Blinding in Clinical Trials

Site: EUPATI Open Classroom
Course: Clinical Trials and Trial Management
Book: Blinding in Clinical Trials
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Date: Wednesday, 29 June 2022, 2:06 PM

1. Blinding of The Trial

Blinding is a procedure in which one or more parties in a trial are kept unaware of which treatment arms participants have been assigned to, i.e. which treatment was received.

Blinding is an important aspect of any trial. How a trial was blinded should be accurately recorded in order to allow readers to interpret the results of a study. If blinding is ever broken during a trial on individual participants, it needs to be justified and explained.

2. Why Do We Blind?

Blinding is used to prevent conscious or unconscious bias in the design of a clinical trial and how it is carried out. This is important because bias can affect recruitment and allocation, care, attitudes, assessments, etc.

It is used to ensure the objectivity of participants, study staff, clinicians, data collectors, outcome adjudicators and data analysts.

3. What Are The Potential Sources Of Bias in a Trial and Who Can And Should Be Blinded?

The relevance of blinding in a randomised clinical trial will vary according to circumstances.

  • The trial participant
    Blinding participants to the treatment they have received is particularly important when the response criteria are subjective, such as alleviation of pain, but less important for objective criteria, such as disease progression (e.g. cancer). If participants are not blinded, knowledge of group assignment may affect their behaviour in the trial and their responses to subjective outcome measures. For example, a participant who is aware that he is not receiving active treatment may be less likely to comply with the trial protocol. Those aware that they are receiving or not receiving therapy are more likely to provide biased assessments of the effectiveness of the intervention — most likely in opposite directions — than blinded participants.

  • Clinical staff administering treatment
    Similarly, medical staff and clinicians caring for patients should be blinded to treatment allocation to minimise possible bias in patient management and in assessing disease status. Blinded clinicians are much less likely to transfer their attitudes to participants or to provide differential treatment to the active and control (placebo) groups than are unblinded clinicians.

  • The doctor assessing treatment
    Blinding of data collectors and outcome adjudicators (sometimes the same individuals) is crucial to ensure unbiased ascertainment of outcomes. For example, in a randomised controlled trial in patients, neither active treatment regimen (tested medication vs. comparator) was superior to placebo when assessed by blinded specialists, but there was an apparent benefit of treatment with the test medication, when unblinded specialists performed the assessments.

  • The team interpreting results
    Bias may also be introduced during the statistical analysis of the trial through the selective use and reporting of statistical tests. This may be a subconscious process spurred by investigators eager to see a positive result, but the consequences are profound. The best method to avoid this potential bias is blinding of the data analyst until the entire analysis has been completed.

4. Types of Blinding

Type

Description

Unblinded or open label 

All are aware of the treatment(s) 

Single blind or single-masked 

The participants are blinded but no one else is 

Double blind or double-masked 

The participants and clinicians / data collectors are blinded 

Triple blind 

The participants, clinicians / data collectors and outcome adjudicators / data analysts are blinded 


5. Unblinded

An open-label trial is one in which no blinding is used and all parties are aware of the allocation of participants to treatment groups.

Open-label trials may be used:

  • For surgical procedures*.
  • When changes in lifestyle are required.
  • When endpoints are objective and cannot be interpreted in different ways.
  • For studies in life-threatening situations.
  • In post-marketing surveillance.
  • When ethical considerations do not permit blinding.
  • When no control group can be used. 
* It should be noted that surgical procedures can be blinded but are extremely difficult to blind. This is very hard especially if participants can be compared.

6. Single Behind

A trial in which one party, the investigator or, usually, the participants, is unaware of what medicine the participant is receiving. Also called single-masked studies they provide some control when double blinding is impossible or not appropriate.

Single-blind trials are used where the experimenters either must know the full facts (for example, when comparing sham to real surgery) and so the experimenters cannot themselves be blind, or where the experimenters will not introduce further bias and so need not be blind. However, there is a risk that subjects are influenced by interaction with the researchers – known as the experimenter's bias.

7. Double Blind

A clinical trial design in which neither the participants nor investigators know which participants are receiving the experimental medicine and which are receiving a placebo (or comparator therapy). Double-blind trials are thought to produce objective results, since the expectations of the investigator and the participant do not affect the outcome. Also called double-masked trial.

  • Considered best-controlled trial design.
  • Decreased chance of preconceived notions or physical cues (e.g. the placebo effect, observer bias, experimenter's bias) to distort the results.
  • The key that identifies the participants and which group they belonged to is kept by a third party, and is not revealed to the researchers until the study is over.
  • Should be used whenever possible.
In trials in studies comparing two active compounds (test medicine and comparator) and when the two treatments cannot be made identical, double dummy is a technique for retaining the blind. Supplies are prepared for Treatment A (active and indistinguishable placebo) and for Treatment B (active and indistinguishable placebo). Participants then take two sets of treatment; either A (active) and B (placebo), or A (placebo) and B (active).

For example, if we want to compare two medicines, one presented as green tablets and one as pink capsules, we could also supply green placebo tablets and pink placebo capsules so that both groups of patients would take one green tablet and one pink capsule.

8. Triple Blind

A triple blind trial means that participants, clinicians, data collectors, outcome adjudicators and data analysts do not have access to details of group assignment. This ensures that bias for or against the tested treatment is very unlikely to occur.

  • Medicine may still be labelled as A or B during analysis.
  • Analyst is blinded to which treatment is which.
  • Helps to avoid bias in the analysed results.

9. Unblinding The Trial

Unblinding is the process by which the allocation code is broken so that the appropriate persons e.g. investigator, clinical staff, participants, and/or the trial statistician become aware of the intervention for a participant in a trial.

Unblinding must be undertaken by a pre-determined process to ensure that participants are not unblinded unnecessarily and the study results are not compromised. Equally, unblinding should occur in a responsive manner when it is clinically indicated.

Unblinding is required:
  • To make clinical treatment decisions or when an unexpected serious adverse event occurs and the intervention must be made known. This is called emergency unblinding (to protect the participant). Unblinding should only occur for that participant and not the entire study.
  • During an unmasked analysis in accordance with the study analysis plan (e.g. a planned interim analysis).
  • At the request of the Data Safety Monitoring Board.
  • At the conclusion of the study to determine the effect of the intervention.
It may be done by:
  1. Contacting the holder of the blinding information (e.g. sponsor, CRO, etc.) to find out details of what treatment a participant received.
  2. Contacting an automated service.

10. Ways Patient Experts Can Contribute

An example of how patients can be involved can be discovered in the IPERGAY trial that can be found on the European AIDS Treatment Group website.