Objective The determination of non-inferiority margin is an important and confusing issue which directly influences the acceptability of a new medication. We reviewed the published literature, International Conference...Objective The determination of non-inferiority margin is an important and confusing issue which directly influences the acceptability of a new medication. We reviewed the published literature, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use （ICH） Guidelines and Committee for Proprietary Medicinal Products （CPMP） papers on the selection of non-inferiority margin and the corresponding statistical tests in clinical trials, in order to provide practical recommendations and suggestions for establishing reference criteria for the non-inferiority margin in China. Data sources The literature on the selection of a non-inferiority margin and statistical tests was mainly extracted from relevant English articles on non-inferior clinical trials published from 1990 to 2007. The starting point （1990） was chosen due to lack of such papers published prior to 1990. This literature was searched via PubMed, Medline and Chinese Knowledge Information （CNKI）. ICH guidelines and CPMP papers were downloaded from their official websites. The keywords ＂clinical trial＂, ＂non-inferiority＂ and ＂non-inferiority margin＂ were used. Study selection Forty-three original articles and critical reviews, ICH El0 guideline and CPMP papers were selected. Results The non-inferiority testing with treatment difference and ratio are commonly used, where the non-inferiority margin is determined with and without historical data. Traditionally, this margin is treated as a fixed value, while developed methods take the variation into account in the determination of this margin, on which the test depends is more convincing. The mixed margin consisting of a margin based on treatment difference and a margin based on treatment ratio can exactly control the type I error at the desirable level and obtain a better power. In this review, we also provide some recommendations and suggestions for the selection of the non-inferiority margin in the western countries and China. C展开更多
Objective： To evaluate the effectiveness and safety of lyophilized Salvia salt of lithospermic acid powder for injection （SSLA） in treating coronary heart diseases angina pectoris （CHD-AP） of Xin-blood stasis syn...Objective： To evaluate the effectiveness and safety of lyophilized Salvia salt of lithospermic acid powder for injection （SSLA） in treating coronary heart diseases angina pectoris （CHD-AP） of Xin-blood stasis syndrome type, and to conduct the non-inferiority trial with Danshen injection （丹参注射液, DSI） as positive control. Methods： An non-inferiority clinical layered, segmented, randomized, and blinded trial on three parallel and multiple centered groups was conducted in 480 patients with stable effort angina grade Ⅰ , Ⅱand Ⅲ, who had two or more times of attack every week. The 240 patients in test group A were treated with SSLA 200 mg added in 250 ml of 5% glucose solution for intravenous dripping every day; the 120 patients in test group B were treated with SSLA but the dosage doubled; and the 120 patients in the control group were treated with DSI 20 ml daily in the same method as SSLA was given. The clinical effectiveness and safety were evaluated after the patients were treated for 14 days. Results： The results showed that the markedly effective rate in test groups A, B and control group was 37.45 %, 36.75 % and 30.09 % respectively, while the total effective rate in them was 88.09%, 89.74% and 67.26% respectively. Statistical significance was shown in comparisons of the therapeutic effect between control group with test group A and test group B, with that in the two test groups superior to that in the control group, and non-inferiority trial showed eligibility （P〈0.01）. Adverse reaction appeared in 8 patients in the test groups and 2 in the control group. Conclusion： SSLA has definite therapeutic effect in treating patients with CHD-AP, with its effect not inferior to that of DSI, and no evident toxic-adverse reaction.展开更多
Objective:To evaluate the non-inferiority of pramipexole extended-release(ER)versus immediate-release(IR)in Chinese patients with Parkinson’s disease(PD)in a double-blind,randomized,parallel-group study.Methods:Subje...Objective:To evaluate the non-inferiority of pramipexole extended-release(ER)versus immediate-release(IR)in Chinese patients with Parkinson’s disease(PD)in a double-blind,randomized,parallel-group study.Methods:Subjects were Chinese patients with idiopathic PD with diagnosis≥2 years prior to trial,age≥30 years old at diagnosis,and Modified Hoehn and Yahr score 2-4 during‘on’-time.Subjects received treatment with pramipexole ER(n=234)or IR(n=239).Non-inferiority was based on the primary endpoint,the change from baseline to end of maintenance(week 18)in the UPDRS(Parts II+III)total score.Results:For the primary endpoint,the adjusted mean changes(standard error)of UPDRS Parts II+III at week 18 were−13.81(0.655)and−13.05(0.643)for ER and IR formulations,respectively,using ANCOVA adjusted for treatment and centre(fixed effect)and baseline(covariate).The adjusted mean between group difference was 0.8 for the 2-sided 95%CI(−1.047,2.566).Since the lower limit of the 2-sided 95%CI(−1.047)for treatment difference was higher than the non-inferiority margin of−4,non-inferiority between pramipexole ER and IR was demonstrated.The incidence of adverse events(AEs)was 68.8%in the ER arm and 73.6%in the IR arm with few severe AEs(ER:2.1%;IR:3.8%).Conclusion:Based on the UPDRS II+III score,pramipexole ER was non-inferior to pramipexole IR.The safety profiles of pramipexole ER and IR were similar.These results were based on comparable mean daily doses and durations of treatment for both formulations.展开更多
