Advanced Therapy medicinal products for autologous chondrocytes and comparison of regulatory systems in target countries.

Introduction: Autologous chondrocytes (ACs) are Human cell/tissue-based products used for the treatment of joint cartilage defects. Regulatory agencies have established regulations related to ACs to ensure their safety and efficacy. This study investigated the status and characteristics of ACs approved worldwide. Furthermore, the AC-related regulations were compared by country to provide reference materials for the development of product approval procedures. Methods: This study reviewed the current status of global AC products over the past 20 years by referring to the AC approval list provided on the International Society for Cell & Gene Therapy (ISCT) website. Based on the review report provided by the regulatory agencies that approved the products, major nonclinical/clinical data and product characteristics were reviewed; and the classification and definition of ACs and the approval review procedures were compared through the regulatory agencies' websites. The development status of ACs was also analyzed using a clinical trial registration site. Results: Eight ACs were approved during the study period in Europe, the US, Japan, Australia, and Korea. Two products were withdrawn owing to marketability problems. Human cell/tissue-based products in each country are classified and defined distinguished from biopharmaceuticals, but the approval process for both products is the same. The approval period differs by country, with an average of 282.4 days and the shortest being in Korea (115 days). On Clinical Trials.gov, we screened 46 clinical trials related to ACs, which were conducted in Europe (41%), Korea (20%), and the US (17%). The knee accounted for the largest portion of the indication (37/46, 80%), followed by the ankle or hip joints. Measurements of improvements in function and pain were the main endpoints used to evaluate the efficacy of ACs. Observational studies were conducted to confirm the long-term safety of these products. Conclusions: This is the first study comparing the current status and characteristics of globally approved AC products, as well as their classification and definition by country. In the past two decades, clinical trials have been conducted on the application of ACs in tissue engineering to treat joint cartilage defects. ACs are expected to be used for the treatment of cartilage defect diseases.

Trends in Ambulatory Analgesic Usage after Myocardial Infarction: A Nationwide Cross-Sectional Study of Real-World Data.

Although current guidelines for myocardial infarction (MI) recommend caution in using non-steroidal anti-inflammatory drugs (NSAIDs), real-world studies of ambulatory settings are rare. This study aimed to explore the patterns and trends of analgesic prescriptions (especially NSAIDs) among patients with a history of MI in ambulatory care settings in Korea. We analyzed real-world data from the Korea National Health Insurance Service database. Patients aged 20 years or older hospitalized with incident MI were identified between January 2007 and December 2015. Ambulatory analgesics were administered after discharge from incident hospitalization for MI, and annual trends in the prescriptions of individual analgesics were evaluated. Among the 93,597 patients with incident MI, 75,131 (80.3%) received a total of 2,081,705 ambulatory analgesic prescriptions. Prescriptions were mainly issued at primary care clinics (80.3%). Analgesics were most frequently prescribed for musculoskeletal diseases (often NSAIDs, 70.7%); aceclofenac (13.7%) and diclofenac injection (9.4%) were the frequently used NSAIDs. Additionally, significant changes were observed in the trends for some analgesics, such as loxoprofen. This study suggested that NSAIDs are commonly prescribed to patients with a history of MI. Future real-world studies are needed to elucidate the drug-disease interactions of NSAIDs prescribed after MI, especially for patients with musculoskeletal diseases.

Protein Stability of Pyruvate Kinase Isozyme M2 Is Mediated by HAUSP.

The ubiquitin-proteasome system (UPS) is responsible for proteasomal degradation, regulating the half-life of the protein. Deubiquitinating enzymes (DUBs) are components of the UPS and inhibit degradation by removing ubiquitins from protein substrates. Herpesvirus-associated ubiquitin-specific protease (HAUSP) is one such deubiquitinating enzyme and has been closely associated with tumor development. In a previous study, we isolated putative HAUSP binding substrates by two-dimensional electrophoresis (2-DE) and identified them by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF/MS) analysis. The analysis showed that pyruvate kinase isoenzyme M2 (PKM2) was likely to be one of the substrates for HAUSP. Further study revealed that PKM2 binds to HAUSP, confirming the interaction between these proteins, and that PKM2 possesses the putative HAUSP binding motif, E or P/AXXS. Therefore, we generated mutant forms of PKM2 S57A, S97A, and S346A, and found that S57A had less binding affinity. In a previous study, we demonstrated that PKM2 is regulated by the UPS, and that HAUSP- as a DUB-acted on PKM2, thus siRNA for HAUSP increases PKM2 ubiquitination. Our present study newly highlights the direct interaction between HAUSP and PKM2.

