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 (N-1,916) Average Age (yrs) Male (%) White (%) Systolic BP Diastolic BP Heart rate Cholesterol Current smoker (%) 55.2 83.8 89.3 112.3 72.6 76.2 212.7 57.3 Placebo (N-1,921) 55.5 85.2 88.4 111.7 72.3 75.7 213.6 56.8
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Randomization Basis for Tests of Hypotheses

The use of randomization provides a basis for an assumptionfree 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 ;c 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 Population Model B. Randomization Model

Population a y~G(y|Ua)

Population b y~G(y|Ub)

Study Sample

Sample at Random

Sample at Random

na patients yaj~G(y|Ua)

nb patients ybj~G(y|Ub)

n = nb + nb patients

Randomization

na patients

nb patients 542-04-#7

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% p80% 66-33 split reduces power 90% p87%

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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 0.19 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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Randomization & Balance (1) Coin Flip

n = 100 tosses of a coin p = for a fair coin s = # heads E(s) = n p = 50 V(s) = npq = 100 = 25 Probability of a 60:40 split

P_ u 60a ! PS - u 60 - 50 S S  np 60  50 ! P u 25 25 10 ! P u 5 ! P u 2 ! .025
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Randomization & Balance (2)

n = 20 p= E(s) = np = 10 V(s) = npq = 20/4 = 5 Probability of a 12:8 split or worse

S np 12 10 PS u 12 ! P u V(s) 5 2 ! P u 5 = 0.19
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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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PermutedPermuted-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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PermutedPermuted-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 Pts 1234 BABA 5678 ...... 9 10 11 12
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PermutedPermuted-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 any order A A B B Random Number 0.07 0.73 0.87 0.31 Trt in rank order A B A B
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Rank 1 3 4 2

PermutedPermuted-Block Randomization (4)

Concerns - If blocking is not masked, the sequence become
somewhat predictable (e.g. 2m = 4) ABAB BAB? Must be A. Must be B B. AA - 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(E, F) & two Trts (A,B)
0. Urn with E white, E red balls to start 1. Ball is drawn at random & replaced 2. If red, assign B If white, assign A 3. Add F balls of opposite color (e.g. If red, add F 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

TN
i i !1

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 M L

Sex (M,F) and Risk (H,L)

F

1 2
H L

2 Factors X 2 Levels in each 4 Strata

3 4

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 40 41-60 >60 Male ABBA, BAAB, BBAA, ABAB, ... AABB, ABBA, ... Female BABA, BAAB, ... ABAB, BBAA, ... 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 16 10 13 9 4 6 13 7 26 Trt B 14 10 12 6 6 4 16 4 24

Sex Age

Disease

Male Female < 40 41-60 > 60 Stage I Stage II Stage III

Total

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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 1 542-04-#33

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 Biometrika,
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) Factor 2 - 3 levels (High, Medium & Low Risk) 2 Let B(t) = 7 W i 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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Fact r l ati t Gr tal

( ( ) *

) (F)

( i ) ( ) ( ) ( ) *

tal

N w d t rmi

B( ) and B( ) f r ati nt # (t = )

If assigned reatment

(a) Calculate B(t) (Assign t # ( ) Fact r , evel ( ale) K 1 2

t trt ) t =

Trt Group

N w r sed X K p X11K 16 17 14 14
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Range =|17-14| = 3

Factor Level Patient 1 Group 2 Total

1(Sex) 1(M) 2(F) 16* 10 14 10 30 20

2(Risk) 1(H) 2(M) 3(L) 13 9 4* 12 6 6 25 15 10

Total 26 24 50

(a) Calculate B(t) (Assign Pt #51 to trt 1) (2) Factor 2, Level 3 (Low Risk) K 1 2 X2K X12K 4 p 5 6 6

t=1

Trt Group

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 with probability 2/3 1/3

t 2 1

B(t) 9 11

* 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-thePlay-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 TRT B SSF SF SSSF

Patient 1 2 3 4 5 6 7 8 9 ......
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TwoTwo-armed Bandit or Randomized Play-the-Winner Rule Play-the 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 p ECMO B ball p Standard control If success on A, add another A ball .

Wei & Durham JASA (1978)

Randomized Consent Design Results

ECMO CONTROL 1 S 2* F 3 S 4 S

5 S

6 S

7 S

8 S

9 S

10 S

*sickest patient

P-Values, depending on method, values ranged .001 .05 .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 Stay with best treatment
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2nd

Harvard ECMO Trial (2)

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

* less severe patients

P = .054 (Fisher)
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MultiMulti-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. 2. 3. Sequenced sealed envelopes (prone to tampering!) Sequenced bottles/packets Phone call to central location - Live response - Voice Response System One site PC system Web based
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4. 5.

Best plans can easily be messed up in the implementation

Example of Previous Methods (1)

20 subjects, treatment A or B, risk H or L
Subject 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Risk H L L H L L L L H L H H H H L L H H L H Randomize Using 1. Simple 2. Blocked (Size=4) 3. Stratify by risk + use simple 4. Stratify by risk + block For each compute 1. Percent pts on A 2. For each risk group, percent of pts on A 10 subjects with H 10 subjects with L
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Example of Previous Methods (2)

1. Simple (a) (b) 1st Try 9/20 A's H: 5/10 A's L: 4/10 A's 2nd Try 7/20 A's 3/10 A's 4/10 A's OVERALL BY SUBGROUP

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 (b) H: 5 A's & 5 B's L: 5 A's & 5 B's MUST BLOCK TO MAKE STRATIFICATION PAY OFF
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Allen Centennial Gardens

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