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Randomization & Blinding Dr. Aparna Walanj Clinical Research Head Ethika Clinical Research Center

Randomization & Blinding

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Randomization & Blinding. Dr. Aparna Walanj Clinical Research Head Ethika Clinical Research Center. Pr ocess of assigning clinical trial participants to treatment groups - PowerPoint PPT Presentation

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Page 1: Randomization  &  Blinding

Randomization &

Blinding Dr. Aparna Walanj Clinical Research Head Ethika Clinical Research Center

Page 2: Randomization  &  Blinding

Randomization Process of assigning clinical trial participants to

treatment groups

Gives each participant a known (usually equal) chance of being assigned to any of the groups

Successful randomization requires that group assignment cannot be predicted in advance

Page 3: Randomization  &  Blinding

Why Randomize? If, at end of a clinical trial, difference in outcomes

occurs between two treatment groups (say, intervention and control) possible explanations for this difference would be:

Intervention exhibits a real effect

Outcome difference is solely due to chance

There is a systematic difference (or bias) between the groups due to factors other than the intervention

Randomization aims to obviate the third possibility

Page 4: Randomization  &  Blinding

All Rx groups should have

Equal no. of patients:◦ Young/ Old (different physiology)

◦ Male/ Female (different physiology)

◦ Mild/ Severe/ Complicated (other diseases)

Only Randomization can achieve this !Only Randomization can achieve this !

Page 5: Randomization  &  Blinding

All Rx groups should have

Equal no. of patients:

◦ fasting/ taking excess coffee etc

◦ with relevant factors

Only Randomization can achieve this !Only Randomization can achieve this !

Page 6: Randomization  &  Blinding

All treatment groups should have ◦ Statistical requirements met properly

Only Randomization can achieve this !Only Randomization can achieve this !

Page 7: Randomization  &  Blinding

Randomization

Definition:Randomization is a process based on Chance allocation of subjects to different treatments planned in a clinical trial

Page 8: Randomization  &  Blinding

Randomization

Treatments

A-Drug A

B-Drug B

C-Drug C

D-Placebo P

Treatments

A-Drug A

B-Drug B

C-Drug C

D-Placebo P

Patients1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,2122,23,24,25,26,27,28,29,30

Patients1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,2122,23,24,25,26,27,28,29,30

Randomization decides which patient will get what treatment...

Page 9: Randomization  &  Blinding

Purpose Randomization produces patient groups which

are:

Balanced with respect to factors which can influence outcome of a trial

Allows to make a strong Causal connection between treatment and their effects

Page 10: Randomization  &  Blinding

Inappropriate Methods

Assigning patients alternately to treatment group is not random assignment

Assigning the first half of the population to one group is not random assignment

Assignments by methods based on patient characteristics such as date of birth, order of entry into the clinic or day of clinic attendance, are not reliably random

Page 11: Randomization  &  Blinding

Forms of Randomization

Simple Randomization

Permuted Block Randomization

Stratified Block Randomization

Dynamic (adaptive) random allocation

Page 12: Randomization  &  Blinding

Simple Randomization

Coin Tossing for each trial participant (not usually performed, as issues of concealment,

validation and reproducibility arise )

Random Numbers Tables from statistical textbooks

Computer generated sequence of random nos.

Page 13: Randomization  &  Blinding
Page 14: Randomization  &  Blinding

Random number tables Choose randomly a row and block

Suppose the sequence is 71146

Give even numbers treatment A and odd numbers treatment B

Treatment schedule will be BBBAA

Random number table may not give equal numbers in the 2 treatment arms

Page 15: Randomization  &  Blinding

Computer Generated Random Number TableComputer Generated Random Number Table

Page 16: Randomization  &  Blinding

Computer Generated Random nos.The computer generated sequence: 4,8,3,2,7,2,6,6,3,4,2,1,6,2,0,…….

Two Groups (criterion: even-odd): AABABAAABAABAAA……

Three Groups: (criterion:{1,2,3}~A, {4,5,6}~B, {7,8,9}~C; ignore 0’s) BCAACABBABAABA……

Two Groups: different randomization ratios(eg.,2:3):(criterion:{0,1,2,3}~A, {4,5,6,7,8,9}~B) BBAABABBABAABAA……..

