5

2
2 [1]

3

3
145

Les5-p 145-170.indd 145

7/9/12 1:14 PM

[ 1]

[2]



(blinding)[1,3]

(random allocation)[1,4,
5-7]


[ 5,8]

[9,10]


(allocation)

[6]

2
(condition)
2

[11,12]
(random
sampling)

[13]

146
Les5-p 145-170.indd 146

7/9/12 1:14 PM

(stratified randomization) [7]

[14]
1.

2.

3.

4.

1.

(stratification)

2.

(informed consent)

( 1)




(randomization list)

[7]



(double-blind)

147

Les5-p 145-170.indd 147

7/9/12 1:14 PM

001

17.01.2550

9.03.2503

AP

002

24.01.2550

28.06.2512

JD

003

4.02.2550

1.08.2526

MC

004

5.02.2550

13.07.2521

PD

[12]

(unrestricted randomization)

148
Les5-p 145-170.indd 148

7/9/12 1:14 PM

(restricted randomization)

1. (Simple
randomization)

[1,15-17]

(placebo)

1.1



[17]

(randomized trial)
2 A
B
A
B

1.2 (tables
of random numbers)
0 9

( 2)

2
A B


[18]
149

Les5-p 145-170.indd 149

7/9/12 1:14 PM

2 [23]
05
59
25
30
68
73
70
28
15
00
99
36
29
54
02
73
90
61
70
83
73
76
43
05
06
69
21
47
25
56
48

27
72
98
36
15
65
10
15
66
21
67
80
19
63
27
25
28
33
77
64
32
63
28
66
14
77
48
69
57
52
36

84
40
43
65
67
83
07
33
72
82
38
53
29
60
24
68
67
93
11
07
58
00
90
01
37
85
63
56
75
88
73

37
23
89
13
75
78
54
12
93
32
32
38
18
31
60
32
26
62
57
22
86
88
45
51
74
14
97
17
83
74
75

41
63
52
1 8
75
10
13
83
09
00
54
15
84
65
57
44
97
40
21
93
25
74
79
72
12
96
79
58
31
51
39

68
18
84
77
34
79
01
90
24
68
83
21
09
35
05
61
63
60
34
32
04
23
05
87
89
18
20
68
91
63
59

38
50
64
60
88
75
96
20
61
36
25
21
90
95
16
25
04
68
46
55
66
95
23
35
16
40
31
29
43
24
98

51
26
42
09
08
59
69
25
17
59
33
48
87
45
47
97
27
99
11
91
00
81
58
16
27
63
21
25
79
01
25

56
09
75
43
88
99
95
15
91
73
95
30
04
14
50
96
56
19
24
53
58
26
79
89
75
43
56
95
77
65
72

96
96
44
68
65
73
53
57
40
45
63
53
93
08
22
22
24
02
72
63
39
71
16
96
20
83
03
31
03
69
58

81
92
92
05
21
89
35
00
60
34
52
78
39
79
01
99
80
03
42
78
01
48
42
24
40
52
19
09
55
20
94

80
18
81
95
28
83
64
04
25
50
21
91
03
68
26
91
11
32
44
07
58
69
75
55
48
25
23
89
88
73
13

47
85
86
17
12
84
46
47
15
05
49
34
90
04
49
42
01
87
92
75
30
71
62
09
36
95
43
68
75
86
17

88
03
93
52
89
58
16
47
28
66
50
77
41
99
54
50
63
74
61
87
93
96
43
25
39
57
84
60
69
73
27

74
79
22
42
55
32
56
44
33
96
34
27
79
99
93
43
34
64
59
12
06
99
84
66
27
68
62
59
20
21
55

