An updated meta-analysis comparing the efficacy and safety of biosimilar medicinal products to the original follitropin alfa.

INTRODUCTION: The aim of this study was to provide an updated meta-analysis assessing the therapeutic equivalence between follitropin alfa biosimilars and the reference medication in women undergoing assisted reproductive technologies (ART). EVIDENCE ACQUISITION: The studies included in the analysis were pooled together in order to estimate the log odds ratio (OR) for binary outcomes and the mean difference (MD) for continuous outcomes along with the corresponding 95% confidence intervals (CI) by using a random effects model. The heterogeneity between the studies was evaluated with the Higgins and χ2 tests. EVIDENCE SYNTHESIS: No differences were found concerning the number of oocytes retrieved at ovum pick-up, the primary endpoint recommended by the European Medicines Agency (EMA) (MD -0.04 CI [-0.78, 0.71], P=0.92). A significantly higher clinical pregnancy rate (OR 0.70 CI [0.53, 0.93], P=0.01) was observed in the reference product group in comparison to the biosimilar follitropin alfa, whereas no statistically significant differences were found for biochemical pregnancy rate, take home baby rate, total follitropin alfa dose, duration of stimulation, and ovarian hyperstimulation syndrome risk. CONCLUSIONS: The non-inferiority of biosimilar formulations in comparison to the reference product, with respect to number of oocytes retrieved at ovum pick-up, was shown.

Density estimation for circular data observed with errors.

Until now the problem of estimating circular densities when data are observed with errors has been mainly treated by Fourier series methods. We propose kernel-based estimators exhibiting simple construction and easy implementation. Specifically, we consider three different approaches: the first one is based on the equivalence between kernel estimators using data corrupted with different levels of error. This proposal appears to be totally unexplored, despite its potential for application also in the Euclidean setting. The second approach relies on estimators whose weight functions are circular deconvolution kernels. Due to the periodicity of the involved densities, it requires ad hoc mathematical tools. Finally, the third one is based on the idea of correcting extra bias of kernel estimators which use contaminated data and is essentially an adaptation of the standard theory to the circular case. For all the proposed estimators, we derive asymptotic properties, provide some simulation results, and also discuss some possible generalizations and extensions. Real data case studies are also included.

Efficacy and safety of follitropin alpha biosimilars compared to their reference product: a Meta-analysis.

AIM: Recently published multicentre, randomized phase III studies suggested the therapeutic equivalence of biosimilar follitropin alpha medicaments compared to the reference product. The aim of this meta-analysis is to pool the results of the three phase III trials in order to provide an overall analysis about the clinical bioequivalence between biosimilars and the originator. METHODS: The studies included in the analysis were pooled together in order to estimate the log odds ratio (OR) for binary outcomes and the weighted mean difference (WMD) for continuous outcomes along with the corresponding 95% confidence intervals (CI) by using a random effects model. The heterogeneity between the studies was evaluated with the Higgins and Chi-square tests. RESULTS: No differences were found in term of number of oocytes retrieved at ovum pick-up, the primary endpoint recommended by the European Medicines Agency. No statistical differences were also found for biochemical pregnancy rate, take home baby rate, total follitropin alpha dose, duration of stimulation, and OHSS risk. A significantly higher clinical pregnancy rate (p = .03) was observed in the originator group in comparison to the biosimilar follitropin alpha. CONCLUSION: Biosimilar follitropin alpha medicaments resulted comparable in comparison to the reference product with respect to the number of oocytes retrieved, that is the primary endpoint recommended by the European Medicines Agency .Further study is needed to evaluate the therapeutic bioequivalence between follitropin alpha biosimilar and the reference medication with respect to secondary endpoints.

Maternal use of fluconazole and congenital malformations in the progeny: A meta-analysis of the literature.

Fluconazole is a bis-triazole agent used in the treatment of superficial and systemic fungal infections, with vaginal candidiasis being one of the commonest indications to fluconazole treatment. There is increasing concern regarding the teratogenic potential of fluconazole. The aim of this meta-analysis is to pool the literature data in order to evaluate the possible association between fluconazole exposure during pregnancy and birth defects. A total of nine studies were included in the meta-analysis. Results were expressed as odds ratios (OR) with 95 % confidence intervals (CI) and statistical heterogeneity between the studies was evaluated with Higgins index (I2) and Q-test (Q). A p-value < 0.05 referred to the effect was considered statistically significant. The maternal exposure to fluconazole during the first trimester of pregnancy is correlated with increased prevalence of heart defects in the offspring for both low dose (OR 1.95, 95 % CI 1.18-3.21; P = 0.01) and any dose (OR 1.79, 95 % CI 1.18-2.71; P = 0.01). No association was found between gestational exposure to fluconazole and increased risk of spontaneous abortion or stillbirth. Fluconazole should be regarded as a human teratogen and should be cautiously prescribed to pregnant women and to women of childbearing potential.

Cigarette smoking impairs clinical outcomes of assisted reproductive technologies: A meta-analysis of the literature.

There is convincing evidence that cigarette smoking can impair female reproductive potential. This meta-analysis updates the knowledge regarding the effects of cigarette smoking on clinical outcomes of assisted reproductive technologies (ART). Twenty-six studies were included in this meta-analysis. Results were expressed as odds ratios (OR) with 95% confidence intervals (CI) and statistical heterogeneity between the studies was evaluated with Higgins (I2), Breslow (τ2), Birge's ratio (H2) indices and Chi-square test (χ2). A P-value < 0.05 was considered statistically significant. The analysis showed a significant decrease in live birth rate per cycle for smoking patients (OR 0.59, 95% CI 0.44-0.79; P = 0.0005), a significant lower clinical pregnancy rate per cycle for smoking women (OR 0.53, 95% CI 0.41-0.68; P < 0.0001), and a significant increase in terms of spontaneous miscarriage rate (OR 2.22, 95% CI 1.10-4.48; P = 0.025) for smokers. These findings demonstrate clear negative effects of cigarette smoking on the outcome of ART programs.

Corifollitropin alfa compared to daily FSH in controlled ovarian stimulation for in vitro fertilization: a meta-analysis.

The present study offers a meta-analysis of published randomized controlled trials (RCTs) evaluating the outcomes of in vitro fertilization (IVF) cycles using corifollitropin alfa for controlled ovarian stimulation (COS) in comparison with daily recombinant FSH (rFSH). The study examined seven RCTs including 2138 patients receiving corifollitropin alfa and 1788 women receiving daily rFSH for COS. As a novel aspect, this meta-analysis included two specific subpopulations of IVF patients, i.e. egg donors and poor responders. There were no significant differences between corifollitropin alfa and rFSH with respect to the majority of the clinical parameters considered, and comparable were the outcomes in terms of live birth rate, ongoing pregnancy rate, and clinical pregnancy rate. Women receiving corifollitropin alfa had a significantly higher number of metaphase II oocytes at ovum pick-up, and number of formed embryos, in comparison to rFSH. The risk of cycle cancellation due to overstimulation was significantly higher in the corifollitropin alfa group. Ovarian hyperstimulation syndrome (OHSS) incidence was statistically comparable between patients receiving long lasting or daily rFSH. Nevertheless, in view of the fact that corifollitropin alfa resulted in a higher number of metaphase II oocytes collected and a higher number of cycles cancelled due to overstimulation, corifollitropin alfa should be cautiously considered in women with the potential of being hyper responders.