Pharmacokinetic and pharmacodynamic similarity of biosimilar natalizumab (PB006) to its reference medicine: a randomized controlled trial.

BACKGROUND: PB006 (Polpharma Biologics S.A; marketed as Tyruko®, Sandoz) is an approved biosimilar to natalizumab (Tysabri®; Biogen [ref-NTZ]). This multicenter, double-blind, randomized, single-dose study was conducted to demonstrate pharmacokinetic/pharmacodynamic (PK/PD) similarity between PB006 and ref-NTZ. RESEARCH DESIGN AND METHODS: Healthy participants (N = 453) were randomized to receive 3 mg/kg infusion of PB006, US-licensed, or EU-approved ref-NTZ before an 85-day follow-up. Primary PK endpoint was total natalizumab serum concentration over time; secondary PK endpoints explored concentration changes. Primary PD endpoints compared CD19+ cell counts and percentage α4-integrin receptor saturation, per natalizumab's mechanism of action. Secondary PD endpoints explored serum changes in sVCAM-1 and sMAdCAM-1, CD34+, and CD19+ cells. Safety, tolerability, and immunogenicity were assessed. RESULTS: The primary PK endpoint was met, with 90% confidence intervals (CIs) of the geometric mean for serum test/reference ratios contained within a prespecified margin (0.8-1.25). All primary PD endpoints were met, with 90% and 95% CIs within this similarity margin for baseline-adjusted CD19+ cell counts and percentage α4-integrin receptor saturation. All secondary endpoints were similarly contained, except sVCAM. No notable differences in safety, tolerability, or immunogenicity were observed. CONCLUSION: Similarity was confirmed, with PB006 demonstrating PK/PD behavior consistent with that of ref-NTZ. CLINICAL TRIAL REGISTRATION: EudraCT number 2019-003874-15.

PB006 (developed by Polpharma Biologics S.A; and marketed as Tyruko® by Sandoz) is an approved biosimilar to the reference medicine, natalizumab (Tysabri®, Biogen [ref-NTZ]) used to treat relapsing forms of multiple sclerosis. Approved biosimilar medicines have been shown to be as safe and effective as their reference medicines via different types of comparisons to the reference medicine, confirming that physicians and patients can expect the same clinical outcome.This study was conducted to confirm that PB006 acts the same way in the body as ref-NTZ. Healthy participants received one dose of either PB006, ref-NTZ from the US or ref-NTZ from Europe. During the study, blood samples were tested to confirm how much of each medicine was present in participants' blood, as well as to assess changes in immune cells or proteins related to how natalizumab works. The study also measured whether any treatment caused unwanted side effects or caused any changes in the immune system that may stop the medicine working.The results showed that PB006 behaved in the same way as ref-NTZ in the blood. All reported side effects were similar between groups and were as expected for this medicine, and neither PB006 nor ref-NTZ caused any important or unexpected changes to the immune system. This study showed that biosimilar natalizumab, PB006, behaves in the same way as ref-NTZ, and the same treatment outcomes can be expected.

Efficacy and Safety of Proposed Biosimilar Natalizumab (PB006) in Patients With Relapsing-Remitting Multiple Sclerosis: The Antelope Phase 3 Randomized Clinical Trial.

