August 18, 2022

In Clinical Trials, it’s all about the Blind

What is Clinical Trial Blinding?

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, to avoid bias.

Blinding is the controlled process by which we prevent any information that will directly, or indirectly, inform a party of the treatment given to a subject or subjects, or of the contents of blinded, investigational product units.

ICH Guidelines

The ICH E9 [4] definition of blinding is as follows:

“Blinding or masking is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial arising from the influence that the knowledge of treatment may have on:

  • The recruitment and allocation of subjects
  • Their subsequent care
  • The attitudes of subjects to the treatments
  • The assessment of endpoints
  • The handling of withdrawals
  • The exclusion of data from analysis, and so on…

The essential aim is to prevent identification of the treatments until all such opportunities for bias have passed.”

Open Label

Unblinding data is defined as data that can reveal the treatment or pack regime of past or future trial subjects or the contents of medication packs.

It does not matter if the study is an open-label design.

The main point is that open label studies do not exist; the definition of unblinding data remains the same, even when there may be many unblinded user roles in the study.

Other considerations are:

  • In open label studies some study data can still be considered unblinding to certain user roles
  • Some studies may evolve from an initial open label phase to a later blinded phase

Partial Unblinding

Partial unblinding can become full unblinding if one patient code is broken, for example when:

  • It is known that two patients are on the same treatment arm, or two packs contain the same medication​
  • It is known that two patients are on different treatment arms, or two packs contain different treatments​

Can Unblinding Occur with IRT?

The FDA released a recording of a 2020 MHRA meeting entitled, “Unblinding – Let Me Count the Ways.” During this meeting, they raised the question, “Why Blind?” with the responses:

  • Reduce bias
  • Prevent conduct of aggregate analyses by treatment group prior to database lock
  • Protect the blind to maintain the integrity of the data

Related to the use of IRT for randomization and trial supply management (RTSM), FDA shared examples of how unintentional unblinding has occurred, including:

IRT Reporting

  • Phase 1 double blind SAD & MAD, with 8 cohorts
  • Blinded IRT reports included the IMP Lot Numbers, which unblinded the treatment allocation
  • The issue was not noted until the 8th cohort, near the end of the trial

IRT Reporting

  • One treatment arm required 2 kits of one medication type to be dispensed at each visit (so it was possible to determine the arm based on number of kits allocated)
  • Blinded IRT reports included the quantity of kits & the patient these were dispensed to

IRT Design

  • Double blind study with 2 treatments
  • Recruitment was faster than expected, so IMP began to run out and a site-to-site transfer process was initiated
  • Delivery issues meant that sites received incorrect supplies and patients could not be dosed
  • The Site unintentionally unblinded several times when attempting to supply IMP, as they knew what was in the pharmacy but the IRT stated that there was no medication

IRT User Access

  • Double blind study with 2 treatments
  • Emergency unblinding (code break) available via IRT for sites
  • Global unblinding access was granted to over 100 sites and study team members
  • An entire cohort of patients was lost

Click here for the second installment to this series, where we review various scenarios within a clinical trial in which unblinding can unintentionally occur, including randomization, site supply, inventory management, patient supply, reporting, and live study management.

Contact [email protected] or visit Calyx.ai/IRT to learn how Calyx RTSM experts can support you in identifying potential unblinding risks inherent in your trial and packaging design.


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