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Biosimilars are increasingly available for the treatment of many serious disorders, however some concerns persist about switching a patient to a biosimilar whose condition is stable while on the reference biologic. Randomized controlled studies and extension studies with a switch treatment period (STP) to or from a biosimilar and its reference biologic were identified from publicly available information maintained by the U.S. Food and Drug Administration (FDA). These findings were augmented with data from peer reviewed publications containing information not captured in FDA reviews. Forty-four STPs were identified from 31 unique studies for 21 different biosimilars. Data were extracted and synthesized following PRISMA guidelines. Meta-analysis was conducted to estimate the overall risk difference across studies. A total of 5,252 patients who were switched to or from a biosimilar and its reference biologic were identified. Safety data including deaths, serious adverse events, and treatment discontinuation showed an overall risk difference (95% CI) of -0.00 (-0.00, 0.00), 0.00 (-0.01, 0.01), -0.00 (-0.01, 0.00) across STPs, respectively. Immunogenicity data showed similar incidence of anti-drug antibodies and neutralizing antibodies in patients within a STP who were switched to or from a biosimilar to its reference biologic and patients who were not switched. Immune related adverse events such as anaphylaxis, hypersensitivity reactions, and injections site reactions were similar in switched and non-switched patients. This first systematic review using statistical methods to address the risk of switching patients between reference biologics and biosimilars finds no difference in the safety profiles or immunogenicity rates in patients who were switched and those who remained on a reference biologic or a biosimilar.

OBJECTIVE: This multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m² in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC). RESEARCH DESIGN AND METHODS: Urinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation. RESULTS: A total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m² (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%). Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30-300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease. Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs. 1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m² (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR. CONCLUSIONS: Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m². However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.

The aim of this study was to examine differences between adolescents and adults in persistence of the benefits of intensive therapy 10 years after completion of the Diabetes Control and Complications Trial (DCCT). During the Epidemiology of Diabetes Interventions and Complications (EDIC) study, progression of retinopathy from DCCT closeout to EDIC year 10 was evaluated in 1,055 adults and 156 adolescents. During 10 years of follow-up, HbA(1c) (A1C) was similar between original intensive (INT) and conventional (CON) groups and between former adolescents and adults. At EDIC year 10, adults in the former INT group continued to show slower progression of diabetic retinopathy than those in the CON group (adjusted hazard reduction 56%, P < 0.0001), whereas in adolescents this beneficial effect had disappeared (32%, P = 0.13). Seventy-nine percent of observed differences in the prolonged treatment effect between adults and adolescents at year 10 were explained by differences in mean A1C during DCCT between adolescents and adults (8.9 vs. 8.1%), particularly between INT adolescents and adults (8.1 vs. 7.2%). Prior glycemic control during DCCT is vital for the persistence of the beneficial effects of INT therapy 10 years later. Lowering A1C to as close to normal as safely possible without severe hypoglycemia and starting as early as possible should be attempted for all subjects with type 1 diabetes. These results underscore the importance of maintaining A1C at target values for as long as possible because the benefits of former INT treatment wane over time if A1C levels rise.