150
Les5-p 145-170.indd 150

7/9/12 1:14 PM

0-4 = A 5-9 =
B
2 3

7

B A A A A A B A A B B A A B A B B B B A

2 = A = B
()
()
72
B

40
B

23
A

63
A

18
B

50
B

26
B

09
A

96
B

92
B

2 00-49 = A
50-99 = B
3 A, B
C 3 1-3 =
A, 4-6 = B, 7-9 = C
0 = [18] 2 3
() ()
7 2 4 0 2 3 6 3 1 8 5 0 2 6 0 9 9 6 9 2
C A B - A A B A A C B - A B - C C B C A

2 01-33 = A,
34-66 = B, 67-99 = C 00
()
()
151
Les5-p 145-170.indd 151

7/9/12 1:14 PM


72
C

40
B

23
A

63
B

18
A

50
B

26
A

09
A

96
C

92
C

4 A B
C D 4
1-2 = A, 3-4 = B, 5-6 = C,
7-8 = D 0 9
2 3 ()
()
7 2 4 0 2 3 6 3 1 8
D A B - A B C B A D

5 0 2 6 0 9 9 6 9 2
C - A C - - - C - A

A B
20 A
11 B
9


200

152
Les5-p 145-170.indd 152

7/9/12 1:14 PM

2.
(Block randomization)




(block)
4 8
20

1:1 2:1 3:1

[1,7,15-17]
4
2 A
B

2 1:1
A
2 B
2

= N! / [T! * (N-T)!]
N = = 4
T =
= 2

= (4x3x2x1)/(2x1)(2x1)
= 6

A B
4 6
AABB, BBAA, ABAB, BABA, ABBA
BAAB[18]

3
3
1 = ABC, 2 = ACB,
3 = BAC, 4 = BCA, 5 = CAB
6 = CBA 0, 7, 8, 9

153
Les5-p 145-170.indd 153

7/9/12 1:14 PM

( 2) 2 3

7
-

2
ACB

4
BCA

0
-

2
ACB

3
BAC

6
CBA

3
BAC

1
ABC

8
-

2 4
1 = AABB, 2 = ABAB,
3 = ABBA, 4 = BBAA, 5 = BABA 6 = BAAB 0,7,8,9
( 2) 2 3

7
2
4
0
2
3
6
3
1
8
- ABAB BBAA - ABAB ABBA BAAB ABBA AABB -

(strata)

20


100 20
2 A
B
0 19

0-9 = A
10-19 = B ( 3)
10

154
Les5-p 145-170.indd 154

7/9/12 1:14 PM

1
13 18 9 6 5 17 19 0 8 10 15 7 11 3 12 4 16 1 2 14
B B A A A B B A A B B A B A B A B A A B

2
9 3 4 17 18 2 13 14 15 11 0 8 1 7 6 19 16 12 10 5
A A A B B A B B B B A A A A A B B B B A

3 15
1-5 = A, 6-10 = B 11-15 = C 0, 16-19 3
10
1
13 18 9 6 5 17 19 0 8 10 15 7 11 3 12 4 16 1 2 14
C - B B A - - - B B C B C A C A - A A C

2
9 3 4 17 18 2 13 14 15 11 0 8 1 7 6 19 16 12 10 5
B A A - - A C C C C - B A B B - - C B A

3
10 10 1019

2
2 4
6 [18]

3
3
6 9 [7,18]

155

Les5-p 145-170.indd 155

7/9/12 1:14 PM

3 (Random permutation)
20 0 19 [16]
11
14
5
8
11
17
14
0
11
13
9
2
14
5
3
13
0
10
2
18
9
15
12
15
1
5
9
9
9
6
11
17
1
8
12
17
7
5
15
8
13
3
10
16
19
0
3
14
3
11

19
12
17
13
6
18
19
3
19
18
3
9
8
9
19
3
5
15
16
15
14
18
1
11
17
9
8
2
4
4
6
2
11
19
11
7
11
8
11
1
1
12
3
5
1
10
16
16
1
17

