Sponsor Q&A: Building Flexibility into Early Phase Oncology Trials

We met with early phase oncology experts on how to use Interactive Response Technology (IRT) systems to optimize oncology trials. In this lively question and answer session, Kim Davis, Senior Clinical Trial Manager at Corcept Therapeutics and Bryan O’Neill, Senior Director of Clinical Supply Operations at Daiichi-Sankyo explained how IRT has helped them manage their studies more flexibly to increase visibility, reduce waste, contain costs, and mitigate challenges in increasingly complex global early phase oncology trials.

Why is it important to use IRT for early phase oncology trials? What criteria do you look for in an IRT vendor?

Kim Davis: IRT can help optimize how you ship and supply drug in order to contain costs. From my perspective, I'm seeing a lot of these early phase studies go multinational even at Phase I, and I'm seeing more complex protocol designs, randomization, and blinding. For that matter, I really need IRT to help control those specific complexities. Having a really well-designed IRT system will help you achieve the goal of a successful study.

When looking for vendors, I look for ease of implementation, how quick startup will be, and how easy the systems will be to use—not just for my study team but for sites to leverage the systems efficiently. I also look for the ability to easily make mid-study changes to mitigate cost and time constraints.

For complex Phase I oncology studies, some pretty substantial amendments can impact IRT. For this reason, I am looking for something that offers flexibility. The system needs to be like a chameleon so it can adapt to what's going on in the study. If I have to update dose titrations for patients or cohorts, I want to have the flexibility to monitor these aspects of a study and manage them easily. I am seeing a lot of crossovers being built into protocols—the ability to manage that within an IRT system as well is super helpful.

What are some of the biggest challenges you face in managing clinical supply for early phase trials?

Bryan O’Neill: One of the main challenges for me is persuading academic research organizations (AROs) to use an IRT system for early phase studies. In my experience, many AROs would prefer to use more manual site processes to manage drug and patient activities. Educating the AROs around the benefits of IRT is a frequent point of negotiation and collaboration.  

Kim Davis: For Phase I studies, it can be a challenge to get clinical sites to enter in data. You want to make sure that data goes in quickly so you can make decisions fast. I like to build an integration between IRT and EDC systems. It's a huge plus because the IRT allows you to push patients automatically into the EDC and incorporate components of screening so the data is pre-populated for sites between both systems. Sites certainly appreciate that you've helped get that first step done for them.

How have you managed complexities in your early phase oncology trials, particularly around dose escalations and cohort management?

Bryan O’Neill: The IRT provider that you select should definitely have a module for sponsors to dynamically manage cohorts and a drug dispensation module that goes hand-in-hand with that level of cohort management. This ensures that you’re able to react on the fly to changes that the study team may not have anticipated—without having to redesign the system. Otherwise there will be study delays, additional money spent, and that may not leave the best impression on people involved in the study.

Kim Davis: I have done a number of Phase I studies where we have multiple cohorts and have to manage things like intrapatient titrations amongst cohorts, dose escalations, and so on. It’s a lot more challenging without IRT because you have to be so hands-on with your sites. Our studies that have implemented IRT systems from Phase I onward benefit from more control of cohorts and doses—so long as they’re designed with that flexibility. 

For cohort management, the first thing I look at is making sure all our thresholds are set correctly at the study level so we don’t exceed a maximum number of patients enrolled or screened. Next, I make sure site-level thresholds are set up correctly either in terms of their site contracts or based on site feasibility estimates. I also set up study-level cohort and site-level enrollment notification thresholds at 50, 90, and 100 percent. These notifications go straight to the inboxes of my study team and myself.

The notifications remind us to check the IRT system periodically to see if we need to make any adjustments. They also remind us to follow up with sites if things seem to be going too quickly and then prepare to close any cohorts that need to be. So, a good IRT system adds an added level of comfort in managing your cohorts because everything is centralized, and you're not having to rely on communicating piecemeal to all your different sites. You're getting your information as close to real-time as possible.

How do you monitor/manage sites in terms of enrollment and their completion of workflows in the IRT system?

Kim Davis: We usually use notifications to see which sites or cohorts are under-enrolling. I am checking the system beyond just when notifications are received to see what's going on. It may drive me to look at high enroller sites and see how they're doing on other aspects such as data entry to make sure we're getting data in and they're able to handle workflows as they put patients on the protocol.

How does manufacturing-on-demand help you manage the supply chain in your early phase trials?

Bryan O’Neill: Essentially, we use the term manufacturing-on-demand to mean ‘deferred customization’. If we have a drug product in vial, we would have it pre-labelled with the carton label as well, but we wouldn’t have the protocol number and the expiry or shelf life on the label. So, we defer protocol and expiry date assignment until the time of known demand when we have patients who have entered screening. By taking this approach with clinical drug candidates in high demand, it allows us to keep inventory maximally flexible. Doing that without a global system across upwards of 50 clinical studies that are pulling from the same drug product is very challenging if not impossible to do effectively.

