Current state of biologic pharmacovigilance in the European Union: improvements are needed

Introduction: Pharmacovigilance is essential to monitoring the safety profiles of authorized medicines. Compared with small-molecule drugs, biological drugs are more complex, more susceptible to structural variability due to manufacturing processes, and have the potential to induce immune-related reactions, underscoring the importance of safety monitoring for these products. Although highly similar to reference products, biosimilars are not expected to be structurally identical. For these reasons, proper reporting of potential adverse drug reactions (ADRs) using distinguishable names and batch numbers is essential for accurate tracing of all biological drugs. To address the need for robust pharmacovigilance, the European Parliament and Council of the European Union provided legislation regarding pharmacovigilance of biologics in 2010.

Areas covered: This narrative review examines the current state of pharmacovigilance for biologics in the European Union (EU) and discusses relevant information on pharmacovigilance of biosimilars, the current EU pharmacovigilance system, and areas that could be improved.

Expert opinion: Although steps have been taken to improve pharmacovigilance of biologics in the EU, several enhancements can still be made, including additional training for healthcare professionals on ADR reporting, the use of 2D barcodes that enhance traceability, and an open discussion of potentially missed opportunities in the pharmacovigilance of biosimilars.     

Rapid Immunofluorescence Microscopy for Diagnosis of Melioidosis

An immunofluorescent (IF) method that detects Burkholderia pseudomallei in clinical specimens within 10 min was devised. The results of this rapid method and those of an existing IF method were prospectively compared with the culture results for 776 specimens from patients with suspected melioidosis. The sensitivities of both IF tests were 66%, and the specificities were 99.5 and 99.4%, respectively.     

复合树脂预热的研究现状和临床应用

复合树脂作为临床常用牙科充填材料存在耐磨性差、聚合收缩大和牙本质边缘适应性不佳等问题。近年有研究发现预热可以改善复合树脂的性能,本文就预热复合树脂对其单体转化率、边缘微渗漏、机械性能以及牙髓的影响等方面进行探讨,以供临床参考。     

Trachoma: 1985 update in Western Australia

Aboriginal preschool and school children were surveyed in the Eastern Goldfields Region and the Eastern Kimberley Region of Western Australia between 1979 and 1985. Statistics from these surveys show that there has been an apparent change in pattern of follicular trachoma since the National Trachoma and Eye Health Programme in some of the communities. The prevalence of follicular trachoma in the 0 to 9 year old age groups had declined from 26.4% in 1977 to 8.8% in 1984/1985 in the Eastern Goldfields and Red Centre combined (0.10 greater than p greater than 0.05). The prevalence reduction occurred in areas where there have been improvements in school hygiene and housing. The prevalence of cicatricial trachoma has also apparently declined from 65% in 1977 to 39% in 1985 in the Red Centre, from 39% in 1977 in the Eastern Goldfields to 21.7% in 1985, and from 58% in 1977 to 24.9% in 1985 in the Eastern Kimberley, Communities at risk were identified and recommendations made for frequency of continued screening, depending on age, distribution and location.     

Recurrent melioidosis in patients in northeast Thailand is frequently due to reinfection rather than relapse

Human melioidosis is associated with a high rate of recurrent disease, despite adequate antimicrobial treatment. Here, we define the rate of relapse versus the rate of reinfection in 116 patients with 123 episodes of recurrent melioidosis who were treated at Sappasithiprasong Hospital in Northeast Thailand between 1986 and 2005. Pulsed-field gel electrophoresis was performed on all isolates; isolates from primary and recurrent disease for a given patient different by one or more bands were examined by a sequence-based approach based on multilocus sequence typing. Overall, 92 episodes (75%) of recurrent disease were caused by the same strain (relapse) and 31 episodes (25%) were due to infection with a new strain (reinfection). The interval to recurrence differed between patients with relapse and reinfection; those with relapses had a median time to relapse of 228 days (range, 15 to 3,757 days; interquartile range [IQR], 99.5 to 608 days), while those with reinfection had a median time to reinfection of 823 days (range, 17 to 2,931 days; IQR, 453 to 1,211 days) (P = 0.0001). A total of 64 episodes (52%) occurred within 12 months of the primary infection. Relapse was responsible for 57 of 64 (89%) episodes of recurrent infection within the first year after primary disease, whereas relapse was responsible for 35 of 59 (59%) episodes after 1 year (P < 0.0001). Our data indicate that in this setting of endemicity, reinfection is responsible for one-quarter of recurrent cases. This finding has important implications for the clinical management of melioidosis patients and for antibiotic treatment studies that use recurrent disease as a marker for treatment failure.     

