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.

Clinical trial design is getting more complicated, time pressures to deliver on trials are increasing, and sponsors are looking to save costs wherever possible.

Typically, Investigational Drug/IMP is protocol-specific with the protocol added to the label following manufacturing and packaging. If a kit labeled in this usual way does not get used by a patient, it is wasted.

But by sharing medication kits across a suite of protocols/programs, sponsors can minimize the amount of IMP wasted during clinical trials and reduce packing, shipping, and costs. And sponsors recognize an additional benefit of aligning with program-level medication management initiatives.

Here we review additional factors sponsors should consider to fully maximize savings through medication pooling.

Site vs. Depot-level Pooling

In a previous blog, we demonstrated how medication pooling can help reduce wastage with a focus on the options of and considerations for:

• Site-level Pooling: medication is only allocated to a protocol at the time of dispensing to the patient
• Depot-level Pooling: medication is allocated to a specific protocol upon inclusion in a shipment

A recent review of how Calyx customers have leveraged pooling over the years has revealed additional variants and considerations for successful medication pooling strategies. Calyx has experience supporting sponsors with five different variants of depot-level pooling alone.

Additional Considerations for Effective Medication Pooling

The five variants of medication pooling managed by Calyx IRT are governed by responses to the following questions:

• Where is the packaging list held?
• Who manages the pooling: sponsor or IRT?
• When do the kits become protocol-specific?
• What is on the label?
• When are the kits labeled?

Depending on the response to these questions, a combination of approaches can be used.

It is important to note that all these variants impact the sponsor’s processes and labeling plan with regulators.

Does Pooling Affect RTSM Setup?

Pooling may not impact the RTSM setup if handled manually by the sponsor outside of the IRT. If the packaging list for a program of studies is held by the sponsor, they may not share the whole list with the IRT vendor up front.

Medication is packaged and labeled in the usual way; however, it is done using a central list shared across all studies in a program. The next ‘section’ of the program list will be released in an individual IRT study when it needs additional medication.

The pre-planning of the packaging design for the program allows for flexibility and use across studies. But the medication is still released in the normal way and is dedicated to a protocol after labeling.

The impact on IRT is that for each packaging run, the next section of the central list and its medication numbers will need to be added into the individual IRT studies in a timely fashion.

The alternative approach is to hold the whole packaging kit list within each study in the program, but this can increase the risk of error and may affect the speed of some IRT systems for an extremely large list.

When Calyx is consulted early, our trial supplies experts can discuss pooling options and tailor the IRT to the optimal design for the study suite/program needs.

Supporting Depot-level Pooling

Calyx IRT can assist depot-level pooling by:

• Controlling the sharing of packs across protocols for certain common batches
• Facilitating just-in-time labeling of kits, including tailored reports and integrations

This type of depot-level pooling typically has a different label design when compared to the simple form of pooling mentioned previously. In the simple case, the IMP label is protocol specific.

If the medication label can be approved with multiple protocol numbers on it, an IRT can hold the central packaging list for the generic packs in a ‘parent’ study (database which holds the central list) that can talk to the ‘child’ studies (database for each protocol) within the program (See Figure).

These generically labeled kits can be released into the parent study and shipped to a child study as and when required. Within the IRT system, these kits will be used in one protocol, after the point of shipping. An IRT design may use a mixture of generically labeled kits and protocol-specific kits; Calyx IRT can apply a priority to their use if they are of the same type.

Just-in-Time Labeling

In many cases, it is considered difficult to obtain approval for a label with multiple protocols. This may be related to the size of the kit and the confusion for the user handling kits at different points in the supply chain.

A recent trend Calyx has observed is to move to a just-in-time (JIT) labeling approach to assign protocol numbers as they are needed for shipping. So, a generic label is seen initially, but only a protocol-specific kit will leave the depot in a shipment.

Just-in-time labeling therefore also impacts the depot process. As a result, ‘over-labeling feasibility checks’ are important.  As part of this process, kit numbers are requested by the IRT for a shipment to a site and an extra physical label is typically added manually to each kit in that shipment to display the protocol number. The size of consignments and the impact on resource hours, as well as lead time, are important considerations.

Calyx IRT can support a JIT labeling approach, so sponsors can realize the benefits of labeling study drug as it’s needed, rather than much earlier/at one time in large batches. The benefits include a reduction of drug wastage and the more efficient use and distribution of study drug.

Follow these Rules for Maximum Benefits

All these methods are exciting and can help to reduce waste when applicable. Much experience has been gained from their use in the industry in recent years. But, in some cases, the experience has not always provided the savings expected.

If these general rules are considered for pooling protocols, the added flexibility and potential waste reduction cannot be ignored:

• The packaging design is suitable for multiple protocols
• The timelines of the protocols overlap to allow the use of the same batch across multiple protocols
• The supply chain storage points (e.g., local depots) overlap for multiple protocols within a program of studies
• A suitable labeling process can be agreed

Conclusion

Many factors can change after initial design choices are made, for example, the study timelines may change, the ability of a depot to over-label kits at the point of shipment may change or increase which impacts the lead time and costs of the process, and protocol amendments can impact the design. But the underlying benefit of flexibility still exists when these tools are utilized.

At Calyx, we believe there is further experience to be shared and gained in this area and that the most efficient use of pooling is yet to come.

When considering Interactive Response Technology (IRT), many think only about its base functionality – ensuring effective randomization and trial supply management (RTSM) while maintaining the blind during clinical trials. However, today, these critical functions have become a baseline for what the industry expects of this technology.

Since its inception over three decades ago, IRT has evolved to meet the ever-changing needs of the clinical development industry. Gone are the days of IRT only being used for basic RTSM functions in large, late-phase trials. Today, IRT is frequently relied on to:

• Support Phase I trials
• Accommodate all trial designs, including cohort and  adaptive/platform trials
• Perform complex calculations and logic as per complex protocols

Clinical trial sponsors also expect more from the people behind their IRT solutions. A reliable IRT vendor should act as a partner and provide expert advice and guidance about the proper and efficient implementation of their IRT system. They should work to understand and analyze each study’s unique requirements and develop a strategy to meet the trial’s goals, identify and mitigate risks, and allow flexibility for the future.

Here we present specific examples of what an advanced IRT system and the people behind it can deliver, beyond the basic expectations of RTSM.

Randomization

Using an IRT for randomization functionality not only helps to ensure data and study integrity by eliminating bias, but it also manages the risks of randomization imbalance.

Randomization and Beyond

Although blocked randomization is the methodology used for most clinical trials, IRT systems are increasingly being used to accommodate highly complex dynamic allocation methods. For example, minimization helps reduce imbalances across treatment arms while considering prognostic factors such as disease stage.

An advanced IRT can be used to facilitate this and other equally complex dynamic allocation methods, such as Zelen’s, hierarchical dynamic, Urn methods, and Bayesian response. Adaptive and platform studies can also be supported. You should be able to rely on your IRT vendor to provide expert guidance on the most appropriate methodology to meet your study’s randomization needs.