The clinical trial transparency in oncology significantly increased over the recent years.

OBJECTIVE: Persistent efforts have been made to promote clinical trial transparency, which included encouraging trial registration and prospective registration, as well as protocol disclosure. This study aims to analyze the extent of registration, prospective registration and protocol disclosure in oncology clinical trials and their changing trends. STUDY DESIGN AND SETTING: All phase II and phase III oncology clinical trials published in 5 major journals, the Annals of Oncology, the Journal of Clinical Oncology, JAMA Oncology, The Lancet Oncology, and The New England Journal of Medicine, between January 2013 and December 2017, were included. Data on trial characteristics as well as registration status and availability of protocol and its location were collected. RESULTS: In total, 625 articles were included, 92% were registered, of which 76% were prospectively registered. Overall, 27% provided protocols. Increasing trends were observed in registration, prospective registration, and protocol disclosure (all P < 0.001). Studies with enrollment number larger than median number were more likely to be registered (adjusted odds ratio (aOR), 3.14 [95% confidence interval (CI), 1.21-8.15]) and to provide protocols (aOR, 3.84 [95% CI, 2.24-6.57]) than those with smaller enrollment number. Studies with nonindustry funding was less likely to be prospectively registered (aOR, 0.37 [95% CI, 0.25-0.55]) but more likely to provide protocols (aOR, 1.69 [95% CI, 1.13-2.52]) than those with industry funding only. CONCLUSION: Although the rates of registration, prospective registration, and protocol disclosure of oncology trials have significantly increased over the years, there is still room for improvement.

Steroid phobia among general users of topical steroids: a cross-sectional nationwide survey.

OBJECTIVE: The aim of this study was to assess steroid phobia among general users of topical corticosteroids and to analyze factors associated with steroid phobia. METHODS: A cross-sectional nationwide survey was conducted using an online panel with participants stratified by age, sex, and region. Those aged 18-65 years with experience of topical steroid use within the past 1 year were included. RESULTS: Of the 3000 respondents included, 929 (31%) had steroid phobia. Among those with steroid phobia, 322 (35%) reported that their fear developed after obtaining information from the media. Weight gain, asthma, skin thinning, growth stunting, and skin aging were the side effects cited as the main reasons behind development of steroid phobia. Female respondents and those with experience of the side effects of topical steroids were more likely to have steroid phobia, while those who obtained information on topical steroid use from a healthcare professional were less likely to have steroid phobia. CONCLUSIONS: Steroid phobia among general users of topical steroids appears to be relatively high despite most of them being non-chronic topical steroid users. Healthcare professionals should not refrain from counseling patients, but instead actively address the issues leading to fears in patients.

Strategic inclusion of regions in multiregional clinical trials.

BACKGROUND: With the recent publication of the International Conference on Harmonisation E17 guideline and major reforms in China underway, the platform for clinical trial conduct is expected to change. This study aims to assess the strategic inclusion of regions in clinical trials and its change in trends over the past decade. METHODS: The ClinicalTrials.gov registry was searched for clinical trials registered by the top 10 pharmaceutical companies between 1 January 2008 and 31 December 2017. Extracted data included phase, disease type, intervention, study start year, and region. Trial type was classified as either a local study or a multiregional clinical trial as per the International Conference on Harmonisation E17 guideline. RESULTS: Of 2488 phase I, 1855 phase II, and 1999 phase III trials included, the majority of phase I trials were local studies (76.8%), while the majority of phase II (66.0%) and phase III (72.2%) trials were multiregional clinical trials. The proportion of multiregional clinical trials showed an increasing trend for all phases ( p < 0.01). Although North America and Europe remained the main locations, increasing trends of inclusion of other regions, such as East Asia, were noted. CONCLUSION: Globalization of drug development is evident with the increasing trend of multiregional clinical trial. Regulatory authorities as well as the pharmaceutical industry should prepare for the evolving setting of clinical research and problems that can arise from these changes.

