2 医疗器械临床试验统计学要求
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• OBJECTIVE: To compare PCI with sirolimus-eluting stents and CABG surgery for optimal revascularization of patients with ULMCA stenosis.
N Engl J Med 2011;364:1718-27
HTN1: Hypertension. 2011;57:911-917; HTN2: Lancet 2010; 376: 1903–09 HTN3: NEJM published online March 29, 2014
试验设计与证据级别
Coronary Revascularization in Diabetic Patients: A Comparison of the Randomized and Observational Component of the Bypass Angioplasty Revascularization Investigation (BARI)
PRIMI: Multivessel vs. Culprit PCI
Wald DS, et al. N Engl J Med 2013; 369:1115-1123
样本量计算
影响因素
效应值 (Effect Size) 的影响
1%
2% 10%
20%
样本量计算 决定样本量的关键因素—”变异”
体重: 3.8 - 42.6kg 血压下降: 20 ± 36 mmHg N=68/group
对照组的最低获益程度
对照组与安慰 剂的疗效差异 8% vs. 20%
-4 -2 0 2 4
试验组与对照 组的疗效差异 1/3 ~ 1/4
-4
非劣效界值= Fraction * (C-P)
-2
0
2
4
NI 界值
PROMISE study
Pamela SD, et al. N Engl J Med 2015; 372:1291-1300
100
0.048
如有效例数： A组90 vs. B组81例, 组间差异则不显著！
统计在试验设计中的作用
• 统计 = 计算样本量？
总体设计 研究目的
研究假设
试验设计 目标人群 入排标准
样本量
预期疗效 估计
观察时间
主要指标 评价方法 文献 评价标准 定义
SIMPLICITY系列试验的启示
32mmHg *
• A final sample size : 600 patients (300 per
group) assuming 5% of loss
N Engl J Med 2011;364:1718-27
Non-inferiority Test for
Primary End Point of 1-Year MACCE
Non-inferior
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0 %
Upper one-sided 95% CI
Primary Non-Inferiority Endpoint Met
PRECOMBAT Trial
Design
• DESIGN: A prospective, open-label, randomized trial
1,829 patients (19% with DM) with MVD were randomized to CABG or PTCA 2010 eligible patients (17% with DM) did not consent in RCT entered into registry
Detre KM, et al. Circulation 1999; 99: 633-40
目标人群与研究人群 选择偏倚 vs. 外部真实性
RESOLUTE All Comers
Stent Thrombosis to 5 Years: Definite / Probable
10 Cumulative Incidence of ARC Definite/Probable ST (%) Resolute™ ZES (N = 1140) Xience V™ EES (N = 1152)
Secondary Angiographic Endpoint: In-stent Percent Diameter Stenosis at 13 Months
1.5 lesions would be treated per patient
% DS at 13 months would be 16 ± 16% and equal in both groups
PEGASUS TIMI-54, NEJM, 2015
如何对试验结果进行判定
Superior Non-inferior
Non-inferior Non-inferior?
Inconclusive
Inconclusive
Inconclusive? Inferior
∆ Treatment Difference with 95% CI
Diabetic patients in BARI randomized to PTCA had significantly worse 5-year survival than patients assigned to CABG. This difference was not seen among BARI-eligible patients who opted to select their mode of revascularization.
Log rank P = 0.22
8
6 4 2 0 0 1 2 3 4 5 Time After Initial Procedure (years)
2.4% 1.7%
No. at risk Resolute Xience V 1140 1152 1134 1150 1098 1104 1072 1083 1044 1051 1005 1021
(Composite of cardiac death, target vessel MI and clinically driven TLR)
Event rate at 12-months would be 8% and equal in both groups
Non-inferiority margin of 3.5% and one-sided type I error of 0.05 • 2300 patients would yield >90% power to detect non-inferiority
* After adjustment for all differences between treatment groups. • More registry patients were white, more educated, more physically active and reported better quality of life.
• 结果 • 16 次试验 (100个中) 未能显示出显著性差异
把握度 (power) 分析
临床试验统计方法学讨论
医疗器械临床试验统计学要求
国家心血管病中心 医学统计部 王杨
临床试验设计 P值Fra Baidu bibliotek含义
• 两组比较: 有效率 90% vs. 80% • 是否有显著差异?
