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.
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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:
“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.”
“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.”
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