Sometimes a clinical trial sponsor asks their RTSM/IRT provider to deliver something which conflicts with good design principles; of course, it’s being requested for a valid reason, but will have consequences. A good provider will first seek to understand that reason by asking “Why?” and provide a solution that avoids those consequences.

Even with over 30 years of industry experience under their collective belts, Calyx’s RTSM solutions designers would never make assumptions regarding the sponsor’s needs. By understanding the reason behind a request and what the study team really wants to achieve, they can find the optimal solution while mitigating or avoiding risk. Their experience from having built and managed all types of trials gives them a deep understanding of those potential risks.

Designing the Optimal IRT for Your Trial

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If your IRT/RTSM provider says ’yes’ to every request without understanding your needs, you could end up with a less-than-optimal, higher-risk design that:

– Isn’t right for the life of the trial
– Isn’t easy for sites
– Doesn’t avoid data reconciliation issues
– Has no flexibility to manage future amendments
– Doesn’t meet regulatory authority obligations
– Doesn’t minimize unintentional unblinding risks
– Doesn’t best manage the specific risks of the protocol and packaging plan

At Calyx, we strive to find the right RTSM solution that meets our customers’ needs throughout the life of the trial. This includes being great communicators, from understanding those needs to explaining the “Yes but…” with proposals, solutions, recommendations, and risks.

We have the same end goal – the success of your study. For the Calyx team, success means finding the optimal design that keeps the interests of your study, your data, the sites, and ultimately the patients at heart.

When it comes to IRT/RTSM design requests, it’s not a question of ‘Can we do it?’ (that answer is always,” Yes, we can!”) It’s more a question of, ‘Should we do it?’ then ‘How can we best achieve it?’

Evolution, Acronyms & Advances in Clinical Trials

In an industry so full of acronyms, no two are more often interchanged than IRT (Interactive Response Technology) and RTSM (Randomization and Trial Supply Management). Here we look at the system behind the letters, how over time, the terms have come to be used interchangeably, and how the technology is only one component of an effective RTSM solution.

The Evolution of IRT (or Do We Mean RTSM)

In our industry, an IRT system is a central piece of clinical trial execution that enables patient randomization and real-time drug allocation. Put simply, RTSM is the role of the IRT system. But it’s had different acronyms over the decades.

Looking back, some of us remember using 3-part, NCR paper forms for CRFs and the excessive effort that was needed for double data entry. Even once the first interactive voice response systems (IVRS) were introduced in the 1980s for randomizing patients over the phone, paper CRFs were still being used into the 1990s – including a short time when it wasn’t unusual to fax completed CRFs to get the data in faster.

Since the 2000s the internet has enabled the use of web-based systems, which were initially referred to as IWRS. This led to another, often-confusing term, IxRS, which was used to describe when study users could access the system both via the phone and the web.

Today, we’ve tossed the modality aside from the acronym and simply refer to IRT as the tool, or system, for delivering RTSM in clinical trials.

IRT’s Greatest Impact

Most would agree that IRT has delivered many benefits through the decades, but one of its greatest feats was separating randomization and drug supply into two distinct processes. Prior to IRT, randomization was built into the packaging. For example, a site would randomize a patient by selecting the lowest-numbered kit in their inventory. And this kit had all the drug intended for a patient throughout the entire study, which led to wastage in many forms.

Once IRT was established, the relationship between randomization and patient-specific supply packaging was severed. Kits could now be used for any patient, leading to a great reduction in wastage. This is perhaps the biggest impact IRT has had on clinical trials because it allowed for a more dynamic approach to both randomization and supply chain management, which we dig into deeper below.

Since 1993, the world’s leading biopharmaceutical companies and CROs repeatedly turn to Calyx IRT to meet their RTSM needs. That’s 30 years of experience built into the technology, processes, and people who understand what’s needed to ensure effective RTSM and reduce your trial risks.

Randomization: Putting the ‘R’ in RTSM

An IRT system ensures patients are randomized to the appropriate treatment arm and receive the correct medication throughout a clinical trial per the protocol.