15
0
2
3
8
3
13
2
2
9
4
17
11
11
11
9
18
0
13
5
3
4
7
3
16
16
0
17
14
17
14
14
5
5
6
11
18
0
1
9
17
9
8
9
9
3
15
15
17
13

5
1
4
12
0
6
16
13
6
6
17
12
2
3
17
11
12
16
19
11
6
12
13
10
10
12
7
7
1
14
13
8
9
15
18
4
0
2
12
10
14
4
15
1
16
5
13
7
18
19

9
19
16
10
1
9
1
7
12
5
18
6
13
7
18
2
3
7
8
6
16
1
19
14
15
6
4
16
5
16
10
4
4
9
7
3
17
3
7
6
11
6
2
15
3
13
7
4
19
16

0
8
19
5
10
15
9
8
15
17
2
19
6
14
10
7
11
5
6
3
1
7
8
9
18
17
17
14
0
2
4
11
17
14
13
15
19
13
14
15
16
15
16
18
11
17
9
17
0
18

6
7
10
17
13
14
18
19
17
19
13
14
5
19
6
0
8
4
17
14
0
11
6
16
0
19
19
5
6
1
7
9
14
4
3
16
15
15
13
4
3
5
19
17
8
19
0
2
5
2

13
17
11
2
18
5
0
12
0
0
14
4
0
15
4
15
15
13
9
13
11
10
4
2
7
15
3
15
10
8
18
12
7
1
2
9
12
19
19
19
5
16
4
12
15
8
2
10
9
15

7
11
14
6
12
4
5
5
10
8
15
1
10
0
14
19
6
12
14
7
4
5
10
5
11
2
5
19
15
15
19
3
6
18
14
8
10
6
2
0
7
17
1
10
4
7
18
3
14
1

2
18
7
7
14
19
15
9
3
10
11
7
12
17
2
4
16
1
4
0
2
17
14
17
9
14
6
8
17
11
12
18
12
16
19
0
5
18
16
18
9
18
5
19
13
16
14
1
10
8

16
2
12
16
17
2
4
16
4
15
0
5
19
2
1
14
9
17
12
9
10
14
0
18
2
11
13
13
8
3
15
6
0
11
10
5
8
1
10
2
0
7
13
8
12
14
5
8
8
7

1
15
15
19
7
1
12
6
14
7
8
3
4
12
16
10
4
3
3
17
12
8
18
19
14
0
15
6
16
0
2
13
10
0
9
18
3
10
6
7
15
2
14
13
18
9
10
11
2
10

12
5
1
0
4
0
10
4
7
11
1
10
16
18
9
12
7
9
1
2
19
2
15
4
3
3
16
0
19
10
8
1
19
3
16
10
9
9
18
16
19
19
6
6
0
11
17
18
15
14

18
9
18
1
5
8
11
17
5
3
7
13
15
4
5
6
2
14
11
1
13
0
9
6
5
10
10
4
18
18
5
19
15
12
0
19
13
12
8
13
6
11
7
11
10
12
4
0
4
6

4
4
6
4
3
11
2
15
16
12
6
0
9
13
7
5
19
11
5
8
7
3
17
13
13
8
11
18
7
5
17
7
8
17
4
2
4
14
3
5
18
14
11
4
7
4
19
19
12
0

17
16
9
11
9
13
3
14
13
4
19
18
17
16
8
1
17
8
15
10
15
6
16
1
12
18
12
3
2
13
3
0
16
13
15
13
14
16
17
3
12
8
0
14
6
6
11
12
6
9

10
10
0
14
19
7
8
1
1
16
16
8
7
10
12
17
14
6
0
12
18
9
11
8
6
1
1
10
11
19
1
16
3
7
5
12
1
4
0
11
4
1
17
7
2
2
12
6
16
4

8
6
3
15
16
12
6
11
8
1
12
15
18
1
13
16
10
18
10
19
8
19
2
0
4
4
14
11
13
7
16
5
13
10
8
14
2
7
5
14
10
13
12
3
14
18
1
13
7
5