Importance: Proposed biosimilar natalizumab (biosim-NTZ) PB006 is the first biosimilar monoclonal antibody therapy developed for multiple sclerosis (MS) treatment. Objective: To evaluate matching efficacy, safety, and immunogenicity between biosim-NTZ and reference natalizumab (ref-NTZ) in patients with relapsing-remitting MS (RRMS). Design, Setting, and Participants: The Antelope trial was a phase 3, parallel-group, randomized, active-controlled study, conducted between October 2019 and March 2021, with last patient follow-up visit on August 23, 2021. The study took place in 48 centers in 7 countries. Of 531 patients with RRMS aged 18 to 60 years screened, 266 were excluded before randomization in line with study criteria. Eligible participants had 1 or more documented relapse within the previous year and either 1 or more gadolinium-enhancing T1-weighted or 9 or more T2-weighted brain lesions, Kurtzke Expanded Disability Status Scale score of 0 to 5.0 (inclusive), and John Cunningham virus index of 1.5 or less at screening. One patient withdrew consent before dosing. Interventions: Intravenous infusions every 4 weeks of biosim-NTZ, 300 mg, or ref-NTZ, 300 mg (1:1 randomization), from week 0 to week 44 (end-of-study visit: week 48). At week 24, the ref-NTZ group was rerandomized and 30 patients were switched to biosim-NTZ for the remainder of the study. Main Outcomes and Measures: The primary end point was the cumulative number of new active lesions on magnetic resonance imaging (new gadolinium-enhancing T1-weighted lesions and new/enlarging T2-weighted lesions without double counting) over 24 weeks. Additional end points included further magnetic resonance imaging parameters, annualized relapse rate, and Kurtzke Expanded Disability Status Scale score. Safety, tolerability, and immunogenicity assessments included adverse events, laboratory evaluations, and positivity for anti-John Cunningham virus antibodies and antinatalizumab antibodies. Results: A total of 264 participants (mean [SD] age, 36.7 [9.38] years; 162 [61.4%] female) received treatment with biosim-NTZ (n = 131) or ref-NTZ (n = 133). At week 24, the model-based mean difference in cumulative number of new active lesions between biosim-NTZ and ref-NTZ treatment groups was 0.17 (least square means [SE]: biosim-NTZ, 0.34 [0.34]; ref-NTZ, 0.45 [0.28]; 95% CI, -0.61 to 0.94 within the prespecified margins of ±2.1). No significant differences between treatment groups were observed across secondary efficacy end points, safety, tolerability, or immunogenicity assessments. Conclusions and Relevance: Biosim-NTZ matched ref-NTZ in efficacy, safety, and immunogenicity for patients with RRMS in the tested setting. This phase 3 trial supports proposed biosim-NTZ as a biosimilar alternative to ref-NTZ for treating RRMS. Trial Registration: ClinicalTrials.gov Identifier: NCT04115488.

Nailfold capillaroscopy and deep learning in diabetes.

OBJECTIVE: To determine whether nailfold capillary images, acquired using video capillaroscopy, can provide diagnostic information about diabetes and its complications. RESEARCH DESIGN AND METHODS: Nailfold video capillaroscopy was performed in 120 adult patients with and without type 1 or type 2 diabetes, and with and without cardiovascular disease. Nailfold images were analyzed using convolutional neural networks, a deep learning technique. Cross-validation was used to develop and test the ability of models to predict five5 prespecified states (diabetes, high glycosylated hemoglobin, cardiovascular event, retinopathy, albuminuria, and hypertension). The performance of each model for a particular state was assessed by estimating areas under the receiver operating characteristics curves (AUROC) and precision recall curves (AUPR). RESULTS: A total of 5236 nailfold images were acquired from 120 participants (mean 44 images per participant) and were all available for analysis. Models were able to accurately identify the presence of diabetes, with AUROC 0.84 (95% confidence interval [CI] 0.76, 0.91) and AUPR 0.84 (95% CI 0.78, 0.93), respectively. Models were also able to predict a history of cardiovascular events in patients with diabetes, with AUROC 0.65 (95% CI 0.51, 0.78) and AUPR 0.72 (95% CI 0.62, 0.88) respectively. CONCLUSIONS: This proof-of-concept study demonstrates the potential of machine learning for identifying people with microvascular capillary changes from diabetes based on nailfold images, and for possibly identifying those most likely to have diabetes-related complications.

Temporal control of the integrated stress response by a stochastic molecular switch.

Stress granules (SGs) are formed in the cytosol as an acute response to environmental cues and activation of the integrated stress response (ISR), a central signaling pathway controlling protein synthesis. Using chronic virus infection as stress model, we previously uncovered a unique temporal control of the ISR resulting in recurrent phases of SG assembly and disassembly. Here, we elucidate the molecular network generating this fluctuating stress response by integrating quantitative experiments with mathematical modeling and find that the ISR operates as a stochastic switch. Key elements controlling this switch are the cooperative activation of the stress-sensing kinase PKR, the ultrasensitive response of SG formation to the phosphorylation of the translation initiation factor eIF2α, and negative feedback via GADD34, a stress-induced subunit of protein phosphatase 1. We identify GADD34 messenger RNA levels as the molecular memory of the ISR that plays a central role in cell adaptation to acute and chronic stress.

Sharing Matters for Generalization in Deep Metric Learning.

Learning the similarity between images constitutes the foundation for numerous vision tasks. The common paradigm is discriminative metric learning, which seeks an embedding that separates different training classes. However, the main challenge is to learn a metric that not only generalizes from training to novel, but related, test samples. It should also transfer to different object classes. So what complementary information is missed by the discriminative paradigm? Besides finding characteristics that separate between classes, we also need them to likely occur in novel categories, which is indicated if they are shared across training classes. This work investigates how to learn such characteristics without the need for extra annotations or training data. By formulating our approach as a novel triplet sampling strategy, it can be easily applied on top of recent ranking loss frameworks. Experiments show that, independent of the underlying network architecture and the specific ranking loss, our approach significantly improves performance in deep metric learning, leading to new the state-of-the-art results on various standard benchmark datasets.

