Regional consistency and sample size considerations in a multiregional equivalence trial.

The main objective of a confirmatory multiregional clinical trial (MRCT) is to demonstrate the overall efficacy of test drugs in all participating regions as well as to evaluate the possibility of extrapolating the overall results to each region. With the emergence of the demands of biosimilar drugs development, some guidelines recommended using equivalence design to demonstrate the comparability of efficacy between biosimilar and reference drugs. Previous discussions about assessing regional consistency in MRCT are mainly focused on superiority or non-inferiority designs, while the extensions to equivalence designs were limited. In this work, we proposed a flexible regional consistency criterion for the MRCT with equivalence design. Based on this criterion, sample size determination and sample allocation were also discussed.

Treatment of idiopathic oligozoospermia with recombinant human follicle-stimulating hormone: a prospective, randomized, double-blind, placebo-controlled clinical study in Chinese population.

OBJECTIVE: Follicle-stimulating hormone plays a crucial role in spermatogenesis. The aim of this study was to evaluate the efficacy of treatment with FSH in Chinese infertility population. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical study. PATIENTS: A total of 354 men affected by idiopathic oligozoospermia from three medical centres. MEASUREMENTS: This study contained three parts: (i) treatment with different doses of rhFSH (50 IU, 100 IU, 200 IU and 300 IU); (ii) the efficacy of rhFSH at different periods (2, 3, 4, 5 months); (iii) FSH treatment in patients with different levels of inhibin B (normal-level group, low-level group and high-level group). Semen parameters were evaluated in all subjects. The patients who had not reached spontaneous pregnancy underwent assisted reproductive techniques. RESULTS: Sperm number was significantly increased after treatment with FSH at doses of at least 200 IU, and the improvement was observed beginning at the third month. The significant improvement in both morphology and forward motility was observed beginning at the fifth month. Moreover, 300 IU rhFSH administration for 5 months could significantly improve the spontaneous pregnancy rate (12/40) and ART pregnancy rate (14/28), while the rates for placebo group were two of twenty-nine and five of twenty-seven, respectively. The seminal parameters (total sperm count, sperm concentration, forward motility and morphology) were significantly improved in the normal- and low-level inhibin B groups, but no significant variation was observed in the high-level group at the end of the study. CONCLUSIONS: The efficacy of FSH treatment was associated with the dose of FSH and duration of treatment, and FSH therapy was more effective in patients with normal level and low level of inhibin B.

[Quality control of statistical analysis in data management of clinical trials].

Data is the basis and soul of clinical trials. To obtain accurate data, strict and standard data management is essential, which can be effectively supported by quality control in statistical analysis. In this paper, we briefly introduce the concept of the quality control in clinical trials, and describe its contents and methods. We hope that this work will be helpful to the application of statistical quality control in data management of clinical trials.

Effect and safety of dual anti-human epidermal growth factor receptor 2 therapy compared to monotherapy in patients with human epidermal growth factor receptor 2-positive breast cancer: a systematic review.

BACKGROUND: Dual anti-human epidermal growth factor receptor 2 (HER2) therapies have been shown to improve outcomes of HER2-positive breast cancer patients. We undertook a systematic review to compare treatment outcomes for patients who received single or combined anti-HER2 therapies. METHODS: We identified randomized control trials that compared dual anti-HER2 therapy and anti-HER2 monotherapy in patients with HER2-positive breast cancer. Outcomes included pathologic complete response (pCR), overall survival (OS), progression-free survival (PFS), and adverse events. Included in the analysis were seven trials that recruited 2,609 patients. RESULTS: In the neoadjuvant setting, the pooled pCR rate in the dual anti-HER2 therapy and monotherapy groups in combination with chemotherapy was 54.8% and 36%, respectively. This difference was statistically significant (relative risk, 1.56; 95% confidence interval (CI), 1.23-1.97; p < 0.001). In the metastatic setting, dual anti-HER2 therapy demonstrated significant benefits in both PFS (hazard ratio (HR), 0.71; 95% CI, 0.62-0.81; p < 0.001) and OS (HR, 0.68; 95% CI, 0.57-0.82; p < 0.001). Subgroup analyses indicated that the addition of chemotherapy to dual anti-HER2 therapy could greatly improve pCR in the neoadjuvant settings. However, in the metastatic setting, similar PFS and OS were found in patients receiving dual anti-HER2 therapy with or without chemotherapy. Dual anti-HER2 therapy was associated with more frequent adverse events than monotherapy, but no statistical differences were observed in cardiac toxicity. CONCLUSIONS: This systematic review provides a summary of all the data currently available, and confirms the benefits and risks of dual anti-HER2 therapy for HER2-positive breast cancer.

Egg consumption and risk of bladder cancer: a meta-analysis.