Glycation and Carboxymethyllysine Levels in Skin Collagen Predict the Risk of Future 10-Year Progression of Diabetic Retinopathy and Nephropathy in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications Participants With Type 1 Diabetes Saul Genuth 1 , Wanjie Sun 2 , Patricia Cleary 2 , David R. Sell 3 , William Dahms 4 , John Malone 5 , William Sivitz 6 , Vincent M. Monnier 3 7 and for the DCCT Skin Collagen Ancillary Study Group * 1 Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 2 Biostatistics Center, George Washington University, Rockville, Maryland 3 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 4 Department of Pediatrics, Rainbow Babies and Children’s Hospital and University Hospitals of Cleveland, Cleveland, Ohio 5 Department of Pediatrics, University of South Florida, Tampa, Florida 6 Department of Medicine, Veterans Administration Hospital, University of Iowa, Iowa City, Iowa 7 Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio Address correspondence and reprint requests to Saul Genuth, MD, Case Western Reserve University, Cleveland, OH 44106. E-mail: smg15{at}cwru.edu Abstract Several mechanistic pathways linking hyperglycemia to diabetes complications, including glycation of proteins and formation of advanced glycation end products (AGEs), have been proposed. We investigated the hypothesis that skin collagen glycation and AGEs predict the risk of progression of microvascular disease. We measured glycation products in the skin collagen of 211 Diabetes Control and Complications Trial (DCCT) volunteers in 1992 who continued to be followed in the Epidemiology of Diabetes Interventions and Complications study for 10 years. We determined whether the earlier measurements of glycated collagen and AGE levels correlated with the risk of progression of retinopathy and nephropathy from the end of the DCCT to 10 years later. In multivariate analyses, the combination of furosine (glycated collagen) and carboxymethyllysine (CML) predicted the progression of retinopathy (χ 2 = 59.4, P < 0.0001) and nephropathy (χ 2 = 18.2, P = 0.0001), even after adjustment for mean HbA 1c (A1C) (χ 2 = 32.7, P < 0.0001 for retinopathy) and (χ 2 = 12.8, P = 0.0016 for nephropathy). The predictive effect of A1C vanished after adjustment for furosine and CML (χ 2 = 0.0002, P = 0.987 for retinopathy and χ 2 = 0.0002, P = 0.964 for nephropathy). Furosine explained more of the variation in the 10-year progression of retinopathy and nephropathy than did CML. These results strengthen the role of glycation of proteins and AGE formation in the pathogenesis of retinopathy and nephropathy. Glycation and subsequent AGE formation may explain the risk of these complications associated with prior A1C and provide a rational basis for the phenomenon of “metabolic memory” in the pathogenesis of these diabetes complications. AER, albumin excretion rate AGE, advanced glycation end product CML, Nε-(carboxymethyl)-lysine DCCT, Diabetes Control and Complications Trial EDIC, Epidemiology of Diabetes Interventions and Complications Footnotes * * A complete list of the members of the DCCT Skin Collagen Ancillary Study Group can be found in the appendix . † † Deceased. Accepted July 28, 2005. Received May 6, 2005. DIABETES

The coal pillar is an important structure to control the stability of the roadway surrounding rock and maintain the safety of underground mining activities. An unreasonable design of the coal pillar size can result in the failure of the surrounding rock structure or waste of coal resources. The northern Shaanxi mining area of China belongs to the shallow buried coal seam mining in the gully area, and the gully topography makes the bearing law of the coal pillar and the development law of the internal fracture more complicated. In this study, based on the geological conditions of the Longhua Mine 20202 working face, a PFC2D numerical model was established to study the damage characteristics of coal pillars under the different overlying strata base load ratios in the gentle terrain area and the different gully slope sections in the gully terrain area, and the coal pillar design strategy based on the fractal characteristics of the fractures was proposed to provide a reference for determining the width of the coal pillars in mines under similar geological conditions. The results show that the reliability of the mathematical equation between the overlying strata base load ratio and the fractal dimension of the fractures in the coal pillar is high, the smaller the overlying strata base load ratio is, the greater the damage degree of the coal pillar is, and the width of the coal pillar of 15 m under the condition of the actual overlying strata base load ratio (1.19) is more reasonable. Compared with the gentle terrain area, the damage degree of the coal pillar in the gully terrain area is larger, in which the fractal dimension of the fracture in the coal pillar located below the gully bottom is the smallest, and the coal pillar in the gully terrain should be set as far as possible to make the coal pillar located below the gully bottom, so as to ensure the stability of the coal pillar.

