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Randomization
- 1. RANDOMIZATION Presenter: Dr SubhradeepSonowal, Post Graduate Trainee 2nd year, Department of Community Medicine
- 2. OUTLINES 1. Background ofclinical trial 2. Randomized controlled trial 3. Randomization 4. Advantages of Randomization 5. Types of Randomization 6. Bias in RCT 7. Allocation Concealment 8. Blinding and its types 9. Conclusion
- 3. BACKGROUND First plannedtrial on scurvy by James Lind in 1747. James Lind, a Scottish surgeon took 12 sailors suffering from scurvy and divided them into 6 pairs. Each pair received 6 different treatments for scurvy. The two patients who were given lemons and oranges recovered most quickly, suggesting a beneficial effect of citrus. Dunn PM. James Lind (1716-94) of Edinburgh and the treatment of scurvy. Arch Dis Child Fetal Neonatal Ed. 1997;76(1):F64-F65. doi:10.1136/fn.76.1.f64 3
- 4. In 1914,conductedtrials on asylum inmates and children in orphanages . Proved Pellagra to be nutritional deficiency disease and not infectious disease. 172 pellagra patients and 162 non pellagra orphans had been followed for 2 years. There was a single recurrence in an orphan, and no incident cases. Evans BK; Feinstein AR (1 September 1994). "Joseph Goldberger: an unsung hero of American clinical epidemiology". Ann Intern Med. 121 (5): 372–75. 4
- 5. RANDOMIZED CONTROL TRIAL An epidemiological experiment in which subjects in a population are randomly allocated into groups, usually called study and control groups, to receive or not to receive an experimental, preventive or therapeutic procedure, maneuver, or intervention (John M Last Dictionary of Epidemiology , 5th Edition)
- 6. Bhalwar R. TextBook of Public Health and Community Medicine. Department of Community Medicine, AFMC,Pune, 2009: 341-42
- 7. RANDOMIZATION Randomization is astatistical procedure by which the participants are allocated into groups called “study” and “control” groups, to receive or not to receive an experimental preventive or therapeutic procedure, manoeuvre or intervention. (Park K. Park’s textbook of preventive and social medicine. 25th ed. Jabalpur: M/S Banarsidas Bhanot; 2019:403-407)
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- 9. ADVANTAGES OF RANDOMIZATION 1. Eliminatesselection bias. 2. Allows comparability. 3. Balances arms with respect to prognostic variables
- 10. TYPES OF RANDOMIZATION Randomization SimpleBlock Stratified Unequal
- 11. SIMPLE RANDOMIZATION Thismethod is equivalent to tossing a coin for each subject that enters a trial, such as Heads = Active, Tails = Placebo. It is usually carried out using: - A random-number table - A computerized random number generator
- 12. Allot participants intoGroup A or Group B by: • Even no.: Group A Odd no.: Group B OR • 0-4: Group A and 5-9: Group B
- 13. LIMITATION Might have unequaldistribution in each group which might imbalance the randomization procedure. To solve this issue block randomization is done.
- 14. BLOCK RANDOMIZATION Thebasic idea of block randomization is to divide potential patients into m blocks of size 2n randomize each block such that n patients are allocated to A and n to B. then choose the blocks randomly. This method ensures equal treatment allocation within each block if the complete block is used. ICH Harmonised Tripartite Guideline Statistical Principles for Clinical Trials, E9
- 15. EXAMPLE Two treatmentsof A, B and Block size of 2 x 2= 4 Possible treatment allocations within each block are (1) AABB, (2) BBAA, (3) ABAB, (4) BABA, (5) ABBA, (6) BAAB
- 16. LIMITATION If blocking isnot masked in open-label trials, the sequence becomes somewhat predictable (e.g. 2n= 4): B A B ? Must be A. AA ? ? Must be B B. This could lead to selection bias
- 17. STRATIFIED RANDOMIZATION Itis often called Prognostic Stratification The randomization process is restricted by grouping the experimental units into more or less homogenous strata before the process of random allocation Investigator decides which strata are important and how many stratification variables can be considered
- 18. Gordis L. Epidemiology.Fifth edition. Philadelphia, PA: Elsevier Saunders, 2014.
- 19. UNEQUAL RANDOMIZATION Whentwo or more treatments under evaluation have a cost difference it may be more economically efficient to randomize fewer patients to the expensive treatment and more to the cheaper one. The subject survival time depends on which treatment they receive. More extreme allocation may be used in these trials to allocate fewer patients into the placebo group. Generally, randomization ratio of 3:1 will lose considerable statistical power, more extreme than 3:1 is not very useful, which leads to much larger sample size.
