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Basics ofRandomization
Randomization is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial arising from the influence that the knowledge of the impending treatment assignment may have on the recruitment and allocation of subjects.
Purpose of Randomization
How Does Randomization Limit Bias?
If allocation of a patient to a treatment is done ‘randomly’, then personnel at a site can not predict the next treatment assignment (ie., there is no pattern upon which to make a prediction).
How is RandomizationImplemented?
• Via a Randomization Scheme (aka, Rand Scheme)
• A Rand Scheme is a list which dictates the order of treatment assignments (e.g. Active, Placebo) within a clinical trial.
A list which dictates the order of
treatment assignments.
Characteristics:
Blocked vs. Simple
Central vs. By Site
Stratified vs. Not Stratified
Randomization Scheme
Example of SimpleRandomization
• Just like flipping a coin (heads or tails)
• A simple rand scheme contains no blocking.
Patient Treatment
1 A
2 A
3 B
4 B
5 A
6 A
7 B
8 A
9 B
10 B
Simple Randomization
Simple Randomization
So, why not always use a simple rand scheme?
Patient Treatment
1 A
2 A
3 A
4 A
5 A
6 A
7 A
8 A
9 B
10 B
There are two problems: Hint 1: Does the list look random?
Hint 2: What if we want a 1:1 ratio of A to B?
What is blocking?
• Breaks the rand scheme into defined units = Blocks
• Within each unit (block), the treatment ratio is maintained.
Block Patient
Treatment
1 001 A
1 002 A
1 003 B
1 004 B
2 005 B
2 006 A
2 007 B
2 008 ABlock size (which is 4 in the above case!) is confidential!
Blocked Randomization
✺
✺
✺
✺
✺
✺
✺
✺
Why block?
1) Promotes an appropriate treatment ratio
2) Promotes randomness throughout the rand scheme.
Block Patient
Treatment
1 001 A
1 002 A
1 003 B
1 004 B
2 005 B
2 006 A
2 007 B
2 008 A
Blocked Randomization
Use a stratified randomization whenpatient characteristics greatly influencethe effectiveness of the treatment.
Promotes an equal distribution oftreatments across patient populations.
Examples Weight Age Severity of disease state
Stratified vs. Not Stratified
Which treatment is likely to have the fewest heart attacks? 1. Treatment A
2. Treatment B
50 % 50 %
1 2
Example: Not StratifiedTreatment A Treatment B
If stratified on Age (Patients <55 and Patients >=55 ), the result is essentially two rand schemes:
For Patients < 55
Patient Treatment
1 A
2 B
3 B
4 A
For Patients >=55
Patient Treatment
1 A
2 B
3 A
4 B
Stratified Randomization
Stratified Randomization
Terminology Note:
Stratification Factor: The characteristic of interest (e.g. Age)
Stratification Level (Strata): The groups within the stratification factor (e.g. Age<55 vs. Age>=55)
Stratified Randomization
Another Example:
Let’s stratify patients on hair color like:
• Blonde• Brown• Red
Stratified Randomization
• So, what is the stratification factor?
Hair Color!
• And, what are the stratification levels?
• Blonde• Brown• Red
Stratified Randomization
Now, how many separate rand schemes are created?
BlondePatient Trt
1 A
2 A
3 B
4 B
BrownPatient Trt
1 A
2 B
3 A
4 B
RedPatient Trt
1 A
2 B
3 B
4 A
Stratified Randomization
• For convenience, these 3 schemes are combined into one list as such:
Seq Order Hair Color Trt
1 Blonde A
2 Blonde A
3 Blonde B
4 Blonde B
5 Brown A
6 Brown B
7 Brown A
8 Brown B
9 Red A
10 Red B
11 Red B
12 Red A
Central By Site (site stratified)
Typically smaller trials
(25-100 pts)
Larger trials (>100 pts)
All patients are randomized from the same rand scheme.
A portion of the rand scheme is allocated to each site and
patients are randomized based upon the site at which
they are enrolled.
Central vs. By Site Randomization
Central RandomizationRand Scheme
Site 1
Site 2
Site 3
Patient Trt
1 A
2 B
3 B
4 A
5 B
6 A
2
5
1
3
4
6
A
B
B
A
B
A
Note: Order of assignments does not vary based upon where patient was randomized.
For example, the third patient will always be assigned to ‘B’ regardless of which site recruits the third patient.
Central Randomization
Site 1
Site 2
Site 3
2
5
1
3
4
6
A
B
B
A
B
A
Ask yourself:
Would you have known to only send ‘B’ kits to Site 1?
OR only send ‘A’ kits to Site 3?
No….there is no way to predict which drug will be used where because it depends on when patients arrive for treatment.
By Site RandomizationPatient Trt
1 A
2 B
Site 1
Site 2
Site 3
1
2
1
2
1
2
B
A
A
B
B
A
Patient Trt
1 B
2 A
Site 1 Rand Scheme
Site 2 Rand Scheme
Patient Trt
1 B
2 A
Site 3 Rand Scheme
By Site RandomizationPatient Trt
1 A
2 B
Site 1
Site 2
Site 3
1
2
1
2
1
2
B
A
A
B
B
A
Patient Trt
1 B
2 A
Patient Trt
1 B
2 A
Note: The order of the drug assignment at the site is known…it follows the site’s rand scheme.