We propose a Bayesian population modeling and virtual bioequivalence assessment approach to establishing dissolution specifications for oral dosage forms. A generalizable semi-physiologically based pharmacokinetic absorption model with six gut segments and liver, connected to a two-compartment model of systemic disposition for bupropion hydrochloride oral dosage forms was developed. Prior information on model parameters for gut physiology, bupropion physicochemical properties, and drug product properties were obtained from the literature. The release of bupropion hydrochloride from immediate-, sustained- and extended-release oral dosage forms was described by a Weibull function. In vitro dissolution data were used to assign priors to the in vivo release properties of the three bupropion formulations. We applied global sensitivity analysis to identify the influential parameters for plasma bupropion concentrations and calibrated them. To quantify inter- and intra-individual variability, plasma concentration profiles in healthy volunteers that received the three dosage forms, each at two doses, were used. The calibrated model was in good agreement with both in vitro dissolution and in vivo exposure data. Markov Chain Monte Carlo samples from the joint posterior parameter distribution were used to simulate virtual crossover clinical trials for each formulation with distinct drug dissolution profiles. For each trial, an allowable range of dissolution parameters (“safe space”) in which bioequivalence can be anticipated was established. These findings can be used to assure consistent product performance throughout the drug product life-cycle and to support manufacturing changes. Our framework provides a comprehensive approach to support decision-making in drug product development.

Background We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies obtained at DCCT study closeout and the long-term progression of microvascular disease in EDIC, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs (fluorescence to be reported elsewhere) correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC) at EDIC year 7–9 (n = 187), change of carotid intima-media thickness (IMT) from EDIC year 1 to year 6 and 12 (n = 127), and cardiac MRI outcomes at EDIC year 15–16 (n = 142). Methods Skin collagen AGE measurements obtained from stored specimens were related to clinical data from the DCCT/EDIC using Spearman correlations and multivariable logistic regression analyses. Results Spearman correlations showed furosine (early glycation) was associated with future mean CAC (p < 0.05) and CAC >0 (p = 0.039), but not with CAC score <100 vs. >100. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change from year 1 to 6(all P < 0.05). Left ventricular (LV) mass (cMRI) correlated with MG-H1, and inversely with pepsin solubility (both p < 0.05), while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1 (both p < 0.05), and highly with CML (p < 0.01). In multivariate analysis only furosine (p = 0.01) was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane, Conclusions In type 1 diabetes, multiple AGEs are associated with IMT progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation. Trial registration: Registered at Clinical trial reg. nos. NCT00360815 and NCT00360893, http://www.clinicaltrials.gov

The Effect of Intensive Glycemic Treatment on Coronary Artery Calcification in Type 1 Diabetic Participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Patricia A. Cleary 1 , Trevor J. Orchard 2 , Saul Genuth 3 , Nathan D. Wong 4 , Robert Detrano 5 , Jye-Yu C. Backlund 1 , Bernard Zinman 6 , Alan Jacobson 7 , Wanjie Sun 1 , John M. Lachin 1 , David M. Nathan 7 and for the DCCT/EDIC Research Group * 1 Biostatistics Center, George Washington University, Rockville, Maryland 2 University of Pittsburgh, Pittsburgh, Pennsylvania 3 Case Western Reserve University, Cleveland, Ohio 4 University of California, Irvine, California 5 Harbor UCLA (University of California, Los Angeles) Medical Center, Torrance, California 6 University of Toronto, Toronto, Canada 7 Harvard Medical School, Boston, Massachusetts Address correspondence to David M. Nathan MD, Diabetes Unit, Massachusetts General Hospital, 32 Fruit St., Boston, MA 02114-2698. E-mail: dnathan{at}partners.org . Reprint requests can be addressed to the DCCT/EDIC Research Group, Box NDIC/DCCT/EDIC, Bethesda, MD 20892 Abstract The Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up of the Diabetes Control and Complications Trial (DCCT) type 1 diabetes cohort, measured coronary artery calcification (CAC), an index of atherosclerosis, with computed tomography (CT) in 1,205 EDIC patients at ∼7–9 years after the end of the DCCT. We examined the influence of the 6.5 years of prior conventional versus intensive diabetes treatment during the DCCT, as well as the effects of cardiovascular disease risk factors, on CAC. The prevalences of CAC >0 and >200 Agatston units were 31.0 and 8.5%, respectively. Compared with the conventional treatment group, the intensive group had significantly lower geometric mean CAC scores and a lower prevalence of CAC >0 in the primary retinopathy prevention cohort, but not in the secondary intervention cohort, and a lower prevalence of CAC >200 in the combined cohorts. Waist-to-hip ratio, smoking, hypertension, and hypercholesterolemia, before or at the time of CT, were significantly associated with CAC in univariate and multivariate analyses. CAC was associated with mean HbA 1c (A1C) levels before enrollment, during the DCCT, and during the EDIC study. Prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced levels of A1C during the DCCT. CAC, coronary artery calcification CT, computed tomography CVD, cardiovascular disease DCCT, Diabetes Control and Complications Trial EDIC, Epidemiology of Diabetes Interventions and Complications IMT, intima-media thickness ROC, receiver operating characteristics Footnotes * * A complete list of individuals and institutions participating in the DCCT/EDIC Research Group appears in the appendix . The Writing Group of the DCCT/EDIC Research Group takes responsibility for the contents of this article. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 23, 2006. Received May 11, 2006. DIABETES

