It’s well-accepted that unintentional unblinding during clinical trials can have serious ramifications for data integrity. But what’s not as commonly recognized is how data itself can be the catalyst for unblinding, especially during transfers.
In a recent webinar from our series on unintentional unblinding, which includes randomization and drug supply risks, Calyx RTSM experts reviewed scenarios of how study data can lead to unintentional unblinding.
Here we address some of the questions that arose during the webinar related to Calyx’s approach and suggestions for minimizing unblinding risks related to data during clinical trials
Sometimes IRT vendors provide a data dump, so you are sent the whole table or a segregation of the table. Can Calyx create tailored data sets?
Yes. We believe that data dumps in general are not very useful. We can create specific/tailored datasets that enable you to pick and choose what you want to see and how through a data transfer request form.
Part of the risk discussion around creating a data set will be what you need and why – what combination of all the data stored in the IRT system the statistical programmer needs in one report/transfer.
Our SaaS reports team can select data from all the different places the IRT system stores it, bringing it all into one data set and tailoring it to the format and the labeling and transmission process that the sponsor or the statistical programmer needs.
When you’re combining data, we just need to be very careful that when you create that picture in that one data set, you’re not showing those differences and highlighting something that could lead to unblinding.
Can you provide audit trail data?
Yes, absolutely we can provide audit trail data. We have some packages we can create easily and quickly because this is a very common request during regulatory audits, but we can provide any audit trail of what happened to data over time.
Using an example of IMP/kit data, maybe you want to know the status of how a kit went from arriving at the site all the way to being shipped to the return depot for destruction. Sometimes people want to see what happened to that kit all along the way.
We’re able to provide audit trail data for any data point that is collected in the IRT system.
How do you allow auditors access to blinded data during audits?
Usually, a specific request is formed during an inspection and then brought to us for consultation on how to best meet those needs (if the data is not already available in a pre-validated report).
Maybe the site can show data they have in an existing web report, or the sponsor team has access to data that they can display. But sometimes customer requests arise, like audit trail data which require an ad hoc data set; this can be provisioned to the authorized recipients who can determine how they want to deliver that to an auditor as appropriate.
What are the timelines for critical requests?
We do manage critical requests – the delivery timeline is dependent on what you need, when you need it, and the reason for the request e.g., is it for an inspection or an audit happening now?
We will always work together to respond to critical requests as quickly as possible, provide high-quality data, manage any risks (including unblinding), and make sure you have what you need within the timeline you need.
For double-blind trials, our clinical supplies team would like to provide extra expiry dates to sites to help them prepare for relabeling activities. Can you speak to how 2 different lots with different expiry dates can impact the blinded site team members?
Before relabeling starts, we need to create a plan and decide which kits will be relabeled.
If the expiry date is on the label, some kits with the old expiry will be needed to allow patient scheduled dispensing and site shipments to take place while relabeling is being completed.
Whether some kits need to be returned to a central depot should be considered. But it is also usual to see some kits reserved for relabeling at the depot where the relabeling will take place. This can be achieved by updating the status of the chosen kits in the IRT system, to avoid them being shipped to the site or dispensed.
We also need to understand how the kits are going to be relabeled. For example, is it just expiry that’s being relabeled, or is the actual kit number being over-labeled too?
Where relabeling of kits takes new kit numbers from the medication packaging list, this is not usually a concern as the list would typically already have overage built in. Moreover, with a scrambled kit number used in the original list, assigning a new kit number after the relabeling will mean it is indistinguishable from an old kit number.
The relabeling activity at the depot should not allow the new batch release at the depot to affect the blinding of the study. Including overage at the start in the packaging list will avoid a visible separation of numbers across batches.
We always need to consider, “Is there a difference? What difference are we going to see?”
The switch to assigning a new expiry date (when expiry date is visible to blinded staff) for only one treatment group may be a risk. If the newly re-labeled kits are only supplied when the old expiry date kits can no longer be allocated, then there is no risk. But to avoid failed shipments, it is likely that kits with a new expiry date on the label would arrive on-site before the expiry of the old kits. If one medication type is depleted within site stocks from the expiring kits, then the remaining old kits should be removed from site stock to avoid any observable difference. At a low recruiting site, this may not be a concern.
When lot number is unblinding
We do manage studies that have unblinding lot numbers, where the lot only contains one medication type and that’s obviously a big challenge.
In addition to blinding the lot number, if you had one lot/medication type that was not being relabeled and another lot where some of it is relabeled, that new expiry date is only going to relate to one medication type. In this case, we will see some segregation of kit/IMP types.
If we have different expiry dates for active and placebo, for example, one of the options that we propose is using the earliest expiry date for both batches.
You cannot use the longest, but using the earliest expiry date for both has the potential to increase wastage for the medication type that lasts longer. An extra packaging run of the other IMP type later could enable us to match the expiry dates for both types again, or allow the use of a new ‘earliest expiry date’ when released. Ongoing management of the expiry dates could be needed to make the best use of the medication.
Once again, our aim is to try and remove the visible difference, if there is a blinding concern.
When an unblinded pharmacist is the only person who can see the actual original kit type before it’s made up and handed to the person doing the dosing, this certainly simplifies the actions needed to maintain the blind.
This answer covers several scenarios, but it really mimics the sort of IRT/RTSM questions about relabeling we discuss with the sponsor study team. Brainstorming, discussing, and looking to see what we can do in the system to remove differences, to dial out the risk and investigate what is practically achievable.