The findings of epidemiologic studies on the association between egg consumption and bladder cancer risk remain conflicting. We conducted a meta-analysis to clarify the potential association between egg consumption and bladder cancer risk. Four cohort studies and 9 case-control studies in the PubMed database through February 2012 were identified on egg consumption and risk of bladder cancer involving 2715 cases and 184,727 participants. Random-effects models were used to calculate the summary relative risk estimates (SRRE) based on the highest compared with the lowest category of egg consumption. In addition, we performed stratified analyses and sensitivity and dose-response analyses to examine the association. Overall, no significant association was observed between egg consumption and bladder cancer (SRRE = 1.11 95% CI: 0.90-1.35). However, increased risk of bladder cancer was detected in North/South America (SRRE = 1.40 95% CI: 1.05-1.86) and, moreover, fried egg intake positively associated with bladder cancer as well (SRRE = 2.04, 95% CI: 1.41-2.95). In conclusion, our findings suggest no significant association between egg consumption and bladder cancer risk, except for a possible positive relationship with the intake of fried eggs based on the limited number of studies. Additional studies, especially large prospective cohort studies, are warranted to confirm these findings.

Ileal versus sigmoid neobladder as bladder substitute after radical cystectomy for bladder cancer: A meta-analysis.

PURPOSE: To evaluate and compare the functional outcomes of ileal and sigmoid neobladders in patients underwent radical cystectomy. METHODS: Relevant studies were identified by searching PubMed, Embase, and Cochrane Library. The studies comparing the functional outcomes of sigmoid neobladder (SN) and ileal neobladder (IN) in patients underwent radical cystectomy were included. RESULTS: A total of 12 cohort studies were included in this meta-analysis. From our analysis, more early complications were observed in SN group than in IN group (RR = 1.37, 95% CI: 1.03-1.81). Both daytime and nighttime continence rates were significantly better in IN group than in SN group (RR = 0.87, 95%CI: 0.81-0.94) (RR = 0.73, 95%CI: 0.60-0.90). More patients could spontaneous voiding in SN group than in IN group (RR = 1.12, 95%CI: 1.00-1.26). According to the urodynamic study, ileal neobladder exhibited bigger capacity (WMD = -84.93, 95%CI: -160.36 to -9.50), lower pressure at capacity (WMD = 11.18, 95%CI: 4.29-18.06), better compliance (WMD = -25.55, 95%CI: -32.45 to -18.64), and greater post-void residual volume(WMD = -23.48, 95%CI: -36.75 to -10.21); There was no significant difference in the max voiding flow rate or void volume between the two groups (WMD = -1.00, 95%CI: -3.73-1.73) (WMD = -27.00, 95%CI: 70.05-16.06). No significant difference was found in the serum creatinine between the two groups (WMD = -0.05, 95%CI: -0.12-0.03). CONCLUSIONS: Ileal neobladder seems able to provide more favorable patient's satisfaction, while sigmoid neobladder may provide a better chance of spontaneous voiding. This meta-analysis may provide some useful evidences for urological surgeons to choose the ideal bladder substitute for patients underwent radical cystectomy.

Risk of treatment-related mortality with sorafenib in patients with cancer.

BACKGROUND: Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). We here performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib. METHODS: Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen. RESULTS: 13 trials recruiting 5,546 patients were included in our analysis. The overall incidence of FAEs with sorafenib was 1.99% (95%CI, 0.98-4.02%). Patients treated with sorafenib had a significantly increased risk of FAEs compared with patients treated with control medication, with an RR of 1.77 (95%CI 1.25-2.52, P=0.001). Risk varied with tumour type, but appeared independent of therapy regimen. A significantly increased risk of FAEs was observed in patients with lung cancer (RR 2.26; 95% CI 1.03-4.99; P= 0.043) and renal cancer (RR 1.84; 95% CI 1.15-2.94; P= 0.011). The most common causes of FAEs were hemorrhage (8.6%) and thrombus or embolism (4.9%). CONCLUSIONS: It is important for health care practitioners to be aware of the risks of FAEs associated with sorafenib, especially in patients with renal and lung cancer.

Adverse drug reactions of spontaneous reports in Shanghai pediatric population.

BACKGROUND: Knowledge of drug safety in the pediatric population of China is limited. This study was designed to evaluate ADRs in children reported to the spontaneous reporting system (SRS) of Shanghai in 2009. METHODOLOGY AND PRINCIPAL FINDINGS: Crude ADR reports submitted to Shanghai SRS in 2009 for individuals aged from birth to 17 years (including 17 years) were included. Data were analyzed with respect to age, gender, category of ADR (System Organ Class [SOC]), the severity of reports and type of reporter. RESULTS: A male overrepresentation was observed regarding the total number of reports. The most frequently reported group of drugs were vaccines (42.15%). Skin rash and fever were the commonest symptoms reported in the total pediatric dataset. The proportion of children that suffered from a serious ADR was 2.16% and that for drug related deaths was 0.34%. And we found that the multiple drug exposure experienced a high proportion of serious ADRs compared with the single drug use (χ²â€Š= 15.99, P<0.0001). Sixty-five percent of ADRs were for children less than 6 years of age. And more than half of reports were from doctors. CONCLUSIONS: In our study, consumers were more likely to report new ADRs though they appear to contribute a relatively small percentage of total reports. We propose that patients would take an active role in reporting ADRs. More researches are needed in order to achieve better understanding the characteristics of ADRs in pediatric population of China.