Background:The pharmacokinetic and clinical behaviors of many proton pump inhibitors(PPIs)in peptic ulcer treatment are altered by CYP2C19 genetic polymorphisms.This non-inferiority study evaluated the efficacy and sa...Background:The pharmacokinetic and clinical behaviors of many proton pump inhibitors(PPIs)in peptic ulcer treatment are altered by CYP2C19 genetic polymorphisms.This non-inferiority study evaluated the efficacy and safety of the novel PPI anaprazole compared with rabeprazole.We also explored the influence of Helicobacter pylori(H.pylori)infection status and CYP2C19 polymorphism on anaprazole.Methods:In this multicenter,randomized,double-blind,double-dummy,positive-drug parallel-controlled,phase Ⅲ study,Chinese patients with duodenal ulcers were randomized 1:1 to receive rabeprazole 10 mg+anaprazole placebo or rabeprazole placebo+anaprazole 20 mg once daily for 4 weeks.The primary efficacy endpoint was the 4-week ulcer healing rate assessed by blinded independent review.Secondary endpoints were the proportion of patients with improved overall and individual duodenal ulcer symptoms at 4 weeks.Furthermore,exploratory subgroup analysis of the primary endpoint by H.pylori status and CYP2C19 polymorphism was conducted.Adverse events were monitored for safety.Non-inferiority analysis was conducted for the primary endpoint.Results:The study enrolled 448 patients(anaprazole,n=225;rabeprazole,n=223).The 4-week healing rates were 90.9%and 93.7%for anaprazole and rabeprazole,respectively(difference,-2.8%[95%confidence interval,-7.7%,2.2%]),demonstrating non-inferiority of anaprazole to rabeprazole.Overall duodenal ulcer symptoms improved in 90.9%and 92.5%of patients,respectively.Improvement rates of individual symptoms were similar between the groups.Healing rates did not significantly differ by H.pylori status or CYP2C19 genotype for either treatment group.The incidence of treatment-emergent adverse events was similar for anaprazole(72/220,32.7%)and rabeprazole(84/219,38.4%).Conclusions:The efficacy of anaprazole is non-inferior to that of rabeprazole in Chinese patients with duodenal ulcers.Registration:ClinicalTrials.gov,NCT04215653.展开更多
Context: In recent years there has been increasing interest on publication bias and on initiatives to decrease bias, in- cluding trial registration. Objective: To test whether there has been an increase in reports of ...Context: In recent years there has been increasing interest on publication bias and on initiatives to decrease bias, in- cluding trial registration. Objective: To test whether there has been an increase in reports of randomized control trials (RCT’s) with negative outcomes in major journals and to identify factors associated with these reports. Design: Retrospective review of reports of RCT’s published in the Journal of the American Medical Association, The Lancet and the New England Journal of Medicine before (2002-’03, pre-registration era) and after (2007-’08, registration era) the institution of mandatory trial registration. Main Outcome Measure: The primary outcome was the proportion of RCT reports with negative outcomes compared across the two eras. Secondary outcome includes other factors affecting pub-lication. Results: We identified 917 reports of RCT’s published in the two study eras. No publications in the pre-registration era reported trial registration compared with 94.4% in the registration era (p 0.001). There was a non-significant increase in negative trials from the pre-registration to the registration era (29.1% vs. 34.1%, p = 0.10, OR 1.26, 95% CI 0.96 - 1.67). Study characteristics associated with negative outcomes include trials of drugs (OR 1.62, 95% CI 1.08 - 2.43), procedures or devices (OR 2.08, 95% CI 1.29 - 3.35), explicit identification of a single primary endpoint (OR 1.70, 95% CI 1.40 - 2.47), and increasing sample size (OR 3.08, 95% CI 1.78 - 5.34). Non-inferiority study design was associated with a decreased likelihood of a negative outcome (OR 0.13, 95% CI 0.05 - 0.31). Conclusions: The proportion of published RCT reports with negative outcomes in three major medical journals has not significantly increased since the mandatory clinical trial registration policy. The observed prevalence of negative trials is associated with increases in sample size and greater specificity in trial endpoints.展开更多
基金This study was supported by a grant from the National Natural Science Foundation of China （No. 30371253）.