[Association between Safety Culture and Risk of Burnout: A Survey of Non-Medical Rescue Workers]. / Der Zusammenhang zwischen Sicherheitskultur und Burnout-Risiko: Eine Befragung nicht-ärztlicher Mitarbeiter im Rettungsdienst.

BACKGROUND: Stressors such as safety culture in organizations that increase the risk of burnout have been studied in nursing and inpatient care settings. However, investigations in the setting of preclinical emergency medical services (EMS) are still limited. The study aims at (1) investigating burnout in health care workers in preclinical EMS and their perceived safety culture, and (2) analyzing the association between the two. METHODS: Using the Maslach Burnout Inventory (MBI) and the Emergency Medical Services - Safety Attitudes Questionnaire (EMS-SAQ), an online survey was conducted with non-medical health care workers in preclinical EMS. Descriptive analyses were performed using frequencies, mean values, percentages and the Pearson correlation coefficient. A logistic regression model was used to determine the relationship between safety culture and the risk of burnout. RESULTS: A total of 1,101 questionnaires was considered for analysis. Most of the participants were male (86.2%) and younger than 40 years (73.2%). A high risk of burnout for participants was found for the dimensions of emotional exhaustion and depersonalization (EE 26.3% and DP 40.2%). In the context of measuring safety culture, especially management, working conditions, and safety climate were negatively perceived by the participants. Furthermore, high stress recognition (EE: OR=3.317, p<0.01; DP: OR=1.910, p<0.01), negative job satisfaction (EE: OR=0.297, p<0.01; DP: OR=0.576, p<0.01) and negatively perceived working conditions (EE: OR 0.598, p<0.05; DP: 0.937, p<0.05) were significantly associated with a high risk of burnout. CONCLUSION: This is the first large scale study investigating burnout among non-medical health care workers in preclinical EMS and their perceived safety culture in Germany as well as the association between the two. The results show the necessity to focus on perceived dimensions of safety culture in organizations, to develop measures reducing stress and improve job satisfaction and working conditions. In the context of increasing skills shortage, this is especially relevant with regard to the challenges of patient safety and quality of outcomes in care.

Predicting COVID-19 Pneumonia Severity on Chest X-ray With Deep Learning.

Introduction The need to streamline patient management for coronavirus disease-19 (COVID-19) has become more pressing than ever. Chest X-rays (CXRs) provide a non-invasive (potentially bedside) tool to monitor the progression of the disease. In this study, we present a severity score prediction model for COVID-19 pneumonia for frontal chest X-ray images. Such a tool can gauge the severity of COVID-19 lung infections (and pneumonia in general) that can be used for escalation or de-escalation of care as well as monitoring treatment efficacy, especially in the ICU. Methods Images from a public COVID-19 database were scored retrospectively by three blinded experts in terms of the extent of lung involvement as well as the degree of opacity. A neural network model that was pre-trained on large (non-COVID-19) chest X-ray datasets is used to construct features for COVID-19 images which are predictive for our task. Results This study finds that training a regression model on a subset of the outputs from this pre-trained chest X-ray model predicts our geographic extent score (range 0-8) with 1.14 mean absolute error (MAE) and our lung opacity score (range 0-6) with 0.78 MAE. Conclusions These results indicate that our model's ability to gauge the severity of COVID-19 lung infections could be used for escalation or de-escalation of care as well as monitoring treatment efficacy, especially in the ICU. To enable follow up work, we make our code, labels, and data available online.

Diffuse domain method for needle insertion simulations.

We present a new strategy for needle insertion simulations without the necessity of meshing. A diffuse domain approach on a regular grid is applied to overcome the need for an explicit representation of organ boundaries. A phase field function captures the transition of tissue parameters and boundary conditions are imposed implicitly. Uncertainties of a volume segmentation are translated in the width of the phase field, an approach that is novel and overcomes the problem of defining an accurate segmentation boundary. We perform a convergence analysis of the diffuse elastic equation for decreasing phase field width, compare our results to deformation fields received from conforming mesh simulations and analyze the diffuse linear elastic equation for different widths of material interfaces. Then, the approach is applied to computed tomography data of a patient with liver tumors. A three-class U-Net is used to automatically generate tissue probability maps serving as phase field functions for the transition of elastic parameters between different tissues. The needle tissue interaction forces are approximated by the absolute gradient of a phase field function, which eliminates the need for explicit boundary parameterization and collision detection at the needle-tissue interface. The results show that the deformation field of the diffuse domain approach is comparable to the deformation of a conforming mesh simulation. Uncertainties of tissue boundaries are included in the model and the simulation can be directly performed on the automatically generated voxel-based probability maps. Thus, it is possible to perform easily implementable patient-specific elastomechanical simulations directly on voxel data.