Page 17: Randomization  &  Blinding

Computer Generated Random nos.. Each digit (1,2,3 etc) has the probability of occurring 1/10,

Each pair(11,15,26) has the probability of occurring 1/100,

Each triplicate (221,125,458) has the probability of occurring 1/1000

We can begin at any place in the Random table and still the probabilities will remain the same

Page 18: Randomization  &  Blinding

Permuted Block Randomization Used for small studies to maintain good treatment balance

among groups

In a two group design, Blocks having equal numbers of As and Bs (A = intervention and B = control, for example) are used, with the order of treatments within the block being randomly permuted

Page 19: Randomization  &  Blinding

Block Randomization

With a block size of 4 for two groups(A,B), there are 6 possible permutations and they can be coded as:

1=AABB, 2=ABAB, 3=ABBA, 4=BAAB, 5=BABA, 6=BBAA

Each number in the random number sequence in turn selects the next block, determining the next four participant allocations (ignoring numbers 0,7,8 and 9)

e.g. Sequence 67126814…. will produce BBAA AABB ABAB BBAA AABB BAAB

Page 20: Randomization  &  Blinding

Blocked Randomization

Blocks are allotted to different centers

All treatments are present in every block

Equal treatments are present in every group

No. of patients in different treatment groups remains same

Page 21: Randomization  &  Blinding

Blocked Randomization

DisadvantagesDisadvantages

Block 1 Block 3 ABBA BABA Block 1 Block 3 ABBA BABA

• Last treatment may reveal itself due to a particular drug effect like colored urine or loose stools etc.

• Investigator can be made blind to the block length/ blocks of different lengths can be made

Page 22: Randomization  &  Blinding

Stratified Block Randomization

◦Stratification simply means having separate block randomisation schemes for each combination of characteristics (‘stratum’)

Typical examples of such characters are◦ severity of disease condition◦ age group◦ sex of patient

Page 23: Randomization  &  Blinding

Stratified Randomization E.g. In a trial of Chemotherapy for abdominal cancer, stratification factors may be as shown in below

table

Set of permuted blocks is generated for Female & 40-60 yrs, another set for Female & > 60 yrs, and so on..

Stratification Blocks

Sex Age Block 1 Block 2 Block 3

F 40-60 ABAB BBAA AABB

F > 60 BAAB ABBA BBAA

M 40-60 BAAB ABBA BBAA

M > 60 AABB BAAB BABA

Page 24: Randomization  &  Blinding

Stratified Randomization Advantages

◦Stratification can add to the credibility of a trial, as it ensures treatment balance on these known prognostic factors, allowing easy interpretation of outcomes without adjustment

◦Increases the power to detect differences

Disadvantages◦Delays randomization reaching different centers

◦Misclassification of patients to different strata may alter the result at end of study

Page 25: Randomization  &  Blinding

Dynamic Randomization

When factors requiring randomization are too many, some groups may have less patients in the end

Hence minimization is done to bring back the balance and increase efficiency of the study

Page 26: Randomization  &  Blinding

Dynamic Randomization In Simple/ Block randomization allocation sequences

are set up, before start of trial

In contrast, dynamic randomization allocates patients to treatment group by checking allocation of similar patients already randomized, and allocating next treatment group "live" to balance treatment groups across all stratification variables

Page 27: Randomization  &  Blinding

Example of randomization using the minimization method in a trial of chemotherapy for breast cancer, with stratification factors of clinic site, estrogen receptor status (ER+ or ER–) and menopausal status

Characteristic Treatment A Treatment B

Site 1 7 8

Site 2 10 9

ER+ 5 6

ER– 12 11

Premenopausal 8 9

Postmenopausal 9 8

Total 17 17

Page 28: Randomization  &  Blinding

Dynamic Randomization The next participant (no. 35) is Site 2, ER+, postmenopausal

Subtotals for treatment allocation to this profile of characteristics are 10 + 5 + 9 = 24 for Treatment A and 9 + 6 + 8 = 23 for Treatment B (note subjects are counted more than once)

Participant no. 35 would therefore be allocated to Treatment B

When the tallies on A and B are equal within a profile, the next participant is randomly allocated.