Complaints addressed by regulatory authorities in drug advertising targeted at consumers: Cases across three, different countries.

BACKGROUND: Misleading advertisements can affect behavior of both consumers and prescribers and may lead to inappropriate use of medications. OBJECTIVE: To analyze the complaints upheld by regulatory authorities in the United Kingdom, Canada, and Australia regarding pharmaceutical advertising directed at consumers. METHODS: Complaints addressed between January 2014 and June 2017 were retrieved from the websites of regulatory authorities. Complaints addressed by self-regulatory bodies were not included due to the poor availability of data. RESULTS: Sixty complaints, 374 complaints, and 223 complaints from the United Kingdom, Canada, and Australia, respectively, were analyzed. In the United Kingdom, the most frequent type of violation was advertising of prescription drugs (70.5%); most of these violations involved botulinum toxin. In Canada, advertising on online media was more likely to be associated with prescription drugs than that on traditional media (P < 0.001). In Australia, advertising of prescription drugs accounted for less than 10% of complaints, but all were associated with online media. CONCLUSIONS: In countries where direct-to-consumer advertising of prescription drugs is prohibited, regulatory authorities may need to devise further strategies to safeguard the public as this is an unresolved issue and is predicted to become more problematic with the increased use of online media.

Assessing reporting quality of randomized controlled trial abstracts in psychiatry: Adherence to CONSORT for abstracts: A systematic review.

BACKGROUND: Reporting quality of randomized controlled trial (RCT) abstracts is important as readers often make their first judgments based on the abstracts. This study aims to assess the reporting quality of psychiatry RCT abstracts published before and after the release of Consolidated Standards of Reporting Trials for Abstracts (CONSORT-A) guidelines. METHODS: MEDLINE/PubMed search was conducted to identify psychiatric RCTs published during 2005-2007 (pre-CONSORT) and 2012-2014 (post-CONSORT). Two independent reviewers assessed abstracts using a 18-point overall quality score (OQS) based on the CONSORT-A guidelines. Linear regression analysis was conducted to analyze factors associated with reporting quality. RESULTS: Among 1,927 relevant articles, 285 pre-CONSORT and 214 post-CONSORT psychiatric RCT abstracts were included for analysis. The mean OQS improved from 6.9 (range: 3-13; 95% confidence interval (CI): 6.7-7.2) to 8.2 (range: 4-16; 95% CI: 7.8-8.5) after the CONSORT-A guidelines. Despite improvement, methods of randomization, allocation concealment, and funding source remained to be insufficiently reported (<5%) even after the release of CONSORT-A. High-impact general medical journals, multicenter design, positive outcome, and structured abstracts were associated with better reporting quality. CONCLUSIONS: The reporting quality in psychiatric RCT abstracts, although improved, remains suboptimal. To improve reporting quality of psychiatry RCT abstracts, greater efforts by both investigators and journal editors are required to enhance better adherence to the CONSORT-A guidelines.

Pediatric fluoroquinolone prescription in South Korea before and after a regulatory intervention: A nationwide study, 2007-2015.

OBJECTIVE: To investigate the impact of national implementation of age restriction on fluoroquinolone prescription in children and adolescents. METHODS: Data collected from the database of Health Insurance Review and Assessment Service in South Korea, a national health insurance system to analyze fluoroquinolone prescribing practice in children and adolescents younger than 18 years, between 2007 and 2015. The age restriction was implemented in December 2009. The annual prescription rate of FQ per 100,000 person-years was calculated and an autoregressive model was used to predict the prescription pattern if an intervention had not occurred. RESULTS: A total of 505,859 children received systemic fluoroquinolone during the study period-297,054 ciprofloxacin, and 208,805 levofloxacin. After implementation of the drug utilization review program, the annual prescription rate for ciprofloxacin declined by 97.5% (from 840 to 21 per 100,000 person-years, P < 0.001), and for levofloxacin by 96.4% (from 598 to 11 per 100,000 person-years, P < 0.001). The decline was more dramatic in the outpatient setting than in the inpatient setting for both drugs. CONCLUSION: The dramatic and sustained decline in prescription number and change in prescription pattern after the regulatory action suggests that the implementation under drug utilization review program was successful in controlling excessive and inappropriate use of fluoroquinolones in children, possibly guiding towards more judicious and selective prescription behavior.

