As I discussed in my previous blog post, Novel Clinical Trial Designs and Their Impact on the Role of RTSM– Part I, adaptive trials, master protocols and the use of direct-to-patient (DtP) clinical supply chains are increasing the complexity of clinical trial designs and the Randomization & Trial Supply Management (RTSM) and Interactive Response Technology (IRT) systems that support them. During the Clinical Trial Management track at SCOPE 2020 in Orlando, Florida, I presented this topic, including the key considerations when using IRT, RTSM and supply chain forecasting/optimization systems in these newer trial approaches, specifically Direct-to-Patient (DtP), which I’ll also discuss here.

Adaptive Trials and Master Protocols
Because of their inherently changing nature, both adaptive trial and master protocol approaches require highly sophisticated RTSM design capabilities and the ability to quickly and efficiently introduce protocol adjustments during study execution. 

When designing RTSM for adaptive trials and master protocols, you should carefully think through the system’s ability to handle multiple subject cohorts, randomization schema, dosing and visit schedules, open label and blinded products, and pooled investigational products – all key to the conduct of novel trial designs. In addition, consider your data integration and RTSM reporting requirements. It is also critical to think through how data will be shared across multiple systems to support the necessary decision making when determining protocol adaptations. Having to manually reconcile data across your clinical trial systems, such as EDC and CTMS, delays access to your data, and a lack of reporting makes key decisions regarding protocol changes, recruitment and randomization extremely challenging.

To understand which design elements and functionality are critical to achieving your study goals, explore several options through RTSM prototyping. Challenges can be identified and mitigated before executing within the actual study timeline. I would also suggest determining how and by whom protocol adjustments will be implemented, ideally before the study is initiated, to minimize disruption to the study at the time of any adjustments. These processes should be well understood by all stakeholders and tested as part of the User Acceptance Testing (UAT) activities. Supply chain simulations can be run with the different randomization or packaging choices that are likely for your study. Early use of these simulations helps avoid the worst case scenario – a potential stock-out and the inability to assign the drug to the patient. 

With the simulation results, you can plan for probable protocol modifications and build contingencies for these into the system. And, to make it easier for mid-study changes, leverage standard RTSM configurability as much as possible. When changes do become necessary, you avoid having to modify complicated code. However, some mid-study changes might require customization to the standard functionality, so you’ll also want to ensure that your RTSM can support this. 

Direct-to-Patient (DtP) Drug Distribution
In trials with DtP approaches, investigational products are delivered to and administered at the patient’s home, typically by a specialized at-home clinical trial organization. RTSM systems must account for the specific shipping process, including the triggering and timing of scheduled DtP shipments, process for ordering unscheduled shipments and confirmation of drug administration.

Because patient information is used to address the shipments, data privacy becomes a concern. However, in this scenario, the depot has the subject information and complies with in-country privacy requirements. Inadvertent unblinding at any point in the end-to-end DtP supply chain should also be avoided, by ensuring that all stakeholders understand their responsibility to protect the study blind – especially if investigational products are being supplied through multiple routes.

The system must allow for a clearly defined, yet flexible supply chain. Because DtP and non-DtP supply models might occur concurrently in the same study, both supply models need to be accommodated within the same IRT configuration for different countries or sites. At the same time, the system should be able to manage not only the investigational product but also the ancillary supplies. Data change procedures need to be updated to reflect the nuances of DtP, such as the fact that the date of dispensation is not necessarily the date of administration. In some DtP implementations, in addition to IRT, the distribution depot may also store the relationship between subject and treatment and so, in a blinded study, great care needs to be exercised to understand how that information may be reported in the depots systems in order to protect the study blind. Finally, procedures for cancelling shipments need to be clearly defined in the event of error due to incorrect subject information.

How to Accommodate Novel Trial Designs in Your RTSM 
Novel trial approaches can present new challenges to RTSM design, implementation and support. To ensure you’re ready for any scenario, there are a few key considerations. First, collaborate with your RTSM partner(s) early to identify their true ability to design, implement and support your upcoming trial design. Ensure they fully understand and can support the detailed supply logistics.

Remember that custom functionality might be required to meet the nuances of some protocols, but only customize when essential. Keep it as easy as possible to make changes later by not creating complex code.

Plan to engage stakeholders in the design discussions and UAT, with plans made early to incorporate their feedback. UAT should include discussions around how support will be administered and how changes will be introduced into the RTSM system. Then, everyone is on the same page from the beginning, and you can be confident that your design is as robust as possible going into the study.

An agile development process encourages early stakeholder involvement and avoids the traditionally long build times for many clinical trial systems. Early visibility into a working prototype introduces the team to the functionality, which evolves using an iterative approach through to the final design. This essentially means that you are building and specifying the design in parallel, saving time and effort in the review and approval of the specification.  

This system also avoids late design changes, which often occur at the time of UAT, because the team has been exposed to the system throughout the process rather than seeing it for the first time at UAT.

While novel trial designs present certain challenges for clinical trial systems including RTSM, they are not unsurmountable, particularly when time is dedicated to its planning early in the process. Prototyping and simulations can identify issues before the study starts, allowing mitigation plans to be put in place or the system design to be modified to better handle the protocol design. Working with your RTSM partner, you can achieve a system that handles all trials—from small to large, simple to complex.