Pharmacokinetic similarity of switching SAR341402 insulin aspart biosimilar and NovoLog insulin aspart versus continuous use of NovoLog in adults with type 1 diabetes: The GEMELLI X trial.

AIM: To assess whether multiple switches between SAR341402 biosimilar insulin aspart (SAR-Asp) and the insulin aspart reference product (NovoLog; NN-Asp) leads to equivalent pharmacokinetic (PK) exposure compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D). MATERIALS AND METHODS: This multicentre, open-label, phase 3 study randomized (1:1) 210 subjects with T1D treated with once-daily insulin glargine U100 as basal insulin to four 4-week periods of alternating multiple daily injections of SAR-Asp and NN-Asp (NN-Asp for the first 4 weeks, SAR-Asp in the last 4 weeks; switching group) versus 16 weeks of continuous NN-Asp (non-switching group). At week 16, a single dose (0.15 U/kg) of SAR-Asp in the switching group (n = 95) or NN-Asp in the non-switching group (n = 105) was given in the morning before breakfast. Primary PK endpoints were area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax ) of SAR-Asp versus NN-Asp after the single dose at week 16. RESULTS: The extent of PK exposure was similar between the two treatments (SAR-Asp in the switching group and NN-Asp in the non-switching group) at week 16, with point estimates of treatment ratios close to 1. The 90% confidence intervals for AUC treatment ratios were contained within 0.8-1.25. For Cmax in the primary analysis set, the upper confidence limit was 1.32. This was because of the profiles of three participants with implausible high values. A prespecified sensitivity analysis excluding implausible values showed results contained within 0.8-1.25. CONCLUSIONS: PK exposure of SAR-Asp (switching group) and reference NN-Asp (non-switching group) were similar, supporting interchangeability between these two insulin aspart products.

A comparison of Scansys and Sirius tomography in healthy eyes.

PURPOSE: To assess the level of agreement and evaluate the reliability of measurements between two Scheimpflug imaging modalities, Scansys (MediWorks, China) and Sirius (CSO, Italy), in quantifying the anterior segment parameters in healthy eyes. METHODS: In a cross-sectional study, the right eyes of 38 healthy participants without any ocular or systemic diseases were examined. A range of anterior segment parameters including anterior and posterior flat and steep keratometry, central corneal thickness (CCT), thinnest corneal thickness (TCT), anterior chamber depth (ACD), anterior chamber angle (ACA), corneal volume, anterior chamber volume, and horizontal white to white diameter, derived from the sagittal curvature maps were measured. To evaluate the reliability of the measurements, intraclass correlation coefficient (ICC) and correlation coefficient were measured. Additionally, Bland-Altman plots were employed to examine the agreement in mean (bias line) and 95% limits of agreement between the two devices. RESULTS: The mean age was 31.5 ± 6.9 (range: 19-47) years. The ICC indicated that the majority of anterior segment parameters had an excellent or good level of reliability, surpassing the threshold of 0.9. Nevertheless, CCT and ACA exhibited a moderate level of reliability, with ICC values of 0.794 and 0.728, respectively. The correlation analysis showed a strong correlation for all the variables tested. The Bland-Altman plots revealed that the bias line was near zero and the 95% limits of agreement were narrow for most variables, except for the anterior flat and steep keratometry, which were found to range from - 0.57 to 0.84 D and - 0.68 to 0.87 D, respectively. CONCLUSION: Scansys and Sirius devices can be effectively used interchangeably for the evaluation of most anterior segment parameters; however, for anterior corneal curvatures, CCT and ACA, their alternative use is not recommended.

The level of agreement between the numerical rating scale and visual analogue scale for assessing pain intensity in adults with chronic pain.

