Basics of Randomization

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. Emphasize the words in red. The focal point of this slide is that to create a fair test of the treatments studied, we must limit the influence that possible bias may have on the conduct of a trial. If a clinician feels that one treatment is far superior to another treatment (e.g. the active treatment must be better than placebo), then if the doctor knows the identity of the next treatment assignment, they may decide to OR not to enrolled a patient b/c of the patient’s characteristics. For example, if a patient is very ill, the clinician may not enroll the patient in the trial if he believes the next treatment is placebo (as the patient will not benefit from being in the study).

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). The idea behind randomization is to introduce a treatment allocation which is not reasonably predictable. The allocation is not always without pattern as we do introduce pattern by adding blocking and stratification factors (which we will take about later). However, when these are added, we do so in a way that makes predicting the next assignment improbable.

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. The idea behind randomization is to introduce a treatment allocation which is not reasonably predictable. The allocation is not always without pattern as we do introduce pattern by adding blocking and stratification factors (which we will take about later). However, when these are added, we do so in a way that makes predicting the next assignment improbable.

Randomization Scheme A list which dictates the order of treatment assignments. Characteristics: Blocked vs. Simple Central vs. By Site Stratified vs. Not Stratified Emphasize that these are methods of randomization a patient to a treatment group. At this stage, we are not talking about drug kit assignment, but just assignment to a treatment group (e.g. Active or Placebo).

Simple Randomization Example of Simple Randomization Just like flipping a coin (heads or tails) A simple rand scheme contains no blocking. Patient Treatment 1 A 2 3 B 4 5 6 7 8 9 10 Simple randomization is just that….each patient / row in the list is randomly assigned to A or B. There is no blocking or requirement that there be a set number of A’s and B’s…it is the luck of the draw…. In this example, the random list includes 10 rows / patients with 5 randomized to A and 5 randomized to B.

Simple Randomization So, why not always use a simple rand scheme? Patient Treatment 1 A 2 3 4 5 6 7 8 9 B 10 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? Another example of simple randomization. The above example could be a result of a ‘random’ allocation process. However, there are two problems with this list: 1) The list does not look random – 5 As and then 5 Bs 2) If only 6 patients are enrolled, there would be a total of 5 As and only 1 B. Since the allocation is ‘random’, any row could be A or B….there is no requirement that there are an equal number of As and Bs.

Blocked Randomization 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 002 003 B 004 2 005 006 007 008 ✺ ✺ ✺ ✺ ✺ With a blocked randomization, we ensure that within a set number of patients, we can better achieve the treatment ratio (in this case 1:1) which is desired. In this case, if only 6 patients are enrolled, we now have 3 A’s and 3 B’s. ✺ ✺ ✺ Block size (which is 4 in the above case!) is confidential!

Blocked Randomization Why block? Promotes an appropriate treatment ratio 2) Promotes randomness throughout the rand scheme. Block Patient Treatment 1 001 A 002 003 B 004 2 005 006 007 008 With a blocked randomization, we ensure that within a set number of patients, we can better achieve the treatment ratio (in this case 1:1) which is desired. In this case, if only 6 patients are enrolled, we now have 3 A’s and 3 B’s.

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 No notes…

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

Stratified Randomization 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 4 For Patients >=55 Patient Treatment 1 A 2 B 3 4 By having two lists, as patients under 55 are enrolled, we can ensure that we have an appropriate number of A’s and B’s assigned. Likewise, for patients over 55. Animation alert: Describe that there are two lists. Then click and the list for patients <55 will appear. Likewise, click, and the list for patients >=55 will appear.

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) By having two lists, as patients under 55 are enrolled, we can ensure that we have an appropriate number of A’s and B’s assigned. Likewise, for patients over 55. Animation alert: Describe that there are two lists. Then click and the list for patients <55 will appear. Likewise, click, and the list for patients >=55 will appear.

Stratified Randomization Another Example: Let’s stratify patients on hair color like: Blonde Brown Red Another example to clarify terminology and emphasize that for each stratification group (e.g. blonde, brown, red, gray), a separate rand scheme is created (next slide…)

Stratified Randomization So, what is the stratification factor? Hair Color! And, what are the stratification levels? Blonde Brown Red Clarifying terminology

Stratified Randomization Now, how many separate rand schemes are created? Blonde Patient Trt 1 A 2 3 B 4 Brown Patient Trt 1 A 2 B 3 4 Red Patient Trt 1 A 2 B 3 4 Further explain that for each stratification level, a separate rand scheme is produced to ensure the appropriate distribution of treatment assignments within the patient population.

Stratified Randomization Seq Order Hair Color Trt 1 Blonde A 2 3 B 4 5 Brown 6 7 8 9 Red 10 11 12 For convenience, these 3 schemes are combined into one list as such: Further explain that for each stratification level, a separate rand scheme is produced to ensure the appropriate distribution of treatment assignments within the patient population.

Central vs. By Site Randomization 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. Emphasis should be placed upon the fact that central involves patients being randomized from ONE list, by site means that they are randomized from a list for EACH site. This information is often not clearly stated in a clinical protocol. If you are not sure of the type of randomization, ask the sponsor.

