This document discusses randomization in clinical trials. It begins with an overview of the benefits of randomization and different methods for generating allocation sequences, such as simple randomization and restricted randomization. The history of randomization in clinical research is reviewed, from its origins in agricultural studies to its first use in a randomized controlled trial comparing streptomycin to bed rest for tuberculosis. Key definitions of randomization and randomized controlled trials are provided. The document also compares randomization to random sampling and explains why randomization is used to eliminate systematic differences between groups. Criteria for randomization methods and techniques for allocation concealment are outlined.

1. RANDOMIZATION
Dr Roshni SS

2. OVERVIEW
 Benefits of randomization
 Methods of generation of allocation sequence
 Advantages and disadvantages
 Allocation concealment

3. HISTORY OF RANDOMIZATION
 RA Fischer – ‘Design of Experiments’ in 1935
- Agricultural research
- True treatment effect separated from other effects
 Sir Austin Bradford Hill
- First RCT of streptomycin in
pulmonary Tb – 1946
- Bed rest only: 4/52 cured
- Bed rest + streptomycin: 28/55 cured

4. DEFINITION OF RCT
 A clinical-epidemiological experiment in which subjects are
randomly allocated into groups, usually called test and control
groups, to receive or not to receive a preventive or a therapeutic
procedure or intervention ”
John M.Last, 2001

5. DEFINITION OF RANDOMIZATION
 Statistical procedure by which participants are allocated into groups
called study and control to receive or not receive an experimental
preventive/therapeutic procedure, manoeuvre, intervention.
 Heart of RCT ; only unique feature
 Allows equal chance for participants to get assigned to either group
 Group assignment can’t be predicted

6. RANDOMIZATION VS RANDOM SAMPLING
 Random sampling –random selection of study sample from
population
 External validity and Generalisability
 Randomization
Internal Validity

7. WHY RANDOMIZE?
 Difference in outcome between two groups can be explained as
1. Intervention exhibits a real effect
2. Outcome difference is solely due to chance
3. There is a systematic difference( or bias) b/w groups due to
factors other than intervention
o Randomization aims to obviate the third possibility.

8. GOAL OF RANDOMIZATION
 To eliminate possibility – investigator knows about next patient
allocation
 If known – bias in treatment assignment
 Selection bias

9. BENEFITS OF RANDOMIZATION
1. Prevent Selection Bias – selective enrolment of patients to trial
based on next treatment allocation
2. Ensuring comparability of groups

10. CONTD..
 Both measurable and immeasurable/unrecognised variables
 Randomization doesn’t guarantee comparability – role of chance
 Large group – tend to be similar
 Matching – only factors known to be important
3. Randomization guarantees that statistical tests of significance will
be valid .

11. CRITERIA FOR RANDOMIZATION
 Unpredictability
 Balance
 Simplicity

12. UNIT OF ANALYSIS IN RANDOMIZATION
 Individual people
 Groups
 CLUSTER RANDOMIZATION
 Eg – training of health professional
 Disadvantage – large sample size, ethical problems
 Order in which measurements are obtained from each participant
 Eg – evaluating effect of morphine in cancer patients - randomize the order
in which analgesia, adverse events, quality of life are assessed

13. RANDOMIZATION IN RCT
 Depends on
1. Generation of unpredictable randomized allocation sequence
2. Concealment of that sequence until assignment occurs
( Allocation Concealment)

14. WHAT IS NOT RANDOMIZATION
 Alternate assignment
 Quasirandom methods –
 DOB, Case record number, Date of presentation
 Systematic occurrences – no allocation concealment – selection bias

15. METHODS OF GENERATION OF ALLOCATION SEQUENCE
Fixed Procedures Dynamic / Adaptive Procedures
Simple randomization Urn Randomization
Restricted Randomization Covariate Adaptive Randomization
Stratified Randomization Response Adaptive Randomization
Minimization

16. SIMPLE RANDOMIZATION
 Analogous to repeated fair coin-tossing
 Preserves complete unpredictability
 Coin tossing, dice throwing, previously shuffled card, Table of
random numbers, Computer generated random numbers, STATA