Randomized clinical trials have long been considered the gold standard in clinical research. Using an IRT for randomization not only helps to eliminate bias to ensure data and study integrity, but it also manages the risks of randomization imbalance, or mis-dispensing, which can have implications for protocol compliance and patient safety.

If randomization is implemented incorrectly, the scientific integrity of the entire study could be called into question. However effective and reliable randomization requires more than just technology. Insight, expertise, and precise focus on the protocol’s needs are required to get randomization right, regardless of the protocol’s complexity.

Calyx’s wide range of fully validated randomization algorithms are configured to meet the needs of each individual study, and our proven IRT platform can be customized to any randomization algorithm, no matter how complex.

LG Chem

Calyx’s IRT experts routinely design RTSM solutions that ensure the right balance between treatment arms, even in protocols with complex randomization needs.

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Trial Supply Management: Putting the ‘TSM’ in RTSM

IRT supports the challenging task of efficiently managing trial supplies/study drugs across global investigative sites, ensuring they have the right drug available for the right patient at the right time, every time.

At a minimum, an IRT must:

  • Track study drug to the smallest unit throughout its journey from QP approval/release to patient allocation to destruction
  • Manage the efficient supply of drugs  across global sites
  • Manage expiry to remove the risk of medication expiring and interrupting patient treatment, which is especially challenging in oncology clinical trials
  • Minimize unblinding risks to drive the integrity of the trial

But an advanced IRT can do so much more than this. Coupling the expertise of our RTSM specialists with robust standard and advanced inventory management approaches, Calyx IRT helps you:

Reduce your Effort
Calyx IRT reduces the burden of monitoring site stock against patient needs, automatically adapting a site’s stock to its recruitment rate.

Improve your Carbon Footprint
Calyx IRT supports all of your drug supply management aims, from limiting overage and keeping wastage to a minimum, to reducing the number of shipments raised.

Execute Complex Trial Designs
Over the decades, Calyx IRT has successfully supported a range of increasingly complex trial designs – including adaptive trials – across all therapeutic areas and phases.

Improve Trial Efficiencies
Calyx’s in-house expert statistical design and trial supply consultants can run a Supply Simulation to help sponsors make informed decisions about the optimal quantity of medication to produce for use in clinical development.

Regardless of the acronym, an IRT system is fundamental to the success of a clinical trial. As you consider your RTSM needs, make sure your IRT provider has the right people and a robust solution to drive your trial’s success.

At Calyx, our RTSM specialists leverage their combined 92 years of IRT experience to advise how to best implement trial designs and account for planned or unplanned situations. They lean on their vast experience and a system based on 30 years of evolution to deliver an optimal IRT solution based on a comprehensive understanding of your protocol, packaging plan, recruitment rates, and ongoing study needs.

The result? An adaptable, flexible, and reliable system ready to meet your trial’s current and future RTSM challenges.

A Randomization and Trial Supply Management system (RTSM) is partly a risk mitigation tool. It is used by trial teams, monitoring teams, and investigative sites to reduce some of the risks related to clinical trial execution, including:

  • Risk of sites not having enough medication for patient visits
  • Risk of sites dispensing the wrong kit to patients
  • Risk of reaching recruitment targets without enough patients in some treatment arms, necessitating recruiting additional patients, extending study timelines, and delaying data analysis
  • Risk of accidentally revealing a patient’s treatment arm, voiding the patient’s participation in the trial

Although a lot of those risks are inherently managed by the RTSM system, no two trials are the same. Trial-specific adaptations require in-depth risk analysis to reduce the chance of something unwanted happening during trial execution. The process of risk identification, assessment, and mitigation is one of the most important steps in the RTSM system setup phase, one that cannot be overlooked.

Should risk analysis start from a blank piece of paper for each trial?

No, this would be a recipe for disaster. Starting the RTSM risk analysis from scratch every time would put too much reliance on the RTSM vendor’s team. They could easily miss trial risks that may not be obvious, which could lead to complications further down the line.