The Path Towards a Tailored Clinical Biosimilar Development.

Since the first approval of a biosimilar medicinal product in 2006, scientific understanding of the features and development of biosimilar medicines has accumulated. This review scrutinizes public information on development programs and the contribution of the clinical studies for biosimilar approval in the European Union (EU) and/or the United States (US) until November 2019. The retrospective evaluation of the programs that eventually obtained marketing authorization and/or licensure revealed that in 95% (36 out of 38) of all programs, the comparative clinical efficacy studies confirmed similarity. In the remaining 5% (2 out of 38), despite meeting efficacy outcomes, the biosimilar candidates exhibited clinical differences in immunogenicity that required changes to the manufacturing process and additional clinical studies to enable biosimilar approval. Both instances of clinical differences in immunogenicity occurred prior to 2010, and the recurrence of these cases is unlikely today due to state-of-the-art assays and improved control of process-related impurities. Biosimilar candidates that were neither approved in the EU nor in the US were not approved due to reasons other than clinical confirmation of efficacy. This review of the development history of biosimilars allows the proposal of a more efficient and expedited biosimilar development without the routine need for comparative clinical efficacy and/or pharmacodynamic studies and without any compromise in quality, safety, or efficacy. This proposal is scientifically valid, consistent with regulation of all biologics, and maintains robust regulatory standards in the assessment of biosimilar candidates. Note: The findings and conclusion of this paper are limited to biosimilar products developed against the regulatory standards in the EU and the US.

Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of Pelmeg®, a pegfilgrastim biosimilar in healthy subjects.

A pharmacokinetics (PK)/pharmacodynamics (PD) study (EudraCT number 2015-002966-21) was conducted to investigate the biosimilarity of Pelmeg® (pegfilgrastim), a biosimilar to EU-authorized Neulasta®, which is used in the clinic for prevention of chemotherapy-induced neutropenia. The single-dose, randomized, double-blind, two-way crossover study comprised 171 healthy male subjects, receiving Pelmeg and Neulasta (6 mg as subcutaneous injection) in a sequential manner. Primary PK endpoints were the area under the concentration curve from time zero to last measurable concentration (AUC0-last) and the maximum concentration (Cmax). The primary PD endpoint was the area under the effect curve (AUEC0-last) for absolute neutrophil count (ANC). Safety and immunogenicity were also assessed. Comparability was demonstrated for both PK endpoints, with geometric mean ratios (test/reference) for AUC0-last and Cmax of 95.2% and 92.8%, respectively. The corresponding confidence intervals (CIs; 94.3%) were [86.6%;104.7%] for AUC0-last and [84.4%;102.2%] for Cmax, both being within the equivalence margin of 80.0% to 125.0%. Likewise, PD comparability was demonstrated, with the geometric mean ratio (test/reference) of AUEC0-last of 100.2%, with a corresponding CI (95%) of 98.7%-101.8%. No clinically meaningful differences were observed for safety and immunogenicity between Pelmeg and Neulasta. Pelmeg was found to be highly similar to the reference product.

Pharmacodynamics, safety, and immunogenicity of Pelmeg®, a pegfilgrastim biosimilar in healthy subjects.