[Expression of Gluc-Fluc dual luciferase plasmid after transfection into MB49 bladder cells].

OBJECTIVE: To investigate the expression characteristics of Gluc-Fluc dual luciferase plasmid after its transfection into MB49 bladder cells. METHODS: pAAV2neoCAG-Gluc-2A-Fluc and pAAV2neo-Gluc plasmids were separately transfected into MB49 cells via LipofectamineTM2000. The Gluc activity in the cell culture supernatant and the Fluc activity in the cells were detected by luminometer and Lumina Imaging system. RESULTS: The luminometer result showed that the activity of Gluc in the supernatant increased gradually in a cell number- and time-dependent manner, while Fluc activity in the cells increased with the cell number but not with time. The Lumina Imaging system showed that Gluc-Fluc was successfully expressed in MB49 bladder cells and cell lines with stable Gluc-Fluc expression were obtained after G418 selection. CONCLUSION: Gluc in the dual luciferase plasmid retains its expression characteristics. Due to the advantages of Fluc in localization in living imaging and the easy quantitative detection of Gluc, the dual luciferase plasmid, after transfection in MB49 bladder cells, allows reliable and dynamic detection of tumor growth in animal models.

[A comparative analysis of the methods for titering adenoviruses].

OBJECTIVE: To compare different methods commonly used for titering adenovirus and analyze the advantages and limitations of each method. METHODS: Four recombined adenoviruses (Ad-G-AT2R-EGFP, Ad-CMV-EGFP, Ad-mif-shRNA-EGFP and Ad-CBA-GFP) were amplified and purified, and each was titered by optical absorbance, real-time PCR, green fluorescent protein (GFP)-labeled method, immunoassay, and cytopathic effect (CPE). The results were then comparatively analyzed. RESULTS: No significant difference was found in the titer amounts derived from GFP-labeled method, immunoassay, and cytopathic effect method (P>0.1). A positive correlation was noted in the titer amounts determined by real-time PCR and immunoassay (r=0.965), even though the value (vg/ml) obtained by real-time PCR was 10 times higher than that by immunoassay (ifu/ml). CONCLUSION: GFP-labeled method and immunoassay allow rapid determination of the adenoviral titer. Real-time PCR can not directly determine the real infectious titer of the adenovirus, but the result is well correlated to that of immunoassay and reflects, though indirectly, the actual infectious titer of adenovirus. Considering the procedural convenience and shorter time consumption, real-time PCR is still a practical method for adenoviral titration.

Adjuvant chemotherapy, with or without taxanes, in early or operable breast cancer: a meta-analysis of 19 randomized trials with 30698 patients.

BACKGROUND: Taxanes have been extensively used as adjuvant chemotherapy for the treatment of early or operable breast cancer, particularly in high risk, node-negative breast cancer. Previous studies, however, have reported inconsistent findings regarding their clinical efficacy and safety. We investigated disease-free survival (DFS), overall survival (OS), and drug-related toxicities of taxanes by a systematic review and meta-analysis. METHODOLOGY AND PRINCIPAL FINDINGS: We systematically searched PubMed, EMBASE, the Cochrane Center Register of Controlled Trials, proceedings of major meetings, and reference lists of articles for studies conducted between January 1980 and April 2011. Randomized controlled trials (RCTs) comparing chemotherapy with and without taxanes in the treatment of patients with early-stage or operable breast cancer were eligible for inclusion in our analysis. The primary endpoint was DFS. Nineteen RCTs including 30698 patients were identified, including 8426 recurrence events and 3803 deaths. Taxanes administration yielded a 17% reduction of hazard ratio (HR) for DFS (HR = 0.83, 95% CI 0.79-0.88, p<0.001) and a 17% reduction of HR for OS (HR = 0.83, 95% CI 0.77-0.90, p<0.001). For high risk, node-negative breast cancer, the pooled HR also favoured the taxane-based treatment arm over the taxane-free treatment arm (HR = 0.82, 95% CI 0.77-0.87, p = 0.022). A significantly increased rate of neutropenia, febrile neutropenia, fatigue, diarrhea, stomatitis, and oedema was observed in the taxane-based treatment arm. CONCLUSIONS/SIGNIFICANCE: Adjuvant chemotherapy with taxanes could reduce the risk of cancer recurrence and death in patients with early or operable breast cancer, although the drug-related toxicities should be balanced. Furthermore, we also demonstrated that patients with high risk, node-negative breast cancer also benefited from taxanes therapy, a result that was not observed in previous studies.