Basics of Randomization

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


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)


Another Example:

Let’s stratify patients on hair color like:

• Blonde• Brown• Red


• So, what is the stratification factor?

Hair Color!

• And, what are the stratification levels?

• Blonde• Brown• Red


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


• 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.

http://www.mystrategy-roulette.com/images/ruleta1b3.jpg

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.


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)


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

Basics of Randomization

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