The numerical rating scale and visual analogue scale are used to quantify pain intensity. However, it has not yet been explored whether these scores are interchangeable in adults with chronic pain. Data from the prospective multicentre cross-sectional INTERVAL study were used to evaluate the one-dimensionality and agreement between numerical rating scale scores and visual analogue scale scores in adults with chronic pain. Pain intensity scores using the numerical rating scale and visual analogue scale were provided by 366 patients with chronic pain for current, average, minimal and maximal pain. To evaluate whether pain intensity scales are completed in accordance with each other, the proportion of patients who satisfied the following condition was calculated: minimal pain intensity ≤ maximal pain intensity. A factor analysis confirmed the one-dimensionality of the pain measures. A significant difference was found between numerical rating scale and visual analogue scale scores for average, current, minimum and maximum pain. Intra-class correlation coefficient estimates ranged from 0.739 to 0.858 and all measures failed to show sufficient and acceptable agreement at the 95% level. The strength of agreement between pain severity categories was classified as 'moderate' for average and minimal pain and 'substantial' for current and maximal pain. The proportion of patients who scored minimal pain ≤ maximal pain was 97.5% for the numerical rating scale and 89.5% for the visual analogue scale. This study failed to show an acceptable agreement between the numerical rating scale and visual analogue scale when pain intensity was rated by adults with chronic pain, despite showing both scales measure the same information.

Within-subject pharmacokinetic variability has a strong influence on individual exposure ratios in bioequivalence studies, hence on drug formulation interchangeability.

INTRODUCTION: Bioequivalence between a reference and a generic drug is based on the hypothesis that a ± 20% change in blood exposure (or ± 10% for drugs with narrow therapeutic index, NTI) following the generic/reference switch will not have any therapeutic consequences. However, the individual exposure ratio between generic and reference can be higher than 1.20 (or 1.10). This study aims to analyse the different parameters influencing the individual exposure ratio, hence the conditions for reference/generic interchangeability. METHODS: Bioequivalence studies with a double cross-over design for a virtual drug were simulated using 100 random sets of 12, 24, 48 or 100 pairs of areas under the curve (AUC), varying the generic/reference AUC geometric mean ratios between 0.80 and 1.25 and the within-subject exposure variance of the reference and the generic formulations. RESULTS: The proportion of subjects with an exposure generic/reference ratio outside the ± 10% or ± 20% acceptance intervals increases when (1) the reference within-subject variance increases; (2) the ratio of the generic within-subject variance on the reference within-subject variance increases; and (3) the generic/reference mean AUC ratio diverges from 1.0. When only considering replicated administrations of the reference, the individual exposure ratio increases with the within-subject variance, yielding values outside the usually accepted individual exposure ratio range of 0.5 to 2 for drugs with narrow therapeutic index as soon as the within-subject variance standard deviation is ≥ 0.25 (equivalent to within-patient CV% > 25%). CONCLUSIONS: Interchangeability between reference and generic formulations, especially for drugs with narrow therapeutic index can only be assumed if, the within-subject variance of generic is less or equal to the within-subject variance of reference or, if this is not the case, if the distribution of the generic/generic individual exposure ratios is included within the therapeutic margins of the reference drug.

Interchangeable utilization of metals: New perspectives on the impacts of metal ions employed in ancient and extant biomolecules.

Metal ions provide considerable functionality across biological systems, and their utilization within biomolecules has adapted through changes in the chemical environment to maintain the activity they facilitate. While ancient earth's atmosphere was rich in iron and manganese and low in oxygen, periods of atmospheric oxygenation significantly altered the availability of certain metal ions, resulting in ion replacement within biomolecules. This adaptation mechanism has given rise to the phenomenon of metal cofactor interchangeability, whereby contemporary proteins and nucleic acids interact with multiple metal ions interchangeably, with different coordinated metals influencing biological activity, stability, and toxic potential. The ability of extant organisms to adapt to fluctuating metal availability remains relevant in a number of crucial biomolecules, including the superoxide dismutases of the antioxidant defense systems and ribonucleotide reductases. These well-studied and ancient enzymes illustrate the potential for metal interchangeability and adaptive utilization. More recently, the ribosome has also been demonstrated to exhibit interchangeable interactions with metal ions with impacts on function, stability, and stress adaptation. Using these and other examples, here we review the biological significance of interchangeable metal ions from a new angle that combines both biochemical and evolutionary viewpoints. The geochemical pressures and chemical properties that underlie biological metal utilization are discussed in the context of their impact on modern disease states and treatments.

Use of follow-on disease-modifying treatments for multiple sclerosis: Consensus recommendations.

