If you ask any early-phase clinical operations professional about one of the most stressful and critical milestones in their trial, they will undoubtedly mention dose escalation. During this phase of a clinical trial, the focus is on rapidly collecting and reviewing critical safety data, pharmacokinetic (PK) data, pharmacodynamic (PD), pharmacogenomic (PG) data, and other relevant information to determine whether it supports proceeding to the next dose level.
In complex trials like oncology, where the patients are often seriously ill, it is crucial to achieve a tolerated dose level as rapidly as possible. Delaying dose escalation not only prolongs the time it takes for patients to potentially benefit from the treatment but also introduces additional costs and risks to the trial.
Sample management plays a crucial role in enabling dose escalation, but it is vulnerable to preventable issues. Lack of comprehensive knowledge about sample status, including collection, processing, location, storage, shipping timelines, arrival at the lab, and testing schedules, can impede the availability of vital data required for dose escalation. In this blog, we outline the top five mistakes frequently made by early-phase clinical operations professionals that hinder dose escalation.
One of the most common reasons for delaying dose escalation is not having enough available data to consolidate and analyze to make the decision. Many times, this is the result of logistics and study management issues including missed samples, lost samples, samples taken out of window, delays in sample processing, etc.
Consider this scenario as an example: The study protocol mandates the inclusion of a specific biomarker for patients participating in the clinical trial. Once enrolled, the patients undergo treatment, and multiple serial PKs (pharmacokinetics) and corresponding PD (pharmacodynamics) samples are essential for analysis. However, missing PK data at different time points disrupts the ability of the sponsor to observe drug exposure levels continuously, making it challenging to determine drug clearance accurately.
Furthermore, the correlation between adverse events experienced by patients during the trial and PK data plays a critical role in understanding whether there is an expected relationship with drug levels. What if your sites have not indicated that their patient has cleared the dose limited toxicity (DLT) period, i.e., they have not gone the full 28 days on the study drug? That data is needed alongside the PK data to be able to confirm that the patient has made it through the testing period and they are ready, safety-wise, to go to the next dose level. Sample data is also used to show that the study drug does not have a toxic effect. Not having enough of these data to statistically prove the current dose is safe can prevent dose escalation.
Early-phase clinical operations professionals engage in dose escalation planning from the moment the first patient in a dose cohort enrolls and proactively estimating the projected last patient to schedule the dose escalation meeting. As a part of planning, it is vital to oversee proper collection, shipping, and receipt of all required samples at the laboratory to gather the necessary clinical data for dose escalation.
This is where the chaos comes in. There needs to be an understanding that all patients are enrolled or that are expected to enroll in a specific cohort. Based on that, the timing that the samples from those patients will be collected, processed, stored, and/or shipped to the appropriate locations is mapped. Without visibility into enrollment and sample management, clinical operations professionals are chasing a moving target when planning for dose escalation.
Lack of sample visibility prevents the ability to be proactive in enrolling more patients when necessary, and can actually cause patient attrition due to lost or misplaced samples, invalid samples that are collected out of window, and enrolling patients that do not meet the inclusion criteria. Any of these scenarios can cause inevitable study delays when the data from these individuals is crucial for dose escalation.
Another thing that can prevent dose escalation is if sites are not performing study operations according to the lab manual or the protocol. Sites are often challenged with deciphering lab manuals for complex sample management collection, processing, and shipping instructions. Given the risk of human error with manual processes, it is possible that sites may misinterpret instructions or miss required sampling procedures.
Sponsors should take the steps necessary to ensure that their sites are properly trained in the study protocol and lab manual, as well as ensuring they have the proper tools to help guide site operations, ensure quality data, and compliance with study requirements.
Without the correct kits on-hand at the site, samples cannot be collected, and visits cannot be completed. As we detailed in our previous blog on the vicious cycle of inventory management, the process for supplying research sites with lab kits and associated inventory is chaotic. There is no visibility into patient demand, so the solution tends to be sending bulk supply which often expires before it is needed — leading to reordering, and more waste. Additionally, site coordinators are overburdened by mountains of lab kits, often having too much of what they don’t need, not enough of what they do, and most importantly, no idea of what they actually have on hand.
To ensure that clinical research sites always have the supply they need to conduct the visits and to collect the required samples is essential to reach dose escalation. Clinical research sites need a better way to manage their clinical inventory.
Our last item on the list is all too common, and it is an unfortunate reason to ever miss dose escalation: there just isn’t availability at the labs to batch run your samples.
Why does this happen?
Let’s imagine that you are trying to schedule a batch run with your vendor that is going to run your PK, PD, or PG samples. As a clinical operations professional, most likely you are tracking it on spreadsheets (if you have the bandwidth) by exporting records from the EDC. But what if your patients aren’t entered into EDC, and you’ve received a sample at a lab? First, you need to determine if it is an actual patient and there is just a data lag with entry into the EDC.
Adding to the complexity, dose escalation is usually dependent on batch runs. The lab won’t run the samples until the entire batch is received and the sponsor or CRO triggers the batch to be run. Results can be delayed simply because they are waiting for the entire batch. There is a ton of manual oversight on the part of the sponsor. It is a balancing act between projecting enrollment, balancing when the samples arrive at the lab, and the timing of when they will arrive at the lab.
The main issue? If timelines shift, as they inevitably do, and neither the sponsor, CRO, or lab has full visibility into the real-time status of the samples, the lab may not have any batch run available on their line because the study timeline shifted. In other words, the lab cannot proactively plan to test your samples. The last thing you want is to delay your dose escalation due to a scheduling issue.
These five sample management issues are preventable. With the Slope clinical trial execution platform, sites are guided according to the study protocol and lab manual, and sponsors have real-time visibility to all sample activities from kitting to collection at the site, to shipping and lab to lab transfers, to their final destination at biobanks. Dose escalation is such a critical stage of a clinical trial, and proactively avoiding delays should be everyone’s objective.