有效率 (A vs B) 9 vs. 8 45 vs. 40 每组 N 10 50 p值 0.53 0.16
90 vs. 80
1-Year MACCE rate CABG: 6.7% PCI: 8.7%
Pre-specified noninferiority margin: 7%
Difference, 2% 95% CI, -1.6 to 5.6% Non-inferiority p= 0.001
-2
-1
0
1
2
3
4
5
6
7
8
Primary End Point
• A composite of major adverse cardiac or
cerebrovascular events (MACCE) for the 12month period after randomization
Death from any cause Myocardial infarction (MI) Stroke Ischemia-driven target vessel revascularization (TVR)
5-Year Mortality Rates for Randomized and Registry Diabetic Patients Randomized PTCA CABG p Value RR All-cause mortality (%) 34.5 19.4 0.0024 1.87 Cardiac mortality (%) 23.4 8.2 0.0002 3.10 Registry All-cause mortality (%) 14.4 14.9 0.86 1.29* Cardiac mortality (%) 7.5 6.0 0.73 1.41*
Non-inferiority margin of 5% and one-sided type I error of 0.05 Attrition rate 20%
•
460 patients would yield >90% power to detect non-inferiority
评价标准 非劣效界值的确定
体重: 17 - 23kg 血压下降: 20 ± 9 mmHg N=6/group
把握度 (power) 分析
计算机模拟举例 -1
• 假设
试验组死亡率为 20% (x%) 对照组死亡率为 50% (y%) 试验组和对照组的样本量均为 (n) = 50 重复100 (m) 次试验 (随机抽样) 显著性水平为双侧 0.05 检验方法 = 卡方检验
从研究目的到研究假设
• 研究目的
在ACS患者中，比较替格瑞洛和氯吡格雷 在All Comers中，对ZES与EES进行比较
• 研究假设
在ACS患者中，替格瑞洛与氯匹格雷相比是否 能够降低复合终点事件的发生（优效） 在All Comers中，ZES与EES的复合终点事件率 是否相当（非劣效）
R-ZES (N = 1140) EES (N = 1152)
Non-inferiority P value
Difference Upper 1-sided 95% CI
: -0.1% : 1.8%
8.2%
8.3%
<0.001
Zone of non-inferiority Pre-specified margin = 3.5%
9
10
Difference (%) of 1-year MACCE rate between (PCI – CABG)
N Engl J Med 2011;364:1718-27
RESOLUTE All Comers Trial Statistical Assumptions
Primary Clinical Endpoint: Target Lesion Failure at 12 Months
0
← New Treatment Better
New Treatment Worse →
Primary Endpoint Analysis of the RESOLUT ALL Comers Trial
(Cardiac death, target vessel MI, and clinically driven TLR) at 1 year
N Engl J Med 2011;364:1718-27
Power Calculation
• Assumed primary end point of 1-year MACCE
in the CABG group : 13% • A non-inferiority margin : 7% • A one-sided type I error rate : 0.05 • Power : 80%
N Engl J Med 2011;364:1718-27
HTN1: Hypertension. 2011;57:911-917; HTN2: Lancet 2010; 376: 1903–09 HTN3: NEJM published online March 29, 2014
试验设计与证据级别
Coronary Revascularization in Diabetic Patients: A Comparison of the Randomized and Observational Component of the Bypass Angioplasty Revascularization Investigation (BARI)
PRIMI: Multivessel vs. Culprit PCI
Wald DS, et al. N Engl J Med 2013; 369:1115-1123
样本量计算
影响因素
效应值 (Effect Size) 的影响
1%
2% 10%
20%
样本量计算 决定样本量的关键因素—”变异”
体重: 3.8 - 42.6kg 血压下降: 20 ± 36 mmHg N=68/group
对照组的最低获益程度
对照组与安慰 剂的疗效差异 8% vs. 20%
-4 -2 0 2 4
试验组与对照 组的疗效差异 1/3 ~ 1/4
-4
非劣效界值= Fraction * (C-P)
-2
0
2
4
NI 界值
PROMISE study
Pamela SD, et al. N Engl J Med 2015; 372:1291-1300
100
0.048
如有效例数： A组90 vs. B组81例, 组间差异则不显著！
统计在试验设计中的作用
• 统计 = 计算样本量？
总体设计 研究目的
研究假设
试验设计 目标人群 入排标准
样本量
预期疗效 估计
观察时间
主要指标 评价方法 文献 评价标准 定义
SIMPLICITY系列试验的启示
32mmHg *
• A final sample size : 600 patients (300 per
group) assuming 5% of loss
N Engl J Med 2011;364:1718-27
Non-inferiority Test for
Primary End Point of 1-Year MACCE
Non-inferior
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0 %
Upper one-sided 95% CI
Primary Non-Inferiority Endpoint Met
PRECOMBAT Trial
Design
• DESIGN: A prospective, open-label, randomized trial
1,829 patients (19% with DM) with MVD were randomized to CABG or PTCA 2010 eligible patients (17% with DM) did not consent in RCT entered into registry
Detre KM, et al. Circulation 1999; 99: 633-40
目标人群与研究人群 选择偏倚 vs. 外部真实性
RESOLUTE All Comers
Stent Thrombosis to 5 Years: Definite / Probable
10 Cumulative Incidence of ARC Definite/Probable ST (%) Resolute™ ZES (N = 1140) Xience V™ EES (N = 1152)
Secondary Angiographic Endpoint: In-stent Percent Diameter Stenosis at 13 Months
1.5 lesions would be treated per patient
% DS at 13 months would be 16 ± 16% and equal in both groups
PEGASUS TIMI-54, NEJM, 2015
如何对试验结果进行判定
Superior Non-inferior
Non-inferior Non-inferior?