BACKGROUND: As patents for multiple sclerosis (MS) therapies expire, follow-on disease-modifying treatments (FO-DMTs) become available at reduced cost. Concerns exist that cheaper FO-DMTs are used simply to reduce healthcare costs. However, the well-being of people with MS should take priority. OBJECTIVES: To identify best practices for FO-DMT development and use by agreeing on principles and consensus statements through appraisal of published evidence. METHODS: Following a systematic review, we formulated five overarching principles and 13 consensus statements. Principles and statements were voted on by a multidisciplinary panel from 17 European countries, Argentina, Canada and the United States. RESULTS: All principles and statements were endorsed by >80% of panellists. In brief, FO-DMTs approved within highly regulated areas can be considered effective and safe as their reference products; FO-DMTs can be evaluated case by case and do not always require Phase III trials; long-term pharmacovigilance and transparency are needed; there is lack of evidence for multiple- and cross-switching among FO-DMTs; and education is needed to address remaining concerns. CONCLUSION: Published data support the use of FO-DMTs in MS. The consensus may aid shared decision-making. While our consensus focused on Europe, the results may contribute to enhanced quality standards for FO-DMTs use elsewhere.

Interchangeability of generic drugs for subpopulations: Bioequivalence simulation from a nonparametric PK model of gabapentin generic drugs.

Patients are often switched between generic formulations of the same drug, but in some cases generic interchangeability is questioned. For generic drugs to be approved, bioequivalence with the innovator drug should be demonstrated, but evidence of bioequivalence is not required in the intended patient population or relative to other approved generics. AIM: We aim to identify pathophysiological pharmacokinetic subpopulations for whom there is a difference in comparative bioavailability compared to a healthy population. METHODS: We used simulated exposures from a nonparametric model of multiple generics and the originator gabapentin. Exposure was simulated for virtual populations with pharmacokinetic characteristics beyond those of healthy subjects with regard to rate of absorption, volume of distribution and reduced renal function. Virtual parallel design bioequivalence studies were performed using a random sample of 24 simulated subjects, with standard acceptance criteria. RESULTS: Results indicated increased pharmacokinetic variability for patient populations with a lower rate of absorption or a reduced renal function, but no change in the average comparable bioavailability ratio. This increased variability results in a reduced likelihood of demonstrating bioequivalence. Observations were similar for comparisons between all different formulations, as well as between subjects who received the identical formulation in a repeated fashion. No relevant effect was observed for simulations with increased volume of distribution. CONCLUSION: Our simulations indicate that the reduced likelihood of demonstrating bioequivalence for subjects with altered pharmacokinetics is not influenced by a formulation switch, nor does the average comparable bioavailability ratio change, therefore these results support generic interchangeability and current approval requirements for generics.

Assessing an aflatoxin exposure biomarker: Exploring the interchangeability and correlation between venous and capillary blood samples.

Exposure to dietary aflatoxins has been recognized as a potential threat to child nutrition and growth, in addition to being a known carcinogen. The ability to accurately assess concentration of aflatoxin in the blood of at-risk individuals is therefore very important to inform public health policies and on-the-ground programs around the world. Venous blood is frequently used to quantify biomarkers of exposure such as AFB1-lysine adducts. However, venous blood collection methods are invasive, requiring highly trained staff, which makes this method challenging to implement, especially in resource-limited settings. In contrast, capillary blood collection by fingerprick is less invasive and has the potential for application in point-of-need monitoring. The aim of this exploratory study was to investigate the correlation and interchangeability of capillary and venous human blood samples in the quantification of AFB1-lysine adduct concentration. A total of 72 venous and capillary blood samples were collected from 36 women of reproductive age (16-49 years) in northern Uganda. All sample specimens were analyzed using high-performance liquid chromatography with fluorescence detection. Regression analysis and Bland-Altman analysis were performed to compare AFB1-lysine concentrations between venous and capillary sample pairs. Bland-Altman analysis of albumin-normalized AFB1-lysine data-bias was -0.023 pg/mg-albumin and the 95% limits of agreement were 0.51 to -0.56 pg/mg-albumin for log-transformed data. There was a positive correlation between albumin-normalized venous and capillary AFB1-lysine concentrations with r of 0.71 (p < .0001). A lack of any accepted clinical cutoff for aflatoxin exposure makes definition of an 'acceptable' limit for statistical analysis and comparison of methods challenging. Our data suggests a positive correlation between albumin-normalized AFB1-lysine concentrations in venous and capillary sample pairs, but relatively weak agreement and interchangeability based on Bland-Altman analysis.

