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.     

Impact and Predictors of Noncircular Left Ventricular Outflow Tract Shapes on Estimating Aortic Stenosis Severity by Means of Continuity Equations

Determining aortic stenosis (AS) severity is clinically important. Calculating aortic valve (AV) area by means of the continuity equation assumes a circular left ventricular outflow tract (LVOT). The full impact of this assumption in calculating AV area is unknown. Predictors of noncircular LVOT shape in patients with AS are undefined.In 109 adult patients with AS who underwent multiplanar transesophageal echocardiography, we calculated AV area by means of the standard continuity method and by a modified method involving planimetric LVOT area.We found 54 circular, 37 horizontal-oval, 8 vertical-oval, and 10 irregular LVOTs. Area derived by direct planimetry correlated better with the modified than the standard continuity method (r=0.89 vs r=0.85; both P=0.0001). Valve areas of patients with mild, moderate, or severe AS by planimetry were more often mischaracterized with use of the standard than modified method (29 vs 18; P <0.0001). Horizontal-oval AV area derived by planimetry (1.28 ± 0.55 cm²) was underestimated by the standard method (1.05 ± 0.47 cm²; P=0.001), but not by the modified method. Congenital AV morphology and low cardiac index were the only multivariate predictors of horizontal-oval shape. Low cardiac index was the only predictor of noncircular shape.More than half our patients with AS had noncircular LVOTs. Using the modified method reduces mischaracterizations of AS severity. Congenital AV morphology and low cardiac index predict horizontal-oval or noncircular shape. These data suggest the value of direct LVOT measurement to calculate AS severity in patients who have congenital AV or a low cardiac index.     

Robotic surgery does not affect upstaging of T1 renal masses

Partial nephrectomy is the mainstay of treatment for localized kidney cancer. A proportion of patients are upstaged post-operatively to locally advanced di     

Alterations in hepatic microsomal mixed-function oxidase system during different levels of food restriction in adult male and female rats

Wistar strain adult male and female rats were given 25, 50 and 75% less food than an ad libitum-fed group of rats for 45 d and the effects of food restriction on hepatic drug metabolizing enzymes, microsomal electron transport components, NADPH-dependent lipid peroxidation and glutathione-S-transferase activities were studied. Compared to ad libitum-fed controls, the cytochrome P-450 levels were higher in food restricted male rats, while they were lower in food restricted females. The activities of NADPH cytochrome c reductase were lower in food restricted females than in ad libitum-fed controls. The activities of drug metabolizing enzymes, aminopyrine N-demethylase and acetanilide hydroxylase were higher in food restricted males, whereas in food restricted females these activities were lower than in respective groups fed ad libitum. Microsomal, NADPH-dependent lipid peroxidation was higher in 25 and 50% food restricted females while in 50 and 75% food restricted males it was lower than in ad libitum controls of the same sex. The cytosolic glutathione-S-transferase activities were lower in food restricted rats of both the sexes than in the same sexed controls. Another group of male and female rats were given 75% less food than the ad libitum-fed rats and refed for 3 d prior to killing. Here also, the effects of restriction were different between sexes. It is concluded that hepatic microsomal mixed-function oxidase system (MFOS) is altered due to feed restriction and food restriction followed by refeeding, in a sex-related manner.     

Circulating immune complex levels in patients with schistosomiasis and complications

Circulating immune complexes (CIC), adult schistosome antibody, and total immunoglobulin concentrations were estimated in sera from 35 chronic Schistosoma mansoni patients with different infection intensities and different pathological complications. High CIC levels were present in about one-third (10/35) of the sera. Most of the patients (9/10) with elevated CIC levels also had hepatomegaly or hepatosplenomegaly. This finding is significant in the pathogenesis of schistosomal liver fibrosis and may also apply to other liver diseases, especially cirrhosis. No correlation was found between infection intensity as judged by stool egg counts and CIC levels. A reverse relationship was observed between the level of anti-adult worm IgG and CIC levels. CIC levels were elevated within 7 and 28 days after treatment in most patients. Hypergammaglobulinaemia was detected in most sera.     

Assessment of the durability of robot-assisted laparoscopic sacrocolpopexy for treatment of vaginal vault prolapse

Transabdominal sacrocolpopexy has been shown, in multiple long-term studies of its success and durability, to be the definitive treatment option for post-hysterectomy vaginal vault prolapse. It is, however, associated with greater morbidity than vaginal repair. We describe a minimally invasive technique for vaginal vault prolapse repair and present our experience with a minimum of one-year follow-up. The surgical technique involves five laparoscopic ports—three for the da Vinci robot and two for the assistant. After appropriate dissection a polypropylene mesh is attached to the sacral promontory and to the vaginal apex by use of Gore-Tex sutures. The mesh material is then covered by the peritoneum. Patient analysis focused on complications, urinary continence, patient satisfaction, and morbidity, with a minimum of 12 months follow-up. Forty-two patients with post-hysterectomy vaginal vault prolapse underwent robot-assisted laparoscopic sacrocolpopexy at our institute and 35 have a minimum of 12 months follow-up, with a mean follow-up of 36 months (range 12–48) in the group. Mean age was 67 (47–83) years and mean operating time was 3.1 (2.15–4.75) h for the entire cohort. All but one patient were discharged home on postoperative day one; one patient left on postoperative day two. One developed recurrent grade three rectocele, one had recurrent vault prolapse, and two suffered from vaginal extrusion of mesh. All patients were satisfied with their outcome. The robot-assisted laparoscopic sacrocolpopexy is a minimally invasive technique for vaginal vault prolapse repair, combining the advantages of open sacrocolpopexy with the reduced morbidity of laparoscopy. We observed reduced hospital stay, low occurrence of complications, and high patient satisfaction, with a minimum of 1-year follow-up. Most importantly, the long-term results of the robotic repair are similar to those of open repair, but with significantly less morbidity.