3
13
13
18
2
10
7
18
9
2
10
11
1
6
0
18
1
2
7
4
17
13
5
7
19
7
2
1
3
12
9
10
2
2
17
1
16
17
4
17
8
10
18
0
5
15
8
5
13
3

14
3
8
9
15
16
17
10
18
14
5
16
3
8
15
8
13
19
18
16
5
16
3
12
8
13
18
12
12
9
0
15
18
6
1
6
6
11
9
12
2
0
9
2
17
1
6
9
11
12

156
Les5-p 145-170.indd 156

7/9/12 1:14 PM

3.
(Stratified randomization)

100

[1,7,8,16,17]


[10,18,19]

(prognostic
variable)[19,20]

2

2


(prospective study)
(retrospective study)

2
3.1

(random permuted blocks

within strata)

2


2
1-3
157

Les5-p 145-170.indd 157

7/9/12 1:14 PM

4
2 50
50
2
50

2
2
- (L-Pam)

2 x 2 = 4
(block randomization) 4
3 ( 4)


(prognostic important)

4
(A=L-Pam, B=)[17]
()
<50


1-3


B

A

B

A

A

B

A

B

>50

<50

>50

1-3

>4

>4

B
B
A
A
A
A
B
B

A
A
B
B
B
A
B
A

B
A
A
B
A
B
B
A

A
B
B
A

B
A
A
B

B
A
B
A

B
B
A
A

B
B
A
A

A
B
B
A

B
A
A
B

A
B
A
B

158
Les5-p 145-170.indd 158

7/9/12 1:14 PM

(multicenter study)

(center)

(stratifying variable)

1 2 , 2
2 , 3 2
4 3
2 x 2 x 2 x 3 = 24
(block
randomization)
24




( 5)
minimization

5
[17]

()
()

<50

>50

<50

>50

<2

>2

<2

>2

<2

>2

<2

>2

13

159
Les5-p 145-170.indd 159

7/9/12 1:14 PM

3.2 Minimization


1 2-3
minimization



[1,4]

2
minimization

100


minimization
(non-random method)

minimization




minimization

(multicenter trial)
[4]

(mustine)
(talc)
(pleural effusions)



( 6)

minimization
minimization

4:1

160
Les5-p 145-170.indd 160

7/9/12 1:14 PM

80

minimization
4
2 2

()

<50

>50

1 2

3 4

()

<30

>30

6 (mustine) (talc)
[4]
Mustine
(n=23)

Talc
(n=23)

(
)

50.3(1.5)

55.3(2.2)

1 2
3 4

52%
48%

74%
26%

(
)

33.1(6.2)

60.4(13.1)

43%

74%

()

()

161
Les5-p 145-170.indd 161

7/9/12 1:14 PM

29

minimization
4
( 7)

57 3

22

minimization

( )

minimization

minimization

7 29 Minimization
(mustine) (talc) 4 [4]
Mustine
(n=15)

Talc
(n=14)

<50
>50

7
8

6
8

1 2
3 4

11
4

11
3

()

<30
>30

6
9

4
10

7
8

5
9

()

162
Les5-p 145-170.indd 162

7/9/12 1:14 PM

2
1.

(systematic pseudo random method)[4]

A
B

2.
(nonrandom method)
2

2.1

[4]
2.2

[4]

163

Les5-p 145-170.indd 163

7/9/12 1:14 PM

(blinding
masking)[1,3,4,16,21]

(single-blind)



(open study) (non-blind)

[21]

2 2

1.
2
2

164
Les5-p 145-170.indd 164

7/9/12 1:14 PM

2.

3.