Exogenous Pubertal Induction by Oral versus Transdermal Estrogen Therapy

Hypogonadal adolescent girls need estrogen therapy for the induction of puberty. For years, oral conjugated estrogens have been used for this purpose, starting at a very low dose, with gradual increments over time, to allow for the maturation of the reproductive organs, in order to mimic physiologic conditions. Several concerns, mainly due to first pass through the liver, are manifest with oral estrogen therapy. With the advent of transdermal estrogens and its improved efficacy profile as well as reduced side effects, it seems reasonable to consider it for pubertal induction. The primary objective of this study was to compare and contrast oral versus transdermal estrogen with regard to metabolism and physiology and to review current available data on transdermal estrogens with respect to exogenous pubertal induction.     

Ultrasound-Guided Versus Landmark-Guided Local Corticosteroid Injection for Carpal Tunnel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objective

To review the literature and assess the comparative effectiveness of ultrasound-guided versus landmark-guided local corticosteroid injections in patients with carpal tunnel syndrome (CTS).

Clinical trial transparency update: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved in Europe in 2012

Background:

The objective of this study was to assess the timely disclosure of results of company-sponsored clinical trials related to all new medicines approved by the European Medicines Agency (EMA) during 2012. This is an extension of the previously reported study of trials related to all new medicines approved in Europe in 2009, 2010 and 2011, which found that over three-quarters of all these trials were disclosed within 12 months and almost 90% were disclosed by the end of the study.

Methods:

The methodology used was exactly as previously reported. Various publicly available information sources were searched for both clinical trial registration and disclosure of results. All completed company-sponsored trials related to each new medicine approved for marketing by the EMA in 2012, carried out in patients and recorded on a clinical trials registry and/or included in an EMA European Public Assessment Report (EPAR), were included. Information sources were searched between 1 May and 31 July 2014.

Outcome measures and results:

The main outcome measure was the proportion of trials for which results had been disclosed on a registry or in the scientific literature either within 12 months of the later of either first regulatory approval or trial completion, or by 31 July 2014 (end of survey). Of the completed trials associated with 23 new medicines licensed to 17 different companies in 2012, results of 90% (307/340) had been disclosed within 12 months, and results of 92% (312/340) had been disclosed by 31 July 2014.

Conclusions:

The disclosure rate within 12 months of 90% suggests the industry is now achieving disclosure in a timely manner more consistently than before. The overall disclosure rate at study end of 92% indicates that the improvement in transparency amongst company-sponsored trials has been maintained in the trials associated with new medicines approved in 2012.     

Surveillance of Artemisinin Resistance in Plasmodium falciparum in India Using the kelch13 Molecular Marker

Malaria treatment in Southeast Asia is threatened with the emergence of artemisinin-resistant Plasmodium falciparum. Genome association studies have strongly linked a locus on P. falciparum chromosome 13 to artemisinin resistance, and recently, mutations in the kelch13 propeller region (Pfk-13) were strongly linked to resistance. To date, this information has not been shown in Indian samples. Pfk-13 mutations were assessed in samples from efficacy studies of artemisinin combination treatments in India. Samples were PCR amplified and sequenced from codon 427 to 727. Out of 384 samples, nonsynonymous mutations in the propeller region were found in four patients from the northeastern states, but their presence did not correlate with ACT treatment failures. This is the first report of Pfk-13 point mutations from India. Further phenotyping and genotyping studies are required to assess the status of artemisinin resistance in this region.     