A pharmacodynamics (PD) and immunogenicity study was conducted to investigate biosimilarity of Pelmeg®, a pegfilgrastim biosimilar to EU-authorized Neulasta®. The multiple-dose, randomized, double-blind, two-sequence, and three-period cross-over study comprised 96 healthy male subjects, receiving Pelmeg (Test [T]) and Neulasta (Reference [R]) in a sequential manner (T-T-R vs R-R-T). Subjects were dosed with 3 mg pegfilgrastim, as this dose was previously shown to be in the ascending part of the dose-response curve for PD. The primary PD endpoint was the area under the effect curve (AUEC0-last) for absolute neutrophil count (ANC). The primary immunogenicity endpoint was proportion of anti-drug antibody (ADA)-positive subjects at the end of Period 2 (ie, after administration of two doses of the same study drug). Comparability was demonstrated for the PD endpoint, with the geometric mean ratio (T/R) of AUEC0-last being 101.59%, with a corresponding 95% CI of [99.58; 103.63]. Of note, when using tighter acceptance limits (90.00%-111.00%), comparability between test and reference was shown as well. Only two confirmed ADA positive samples were detected, one after treatment with Pelmeg and one after Neulasta. These had a low ADA titer, no filgrastim reactivity, and no neutralizing capacity. No clinically meaningful differences in safety between Pelmeg and Neulasta were observed. Overall, the results from this study confirmed the biosimilarity of Pelmeg and Neulasta for PD and immunogenicity, as shown already at the bioanalytical level and in the pivotal PK/PD study with Pelmeg.

Burnout and safety outcomes - a cross-sectional nationwide survey of EMS-workers in Germany.

BACKGROUND: The association between burnout and patient safety has been analyzed in many studies for nurses, physicians, and residents. However, studies concerning prehospital emergency medical services (EMS) workers are limited, although they are particularly under risk for emotional stress. This study aims to descriptively analyze the overall degree of burnout among EMS-workers, and potential adverse events that might harm patients as well as the relationship between burnout and perceived safety outcomes for EMS-workers in Germany. METHODS: EMS-workers were recruited via German EMS-journals, social media and a professional association to participate in an online survey. The questionnaire includes the ´Maslach Burnout Inventory´ (MBI), the 'Emergency Medical Services Safety Inventory' (EMS-SI), and items about job satisfaction and the individual person. Data was descriptively analyzed by calculating frequencies, means, percentages and Pearson correlation coefficients. The association between burnout and patient safety was analyzed using linear and logistic regression models. RESULTS: A total of n = 1101 questionnaires were considered for data analysis. The vast majority of participants were male, younger than 40 years old, and full-time employees with an EMS-experience of 12 years on average. Between 19.9 and 40% of the participants showed a high degree of burnout in one of the burnout dimensions. Safety compromising behavior was the outcome measure with the highest percentage of participants reporting a negative outcome measure. The dimensions emotional exhaustion and depersonalization were positively associated with the safety outcomes injury and safety compromising behavior. Additionally, experiences, job satisfaction and the intention to leave the current job were significantly associated with the outcome measures. CONCLUSION: This is the first study that examines the association between the degree of burnout and patient safety for EMS-workers. The results suggest that an expansion of psychological support for EMS-workers should be considered. Further research should concentrate on the complex relations between working conditions, burnout and patient safety.

Prospective multicenter study of HX575 (biosimilar epoetin-α) in patients with chronic kidney disease applying a target hemoglobin of 10--12 g/dl.

HX575 was approved in the European Union in August 2007 as the first-ever biosimilar epoetin-α product. The present study extended the safety database on HX575 by monitoring adverse events (AEs) in clinical practice. Hemoglobin (Hb) levels and HX575 doses were recorded for the assessment of efficacy. This open, 6-month single-arm study was conducted in 10 European countries with a target enrollment of 1,500 patients with anemia due to chronic kidney disease (CKD). HX575 was intravenously (i.v.) administered aiming at an Hb target of 10 - 12 g/dl. Most patients (92.3%) had already received erythropoiesis stimulating agents (ESAs) treatment before enrolment into this study; the recorded treatments mainly comprised i.v. or subcutaneous (s.c.) administration of epoetin-α, epoetin-ß or darbepoetin. The study period covered 770 patient years. The observed AE profile was in line with expectations for this patient population. Thrombotic vascular events (TVEs) were reported in 11.9% of patients (0.2612 per patient year). Tumor incidence was 1.4% (0.0299 per patient year). No subject developed anti-epoetin antibodies. Mean Hb levels were effectively maintained between 11.2 and 11.3 g/dl following the conversion from a broad spectrum of pre-study ESA treatments with stable overall mean i.v. HX575 doses. The proportion of patients within the Hb target range increased from 57.5% at baseline to 66.8% at study end.

Safety, immunogenicity and efficacy of subcutaneous biosimilar epoetin-α (HX575) in non-dialysis patients with renal anemia: a multi-center, randomized, double-blind study.