- 20. OTHER METHODS Covariate-Adaptive Randomization Covariate randomization designs aim to balance the covariates across the treatment groups This randomization assigns the next patient to the group that causes the smallest imbalance across the covariate groups Singh, Rajneesh & Saroj, Rakesh & K. H. H. V. S. S., Narasimha & Murthy, & Supervisor,. (2018). A Conventional Approach of Covariate Adaptive Randomization Method in Clinical Trials-A Review.
- 21. MINIMIZATION Treatment allocationis only done randomly for the first unit; after that it depends on the characteristics of those units already allocated Minimizes the imbalance between the number of patients in each treatment group over a number of factors Calculates the imbalance within each factor should the patient be allocated to a particular treatment group. Pocock, Stuart J.; Simon, Richard (Mar 1975). "Sequential Treatment Assignment with Balancing for Prognostic Factors in the Controlled Clinical Trial". Biometrics. International Biometric Society. 31 (1): 103– 115. doi:10.2307/2529712
- 22. BIAS IN RCT Bias is any systemic error in the determination of association between exposure and disease In RCT, bias may arise from the errors of assessment of the outcome due to human element
- 23. SOURCES OF BIASIN RCT Subject Variation • Participants report improvement on knowing that they are receiving a new form of treatment Observer Bias • Investigator get influenced on knowing beforehand the particular procedure or therapy Evaluation Bias • Investigator may subconsciously give a favourable report of the outcome of trial
- 24. ALLOCATION CONCEALMENT AllocationConcealment is a technique used to prevent selection bias in Randomised Controlled Trials (RCT’s) by concealing the allocation sequence from those assigning participants to the intervention groups, until the moment of assignment. Thus it prevents researchers from (unconsciously or otherwise) influencing which participants are assigned to the intervention or control group.
- 25. IMPORTANT ASPECTS Adequate generationof the allocation sequence Concealment of the allocation sequence until assignment occurs
- 26. BLINDING Blinding refers tothe concealment of group allocation from one or more individuals involved in a clinical research study, most commonly a randomized controlled trial (RCT). Karanicolas PJ, Farrokhyar F, Bhandari M. Practical tips for surgical research: blinding: who, what, when, why, how?. Can J Surg. 2010;53(5):345-348.
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- 28. 1. Open trial: Participant and Investigator knows who is getting which intervention. 2. Single blind trial: Participant not aware. 3. Double blind trial : Neither investigator nor participant is aware. 4. Triple blind trial : Investigator,participant and analyst are not aware.
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- 30. CONCLUSION Randomization isoften called the “heart” of a control trial Gives the greatest confidence that groups are comparable Ensures that the investigator has no control over allocation ofthe subjects to either group Every individual has an equal chance of being allocated into either group
- 31. REFERENCES 1. Park K.Park’s textbook of preventive and social medicine. 25th ed. Jabalpur: M/S Banarsidas Bhanot; 2019:403-407 2. Dunn PM. James Lind (1716-94) of Edinburgh and the treatment of scurvy. Arch Dis Child Fetal Neonatal Ed. 1997;76(1):F64-F65. doi:10.1136/fn.76.1.f64 3. Evans BK; Feinstein AR (1 September 1994). "Joseph Goldberger: an unsung hero of American clinical epidemiology". Ann Intern Med. 121 (5): 372–75. 4. Bhalwar R. Text Book of Public Health and Community Medicine. Department of Community Medicine, AFMC,Pune, 2009: 341-42
- 32. 5. ICH HarmonisedTripartite Guideline Statistical Principles for Clinical Trials, E9 6. Gordis L. Epidemiology. Fifth edition. Philadelphia, PA: Elsevier Saunders, 2014. 7. Singh, Rajneesh & Saroj, Rakesh & K. H. H. V. S. S., Narasimha & Murthy, & Supervisor,. (2018). A Conventional Approach of Covariate Adaptive Randomization Method in Clinical Trials-A Review.
- 33. 8. Pocock, StuartJ.; Simon, Richard (Mar 1975). "Sequential Treatment Assignment with Balancing for Prognostic Factors in the Controlled Clinical Trial". Biometrics. International Biometric Society. 31 (1): 103–115. 9. Karanicolas PJ, Farrokhyar F, Bhandari M. Practical tips for surgical research: blinding: who, what, when, why, how?. Can J Surg. 2010;53(5):345-348.