No two classes of biosimilars: Urgent advice to the US Congress and the FDA.

WHAT IS KNOWN AND OBJECTIVE: The United States is the only country with legislation to approve two classes of biosimilars. One has "no clinically meaningful difference" from the reference product, and when it is tested for switching and alternating, it can receive an interchangeable status. The objective of this review is to establish whether it is possible from the switching and alternating studies to evaluate additional safety or efficacy. METHODS: Analysed published data to ascertain if the testing with switching and alternating provide additional proof of safety or efficacy. Political and scientific rationale of creating a new class of biosimilars and how this affects the confidence in biosimilars. RESULTS AND DISCUSSION: There is no safety or efficacy concern when switching or alternating biosimilars with the reference product. Unfortunately, the rationale for interchangeability is more political than scientific, and it has brought more confusion and mistrust in using biosimilars in the United States. WHAT IS NEW AND CONCLUSION: The US Congress is requested to remove the interchangeability clause from the Biological Price and Competition Act to enable faster acceptance of biosimilars and remove the threat of lack of confidence in the safety of biosimilars.

Comparison of Different Physical Activity Measures in a Cardiac Rehabilitation Program: A Prospective Study.

Concordant assessments of physical activity (PA) and related measures in cardiac rehabilitation (CR) is essential for exercise prescription. This study compared exercise measurement from an in-person walk test; wearable activity tracker; and self-report at CR entry, completion (8-weeks) and follow-up (16-weeks). Forty patients beginning CR completed the Six-Minute Walk Test (6MWT), Physical Activity Scale for the Elderly (PASE), and wore Fitbit-Flex for four consecutive days including two weekend days. The sample mean age was 66 years; 67% were male. Increased exercise capacity at CR completion and follow-up was detected by a 6MWT change in mean distance (39 m and 42 m; p = 0.01, respectively). Increased PA participation at CR completion was detected by Fitbit-Flex mean change in step counts (1794; p = 0.01). Relative changes for Fitbit-Flex step counts and a 6MWT were consistent with previous research, demonstrating Fitbit-Flex's potential as an outcome measure. With four days of data, Fitbit-Flex had acceptable ICC values in measuring step counts and MVPA minutes. Fitbit-Flex steps and 6MWT meters are more responsive to changes in PA patterns following exposure to a cardiac rehabilitation program than Fitbit-Flex or PASE-estimated moderate-vigorous PA (MVPA) minutes. Fitbit-Flex step counts provide a useful additional measure for assessing PA outside of the CR setting and accounts for day-to-day variations. Two weekend days and two weekdays are needed for Fitbit-Flex to estimate PA levels more precisely.

[Use of biosimilars in the treatment of rheumatoid arthritis : An overview]. / Einsatz von Biosimilars in der Behandlung der rheumatoiden Arthritis : Ein Überblick.

Biologics have been an integral part of the treatment of rheumatoid arthritis for approximately 20 years. As patents for pharmaceuticals generally expire after 10 years, in recent years biosimilars have come onto the market. Many studies have shown that they are an equivalent alternative to the reference drug with comparable safety and efficacy. In some cases, they even showed lower rates of adverse drug reactions compared to the reference drugs. Furthermore, considerable costs can be saved by biosimilars, which amount to an annual three-digit million sum in Germany alone. Large regional differences in the prescription frequency of biosimilars in Germany can be identified, which are also reflected in the savings potential. A switch to a biosimilar is possible and desirable with the involvement of the patient. In this sense, the initial prescription of a biosimilar instead of the reference drug is also to be advocated.

Computerized testing in reading comprehension skill: investigating score interchangeability, item review, age and gender stereotypes, ICT literacy and computer attitudes.