Central Randomization Rand Scheme Site 1 2 Patient Trt 1 A 2 B 3 4 5 6 B 5 B 1 Site 2 A 3 B The Rand List provided here is a central rand. As each patient is enrolled (regardless of site), the patient is assigned the next assignment in the list. Animation alert: Click and describe each patient entering. The colored blocks will move to the patient assigned to the treatment. 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

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. The Rand List provided here is a central rand. As each patient is enrolled (regardless of site), the patient is assigned the next assignment in the list. Animation alert: Click and describe each patient entering. The colored blocks will move to the patient assigned to the treatment. 4 A Site 3 6 A

By Site Randomization 1 A 2 B 1 B 2 A 1 B 2 A 1 A 2 B 1 B 2 A 1 B 2 A Patient Trt 1 A 2 B Site 1 1 A Site 1 Rand Scheme 2 B 1 Patient Trt 1 B 2 A Site 2 B Site 2 Rand Scheme 2 A The Rand List provided here is a central rand. As each patient is enrolled (regardless of site), the patient is assigned the next assignment in the list. Animation alert: Click and describe each patient entering. The colored blocks will move to the patient assigned to the treatment. 1 B Patient Trt 1 B 2 A Site 3 Site 3 Rand Scheme 2 A

By Site Randomization 1 A Patient Trt 1 A 2 B 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 Patient Trt 1 B 2 A 1 Site 2 B 2 A The Rand List provided here is a central rand. As each patient is enrolled (regardless of site), the patient is assigned the next assignment in the list. Animation alert: Click and describe each patient entering. The colored blocks will move to the patient assigned to the treatment. 1 B Patient Trt 1 B 2 A Site 3 2 A

By Site Randomization 1 A 2 B 3 4 5 6 Patient Trt Site 5 Rand Scheme for Site 5 Patient Trt 1 A 2 B 3 4 5 6 Site 5 A B The Rand List provided here is a central rand. As each patient is enrolled (regardless of site), the patient is assigned the next assignment in the list. Animation alert: Click and describe each patient entering. The colored blocks will move to the patient assigned to the treatment. B If we planned to ship 3 kits to Site 5, what kit types would we ship?

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 Animation alert (4 messages) First Click – Central Rand Second Click – Central and Stratified Third Click – By Site and Stratified Fourth Click – A note about blocking – We discussed this phrase and need to point out that all rand schemes are blocked. 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? By site By site stratified Central Central stratified

What type of Rand Scheme? By site By site stratified Central Central stratified

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.’ This style of randomization is not used very often and requires a custom programmed IVRS system to function.

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) Emphasis should be placed upon the items in red. We’ve spent the prior slides discussing randomization to a treatment (A or B or C)….however, we now have to figure out which kit to assign (eg. Kit 229, 441, 448?)

Random Lists Randomization Scheme: Links patients to treatments Trt 1 A 2 B Note: The patient and treatment assigned are present, but NO Kit # is listed. Kit List: Links kit numbers to kit types Emphasis should be placed upon the items in red. We’ve spent the prior slides discussing randomization to a treatment (A or B or C)….however, we now have to figure out which kit to assign (eg. Kit 229, 441, 448?) Kit # Kit Type 8432 A 4492 B Note: The Kit # and Kit Type are present, but which patient is NOT listed.

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) Now, transition to kit lists - Let’s define what a kit list is and emphasize that there is a element of randomness to a list.

Kit Lists Why ‘random’? We want the number on the kit to, in no way, indicate what the kit contains (assists with blinding). If the site can not determine the contents of the kit based upon the number on the kit, they can remain blinded to the treatment assignment. This helps to limit the possibility of bias. 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. The type of kit list used for a project depends upon the way kits will be allocated to a patient (via IVRS, via WebRand, consecutively assigned at the site, etc…) We’ll get into how to decide which type to use in a more advance section.

Kit Lists Examples: Sequential vs. Random Numbers Kit # Kit Type 101 4mg Active 102 2mg Placebo 103 4mg Placebo 104 2mg Active Kit # Kit Type 332 Visit 1 Active 638 Visit 1 Placebo 123 Visit 2 Active 875 Visit 2 Placebo Let’s review briefly what kit lists look like and the fundamental purpose of the list. Here are a couple of examples and let’s look at each one Sequential Numbered Random Numbered

Kit List Characteristics 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. The purpose of these slides is not to explain WHEN each type of kit list is used, but to point out general characteristics. Animation (click): This list has consecutively numbered kits. Sometimes, kit lists are consecutively numbered with no gaps in the number sequence (ie., from 101 to 120, inclusive) Animation (click): Note that there are 4 different kits used in this trial which are distinguished by dose and medication type. Animation(click): The most important thing to note is that we are associating the kit number to a kit type, not necessarily a treatment (Active vs. Placebo) 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 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 For this kit list, Animation(click): The kit numbers appear random and non-consecutive. Animation(click): There are 4 types of kits used in this list and the kit types vary based upon medication content and which visit the kit will be used. 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. After the last point – remember the rand scheme includes information about the Treatment…the kit list includes information about the Kit TYPE!

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

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 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)

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. Now we’re going to discuss how random lists are managed at Almac Clinical Services At Clinical Services, the term ‘Random Lists’ is used to describe the two types of random lists we use: Randomization Schemes and Kit Lists

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 kit to a patient: Single Randomization 2) Double Randomization Emphasis should be placed upon the items in red. We’ve spent the prior slides discussing randomization to a treatment (A or B or C)….however, we now have to figure out which kit to assign (eg. Kit 229, 441, 448?)

Single vs. Double Method of Randomization One Random List Two Random Lists Let’s introduce some concepts and terminology. The ‘method of randomization’ indicates the process in which the randomization assignment is conveyed to the site. Manual process (No automation) Automation required (IVRS, IWRS, WebEZ) Non-consecutive Kit Numbers Consecutive Kit Numbers