In a traditional pharmacokinetic (PK) bioequivalence (BE) study, a two‐way crossover study is conducted, PK parameters (namely the area under the time‐concentration curve [AUC] and the maximal concentration [Cmax]) are obtained by noncompartmental analysis (NCA), and the BE analysis is performed using the two one‐sided test (TOST) method. For ophthalmic drugs, however, only one sample of aqueous humor, in one eye, per eye can be obtained in each patient, which precludes the traditional BE analysis. To circumvent this issue, the U.S. Food and Drug Administration (FDA) has proposed an approach coupling NCA with either parametric or nonparametric bootstrap (NCA bootstrap). The model‐based TOST (MB‐TOST) has previously been proposed and evaluated successfully for various settings of sparse PK BE studies. In this paper, we evaluate, via simulations, MB‐TOST in the specific setting of single sample PK BE study and compare its performance to NCA bootstrap. We performed BE study simulations using a published PK model and parameter values and evaluated multiple scenarios, including study design (parallel or crossover), sampling times (5 or 10 spread across the dosing interval), and geometric mean ratio (of 0.8, 0.9, 1, and 1.25). Using the simulated structural PK model, MB‐TOST performed similarly to NCA bootstrap for AUC. For Cmax, the latter tended to be conservative and less powerful. Our research suggests that MB‐TOST may be considered as an alternative BE approach for single sample PK studies, provided that the PK model is correctly specified and the test drug has the same structural model as the reference drug.

Determining the stability of stored samples for assays that were not available at the time of original collection is problematic. To assess sample stability for a relatively new assay of glycated albumin (GA), we first measured GA in fresh samples and in samples stored for 19-23 years. We then compared the regression of the contemporaneous glycohemoglobin (Hb A(1c)) values against the GA results from fresh vs stored samples, reasoning that similar slopes and intercepts would provide strong, albeit indirect, support for the stability of the stored samples for GA measurements. We assayed 90 samples frozen for 19-23 years and 90 fresh samples from participants in the Diabetes Control and Complications trial cohort for GA. Hb A(1c) was measured contemporaneously in fresh samples at each time period. A single normal-errors linear model regressed the Hb A(1c) values on the GA, with an additional effect for collection period (fresh vs stored for GA) and the interaction of period and GA. Analysis of the regressions lines between GA and Hb A(1c) revealed intercepts (3.69 and 2.97 for the fresh and stored samples, respectively) and slopes (0.198 vs 0.187) that were not significantly different (P = 0.182 and P = 0.639, respectively). This simple approach can be used to assess the stability of stored samples in new assays. Samples stored for as long as 23 years are suitable for the GA assay.