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.

2023 brought many healthcare advances and opportunities for life science professionals to stay current on the research, technologies, and processes that are driving change in how new medical treatments are developed and ultimately approved for worldwide use.

So here, in case you missed them, are the most sought-after articles, videos, case studies, and more produced by Calyx scientific, technical, and regulatory experts this year. Each provides direction and perspective on optimizing and accelerating the clinical development and approval of medical treatments.

We hope you find them as insightful and valuable to you now as they were the first time around.

De-risking Medical Imaging in Solid Tumor Trials

During anti-tumor treatment development, imaging modalities, criteria, and regulators’ expectations change frequently. Without the direction of imaging scientists who work day in and day out in clinical trial imaging, it would be difficult, if not impossible to keep track of and react to changes during these critical and often, lengthy trials.

Successful medical imaging in solid tumor trials requires professionals with therapeutic experience, expertise in the modalities required to demonstrate safety and efficacy, and first-hand insight into what global regulators will look for in your submissions.

This blog presents examples of scientific advances and regulatory changes that are currently impacting anti-tumor treatment research, demonstrating the need for an imaging partner who is immersed in the regulations, scientific learnings, and trends that could impact the success of your development program.

READ THE BLOG

Overcoming Oncology RTSM Challenges with Advanced IRT

Sponsors of oncology trials face unique randomization and trial supply management (RTSM) challenges, including:

  • Central vs. local sourcing of standard-of-care treatments
  • Unknown patient treatment duration
  • Impact of rescue medication on study drug expiration
  • High cost of treatments / need to reduce excessive drug wastage

Learn about these and other supply challenges and how a flexible IRT system can reduce errors, ensure patient safety, and meet changing RTSM during lengthy oncology trials in this article by Calyx’s Malcolm Morrissey, published in International Clinical Trials®.

READ THE ARTICLE

Exceeding Timelines for Accelerated Approval: Calyx Medical Imaging

In oncology clinical development, every day matters. Even more so when your compound has been fast-tracked for approval by global regulators.

Which is why so many clinical trial sponsors rely on Calyx Medical Imaging. Calyx’s collaborative approach, ability to meet each sponsor’s unique needs, and expertise in image acquisition and analysis have repeatedly been proven to help clinical development programs succeed.

Like in this example, where Calyx Medical Imaging delivered critical imaging data in advance of deadlines on an already expedited timeline to help a leading pharmaceutical company receive accelerated FDA approval for a Multiple Myeloma treatment.

WATCH THE VIDEO

How IRT Expertise Surfaces – and the Difference it Makes

An IRT system is a critical part of a clinical trial. The implications for failing to get it right can be impactful not only to study goals but to participants as well.

Here, Calyx’s Craig Mooney gives examples of the consequences that can arise if a study’s IRT system isn’t implemented with insight and precise focus on the protocol’s needs and why expertise matters throughout the clinical trial lifecycle.

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Calyx RIM Supports Successful FDA eCTD 4.0 Pilot

Calyx RIM has been successfully used by a global market-leading pharmaceutical company in FDA’s eCTD 4.0 implementation pilot program.

Calyx’s regulatory experts worked closely with this leading company and the FDA throughout the pilot and advanced Calyx RIM based on their feedback and lessons learned.

Learn why you can rely on Calyx RIM as you adopt eCTD 4.0 as part of your global regulatory processes.

READ THE ANNOUNCENENT

Neuroimaging in Alzheimer’s Disease Trials

As our understanding of Alzheimer’s Disease (AD) pathophysiology continues to evolve, we’re seeing advanced approaches for assessing treatment effects in clinical development, including AI/machine learning to measure subtle changes that are difficult for the human eye to detect.

Calyx Medical Imaging delivers neuroimaging expertise to help sponsors meet the unique and emerging needs of early to late-phase AD clinical trials. This paper outlines Calyx’s capabilities and experience, which includes confirmation of eligibility and brain safety assessments with rapid turn-around times as well as advanced quantitative analyses for PET and MRI data to help your AD trial succeed.

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Mitigate Unblinding Risks with Calyx IRT

Every clinical trial runs the risk of unintentional unblinding. With 30 years of experience designing reliable RTSM solutions and the processes behind it, Calyx IRT is the solution you can rely on to minimize these risks and ensure the integrity of your clinical trial.

The solution design and technical experts behind Calyx IRT have published a variety of papers, webinars, and blogs to demonstrate where and how unblinding can occur and more importantly, how to minimize those risks.

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Calyx CTMS Select: Scalable for Small/Mid-sized Biopharma and CROs

The features of Calyx CTMS deliver significant benefits for studies of all shapes and sizes. However, not all studies have the same needs.

