD were considered transient in 21 (15%) and persistent in 14 (10%) cases. Patients with persistent SD were older (66 ± 16 vs 58 ± 15 years), had lower bodyweight at admission (76 ± 15 vs 87 ± 23 kg) and received less often neuromuscular blocking agents (36% vs 66%) compared to patients without or with only transient SD. Patients with persistent SD had longer duration of Intensive Care Unit (ICU) stay after first extubation and longer delay to oral feeding than patients without or with only transient SD, respectively, 11 ± 9 vs 7 ± 6 days and 23 ± 33 vs 5 ± 7 days. CONCLUSIONS: Based on a specific standardized clinical test, 25% of patients mechanically ventilated more than 7 days exhibited clinical manifestations of SD. However, SD were considered as persistent after extubation in only 10% of them. Persistent SD were associated with longer duration of ICU stay after extubation and longer time of enteral feeding. TRIAL REGISTRATION: The study is registered with Clinical Trials (NCT01360580).

[Interchangeability and substitution of biosimilars]. / Interchangeabilité et substitution des biosimilaires.

The rationality of the interchangeability of biosimilars is based on broad scientific evidence and numerous clinical experiences in real life which show no sign of reduced efficacy or different tolerance compared to the original molecule. The substitution of biosimilars (pharmaceutical act) remains widely contested in many countries, notably in France. However, it would make it possible to make very significant savings in a context of major acceleration in health spending. This reluctance is unfounded in light of the quality of biosimilars authorized in Europe and their rigorous evaluation. It is therefore essential to improve the information of health professionals and patients on these biosimilars.

Extended stability of the rituximab biosimilar CT-P10 in its opened vials and after dilution and storage in polyolefin bags.

The stability of the rituximab biosimilar CT-P10, in 50mL vials at a concentration of 10mg/mL, and after dilution to final concentrations of 1 and 4mg/mL and storage in polyolefin bags at 4°C and 25°C was studied by several orthogonal and complementary methods. No significant change (as defined by a magnitude greater than the inter-batch variability) was observed, for each of the parameters characterizing physical and chemical stability studied, for the two concentrations and temperatures tested, or for any of the three batches tested. This implies that cold-chain rupture and exposure to room temperature up to 15 days both for vials and diluted bags have no deleterious consequence on the quality of the product. Moreover, this extended stability permits safe in-advance preparation, dose-banding or flat-dose, that to avoid unnecessary delays in the management of the patient, improvement of the pharmacy and nurse workload and money saving by avoiding non justified losses of this expensive drug.

_{36}

Prompt γ-ray spectroscopy of the neutron-rich ^{96}Kr, produced in transfer- and fusion-induced fission reactions, has been performed using the combination of the Advanced Gamma Tracking Array and the VAMOS++ spectrometer. A second excited state, assigned to J^{π}=4^{+}, is observed for the first time, and a previously reported level energy of the first 2^{+} excited state is confirmed. The measured energy ratio R_{4/2}=E(4^{+})/E(2^{+})=2.12(1) indicates that this nucleus does not show a well-developed collectivity contrary to that seen in heavier N=60 isotones. This new measurement highlights an abrupt transition of the degree of collectivity as a function of the proton number at Z=36, of similar amplitude to that observed at N=60 at higher Z values. A possible reason for this abrupt transition could be related to the insufficient proton excitations in the g_{9/2}, d_{5/2}, and s_{1/2} orbitals to generate strong quadrupole correlations or to the coexistence of competing different shapes. An unexpected continuous decrease of R_{4/2} as a function of the neutron number up to N=60 is also evidenced. This measurement establishes the Kr isotopic chain as the low-Z boundary of the island of deformation for N=60 isotones. A comparison with available theoretical predictions using different beyond mean-field approaches shows that these models fail to reproduce the abrupt transitions at N=60 and Z=36.

[Evaluation of professional practices: Implication of hospital pharmacist in improving care for vulnerable patients]. / Évaluation des pratiques professionnelles : implication du pharmacien hospitalier dans l'amélioration de la prise en charge des patients en précarité.

As drug delivery activity to outpatients in precarious situation is rising continuously, the goal of this work was to perform an assessment of the professional practices of the care pathway of these patients, called PASS in France (permanence d'accès aux soins de santé). At first, two pharmacists did an audit of this care pathway. Then, options for improvement were suggested and established after a multidisciplinary work with pharmacists, physicians and social workers of the relevant services. Finally, after six months, those actions and their impact were evaluated. Over a three-year period, the audit showed an increase by a factor of 1.77 of the average number of prescriptions provided per year. Over the same period, the number of dispensed lines was increased by 2.2 and the annual costs were multiplied per 1.82. The pharmacy department suggested several corrective actions: at first, initiating new schedules suited to the activity; then, making adjustments in the reception zone; but also, establishing two new specific prescriptions and 89 helps cards about the most frequently delivered medications. As a result, the time dedicated to drug delivery has been cut in half while the number of pharmaceutical actions remained constant. This assessment of the professional practices showed how hard it is to formalize a transversal circuit as the PASS in hospital. The actions established had improved the organization and the drug delivery activity in the pharmacy department.

One-month stability study of a biosimilar of infliximab (Remsima®) after dilution and storage at 4°C and 25°C.