17.  Adv – easy to implement
 Diasadv - In small samples highly disparate sample sizes in the
groups by chance alone
 Imbalance negligible with trial sizes greater than 200

18. TABLE OF RANDOM NUMBERS

19. RESTRICTED RANDOMIZATION
 Balanced randomization
 Groups of equal size
Methods
 Blocking
 Random Allocation Rule
 Replacement Randomization

20. BLOCK RANDOMIZATION
 Random permuted blocks
 Same size comparison groups throughout trial
 Steps
1. Select block size

21. 2.List all possible permutations of treatment in a block
3.Random selection of blocks

22.  Method 2:
 Allocation ratio can be uneven
 Can be extended to more than one group

23.  Advantage - Balanced study arms even with small sample size
- Useful during interim analysis
 Disadvantage
 Last participants’ group in each block predictable if block size is known
 Unequal distribution of relevant covariates
 Longer block sixes (10/20) and random variation of bock size – preserve
unpredictability

24. RANDOM ALLOCATION RULE
 Simplest form
 Total sample size identified subset of sample to one group
remainder other group
 Represent one large permuted block
 Random assignment without replacement

25.  Restricted shuffle approach –cards prepared for each treatment as
per allocation ratio, kept in envelope and shuffled
 Unpredictability : >permuted block ; < simple random
 Disadvantage
 Equal size only at end of trial
 Chance confounding – trivial with larger sample size

26. REPLACEMENT RANDOMIZATION
 Earliest from of restricted randomization
 Simple randomisation
 Allowable disparity fixed
 Repeats simple randomisation scheme till desired balance achieved
 Advantage – easy, ensure reasonable balance , yields
unpredictability
 Disadvantage – do not ensure balance for interim analysis

27. STRATIFIED RANDOMIZATION
 To control influence of covariates
 Avoid imbalance on important prognostic factors
Generate separate block for
each combination of covariate
Subjects assigned to respective
blocks
Restricted randomisation in
each subset

28. CONTD...
 Stratification without restriction accomplishes nothing
 Useful in multicentric trials- stratification by centre
 Little use in large trials
 Useful in small trials
 Gain from stratification minimal once number of participants/ group > 50
 Disadvantage – Requires baseline characteristics of all, All participants to
be identified before group assignment,

29. ADAPTIVE / DYNAMIC RANDOMIZATION
 New participant is assigned to a particular treatment group by
taking into account the specific covariates and previous assignments
of participants.
 Here the participant has no equal chance , but a definite chance to
be in either of the groups

30. URN RANDOMIZATION
 Adaptive biased – coin design
 Alter probability based on magnitude of imbalance
 Start with two coloured balls in an urn
 One ball drawn at random and replaced
 Extra ball of opposite colour to the one selected added
 Process repeated

32. COVARIATE ADAPTIVE RANDOMIZATION
 First described by Taves
 Only 1st assignment random
 Remaining depends on specific covariate and previous assignment group
 Uses biased coin element at every allocation
 To make small groups closely similar
 Reduce covariate imbalance
 Disadvantage – decision to be made case by case

33. MINIMIZATION
 Described independently by Taves (1974) and Pocock and Simon
(1975).
 Eg - 3 prognostic factors – Old age, Diabetes, Co - drug
1 1 1
Treatment
A
Treatment
B
No of
patients
20 20
Total Points 15 13
Patient no 41
•40 years
•Non-Diabetic
•Co-drug
Treatment
A
Treatment
B
No of
patients
20 21
Total Points 15 14

34.  Advantages
 Offers better balancing than standard randomization methods.
 Can incorporate a larger number of stratifying factors than stratified
randomization methods.
 Disadvantages
 More complex than using other standard randomization methods.
 Randomization lists cannot be generated in advance.

