STATISTICS 542

Introduction to Clinical Trials

RANDOMIZATION METHODS

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RANDOMIZATION

Why randomize

What a random series is

How to randomize

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 Randomization (1)
Rationale

Reference: Byar et al (1976) NEJM 274:74-80.

Best way to find out which therapy is best

Reduce risk of current and future patients of being
on harmful treatment

Example: Retrolental Fibroplasia

(Silverman: Scientific American 236:100-107, 1977)

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 Randomization (2)

Basic Benefits of Randomization

Eliminates assignment basis
Tends to produce comparable groups
Produces valid statistical tests

Basic Methods
Ref: Zelen JCD 27:365-375, 1974.
Pocock Biometrics 35:183-197, 1979

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Goal: Achieve Comparable Groups to Allow
Unbiased Estimate of Treatment

Beta-Blocker Heart Attack Trial

Baseline Comparisons
Propranolol Placebo
(N-1,916) (N-1,921)

Average Age (yrs) 55.2 55.5

Male (%) 83.8 85.2
White (%) 89.3 88.4
Systolic BP 112.3 111.7
Diastolic BP 72.6 72.3
Heart rate 76.2 75.7
Cholesterol 212.7 213.6
Current smoker (%) 57.3 56.8

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 Randomization Basis for
Tests of Hypotheses

The use of randomization provides a basis for an assumption-free

statistical test of the equality of treatments

Such tests were originally proposed by Fisher and are known as

randomization or permutation tests

With sample sizes na and nb , the conditional reference set Wc

consists of n choose na possible combinations of na patients on
treatment a out of n patients

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Statistical Properties of Randomization
A. Sampling-Based B. Randomization
Population Model Model

Population a Population b Study Sample

y~G(y|a) y~G(y|b)

Sample at Sample at
Random Random

na patients nb patients n = nb + nb patients

yaj~G(y|a) ybj~G(y|b)

Randomization

na patients nb patients

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 Randomization Model
Under H0, observed responses independent of treatment
Observed group differences depends ONLY on sequence
of n assignments (random).

Conditional Reference Set Sc

Sc = nCna possible combinations, given na out of n

How many ways could na of the outcomes be assigned to

treatment group A?

Permutation tests usually based on Sc, conditional reference

set.

Under simple randomization, permutation test is

asymptotically equal to homogeneous population model test.
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 Nature of Random Numbers
and Randomness
A completely random sequence of digits is a mathematical
idealization
Each digit occurs equally frequently in the whole sequence
Adjacent (set of) digits are completely independent of one another
Moderately long sections of the whole show substantial regularity

A table of random digits

Produced by a process which will give results closely approximating
to the mathematical idealization
Tested to check that it behaves as a finite section from a
completely random series should
Randomness is a property of the table as a whole
Different numbers in the table are independent

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Table of Random Numbers

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Allocation Procedures
to Achieve Balance
Simple randomization

Biased coin randomization

Permuted block randomization

Balanced permuted block randomization

Stratified randomization

Minimization method
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 Treatment Imbalance
Statistical Properties of Randomization

75-25 split reduces power 90% 80%

66-33 split reduces power 90% 87%

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 Randomization & Balance (1)

n = 100
p=
s = #heads V(s) =
npq = 100 = 25
E(s) = n p = 50

PS 60 PS - np 60 - 50
S np 60 50
P
25 25
10
P
5
P 2 .025
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 Randomization & Balance (2)

n = 20
p=
E(s) = 10
V(s) = np = 20/4 = 5

S np 12 10
PS 12 P
V(s) 5
2
P
5

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 Simple Random Allocation
A specified probability, usually equal, of patients assigned
to each treatment arm, remains constant or may change
but not a function of covariates or response

a. Fixed Random Allocation

n known in advance, exactly
n/2 selected at random & assigned to Trt A, rest to Trt B

b. Complete Randomization (most common)

n not exactly known
marginal and conditional probability of assignment = 1/2
analogous to a coin flip (random digits)

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 Simple Randomization
Advantage: simple and easy to implement