Enter Calyx CTMS Select, a pre-configured and validated clinical trial management system for small to mid-tier biopharmaceutical companies and CROs who want reliability and global support but don’t require CTMS customization.

Calyx CTMS Select enables SMID organizations to scale as their operations require and includes the rich features required for clinical trial management oversight and monitoring at lower costs than comparable solutions.

READ THE ANNOUNCENENT

Cookie Cutter Solutions don’t Cut it in Clinical Trial Imaging

When medical imaging is used as a clinical trial biomarker, your centralized core lab provider needs therapeutic/modality and operational expertise to help you meet your development objectives, regardless of where you are in the clinical development spectrum.

Here we review how a small biotech captured the imaging data needed to secure funding and advance their early-stage research on a rare neurological disease compound. And, how a top 5 global pharma captured reliable primary efficacy endpoint data in a pivotal phase III study to achieve regulatory approval on a prostate cancer compound. All supported by Calyx Medical Imaging.

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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 and its Many Names

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

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.

Read the Case Study

Trial Supply Management

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.

Craig Mooney, VP, Scientific e-Tech Enabled Services, Calyx

In this dynamic industry with so many moving parts, some consider the use of IRT for randomization and trial supply management (RTSM) to be an easy-to-master technology, even touting that becoming an expert can happen in just one day.

This couldn’t be further from the truth. Minimizing the strategic planning that must go into the design of an effective IRT system, as well as the proper management of its lifecycle demonstrates a lack of understanding about how impactful IRT can be to clinical trial outcomes. There are significant consequences that can arise if a study’s IRT system isn’t implemented with insight, expertise, and precise focus on the protocol’s needs.

Randomization Risks

For example, if randomization is implemented incorrectly, the scientific integrity of the entire study could be called into question. This has been evidenced across numerous studies where a sponsor’s primary objectives or endpoints could not be met due to a failed randomization implementation.

Effective and reliable randomization requires more than loading a list. It involves determining how the list will be implemented, i.e.:

  • Should blocks be assigned by a site when the site is activated?
  • Should they be assigned dynamically to a site as needed?
  • How will mis-randomizations or ‘randomized in error’ be handled?

Click here for additional considerations and examples of how randomization can go wrong if an IRT system isn’t designed accurately.

Allocation of Study Drug and Supply Management Risks

Like randomization, if allocation of study drug is not implemented according to the protocol the entirety of the study could be called into question. It would not be unusual given modern study designs for participants to have a crossover or other complicated dosing options. These add to the complications for implementation and ensuring the right medication maxim.

Allocation/assignment will only work if the medication is available where needed. Without a proper understanding of system workflows/inputs, logistics processes, and use/availability calculations, you will struggle to meet the baseline of the right medication, for the right participant, at the right time, every time.

This is another area best left to experts. The complications and details are so fine that they cannot be covered adequately here. But one truth about drug supply management and calculations is that it is never an understanding of the number of participants, it is always about trying to predict when and where the participants will show up.

Click here for additional considerations and examples of how drug allocation and supply management can go wrong if an IRT system isn’t designed accurately.

How IRT Expertise Surfaces

Calyx’s IRT design and management experts extend their deep experience to you and deliver valuable insights that can make a real difference in ensuring effective RTSM throughout your clinical trial. For example, they can demonstrate to you:

  • Why an IRT should be designed for its primary objectives and not as a catch-all or EDC replacement
  • The nuances of integration data flow and its impact on system development timelines and process
  • What data should and should not be distributed/reconciled and why
  • The practical difference and implications between visit dates and cycles in oncology studies
  • Why randomization block size and ratio could have an impact on drug supply management algorithms
  • All the implications of screen failure, rescreening, rerandomization, and randomization replacement
  • Why visit dates and transaction dates are not the same and shouldn’t be treated as such
  • Where the hidden opportunities for unblinding are in the drug assignment process
  • What the basics of resupply are and why trusting the system matters
  • Novel approaches to waste reduction such as medication pooling, fractional calculation, and automated algorithm switching
  • Why the accuracy of inventory in open-label studies is a challenge to maintain and the tools to mitigate this problem

Conclusion

An IRT system is a critical part of a clinical trial. The implications for failing to get it right can be impactful not only to study goals but to participants as well. For this reason, it requires experts who have many years of experience across many protocols. It is certainly not the type of experience you can get from an afternoon seminar. Don’t moonlight in IRT, because getting it right is serious business.

This is the second of two articles on the consequences that could arise if an interactive response technology (IRT) system isn’t designed and/or implemented correctly and how a trial could quickly go off track based on risks related to randomization, drug allocation, and trial supply.

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