Monitoring the double-blind study: unblinded pharmacist, unblinded monitor, and drug kit

In many clinical trials with biological products, the investigational products usually need to be reconstituted before the use. If the study is a double-blind study, the reconstitution of the investigational products can not be performed by the investigator in order for the investigator to remain blinded to the treatment assignment.

There are two ways to tackle this issue.

1. Using a third party (unblinded pharmacist).

With this option, the unblinded pharmacist at the investigational site will be the only person who knows the treatment assignment. The unblinded pharmacist will obtain the randomization number and treatment assignment information from the randomization envelope (manual process) or from IRT (interactive response technology including IVR or IWR) system. The unblinded pharmacist will then prepare and reconstitute the study drug, and then give to the investigator for administration.

The unblinded pharmacist must not communicate with the investigator about the subject treatment assignment.

The unblinded pharmacist must maintain the records for drug accountability for auditing and inspections.

With this option, the study team will need to include an unblinded CRA (clinical research associate) for the purpose of checking the drug accountability. In other words, there should be separate roles for two type of clinical monitors:

• Blinded Monitor: A monitor designated to perform site monitoring activities except for pharmacy, drug accountability, and reconciliation of the blinded investigational products.
• Unblinded Monitor: A monitor designated to perform the site monitoring activities for pharmacy, drug accountability, and reconciliation of the blinded investigational products.

 Some of the references for this approach:

• Unblinded Monitoring Programs: Design and Education
• Unblinded Monitoring in HCV Trials
• Integrated monitoring: Setting new standards for the next decade of clinical trial practice

2. Using the blinded drug kit for the investigational product  

With this approach, in addition to the randomization schedule (containing the  randomization number and the treatment assignment), additional list of drug kit numbers (and the linked batch or lot number corresponding to the investigational products) will be generated. Through the packaging, the label for the investigational product kit will contain only the kit number. Investigators can dispense or administer the investigational products to the patients based on the kit number without knowing the actual contents and the treatment assignments.

There is no need to have separate roles for site monitoring (ie, unblinded monitor and blinded monitor). The same monitor can cover the study activities and the pharmacy/drug accountability.

This approach can also be used for pills (non-biological products). It is especially useful when the investigational products are dispensed to the patients for their self-administration.  

A couple of examples for using this approach are listed below:

• Tenecteplase (TNK) study in AMI

“Randomization was to be blocked by study site, based on a SAS-generated code. Treatment assignment was made through a call to a centralized interactive voice response system for a drug kit number. Subjects were considered randomized upon verbal assignment of kit number.”

• A Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine Extended Release in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder

“Patients were randomly assigned to 1 of 3 groups of GXR treatment (2, 3, or 4 mg/day) or placebo, in a 1:1:1:1 ratio. Matching GXR and placebo tablets were provided to patients in the form of weekly prepackaged individual study drug kits, identical in appearance, according to the randomization schedule. Every morning during the double-blind treatment period, patients took a total of 4 tablets, without regard to meals. Patients who completed the screening and washout periods were assigned to the treatment group of the next available drug kit in ascending order of the drug kit number (or randomization number), which was recorded on the case report form.”