Disadvantage: At any point in time, there may be

an imbalance in the number of subjects on each
treatment
With n = 20 on two treatments A and B, the chance
of a 12:8 split or worse is approximately 0.5
With n = 100, the chance of a 60:40 split or worse is
approximately 0.025
Balance improves as the sample size n increases

Thus desirable to restrict randomization to

ensure balance throughout the trial
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 Restricted Randomization
Simple randomization does not guarantee
balance over time in each realization
Patient characteristics can change during
recruitment (e.g. early pts sicker than later)
Restricted randomizations guarantee
balance
1. Permuted-block
2. Biased coin (Efron)
3. Urn design (LJ Wei)

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Permuted-Block Randomization (1)
Simple randomization does not guarantee balance in numbers
during trial
If patient characteristics change with time, early imbalances
can't be corrected
Need to avoid runs in Trt assignment

Permuted Block insures balance over time

Basic Idea
Divide potential patients into B groups or blocks of size 2m
Randomize each block such that m patients are allocated to A and m to B
Total sample size of 2m B
For each block, there are 2mCm possible realizations
(assuming 2 treatments, A & B)
Maximum imbalance at any time = 2m/2 = m

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Permuted-Block Randomization (2)
Method 1: Example

Block size 2m = 4
2 Trts A,B } 4C2 = 6 possible

Write down all possible assignments

For each block, randomly choose one of the six

possible arrangements

{AABB, ABAB, BAAB, BABA, BBAA, ABBA}

ABAB BABA ......

Pts 1234 5678 9 10 11 12

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Permuted-Block Randomization (3)

Method 2: In each block, generate a uniform

random number for each treatment (Trt), then
rank the treatments in order

Trt in Random Trt in

any order Number Rank rank order

A 0.07 1 A
A 0.73 3 B
B 0.87 4 A
B 0.31 2 B

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Permuted-Block Randomization (4)
Concerns
- If blocking is not masked, the sequence become
somewhat predictable (e.g. 2m = 4)
ABAB BAB? Must be A.
AA Must be B B.
- This could lead to selection bias

Simple Solution to Selection Bias

* Do not reveal blocking mechanism
* Use random block sizes

If treatment is double blind, no selection bias

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 Biased Coin Design (BCD)
Efron (1971) Biometrika
Allocation probability to Treatment A changes to keep
balance in each group nearly equal
BCD (p)
Assume two treatments A & B
D = nA -nB "running difference" n = nA + nB
Define p = prob of assigning Trt > 1/2
e.g. PA = prob of assigning Trt A

If D = 0, PA = 1/2
D > 0, PA = 1 - p Excess A's
D < 0, PA = p Excess B's
Efron suggests p=2/3
D > 0 PA = 1/3 D < 0 PA = 2/3

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 Urn Randomization
Wei & Lachin: Controlled Clinical Trials, 1988
A generalization of Biased Coin Designs
BCD correction probability (e.g. 2/3) remains constant
regardless of the degree of imbalance
Urn design modifies p as a function of the degree of
imbalance
U(, ) & two Trts (A,B)
0. Urn with white, red balls to start
1. Ball is drawn at random & replaced
2. If red, assign B
If white, assign A
3. Add balls of opposite color
(e.g. If red, add white)
4. Go to 1.
Permutational tests are available, but software not as easy.

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 Analysis & Inference
Most analyses do not incorporate blocking

Need to consider effects of ignoring blocks

Actually, most important question is whether we should use complete
randomization and take a chance of imbalance or use permuted-block
and ignore blocks

Homogeneous or Heterogeneous Time Pop. Model

Homogeneous in Time
Blocking probably not needed, but if blocking ignored, no problem
Heterogeneoous in Time
Blocking useful, intrablock correlations induced
Ignoring blocking most likely conservative

Model based inferences not affected by treatment allocation

scheme. Ref: Begg & Kalish (Biometrics, 1984)
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 Kalish & Begg
Controlled Clinical Trials, 1985

Time Trend
Impact of typical time trends (based on ECOG pts)
on nominal p-values likely to be negligible