From the Cover: Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function

cAMP signaling in the brain mediates several higher order neural processes. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels directly bind cAMP through their cytoplasmic cyclic nucleotide binding domain (CNBD), thus playing a unique role in brain function. Neuronal HCN channels are also regulated by tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), an auxiliary subunit that antagonizes the effects of cAMP by interacting with the channel CNBD. To unravel the molecular mechanisms underlying the dual regulation of HCN channel activity by cAMP/TRIP8b, we determined the NMR solution structure of the HCN2 channel CNBD in the cAMP-free form and mapped on it the TRIP8b interaction site. We reconstruct here the full conformational changes induced by cAMP binding to the HCN channel CNBD. Our results show that TRIP8b does not compete with cAMP for the same binding region; rather, it exerts its inhibitory action through an allosteric mechanism, preventing the cAMP-induced conformational changes in the HCN channel CNBD.Hyperpolarization-activated cyclic nucleotide-gated (HCN1–4) channels are the molecular determinants of the h-current (I_h), which regulates critical neuronal properties, including membrane resting potential, dendritic excitability, and intrinsic rhythmicity (1). HCN channels are dually regulated by voltage and by binding of cAMP to the cyclic nucleotide binding domain (CNBD), which is found on the cytoplasmic C-terminal tail of the channel. The CNBD exerts a tonic inhibition on the channel pore, with the opening transition of the channel being allosterically coupled to the conformational changes in the CNBD induced by cAMP binding (2). Thus, the closed-to-open transition of the channel is thought to reflect the transition from the cAMP-free conformation to the cAMP-bound conformation of the CNBD, which stabilize, respectively, the closed and open states of the channel (2, 3). The C-linker, an α-helical folded domain that connects the CNBD to the pore region, conveys the regulation of channel gating from the CNBD to the pore (4–6). As a result of this allosteric mechanism, the binding of cAMP shifts the voltage dependence of the HCN channel opening to more positive potentials and increases maximal I_h at extreme negative voltages, where voltage gating is complete.In addition to cAMP, HCN channels in the brain are regulated by auxiliary proteins, such as TRIP8b, a cytosolic β-subunit of neuronal HCN channels, which inhibits channel activation by antagonizing the effects of cAMP (7–9). We have previously shown that TRIP8b_core, an 80-aa sequence located in the TRIP8b protein core that directly interacts with the C-linker/CNBD region of HCN channels, is necessary and sufficient to prevent all of the effects of cAMP on the channel (10, 11). TRIP8b_core decreases both the sensitivity of the channel to cAMP [half maximal concentration (k_1/2)] and the efficacy of cAMP in inducing channel opening [half activation voltage (V_1/2)]; conversely, cAMP binding inhibits these actions of TRIP8b. These mutually antagonistic effects are well described by a cyclic allosteric model in which TRIP8b binding reduces the affinity of the channel for cAMP, with the affinity of the open state for cAMP being reduced to a greater extent than the cAMP affinity of the closed state (11).A second important action of TRIP8b is to reduce maximal current through HCN channels in the absence of cAMP (11). As a consequence, application of cAMP produces a larger increase in maximal I_h in the presence of TRIP8b than in its absence. The observation that TRIP8b exerts opposing influences on the two major actions of cAMP on HCN channel function, namely, reduces the effect of cAMP to shift the voltage dependence of channel gating but enhances the effect of cAMP to increase maximal current, has important implications for the ability of cAMP to modulate neuronal excitability in vivo. Thus, the relative extent by which neuromodulatory transmitters alter maximal I_h or shift the voltage dependence of HCN channel gating can vary widely among distinct classes of neurons (12–14). The differential expression of TRIP8b may provide a mechanistic explanation for this finding, because in neurons with high levels of TRIP8b expression, cAMP will exert a larger action to enhance maximal current, and a smaller action to alter the voltage dependence of channel gating, compared with neurons in which TRIP8b expression is low. Such fine-tuning broadens the range of physiological actions that cAMP can exert to modulate neuronal firing.In the present study, we address the structural basis for the mutually antagonistic effects of cAMP and TRIP8b on HCN channel function. Although our previous biochemical and electrophysiological data strongly support the hypothesis that TRIP8b and cAMP binding sites do not overlap, direct structural information on the TRIP8b–CNBD complex is required to validate the allosteric antagonism model of interaction between the two ligands. A plausible hypothesis for the antagonistic effect of TRIP8b and cAMP is that each of the two ligands stabilizes the CNBD in a conformation that decreases the affinity for the other. To test this hypothesis, we first generated the 3D structure of the cAMP-free HCN2 channel CNBD using solution NMR spectroscopy and then characterized its interaction with the TRIP8b_core fragment. By comparing the cAMP-free with the available cAMP-bound HCN2 channel CNBD structure (15, 16), we reconstruct the full conformational changes induced by cAMP binding, revealing critical transitions occurring in the P- and C-helices of the CNBD, and further highlighting the role of the N-terminal helical bundle in transducing the movements of the CNBD to the channel pore. We next identify, through NMR titration, site-directed mutagenesis, and biochemical interaction assays, the binding site of TRIP8b_core on the cAMP-free form of the HCN2 channel CNBD. Our results demonstrate that cAMP and TRIP8b do not directly compete for the same binding region and support a model of mutual allosteric inhibition between cAMP and TRIP8b. Finally, our results clarify the mechanism by which TRIP8b antagonizes the effect of cAMP on channel gating: TRIP8b directly interacts with two mobile elements that drive the ligand-induced conformational changes in the CNBD. TRIP8b binding to the CNBD therefore prevents the cAMP-induced transition and stabilizes the channel in the cAMP-free conformation.