Boronate-functionalized hydrogel as a novel biosensing interface for the glycated hemoglobin A1c (HbA1c) based on the competitive binding with signaling glycoprotein.

According to recent increases in public healthcare costs associated with diabetes mellitus, the development of new glycemic monitoring techniques based on the biosensing of glycated hemoglobin A1c (HbA1c), a promising long-term glycemic biomarker, has become a major challenge. In the development of HbA1c biosensors for point-of-care applications, the selection of an effective biorecognition layer that provides a high reaction yield and specificity toward HbA1c is regarded as the most significant issue. To address this, we developed a novel HbA1c biosensing interfacial material by the integration of boronate hydrogel with glass fiber membrane. In the present study, a new boronate-functionalized hydrogel was designed and spatio-selectively photopolymerized on a hydrophilic glass fiber membrane by using N-hydroxyethyl acrylamide, 3-(acrylamido)phenylboronic acid, and bis(N,N'-methylene-bis-acrylamide). Using this approach, the boronic acid group, which specifically recognizes the cis-diol residue of glucose on the HbA1c molecule, can be three-dimensionally coated on the surface of the glass fiber network with a high density. Because this network structure of boronate hydrogel-grafted fibers enables capillary-driven fluid control, facile HbA1c biosensing in a lateral flow assay concept could be accomplished. On the proposed HbA1c biosensing interface, various concentrations of HbA1c (5-15%) in blood-originated samples were sensitively measured by a colorimetric assay using horseradish peroxidase, a glycoenzyme can generate chromogenic signal after the competitive binding against HbA1c to the boronic acid residues. Based on the demonstrated advantages of boronate hydrogel-modified membrane including high analytical performance, easy operation, and cost-effectiveness, we expect that the proposed biorecognition interfacial material can be applied not only to point-of-care HbA1c biosensors, but also to the quantitative analysis of other glycoprotein biomarkers.

Effect of parity on bone mineral density: A systematic review and meta-analysis.

INTRODUCTION: Parity has been suggested as a possible factor affecting bone health in women. However, study results on its association with bone mineral density are conflicting. METHODS: PubMed, EMBASE, the Cochrane Library, and Korean online databases were searched using the terms "parity" and "bone mineral density", in May 2016. Two independent reviewers extracted the mean and standard deviation of bone mineral density measurements of the femoral neck, spine, and total hip in nulliparous and parous healthy women. RESULTS: Among the initial 10,146 studies, 10 articles comprising 24,771 women met the inclusion criteria. The overall effect of parity on bone mineral density was positive (mean difference=5.97mg/cm2; 95% CI 2.37 to 9.57; P=0.001). The effect appears site-specific as parity was not significantly associated with the bone mineral density of the femoral neck (P=0.09) and lumbar spine (P=0.17), but parous women had significantly higher bone mineral density of the total hip compared to nulliparous women (mean difference=5.98mg/cm2; 95% CI 1.72 to 10.24; P=0.006). No obvious heterogeneity existed among the included studies (femoral neck I2=0%; spine I2=31%; total hip I2=0%). CONCLUSION: Parity has a positive effect on bone in healthy, community-dwelling women and its effect appears site-specific.

The significance of the trial outcome was associated with publication rate and time to publication.