Score interchangeability of Computerized Fixed-Length Linear Testing (henceforth CFLT) and Paper-and-Pencil-Based Testing (henceforth PPBT) has become a controversial issue over the last decade when technology has meaningfully restructured methods of the educational assessment. Given this controversy, various testing guidelines published on computerized testing may be used to investigate the interchangeability of CFLT and PPBT mean scores to corroborate if test takers' testing performance is influenced by the effects of testing administration mode; specifically, if validity and reliability of two versions of the same test are affected. This research was conducted to probe not only score interchangeability across testing modes but also to explore the role of age and gender stereotypes, item review, ICT literacy and attitudes towards computer use as moderator variables in test takers' reading achievement in CFLT. Fifty-eight EFL learners homogeneous in both general English and reading skills assigned into one testing group participated in this study. Three different versions of TOEFL reading comprehension test, Computer Attitude Scale (CAS), and ICT literacy Scale of TOEFL Examinees were used in this crossover quasi-controlled empirical study with a common-person and pretest-posttest design to collect data. The findings demonstrated that although the reading scores of test takers were interchangeable in both CFLT and PPBT versions regarding testing administration modes, they were different regarding item review. Furthermore, no significant interaction was found between age, gender, and ICT literacy and CFLT performance. However, attitudes towards the use of computer led to a significant change in testing achievement on CFLT.

Reducing the effects of control materials based on interchangeability of estimates of day-to-day imprecision between commercial control materials and serum samples.

BACKGROUND: Reduce the effects in the storage-and-thawing process of commercial control materials based on their interchangeability evaluation. METHODS: Seven assays-anti-streptolysin O, complement 3, carcinoembryonic antigen, urea, ferritin, total bilirubin, and glucose-were selected. Commercial control materials and serum samples with similar concentrations were chosen as samples. The experiment was carried out in three stages. In the first stage, the assays with statistical differences in imprecision were screened. In the second stage, two specimens were sealed with parafilm and frozen at -80°C and thawed in the water bath, and the imprecision differences were compared again. Finally, the effective means to reduce the effects were included in the standard operating procedure to repeat confirmation. RESULTS: In the first stage, there was only a statistical difference (p < 0.05) in the imprecision of glucose and total bilirubin between two specimens, and the imprecision of control materials was higher than the serum samples. In the second stage, glucose imprecision was not statistically different (p > 0.05) and lower than in the first stage. In the third stage, the methods from the second stage were confirmed to be effective at reducing control material effects. CONCLUSION: Finding variation factors and confirming and standardizing the measures will help lessen commercial control material effects.

Comparing the Mutual Interchangeability of ECOM, FloTrac/Vigileo, 3D-TEE, and ITD-PAC Cardiac Output Measuring Systems in Coronary Artery Bypass Grafting.

OBJECTIVE: The aim of this study was to compare the mutual interchangeability of 4 cardiac output measuring devices by comparing their accuracy, precision, and trending ability. DESIGN: A single-center prospective observational study. DESIGN: Nonuniversity teaching hospital, single center. PARTICIPANTS: Forty-four consecutive patients scheduled for elective, nonemergent coronary artery bypass grafting (CABG). INTERVENTIONS: The cardiac output was measured for each participant using 4 methods: intermittent thermodilution via pulmonary artery catheter (ITD-PAC), Endotracheal Cardiac Output Monitor (ECOM), FloTrac/Vigileo System (FLOTRAC), and 3-dimensional transesophageal echocardiography (3D-TEE). MEASUREMENTS AND MAIN RESULTS: Measurements were performed simultaneously at 5 time points: presternotomy, poststernotomy, before cardiopulmonary bypass, after cardiopulmonary bypass, and after sternal closure. A series of statistical and comparison analyses including ANOVA, Pearson correlation, Bland-Altman plots, quadrant plots, and polar plots were performed, and inherent precision for each method and percent errors for mutual interchangeability were calculated. For the 6 two-by-two comparisons of the methods, the Pearson correlation coefficients (r), the percentage errors (% error), and concordance ratios (CR) were as follows: ECOM_versus_ITD-PAC (r = 0.611, % error = 53%, CR = 75%); FLOTRAC_versus_ITD-PAC (r = 0.676, % error = 49%, CR = 77%); 3D-TEE versus ITD-PAC (r = 0.538, % error = 64%, CR = 67%); FLOTRAC_versus_ECOM (r = 0.627, % error = 51%, CR = 75%); 3D-TEE_versus ECOM (r = 0.423, % error = 70%, CR = 60%), and 3D-TEE_versus_FLOTRAC (r = 0.602, % error = 59%, CR = 61%). CONCLUSIONS: Based on the recommended statistical measures of interchangeability, ECOM, FLOTRAC, and 3D-TEE are not interchangeable with each other or to the reference standard invasive ITD-PAC method in patients undergoing nonemergent cardiac bypass surgery. Despite the negative result in this study and the majority of previous studies, these less-invasive methods of CO have continued to be used in the hemodynamic management of patients. Each device has its own distinct technical features and inherent limitations; it is clear that no single device can be used universally for all patients. Therefore, different methods or devices should be chosen based on individual patient conditions, including the degree of invasiveness, measurement performance, and the ability to provide real-time, continuous CO readings.