35. RESPONSE ADAPTIVE RANDOMIZATION
 Randomize patients based on response of previous subjects
 Controversial and not commonly used
 Play-the-winner (PW) design
 When patient response determined quickly
 First subject treatment assigned by tossing a coin
 If response success, second patient receives same treatment, if
failure, other treatment

36. CONTD..
 Advantage - more receive better treatment
 Disadvantage - Investigator aware of next assignment
- Loss of statistical power if final sample size quite unequal

37. CONTD...
 Two – armed bandit
 Treatment assignment probabilities depend on observed success
probabilities at each time point
 Advantage – maximum number in superior treatment
 Disadvantage – unequal groups – loss of statistical power

38. UNEQUAL RANDOMIZATION
 When equal allocation to treatment and control group
economically/ clinically/ practically feasible
2:1 ratio- power 0.95 to 0.925
4:1 ratio- power 0.95 to 0.82
Ratio> 3:1 not useful; large sample size

39. FLOWCHART FOR SELECTING PROPER RANDOMIZATION TECHNIQUE
SAMPLE SIZE
Are there covariates that need to
be controlled?
Are participants enrolled to study
continually or all at same time
COVARIATE ADAPTIVE
RANDOMIZATION
BLOCK RANDOMIZATION
SIMPLE RANDOMIZATION
STRATIFIED RAMDOMIZATION
Small,
≤200
Large,
>200
NoYes
Same
time
continues

40. ALLOCATION CONCEALMENT
 Concealment of generated allocation sequence atleast until patients
have been assigned to their groups
 Shields those who admit participants to trial from
knowing upcoming assignment – eliminate BIAS
 Unpredictable allocation sequence generation
ineffective without allocation concealment
 Countless attempts made by researcher to
decipher the allocation concealment scheme

41. METHODS FOR ALLOCATION CONCEALMENT
 Sequentially numbered opaque sealed envelope (SNOSE)
 Envelope numbered in advance, opened sequentially, and only after the
participant’s name and other details are written on the envelope
 Use of carbon paper inside envelope
 Cardboard/aluminium foil inside envelope
 Sequentially numbered containers
 All containers tamper-proof, equal in weight & similar in appearance with
audit trail established.

42. CONTD...
 Central randomization
 Secure computer – assisted method
 Different persons perform different parts of the event

43. BLINDING
 Bias from errors of assessment of outcome. From 3 sources
 Participants
 Observer bias
 Bias in evaluation
o For proper assessment of outcome BLINDING

44. BLINDING VS ALLOCATION CONCEALMENT
Allocation concealment Blinding
Prevent selection bias Prevent ascertainment bias
Can always be implemented Can’t be implemented always
Protect randomization sequence
before and until the interventions
are given to study participants
Protect after allocation

45. CONCLUSION
 Randomization is the only unique feature of RCT
 Only way to avoid selection and confounding biases
 Generation of randomization sequence takes little time and
contribute much to scientific accuracy and credibility
 Simple, Restricted, Stratified and Adaptive randomization
techniques are the commonly used methods
 Proper randomization hinges on adequate allocation concealment

46. REFERENCES
 Park K. Park’s textbook of preventive and social medicine. 24th ed. Jabalpur
M/s Banarasidas Bhanot Publishers 2016; p.75-87
 Schulz KF, Grimes DA. Generation of allocation sequences in randomised
trials: chance, not choice. The Lancet. 2002 Feb 9 ; 359: 515–19
 Leon Gordis. Epidemiology. 5th ed. Elsevier Saunders 2014; p.179-242
 Schulz KF, Grimes DA. Allocation concealment in randomised trials: defending
against deciphering. The Lancet. 2002 Feb 16 ; 359: 614–18
 Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. The
Lancet. 2002 Feb 23; 359: 696–700

47.  Arun Bhatt. Evolution of Clinical Research: A History Before and Beyond
James Lind . Perspect Clin Res. 2010 Jan-Mar; 1(1): 6–10
 Armitage P. Fisher, Bradford Hill, and randomization. International Journal
of Epidemiology 2003;32:925–928
 Baghbaninaghadehi F, Armijo-Olivo S, Woodhouse L. Fundamentals of
randomization in clinical trial. International Journal of Advanced
Nutritional Health Science. 2016 Feb 22;4:174-87.
 Jadad AR, Enkin MW. Randomized controlled trials: questions, answers and
musings. John Wiley & Sons; 2008 Apr 15.

48. THANK YOU