A very strong time trend can have non-negligible

effect on p-value

If time trends cause a wide range of response

rates, adjust for time strata as a co-variate. This
variation likely to be noticed during interim
analysis.
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 Balancing on
Baseline Covariates

Stratified Randomization

Covariate Adaptive
Minimization
Pocock & Simon

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 Stratified Randomization (1)
May desire to have treatment groups balanced with respect
to prognostic or risk factors (co-variates)
For large studies, randomization tends to give balance
For smaller studies a better guarantee may be needed

Divide each risk factor into discrete categories

f

Number of strata
i 1
i

f = # risk factors;
li = number of categories in factor i
Randomize within each stratum

For stratified randomization, randomization must be

restricted! Otherwise, (if CRD was used), no balance is
guaranteed despite the effort.
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 Example

H 1 2 Factors
Sex (M,F) X
M L
2 2 Levels in
and each
Risk (H,L)
F H 4 Strata
L 3

For stratified randomization, randomization must be restricted!

Otherwise, (if CRD was used), no balance is guaranteed despite
the effort!

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 Stratified Randomization (2)
Define strata

Randomization is performed within each stratum

and is usually blocked

Example: Age, < 40, 41-60, >60; Sex, M, F

Total number of strata = 3 x 2 = 6

Age Male Female

40 ABBA, BAAB, BABA, BAAB, ...

41-60 BBAA, ABAB, ... ABAB, BBAA, ...
>60 AABB, ABBA, ... BAAB, ABAB, ..
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 Stratified Randomization (3)
The block size should be relative small to maintain balance in
small strata, and to insure that the overall imbalance is not too
great

With several strata, predictability should not be a problem

Increased number of stratification variables or increased

number of levels within strata lead to fewer patients per stratum

In small sample size studies, sparse data in many cells defeats

the purpose of stratification

Stratification factors should be used in the analysis

Otherwise, the overall test will be conservative

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 Comment
For multicenter trials, clinic should be a factor
Gives replication of same experiment.

Strictly speaking, analysis should take the particular

randomization process into account; usually ignored
(especially blocking) & thereby losing some sensitivity.

Stratification can be used only to a limited extent,

especially for small trials where it's the most useful;
i.e. many empty or partly filled strata.

If stratification is used, restricted randomization within

strata must be used.

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 Minimization Method (1)
An attempt to resolve the problem of empty strata when trying
to balance on many factors with a small number of subjects
Balances Trt assignment simultaneously over many strata
Used when the number of strata is large relative to sample
size as stratified randomization would yield sparse strata
A multiple risk factors need to be incorporated into a score
for degree of imbalance
Need to keep a running total of allocation by strata
Also known as the dynamic allocation
Logistically more complicated
Does not balance within cross-classified stratum cells;
balances over the marginal totals of each stratum, separately

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Example: Minimization Method (a)
Three stratification factors: Sex (2 levels),
age (3 levels), and disease stage (3 levels)
Suppose there are 50 patients enrolled and the
51st patient is male, age 63, and stage III

Trt A Trt B
Sex Male 16 14
Female 10 10
Age < 40 13 12
41-60 9 6
> 60 4 6
Disease Stage I 6 4
Stage II 13 16
Stage III 7 4
Total 26 24 542-04-#33
Example: Minimization Method (b)

Method: Keep a current list of the total patients on

each treatment for each stratification factor level

Consider the lines from the table above for that

patient's stratification levels only
Sign of
Trt A Trt B Difference
Male 16 14 +
Age > 60 4 6 -
Stage III 7 4 +
Total 27 24 2 +s and 1 -

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Example: Minimization Method (c)

Two possible criteria:

Count only the direction (sign) of the difference in

each category. Trt A is ahead in two categories
out of three, so assign the patient to Trt B

Add the total overall categories (27 As vs 24 Bs).