The IRT system allows you to do it systematically by seeing where your inventories are. If you have many Phase I studies that are not in that model, you have a lot of uncertainty in your inventory management. In that case, you really don’t know how much inventory you have at those sites and when the next round of resupplies will need to happen. This is especially important in a constrained supply chain. IRT is essential for that process. I think with the right coaching and education with clinical colleagues and their CROs and sites, we can create a situation whereby we take this ‘just-in-time’ manufacturing approach. By employing manufacturing on demand we create less waste, therefore supporting more studies with the same amount of clinical drug product. This benefits everyone—especially patients looking to access highly innovative and effective therapies.

How do you manage comparator and standard of care sourcing?

Bryan O’Neill: When you're centrally supplying standard of care medication or comparators, you want to have that real-time visibility into enrollment at sites. That helps to manage waste of commercial products that we as the sponsor centrally supply and control.

Kim Davis: We make sure we look at all the different suppliers and the costs up front to make sure we're receiving fair market value prices. We also consider how we set up our agreements and contracting. We may set up a design where we purchase 20% of a drug at a certain milestone so we don't incur 100% of those costs if we don’t need it. This staged procurement process helps to manage costs.

Another factor we look at when procuring the drug is expiry. We make sure we're not buying a lot of drug that will expire in the next 6-8 months, for instance. But this expiry consideration heavily depends on how much drug is needed and when within a given study. We strategize procuring just the right amount of drug. That means not too much where we'll need to destroy a lot of it, and not so little that we're going to run out. So we carefully design our work orders out when initially looking to purchase the product we need for trials.

What are some use cases where you needed to change supply strategies, and how did you manage that process efficiently?

Kim Davis: At one point we decided to change capsule types in a global study partially via a protocol amendment. We phased out one combination of capsule strengths for another combination of capsule strengths within a significantly short timeline because the old drug type was set to expire soon. It required an update to the IRT system to add that new drug type as it was not originally in the study, and this needed to be reviewed by each country's IRB. We ended up adding in drug types as well as the ability to turn drug types on and off at the site level. This made sure we wouldn't have to wait until the last site received the new drug supply to make the change in the system. While it required a change order, it allowed us to meet our timeline.

In another case, we as a sponsor reduced our own drug in combination with a standard of care therapy in a treatment arm for an early phase study. The assumption at the start of the study was that we would be using commercial supply, and sites would be able to source it locally. Therefore we would not need to build that aspect into the IRT system. After site feasibility was performed, we learned that specific sites in these various regions wouldn’t be able to source the standard of care. We had to add in the functionality to be able to add in drug types, and for those select countries we had to make sure that shipment was turned on for that standard of care to be shipped to sites. I now consider adding all drug types into the IRT at the beginning of the study even if we plan for sites to source certain comparators or standards of care locally. Having that flexibility built into a system can help to mitigate change orders.

Where do you see the biggest advantage in using IRT for early phase oncology?

Bryan O’Neill: Real-time visibility is important. In one of my past jobs I was training pharmacists at sites across the US on how to prepare and administer investigational product for studies. I noticed how busy these site pharmacies were. For instance, I visited a site that was running over 100 clinical studies. I saw the value in giving these sites relief from inventory management workflows. And to make sure that sites are adequately supplied for returning patient visits without having to urgently request resupply from sponsors and distribution vendors. Using an IRT system for this reason is beneficial for sponsor teams as well as for investigational pharmacies to better manage their staff resources.

What would you do differently since you first set up an IRT for one of your early phase studies?

Kim Davis: It all goes back to flexibility. If you design your IRT to be very static, it doesn't bode well when you have to amend or change some aspect of a study. I've had a couple of studies with lead-in periods built into the IRT system in a way we couldn't directly change. In some cases, we had to completely remove the lead-in period. So, in terms of a future consideration, having the ability to turn lead-in periods on and off would be incredibly helpful. 

Think at the design stage what will be most flexible for your study. Make sure you have that open dialogue with your IRT vendor to ensure whether you can change the system in real time or if it will need to be a change order.

Bryan O’Neill: I initially wanted to bake in some ways of working with the supply chain that I perceived as efficient from the sponsor perspective. One of those was pooling inventory across studies. But I did not check in well enough with investigational pharmacies inventorying the drug and preparing it. Specifically, many clinical sites have their own inventory management systems which require the drug be assigned to a protocol at time of receiving, which negates the ability to pool drug across studies up until patient dosing. As a result, we had to do a couple change orders to meet site needs. I learned the importance of partnering with investigational sites up front to understand how product flows into their shop and how it's inventoried. This ensures that the IRT's inventory management workflow accords with the workflows they're used to with their inventory management systems. So, I think it's important to find points to engage with the sites to meet their requirements in designing specifications for an IRT system. It educates them in advance about the IRT and it also builds a level of acceptance and comfort around the benefits of using an IRT system versus using a manual process to manage clinical supply.


Listen to the full conversation here.

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