OBJECTIVES: This study aims to comprehensively assess the publication of clinical trial results and factors associated with their publication. STUDY DESIGN AND SETTING: Phase II and III trials of advanced breast cancer registered on ClinicalTrials.gov between October 1, 2000, and September 30, 2012, were identified. Publications were searched by using PubMed and reviewing those listed on the registry site. The main outcomes were publication rate, public availability of results, and time to publication. RESULTS: Of 352 phase II and 74 phase III trials, 12.5% and 31.1% were published, whereas 46.9% and 58.1% had publicly available results, respectively. Compared to those with significant results, studies with nonsignificant results had delays in time to publication (P < 0.001). Even after adjusting for funding source and phase type, the significance of study outcomes was a significant factor that affected time to publication (hazard ratio = 6.02; 95% confidence interval: 3.59, 10.07; P < 0.001), with trials with significant outcomes taking less time to publish than those with nonsignificant outcomes. CONCLUSION: Underreporting of results and nonpublication or delays in the publication of negative results were identified in registered trials of advanced breast cancer. Thus, further initiatives appear necessary to urgently address such publication bias.

Trends in endpoint selection in clinical trials of advanced breast cancer.

PURPOSE: The selection of appropriate endpoints is crucial for the evaluation of clinical benefits and approval of novel anticancer agents. To our knowledge, this is the first study to evaluate endpoint selection and the shift in trends in phase II and phase III trials of advanced breast cancer treatment. METHODS: All phase II and phase III trials of advanced breast cancer registered in the ClinicalTrials.gov registry between October 2000 and September 2012 were included in our study. Two study periods were considered for comparison: October 2000 to September 2007 (cohort A) and October 2007 to September 2012 (cohort B). Information on primary and secondary outcome measures, as well as trial characteristics, was extracted by two independent reviewers. RESULTS: Of the 398 phase II and 120 phase III trials, the most frequently intended primary endpoint was progression-free survival (phase II: 28.1 %; phase III: 50.0 %). For phase II trials, a shifting trend in primary outcome was observed from cohort A to cohort B: the use of objective response rate, the most frequently intended primary outcome, significantly declined (cohort A: 60.6 %; cohort B: 39.0 %; P < 0.001), while the use of progression-free survival significantly increased (cohort A: 35.9 %; cohort B: 66.1 %; P < 0.001). CONCLUSIONS: Progression-free survival is the most frequently intended primary outcome measure in phase II and phase III trials of advanced breast cancer treatment, with a shifting trend observed from objective response rate to progression-free survival in phase II trials.

Bioelectrocatalytic detection of glycated hemoglobin (HbA1c) based on the competitive binding of target and signaling glycoproteins to a boronate-modified surface.

We developed an electrochemical glycated hemoglobin (HbA(1c)) biosensor for diagnosing diabetes in whole human blood based on the competitive binding reaction of glycated proteins. Until now, no studies have reported a simple and accurate electrochemical biosensor for the quantification of HbA(1c) in whole blood. This is because it is very difficult to correctly distinguish HbA(1c) from large amounts of hemoglobin and other components in whole blood. To detect glycated hemoglobin, we used electrodes modified with boronic acid, which forms a covalent bond between its diol group and the cis-diol group of the carbohydrate moiety of glycated proteins. For accurate HbA(1c) biosensing, we first removed blood components (except for hemoglobin) such as glycated proteins and blood glucose as they interfere with the boronate-based HbA(1c) competition analysis by reacting with the boronate-modified surface via a cis-diol interaction. After hemoglobin separation, target HbA(1c) and GOx at a predetermined concentration were reacted through a competition onto the boronate-modified electrode, allowing HbA(1c) to be detected linearly within a range of 4.5-15% of the separated hemoglobin sample (HbA(1c)/total hemoglobin). This range covers the required clinical reference range of diabetes mellitus. Hence, the proposed method can be used for measuring %HbA(1c) in whole human blood, and can also be applied to measuring the concentration of various glycated proteins that contain peripheral sugar groups.

Chip-based cartilage oligomeric matrix protein detection in serum and synovial fluid for osteoarthritis diagnosis.