Since Trt A is ahead, assign the patient to Trt B

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 Minimization Method (2)
These two criteria will usually agree, but not always

Choose one of the two criteria to be used for the

entire study

Both criteria will lead to reasonable balance

When there is a tie, use simple randomization

Generalization is possible

Balance by margins does not guarantee overall

treatment balance, or balance within stratum cells

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 Covariate Adaptive Allocation
(Sequential Balanced Stratification)
Pocock & Simon, Biometrics, 1975;
Efron, Biometrika, 1971

Goal is to balance on a number of factors but with "small"

numbers of subjects

In a simple case, if at some point Trt A has more older patients that
Trt B, next few older patients should more likely be given Trt B
until "balance" is achieved

Several risk factors can be incorporated into a score for degree of

imbalance B(t) for placing next patient on treatment t (A or B)

Place patient on treatment with probability p > 1/2 which causes

the smallest B(t), or the least imbalance

More complicated to implement - usually requires a small "desk

top" computer
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Example: Baseline Adaptive Randomization
Assume 2 treatments (1 & 2)
2 prognostic factors (1 & 2) (Gender & Risk Group)
Factor 1 - 2 levels (M & F)
2
Factor 2 - 3 levels (High, Medium & Low Risk)
Let B(t) = Wi Range (xit1, xit2) wi = weight for each factor
i 1
e.g. w1 = 3 w1/w2 = 1.5
w2 = 2
xij = number of patients in ith factor and jth treatment
xitj = change in xij if next patient assigned treatment t

Let P = 2/3 for smallest B(t) Pi = (2/3, 1/3)

Assume we have already randomized 50 patients
Now 51st pt.
Male (1st level, factor 1)
Low Risk (3rd level, factor 2)
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 Factor 1(Sex) 2(Risk)
Level 1(M) 2(F) 1(H) 2(M) 3(L) Total
Patient 1 16* 10 13 9 4* 26
Group 2 14 10 12 6 6 24
Total 30 20 25 15 10 50

Now determine B(1) and B(2) for patient #51.

If assigned Treatment 1 (t = 1)

(a) Calculate B(t) (Assign Pt #51 to trt 1) t = 1

(1) Factor 1, Level 1
(Male)
Now Proposed
K X1K X11K
Trt Group 1 16 17
2 14 14
Range =|17-14| = 3 542-04-#39
 Factor 1(Sex) 2(Risk)
Level 1(M) 2(F) 1(H) 2(M) 3(L) Total
Patient 1 16* 10 13 9 4* 26
Group 2 14 10 12 6 6 24
Total 30 20 25 15 10 50

(a) Calculate B(t) (Assign Pt #51 to trt 1) t=1

(2) Factor 2, Level 3

(Low Risk)

K X2K X12K
Trt Group 1 4 5
2 6 6

Range = |5-6|, = 1

* B(1) = 3(3) + 2(1) = 11

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(b) Calculate B(2) (Assign Pt #51 to trt 2) t=2

(1) Factor 1, Level 1

(Male)
K X1K X21K
Group 1 16 16
2 14 15
Range = |16-15| = 1

(2) Factor 2, Level 3

(Low Risk)
K X2k X22k
Group 1 4 4
2 6 7
Range = |4-7| = 3

* B(2) = 3(1) + 2(3) = 9

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(c) Rank B(1) and B(2), measures of imbalance

Assign t
t B(t) with probability
2 9 2/3
1 11 1/3

* Note: minimization would assign treatment

2 for sure

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 Response Adaptive
Allocation Procedures
Use outcome data obtained during trial to influence
allocation of patient to treatment
Data-driven
i.e. dependent on outcome of previous patients
Assumes patient response known before next patient
The goal is to allocate as few patients as possible to
a seemingly inferior treatment
Issues of proper analyses quite complicated
Not widely used though much written about
Very controversial

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 Play-the-Winner Rule
Zelen (1969)
Treatment assignment depends on the outcome of
previous patients
Response adaptive assignment
When response is determined quickly
1st subject: toss a coin, H = Trt A, T = Trt B
On subsequent subjects, assign previous treatment if it was
successful
Otherwise, switch treatment assignment for next patient
Advantage: Potentially more patients receive the better
treatment
Disadvantage: Investigator knows the next assignment
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 Response Adaptive
Randomization

Example
"Play-the-winner Zelen (1969) JASA

TRT A SSF SSSF

TRT B SF

Patient 1 2 3 4 5 6 7 8 9 ......