What the RTSM vendor should have is a list of potential risks that can be assessed by the system which the sponsor team can review to confirm if they apply to the trial. I always think that you can measure an RTSM vendor’s experience based on the length of the list of potential risks. This list will have been developed based on what the vendor has seen in previous trials. Hence, the more trials they have delivered, the more complete the list of potential risks.

Calyx IRT project teams follow a structured process when performing trial-specific risk analysis:

1. Review the list of pre-defined risks; for each risk, define the likelihood of it occurring and the severity of the impact on the trial.

2. Assess any risks that are driven directly by the trial design and environment that are not already in the pre-defined list.

3. For any risk that has a high likelihood/severity score, identify the most efficient mitigating actions. As an IRT vendor, our mitigating actions are mainly focus on reducing risks through system design. However, some mitigating actions may be owned by the study team as well.

4. Present the high risks and corresponding mitigating actions to the client team.

5. Track the completion of mitigating actions

This process is followed every time a change in the system and/or trial environment occurs, to control any impact on the IRT-related risks.

Why does expertise matter

IRT teams who have delivered RTSM systems time and time again know instinctively how to mitigate some of the trial-specific risks. Complex trials often lead to complex risks, and not all risks have been seen before. IRT experts will know how to tackle risks, even ones they have not seen before, as they know the RTSM system’s capabilities and they have access to in-house subject matter experts who will apply their knowledge to contribute to risk mitigation.

What about protocol amendments?

Changing a system during trial execution introduces new risks. You should have confidence in the experience of the IRT vendor, their established processes, and how they control change. You should also expect the vendor to review the risks logbook, refresh their risk analysis, and complete the mitigation cycle as necessary.

Risk analysis is an ongoing task, not a one-off.

Clinical Trial Managers have a lot to orchestrate during the study start-up phase. One of the most overwhelming aspects is setting up all the different systems that will be used to conduct the trial. Depending on the trial, the team may need up to 20 different systems, most of which will require some level of study-specific configuration.

Study teams rely on experts to help them set up each system to meet their protocol needs. Calyx IRT teams offer their expertise to CROs and sponsors, making recommendations on how the system should be set up to align with the protocol design. They know that words do not suffice when configuring a system though. Study teams, especially those who aren’t used to setting up an IRT, need to see the end result to be confident it matches their expectations.

Traditional IRT systems that rely on programmable implementation do not offer the ability to show the system as it is being built. With configurable systems like Calyx IRT, however, the team can show the system as it is being configured. The system itself becomes the center of specification discussions, instead of focusing on theoretical concepts that often do not mean much to trial teams.
With the right underlying architecture, the IRT vendor can even give the study team access to the system during the setup phase. Study teams can look around the system in their own time, allowing them to anticipate the alignment of system functionalities with end-user workflows, system understanding by non-expert users, and appropriate language usage.

Study teams experience the following benefits when seeing and interacting with the IRT system during setup:

  • Minimized sponsor effort during specification: We see a reduction in the number of questions asked during the specification phase when the study team can see the system as it is being configured. It helps with their understanding of the impact of the decisions they make and helps them picture what the product will look like.
  • Confidence that the system is as expected: Viewing and using the system early in the IRT setup process increases the study team’s confidence that the system will meet protocol requirements. Considering how stressful a trial start-up is, having confidence that a part of the start-up is covered helps study teams focus on other aspects that require their attention.
  • Reduction in last-minute changes: Seeing the system reduces miscommunication or misunderstanding during the specification phase, which has a knock-on effect on the UAT phase. With traditional technology, the system is first discovered during UAT, by which time there is little time left to make extensive changes to the IRT. Seeing it upfront results in smoother UAT and reduces the number of change requests raised late in the setup process.
  • Streamlined UAT: getting access to the system during setup allows study teams to write their UAT scripts knowing what the system looks like. It reduces the number of script errors that are traditionally discovered during UAT execution.

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.

Click here 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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