文摘Objective The determination of non-inferiority margin is an important and confusing issue which directly influences the acceptability of a new medication. We reviewed the published literature, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use （ICH） Guidelines and Committee for Proprietary Medicinal Products （CPMP） papers on the selection of non-inferiority margin and the corresponding statistical tests in clinical trials, in order to provide practical recommendations and suggestions for establishing reference criteria for the non-inferiority margin in China. Data sources The literature on the selection of a non-inferiority margin and statistical tests was mainly extracted from relevant English articles on non-inferior clinical trials published from 1990 to 2007. The starting point （1990） was chosen due to lack of such papers published prior to 1990. This literature was searched via PubMed, Medline and Chinese Knowledge Information （CNKI）. ICH guidelines and CPMP papers were downloaded from their official websites. The keywords ＂clinical trial＂, ＂non-inferiority＂ and ＂non-inferiority margin＂ were used. Study selection Forty-three original articles and critical reviews, ICH El0 guideline and CPMP papers were selected. Results The non-inferiority testing with treatment difference and ratio are commonly used, where the non-inferiority margin is determined with and without historical data. Traditionally, this margin is treated as a fixed value, while developed methods take the variation into account in the determination of this margin, on which the test depends is more convincing. The mixed margin consisting of a margin based on treatment difference and a margin based on treatment ratio can exactly control the type I error at the desirable level and obtain a better power. In this review, we also provide some recommendations and suggestions for the selection of the non-inferiority margin in the western countries and China. C
基金Supported by the Fund of National Project of High.technicResearch and Development,(No.2003AA223269)
文摘Objective： To evaluate the effectiveness and safety of lyophilized Salvia salt of lithospermic acid powder for injection （SSLA） in treating coronary heart diseases angina pectoris （CHD-AP） of Xin-blood stasis syndrome type, and to conduct the non-inferiority trial with Danshen injection （丹参注射液, DSI） as positive control. Methods： An non-inferiority clinical layered, segmented, randomized, and blinded trial on three parallel and multiple centered groups was conducted in 480 patients with stable effort angina grade Ⅰ , Ⅱand Ⅲ, who had two or more times of attack every week. The 240 patients in test group A were treated with SSLA 200 mg added in 250 ml of 5% glucose solution for intravenous dripping every day; the 120 patients in test group B were treated with SSLA but the dosage doubled; and the 120 patients in the control group were treated with DSI 20 ml daily in the same method as SSLA was given. The clinical effectiveness and safety were evaluated after the patients were treated for 14 days. Results： The results showed that the markedly effective rate in test groups A, B and control group was 37.45 %, 36.75 % and 30.09 % respectively, while the total effective rate in them was 88.09%, 89.74% and 67.26% respectively. Statistical significance was shown in comparisons of the therapeutic effect between control group with test group A and test group B, with that in the two test groups superior to that in the control group, and non-inferiority trial showed eligibility （P〈0.01）. Adverse reaction appeared in 8 patients in the test groups and 2 in the control group. Conclusion： SSLA has definite therapeutic effect in treating patients with CHD-AP, with its effect not inferior to that of DSI, and no evident toxic-adverse reaction.
基金Boehringer lngelheim lnternational GmbH sponsored this study.
文摘Objective:To evaluate the non-inferiority of pramipexole extended-release(ER)versus immediate-release(IR)in Chinese patients with Parkinson’s disease(PD)in a double-blind,randomized,parallel-group study.Methods:Subjects were Chinese patients with idiopathic PD with diagnosis≥2 years prior to trial,age≥30 years old at diagnosis,and Modified Hoehn and Yahr score 2-4 during‘on’-time.Subjects received treatment with pramipexole ER(n=234)or IR(n=239).Non-inferiority was based on the primary endpoint,the change from baseline to end of maintenance(week 18)in the UPDRS(Parts II+III)total score.Results:For the primary endpoint,the adjusted mean changes(standard error)of UPDRS Parts II+III at week 18 were−13.81(0.655)and−13.05(0.643)for ER and IR formulations,respectively,using ANCOVA adjusted for treatment and centre(fixed effect)and baseline(covariate).The adjusted mean between group difference was 0.8 for the 2-sided 95%CI(−1.047,2.566).Since the lower limit of the 2-sided 95%CI(−1.047)for treatment difference was higher than the non-inferiority margin of−4,non-inferiority between pramipexole ER and IR was demonstrated.The incidence of adverse events(AEs)was 68.8%in the ER arm and 73.6%in the IR arm with few severe AEs(ER:2.1%;IR:3.8%).Conclusion:Based on the UPDRS II+III score,pramipexole ER was non-inferior to pramipexole IR.The safety profiles of pramipexole ER and IR were similar.These results were based on comparable mean daily doses and durations of treatment for both formulations.