Inconclusive
Inconclusive
Inconclusive? Inferior
∆ Treatment Difference with 95% CI
Diabetic patients in BARI randomized to PTCA had significantly worse 5-year survival than patients assigned to CABG. This difference was not seen among BARI-eligible patients who opted to select their mode of revascularization.
Log rank P = 0.22
8
6 4 2 0 0 1 2 3 4 5 Time After Initial Procedure (years)
2.4% 1.7%
No. at risk Resolute Xience V 1140 1152 1134 1150 1098 1104 1072 1083 1044 1051 1005 1021
(Composite of cardiac death, target vessel MI and clinically driven TLR)
Event rate at 12-months would be 8% and equal in both groups
Non-inferiority margin of 3.5% and one-sided type I error of 0.05 • 2300 patients would yield >90% power to detect non-inferiority
* After adjustment for all differences between treatment groups. • More registry patients were white, more educated, more physically active and reported better quality of life.
• 结果 • 16 次试验 (100个中) 未能显示出显著性差异
把握度 (power) 分析
临床试验统计方法学讨论
医疗器械临床试验统计学要求
国家心血管病中心 医学统计部 王杨
临床试验设计 P值Fra Baidu bibliotek含义
• 两组比较: 有效率 90% vs. 80% • 是否有显著差异?
有效率 (A vs B) 9 vs. 8 45 vs. 40 每组 N 10 50 p值 0.53 0.16
90 vs. 80
1-Year MACCE rate CABG: 6.7% PCI: 8.7%
Pre-specified noninferiority margin: 7%
Difference, 2% 95% CI, -1.6 to 5.6% Non-inferiority p= 0.001
-2
-1
0
1
2
3
4
5
6
7
8
Primary End Point
• A composite of major adverse cardiac or
cerebrovascular events (MACCE) for the 12month period after randomization
Death from any cause Myocardial infarction (MI) Stroke Ischemia-driven target vessel revascularization (TVR)
5-Year Mortality Rates for Randomized and Registry Diabetic Patients Randomized PTCA CABG p Value RR All-cause mortality (%) 34.5 19.4 0.0024 1.87 Cardiac mortality (%) 23.4 8.2 0.0002 3.10 Registry All-cause mortality (%) 14.4 14.9 0.86 1.29* Cardiac mortality (%) 7.5 6.0 0.73 1.41*
Non-inferiority margin of 5% and one-sided type I error of 0.05 Attrition rate 20%
•
460 patients would yield >90% power to detect non-inferiority
评价标准 非劣效界值的确定
体重: 17 - 23kg 血压下降: 20 ± 9 mmHg N=6/group
把握度 (power) 分析
计算机模拟举例 -1
• 假设
试验组死亡率为 20% (x%) 对照组死亡率为 50% (y%) 试验组和对照组的样本量均为 (n) = 50 重复100 (m) 次试验 (随机抽样) 显著性水平为双侧 0.05 检验方法 = 卡方检验
从研究目的到研究假设
• 研究目的
在ACS患者中，比较替格瑞洛和氯吡格雷 在All Comers中，对ZES与EES进行比较
• 研究假设
在ACS患者中，替格瑞洛与氯匹格雷相比是否 能够降低复合终点事件的发生（优效） 在All Comers中，ZES与EES的复合终点事件率 是否相当（非劣效）
R-ZES (N = 1140) EES (N = 1152)
Non-inferiority P value
Difference Upper 1-sided 95% CI
: -0.1% : 1.8%
8.2%
8.3%
<0.001
Zone of non-inferiority Pre-specified margin = 3.5%
9
10
Difference (%) of 1-year MACCE rate between (PCI – CABG)
N Engl J Med 2011;364:1718-27
RESOLUTE All Comers Trial Statistical Assumptions
Primary Clinical Endpoint: Target Lesion Failure at 12 Months
0
← New Treatment Better
New Treatment Worse →
Primary Endpoint Analysis of the RESOLUT ALL Comers Trial
(Cardiac death, target vessel MI, and clinically driven TLR) at 1 year
N Engl J Med 2011;364:1718-27
Power Calculation
• Assumed primary end point of 1-year MACCE
in the CABG group : 13% • A non-inferiority margin : 7% • A one-sided type I error rate : 0.05 • Power : 80%