Page 29: Randomization  &  Blinding

Dynamic Randomization

Advantages: Provides good balance of prognostic factors & increases

efficiency of trial

Disadvantages: Future treatments are decided by earlier treatments, so

not ideal randomization

Communication by Internet/ Fax/ telephone becomes necessary as next patient may be at a different site

Page 30: Randomization  &  Blinding

Response Adaptive Randomization

As per individual and group ethics, each patient should receive best possible treatment

Response adaptive randomization is done

E.g. RPW, urn model etc.

Page 31: Randomization  &  Blinding

RPW-Randomized Play the Winner Design

Treatment balls takenTreatment balls taken

A B

One ball is randomly selected

One ball is randomly selected

Patient takesTreatment

Patient takesTreatment

At the start, 2 treatments representing 2 coloured balls are taken in a bag with closed mouth

B B

Page 32: Randomization  &  Blinding

RPW-Randomized Play the Winner Design At the end, if treatment was successful that respective coloured ball is added to the bag

Every incomingpatient has a better

chance ofselecting bettertreatment ball

Every incomingpatient has a better

chance ofselecting bettertreatment ball

Despite ethical appeal, RPW designs arenot used commonly in clinical trials

Despite ethical appeal, RPW designs arenot used commonly in clinical trials

Successful treatment balls are added to thebag

Page 33: Randomization  &  Blinding

DebateDebate

Many argue that in absence of definitive evidence in favour of one treatment over another, it is neither efficient nor ethically appropriate to assign patients in a different ratio

With use of early stopping rules, benefits from a response-adaptive design relative to equal allocation are greatly lessened; hence ethical need for adaptation is obviated

Page 34: Randomization  &  Blinding

Conclusion

RAR cannot substitute for true randomizationin confirmatory trials

It is important to keep allocation probabilities even for statistical sensitivity to be maximum

(Department of Biostatistics and Medical Informatics, Chicago)

Page 35: Randomization  &  Blinding

35

What is Bias?In lay terms “prejudice or leaning of one’s

opinion favoring one side”

In terms of CR, “systematic error that enters clinical trial and distorts the data obtained”

Bias occurs as a consequence of :◦trial design used, ◦tests used, ◦people involved

Goal of a clinical trial is to attempt to eliminate most, if not all biases

Page 36: Randomization  &  Blinding

Bias

Bias is said to have occurred if results observed reflect other factors in addition to/ instead of effect of treatment given:

Some potential sources of bias:Patient biasCare Provider biasLaboratory biasAnalysis and Interpretation bias

Page 37: Randomization  &  Blinding

Patient Bias Patient's knowledge that patient is receiving a "new" treatment

may substantially affect patient's subjective assessment

Patient's knowledge of treatment may affect outcome of study 

Page 38: Randomization  &  Blinding

Care Provider Bias

Care provider's knowledge of which Rx a patient is receiving may affect how provider

– deals with patient – treats patient

These differences may give patient information (even if incorrect) about treatment, which then may affect

outcome of study

Page 39: Randomization  &  Blinding

Laboratory Bias Knowledge of which treatment patient received may

affect way in which test is run or interpreted

Subjectively graded lab results (pathology slides, photographs, ECG, etc.) may be affected

Page 40: Randomization  &  Blinding

Analysis & Interpretation bias

Knowledge of treatment group may affect results of data analysis by

– Seeking explanation of an "anomalous” finding when one is found contrary to study hypothesis

– Accepting a "positive" finding without fully exploring data

Page 41: Randomization  &  Blinding

Analysis and Interpretation bias Knowledge of treatment group may affect decisions made

by external monitors of a study by

– Terminating a study for adverse events because they fit expectations of the monitors

– Terminating a study for superiority of treatment because it fits expectations of the monitors

Page 42: Randomization  &  Blinding

How to minimize Bias?