There is currently only one monoclonal antibody for which there is a biosimilar: infliximab, which was released onto the French market in 2015. The SPC for the biosimilar (Remsima®) are superimposable on those of the original, including 24-hour stability at both 4 and 25°C. The aim of our study was to determine the stability of this biosimilar during one month at 4 and 25°C. Three different batches at two concentrations (0.7mg/mL or 1.6mg/mL) were used. Physicochemical stability was evaluated by the following methods: turbidity, UV spectrometry, DLS, ion chromatography (CEX), gel exclusion chromatography (SEC), and light microscopy. The analyses were performed in triplicate. All methods used have been demonstrated to be valid for measuring antibody stability. There were no signs of physicochemical instability after seven days (on D7) of storage at 4 or 25°C. From D15, we observed slight changes by ion (percentage distribution of the different isoforms) and gel exclusion chromatography (percentage distribution of different polymers, i.e. dimers, oligomers). However, the areas under the curves were unchanged, and the proportions of polymers remained lower than 0.5%. Tertiary structure analysis also showed a change from D15. All observed changes are consistent with progressive oligomerization by hydrophobic interactions. In conclusion, the reconstituted biosimilar is stable for seven days at 4 and 25°C. Gradual oligomerization is observed from D15 but appears to be less than 0.5%, suggesting instability, albeit very limited, in the longer term; the practical consequences of this remain to be evaluated.

[Study impacto: Descriptive analyzis of pharmacist's clinical practice in onco-hematology]. / Étude impacto : analyse descriptive des pratiques de pharmacie clinique en cancérologie.

Pharmaceutical analyses of chemotherapy prescriptions by hospital pharmacists are activities codified by regulation and rules (bon usage). The involvement of the pharmacists in clinical pharmacy activities in the oncology setting is not clearly identified, justifying the development of a mapping of these activities from a questionnaire addressed to the professionals. One hundred and seven centers have participated to this study at the national level (overall participation rate of 32.4%). More than 95% of them used a computerized ordering system and three quarter of them submit the introduction of new compounds to an analysis by the drug therapeutic committee. Prescription analysis allowed detecting around 2% of errors from the current prescription. Clinical pharmacist participates to tumor boards of onco-hematology (RCP) at a level of 46% for senior pharmacist and 42% for junior pharmacist. This involvement in the RCP allowed anticipating protocol's modification and temporary used authorization. Ninety-two percent of the senior pharmacists estimate that they highlight the risk of no reimbursement for prescription out of the guideline during RCP, resulting to a modification of the prescription for 40% of them. This level of intervention is lower with respectively 64% and 10% for the juniors. This study underlines the expert value of the clinical pharmacist dedicated to oncology setting in pre and post analysis prescriptions. It could be targeted by a prospective analysis of both clinical and pharmacoeconomics impact of these interventions.

Implementation of real-time identification analysis and quantification of chemotherapies preparations with a Multispec(®) analyser.

Post-production analytic control of chemotherapies preparations remains a challenge for hospital pharmacists. Indeed, to be feasible, this control needs to be reliable, fast and easy to implement and to use on real life. This is particularly true for teams not familiar with analytic methods. The Multispec(®) analyser has been specially manufactured for that purpose. After several years of daily use, we wanted to focus on its implementation, abilities and defects that should be corrected on the next analyser. Upon 24 months, 23,350 samples have been analysed. Four percent have been rejected on the first analysis, and finally only 0.37% with another sample after homogenization. Eighty-six preparations have been done another time for non-conformity purpose. Difficulties of implementation were in particular on anthracyclins, oxazophosphorins and monoclonal antibodies. However, compared to liquid chromatography for example, the ultraviolet and infrared combination allows a large number of drugs to be recognized and quantified fastly. As a conclusion this analyser is quite helpful and gives a serious alternative to post-production analytic control for chemotherapies preparations. Some points should however be improved, probably on the next analyser, for instance the sample volume necessary for analysis.

SFPO and ESOP recommendations for the practical stability of anticancer drugs: an update.

The recommendations for the practical stability of anticancer drugs published in 2010 by the French Society of Hospital Pharmacists (SFPO) and the European Society of Oncology Pharmacists (ESOP) have been updated. Ten new molecules have been included (asparaginase, azacitidine, bevacizumab, clofarabine, eribuline mesylate, folinate sodium, levofolinate calcium, nelarabine, rituximab, temsirolimus).

[Evaluation of ownership of an implantable medical device by patients]. / Évaluation de l'appropriation d'un dispositif médical implantable par les patients.

INTRODUCTION: In order to improve the care of patients with pacemakers or defibrillators, a survey was realized to assess the adherence of the cardiac implant of patients PATIENTS AND METHOD: A survey was proposed to assess the level of information assimilation of patients' implant (indication of installation, precautions and conduct...) by patients presenting within the Cardiology Department concerning a first implantation or a change in the device. RESULTS: Early results show that 84% of patients have an indication of implant placement. Only 55% know that they must notify to the medical team they have a cardiac implant, especially when needing MRI. In case of a shock, only 35% of patients with defibrillator know how to behave. The majority of patients say they consult when signs of infection occur or when symptoms reappear. DISCUSSION: The results show that patients are generally well informed about the main precautions and have a good knowledge of their implant. Nevertheless, messages about "what to do if" are not well known. Patients with defibrillators have better assimilated the information than patient with pacemakers. CONCLUSION: Our approach has to account for the level of information and the degree of assimilation of information by patients. It is part of the development of patient's therapeutic education.