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January 23, 2023

Special Considerations for RTSM in Rare Disease Trials: Part 1

All clinical trials are challenging. But when the protocol is evaluating the safety and efficacy of rare disease treatment, the challenges are even greater. This applies to all aspects of the trial, especially the logistics around randomization and trial supply management (RTSM).

For example, while it’s true that in all clinical trials, every patient matters, this takes on new meaning in studies of rare diseases. As there are not many people living with the diagnosis, identifying, enrolling, and keeping patients engaged in clinical trials is critical. Trial sponsors can’t risk failed visits, which could lead to a patient dropping out because the drug wasn’t available for a dispensing visit.

And rare disease trials often require many investigative sites to recruit a small number of patients. Combine this with the reality that rare disease drugs are typically very expensive to produce, and it’s easy to understand the importance of reducing excessive drug wastage during development.

So, ensuring the right sites have the right amount of drug at the right time – without over-producing and shipping drugs to all sites – is critical to a rare disease development program’s success.

In this first series installment, Calyx’s Malcolm Morrissey outlines these and other RTSM factors sponsors should consider and demonstrates how working with a reliable interactive response technology (IRT) provider with subject matter expertise, customizable designs, and dedicated study support can make a big difference in rare disease trials.

What is one of the first RTSM decisions sponsors must make when designing rare disease trials?

There are a lot of questions related to whether rare disease trials should be run the same as trials of other more common indications. Is it necessary to conduct a randomized study with a control group, or will an enrollment-only design suffice? Rare disease trial sponsors typically want to avoid the significant extra cost and recruitment time needed for a randomization study, which includes a control arm. The alternative is to run an enrollment-only study which removes the control and reduces the number of subjects needed but could impact the analysis which for some is a difficult decision to make.

In our discussions with trial sponsors, we present different randomization approaches to help them meet their development objectives. These include traditional techniques such as permuted block randomization through more complex, Bayesian response adaptive trials. With these adaptive techniques, allocation ratios can change, and/or treatments can be dropped as the trial progresses, which is one way of reducing the overall number of patients a rare disease trial requires.

“It’s important to work with a reliable IRT provider with a mature platform that can manage the complex and innovative randomization techniques required to adapt to changing RTSM needs of rare disease trials.”

– Malcolm Morrissey, Head of Statistics and Product Support Services

Are all rare disease trials affected by slow enrollment?

Just like no two rare diseases are the same, no two trials for rare disease treatments are the same. This is apparent throughout the trial, beginning with patient recruitment. In some trials, slow recruitment may very well be the reality, requiring many investigative sites to recruit a few patients, as discussed above.

But slow recruitment is not always a challenge, as in some diseases the patients are already well-known by clinicians who will target them for enrollment. For these trials, Calyx IRT experts understand that an enrollment-only trial design could be considered. This is because there would be no way to truly blind the investigator in a randomized trial, as he/she is so familiar with the patients, any improvement in their symptoms would indicate they are on the active treatment arm. In addition to the blinding aspect, there is also the benefit of these well-known subjects being their own control. In this case a comparison of prior treatment versus new treatment, by the people who know them best, may be possible.

For these reasons, it’s important to work with a reliable IRT provider with a mature platform that is proven to support very long recruitment for traditional protocols and/or can manage the complex and innovative randomization techniques required to adapt to changing RTSM needs of rare disease trials.

How can an IRT system mitigate the risk of failed patient visits during rare disease trials?

There are numerous scenarios that can cause a failed patient visit, including the unavailability of study drug. But sponsors who leverage a robust IRT system can benefit from trial supply designs that minimize this risk. These include as a prediction supply design that considers the visit window and Do Not Dispense (DND) date of the visit, as well other characteristics like the dose level of the patient, when sending medication for upcoming visits. Or an automated supply switch design that ensures each site is appropriately stocked by changing the IMP supply levels to match the site’s current recruitment rate.

Additionally, experienced trial supply professionals can extend their expertise and insight into drug supply risks that could negatively impact depot inventories and, ultimately patients’ access to study drugs.

Considering the expense of rare disease treatments, how can sponsors leverage IRT to reduce drug wastage in these trials?

Calyx IRT can help sponsors optimize drug management by applying clever settings that reduce the amount of drug shipped to sites. Calyx IRT solution designers routinely work with sponsors to determine which advanced trial supply management options are best suited for their trial, including automated supply switching, randomization prediction, and/or medication pooling. All of these have been proven to reduce the amount of drug wastage in clinical trials, reducing the overall cost of clinical development programs.

Stay tuned for Part 2 of the series where we tackle some of the other challenges, including study length, data collection points, cell and gene therapies, etc., and how you can rely on the expertise of Calyx IRT solution design team to deliver a robust, flexible IRT solution to address all of your rare disease trial’s RTSM needs.


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