By Site Randomization
Patient Trt
1 A
2 B
3 B
4 A
5 A
6 B
Rand Scheme for Site 5
Site 5
If we planned to ship 3 kits to Site 5, what kit types would we ship?
A
B
B
Types of Rand Schemes Each of the Rand Scheme characteristics can be combined to
produce different types of Rand Schemes.
Examples are:
• Central
• Central and Stratified
• By Site and Stratified
Note: All of the above Rand Schemes are blocked and a block size must be designated. Simple randomization is rarely used.
What type of Rand Scheme?
1. By site
2. By site stratified
3. Central
4. Central stratified
25 % 25 % 25 % 25 %
1 2 3 4
What type of Rand Scheme?
1. By site
2. By site stratified
3. Central
4. Central stratified
25 % 25 % 25 % 25 %
1 2 3 4
Dynamic (Adaptive) Randomization• Used when randomization needs to be stratified
on various levels and the sample size is very small.
• Special feature is that the study drug assignment is NOT fixed at the beginning of the trial (i.e.., it’s dynamic!).
• The assignment is determined at the time of randomization based upon the type of patients currently enrolled, the characteristics of the current patient and need of the trial to ‘fill all the cells.’
Random Lists
Previous discussion revolved around types and characteristics of rand schemes. However, there are two types of ‘random’ lists used in most trials:
1. Randomization Scheme – List used to associate patients to treatments (e.g. active, placebo).
2. Kit List – List used to associate kit numbers to kit types (e.g. Visit 1- 2mg active kit, Visit 2- 4mg active kit)
• Randomization Scheme: Links patients to treatments
• Kit List: Links kit numbers to kit types
Patient Trt
1 A
2 B
Note: The patient and treatment assigned are present, but NO Kit # is listed.
Kit # Kit Type
8432 A
4492 B
Note: The Kit # and Kit Type are present, but which patient is NOT listed.
Random Lists
Kit Lists
• Definition: A list of kit numbers associated with the content of the kit.
• In a randomized clinical trial, the association between the kit number and the treatment is random (in other words…you can’t guess the contents of
the kit based upon the kit number)
Why ‘random’?
• We want the number on the kit to, in no way, indicate what the kit contains (assists with blinding).
Kit Lists
Note: You may also here the word ‘scrambled’ in reference to kit lists.
Kit Lists
• Like Rand Schemes, Kit Lists have different characteristics.
• The type of kit list generated for a trial will depend upon the method used to assign the kit to a patient.
• We’ll discuss ‘Method of Randomization’ later today.
Kit Lists
Kit # Kit Type
101 4mg Active
102 2mg Placebo
103 4mg Placebo
104 2mg Active
Examples: Sequential vs. Random Numbers
Kit # Kit Type
332 Visit 1 Active
638 Visit 1 Placebo
123 Visit 2 Active
875 Visit 2 Placebo
Sequential Numbered Random Numbered
Kit List Characteristics
Kit # Kit Type
101 4mg Active
102 2mg Placebo
103 4mg Placebo
104 2mg Active
Kit numbers are consecutive (101 – 104)
Kit Type is designated…there are 4 types of kits.
Remember: A Kit List associates a kit number with a kit type (e.g. 2mg Active vs 4mg Active), NOT just a treatment (Active vs. Placebo).
Kit List Characteristics
Kit # Kit Type
332 Visit 1 Active
638 Visit 1 Placebo
123 Visit 2 Active
875 Visit 2 Placebo
Kit Numbers are non-consecutive and randomly ordered
There are 4 types of kits, 2 for Visit 1 and 2 for Visit 2
Again: Kit Type is indicated, NOT treatment!
Kit Lists
Summary:
•Kit Numbers may be consecutive or random.
•Kit Lists establish the relationship between the TYPE of kit and the kit number.
Request that the files are sent in our standard formatDiscuss this with the customer very early in the
processStandard process agreed with Clinical Technologies
Clearly document any relationships between data in the file with the treatment assignmentsE.g. A = placebo, B = active
Generation of Random Lists – Best Practices
Ensure lists (electronic and hard copies) are adequately controlled
Compare the list uploaded into the computer database with the list provided
“Numbers are FREE”Generate more randomization slots than what
you think you will need.
Generation of Random Lists – Best Practices
Kit listsUse a different number of digits in the kit
number vs. patient numberChoose the largest kit number range as
possibleAllow for hyphens on the kit label, to help
with reading long digits (e.g 100-456)
Generation of Random Lists – Best Practices
Random Lists at Clinical Services
• Random Lists include:
• Randomization Schemes
• Kit Lists
• Random List SOP (“Procedure for the Control of Random Lists” - GQA.005) governs the process of requesting, receipt and storage.
There are two methods used to assign a specific drug kit to a patient:
1) Single Randomization
2) Double Randomization
Randomizing Patients
Let’s say, the clinician has received the study drug and has a patient ready to receive drug.
How does the clinician know which kit to give the patient?
???
Single vs. Double
One Random List Two Random Lists
Manual process (No automation)
Automation required (IVRS, IWRS, WebEZ)
Consecutive Kit Numbers
Non-consecutive Kit Numbers
Method of Randomization