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 Two-armed Bandit or
Randomized Play-the-Winner Rule
Treatment assignment probabilities depend on observed
success probabilities at each time point

Example: ECMO trial

Advantage: Attempts to maximize the number of subjects

on the superior treatment

Disadvantage: When unequal treatment numbers result,

there is loss of statistical power in the treatment
comparison

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 ECMO Example
References
Michigan
1a. Bartlett R., Roloff D., et al.; Pediatrics (1985)
1b. Begg C.; Biometrika (1990)

Harvard
2a. ORourke P., Crone R., et al.; Pediatrics (1989)
2b. Ware J.; Statistical Science (1989)
2c. Royall R.; Statistical Science (1991)

Extracoporeal Membrane Oxygenator(ECMO)

treat newborn infants with respiratory failure or hypertension
ECMO vs. conventional care

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 Michigan ECMO Trial
Bartlett Pediatrics (1985)
Modified play-the-winner
Urn model
A ball ECMO
B ball Standard control
If success on A, add another A ball .
Wei & Durham JASA (1978)
Randomized Consent Design
Results
1 2* 3 4 5 6 7 8 9 10
ECMO S S S S S S S S S
CONTROL F
*sickest patient
P-Values, depending on method, values ranged
.001 6 .05 6 .28
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 Harvard ECMO Trial (1)
ORourke, et al.; Pediatrics (1989)

ECMO for pulmonary hypertension

Background
Controversy of Michigan Trial
Harvard experience of standard
11/13 died

Randomized Consent Design

Two stage
1st Randomization (permuted block) switch to
superior treatment after 4 deaths in worst arm

2nd Stay with best treatment

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Harvard ECMO Trial (2)

Results
Survival
1st 2nd*
ECMO 9/9 19/20
CONTROL 6/10
* less severe patients

P = .054 (Fisher)

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 Multi-institutional Trials
Often in multi-institutional trials, there is a marked
institution effect on outcome measures

Using permuted blocks within strata, adding institution

as yet another stratification factor will probably lead to
sparse cells (and potentially more cells than patients!)

Use permuted block randomization balanced within

institutions

Or use the minimization method, using institution as a

stratification factor

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 Mechanics of Randomization (1)

Basic Principle - Analyze What is Randomized

* Timing

Actual randomization should be delayed until just

prior to initiation of therapy

Example
Alprenolol Trial, Ahlmark et al (1976)
393 patients randomized two weeks before therapy
Only 162 patients treated, 69 alprenolol & 93 placebo
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Mechanics of Randomization (2)
* Operational
1. Sequenced sealed envelopes (prone to tampering!)

2. Sequenced bottles/packets

3. Phone call to central location

- Live response
- Voice Response System

4. One site PC system

5. Web based

Best plans can easily be messed up in the implementation 542-04-#53

Example of Previous Methods (1)
20 subjects, treatment A or B, risk H or L
Subject Risk
1 H Randomize Using
2 L
3 L 1. Simple
4 H
5 L 2. Blocked (Size=4)
6 L
7 L 3. Stratify by risk + use simple
8 L
9 H 4. Stratify by risk + block
10 L
11 H
12 H For each compute
13 H
14 H 1. Percent pts on A
15 L
16 L 2. For each risk group, percent of pts on A
17 H
18 H
19 L 10 subjects with H
20 H 10 subjects with L
542-04-#54
Example of Previous Methods (2)
1. Simple 1st Try 2nd Try
(a) 9/20 A's 7/20 A's OVERALL BY
(b) H: 5/10 A's 3/10 A's SUBGROUP
L: 4/10 A's 4/10 A's
2. Blocked (No stratification)
(a) 10 A's & 10 B's
(b) H: 4 A's & 6 B's
L: 6 A's & 4 B's
3. Stratified with simple randomization
(a) 5 A's & 15 B's
(b) H: 1 A & 9 B's
L: 4 A's & 6 B's
4. Stratified with blocking
(a) 10 A's & 10 B's MUST BLOCK TO MAKE
STRATIFICATION PAY
(b) H: 5 A's & 5 B's OFF
L: 5 A's & 5 B's
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