We have developed a method to detect cartilage oligomeric matrix protein (COMP) as a specific biomarker of osteoarthritis (OA). In pathological conditions of the cartilage, COMP is released first into the synovial fluid (SF) and from there into the blood. Thus, measurement of COMP in the blood and SF facilitates OA diagnosis. To determine COMP, we developed a fluoro-microbead guiding chip (FMGC)-based immunoassay. The FMGC has four immunoreactive regions, each with five patterns, to allow multiple assays. A COMP-specific capture antibody was immobilized to the FMGC surface to create a self-assembled interfacial layer. SF or serum samples from patients with OA possessing the target COMP were applied to the COMP-sensing monolayer. To generate binding signal, COMP detection antibody-conjugated fluoro-microbeads were applied and the numbers of fluoro-microbeads bound specifically were counted to determine COMP concentrations. This FMGC-based immunoassay clearly distinguished immunospecific from nonspecific binding by comparing optical signals from inside and outside of the patterns. The optical signals showed linear correlations with serum and SF COMP concentrations. Optical detection and quantification of COMP using fluorescence microscopy correlated well with results from commercial enzyme-linked immunosorbent assay (ELISA). This FMGC-based immunoassay offers a new approach for detecting a clinically relevant biomarker for OA in human blood and SF.

Multienzyme-modified biosensing surface for the electrochemical analysis of aspartate transaminase and alanine transaminase in human plasma.

We investigated the electrochemical detection of aspartate transaminase (AST) and alanine transaminase (ALT) by using a multienzyme-modified electrode surface. Determination of the activities of transaminases in human serum is clinically significant because their concentrations and ratios indicate the presence of hepatic diseases or myocardial dysfunction. For electrochemical detection of AST and ALT, enzymes that participate in the reaction mechanism of AST and ALT, such as pyruvate oxidase (POX) and oxaloacetate decarboxylase, were immobilized on an electrode surface by using an amine-reactive self-assembled monolayer and a homobifunctional cross-linker. In the presence of suitable substrates such as L-aspartate (L-alanine) and α-ketoglutarate, AST and ALT generate pyruvate as an enzymatic end product. To determine the activities of AST and ALT, electroanalyses of pyruvate were conducted using a POX and ferrocenemethanol electron shuttle. Anodically generated oxidative currents from multienzyme-mediated reactions were correlated to AST and ALT levels in human plasma. On the basis of the electrochemical analysis, we obtained calibration results for AST and ALT concentrations from 7.5 to 720 units/L in human plasma-based samples, covering the required clinical detection range.

A fluoro-microbead guiding chip for simple and quantifiable immunoassay of cardiac troponin I (cTnI).

We have developed a fluoro-microbead guiding chip (FMGC) to perform an optical immunoassay of cardiac troponin I (cTnI). The plasma marker protein cTnI is the currently preferred marker to use for a definitive diagnosis and prognosis of myocardial infarction. The FMGC has four immunoreaction regions on a silicon oxide substrate, with five gold patterns imprinted on each region for multiple simultaneous assays. The FMGC assay clearly distinguished immunospecific binding from nonspecific binding by comparing optical signals from inside and outside of the patterns. To detect cTnI, a sandwich immunoassay was performed using antibody-tagged fluoro-microbeads. The cTnI-specific capture antibody was conjugated to the FMGC surface by reaction with 3-3'-dithiobis-propionic acid N-hydroxysuccinimide ester to create a self-assembling antigen-sensing monolayer (DTSP SAM) on the chip. A sample containing cTnI was applied to the antigen-sensing monolayer and allowed to react. To generate a binding signal, a cTnI detection antibody-linked fluoro-microbead preparation was added. The cTnI concentration in a sample was determined by counting the number of biospecifically bound fluoro-microbeads on the corresponding five patterns on the FMGC. The optical signal showed a linear correlation with cTnI concentrations in plasma samples containing from 3.4 pM to 3.4 nM (0.1-100 ng/ml) cTnI. The sensitivity of cTnI detection could be increased by reducing the non-specific binding of the beads to the antigen-sensing surfaces of the chip. Optical detection and quantification of binding by fluorescence microscopy gave results that correlated well with results from a commercial ELISA for cTnI in human plasma. Based on these findings, we propose that the FMGC-based immunoassay system may be adapted to detect and quantify a variety of clinically important targets in human samples.