文摘Background:The pharmacokinetic and clinical behaviors of many proton pump inhibitors(PPIs)in peptic ulcer treatment are altered by CYP2C19 genetic polymorphisms.This non-inferiority study evaluated the efficacy and safety of the novel PPI anaprazole compared with rabeprazole.We also explored the influence of Helicobacter pylori(H.pylori)infection status and CYP2C19 polymorphism on anaprazole.Methods:In this multicenter,randomized,double-blind,double-dummy,positive-drug parallel-controlled,phase Ⅲ study,Chinese patients with duodenal ulcers were randomized 1:1 to receive rabeprazole 10 mg+anaprazole placebo or rabeprazole placebo+anaprazole 20 mg once daily for 4 weeks.The primary efficacy endpoint was the 4-week ulcer healing rate assessed by blinded independent review.Secondary endpoints were the proportion of patients with improved overall and individual duodenal ulcer symptoms at 4 weeks.Furthermore,exploratory subgroup analysis of the primary endpoint by H.pylori status and CYP2C19 polymorphism was conducted.Adverse events were monitored for safety.Non-inferiority analysis was conducted for the primary endpoint.Results:The study enrolled 448 patients(anaprazole,n=225;rabeprazole,n=223).The 4-week healing rates were 90.9%and 93.7%for anaprazole and rabeprazole,respectively(difference,-2.8%[95%confidence interval,-7.7%,2.2%]),demonstrating non-inferiority of anaprazole to rabeprazole.Overall duodenal ulcer symptoms improved in 90.9%and 92.5%of patients,respectively.Improvement rates of individual symptoms were similar between the groups.Healing rates did not significantly differ by H.pylori status or CYP2C19 genotype for either treatment group.The incidence of treatment-emergent adverse events was similar for anaprazole(72/220,32.7%)and rabeprazole(84/219,38.4%).Conclusions:The efficacy of anaprazole is non-inferior to that of rabeprazole in Chinese patients with duodenal ulcers.Registration:ClinicalTrials.gov,NCT04215653.
文摘Context: In recent years there has been increasing interest on publication bias and on initiatives to decrease bias, in- cluding trial registration. Objective: To test whether there has been an increase in reports of randomized control trials (RCT’s) with negative outcomes in major journals and to identify factors associated with these reports. Design: Retrospective review of reports of RCT’s published in the Journal of the American Medical Association, The Lancet and the New England Journal of Medicine before (2002-’03, pre-registration era) and after (2007-’08, registration era) the institution of mandatory trial registration. Main Outcome Measure: The primary outcome was the proportion of RCT reports with negative outcomes compared across the two eras. Secondary outcome includes other factors affecting pub-lication. Results: We identified 917 reports of RCT’s published in the two study eras. No publications in the pre-registration era reported trial registration compared with 94.4% in the registration era (p 0.001). There was a non-significant increase in negative trials from the pre-registration to the registration era (29.1% vs. 34.1%, p = 0.10, OR 1.26, 95% CI 0.96 - 1.67). Study characteristics associated with negative outcomes include trials of drugs (OR 1.62, 95% CI 1.08 - 2.43), procedures or devices (OR 2.08, 95% CI 1.29 - 3.35), explicit identification of a single primary endpoint (OR 1.70, 95% CI 1.40 - 2.47), and increasing sample size (OR 3.08, 95% CI 1.78 - 5.34). Non-inferiority study design was associated with a decreased likelihood of a negative outcome (OR 0.13, 95% CI 0.05 - 0.31). Conclusions: The proportion of published RCT reports with negative outcomes in three major medical journals has not significantly increased since the mandatory clinical trial registration policy. The observed prevalence of negative trials is associated with increases in sample size and greater specificity in trial endpoints.