1.
(Single-blind trial)


[4,22]

2.
(Double-blind trial)


165

Les5-p 145-170.indd 165

7/9/12 1:14 PM

(non-blind)

[3,4,22]



A, B C

3.(Triple-blind)

A, B C

[4,23]
(placebo)

1)




(placebo efficiency)
2)
2

(non-drug trial)

166
Les5-p 145-170.indd 166

7/9/12 1:14 PM

(wrong point)

2 2

(long-term treatment)

1. Altman DG. Chapter 5 Designing

research. Practical Statistics for
Medical Research. London: Chapman & Hall; 1991:74-106.
2. Zelen M. A new design for randomized clinical trials. N Eng J Med
1979; 300: 1242-1245.
3. Day SJ, Altman DG. Statistics
Notes: Blinding in clinical trials and
other studies. BMJ 2000; 321:504.
4. Altman DG. Chapter 15 Clinical
trials. Practical Statistics for Medical Research. London: Chapman &
Hall; 1991:440-476.
5. Armitage P. The role of randomization in clinical trials. Stat Med 1982;
1:345-352.
6. Piantadosi S. Chapter 13 Treatment
allocation. Clinical Trials: A meth167

Les5-p 145-170.indd 167

7/9/12 1:14 PM

odologic perspective. 2nd ed. New

York: John Wiley & Sons; 2005:
331-354.
7. Rosenberger WF, Lachin JM. Randomization in Clinical Trials: Theory
and Practice. New York: Wiley;
2002: 259p.
8. Altman DG. Randomization. BMJ
1991; 302: 1481-1482.
9. Bland M. An introduction to Medical Statistics. 3rd ed. Oxford: Oxford
University Press; 2000: 410p.
10. Kerry SM, Bland JM. Trials which
randomize practices. I: how should
they be analyzed? Family Practice
1998; 15: 80-83.
11. Lefebvre C, Clarke M. Identifying
randomized trials. In: Egger M,
Smith GD, Altman DG eds. Systematic reviews in health care: metaanalysis in context. London: BMJ
Publishing Group; 2001:69-86.
12. Wei LJ, Durham S. The randomized
play-the-winner rule in medical
trials. J Am Statist Assoc 1978; 73:
840-843.
13. Ellenberg S. Randomization designs
in comparative clinical trials. N Eng
J Med 1984; 310: 1404-1408.

14. Pocock SJ. When to stop a clinical

trial. BMJ 1992; 305:235-240.
15. Friedman LM, Furberg CD, DeMets
DL. Fundamentals of Clinical
Trials. 3rd ed. New York; SpringerVerlag; 1998: 361p.
16. Meinert CL. Chapter 10 Randomization and the mechanics of treatment masking. Clinical Trials:
Design, conduct and analysis. New
York: Oxford University Press; 1986:
90-112.
17. Pocock SJ. Chapter 5 Methods of
randomization. Clinical Trials: A
Practical Approach. Chichester:
John Wiley & Sons; 1983:66-99.
18. Altman DG, Bland JM. Statistics
notes: How to randomize. BMJ
1999; 319:703-704.
19. Kerry SM, Bland JM. Trials which
randomize practices. II: sample
size. Family Practice 1998; 15: 8487.
20. Sacks H, Chalmers TC, Smith H.
Randomized versus historical controls for clinical trials. Am J Med
1982; 72: 233-240.
21. Jadad AR, Moore RA, Carroll D, et
al. Assessing the quality of reports

168
Les5-p 145-170.indd 168

7/9/12 1:14 PM

of randomized clinical trials; Is

blinding necessary? Control Clin
Trials 1996; 17: 1-12.
22. Spriet A, Simon P. Chapter 6 Single blind and double blind trials.
Methodology of clinical drug trials.
Basel: Karger; 1985:72-80.

23. Portney LG, Watkins MP. Chapter

9 Experimental Control. Foundations
of Clinical Research: Applications
to practice. 2nd ed. New Jersey:
Prentice-Hall; 2000:153-176.

169
Les5-p 145-170.indd 169

7/9/12 1:14 PM

Les5-p 145-170.indd 170

7/9/12 1:14 PM