BACKGROUND: HX575 is a biosimilar version of epoetin-α that is approved for the treatment of anemia associated with chronic kidney disease (CKD) using the intravenous route of administration. Here we report data from a study of anemic pre-dialysis patients to assess the safety, immunogenicity and efficacy of subcutaneous (s.c.) administration of HX575 vs. Erypo®/Eprex® (Ortho Biotech, Neuss, Germany). METHODS: This was a randomized, double-blind study in adult patients (n = 337) with Stage III - V CKD and a hemoglobin (Hb) level of 7.5 - 11.0 g/dl. Eligible patients were randomized to 52 weeks of treatment with HX575 or Erypo®/Eprex® at a starting dose of 25 IU/kg body weight 3 times weekly or 75 IU/kg body weight once weekly during Weeks 1 - 5. This could be adjusted after 5 weeks to maintain Hb levels between 10 and 12 g/dl. The primary objective was to assess the safety and immunogenicity of HX575 compared with Erypo®/Eprex®. Efficacy endpoints were mean absolute change in Hb from baseline to end of Week 13 and mean weekly epoetin dosage in Weeks 11 - 13. RESULTS: HX575 was equivalent to Erypo®/Eprex® in terms of maintaining Hb levels and epoetin dose requirements. Two patients in the HX575 group developed neutralizing antibodies (NAbs) to erythropoietin, which resulted in the study being terminated prematurely. Aside from these two events, reported adverse events were as expected for patients with Stage III - V CKD and similar in both treatment groups. CONCLUSIONS: This study demonstrated the efficacy and therapeutic equivalence of s.c. HX575 compared with the reference epoetin-α, but 2 patients developed NAbs during treatment with s.c. HX575 in this study. Results of a thorough root-cause analysis reported elsewhere indicate that increased tungsten exposure in pre-filled syringes precipitated immunogenic reactions.

Comparison of the pharmacokinetic and pharmacodynamic profiles of one US-marketed and two European-marketed epoetin alfas: a randomized prospective study.

BACKGROUND: HX575, licensed under the brand names Binocrit®, Epoetin Alfa Hexal®, and Abseamed®, was approved in 2007 as the first biosimilar recombinant human erythropoietin alfa (epoetin alfa) in the EU using Erypo®/Eprex® as reference product. OBJECTIVES: The aim of this study was to investigate the bioequivalence and potency of registered epoetin alfa products that have not been compared before in a randomized controlled clinical study. METHODS: The study was conducted in two parts: part A compared the European-marketed HX575 and the US-marketed Epogen®; part B compared the European-marketed Erypo®/Eprex® and HX575 manufactured at two different drug substance production sites (HX575-TT denoting the already-approved technology-transfer product from an additional manufacturing site). In analyses across both study parts, Epogen® was exploratorily compared with Erypo®/Eprex®. A dense-sampling 48-hour pharmacokinetic profile was recorded at steady state after 11 doses of 100 IU epoetin alfa per kg of bodyweight. The hemoglobin response over 4 weeks of study medication administration was analyzed as the primary efficacy surrogate parameter using an ANCOVA model with the baseline value as co-variate. The per-protocol population comprised a total of 268 subjects, 76 in part A (equally randomized to HX575 or Epogen®) and 192 in part B (equally randomized to HX575, HX575-TT, or Erypo®/Eprex®). Pairs of study arms were compared in terms of the ratio of the mean epoetin alfa area under the curve (AUC) and the ratio of the mean hemoglobin area under the effect curve (AUEC). RESULTS: Bioequivalence was shown in all pair-wise comparisons with the 90% confidence intervals of the AUC ratios falling within the standard bioequivalence limits of 80-125%. Moreover, an equivalent pharmacodynamic response was achieved with all compared epoetin alfa products, as confirmed by the hemoglobin AUEC ratio's 90% CI falling within the predefined acceptance margins of 96.8-103.2%. Thus, bioequivalence and equivalent potency was demonstrated for HX575 and Epogen® in part A of the study, as well as for HX575, HX575-TT and Erypo®/Eprex® in part B of the study. Pair-wise comparison across study parts indicated similar pharmacokinetic and pharmacodynamic profiles of Epogen® and Erypo®/Eprex®. All compared epoetin alfa products were well tolerated and had a similar safety profile. No subject developed anti-erythropoietin antibodies upon administration of study medication. CONCLUSION: The results show, for the first time in a prospective randomized clinical study, equivalent bioavailability at steady state and similar potency of the US-marketed Epogen® and the European-marketed Binocrit®. Differences in the formulation between the epoetin alfa products had no apparent clinical impact. The high degree of similarity between Epogen® and Erypo®/Eprex® provides justification for linking and comparing results from clinical studies that were conducted using either US- or European-marketed epoetin alfa products.