Allocation Concealment: to counter selection bias before randomization

Blinding: Masking of treatment after randomization

Page 43: Randomization  &  Blinding

Allocation Concealment Procedure for protecting the randomization process so

that treatment to be allocated is not known before patient is entered into study

Concentrates on preventing selection bias

Page 44: Randomization  &  Blinding

Allocation Concealment

Safeguards assignment sequence before and until allocation

Can always be successfully implemented in randomized clinical trials

Page 45: Randomization  &  Blinding

Allocation Concealment

Methods:

Sequentially numbered, opaque, sealed envelopes

Pharmacy-controlled allocations

Coded identical containers or kits

Central randomization systems (telephone or web based)

Page 46: Randomization  &  Blinding

Blinding

Blinding relates to the masking of treatments after randomization — from patient, investigator or outcome assessor

Blinding (also called masking or concealment of treatment)

Intended to avoid bias caused by subjective judgment in reporting, evaluation, data processing, and analysis due to knowledge of treatment

Page 47: Randomization  &  Blinding

Blinding Blinding concentrates on preventing study personnel &

participants from determining group to which participants have been assigned

Safeguards the sequence after allocation

Cannot always be implemented

Page 48: Randomization  &  Blinding

Hierarchy of Blinding

Open label: no blinding

Single blind: patient blinded to treatment

Double blind: patient and assessors (who often are also the health care providers and data collectors) blinded to treatment

Complete blind: everyone involved in the study blinded to treatment

Page 49: Randomization  &  Blinding

Open Label Studies • Pilot studies • Dose ranging studies

However, even these applications may be biased by knowledge of treatment given & may result in

• toxicity over (or under) reported • efficacy over estimated

Even a small fraction of patients assigned at random to placebo will reduce these potential problems

Page 50: Randomization  &  Blinding

Single Blind Studies

Blind patient to treatment given

Health care providers and assessors usually know actual treatment given

Justification for single blind is usually that

double-blind is "impractical" because of need to adjust medication, medication affecting laboratory values, potential side effects, etc.

Page 51: Randomization  &  Blinding

Double Blind Studies Subjects & Investigators are kept from knowing

who is assigned to which treatment

Minimizes both potential patient bias & potential assessor bias

Should be used whenever possible, which is whenever it is ethically permissible to blind a patient

Page 52: Randomization  &  Blinding

Double Blinding: Techniques Coded treatments

Placebo for each possible treatment - tablets identical in physical appearance - tablets with similar taste & smell - Carrier for IV infusions in active medication used as placebo

Other treatments "shammed" as far as possible: – minimal power ultrasound therapy when testing effect of physical therapy in back pain – breathing exercises when assessing effect of conditioning exercises

Page 53: Randomization  &  Blinding

Double Blinding: always feasible??

Situations when double blinding might not be possible It might not be ethically permissible to blind a patient. As an

example, it is unlikely that sham surgery would be considered ethical in a study

It might not be possible to blind a patient. For example, it would be hard to blind a patient to the therapy given in an exercise study

It may not be possible to blind a patient while comparing utility of different invasive procedures

Page 54: Randomization  &  Blinding

Double Blind Studies: stumbling blocks

Side effects (observable by patient) are much harder to blind

Side effects are one of the major ways in which blinding is broken

Ethical problems in using placebos to induce side effects in patients

Side effects of all potential therapies should be combined into a single list, so that knowledge of side effects would not indicate therapy (at least to patient)

Page 55: Randomization  &  Blinding

Complete/ Triple Blinding

Patient, Investigator and those who analyze study outcomes or those who monitor the study safety

Probably the best approach which can be used, but requires two groups for data processing, one group to encode data and one group to perform analysis

Normally only available in major drug company studies, and not routinely used even then

Page 56: Randomization  &  Blinding

Blinding: Techniques

Analysis uses coded treatment groups

Analysis uses coded side effects (e.g., side effects coded using non-standard scheme, with only numeric codes available at time of analysis)

Analysis uses coded laboratory tests (e.g., name of test coded numerically at time of analysis, using non-standard code)

Page 57: Randomization  &  Blinding

Thank youThank you