Basics of Randomization

1. Basics of Randomization

2. Purpose of Randomization • 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.

3. 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).

4. How is Randomization Implemented? • 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.

5. Randomization Scheme • A list which dictates the order of treatment assignments. • Characteristics: • Blocked vs. Simple • Central vs. By Site • Stratified vs. Not Stratified

6. Simple Randomization • Example of Simple • Randomization • Just like flipping a coin (heads or tails) • A simple rand scheme contains no blocking.

7. Simple Randomization So, why not always use a simple rand scheme? 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?

8. Blocked Randomization • What is blocking? • Breaks the rand scheme into defined units = Blocks • Within each unit (block), the treatment ratio is maintained. ✺ ✺ ✺ ✺ ✺ ✺ ✺ ✺ Block size (which is 4 in the above case!) is confidential!

9. Blocked Randomization • Why block? • Promotes an appropriate treatment ratio • 2) Promotes randomness throughout the rand scheme.

10. Stratified vs. Not Stratified • Use a stratified randomization when • patient characteristics greatly influence • the effectiveness of the treatment. • Promotes an equal distribution of • treatments across patient populations. • Examples • Weight • Age • Severity of disease state

11. Which treatment is likely to have the fewest heart attacks? Example: Not Stratified Treatment A Treatment B • Treatment A • Treatment B

12. Stratified Randomization If stratified on Age (Patients <55 and Patients >=55 ), the result is essentially two rand schemes:

13. Stratified Randomization • Terminology Note: • StratificationFactor: The characteristic of interest (e.g. Age) • StratificationLevel (Strata): The groups within the stratification factor (e.g. Age<55 vs. Age>=55)

14. Stratified Randomization • Another Example: • Let’s stratify patients on hair color like: • Blonde • Brown • Red

15. Stratified Randomization • So, what is the stratification factor? Hair Color! • And, what are the stratification levels? • Blonde • Brown • Red

16. Stratified Randomization Now, how many separate rand schemes are created?

17. Stratified Randomization • For convenience, these 3 schemes are combined into one list as such:

18. Central vs. By Site Randomization Central By Site (site stratified) Typically smaller trials (25-100 pts) Larger trials (>100 pts) A portion of the rand scheme is allocated to each site and patients are randomized based upon the site at which they are enrolled. All patients are randomized from the same rand scheme.

19. Central Randomization Rand Scheme Site 1 2 B 5 B 1 Site 2 A 3 B 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. 4 A Site 3 6 A

20. Central Randomization Ask yourself: Would you have known to only send ‘B’ kits to Site 1? OR only send ‘A’ kits to Site 3? Site 1 2 B 5 B 1 Site 2 A 3 B No….there is no way to predict which drug will be used where because it depends on when patients arrive for treatment. 4 A Site 3 6 A

21. By Site Randomization Site 1 1 A Site 1 Rand Scheme 2 B 1 Site 2 B Site 2 Rand Scheme 2 A 1 B Site 3 Site 3 Rand Scheme 2 A

22. By Site Randomization Site 1 1 A Note: The order of the drug assignment at the site is known…it follows the site’s rand scheme. 2 B 1 Site 2 B 2 A 1 B Site 3 2 A

23. By Site Randomization Rand Scheme for Site 5 Site 5 A B B If we planned to ship 3 kits to Site 5, what kit types would we ship?

24. 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.

25. What type of Rand Scheme? • By site • By site stratified • Central • Central stratified

26. What type of Rand Scheme? • By site • By site stratified • Central • Central stratified

27. 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.’

28. Random Lists • Previous discussion revolved around types and characteristics of rand schemes. However, there are two types of ‘random’ lists used in most trials: • Randomization Scheme – List used to associate patients to treatments (e.g. active, placebo). • Kit List – List used to associate kit numbers to kit types (e.g. Visit 1- 2mg active kit, Visit 2- 4mg active kit)

29. Random Lists • Randomization Scheme: Links patients to treatments Note: The patient and treatment assigned are present, but NO Kit # is listed. • Kit List: Links kit numbers to kit types Note: The Kit # and Kit Type are present, but which patient is NOT listed.

30. 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)

31. Kit Lists Why ‘random’? • We want the number on the kit to, in no way, indicate what the kit contains (assists with blinding). Note: You may also here the word ‘scrambled’ in reference to kit lists.

32. 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.

33. Kit Lists Examples: Sequential vs. Random Numbers Sequential Numbered Random Numbered

34. Kit List Characteristics 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).

35. Kit List Characteristics 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!

36. Kit Lists • Summary: • Kit Numbers may be consecutive or random. • Kit Lists establish the relationship between the TYPE of kit and the kit number.

37. Generation of Random Lists – Best Practices • Request that the files are sent in our standard format • Discuss this with the customer very early in the process • Standard process agreed with Clinical Technologies • Clearly document any relationships between data in the file with the treatment assignments • E.g. A = placebo, B = active

38. 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.

39. Generation of Random Lists – Best Practices • Kit lists • Use a different number of digits in the kit number vs. patient number • Choose the largest kit number range as possible • Allow for hyphens on the kit label, to help with reading long digits (e.g 100-456)

40. 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.

41. 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? • There are two methods used to assign a specific drug kitto a patient: • Single Randomization • 2) Double Randomization

42. Singlevs.Double Method of Randomization One Random List Two Random Lists Manual process (No automation) Automation required (IVRS, IWRS, WebEZ) Non-consecutive Kit Numbers Consecutive Kit Numbers