Statistical Mechanics and Thermodynamics: Boltzmann's versus Planck's State Definitions and Counting †.

During the physical foundation of his radiation formula in his December 1900 talk and subsequent 1901 article, Planck refers to Boltzmann's 1877 combinatorial-probabilistic treatment and obtains his quantum distribution function, while Boltzmann did not. For this, Boltzmann's memoirs are usually ascribed to classical statistical mechanics. Agreeing with Bach, it is shown that Boltzmann's 1868 and 1877 calculations can lead to a Planckian distribution function, where those of 1868 are even closer to Planck than that of 1877. Boltzmann's and Planck's calculations are compared based on Bach's three-level scheme 'configuration-occupation-occupancy'. Special attention is paid to the concepts of interchangeability and the indistinguishability of particles and states. In contrast to Bach, the level of exposition is most elementary. I hope to make Boltzmann's work better known in English and to remove misunderstandings in the literature.

Iraqi regulatory authority current system and experience with biosimilars.

Biological medicines have significantly altered treatment for many patients with chronic diseases such as cancers, autoimmune diseases, and diabetes. However, the high cost of biological medicines has limited patients' access to them. Iraq is one of the countries that have decided to increase access to these medicines through biosimilars, which are copies of originator biological medicines. Prior to 2019, the Iraqi National Regulatory Authority (NRA) had no clear guidelines in place for biosimilars uptake. Therefore, approvals of many biosimilars were delayed. As a response to that, a new pivotal committee was found within this authority, and the first version of Iraqi basis and guidelines for the approval of biosimilars was enacted. With the implementation of the Iraqi biosimilars guidelines and escalating the cooperation within the Iraqi NRA, many benefits have been attained in a short time including the approval of many essential biosimilar products which has resulted in a total cost savings estimated to exceed 50 million USD in just the year 2020. However, there are still some barriers towards making the utmost benefit from biosimilars in Iraq, such as lack of familiarity of these products among the Iraqi health care providers which requires appropriate biosimilars-awareness enhancement strategies.

Drug switching in the Netherlands: a cohort study of 20 active substances.

BACKGROUND: For a patient, drug switches are not desirable (either between a brand-name drug and a generic drug, or between two generic drugs of the same active substance). Research into the causes of drug switches, and related adverse drug reactions, is hampered by the absence of quantitative data on drug switches. METHODS: We describe the frequency of drug switches in the Netherlands for a selection of active substances. A retrospective cohort study was conducted using the Drug Information System of the National Health Care Institute in the Netherlands. We studied the Dutch patient population from mid-2009 to 2016. The selection of active substances (n = 20) was made based on a report by Lareb, the Netherlands Pharmacovigilance Centre, on adverse drug reactions related to drug switching, and we used qualitative and quantitative descriptive analyses. A drug switch is defined as the replacement of a patient's prescribed drug with a similar drug from a different manufacturer. RESULTS: We identified 23.8 million drug switches on a total of 206 million (11.6%) similar drug dispenses. The frequency of drug switches demonstrated a yearly peak in the period from January to March. In some months, for atorvastatin, losartan, pantoprazole, and irbesartan, more than 60% of similar drug dispenses were drug switches. Most drug switches (80.3%) were between two generic drugs, and 0.12% of these involved a drug from a European parallel import. The proportion of drug switches between two brand-name drugs decreased from 14.5 to 5.53% during our study period, and of these, 86.5% involved a drug from a European parallel import. CONCLUSIONS: Drug switching is common in the Netherlands, and most of the drug switches we studied are between generic drugs. The observed annual peak of drug switches is most likely explained by a specific Dutch reimbursement policy. Not only are the data valuable as is, but they also serve as a first step towards elucidating the reasons for the occurrence of these drug switches. In addition, these data can be used to put into perspective the adverse drug reactions associated with drug switching.

