Randomization

Chance not choice

Mode of deciding treatment

Clinician s discretion Alternation Random allocation

Random allocation
Validates statistical tests of significance Avoids personal preferences Construction of two similar groups

Sound allocation scheme

Assignment masked until initiation of treatment Future assignments cannot be predicted Order of allocation reproducible Documented method of generation Generation process has known mathematical properties Departures from established sequence can be detected
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Patient registration
Patient recruitment Checking eligibility Agreement to randomize Patient consent Formal entry to trial ( reject log ) Random treatment assignment
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Random treatment assignment

Prepare in advance Independent person Sealed envelopes Double-blinded evaluation:
Coded drugs
Individual patient level Coded lots
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Random allocation
Drug A A B B
VH study S.No.: 1 Name: Drug : A

Block 1
RAN S.No.

Block 2
RAN S.No.

Block 3
RAN S.No.

3 1 4 2

3 1 4 2
Chennai

4 2 3 1

8 6 7 5

4 1 2 3

12 9 10 11
Chennai

VH study S.No.: 2 Name: Drug : B

Preparing the randomization list

Simple randomization Restricted randomization Stratified randomization

Simple randomization
Two treatments A or B
A ; Tail = B )

Tossing a coin ( Head =

reasonable, but clumsy and time-consuming

Random number tables

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Simple randomization
Easy process Each treatment assignment unpredictable In the long run patients in each treatment will not be radically different; ONLY in large trials (n>200) the chance of severe imbalance become so remote
Hence, Restricted randomization equal treatment numbers throughout the trial
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Replacement randomization
Any serious inequality in treatment numbers Specify objective criteria for replacement Generate new list

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Restricted randomization
Random permuted blocks More conventional method to ensure
exactly equal treatment numbers at certain equally spaced points (blocks)

For blocks of relatively small size one can use table of random numbers

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Stratified randomization
Ensure similarity patient characteristics Statistical methods allow for lack of comparability Decide on factors to stratify Categorize the factors by 2 or more levels Define strata and prepare restricted randomization list for each stratum
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Stratified randomization
Strata Group Levels Subcutaneous / Low anal / High anal No. of tracks Depth Single / multiple < 3 cm / u 3 cm

Previous surgery Yes / No

3 x 2 x 2 x 2 = 24 strata
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Minimization method
Stratum Group No. of tracks Depth Previous surgery Levels Subcutaneous Low anal High anal Single Multiple < 3 cm u 3 cm Yes No
Treatment arm

K 19 8 13 30 10 31 9 18 22

Next S patient 21 7 12 31 9 32 8 17 23

Next patient: Subcutaneous, multiple, u 3 cm and Yes

Sum for K = 19+ 30 + 9 + 18 = 76 Sum for S = 21+ 31 + 8 + 17 = 77 Next patient receives K 15

Allocation concealment

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The reason that the Medical Research Council s Clinical Trial of streptomycin for pulmonary tuberculosis should be regarded as a landmark is thus not, as is often suggested, because random number tables were used to generate the allocation schedule Rather it is because of the clearly

described precautions that were taken to conceal the allocation schedule from those involved in entering patients

17 Chalmers, 2001

Deciphering the allocation concealment scheme

Posted in bulletin boards Translucent envelopes held up to bright lights Opening unsealed assignment envelopes sensing the differential weight of envelopes Opening unnumbered envelopes until they found a desired treatment
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Deciphering the allocation concealment scheme

Opaque sealed envelopes examined in hot light in the radiology department Asking for next several assignments at once Guessing from the appearance of container labels Ransacking the office files of Principal Investigator for allocation list!
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Adequate allocation concealment schemes

Sequentially numbered, opaque, sealed envelopes Sequentially numbered containers Pharmacy controlled Central randomisation

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Blinding vs. allocation concealment

Blinding
Prevents ascertainment bias Protects the sequence after allocation

Allocation concealment
Primarily to prevent selection bias Protect an assignment sequence before and until allocation
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Potential benefits of successful blinding

Individuals blinded Participants Potential benefits Biased response to intervention Seeking additional adjunct interventions Leave the trial without providing outcome data Compliance Trial investigators Transfer of clinical inclinations or attitudes to participants Differential administration of co-interventions Differential adjustment of dose Differential withdrawal of participants Differential encourage/discourage participants for continuation in the trial Assessors Ascertainment bias
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