20 November 2021 News
According to ICH GCP E6 R2 and other applicable regulations, investigators should follow the trial's randomization procedures (if any). It is also the responsibility of investigators to ensure that the code is broken only in accordance with the protocol. However, in blinded trials, there are some situations where planned or unplanned unblinding is required.
The unplanned unblinding is usually limited to the following scenarios (within regulations):
- accidental unblinding;
- unblinding due to a serious adverse event.
In these cases, investigators should promptly document and explain premature unblinding to sponsors.
The planned unblinding is a different story. Some protocols include unblinding procedures as a part of the process of a clinical trial.
Here we decided to have a look at unblinding processes and share some thoughts from our experience.
The common practice is that in the case of an SAE (incl. SAE associated with a potential overdose) investigator judges upon whether an emergency code break is required to decide on further treatment of the subject.
As a reminder, we would like to note that MainEDC™ provides the necessary functionality for this scenario. The option can be finely tuned to meet the trial requirements, e.g., by setting up warnings, notifications, subject status change, etc.
But some protocols go beyond this scenario and introduce conditions for a planned, i.e., not an emergency, treatment code break.
There are two main reasons for that. The first one comes from the discussions around the ethical side. Once participation in a study is finished (or, sometimes, in ongoing studies), subjects may want to know what exact treatment they received; the reason behind that is simple – it could affect their subsequent treatment.
Moreover, the COVID-19 era also made specific corrections in clinical trials. And unblinding procedures in particular. FDA, for instance, released the guidance for industry related to vaccines development, stating the following:
Efficacy trials should include contingency plans for continued follow-up and analysis of safety and effectiveness outcomes if a safe and effective vaccine becomes available (e.g., as demonstrated in a planned interim study or demonstrated in another clinical trial). In that case, a discussion with the agency may be necessary to address ethical arguments to break the blind and offer vaccines to placebo recipients.
Thus, the unblinding of the Subjects became vital for vaccination-related studies. Here, speed and flexibility play a pivotal role.
The other reason why a subject may need unblinding after completion of a blinded study is the intention to enter its open-label extension or a substudy.
Some technical details.
Without looking deep into the regulatory aspects (we would leave this up to protocol writers and owners, IDMC members, biostatisticians, and other responsible staff), we fully understand that breaking the blind is a sensitive operation in terms of the study data validity.
Technical solutions which allow that should be very flexible in configuration and very robust in access control.
You have to weigh all risks and consider many points, such as:
the process description and RACI matrix,
who becomes unblinded – Sponsor, Investigator or the Subject only,
under what technical conditions, incl. hard stops and data freeze,
is an authorization step required or not,
how and how many times the information about planned unblinding is delivered to whom,
wherein the study database this fact is stamped,
what are the acceptable consequences,
how to prevent errant actions (obviously, by proper training and supervision),
what to do in case of accidental/unintentional actions,
the list can be extended, depending on the study specifics.
Technically, MainEDC™ supports both scenarios: ethical unblinding and subject transfer to a substudy.
No need to say that the correct configuration of the unblinding features can positively affect the study in the long term. The EDC systems should be customized flexibly to avoid unnecessary risks in full accordance with the protocol requirements.
Together with Main EDC, you will tailor the optimal solution to your complete satisfaction in each and every case.