INTERVENTIONS, BLINDING and

ALLOCATION

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INTERVENTIONS
TIDieR CHECKLIST
COMPONENTS OF TIDieR (1)
COMPONENTS OF TIDieR (2)
BLINDING
…enormous ambiguity in the conventional ways of describing
blinding.

…authors and journal editors should abandon the terms single,

double, and triple blind, and substitute descriptions stating
which of the relevant groups were unaware of allocation.

As long as journal reports of RCTs include the term “double

blind”, clinicians will risk inaccurate inferences about the
validity of the studies on which they base their clinical practice.

BMJ. 2005;37:557
IMPLICATIONS OF BEING UNMASKED
Clinicians
• Differentially administer powerful treatments other than those under study
• Influence compliance with study drugs or willingness to continue in the study
• Influence reporting of symptoms
Data Collectors
• Vary intensity of examination or likelihood of repeating a test with unexpected finding
• Vary recording of outcomes
• Differential encouragement during performance testing
Judicial Assessors
• Bias interpretation of marginal findings
Data analysts and authors
• Biased decisions on patient withdrawals
• Biased selection of outcomes to analyze or report
• Biased choice of time points demonstrating maximum or minimum effects
• Many other important decisions in the analysis or reporting process
ALLOCATION
ALLOCATION - OBJECTIVES

§ What is randomized allocation?

§ Why randomize?
§ How to generate a randomized allocation sequence?
§ How to implement a sequence of randomized
allocation while concealing the sequence until
interventions assigned?
RANDOMIZED ALLOCATION

§ Process of allocating an intervention so that:

§ Participants will randomly (not arbitrarily)
receive either I or C
§ Known probability of receiving any of the trial
interventions (usually the same)
COMPARISON OF TWO INTERVENTIONS

Drug X Outcome

Subjects with
Condition of interest

Placebo Outcome
OBJECTIVES

ü What is randomized allocation

§ Why randomize?
§ How to generate a sequence of randomized
allocation?
§ How to implement a sequence of randomized
allocation while concealing the sequence until
interventions assigned?
WHY RANDOMIZE?

§ Facilitates statistical hypothesis testing

§ maximize statistical power
§ BALANCES known and unknown prognostic
factors, including time
 Plos ONE. 2012;7(5):e36677

…if an absolute measure of imbalance <0.05 is deemed

important, 1000 patients per arm is a reasonable size

If trialists are willing to tolerate a slightly bigger

deviation from the true ORR, for instance, no more
than 0.1 …. 2000 patients per arm then seems to be a
reasonable sample size
 J Clin Epidemiol. 2017;84:105

Substantial increase in mean squared error once sample

size falls below 1000 participants
WHAT CAN CONSISTENTLY GOOD
BALANCE IMPLY?

Anaesthesia. 2012;67:521
Anaesthesia. 2017;72:944
WHY RANDOMIZE?

§ Facilitates statistical hypothesis testing

§ Maximize statistical power
§ BALANCES known and unknown prognostic
factors, including time
§ ALLOCATION CONCEALMENT
§ Minimize allocation bias and selection bias
NON-RANDOMIZED STUDY

High-Risk Low-Risk
Patient Patient

80% 20% 35% 65%

New New
Old Drug Old Drug
Drug Drug
WELL-DONE RANDOMIZED STUDY

High-Risk Low-Risk
Patient Patient

50% 50% 50% 50%

New New
Old Drug Old Drug
Drug Drug
POOR ALLOCATION CONCEALMENT

High-Risk Low-Risk
Patient Patient

30% 70% 60% 40%

New New
Old Drug Old Drug
Drug Drug
POOR ALLOCATION CONCEALMENT

JAMA 1995;273:408
Lancet. 1998;352:609
BMC Medical Research Methodology 2016;16:133
ALLOCATION - OBJECTIVES

✓ What is randomized allocation?

✓ Why randomize?
§ How to generate a randomized allocation sequence?
§ How to implement a sequence of randomized
allocation while concealing the sequence until
interventions assigned?
THIS IS NOT RANDOMIZATION

§ Patient order of arrival

§ Day of the week
§ Last digit of an ID or record number
§ Date of birth
METHODS TO RANDOMIZE
1.Fixed randomized allocation:
– Simple randomization
– Randomization by blocks
– Stratified randomization
2. Adaptive randomized allocation:
– Often according to baseline characteristics

BMJ 2012;645:e5840
BMC Medical Research Methodology 2014;14:20
ALLOCATION - OBJECTIVES

✓ What is randomized allocation?

✓ Why randomize?
✓ How to generate a randomized allocation sequence?
§ How to implement a sequence of randomized
allocation while concealing the sequence until
interventions assigned?
GENERAL RECOMMENDATIONS

§ Have someone other than the investigator to

prepare the randomization sequence

§ Minimize time between the allocation of each

subject and the application of the intervention
METHODS FOR CONCEALED ALLOCATION

§ Opaque envelopes: SNOSE

§ Sequentially numbered
§ Opaque
§ Sealed envelopes
METHODS FOR CONCEALED
ALLOCATION

✓ Opaque envelopes
✓ sealed and numbered in sequence
§ Sealed packages with the medications
§ Randomization at central pharmacy
§ Centralized telephone or online randomization
ONLINE RANDOMIZATION SERVICES
INTERVENTIONS, BLINDING and
ALLOCATION

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