[Biosimilars in the European Union: current situation and challenges]. / Biosimilars in der EU: Bestandsaufnahme und neue Herausforderungen.

Biosimilars are medicinal products that are highly similar to approved biopharmaceuticals. Biosimilars enable patient access to biological therapies that would otherwise be restricted or delayed due to cost reasons. After the successful introduction of low-molecular biosimilars in 2006, highly complex monoclonal antibodies have also been available since 2013 as biosimilars for treating autoimmune diseases and oncologic indications. In principle, the biosimilar concept can be applied to all well-characterized biologicals; in the future, blood clotting factors or drugs containing nucleic acids, such as DNA or RNA gene therapy or mRNA vaccines, will also be an option for biosimilar development.In some instances, biosimilarity can be demonstrated by physicochemical and functional similarity, and additional comparative clinical efficacy and safety studies have been considered no longer necessary for several product categories in recent years. Switching a patient from a reference drug to a biosimilar or from one biosimilar to another (interchangeability) has so far been considered harmless. Since February 2020, there has been a provisional decision in Germany that patients should be switched according to an economic prescription method. Further scientific findings on the interchangeability of biosimilars and experiences with the supply practices of biosimilars should be collected and evaluated.In this article, the current situation regarding marketing authorizations of biosimilars in the European Union is reviewed. The role of clinical trials for biosimilars is presented, and challenges of biosimilar development and views on interchangeability are discussed.

[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.

Breath-by-breath oxygen uptake during running: Effects of different calculation algorithms.

NEW FINDINGS: What is the central question of this study? Breath-by-breath gas exchange analysis during treadmill exercise can be disturbed by different breathing patterns depending on cadence, and the flow sensor might be subjected to variable mechanical stress. It is still unclear whether the outcomes of the gas exchange algorithms can be affected by running at different speeds. What is the main finding and its importance? Practically, the three investigated breath-by-breath algorithms ('Wessel', 'expiration-only' and 'independent breath') provided similar average gas exchange values for steady-state conditions. The 'independent breath' algorithm showed the lowest breath-by-breath fluctuations in the gas exchange data compared with the other investigated algorithms, both at steady state and during incremental exercise. ABSTRACT: Recently, a new breath-by-breath gas exchange calculation algorithm (called 'independent breath') was proposed. In the present work, we aimed to compare the breath-by-breath O2 uptake ( V̇O2 ) values assessed in healthy subjects undergoing a running protocol, as calculated applying the 'independent breath' algorithm or two other commonly used algorithms. The traces of respiratory flow, O2 and CO2 fractions, used by the calculation algorithms, were acquired at the mouth on 17 volunteers at rest, during running on a treadmill at 6.5 and 9.5 km h-1 , and thereafter up to volitional fatigue. Within-subject averages and standard deviations of breath-by-breath V̇O2 were calculated for steady-state conditions; the V̇O2 data of the incremental phase were analysed by means of linear regression, and their root mean square was assumed to be an index of the breath-by-breath fluctuations. The average values obtained with the different algorithms were significantly different (P < 0.001); nevertheless, from a practical point of view the difference could be considered 'small' in all the investigated conditions (effect size <0.3). The standard deviations were significantly lower for the 'independent breath' algorithm (post hoc contrasts, P < 0.001), and the slopes of the relationships with the corresponding data yielded by the other algorithms were <0.70. The root mean squares of the linear regressions calculated for the incremental phase were also significantly lower for the 'independent breath' algorithm, and the slopes of the regression lines with the corresponding values obtained with the other algorithms were <0.84. In conclusion, the 'independent breath' algorithm yielded the least breath-by-breath O2 uptake fluctuation, both during steady-state exercise and during incremental running.