How Unintentional Unblinding Occurs in Clinical Trials

Randomization

• Reporting randomization number when blocks are dynamically allocated to strata (with a higher risk with site stratification)
• Reporting randomization number when forced randomization is permitted (with a higher risk with site stratification & if there are only 2 treatment arms)
• What IMP the IRT system checks is available at site before randomization is permitted to proceed (the risk depends on the number of treatment arms & also whether forcing is permitted)
• Replacing patients at the end of the cohort
• Reporting randomization number when patients are being replaced
• If re-randomization is required for a sub-set of treatment arms

Dispensing

• What IMP the IRT system checks is available at site before medication assignment is permitted to proceed (the risk depends on the number of treatment arms)
• Selecting which kits should be dispensed to patients
• When dispensing only a partial amount of required treatment (which could be allowed if the patient can be given sufficient medication until the remainder can be provided)
• When blinded medication is used in an open label manner (i.e., single blind run-in)
• When the dose level is known to Investigators, but the treatment is not
• When one or more treatments are supplied by the site (i.e., the IRT only manages the ‘active’ kit, with the placebo supplied by site: local & central sourcing)
• If third party lab data is required to make a patient treatment decision (see figure)

Shipping

• Selecting which kits should be included in shipments
• If a partial shipment is sent to a site due to a stock out at a depot
• When shipping in boxes, but dispensing individual packs to patients (the risk depends on the number of treatments in a box, whether dispensation is “random” & also whether forcing is permitted)
• When different expiry dates are used across blinded batches

Site Supply

• If there are different trigger & resupply values (buffer stock) for different IMP
• If the initial shipment to the site only contains 1 of each IMP
• When new doses are added e.g., for an adaptive study
• If medication is predicted for all possible treatments for re-randomization when not all patients re-randomize
• If medication is predicted beyond re-randomization for patients who are not re-randomized and not all patients re-randomize
• When predicting for an open label extension where medication is not the same across treatments & is determined by blinded treatment (see figure)

Drug Accountability

• If there is variability in returns and/or destruction procedures for each blinded kit type en-route to or at the destruction facility
• If there are both blinded and unblinded site personnel, and variations in drug accountability process for different blinded kit types at site
• If expiry date is unblinding

Study Management / Data Changes

• If the study is open label, but the Study Team are blinded to treatment group
• If the study is Double blind, but there is open label treatment
• When there are two treatment groups and patients receive a different number of kits based on their treatment group
• When the IRT is only managing one treatment group

Don’t miss the last installment to this series, Clinical Trial Unblinding: What it is and what it isn’t, where Calyx’s Craig Mooney presents issues – some of which might be considered controversial – related to unintentional and partial unblinding in clinical trials.